Needs Assessment: “Online Cancer Support Groups” discusses a compelling issue in cancer support that has heretofore not received enough focus, the needs of patients with limited English proficiency. It also demonstrates how innovative online methodologies can effectively reach this often neglected segment of the cancer patient community.

Learning Objectives:
• Give examples of barriers faced by immigrant women with breast cancer in accessing psychological support.
• List four scales to study the effectiveness of psychosocial interventions targeting cancer patients.
• Describe the potential benefits of online support groups for cancer patients.


Target Audience:
Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: August 21, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by October 1, 2010 to be eligible for credit. Release date: October 1, 2008. Termination date: October 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Primary Psychiatry. 2008;15(10):55-62

 

Dr. Changrani is assistant professor in the Department of Medicine and associate director of the Center for Immigrant Health at New York University (NYU) School of Medicine in New York City. Dr. Lieberman is professor emeritus at the University of California, San Francisco. Dr. Golant is senior vice president of Research & Training at The Wellness Community in Los Angeles, California. Dr. Rios is program director at The Wellness Community-Greater Miami in Florida. Ms. Damman is medical student at the University of California Davis School of Medicine. Dr. Gany is associate professor in the Department of Medicine and director of the Center for Immigrant Health at NYU School of Medicine.

Disclosures: The Virtual Community for Immigrants with Cancer, was supported by the Langeloth Foundation during the study period (the research for which this financial support was granted, which was used for this article, officially ended in 2005). Additional support was received from the Lance Armstrong Foundation (the research for which this financial support was granted, which was used for this article, officially ended in 2006).

Please direct all correspondence to: Jyotsna Changrani, MD, MPH, Center for Immigrant Health, New York University School of Medicine, 550 First Ave, BCD-D-402, New York, NY 10016; Tel: 212-263-8783; Fax: 212-263-8234; E-mail: Jyotsna@med.nyu.edu.


Abstract

Online support groups (OSGs) may be a particularly promising option for immigrants. They can be a cost-effective method that easily addresses geographic isolation and immigrants’ needs for privacy. This article examines the viability of OSGs for Hispanic immigrants with breast cancer and the effectiveness of OSGs for the participants. The authors hypothesized that OSGs are a feasible mechanism for delivering support to Latina women with breast cancer, as immigrant Latinas with breast cancer in OSGs showed significant improvement compared to a control group on depression, in coping with pain, in quality of life, and personal growth. Of 85 potential participants approached, 68 Spanish-dominant speaking immigrant women with breast cancer were recruited into the Virtual Community for Immigrants with Cancer (VCIC). Forty-eight were randomly assigned to OSGs and 20 were assigned to a usual care control group. VCIC participants were grouped into OSGs with eight participants in each. Each group met for 90 minutes once a week for 30 weeks. The groups were facilitated by trained bilingual facilitators and issues of interest to the group were discussed, such as managing symptoms and side effects from medications, family concerns, and alienation. The dropout rate from the groups was 13%. The VCIC experiences suggest that OSGs are acceptable to and feasible for immigrant minorities, including those with limited English proficiency. While none of the outcome measures showed statistically significant change pre-post compared to the control group, statistical trends were noted suggesting beneficial impact on outcomes. When compared to the controls, the experimentals had increases in seeing new possibilities (F=2.81, P=.09) and increased feelings of strength (F=3.59, P=.06).

Introduction

In 2000, the United States was home to 31.1 million immigrants.1 Over 21 million immigrants in the US, including 25% of New York City residents, have limited English proficiency.2,3 The diagnosis of cancer in immigrants is often the cause for much fear and can lead to isolation from family and community.4,5 Immigrants are frequently marginalized from institutional, social, and psychological support, including cancer care.5

The value of cancer support groups is widely accepted. The National Cancer Institute advises that support groups can help people affected by cancer feel less alone and can improve their ability to deal with the uncertainties and challenges that cancer brings.6 A meta-analysis by Rehse and Pulkrop7 summarized the results of 37 published, controlled studies investigating the effectiveness of non-Internet psychosocial interventions on the quality of life (QOL) of adult cancer patients. They found an overall effect size of 0.31 for psychosocial interventions.7 The most important moderating variable identified was the duration of psychosocial intervention, with interventions lasting >12 weeks being significantly more effective than those of shorter duration. Support groups for cancer patients have led to improvement in QOL, reduction of psychological symptoms;,improvement in coping responses, and reduction in pain.8-11

A few studies have examined ethnicity and support groups. Miano and colleagues12 reported that the traditional support group model has not been effective in reaching the Hispanic population. Instead, they developed a program facilitated by Spanish-speaking social workers using other professionals within the institution to promote a multidisciplinary approach to provide support services. They reported that participants experienced an increased sense of social and emotional well being, expanded their knowledge of health-related information, and became aware of other services and benefits available to them. A second study involving cancer patients in Texas13 examined the role of informal and formal social support networks in mitigating barriers to cancer treatment among whites, African Americans, and Hispanics. Minorities were more apt to report that the formal support groups helped patients to continue treatment. In addition, informal social support networks, such as extended families and civic clubs, were seen as more helpful for African-Americans and Hispanics as compared with whites. Finally, Alferi and colleagues14 examined predictors of use of complementary therapies by African American, Hispanic, and non-Hispanic white patients with early-stage breast cancer who also received standard medical treatment. Most patients used ≥1 complementary therapy, most commonly psychotherapy, support groups, meditation, and spiritual healing.

The Internet has enabled non-immigrant patients to help one another through the emotional turmoil of cancer.15 It is estimated that one out of three cancer patients in the developed world is online.16,17 A virtual community is one of the most powerful uses of the Internet, as people can meet, interact, share interests, and exchange social support via online support groups (OSG).

Fifteen million Internet users in the US have visited OSGs.18 Furthermore, when asked whether they visited an OSG on the previous day, 1.6 million responded in the affirmative. Results from a 2007 Harris poll indicated that 160 million US adults searched for health information online.19 In an analysis of a recent National Cancer Institute public data set,20 approximately 50% of the cancer sample comprised of both men and women used the Internet to locate information about cancer and approximately 5% of men and 8% of women had participated in an Internet cancer support group. However, there are few outcomes studies on OSGs. Klemm and colleages21 identified 10 non-controlled, descriptive research studies on cancer OSGs. Nine of the 10 studies concluded that OSGs help people to cope more effectively, but none of them used randomization to groups or a control group. Eysenbach22 conducted a comprehensive, systematic review of online, peer-led OSGs that included efficacy data and found few studies (n=38). Three studies23-25 focused on the effects of OSGs for breast cancer patients. OSGs for breast cancer patients may reduce depression, cancer-related trauma, and perceived stress.23-25 A study26 of The Wellness Community (TWC)-facilitated chat groups for women with breast cancer found that participation in 16 weekly groups significantly reduced depressive symptoms and negative reactions to pain and showed a trend toward increased posttraumatic growth. Sixty-seven percent of patients found the groups beneficial. Several studies examined the processes associated with benefit. They found that greater expression of anger in OSGs for women with breast cancer was associated with higher QOL and lower depression in previous studies, while the expression of fear and anxiety was associated with lower QOL and higher depression.27 Insightful disclosure played a crucial and significant role.28

OSGs may be a particularly promising option for immigrants. One in three Spanish-dominant Hispanics in the US uses the Internet.29 OSGs can be a cost-effective method of intervention with minimal, if any, transportation requirements. OSGs also easily address geographic isolation as well as needs for privacy, both of which may be heightened among immigrants. However, OSGs for immigrants with cancer are sorely lacking. In fact, no previous studies of Latina women with breast cancer and OSGs are available.

This study examines the viability of OSGs for Hispanic immigrants with breast cancer and attempts to bridge the digital divide with a culturally relevant online intervention. The authors test the feasibility of providing professionally led Internet groups for Spanish-speaking immigrant women with breast cancer and attempt to determine if Spanish-speaking immigrant women with breast cancer can be recruited and retained for OSGs. In addition, the authors wanted to gather pilot data on effectiveness of OSGs for the participants. The leadership model and measures used in the current study are similar to the model employed in a previous study reporting statistically significant pre-post changes in depression, reactions to pain and a trend towards increased growth.22

Specifically, the authors tested three central hypotheses. First, OSGs are a feasible mechanism for delivering support to Latina women with breast cancer. Second, immigrant Latina women with a breast cancer diagnosis in online, professionally facilitated support groups will show significant improvement compared to a control group (ie, usual care) on depression, coping with pain, QOL, and personal growth. Last, women with breast cancer who start the group with high levels of distress will show significantly greater improvement than those with lower levels of distress.

Method

In 2001, the Virtual Community for Immigrants with Cancer (VCIC) was launched to bridge the immigrant Internet support group divide. VCIC was developed to advance immigrants’ ability to cope with cancer and to increase their confidence in accessing treatment options. VCIC provides informational, emotional, and social network support to Spanish-speaking women with breast cancer  through an OSG. The study was a replica of a previous study23 of non-Hispanic whites with breast cancer. Both the intervention as well as the outcome measures were identical except that in the present study, the language of intervention and measures was Spanish.

At the program’s inception, three focus groups were conducted with Spanish-speaking breast cancer survivors, including women who had attended face-to-face support groups. The focus groups provided direction to the content and design structure for VCIC’s Web site30 and OSGs in addition to informing topics for chat sessions. A team of web-designers and public health professionals worked together to design a site with culturally appropriate visuals and content, navigable by those with little or no familiarity with the Internet and computer technology.

The authors of this article did not want to restrict VCIC to Internet-savvy participants or those who had computers or Internet access at home. Several participants had never used a computer prior to joining VCIC. The auhtors secured refurbished computers and provided them to the participants, along with dial-up Internet connections. Staff provided one-on-one, at-home, half- to full-day training to the participants on using computers, the Internet, and the VCIC OSG, as needed.

VCIC participants were grouped into OSGs with eight participants in each. Each time eight people enrolled, a new group would begin. Each group met for 90 minutes once a week for 30 weeks. The groups were facilitated by trained bilingual facilitators and issues of interest to the group were discussed, such as managing symptoms and side-effects from medications, family concerns, and alienation.

Sample

Within a 2-year period, the authors identified and approached 85 potential participants. Seventeen declined participation, and 68 Spanish-dominant-speaking immigrant women with breast cancer were recruited into VCIC. Forty-eight were randomly assigned to the OSGs and 20 were assigned to a usual care control group. Of those in the intervention, 42 participated fully and 6 dropped out. Key stakeholders in the community, including volunteer survivors, aided with the recruitment. Sample characteristics of the intervention and control groups are shown in Table 1.

 

 

 

 

Measures

Depression was measured by the Center for Epidemiological Studies Depression Scale Spanish language (CES-D).31 The CES-D scale is a 20-item self-report measure designed to assess depressive symptoms in the general population. It has been found to have high internal consistency (a=.89) with cancer patients and adequate test-retest reliability. The instrument permits comparison with other cancer studies using this measure, is sensitive to intervention effects, and is easily administered.32

 Personal growth was measured by the authors’ translation of the Posttraumatic Growth Inventory (PTGI).33,34 The PTGI was developed to assess positive changes experienced by traumatized individuals. The 21-item scale yields a total score and five subscale scores, namely new possibilities, relating to others, personal strength, spiritual change, and appreciation of life. Items are rated on a 6-point Likert scale, ranging from “I did not experience this change as a result of my crisis” (0) to “I experienced this change to a very great degree as a result of my crisis” (5). While internal consistency of the total score was .95 in a previous sample of cancer survivors, the translated version has never been tested for internal consistency.

QOL was measured by translation of the functional analysis of cancer therapy (FACT-B). The FACT-B measures multidimensional QOL in patients with cancer. The a coefficient total score is a=.90, with subscale a coefficients ranging from .63–.86.35

The authors translated three subscales8 to assess pain, First, pain intensity-Likert scale ranges from 0 (none) to 10 (excruciating). Second, pain interference during household chores, yard work, or shopping; socialization with friends; recreation and hobbies; sexual relations; and physical exercise. Last, reactions to pain (ie, agonizing, intolerable, unbearable, awful, distressing, unpleasant, distracting, uncomfortable, tolerable, bearable, and none).

To score the transcript interaction the authors used the Linguistic Inquiry and Word Count (LIWC).36 The dictionary provides a method for studying the various emotional, cognitive, structural, and process components present in written speech. The dictionary includes 17 standard linguistic dimensions (eg, word count, percentage of pronouns, articles), 25 categories tapping psychological constructs (eg, affect, cognition), 10 dimensions related to “relativity” (time, space, motion), and 19 personal/content concern categories (eg, work, home, leisure activities). This procedure has been extensively utilized in studies examining the beneficial effects of writing about traumatic life events. Two scales were assessed, namely emotional (anger) and cognitive (insight) dimensions. The transcripts of the meetings were first translated in English and then scored using the LIWC scales. All scores are corrected for number of words.

Statistical Analysis

To test improvement compared to a control group (usual care) on depression, coping with pain, QOL, and personal growth over time, a repeated measures multivariate analysis of variance (MANOVA) was used. Four outcome measures wre used, including CES-D, total pain, sum of the FACT-B, and PTGI scales, were used. Three control variables were used as covariates, namely length in the US (proxy for acculturation),  cancer stage, and level of education. A bonferonni correction was used to control for the inter-correlation of the three measures. Because the use of a summed score for both the FACT-B and PTGI may mask some of the possible changes, a separate repeated measures MANOVA with the covariates was used for the subcales of the PTGI and FACT-B.

To test whether women with breast cancer who start the group with high levels of distress will show significantly greater improvement than those with lower levels of distress, the authors used an analysis of variance. Distress was assessed by Time 1 CES-D scores, dividing the sample into those who at Time 1 did not show clinical depression (score of ≤17) and those defined by the CES-D as clinically depressed (score of >17). The dependent variable was CES-D at Time 2. The independent variables were experimental/control and high or low depression at Time 1. Covariates were the three cited in the previous paragraph.

Results

The mean participant age for VCIC was 46.8 years, with a range of 22–84 years of age. The participants hailed from 12 Latin American countries. The top two countries of origin were the Dominican Republic (25.5%) and Colombia (18.2%). The mean age in the United States was 16.7 years, with a range of 0.25–43 years. Forty-point-seven percent of the participants had not completed high school, and 32.7% of the participants were employed outside their home. Eleven-point-three percent of participants did not have health insurance.

Eighty percent of potential participants approached enrolled into VCIC. Reasons for declining included not having a stable place to live, not having a telephone at home to dial in for Internet access, becoming nervous around computers, and family issues such as family member death and illness.

The themes of the chat sessions were varied. They included faith; family as well as lack of family in the US; relationships; financial and insurance issues, including what insurance covers and how they could procure free wigs; and breast reconstruction, sharing personal experiences and concerns. The women expressed fears and provided emotional support. Pain was often discussed, with participants seeking and offering suggestions to decrease symptoms.

The dropout rate from the groups was 13%. Reasons for dropout included participants’ death, eviction from apartment, disconnection of telephone, feeling too tired after work to participate, changes in work schedule, and returning to home country.

Outcomes

Table 2 shows both the repeat measure multivariate analysis of covariance of the summary measures (ie, CES-D, Total Pain, FACT-B, and PTGI) and the repeat measure multivariate analysis of covariance for the subscales of the PTGI and the FACTB. Length of time in the US and previous support group was used as a covariate because of the difference between the experimental and control group. Table 3 shows the adjusted means for all the outcome measures.

 

 

 

 

 

Overall, none of the outcome measures showed statistically significant change pre-post compared to the control group. However, some PTGI subscales, when analyzed separately, showed a statistical trend. A multivariate analysis of the five PTGI scales, using the three covariates described in the main analysis and a bonferroni correction, found an overall trend (F=2.13, P=.07).5 Univariate analysis showed a statistical trend in two of the scales. The experimentals compared to the controls had increases in seeing new possibilities (F=2.81, P=.09) and increased feelings of strength (F=3.59, P=.06). The means of that analysis are also shown in Table 3 for comparison purposes. The significant items on the PTG included: “I am more likely to try to change things which need changing,” “An appreciation for the value of my own life. A feeling of self-reliance,” “A willingness to express my emotions. Being able to accept the way things work out,” “Appreciating each day. Having compassion for others,” “I am able to do better things with my life,” “New opportunities are available which would not have been otherwise,” “Putting effort into my relationships,” “I developed new interests,” and “I established a new path for my life.”

Level of Distress

For this analysis, the authors of this article used 21 controls; 12 were low distress and 11 were high distress. The experimental sample of 40 women was divided; 22 were in low distress and 18 were in high distress. As expected, there was a difference between all the subjects, the high-low yielded an F=25.7, P=.000, indicating that people with high distress in both experimental and control groups show lower (better) scores over time regardless of the experimental conditions.

The authors’ previous research on OSGs with breast cancer patients found that two mechanisms measured by Pennebaker’s LIWC showed significant effects on outcomes. Women who expressed more negative emotions and more insightful behaviors in the groups showed more positive changes. A similar analysis comparing the Latino sample to the non-hispanic whites27,28 found that the critical group characteristics identified (ie, group’s participant expression of negative emotions and insightful disclosure)27 using the Pennebaker text analysis software were significantly linked to positive change. The Latina support groups were significantly lower in these dimensions, as were the facilitators in encouraging this behavior. Mean scores for the expression of anger were .22 (.16) for non-Latina sample, .17 (.11); insight 1.9 (.77) and 1.4 (.85). T-test anger scores were t=4.57, P=.05; insight t=6.95, P=.00.37

Discussion

The VCIC experiences suggest that OSGs are acceptable to and feasible for immigrant minorities, including those with limited English proficiency. The participant feedback has been overwhelmingly encouraging. Participants have commented that VCIC has allowed them “desahogo,” or to “undrown” themselves. They have commented often that they had not been able to talk with anyone about their situation prior to VCIC. Participants have consistently expressed their immense gratitude.

Several obstacles were encountered in setting up this study related to the living situations of the population recruited. These need to be taken into account when implementing OSGs in similar immigrant communities. Space at the participants’ homes was an issue. Several apartments were cramped, and the refurbished computers occupied a large amount of space. The computers purchased after the first batch were considered for their size. Dial-up Internet access was provided free of cost to the participants. However, the authors of this article did not take into account the participants’ limited landline phone access. A few participants had very restricted plans. By dialing up once a week for 90 minutes, they exceeded their monthly telephone minute allowance. This resulted in a higher bill and, for one participant, a reluctance to dial up. Remedial measures were taken to augment the participants’ phone plans, allowing them to continue to participate.

Because of their unfamiliarity with the Internet, participants were provided with the project coordinator’s telephone number for assistance. However, this was limiting. Most participants did not have a second phone, to call the coordinator once they were online. They would have to log off the Internet to place a call, compromising their ability to describe the problem, and the potential for the coordinator to assist them. This would result in missed chat sessions.

Since completing this pilot study, the Wellness Community has been experimenting with providing online support groups through the Virtual Wellness Community-Spanish website.38 It has been learned anecdotally that patients prefer to start their online support group experience with cancer-related specific information (ie, managing side effects from treatment, preparing for chemotherapy). In this model, the first half of the online support group is education and the second half is support. It is easier and more comfortable for Spanish-speaking participants to express emotions in the context of the information presented. It is as if the information provides a safe distraction for participants to express emotions that would otherwise be burdensome on the rest of the group members without the initial focus on education. This insight and practical methodology should be explored in future studies. However, it should be noted that no outcome data is available from the Virtual Wellness Community-Spanish Web site. It is not known if this experiment would yield more robust outcomes.

The Latina women’s change in attitudes towards the future and their feelings of empowerment suggest potential impact of the groups. However, the scales used to measure difference were not transcreated but merely translated, potentially limiting their utility severely. Future studies should consider the use of specifically created and/or validated scales for this population. Additionally, reflections of effectiveness (eg, empowerment in decision making, completion of treatment) were potentially not measured. Unfortunately, there is little guidance from previous studies of both face-to-face and OSGs to provide a context for these findings. There are no studies comparing Latina and non-Latina women in support groups. Alternatively, it may be that women of color have sufficient interpersonal support in their own communities and do not need the extra support offered by these computer-mediated groups, while the Caucasian women are using the group so much for everyday life exchanges because they do not have similarly rich and effective support from their friends or families. Moreover, what they did while they used discussion group was different. Their comments were much less likely to be about day-to-day events than were those of Caucasian women, suggesting that women of color used the discussion group to focus very tightly on breast cancer. Another possible clue to the differences in the Wellness Community studies of breast cancer support groups,31,32 and this study with Latina immigrant women may be found in the quality of the groups themselves. In previous studies on online breast cancer support groups, three critical group and leader characteristics were isolated using the Pennebaker text analysis software that were significantly linked to positive change of the participants the group’s cohesiveness, participant expression of negative emotions, and insightful disclosure.27 The Latina support groups were significantly lower in these dimensions, as were the facilitators in encouraging this behavior. Thus, the absence of significant change in depression, QOL and addressing physical pain may in part have been contributed to by more inexperienced leadership and the low experienced cohesiveness, expression of negative emotions, and insightful disclosure.

Another possible explanation lies in the cultural characteristics of the Latina women. Here the possibilities are broad and varied and obviously do not rise above the level of speculation. That the women in the study emigrated from 12 countries, each with its own special culture, makes an explanation based on culture even more suspect. These individuals represent diverse nationalities, sociopolitical histories, races, ethnicities, and cultures.

Many researchers of Latino culture have attempted to describe some general characteristics of their culture despite the above cited differences.37,39-42 For example, traditional Western values stress the desirability of individualism, autonomy, and competition, whereas Hispanic cultural traditions emphasize the importance of collectivism, interdependence, and cooperation. The data available to the investigators in this study does not provide a source of empirical information on the effects of culture on their attitudes and behavior for OSGs. The following is offered as a speculation on why the effectiveness of OSGs for Latina breast cancer patients was limited.

“Familismo” (ie, family values and the value of family) has been described an allocentric cultural value that stresses attachments, reciprocity, and loyalty to family members beyond the boundaries of the nuclear family.41,42 Allocentrism is a cultural value by which people understand themselves through others, emphasizing social relationships and highlighting group goals rather than individual ones. “Personalismo” refers to a preference for relating on a personal, rather than formal or institutional, level.43 Irrespective of gender, physical touch is used more liberally by Hispanics than Euro-Americans, and the appropriate conversational distance for Hispanics is much closer.44 “Marianismo,” which is rooted in the Roman Catholic reverence for the Mother Mary, refers to some traditional cultural prescriptives assigned to women. With motherhood, women achieve an elevated status of spiritual superiority to men and consequently enjoy a certain amount of power.37 However, in keeping with reverence for the Madonna, mothers are expected to embody the virtues of selflessness and to endure suffering with dignity.39 Though collectivist ideals are consistent with the self-sacrifice of all individuals, because women are considered to be more virtuous than men, they are deemed capable of greater sacrifice. Religion and Spirituality. Faith, rooted in Roman Catholicism, is generally the cornerstone of Hispanic life in many communities.45 The belief that God is the author of one’s destiny is prevalent across the Spanish-speaking world and is evident in widespread references to God’s will.46

How could these common cultural touchstones impact on the study’s intervention? There are no definitive answers. Perhaps the emphasis on closeness and touching influenced their experience of the relative “coolness” of Internet communication. Perhaps the propensity to endure suffering may have limited the women’s willingness to speak of the burdens associated with their breast cancer diagnosis. Perhaps even more important was the use of tools that were not validated in these communities and may not have accurately measured the intervention’s impact.

Threats to the Study’s Validity

Numerous problems mitigate the authors’ conclusions. The randomization protocol was compromised by selecting patients serially as they registered, signed the human subjects forms, and completed the measures. The first eight people were placed in a group, then the next eight people formed the next group, and so on until 48 people were enrolled into 6 groups. Finally, the control group was formed from the last 20 who registered. Reliance on merely translated Spanish versions of the measures raises the question of differences in language usage and cultural norms. The computer analysis of the interaction may be problematic because the translations of the transcripts and the language usage and cultural norms may have a major effect on the authors’ conclusions. Words describing abstract concepts (eg, emotions) are not as readily interpreted.47 The findings from previous studies on the effect of emotional expression and cognitive processes are based on non-Hispanic Caucasians. The authors provide no evidence suggesting that these are critical for the immigrant Latina sample studied.

Conclusion

Virtual communities hold tremendous promise for cancer support. Despite the issues noted, underserved communities, including immigrants, can and must be included. Participants eagerly joined and remained in the groups, expressing much gratitude for their existence. Upon deployment and demonstration of the effectiveness of “e-health” interventions such as VCIC, these interventions will likely present cost-effective alternatives to traditional health interventions for underserved populations. However, sufficient resources need to be devoted to ensure their smooth functioning for communities without prior computer and/or Internet experience. A replication of “e-health” interventions that have been effective in mainstream communities must be carefully tailored to the cultural context of immigrant communities. Further research is important into the content and the processes of online support interventions for immigrants with cancer. PP

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21.    Klemm P, Bunnell D, Cullen M, Soneji R, Gibbons P, Holecek A. Online cancer support groups: a review of the research literature. Comput Inform Nurs. 2003;21(3):136-142.
22.    Eysenbach G. The impact of the Internet on cancer outcomes. CA Cancer J Clin. 2003;53(6):356-371.
23.    Wellman B. An electronic group is virtually a social network. In: Kiesler S, ed. Culture of the Internet. 1st ed. Mahwah, NJ: Lawrence Erlbaum; 1997:170-205.
24.    Lieberman M, Golant M, Giese-Davis J, et al. Electronic support groups for breast carcinoma: a clinical trial of effectiveness. Cancer. 2003;97(4):920-925.
25.    Winzelberg AJ, Classen C, Alpers GW, et al. Evaluation of an internet support group for women with primary breast cancer. Cancer. 2003;97:1164–1173.
26.    Lieberman MA, Golant M, Giese-Davis J, et al. Electronic support groups for breast cancer: a pilot study of effectiveness. Cancer. 2003;97(4):920-925.
27.    Lieberman MA, Goldstein BA. Not all negative emotions are equal: the role of emotional expression in online support groups for women with breast cancer. Psychooncology. 2006;15(2):160-168.
28.    Lieberman M. The role of insightful disclosure in outcomes for women in peer-directed breast cancer groups: a replication study. Psychooncology. 2007;16(10):961-964.
29.    Pew Hispanic Center and Pew Internet Project. Latinos Online. March 14, 2007. Washington, DC. Available at: www.pewinternet.org/pdfs/Latinos_Online_March_14_2007.pdf. Accessed September 3, 2008.
30.    CAVIC. Available at: www.cavic.org. Accessed September 3, 2008.
31.    Cho MJ, Moscicki EK, Narrow WE, Rae DS, Locke BZ, Regier DA. Concordance between two measures of depression in the Hispanic Health and Nutrition Examination Survey. Soc Psychiatry Psychiatr Epidemiol. 1993;28(4):156-163.
32.    Hann D, Winter K, Jacobsen P. Measurement of depressive symptoms in cancer patients: evaluation of the Center for Epidemiological Studies Depression Scale (CES-D). J Psychosom Res. 1999;46(5):437-443.
33.    Tedeschi RG, Calhoun LG. The Posttraumatic Growth Inventory: measuring the positive legacy of trauma. J Trauma Stress. 1996;9(3):455-471.
34.    Tedeschi RG, Calhoun LG. Trauma and Transformation: Growing in the Aftermath of Suffering. 1995. Thousand Oaks: Sage; 1995.
35.    Cella DF, Tulsky DS, Gray G. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570-579.
36.    Lawrence Erlbaum Associates, Linguistic Inquiry and Word Count. Revised. Mahwah, NJ; 2000.
37.    Comas-Diaz L. Culturally relevant issues and treatment implications for Latinos. In: DR Koslow, Pathy E, eds. Crossing Cultures in Mental Health. Washington, DC: SIETAR International; 1989:31-48.
38.    The Wellness Community. Available at: http://espanol.thewellnesscommunity.org. Accessed September 3, 2008.
39.    Stevens EP. Machismo and marianismo. Society. 1973;10(4):57-63.
40.    Sue DW. Multidimensional facets of cultural competence. Couns Psychol. 2001;29(6):790-821.
41.    La Roche MJ. Psychotherapeutic considerations in treating Latinos. Harv Rev Psychiatry. 2002;10(2):115-122.
42.    La Roche MJ, Turner C. Self-orientation and depression level among Dominicans in the United States. Hisp J Behav Sci. 1997;19:479-488.
43.    Delgado M, Humm-Delgado D. Natural support systems: a source of strength in Hispanic communities. Social Work. 1982;27:83-89.
44.    Hall ET. The silent language. In: O’Brien RW, ed. Readings in General Sociology. 4th ed. Boston, MA: Houghton Mifflin; 1969.
45.    Nava Y. It’s All in the Frijoles: 100 Famous Latinos Share Real-life Stories, Time-tested Dichos, Favorite Folktales, and Inspiring Words of Wisdom. New York, NY: Diane Publishing Company; 2000.
46.    Falicov CJ. The cultural meanings of money: the case of Latinos and Anglo-Americans. Am Behav Sci. 2001;45(2):313-328.
47.    Bond MH, Lai TM. Embarrassment and code-switching into a second language. J Soc Psychol. 1986;126(1):179-186.

To the Editor:              

We read with interest the article describing horticultural therapy by Fried and Wichrowski.1  Although they and others2 describe the therapeutic benefits of gardening activities with children, we have been conducting a “gardening group” each summer for the past several years at a state-operated psychiatric facility for adults. The garden itself is located in the fenced-in courtyards adjacent to the day rooms of a specialized clinical research unit jointly operated by Rockland Psychiatric Center and the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York.3 Patients under the guidance of clinical and research staff participate in the selection of which vegetables and flowers to grow, preparing the earth, planting, irrigation, weeding, and harvesting. The edible plants get eaten (waiting until they are ripe and ready for a salad is encouraged but not always successful), and the flowers get sold in the autumn to facility staff. Over time, the gardening group has become one of the most popular voluntary groups on the research unit.

We have observed multiple benefits the gardening group provides to our patients. First and foremost, the garden increases patients’ understanding and appreciation of the natural world. Many of our patients were raised in New York City and have never had the opportunity to see their food grow or work in a garden before. Ideas that the rest of us may take for granted, such as the fact that tomatoes ripen from green to orange to red, can really engage the interest of someone who has never seen this before. The relaxed structure of the group also allows patients with an interest or desire to be more involved to take on leadership roles. For each of the past three summers one or two patients have self-selected into the role of “master gardener,” taking responsibility to watch over the garden on a daily basis and to water and weed on the weekends when the usual staff is unavailable. Harvesting the garden is not only enjoyable and tasty; it also allows staff the opportunity to teach the patients some basic cooking skills. We hope that by having the patients prepare salads, cook vegetables such as green beans and eggplant, and even bake zucchini bread, some will be able to remember and use these lessons in the future.

We highly recommend such “gardening groups” for other intermediate and long-term psychiatric units.

Sincerely,

Rachel T. Ziwich, BS, Charlene Olang, Henry Epstein, LCSW, and Leslie Citrome, MD, MPH

Ms. Ziwich is a research coordinator at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York. Ms. Olang is a rehabilitation assistant and Mr. Epstein is a unit chief at the Rockland Psychiatric Center in Orangeburg, New York. Dr. Citrome is a professor in the Department of Psychiatry at New York University School of Medicine in New York City and the director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

References

1.  Fried GG, Wichrowski MJ. Horticultural therapy: a psychosocial treatment option at the Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders. Primary Psychiatry. 2008;15(7):73-77.
2.  Levin A. Members in the news: psychiatrists sow seeds of good mental health. Psychiatr News. 2007;42(16):14.
3.  Citrome L, Epstein H, Nolan KA, Tremeau F, Elin C, Roy B, Levine J. Integrating state psychiatric hospital treatment and clinical research. Psychiatr Serv. 2008;59(9):958-960.

Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; E-mail: ns@mblcommunications.com.

 

Ms. Kornreich is research associate at New York University (NYU) Department of Social Work in New York City. Ms. Mannheim is manager of Supportive Services at NYU Cancer Institute. Dr. Axelrod is associate professor in the Department of Surgery at NYU School of Medicine and director of Clinical Breast Programs and Breast Surgery at the NYU Cancer Institute.

Disclosures: Ms. Kornreich and Ms. Mannheim report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Axelrod is on the board of trustees for Self-help for Women with Breast and Ovarian Cancer; and is on the medical advisory boards of People Living with Cancer at the American Society of Cancer Oncology and the Young Survival Coalition.

Please direct all correspondence to: Deborah Axelrod, MD, FACS, New York University Cancer Institute, 160 E 34th St, New York, NY 10016; Tel: 212-731-5366; Fax: 212-731-6051; E-mail: deborah.axelrod@nyumc.org.


 

Focus Points

• Children’s understanding of illness and possible reactions vary with age and the individual.
• Parents can ease their children’s distress through a host of mechanisms.
• Coordination of service delivery by the multi-disciplinary team can work to reduce stressors in children whose parents have cancer.
 

Abstract

A parental diagnosis of cancer can have a powerful psychological effect on a child. Although responses vary significantly with age and the individual, children often react with uncertainty, fear, guilt and anxiety. It is up to the parents and the healthcare team to maintain awareness of this growing issue and respond accordingly. Parents can minimize their child’s distress by maintaining open communication throughout the diagnosis, treatment, and recovery processes. Furthermore, an informative, timely, and supportive response from a multidisciplinary healthcare team can successfully reduce stressors and guide the child through the experience. As cancer becomes a more chronic issue, it is becoming imperative that medical physicians address its psychological impacts on the patient and family in order to both improve the quality of life during illness and reduce the long-term negative consequences for years after.

Introduction

According to the National Cancer Institute, one in two men and women will get cancer in their lifetime, and 22.2% of cancer diagnoses will occur between 20–54 years of age.1 While the number of cancer cases is no longer rising, the American Cancer Society estimates that there will be 1,437,180 new cancer cases in the United States in 2008 alone.2 Although cancer predominately appears in an older population (the median age at diagnosis from 2000–2004 for cancer of all types was 67 years old), both men and women have an approximately 1 in 10 chance of developing cancer before age 60.1,2 Cancer has a unique impact on this younger population, in part because the disease not only affects the patient, but also impacts on the patient’s immediate family (including spouses, domestic partners, and oftentimes young children).3 According to the Centers for Disease Control, women increasingly postpone having children until their thirties or forties, and, therefore, have an increased risk of developing cancer while there is still a young child or adolescent living at home.4 A parental cancer diagnosis impinges on a child’s life by changing family routines, altering parent-child interactions, giving the child additional responsibilities, eliciting a fear of potential parental death and increased vulnerability, and adding to already difficult developmental issues.5-7 Children respond differently to the stressors associated with parental illness, and it is important for physicians and parents to understand possible responses in order to anticipate their child’s needs.

Recognition has been slow to address the needs of the family when a parent becomes ill. Despite advances in cancer treatment, even the most sophisticated cancer treatments often bring debilitating physical and emotional side effects. Ensuring quality of life takes many forms. In order to cover the entire landscape—not only addressing the physical but also the emotional, and spiritual aspects of illness—the medical team must include psychiatrists, psychologists, psycho-oncologists, and social workers. The emergence of psycho-oncology is only now being recognized as a crucial part of patient care. As Holland8 stated in an interview in which she describes the slowness to build psycho-social support: “You’ve got to look at the way society has viewed the disease over the years and how it has impacted on people’s responses to the disease.”

It has been difficult in society for adults (let alone children and family) to discuss cancer. During the crisis of parental cancer, childhood behavioral and psychological changes often go unnoticed.6 Perhaps due to this factor, the psychological consequences of parental cancer on a child have rarely been analyzed or acknowledged, and many of the studies that have been performed on the subject show conflicting results. These disparities stem from the fact that researchers used various means of collecting data, methodology, and informant perspectives.9 Because of the inconsistent results, it is difficult to know the exact effect that cancer in a parent will have on a child; however, parental cancer does appear to sometimes elicit numerous negative reactions in a child such as mood and self-esteem changes, academic changes, social and interpersonal alterations, and somatic symptoms.10 Parents can minimize their child’s distress during the diagnosis, treatment, and recovery processes through a host of mechanisms.

Most of the studies that have been performed looked at the effects of maternal breast cancer on children, particularly focusing on the effects of said cancer on adolescent girls.7 It is unclear whether the results of these studies can be applied to children of a broader age group or males. The effects of parental cancer on children do appear to vary based on the age and sex of the child, the sex of the affected parent, the family setting, and the complications associated with the illness.11 Depending on these variables (and existing developmental problems), children and adolescents cope with cancer differently, sometimes in ways that can be psychologically detrimental.

Although cancer remains a major killer of young men and women, overall cancer death rates have gone down considerably in the last 15 years, causing the disease to become a chronic rather than acute illness.1 Thus, childhood psychological distress pertaining to parental care and treatment is becoming more of an issue. In an effort to deal with this growing situation, numerous intervention programs have been developed and standard models have been proposed.9 Many community organizations have developed child support programs with play and “talk” therapy, acknowledging the impact of cancer on children and adolescents. However, these programs are not enough. Physicians must increase their own awareness of the problem by taking not only a full medical history, but a social history as well in order to learn about their patient and their patient’s children. It is up to the parents, teachers, medical team, and social workers to address the issues at hand and provide the proper education and support for children and adolescents throughout the difficult and emotional process of parental diagnosis, surgery, treatment, and recovery.

This article reviews the literature describing possible effects of parental cancer on latency-aged children as well as adolescents and offers examples of pediatric responses from the authors’ personal clinical experiences. Children are divided into two age groups along these lines because a literature search revealed that most studies on pediatric responses to parental cancer separated children into these approximate categories.3,6,11-14 The authors describe what parents can do to minimize the deleterious effects of cancer on their child and conclude that the medical team must act concurrently with social workers and psycho-oncologists in an effort to recognize and reduce the psychological impact of the disease.

Latency-Aged Children (Ages 4–11)

Diagnosis

Despite what many parents believe, a parental cancer diagnosis will affect a young child whether or not the child is informed outright of their parent’s condition. Children can detect the anxiety that will infiltrate their parents’ actions and conversations, and oftentimes cancer will disrupt family routines, affecting a child’s life.12,13,15 Studies show that anxiety levels in children uninformed of their parent’s condition are much greater than anxiety levels in informed children.10,16 Experientially, children worry more when secrets are kept from them than when they know the truth, and it is always worse to overhear bad news than to hear it. When one patient’s 12-year-old son heard about his father’s cancer from a friend, the child confronted his parents, visibly upset that they had not told him first. The family had intended on telling their son after they had elicited the help of family and friends and had “everything in place;” however, it proved too long a wait. A 10-year-old girl discovered that her father’s lung cancer was at end stage when she entered a room full of nervous family members and the conversation stopped. Because the parents were unaware of their daughter’s knowledge, they could not support her when she needed their help. In order to prevent exacerbating an already distressful situation, parents must tell their children of their condition soon after diagnosis.

Latency age children (defined as preschoolers and school-age children) operate in a concrete mind-frame; they can talk about what is happening to them and can express their feelings and thoughts simply, but they are only partially able to use symbolic and abstract language.14 A young child will not be able to grasp many details associated with the disease; therefore, the American Cancer Society recommends that a parent only tell children basic information such as the name of the cancer, the part of the body affected by the cancer, the treatment regiment, and how the child’s life will be affected.15 After informing the child of these basic facts, it is important to anticipate thoughts and concerns the child might have. Children of this age group will care about issues such as parental death and who will care for them; however, they will oftentimes be unable to express these fears.13 On hearing of his mother’s diagnosis, a 6-year-old boy replied “Will I have to move? Will I have to change my room?” Young children will apply abstract concepts to concrete ideas, such as their room and friends, and express their fears through these more concrete thoughts.

Children may also display irrational anxiety concerning their role in their parent’s illness or the nature of the disease itself, believing that they caused the disease or that cancer is contagious.13,15 It is important for parents and health professionals to address these concerns as such fears can lead to severe anxiety which can debilitate a child behaviorally and emotionally.13,16 Healthcare providers should make sure that the child knows that everything possible is being done to help his or her parent, but providers should let the parents judge how much information their child can take in and understand, as parents know their child best. The amount of information given will vary based on each child’s abilities; it is up to parents, healthcare professionals, and social workers to acknowledge this individualism and respect the child’s instincts and worst fears. If a family is religious, the presence of a spiritual leader during this discussion might be useful in order to calm both the parents and children. Parents can attempt to alleviate their child’s fears by reassuring the child that concrete details will not change (such as the child’s room or friends) or by taking the child to the doctor’s office for a casual visit (demonstrating that the doctor’s office is not a scary place). Parents might also want to enlist the help of a friend who has gone through a cancer diagnosis to talk with their child, as the friend can serve as an image of survival. In general, parents should remember that they need to communicate to their children the basics, even if children do not respond with questions; details are unnecessary. Children do not have to know that their mother’s tumor is estrogen receptor positive or that their father is trying a new vascular endothelial growth factor inhibitor.

Coping

Preschoolers and school-aged children are affected by the diagnosis differently than adolescents or adults. Following diagnosis, children are oftentimes unable to verbally express their concerns or fears, and instead they might react by changing their behavior. Children who never cry might cry more often, or children might become more clingy, distractible, or aggressive.13,16 Furthermore, children may demonstrate psychosomatic symptoms or be unable to concentrate in school.16,17

According to a study performed by Compas and colleagues, preadolescents as well as adolescents perceived little control over their parents’ illness. However, the preadolescents used fewer coping strategies than adolescents or young adults.4 Another study demonstrated that children 7–12 years of age cope with the illness by going “in and out” of the situation literally and emotionally. Children in the study were more anxious than their peers, although this anxiety often appeared to be caused by stressors unrelated to their parent’s illness. These children dealt with their anxiety by separating their lives into two spheres, or zones, namely, the zone dominated by cancer, and the “free zone” where they could forget about the disease and escape from the illness. Through this method, children could recreate a balance in their lives and eventually re-establish a routine that would only be disrupted when the disease developed or changed dramatically.16 In general, parents must try to keep routines as much as possible, and “mind the minutia” in order to achieve this goal, ie, ask about the commonplace, specific things in a child’s life, such as the soccer score, or how the child played in a particular game.

School-aged children’s ability to cope depends in part on their family setting. One study that analyzed how sociodemographic and family characteristics affected child functioning in families with parental cancer demonstrated that children have more trouble coping with the illness in single-parent households, when the parents are from smaller families, and when the ill parent is younger. Furthermore, the number of children and the position of the child within the family appeared to be important, as children with siblings had less trouble coping than an only child, and eldest children had more trouble coping than their younger siblings. While no study has looked at the effects of socioeconomic status on children with parental cancer, studies on the general population demonstrate that a lower socioeconomic status is linked to an increased risk of problems in children.11 Because there is limited research looking at how social, economic, and demographic factors will effect these children, it is difficult to know the validity of the results from this study. What does appear to be important is the family’s support during this experience through a strong network of friends, fellow religious congregants, and so forth. Ultimately, the impact that cancer will have on a family will relate to how the family functioned before the illness. If communication and support were present before the cancer came, then it is more likely that it will continue after.

Treatment and Recovery

Diagnosis is not the only time to be concerned about children’s psychological responses to parental cancer. In fact, latency-aged children displayed the most stress-related symptoms when confronted with physical signs of parental illness (oftentimes seen during treatment) such as vomiting and hair loss, as well as during complications and emergency hospitalizations that disrupt a normal routine.9,14 Even before long-term treatment is initiated, a parent might need in-patient hospitalization and surgery. The recovery following surgery can pose a particular threat to young children as many hospitals do not allow children under 14–18 years of age (ie, the minimum age varies with hospital guidelines) on patient floors. These rules are even more stringent when the treatment involves a compromised immune system, such as a bone marrow transplant. Even if these rules are not in effect, there should always be consultation between the medical staff and the family about the possibility of visitation.

The physical separation enforced by hospitalization can be stressful for a child. In order to minimize this separation, ill parents should attempt to maintain communication with their children. Aside from the conventional phone calls, creative communication can include cards, faxes, and even refrigerator magnet postings, and children should be reminded that their parent is thinking about them. In school, teachers, guidance counselors, social workers, and school nurses should all encourage children to engage in creative activities in order to express his or her emotions, and at home parents should attempt throughout treatment to maintain a child’s normal routine and constantly remind the child that the parent has not forgotten about him or her and will be coming back home.13 Physicians should advise parents to give their child an item to hold that the child associates with the parent, such as a set of keys, an eyeglass case, or a coffee mug. This action allows a child to feel as though he or she is protecting their parent’s domain, awaiting their inevitable return. Post-surgery, as cancer becomes more chronic, it might be useful for children to meet with a social worker or establish a strong network of friends and relatives who can be there for them consistently over time. This continuity of building a familial or extended support network can ease both parental and child stressors.

The American Cancer Society offers a list of books geared toward children in this age group which can offer additional information on parental cancer.15 There are also many intervention programs for children in this situation, such as Quest, “For Kids Only,” The Komen Kids, and “Kids Can Cope.”10 These programs aim to improve the mood, quality of life, coping skills, and stress management of these children. Most of the programs that are currently underway involve three components: education, normalization (creating a safe environment), and building on their strengths to help them cope.10 Other community-based organizations throughout the country have children’s programs, such as Noogieland at Gilda’s Club and CancerCare for Kids. Some of these have telephone groups, play therapy, and social events to ease the isolation children are often facing. By utilizing these programs as well as parental communication, school resources, and books, it is possible to minimize a child’s anxiety throughout the diagnosis and treatment process.

Adolescence (Ages 12–18)

Diagnosis

Adolescents (ie, teenagers) are at a very different mental and emotional state than latency-aged children as they maintain greater cognitive abilities and the potential for abstract and symbolic thought.16,18 They are also more aware of their parent’s pain during treatment and the potential loss of a parent that can accompany cancer.17 Studies demonstrate that adolescents respond best when given detailed information at a level they can comprehend soon after parental diagnosis.19 By being better informed, adolescents reported that they found it easier to talk to friends and family about the illness, thereby creating an outlet to discuss their feelings or get their mind off the problems at hand.7 Information should include facts about the cancer, potential treatment side effects, and the seriousness of the disease. Many adolescents expressed a desire not only to be informed second hand about their parent’s illness, but also to be present at appointments and updated on advancements or alterations in their parent’s condition.19 Studies also demonstrate that the emotions expressed by parents when they inform their children of the diagnosis is important; when parents were upset during the initial discussion, children became more upset as well.7 Thus, it is imperative that parents try to remain as composed as possible when informing their adolescents (or younger children) about their diagnosis. Children should be informed in a familiar setting and when they will not be distracted by their phone or friends. The atmosphere is important and helping the child get comfortable may affect the child’s reaction. It can also sometimes be helpful for parents to validate the child’s feelings by expressing their own fears while reassuring the child that they are doing everything they can to eradicate the disease.

A diagnosis of cancer is difficult for an adolescent child in part because it brings on numerous conflicting feelings. Adolescents by nature want to separate from their families and establish an independent identity. However, adolescents in this position realize the potential of parental death and want to spend more time with their ill parent.7 Perhaps because of this pull, some adolescents and parents in families with parental cancer reported that their families were more cohesive, more expressive, and less argumentative with one another than the norm.20 In addition, this and other studies demonstrate that sometimes adolescents in these families had lower levels of anxiety and fewer behavioral problems than their normative samples.20,21

Unfortunately, this analysis is inconsistent with most other results. One recent study looking at posttraumatic stress in adolescents with parental cancer discovered that 1–5 years after diagnosis, 21% of sons and 35% of daughters had clinically significant stress response symptoms.22 These results indicate that a cancer diagnosis can have a significant impact on a child, as increased stress was associated with behavioral and psychological problems. In fact, the study demonstrated that stress was higher amongst children of parents with cancer than amongst children treated for cancer themselves.22 One cancer survivor described her 15-year-old daughter’s experience post-diagnosis:

On the surface, she seemed perfectly functional. In reality, she was struggling. There were little signs. She moved all her things into our bathroom and began using it all the time, she became consumed with cooking and put together elaborate meals several times a week, she would leave her friends early on Friday nights to come home and watch a silly movie with me. She developed an eating disorder that almost got out of control.

For this patient’s daughter, normal adolescent emotions were exacerbated, and for lack of a better outlet she expressed her suffering through self-destructive behavior.

Coping

The coping ability of adolescents in response to parental cancer is highly variable. Like latency-aged children, adolescents feel incapable of controlling their parents’ illness. These older children respond to this feeling of helplessness by using emotion-focused coping, which is ineffective as it implies avoidance of and disengagement from the issues at hand. This coping strategy is linked to lower adaptation and higher anxiety and depression in adolescents who utilize it as compared to controls.5

Certain variables can moderate adolescent anxiety and aid adolescents in coping. One important variable is the maintenance of communication between parents and adolescents throughout the illness.10 While cancer only marginally affects the ability of parents and children to communicate with one another, recurrent disease and lengthy treatments can negatively impact on communication.23 It is therefore imperative that parents work to maintain open communication throughout their illness, even if they can only do so through text messaging or email. It is also important for parents to realize that their child might still be empathizing even if he or she is not verbally expressing this sympathy or distress. One patient’s 15-year-old son said nothing to his ill mother through her surgery, radiation, and chemotherapy despite the fact that his mother was open with him and told him everything. For years, she assumed that her illness had no effect on him. She only discovered its impact when he graduated high school and received an award for a poem he had written about her and dedicated to her that described how much he loved, respected, and admired her. Parents must remember that just because adolescents have trouble expressing their pain does not mean that they are not experiencing any.

Another important variable that affects adolescents’ coping abilities is complications associated with the illness. Studies demonstrate that adolescents have more trouble coping when their parents experience more complications during treatment, possibly because adolescents have a greater ability to empathize with others and therefore are troubled by pain and physical discomfort in their parents.11 While this is an uncontrollable aspect of the disease, parents should be aware of the implications that treatment complications, failures, or cancer recurrences can have on their adolescent.

Treatment and Recovery

As previously mentioned, the treatment of parental cancer will alter family routines, impacting children and those who love them. These modifications affect adolescents differently than latency-aged children as adolescents experience a change in their role in the family. These older children oftentimes have additional responsibilities including both household chores and caretaking tasks when their parents are ill, and these responsibilities can lead to emotional and behavioral problems.8,19,24 These problems partly develop because they have less time to engage in social or leisure activities to unwind and partly because these responsibilities change normal family patterns and routines.19,25 As Cancer Care For the Whole Patient,26 a new book by the Institute of Medicine of the National Academies, describes:

…cancer and its treatment and sequelae can limit the ability of patients and families to perform their usual personal roles and their roles in the family and the larger society. Unaddressed, these limitations can lead to emotional and mental health problems for both patient and family, and the inability to accomplish developmental tasks, such as attaining educational goals and establishing and maintaining social relationships, and to perform meaningful work inside and/or outside of the family.26

This situation can be minimized by building a network of family and friends who can help take on some of the responsibilities associated with parental illness.

Because treatment can last for years (and new treatment options have made cancer increasingly chronic), it is important for healthcare professionals and parents to attempt to normalize these adolescents’ lives in order to minimize anxiety levels. Studies report that adolescents in this situation demonstrate a desire to be a “normal teenager” and spend time with friends, get away from home over summers, and separate from the day-to-day management of parental illness.19 Parents and healthcare advisors should encourage adolescents to continue their normal activities and peer relations. It is important to make sure that children in high school do not feel compelled to stay at home after they graduate and go to a commuter college or no college at all. Parents should let adolescents know that it is okay to separate and move on. If adolescents are having trouble coping, many of the support groups available to younger children are also available to them, and these groups can help minimize behavioral problems and anxiety levels.10,19 Unfortunately, there are too few support groups available for adolescents and teenagers. Therefore, it is imperative that adolescents seek help when necessary from social workers and psychiatrists. Furthermore, professionally facilitated family meetings can be helpful in minimizing the disruption and negative consequences of parental cancer.

It may be pertinent at this juncture when treatment ends to include the child in physician visits. Meeting with the physician or other available members of the healthcare team in an informal manner for a soda or snack may help make adolescents more comfortable with the situation and less concerned for their parent. By establishing trust in the healthcare team, adolescents might also have fewer long-term concerns and be more willing to aid in their parent’s recovery process.

Terminal Illness/Death of a Parent

Despite being prepared for death, it will still be very difficult for a child to cope with parental demise. During these times, intra-familial and other social support can aid the child’s adjustment. Visitation to hospice should be determined by the family and social workers. Mechanisms to preserve the memory of a parent may take the form of videos, book projects, or photo albums. These keepsakes can serve as something tangible to hold onto.
Joelle was 34 years of age when she learned her cancer had metastasized, and despite many attempts to halt the progression of disease her response to treatments were disappointing. Her daughter Halle was 4 years of age at the time and enjoyed reading with her mother. Joelle started “Light One Little Candle” as a book project to encourage young mothers (or fathers) with cancer to read to their young children as a way to connect and to create memories. In the books, both on the nameplate and in the text, the mother can write notes to the child as she reads, thereby not only instilling a love of reading but also creating very specific memories for the child to hold on to. The Light One Little Candle program has given out over 10,000 books thus far from Boston, Massachussetts; Hartford, Connecticut; New York City; and San Diego, California. It is certainly a beautiful legacy and a gift that keeps on giving and has undoubtedly helped children through the grieving process. Joelle herself had many books for Halle with handwritten notes in them, some that she read to her and some that she put away for years to come. In addition, Joelle created memories for Halle through videos and gifts for future birthdays and special occasions.

The death of a parent from cancer brings up numerous separate issues for the child. Studies indicate that children, no matter the age, do indeed mourn, and therefore will severely mourn the death of a parent. However, the nature of children’s mourning differs significantly from that of an adult.27 Death from cancer is generally drawn out and painful, making it a difficult death for children to witness.27 Because a cancer death is generally anticipated, there is time for children to prepare themselves for the loss and for a parent and child to address the issue together. Studies show that people are more able to deal with their grief when the death is anticipated as opposed to acute.27

In general, children tend to have three questions immediately on the death of a loved one, namely, did it happen because of something they did, will it happen to them, and who will take care of them if it does happen? These questions should be addressed (whether they are articulated or not) as soon as possible.27 Children can obtain information through books geared toward their age group such as I Know I Made it Happen for younger children or How it Feels When a Parent Dies for older children.28 Moreover, all lines of communication must be kept open to ensure that these concerns are discussed openly and honestly.

Conclusion

Cancer is a disease that is affecting more Americans each year and will not go away any time soon. It is important for physicians and their medical team to start addressing the psycho-social consequences of the disease on not only the patient, but also on members of the patient’s family. Referrals to appropriate professionals such as social workers, school counselors, or psychiatrists are imperative. Cancer centers now have psycho-oncologists on staff who have obtained post-doctoral training in the field and are qualified to look at the psychological, social, behavioral, and ethical aspects of cancer. Psychosocial support has taken a back burner to virtually every facet of cancer medical care, which is focused on eradicating illness. As people are living longer with cancer, it is about time that we supplement the medical component with the human element of cancer and nurture the families who are impacted day to day by the disease. PP

References

1.    Ries LA, Melbert D, Krapcho M, et al, eds. National Cancer Institute. SEER Cancer Statistics Review, 1975-2005. Available at: http://seer.cancer.gov/csr/1975_2005. Accessed August 27,2008.
2.     Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96.
3.     Compas BE, Worsham N, Epping-Jordan JE, et al. When mom or dad has cancer: markers of psychological distress in cancer patients, spouses, and children. Health Psychol. 1994;13(6):507-515.
4.     Ventura SJ, Abma JC, Mosher WD, Henshaw SK. Estimated pregnancy rates by outcome for the United States, 1990–2004. National vital statistics reports; vol 56 no 15. Hyattsville, MD: National Center for Health Statistics; 2008.
5.     Compas BE, Worsham N, Ey S, Howell DC. When mom or dad has cancer: II. Coping, cognitive appraisals, and psychological distress in children of cancer patients. Health Psychol. 1996;15(3):167-175.
6.     Welch AS, Wadsworth ME, Compas BE. Adjustment of children and adolescents to parental cancer. Parents’ and children’s perspectives. Cancer 1996;77(7):1409-1418.
7.    Huizinga GA, van der Graaf WT, Visser A, Dijkstra JS, Hoekstra-Weebers JE. Psychosocial consequences for children of a parent with cancer: a pilot study. Cancer Nurs. 2003;26(3):195-202.
8.     Rosenthal E. Oncology Times, 10/25/07, Psycho oncology pioneer jimmie holland on her fight to have cancer patients’ distress recognized. Oncology Times. October 25, 2007;29:8-10.
9.    Visser A, Huizinga GA, van der Graaf WT, Hoekstra HJ, Hoekstra-Weebers JE. The impact of parental cancer on children and the family: a review of the literature. Cancer Treat Rev. 2004;30(8):683-694.
10. Su Y, Ryan-Wenger NA. Children’s adjustment to parental cancer: a theoretical model development. Cancer Nurs. 2007;30(5):362-381.
11. Visser A, Huizinga GA, Hoekstra HJ, van der Graaf WT, Hoekstra-Weebers JE. Parental cancer: characteristics of parents as predictors for child functioning. Cancer. 2006; 106(5):1178-1187.
12. American Cancer Society. Helping children when a family member has cancer: dealing with diagnosis. Available at: www.cancer.org/docroot/CRI/content/CRI_2_6X_Dealing_With_Diagnosis.asp. Accessed September 5, 2008.
13. Visser A, Huizinga GA, Hoekstra HJ, van der Graaf WT, Gazendam-Donofrio SM, Hoekstra-Weebers JE. Emotional and behavioral problems in children of parents recently diagnosed with cancer: a longitudinal study. Acta Oncologica. 2007;46(1):67-76.
14. Lacetti M, Vessey J. When a school-age child’s parent has cancer. J Spec Pediatr Nurs. 2007;12(4):297-299.
15. Rosenheim E, Reicher R. Informing children about a parent’s terminal illness. J Child Psychol Psychiatry. 1985;26(6):995-998.
16. Halseth S, Ulfsaet N. Having a parent with cancer: coping and quality of life of children during serious illness in the family. Cancer Nurs. 2003;26(5)355-362.
17. Christ GH, Siegel K, Freund B, et al. Impact of parental terminal cancer on latency-age children. Am J Orthopsychiatry. 1993;63(3):417-425.
18. Christ GH, Siegel K, Sperber D. Impact of parental terminal cancer on adolescents. Am J Orthopsychiatry. 1994;64(4):604-613.
19. Grabiak BR, Bender CM, Puskar KR. The impact of parental cancer on the adolescent: An analysis of the literature. Psychooncology. 2007;16(2):127-137.
20. Gazendam-Donofrio SM, Hoekstra JH, van der Graaf WT, et al. Family functioning and adolescents’ emotional and behavioral problems: when a parent has cancer. Ann Oncol. 2007;18(12);1951-1956.
21. Hoke LA. Psychosocial adjustment in children of mothers with breast cancer. Psychooncology. 2001;10(5):361-369.
22. Huizinga A, Visser A, van der Graaf WT, et al. Stress response symptoms in adolescent and young adult children of parents diagnosed with cancer. Eur J Cancer. 2005;41(2):288-295.
23. Huizinga GA, Visser A, van der Graaf WT, Hoekstra HJ, Hoekstra-Weebers JE. The quality of communication between parents and adolescent children in the case of parental cancer. Ann Oncol. 2005;16(12):1956-1961.
24. Gates MF, Lackery NR. Youngsters caring for adults with cancer. Image J Nurs Sch. 1998;30(1):11-15.
25. Nelson E, Sloper P, Charlton A, While D. Children who have a parent with cancer: a pilot study. J Cancer Educ. 1994;9(1):30-36.
26. Adler NE, Page AE, eds. Institute of Medicine (IOM), 2008. Cancer Care for the Whole Patient Meeting Psychosocial Health Needs. Washington, DC: The National Academies Press; 2008.
27. Koocher GP. Coping with a death from cancer. J Consult Clin Psychol. 1986;54(5):623-631.
28. Stuber ML. “What do we tell the children?”: understanding childhood grief. West J Med. 2001;174(3):187-191.

 

“I’m not asleep… but that doesn’t mean I’m awake.” –Author Unknown

 

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and chief medical officer of Avastra USA.

Disclosures: Dr. Erman is a consultant to Actelion, Cephalon, Mallinckrodt, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Cephalon, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, sanofi-aventis, and Takeda; has received grant/research support from Actelion, Cephalon, Eli Lilly, GlaxoSmithKline, Medicinova, Merck, Organon, Pfizer, sanofi-aventis, Schwarz Pharma, Takeda, Transcept, Vanda, and Wyeth; and owns stock in Cephalon, Forest, Neurocrine, Pfizer, sanofi-aventis, and Somaxon.


 

he disorder we now call narcolepsy was first named and described as a specific disorder by Gelineau1 in France in 1880. It can be argued that this recognition signaled the start of the field of sleep medicine. Gelineau coined the term “narcolepsy” to describe a syndrome of excessive sleepiness, characterized by an irresistable urge to sleep, at times accompanied by falls. These falls, secondary to a sudden loss of muscle tone, are now recognized as cataplexy.

Narcolepsy was well recognized as a disorder throughout the 20th century and, prior to the recognition of the widespread prevalence of sleep apnea in the 1980s, was presumed to be the basis for most complaints of “excessive sleepiness” reported to physicians by their patients. Unfortunately, this led to many patients without classic narcolepsy symptoms being diagnosed with narcolepsy and receiving treatment with classic stimulant medications such as methylphenidate and amphetamines. Since no objective basis for the diagnosis of narcolepsy existed, the complaint of sleepiness associated with various conditions and disorders, such as sleep apnea, inadequate sleep, depression, and chronic fatigue, was often the basis for a diagnosis of narcolepsy and treatment with stimulants. Many patients with complaints of sleepiness and fatigue received a diagnosis of narcolepsy, received amphetamines or other stimulants in treatment of this condition, and established long-term (often lifetime) dependency on the use of these medications to maintain “normal” function.

The discovery of the existence of rapid eye movement (REM) sleep by Aserinsky and Kleitman2 in 1953 using polysomnographic methodology established that formal criteria could be used to define parameters of sleep and wake. In 1960, Vogel3 demonstrated that specific abnormalities in the regulation and timing of REM sleep were associated with narcolepsy. These observations allowed the recognition that appearance of REM sleep during a nap, a frequent event in patients with the narcolepsy, is rarely–if ever–seen in healthy normal individuals without another sleep condition or who are not sleep deprived. When narcoleptics and normal controls are given the opportunity to take a series of naps over the course of the day in a structured testing situation, the presence of pathologic sleepiness overall and the occurrence of REM sleep early after sleep onset in these nap opportunities clearly differentiated healthy normal subjects and sleepy people without narcolepsy from those with narcolepsy.

Much work on the origins of narcolepsy, its diagnosis, and treatment have been performed at the Stanford Center for Narcolepsy Research, directed by William Dement, MD, with active collaboration by a large group of researchers, including Christian Guilleminault, MD, Mary Carskadon, PhD, and Merrill Mittler, PhD.

One of the early practical applications of scientific observations about the phenomenology of narcolepsy occurred in 1982. The realization that patients with narcolepsy would be sleepy when given the opportunity to nap, and that REM sleep would be seen in naps when they occurred, led to the development of a new and objective test for the diagnosis of narcolepsy, the Multiple Sleep Latency Test.4 This test allowed for formal testing of patients with complaints of sleepiness to determine whether objective sleepiness was present. When a diagnosis of narcolepsy could firmly be established, treating physicians could feel more confident about providing stimulant medications in treatment for indeterminate periods of time.

In the early part of the 20th century, it was widely believed that human narcolepsy was a familial disorder. Recent studies have shown that human narcolepsy is not a simple genetic disorder. For example, monozygotic twins are most frequently discordant for narcolepsy, indicating environmental factors in narcolepsy susceptibility.5 Efforts to characterize an immunologic or genetic basis for the development of human narcolepsy lead to the recognition that certain patterns of abnormalities in the immune system of patients with narcolepsy were seen at a disproportionately high level. The observation that narcolepsy is associated with a specific histocompatibility (HLA DR2) complex pattern was first reported in Japan in 1983.6 This finding was quickly confirmed to be present in non-Asian narcolepsy populations in Europe and North America.

The immune system and its relationship to the development of narcolepsy was of great interest to narcolepsy researchers. Patients who developed narcolepsy, usually in their teens or twenties, were typically observed to have been perfectly normal with regard to sleep, alertness, and muscle control (absence of any signs of cataplexy) at earlier ages. However, it was often possible to identify a specific point in time (eg, a specific school grade or work setting) as the onset of their problems with excessive sleepiness.

For many patients, there was a history of a period of stress or a physical illness that seemed to be associated with the onset of sleepiness complaints. This observation, combined with the HLA patterns seen in many patients, led to a hypothesis that narcolepsy could result from an autoimmune insult to the central nervous system. Many years of research at numerous instituions attempted to find such a specific autoimmune basis for the etiology of narcolepsy, without substantive results.

Progress in understanding the etiology of narcolepsy occurred in large part on the recognition that an animal model for the disorder existed. Canine narcolepsy was first described in 1973 at Stanford by Mitler and Dement.7 It was appreciated that an animal model for narcolepsy could help to establish a specific genetic basis for narcolepsy, and a breeding colony of narcoleptic dogs was established at Stanford. However, initial efforts to crossbreed affected animals from several species were not successful; the offspring of affected parents did not show signs of narcolepsy.

In 1975, three Dobermans with narcolepsy (two of which were littermates) were donated to the Stanford colony. The breeding of these animals led to the first successful genetic transmission of narcolepsy, with a litter of affected animals born at Stanford on July 29, 1976. Multiple cases of Labradors with narcolepsy were subsequently reported, and the trait was found to predictably be transmitted as a single autosomal recessive gene.8

In 1999, following years of effort to identify the specific genetic bias for the hereditary transmissibility of canine narcolepsy, According to one report,9 narcoleptic dogs demonstrated abnormalities in receptors for a previously identified neurotransmitter, hypocretin (aka, orexin). Coincidentally, a research group at the University of Texas Southwestern in Dallas, working with orexin knockout mice, made an independent and essentially simultaneous observation that these orexin knockout mice demonstrated sleepiness and cataplexy-like behavior suggestive of another animal model for narcolepsy.10

These neuroactive hormones had been previously identified, thought to possibly play a role in regulation of appetite (thus orexin), and recognized to be synthesized in the hypothalamus (thus hypocretin). Although this substance was shown to have some activating properties, there was no recognition that it could play a critical role in regulating levels of alertness.

The observation of abnormalities in hypocretin as a basis for canine and murine narcolepsy quickly lead to measurement of levels of hypocretin in humans. It was established in 2000, only a year after the publication of data on animal narcolepsy, that humans with narcolepsy do indeed have abnormalities in levels of hypocretin.11 In contrast to the abnormalities in hypocretin receptors seen in animal narcolepsy, humans with this disorder have very low (at times essentially undetectable) levels of hypocretin. Histopathologic studies have demonstrated apparent destruction of hypocretin secreting cells in the brains of patients with narcolepsy.12 This data suggest that autoimmune processes could target the small population of hypothalamic neurons secreting this compound, leading to narcolepsy on an autoimmune basis, as has long been suspected.

What is the import of these discoveries for the future of sleep medicine and sleep disorders? Identification of a specific etiology for a disease has always been critical in helping to identify possible treatments for the disorder. Without understanding what organism may have caused a specific infection, effective therapy cannot be administered.

Does the recognition of abnormalities in the orexin-hypocretin system afford practitioners the opportunity to treat narcolepsy more effectively? At the moment, the answer is no. Although it has been demonstrated that human narcolepsy seems to be caused by the loss of hypocretin secreting cells in the hypothalamus, there is currently no mechanism for administration of hypocretin to affected patients to ameliorate narcolepsy symptoms.

However, understanding of the role that abnormalities in the production or recognition of hypocretin may play in regulation of levels of alertness and sleepiness is already showing a promise as a therapeutic approach to be utilized for patients with several types of sleep disorders. The logic is simple and elegant. If absence of or insensitivity to hypocretin leads a disorder characterized by excessive sleepiness, what would result from production of a chemical compound capable of occupying the hypocretin receptor site in the hypothalamus, interfering with the normal action of hypocretin of promoting alertness? Presumably, the answer would be promotion of sleep initiation (ie, reducing sleep latency), the therapeutic effect  we expect from a hypnotic (“sleeping pill”) medication.

Conversely, could use of a hypocretin receptor agonist generate increased levels of alertness? Several pharmacologic companies are currently pursuing these lines of research, and it is possible that hypocretin receptor antagonists for treatment of insomnia may be available for human use within the next several years.

Animal research has taken the issue of treatment one step further. A recent publication13 showed that intranasal application of hypocretin in sleep-deprived rhesus monkeys could significantly improve performance in a short-term memory task. Deadwyler and colleagues13 noted that this method of administration appeared to produce a pronounced reversal of sleep deprivation-induced changes in brain metabolic activity, raising the question of whether, within a few years time, “natural” stimulants to counteract the symptoms of hypersomnia conditions such as narcolepsy, as well as the impact of inadequate sleep and sleep deprivation, may be available for human administration. PP

References

1. Gélineau J. De la narcolepsie. Gaz Hop (Paris). 1880;53:626-628; 1880;54:635-737.
2. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science. 1953;118(3062):273-274.
3. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry,. 1960;3:421-428.
4. Carskadon MA, Dement WC. The multiple sleep latency test: what does it measure? Sleep. 1982;5(suppl 2):S67-S72.
5. Honda M, Honda Y, Uchida S, Miyazaki S, Tokunaga K. Monozygotic twins incompletely concordant for narcolepsy. Biol Psychiatry. 2001;49(11):943-947.
6. Honda Y, Asake A, Tanaka Y, Juji T. Discrimination of narcolepsy by using genetic markers and HLA. Sleep Res. 1983;1(2):254.
7. Mitler MM, Dement WC. Sleep studies on canine narcolepsy: pattern and cycle comparisons between affected and normal dogs. Electroencephalogr Clin Neurophysiol. 1977;43(5):691-699.
8. Foutz A, Mitler M, Cavalli-Sforza L, Dement WC. Genetic factors in canine narcolepsy. Sleep. 1979;1(4):413-421.
9. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365-376.
10. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437-451.
11. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39-40.
12. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469-474.
13. Deadwyler S, Porrino L, Siegel J, Hampson R. Systemic and nasal delivery of orexin-a (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239-14247.

 

Dr. Kornstein is professor of Psychiatry and Obstetrics/Gynecology, executive director of the Institute for Women’s Health, and executive director of the Mood Disorders Institute at Virginia Commonwealth University in Richmond. Dr. Culpepper is professor and chairman in the Department of Family Medicine at Boston University Medical Center in Massachusetts.

Disclosures: Dr. Kornstein is on the advisory boards of or receives honoraria from Biovail, Bristol-Myers Squibb, Eli Lilly, Forest, Neurocrine, Pfizer, Sepracor, and Wyeth; and receives research support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health,  Novartis, Sanofi-Synthelabo, Sepracor, and Wyeth. Dr. Culpepper is a consultant to Eli Lilly, Forest, Pfizer, and Wyeth; and on the speaker’s bureaus of Forest, Pfizer, and Wyeth.

Acknowledgments: The authors would like to thank Grant Steen, PhD, for his assistance.

Please direct all correspondence to: Susan G. Kornstein, MD, Dept of Psychiatry, Virginia Commonwealth University, PO Box 980710, Richmond, VA 23298-0710; Tel: 804-828-5637; Fax: 804-828-5644; E-mail: skornste@vcu.edu.

 

 

Abstract

 

According to recent data, women are at increased risk for depression during the menopausal transition, even in the absence of a psychiatric history. As a result, it is important to identify biologic, psychiatric, and social risk factors for depression. An English language electronic literature search using the PubMed database (1986–2006) was conducted using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references were extracted and summarized. The authors of this article identified risk factors for menopausal depression reported in at least two primary references. It was found that a variety of biologic, psychiatric, and psychosocial factors interact to increase vulnerability to depression during the menopausal transition. These findings are consistent with a biopsychosocial model for perimenopausal depression. Depression in the context of the menopausal transition may be difficult to recognize. Thus, physicians should be aware of the various factors that can increase an individual patient’s risk for illness during this time period.

 

Introduction

Currently, 21.5 million women 45–54 years of age live in the United States1 and virtually all of these women will have entered menopause within the next decade. Crude calculation suggests that nearly 2 million American women per year will go through the menopausal transition. The life expectancy of women is now approximately 80 years, so many women will live 33% of their lives after menopause.2 Successful transition into menopause enhances health-related quality of life3,4 and may increase satisfaction in the postmenopausal phase.4

This article will summarize relevant evidence regarding the risk of depression during the menopausal transition and discuss contributing factors that can assist clinicians in diagnosing and treating depression in midlife women. The authors conducted an electronic literature search using the PubMed database (1986–2006; English language) using the search terms depression, depressive, depressed, menopause, perimenopause, postmenopause, and climacteric. Relevant references (and cross-references) were extracted and summarized. Risk factors for menopausal depression reported in at least two primary references were identified.

 

The Menopausal Transition

The Stages of Reproductive Aging Workshop (STRAW) standardized terminology relating to menstruation and menopause.5 The final menstrual period typically occurs when women are 42–58 years of age (mean age=52), and this event is the zero point for the STRAW staging system. Menarche marks entry into the reproductive phase of a woman’s life (Stage –5, relative to the zero point), after which it can take several years for a regular menstrual cycle to become established. Reproductive maturity is associated with menstrual periods that occur every 21–35 days (Stages –4 and –3), with the late reproductive stage (Stage –3) characterized by a gradual increase in levels of follicle-stimulating hormone (FSH). The early menopausal transition (Stage –2) begins when rising FSH levels lead to variability in menstrual cycle length, with cycles varying by >1 week from the normal cycle length. The late phase of the menopausal transition (Stage –1) is associated with higher levels of FSH and greater variability of the cycle, with ≥2 skipped cycles and an interval of amenorrhea lasting at least 60 days (Figure 1).5

 

Female reproductive senescence is defined by the depletion of oocytes in the ovary,5 and reproductive aging thus consists of a progressive loss of oocytes through atresia or ovulation. Menopause begins at the final menstrual period, but this point cannot be recognized with surety until after 12 months of amenorrhea. The early postmenopause (Stage +1) lasts 5 years and includes the 12-month period of amenorrhea that defines the beginning of the menopause. The late postmenopause (Stage +2) lasts for the rest of a woman’s life. Many menopausal symptoms, especially vasomotor symptoms such as hot flashes, are most severe during Stage –1 or Stage +1, in what has been called the “perimenopause.”5

The transition to menopause is a normal facet of aging, and most women do not become clinically depressed during this phase.6 However, for some women it may be associated with mood changes, including depressive symptoms—similar to other reproductive life events associated with hormonal fluctuations, including the premenstrual phase of the cycle,7-10 pregnancy,11-13 and the postpartum period.8,12,14-17 Understanding and recognizing physical, psychosocial, and psychiatric factors that increase the risk for depression during the menopausal transition and how these factors interact to modulate the risk imparted by the menopausal transition itself is important, particularly for primary care physicians (PCPs) who are likely to be confronted by these issues frequently as increasing numbers of women approach menopause.

 

Risk of Depression During the Menopausal Transition

The menopausal transition is often associated with an increase in depressive symptoms,18-22 and recent evidence suggests that the transition to menopause is a risk factor for depression in and of itself.17,23 In fact, the menopausal transition has been associated with an increased risk of depression in women with or without a previous history of depression.

A prospective study following 29 asymptomatic premenopausal women through the transition to menopause examined the relationship between the onset of depressive symptoms and perimenopause.24 The study found that the risk of depression during the 2-year period centered at the final menstrual period was 14-fold higher than risk during a 31-year premenopausal phase, and that a psychiatric history was not necessary for women to experience depression during this time.

More recently, two studies examined the risk for perimenopausal depression in women with no prior history of mood disturbance, with consistent findings. One study included 460 premenopausal women, who were followed prospectively for 3 years; menopausal status was determined every 6 months based on menstrual cycle changes ascertained through patient interviews.17 Among women who entered the menopausal transition, 32.5% had a new onset of depressive symptoms, whereas 20.0% of women who remained premenopausal became depressed. The adjusted odds ratio (OR) for depression among women who entered the perimenopause was 1.8, compared with premenopausal women.17 Findings were similar when a more stringent definition of depression was applied. The adjusted OR for severe first onset of depression (defined as women who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]25 criteria for major depressive disorder (MDD), self-reported depression most of the day nearly every day plus symptoms of anhedonia, or had a Center for Epidemiologic Studies Depression Scale score >24) in perimenopausal women compared with premenopausal women was 1.9, with incidence rates of 16.6% versus 9.5%, respectively.

The other study, an 8-year longitudinal study of 436 women, found that high depression scores were 4-fold more likely to occur during the menopausal transition (again determined based on menstrual cycle changes), relative to the premenopausal phase (P<.001).23,26 Increased levels of FSH and luteinizing hormone (LH) as well as increased variability of estradiol, FSH, and LH were all correlated with depressive symptoms. In a multivariate model, depressed women were 4.6-fold more likely to have elevated FSH levels and 3.0-fold more likely to have elevated LH levels (P<.002, for both).23 These relationships remained significant after adjusting for smoking, vasomotor symptoms, poor sleep, health status, employment, and marital status.

Studies that have included women with prior psychiatric diagnoses have found that those with a history of MDD prior to menopause are at particularly high risk for development of depression in the perimenopausal period.26-28 In addition, a history of prior depression related to the reproductive cycle, including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), ovarian cancer-related dysphoria, and/or postpartum MDD is associated with depression during the menopausal transition.29-31

Taken together, these findings suggest that the changing hormonal milieu during the menopausal transition is associated with onset of depression, even among women with no history of mood disturbance. Furthermore, some women may be particularly vulnerable to developing depression during times of hormonal flux. However, the risk for depression during the menopausal transition is influenced by multiple factors, which will be discussed in more detail below.

 

Risk Factors for Depression During the Menopausal Transition

Women at midlife face a unique set of circumstances including physical changes related to aging in general and to the menopause in particular, psychosocial adjustments related to changing roles and responsibilities within the family, and a variety of potential life stressors.32 These issues, in addition to psychiatric considerations (eg, history of or current mood or anxiety disorder), have an impact on the likelihood of depression in women as they transition to menopause.33

 

Physical Context of the Menopausal Transition

Hormonal changes, such as the widely fluctuating hormone levels that are the hallmark of the menopausal transition,32 may be associated with mood changes. Hormonal fluctuations may have direct effects on mood. Although the mechanism is poorly understood, preclinical studies suggest that estrogen has effects on areas of the brain involved in regulation of mood including the prefrontal/frontal cortex, hippocampus, amygdala, hypothalamus, dorsal raphe, and locus coeruleus.34-36 Specifically, estrogens have been reported to influence monoamine systems via modulation of the firing rate, synthesis, release rate, and elimination pathways.37-44 There may also be indirect effects; for example, physical symptoms related to menopause, including hot flashes and insomnia, may be problematic enough to affect mood in a kind of “domino effect” of menopause-related depression.31 Alternatively, complications in the management of chronic medical conditions or comorbidities may also contribute to the risk of depression during the menopausal transition.

Ovarian hormones or fluctuations in hormone levels have been implicated in the regulation of mood and behavior.44 For example, women have about twice the risk of depression as men,15,27 and analysis of the age at onset of depression shows that the risk difference between females and males arises in early adolescence and persists through the mid-50s,27 roughly the ages that correspond to menarche and menopause. Furthermore, psychiatric illnesses—including depression, anxiety, bipolar disorder, schizophrenia, bulimia nervosa, and substance abuse—can undergo cyclic fluctuations in symptom severity, with worsening of symptoms during the premenstrual period.8 These exacerbations may reflect the intensification of an underlying psychiatric disorder and/or the onset of symptoms that occur only during the premenstrual phase of the cycle. In addition, hormonal fluctuations during the postpartum period can also lead to mood disturbance.45 During the menopausal transition, acute hormonal changes that occur during a normal menstrual cycle are superimposed upon gradual menopause-related changes in hormones.46 This hormonal unpredictability can potentially intensify the emotional lability that is a natural part of the menstrual cycle.

As previously mentioned, there is an increased risk of clinical depression associated with the menopausal transition.19,21,26,32,47-51 Yet, the heightened risk of depression related to menopause is transitory19 and changes over time, concurrent with the hormonal changes characteristic of each stage of the menopausal transition. Recent results suggest that the risk of depression increases during early to late perimenopause, but decreases afterward.26,52 The likelihood of depressive symptoms is lower for women with a rapidly increasing FSH profile.26 Since rapid changes in FSH are associated with a relatively short duration of the menopausal transition, this evidence is consistent with the finding that depression is less of a problem if the menopausal transition takes no longer than 27 months.19

In some women of reproductive age there is a cyclic exacerbation of chronic medical conditions during the menstrual cycle, including migraine, epilepsy, asthma, diabetes, rheumatoid arthritis, and irritable bowel syndrome, that is thought to be related to rapid changes in concentrations of circulating ovarian steroids.9,53,54 Likewise, the hormonal fluctuations associated with the menopausal transition may exacerbate symptoms or complicate management of some chronic medical conditions.54-57 Such challenges may have a negative impact on mood for some women.

Approximately 40% of women seek medical attention to alleviate symptoms of the menopausal transition.58 Physical complaints associated with the hormonal fluctuations of the perimenopause include headache, insomnia, vasomotor symptoms (eg, hot flashes and night sweats), and genital atrophy. Hot flashes are the core symptom that reflect the brain’s response to the changing hormonal milieu, particularly fluctuating levels of estrogen.59 Evidence shows that vasomotor symptoms are strongly associated with depression during the menopausal transition. In a cohort of 309 women followed prospectively for 3 years, hot flashes and night sweats increased the odds of depression 1.8-fold and insomnia increased the odds of depression 4.0-fold.18 In another study, perimenopausal women with vasomotor symptoms were 4.4-fold more likely to be depressed than were women without vasomotor symptoms.21

 

Psychosocial Context of the Menopausal Transition

Depression at the menopausal transition may not necessarily be precipitated only by changes in hormones. Many women have a subjective experience of loss or “exit events” at this time, as children mature and leave the home, living circumstances change, elderly parents become ill or pass away, and marriages evolve or end.32 Race and ethnicity appear to influence the risk for depression in middle-aged women until adjustment is made for psychosocial factors such as poverty, at which point racial and ethnic differences are no longer significant.60 In general, having a social support network is protective from depression, whereas a sense of loss of control is a risk factor.61 In some studies, the importance of social factors such as inadequate income was greater than menopausal status in causing depression.20 Although the number of women living alone increases with age, many women report an improvement in mood after the last child leaves the home.62

Adverse life events can have a powerful impact on the risk of depression during the menopausal transition.17,31,63,64 Stressful life events, especially those of a chronic nature, generally increase the risk of depression.33 In addition, women with high levels of trait anxiety or a pessimistic outlook are more prone to depression and more vulnerable to stressful life events.63 Women with negative life events, low self-esteem, a troubled relationship with a life partner or children, or a weak social support network are at greater risk for depression.64 Presence of adverse life events increases the risk of depression during the menopausal transition by approximately 26% compared with women without such events, and the risk is even greater if the life events occur against a background of vasomotor symptoms.17 In short, life stressors such as aging, general health problems, caring for elderly parents, marital problems, career changes, children leaving home, and other life losses may contribute to depression, completely apart from other biologic and psychiatric risk factors.

A prospective cohort study investigated the determinants of depression in Dutch women going through the menopausal transition, after excluding women who used hormone therapy or who were status post hysterectomy or oophorectomy.50 Self-reported depressive symptoms from 2,103 women were analyzed to determine which social factors correlated with depression. A range of social factors was found to increase the risk of depression significantly. The OR for depression was higher in the context of job loss or unemployment (OR=3.1), inability to work (OR=1.7), financial difficulties (OR=2.9), death of a life partner (OR=2.6), death of a child (OR=5.9), or having a previous episode of depression (OR=2.0). It is important to note that because history of MDD was via self-report in this study, some women may have had earlier depressive episodes that remained undiagnosed (and thus were not reported); in addition, recall of social factors (eg, divorce, job loss) was likely to be stronger. Other studies, which will be reviewed in more detail in the next section, have shown stronger associations between psychiatric history and risk during the menopausal transition. Nevertheless, these data provide a clear demonstration of the importance of social factors in depression during menopausal transition.

Another important factor that contributes to the risk of depression is a woman’s attitude toward menopause. While research in the United States tends to focus on the negative aspects of menopause, some cultures are more attuned to the positive outcomes of the menopausal transition.46 For example, in certain African tribes, women are said to relish the increase in freedom and social influence that is attained after menopause.46 Menopause frees women from the burden of childbirth, the worries of contraception, and the cultural restrictions that may apply to women who still menstruate. Many reports suggest that the psychological reaction of women to menopause reflects the values of the society in which they live, and the social status assigned to aging women.46

 

Psychiatric Risk Factors for Depression During the Menopausal Transition

Psychiatric History
The most significant risk factor for developing depression during the menopausal transition is a history of depression.19 A 5-year longitudinal study tracked 2,565 women and found that prior depression is the single best predictor of depression during the menopausal transition, with an adjusted OR of 9.6 (P<.0001).19 Prior depression was a better predictor than was use of hormone replacement therapy (OR=1.0), stage of menopause (OR<2.1), or menopausal symptom severity (OR=3.6). In addition, women who became depressed during a prior reproductive event are at greater risk of menopause-related depression.28-31 For example, women with a history of severe PMS or PMDD appear to be more likely to suffer from depression during the menopausal transition.30,31,51 Interestingly, women with a lifetime history of MDD may be more likely to show an early decline in ovarian function,17,22 suggesting that the relationship between mood and the reproductive system is bi-directional (ie, hormonal changes associated with reproductive life events can influence mood and the presence of mood disorder can influence reproductive life events).


Genetic Factors

Although there has been no research specifically focused on a potential genetic risk for depression during the menopausal transition, genetic factors have been shown to interact with stress to influence the risk for depression. A study of 549 male and female twins found an interaction between stressful life events and a genetic liability for depression.65 Twins with one specific form of the serotonin transporter gene were at significantly greater risk of depression following common life stressors. Twins having alternative forms of the serotonin transporter gene were at lower risk.65 These results replicate an earlier prospective longitudinal analysis of a birth cohort which also found a functional polymorphism in the promoter region of the serotonin transporter gene that varies in a way that moderates the effect of stress on depression.66 People with one specific allele of the serotonin promoter were more likely to show depressive symptoms in relation to stressful life events. This vulnerability revealed a gene-by-environment interaction (ie, an individual’s response to the environment is moderated by their genetic makeup).66 A third analysis of the association between functional variation in the serotonin protein and depression confirmed that people with one particular variant of this gene are at increased risk of depression following relatively mild stressors.65

A second possible genetic component is a potential genetic vulnerability related to the menopausal transition. Although there is not yet direct evidence of a genetic risk specific to menopause, there is evidence demonstrating a genetic component related to premenstrual symptoms that is largely independent of the risk for MDD. Studies investigating the heritability of menstrual and premenstrual symptoms found that the environmental and genetic risk factors for premenstrual symptoms were not closely related to those associated with lifetime MDD.67,68 A similar phenomenon may be associated with other reproductive events including the menopause, ie, there may be a genetic predisposition to depressive symptoms during the menopausal transition.

Neuroendocrine Effects of Estrogen
Estrogen is known to have very powerful neuroendocrine effects in the brain. Acute increases in estrogen can blunt the response to stress, whereas chronic increases in estrogen downregulate serotonin receptors and increase the risk of depression and anxiety.69 Estrogens exert an agonistic effect on serotonergic activity by increasing the number of serotonergic receptors and by increasing the transport and uptake of serotonin. Estrogens also increase synthesis of serotonin, upregulate serotonin receptors, downregulate serotonin receptors, and decrease the activity of an enzyme (monoamine oxidase) involved in serotonin metabolism.70 The cumulative effect of estrogen on the serotonin system is thus to enhance serotonergic activity.

Estrogens appear to also increase noradrenergic activity by increasing receptor turnover, decreasing noradrenergic reuptake, and decreasing both the number and the sensitivity of dopamine-2 receptors.71 Animal studies suggest that there are potent behavioral effects associated with estrogen withdrawal or fluctuations in estrogen; bilateral ovariectomy of mice increases the duration of immobility—which is often taken as a measure of behavioral depression—while estrogen replacement decreases depressive-like behavior.72

 

The Transition Triad: A Biopsychosocial Model of Depression

Women experience depression during the menopausal transition because of a wide range of factors. It is only by understanding biologic, psychiatric, and social risk factors that we can begin to evaluate depression in midlife women.

The morbidity associated with mood disorders during midlife may be quite significant; as life expectancy continues to increase, it will become increasingly important to prevent, recognize, and treat depression during the menopausal transition in order to reduce the possibility of long-term sequelae.31 Women report symptoms of physical illness at higher rates, visit physicians more often, and make greater use of healthcare services than do men.54 This gives PCPs the opportunity to intervene in the lives of women who may not realize that they have a treatable problem. Awareness of the biopsychosocial factors that can impact depression during the menopausal transition may assist clinicians in the challenge of distinguishing symptoms of MDD from menopausal symptoms, and may help in the diagnosis and treatment of women with new-onset depression.

 

Evaluating Depression During the Menopausal Transition

Recognizing depression in the context of the menopausal transition can be challenging. First, there is considerable overlap between menopause-related symptoms and symptoms of MDD, including diminished energy level, poor concentration, sleep disturbance, weight change, and decreased libido (Figure 2).59,73 In addition, it may be difficult to differentiate whether mood symptoms are simply reactions to the myriad life stressors that can affect midlife women or are indicative of a psychiatric diagnosis.

 

 

Screening for depression in primary care can be done relatively quickly and easily by asking just two questions: “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” and “During the past month, have you been bothered by little interest or pleasure in doing things?”74 When 421 patients were given a psychiatric interview and a screening questionnaire comprised of 27 items, these two questions were clinically most useful, offering 97% sensitivity and 67% specificity for a diagnosis of clinical depression.73 If these questions are answered in the affirmative, a more thorough evaluation for depression is needed. Although the study sample included women and men of all ages and this was not a menopause-specific study, this screening tool for depression, used in conjunction with a clinical interview (which should include an assessment of reproductive status and history, current menopausal status, a review of changes in menstrual pattern, and a history of reproductive-related mood disturbance) and an evaluation of the presence and severity of somatic symptoms (which should include vasomotor symptoms, sleep disturbances, and changes in sexual function) provides an efficient and effective means of identifying depression during the menopausal transition in clinical practice.

 

Treating Depression During the Menopausal Transition

Management of depression during the menopausal transition should be part of a comprehensive treatment strategy designed to address the needs of the patient as a whole. As with depression at other times in a woman’s life, antidepressant therapy may be indicated. When selecting a therapy, it is important to consider whether treatment outcomes are affected by factors such as age, sex, and menopausal status.

As discussed previously, the neuroendocrine effects of estrogen are mediated at least in part by serotonergic activity in the brain.71,75 This mechanism could suggest that one therapeutic approach to menopausal depression would be to use antidepressants that modulate serotonin at the synapse.14 Alternatively, if estrogen serves to augment the serotonin system, it is possible that loss of this effect could result in a dampening of the efficacy of purely serotonergic agents in postmenopausal women compared with their use in premenopausal women.44 Unfortunately, relatively few studies have tested these hypotheses in a clinical setting. Of those that have evaluated the effect of gender and/or menopausal status on outcomes76-85 the evidence has not been entirely consistent, though differences could be attributable to small sample sizes and lack of statistical power to detect such interactions in some studies rather than discrepant findings.

In general, several studies have shown that compared with men, women may respond differently to some antidepressants,77,79,81,82 and postmenopausal women may respond differently than premenopausal women.76-83 For example, when the efficacy of sertraline, a selective serotonin reuptake inhibitor (SSRI), was compared to imipramine, a tricyclic antidepressant (TCA), gender- and menopause-related differences in response rates were found. Women were significantly more likely to show a favorable response to the SSRI, whereas men were more likely to benefit from the TCA; among the women, the difference between the two agents was found only in premenopausal women.82 More recently, a study in primary care patients found that menopause negatively affected response to SSRIs in depressed women.79 Specifically, the likelihood of responding to SSRIs was two times greater in premenopausal women compared with postmenopausal women. Other studies evaluating age as a proxy for menopausal status have found that antidepressant response in younger and older women differs, with younger women generally more treatment-responsive to SSRIs.76,80,83 Martenyi and colleagues81 reported that women in their reproductive years (defined in this study as <44 years of age) tended to be more responsive to SSRI treatment than to the predominantly noradrenergic tetracyclic antidepressant maprotiline. A meta-analysis of eight double-blind clinical trials of 2,045 patients randomized to treatment with the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine, SSRIs, or placebo76 found poorer response in the older women compared with the younger women taking SSRIs, with no such difference observed among women taking the SNRI. However, older women taking SSRIs and concomitant hormone therapy had a comparable response to younger women taking SSRIs alone.76

These results are controversial, as some studies have failed to replicate the finding of gender and/or menopausal status differences in antidepressant response.78,80,84 For example, a re-analysis of data from two clinical studies found no evidence that women have a preferential response to SSRIs or that men have a better TCA response.80 Another analysis of data from nine clinical trials found that women and men in all age groups had comparable response rates to TCAs and to the SSRI fluoxetine, although older women did show a superior response to TCAs compared with younger women.78 Finally, a post-hoc analysis of a study in 184 depressed women treated with fluoxetine failed to find a significant difference in response or remission rates among the pre-, peri-, and postmenopausal groups.84 Postmenopausal women did have significantly more residual symptoms following acute-phase treatment, though this difference was no longer significant when adjusted for baseline severity. It is important to note that the lack of statistical differences in this study might have been a function of the small sample sizes in the peri- (N=28) and postmenopausal (N=35) groups and hence low statistical power to detect differences in outcomes.84

It also remains unclear if the potentially diminished antidepressant efficacy in older or postmenopausal women is limited to SSRIs. Available studies suggest that the response to SNRI treatment is comparable in older and younger women.76,85 Prospective studies designed to specifically address the issue of a treatment-by-menopausal-status interaction are warranted to confirm the preliminary data described above.

 

Use of Estrogen in Treatment of Menopausal Depression

Hormone therapy has been used for many years to treat menopausal symptoms, and in more recent years tested as an option for peri- and postmenopausal mood disturbance.16,44,48,59,86 The value of hormone therapy as augmentation for antidepressant response has been evaluated in a handful of studies, with mixed results. In a double-blind study of fluoxetine in elderly depressed patients,87 fluoxetine treatment was significantly more effective than placebo in women who were taking concomitant estrogen therapy but not among those women who were not taking estrogen. A similar analysis in a study of sertraline demonstrated that older depressed women (>60 years of age) taking estrogen had significantly greater global improvement and quality of life than those not receiving estrogen.88 In contrast to these results, a reanalysis of data from a relapse prevention study found similar efficacy in fluoxetine-treated women ≥45 years of age with and without estrogen therapy.89 Finally, a small recently published pilot trial in postmenopausal women found that hormone therapy did not alter the response rate to treatment with sertraline, though hormone therapy may accelerate the treatment effect.90

The efficacy of estrogen as a monotherapy for depression also has been assessed in peri- and postmenopausal women. Preliminary data by Schmidt and colleagues86 suggested a role for estradiol in a double-blind, placebo-controlled, randomized clinical trial of 34 perimenopausal women with predominantly minor depression. These preliminary findings have since been replicated in a somewhat larger group of perimenopausal women91 with MDD, dysthymic disorder, or minor depressive disorder randomized to treatment with transdermal estradiol or placebo. Results were consistent regardless of DSM-IV diagnosis. However, evidence does not support the efficacy of estrogen as monotherapy for postmenopausal depression. In a randomized controlled trial of mild-to-moderate depression in postmenopausal women92 there was no difference between estrogen and placebo after 8 weeks of treatment. The authors concluded that estradiol cannot be considered effective treatment for postmenopausal depression.92

In summary, available evidence suggests a possible role for hormone therapy as monotherapy in perimenopausal women. The use of hormone therapy as an augmenting agent for antidepressant therapy is interesting but remains to be demonstrated prospectively in a randomized controlled trial. A careful consideration of the risks and benefits of these options should be made in conjunction with the patient, particularly in light of the widely publicized potential risks associated with hormone therapy for some patients.93 Although hormone therapy has been the mainstay of treatment for menopausal symptoms for many years, women are now increasingly likely to treat menopausal symptoms with nonhormonal treatments (eg, antidepressants; gabapentin; and alternative therapies, including exercise, herbal products, dietary supplements, and mind-body techniques).94 As such, there may be similar reluctance among some patients to consider estrogen as a therapeutic option for depression. Recently published data from the Women’s Health Initiative trial suggest there is a differential risk-benefit profile depending on years since menopause.95,96 These data should be taken into consideration when assessing options for short-term treatment during the menopausal transition.97  

 

Conclusion

Although we now have a clearer understanding of the risk for depression during the menopausal transition, many unanswered questions remain regarding the approach to treatment in peri- and postmenopausal women. Whether estrogen can be prescribed safely for a brief period of time at the menopausal transition warrants continued study. Some of the larger, prospective clinical trials of antidepressants such as fluoxetine, sertraline, venlafaxine, and duloxetine should be replicated with a larger sample size before recommendations for one treatment class over another can be made with confidence. We must also continue to search for antidepressants that work by different mechanisms, which may prove more effective for perimenopausal women. Finally, management of depression during the menopausal transition should be part of a comprehensive treatment strategy that addresses the needs of the patient as a whole. PP

 

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Latest Clinical Trial Data On Disease-Modifying Therapies from the 2008 International Conference on Alzheimer’s Disease

Clinical trial results examining a diversity of promising Alzheimer’s disease therapies were presented at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease in Chicago. The therapies presented targeted a wide variety of possible mechanisms of action and revealed both advancements and setbacks in the larger effort to develop disease-modifying treatments for Alzheimer’s disease.

Data from the Phase III trials of tarenflurbil, formerly considered one of the more promising potential treatments, were discouraging. Robert C. Green, MD, MPH, of Boston University School of Medicine, reported on the randomized, double-blind, placebo-controlled trials of tarenflurbil, a selective amyloid-lowering compound that was shown in non-clinical trials to modulate gamma secretase activity. Over 1,649 subjects with mild Alzheimer’s disease were given tarenflurbil 800 mg  BID or placebo BID for 18 months. Primary outcome measures were defined as standard measures of cognition on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and activities of daily living on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. The results showed no difference between groups: both declined approximately 7 points on the ADAS-cog and 10 points the ADCS-ADL. While tarenflurbil was generally well tolerated, it showed slightly higher incidences of anemia, infections, and gastrointestinal ulcers than placebo.

“It is definitive that there is no efficacy,” said Dr. Green. Myriad Genetics has discontinued its development of tarenflurbil for Alzheimer’s disease.

Other therapeutic targets showed more promise. PBT2, a metal-protein-attenuating compound, is being explored by Prana Biotechnology for its effect on the toxicity of amyloid-β (Aβ) toxicity on the brain. PBT2 is thought to reduce the toxicity of Aβ by preventing the interaction of Aβ with copper and zinc. A Phase IIa trial of PBT2 was conducted to determine its safety and tolerability and to observe the preliminary efficacy of the compound on memory and thinking. In the randomized, double-blind, placebo-controlled 12-week trial, 29 subjects with mild Alzheimer’s disease received placebo, 20 received PBT2 50 mg/day, and 29 received PBT2 250 mg/day.

Jeffrey L. Cummings, MD, director of the Mary S. Easton Centre for Alzheimer’s Disease at the David Geffen School of Medicine at the University of California, Los Angeles, reported the findings: The 250 mg group showed statistically significant improvement in two of the four executive function tests after 12 weeks. No significant trends were observed on the safety of the compound, no serious adverse events were reported, and tolerability was comparable to placebo. The trial also examined the effect of the compound on Alzheimer’s disease biomarkers, and found that subjects receiving 250 mg of PBT2 produced statistically less cerebrospinal Ab protein than subjects on placebo. 

“There is great interest in finding a biomarker,” said Dr. Cummings. “I think we have shown that.”

Another promising therapy departed from the theory of an amyloid protein mechanism of action, instead targeting tau, the neurofibrillary protein “tangles” originally described by Alois Alzheimer. Claud Wischik, chairman of TauRX Therapeutics, Singapore, and professor of Mental Health at the University of Aberdeen in Scotland, presented Phase IIb data on a methylthioninium chloride (MTC), which had been previously shown to dissolve tau tangles in test tube studies.

A double-blind, randomized, placebo-controlled study of MCT was conducted in 321 subjects with mild or moderate Alzheimer’s disease, with results taken at 24 weeks and 84 weeks. Subjects received oral MTC 30 mg, 60 mg, or 100 mg TID, or placebo. (The 100 mg capsule shell later proved defective.) Primary outcome measures were effects on cognition as measured by the ADAS-cog at 24 weeks. Secondary outcome measures were the effects of MTC on molecular brain imaging at 25 weeks, safety and tolerability, and disease modifying potential at 50 and 84 weeks. At 24 weeks, MTC produced a 5.5-unit improvement on the ADAS-cog in subjects with moderate Alzheimer’s disease receiving 60 mg tid compared to controls. By 50 weeks, MTC subjects showed an 81% reduced rate of decline compared to controls, a 6.8-unit difference on the ADAS-cog. MTC subjects’ ADAS-cog scores at 84 weeks were not significantly different from their scores at baseline. Single photon emission computed tomography and positron emission tomography showed that subjects on 60 mg MTC experienced less regional cerebral blood flow decline than control subjects. This effect was greatest in regions of the brain with the most severe tau accumulation: the hippocampus and entorhinal cortex. Phase III studies of MTC are planned for 2009.

Funding for the Phase III clinical trial on tarenflurbil was provided by Myriad Genetics. Dr. Green received no personal funding from the company. Funding for the Phase IIa trial of PBT2 was provided by Prana Biotechnology. Funding for the Phase IIb trial on MTC was provided by TauRx Therapeutics. (July 29, 2008. Alzheimer’s Association’s International Conference on Alzheimer’s Disease.) –RZ

 

FDA Approves Methlyphenidate HCI for the Treatment of ADHD in Adults 18–65 Years of Age

The United States Food and Drug Administration announced it has approved methlyphenidate HCI (Concerta extended-release, Johnson & Johnson) tablets for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults 18–65 years of age.  The approved dose range is 18–72 mg/day, with a recommended starting dose of 18 or 36 mg/day. Methylphenidate is already indicated for use in children and adolescents with ADHD.

The approval is based on the results of clinical trials in adults 18–65 years of age. Two double-blind, placebo-controlled studies were conducted in 627 adults 18–65 years of age.  The first study was a multicenter, parallel-group trial comparing methlyphenidate 36–108 mg/day with placebo during 7 weeks of dose titration. The second trial was a 5-week multicenter, parallel-group fixed-dose study during which participants received methlyphenidate 18, 36, and 72 mg/day.

The former study demonstrated the treatment effectiveness based on the change to final study visit on the Adult ADHD Investigator Rating Scale. In the latter trial, all three doses of methlyphenidate were, according to results, significantly more effective than placebo in improving Conners’ Adult Scale total scores at double-blind endpoint in adult subjects with ADHD.

The most common adverse reaction (>5%) reported in children and adolescents is upper abdominal pain. The most common adverse reactions (>10%) reported in adults are dry mouth, nausea, decreased appetite, headache, and insomnia.

For more information, please consult the medication’s full prescribing information (http://www.concerta.net/concerta/pages/full.jsp). –JRR

 

Detection and Management of Dementia in General Practice

Depression occurs in approximately 57% of dementia patients, demonstrating a high comorbidity in the conditions. Guidelines from the Royal Australian College of General Practitioners (RACGP) suggest using paper and pencil cognitive evaluations to assess crucial items, such as the possibility of other diagnoses and pathology, for the detection and management of dementia. Dimity Pond, PhD, FRACGP, Dip SSc, MBBS, at the University of Newcastle in Australia, and colleagues, compared findings from both general practitioner audits and the General Practitioner Assessment of Cognition (GPCOG) with that of the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly (CAMCOG) in terms of dementia detection. They also compared geriatric depression scale (GDS) findings to the clinical perspective with respect to concomitant depression.

The researchers sent letters to approximately 160 general practitioners and 2,000 of their patients ≥75 years of age from four Australian cities (Adelaide, Melbourne, Newcastle, and Sydney). Responding practitioners were assigned to either the intervention group or the control group. Their task was to audit patients; identify whether they had “possible,” “probable,” “definite,” or no dementia; and note the methods to their investigation (ie, pathology, radiology, pencil and paper tests, specialist order tests, services, and identification of other diagnoses) for those who answered with any of the first three responses. After the general practitioner’s audit, a research nurse conducted a battery of cognitive assessments, including the CAMCOG and GDS. The GPCOG was administered to each patient by general practitioners trained in intervention.

The general practitioner’s data from the CAMCOG found that 27% of patients scored <81, meaning they suffer from dementia. The GDS characterized 9% of this dementia group as depressed but not cognitively impaired, indicating a different diagnosis of depression than that of the general practitioners. Further, the general practitioners identified three patients with concomitant dementia and depression, one of whom fit the CAMCOG definition for dementia. In actuality, however, none of the three individuals fit the criteria for depression.

These results indicate that general practitioners struggle to make accurate diagnoses between dementia and depression. In addition, that the researchers found obvious patterns of investigation following RACGP guidelines, with radiology and pathology assessments as the most commonly used, suggests a need for improvement in the detection and management of dementia in general practice.

To increase accurate depression and dementia detection rates, the researchers recommend an approach that both acknowledges the need to minimize unnecessary patient anxiety and facilitates the benefits of early diagnosis with complementary services (ie, mobilizing support services, support for families and caretakers). The combination of clinical judgment and appropriate methods of investigation should lead to optimal detection and improved differential diagnoses. Pond and colleagues are further exploring paper and pencil tests with respect to general practitioner’s diagnostic accuracy in cognitive impairment.

Funding for this research was provided by the Australian National Health and Medical Research Council and the Dementia Collaborative Research Center. (ICAD 2008; Poster P1-280). –ML

 

Anosognosia: Assessment Tools for Its Epidemiologic Study in Geriatric Populations with Dementia

Anosognosia, a common feature of dementia that is associated with increased behavioral disturbance and reduced treatment compliance, is difficult to assess in elderly populations with dementia. There are limited methods or clinical tools available for the assessment of anosognosia, but many existing methods may be too lengthy and otherwise difficult to apply to epidemiologic research.

Trevor Buckley, MA, at Utah State University in Logan, and colleagues, tested a 7-item “metacognition questionnaire.” Modified Mini-Mental State Exam (3MS) results were collected at baseline. At 3-year follow-up, the 3MS was administered again, and subjects and informed caregivers both completed the self-report questionnaire. Questionnaire results were compared with two external criteria: change in 3MS scores over the 3-year period, and informed caregiver report using the Informant Questionnaire of Cognitive Decline in the Elderly.

Six hundred eighty-seven adults comprised the study population, of which 157 were classified with dementia. The mean age of all subjects was approximately 82 years of age. Of those with dementia, 61.1% (n=99) were male, and 34.9% (n=53) were female. In subjects without dementia, metacognitive ratings of decline were in alignment with a decline in 3MS ratings (t=2.21, P=.027) and informant ratings (OR=4.0, 95% CI=1.16, 13.85, P=.029). In subjects with dementia, however, metacognitive ratings were inversely associated with a decline in 3MS ratings (t=-1.923, P=.056) but not with informant ratings (OR=1.8, 95% CI=.56, 5.83, P=.32).

As expected, the results indicate that self-perception of cognitive and functional decline in subjects with dementia are likely to run counter to the informed caregivers’ perceptions and to 3MS scores. In contrast, those without dementia reported much more accurate perceptions of their own cognitive and functional decline.

“These findings promote the use of a brief questionnaire of metcognition in conjunction with either informant report or cognitive test performance to assess anosognosia,” said JoAnn Tschanz, PhD, a co-author of the study. “The brevity of each of the measures is a particularly appealing feature that lends itself for use in clinical and research settings.”

Funding for this research was provided by the National Institute on Aging. (ICAD 2008; Poster P2-241). –LS

 

Cognitive Benefits of Hormone Therapy Use in Women Matched for Cardiovascular Risk Factors

According to data from the Women’s Health Initiative study and its Memory Study (WHIMS), there are increased rates of cardiovascular risk, cognitive decline, and dementia in women using hormone therapy during menopause. Further, prior research has reported cardiovascular and cognitive benefits and reduced risk for dementia with menopausal hormone therapy as a result of a “healthy-user” bias. This theory states that women choosing to use hormone therapy during menopausal transition are healthier than women who do not, and as a result, the healthier women experience hormone treatment advantages. However, Carey Gleason, PhD, at the University of Wisconsin in Madison, and colleagues, found that more current findings support both reduced risk of Alzheimer’s disease and beneficial neurobiologic and cognitive effects of menopausal hormonal therapy independent of health-related factors.

To investigate the “healthy-user” bias, the researchers sent questionnaires to 237 women who were part of the Midwest Initiative for Dementia Screening. The surveys assessed one’s health history, menopausal status, and hormone use. One-hundred ninety of 213 patients who responded were stratified into two groups of either users (previous or current; n=95) or non-users (n=95) and were matched for cardiovascular conditions, health-related behaviors, age, and education. Clinical screening involved a neuropsychological set of evaluations, including the Mini Mental State Examination, Cognistat, Trail Making Test A and B, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List, Animal Fluency, the Stroop Color Word Test, and the Geriatric Depression Scale to audit mood.

Participants’ scores were compared using a series of t-tests and adjusted using an overall α=.10 and a Sidak-Holm sequential formula. Results found that the between-group means were statistically different for Cognistat similarities, CERAD delayed recall, and CERAD retention. These findings imply that the “healthy-user” bias does not explain differences in cognitive performance between the two cohorts.

The researchers suggest that it is more likely that developing theories discussing time of hormonal therapy initiation as a factor conducive to neuropsychological benefits and reduced Alzheimer’s disease risk (eg, “critical period” theory) explain data discrepancies among previous research, WHIMS, and current research.

Funding for this research was provided by grants from the National Institute on Aging; the Extendicare Foundation; and the Geriatric Research, Education, and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. (ICAD 2008; Poster P2-393). –ML

 

Condensed Informational Counseling for Potential Genetic Alzheimer’s Disease Risk Effective Communication Tool for Patients

Researchers studying Alzheimer’s disease have identified apolipoprotein E (APOE) as a genetic factor that, if present in asymptomatic patients, may increase the risk of the later development of the neurodegenerative disease. Despite the potential effectiveness of APOE as a genetic marker for Alzheimer’s disease, researchers have cautioned its clinical use until further study is conducted into the impact of susceptibility genotyping and communicating such information to patients.

Currently, studies have shown that APOE genotype information can only be safely communicated to first-degree relatives of Alzheimer’s disease patients following traditional genetic counseling procedures. These procedures include in-person appointments between patients and genetic counselors, which can be time and resource consuming for genetic counselors. Recently, researchers investigated the use of a condensed genetic informational session, which may be more feasible for counselors, and its potential impact for patients. 

J. Scott Roberts, PhD, of the Department of Health Behavior and Health Education at the University of Michigan School of Public Health in Ann Arbor, and colleagues, studied the psychosocial and behavioral impact of condensed APOE genotype disclosure among 352 patients in The Risk Evaluation and Education for Alzheimer’s Disease study, a multi-center, randomized trial. Patients in the study were divided into two groups. one group (n=120) received the extended informational protocol, which included an in-person education session and counseling. The second group (n=232) received the condensed protocol, which included education brochures sent by mail and a question-and-answer session with a counselor. Study outcome measures included clinical cut-off rates on various screening tools, such as the Center for Epidemiologic Studies Depression Scale and the Beck Anxiety Inventory, among others. Patients received follow-up assessments at 6-week, 6-month, and 12-month intervals.

Both groups received neuropsychological and psychiatric screening, and all patients were asymptomatic adult children or siblings of patients with Alzheimer’s disease. Among all study patients, 280 continued to Alzheimer’s disease risk assessment with APOE disclosure (condensed protocol, n=187; extended protocol, n=93).

Roberts and colleagues found that there were few significant differences between the condensed and extended protocol groups in rates of depression or anxiety as well as in self-report health measures. Patients in the condensed protocol group reported higher levels of distress at the 6-week follow-up, however, that difference was not found at the 12-month follow-up. Patients in either group also changed their behavior at similar rates, with the percentage of patients in both groups making any health-related changes following APOE assessment being the same (54%).

In addition, more patients in the condensed protocol group reported understanding of genotype information (60% vs. 59%) and recall of lifetime risk of Alzheimer’s disease (61% vs. 51%) than those in the extended protocol group. The authors concluded that patients in the condensed genotype information protocol group had mean anxiety and depression levels far below cut-off measures and there were no differences in understanding among the two groups. As time demands for counselors in the condensed protocol group were significantly lower than demands for those in the extended protocol group (33 minutes vs. 76 minutes), the authors recommend that further research be conducted to explore the feasibility and effectiveness of alternative models for genetic counseling protocols for Alzheimer’s disease.

Funding for this research was provided by the National Institutes of Health. (ICAD 2008; Poster P2-282). –CP

 

Estrogen May Ease Schizophrenia in Women

According to the National Institute of Mental Health, schizophrenia affects approximately 1.1% of the population ≥18 years of age in any given year. It is usually diagnosed in late adolescence or early adulthood. According to a randomized, double-blind study by Jayashri Kulkarni, MD, of the Alfred and Monash University in Melbourne, Australia, and colleagues, estrogen may have therapeutic effects in women with severe mental illnesses, including schizophrenia.

With the goal of comparing the efficacy of adjunctive transdermal estradiol (a form of estrogen) with that of adjunctive placebo in the treatment of acute psychotic symptoms, female patients were recruited from inpatient acute hospital wards and outpatient clinics of two metropolitan Melbourne general hospitals. Participants included 102 schizophrenic women of childbearing age (73 of whom were outpatients) who were in an acute or chronic stage of their illness. Over the course of 28 days, patients were randomized to receive 100 microg of transdermal estradiol (n=56) or transdermal placebo (n=46). All patients continued to take their regular medications, which most commonly included atypical antipsychotics such as olanzapine. Using the Positive and Negative Syndrome Scale, psychopathalogic symptoms were assessed weekly. Results found that compared to women receiving antipsychotics alone, the addition of 100 microg of transdermal estradiol reduced positive (P<.05) and general psychopathalogic (P<.05) symptoms significantly.

Estrogen therapy may prove useful in schizophrenic women after childbirth and during menopause (when they are more prone to relapse) as well as during low-estrogen phases of a woman’s menstrual cycle. (Arch Gen Psychiatry. 2008;65(8):955-960). –DC

 

Family Meals May Increase Parental Communication and Decrease Substance Abuse for Teenage Girls

Studies have shown that meals between parents and adolescents provide an environment for communication as well as parental monitoring of mood or behavioral changes among adolescents and teenagers. Researchers in the Division of Adolescent Health and Medicine at the University of Minnesota in Minneapolis sought to examine if family meals with adolescents could deter later incidence of substance abuse.

Marla Eisenberg, ScD, MPH, and colleagues studied 806 adolescents (mean age=12.8 years) attending public schools between 1998–1999 to determine how often participants ate meals with parents and if family meals deterred later substance abuse. Adolescents were asked how often their families ate meals together in the past week as well as the presence or frequency of smoking and/or alcohol and marijuana use.

A second survey was conducted by mail 5 years later (2003–2004) which investigated the presence or frequency of family meals and substance abuse among teenagers. Among all participants, 45.4% were male and 54.6% were female, and the mean age at follow-up was 17.2 years.

According to the first survey, approximately 60% of adolescents ate >5 family meals each week, which was the expected result. Rates of family meals were lower for teenagers at the 5-year follow-up evaluation. Regarding substance abuse, the authors found significantly lower rates of smoking and marijuana or alcohol use among female participants who reported >5 family meals per week (approximately 50% lower rates of substance abuse when compared to female teenagers who reported <5 family meals per week). This finding was not significant for male participants.

The authors concluded that frequent family meals may provide increased parental/child communication, which may lead to lower rates of substance abuse. They also found that these lower abuse rates may not be significant for male teenagers due to societal expectations and differences in parental interaction with male children. (J Adolesc Health. 2008;43(2):151-156.) –CP

 

New Medications May Help Drinkers Battle Alcohol Dependence

Alcohol-dependent individuals suffer from destructive symptoms affecting their physicality, mentality, and interpersonal relationships. However, a study by Bankole A. Johnson, DSc, MD, PhD, MPhil, FRCPsych, and colleagues from the Medical University of South Carolina suggest that certain medications may help alcoholics moderate their alcohol consumption and prevent relapse.

Johnson and colleagues studied the effects of topiramate in 371 alcohol-dependent patients during a 14-week, double-blind, randomized controlled trial. While receiving weekly adherence-enhancement therapy, the participants were either given topiramate (≤300 mg/day) or placebo. The researchers compared the physical, mental, and psychosocial effects of topiramate to that of placebo and found that the former was more effective in reducing body mass index (mean difference, 1.08), liver enzyme levels (P<.01 for all), plasma cholesterol level (mean difference, 13.3 mg/dL), and systolic (mean difference, 9.7 mm Hg) and diastolic (mean difference, 6.74 mm Hg) blood pressure. Such reductions may lower risk of fatty liver degeneration, in turn, decreased risk of cirrhosis and cardiovascular disease.

Though the topiramate cohort reported more side effects (eg, paresthesia, taste perversion, anorexia, difficulty with concentration) than those in the placebo group, its members experienced significantly decreased psychological compulsion and improved psychosocial health and quality of life. These benefits reduce risk of relapse and long-term negative outcomes.

Research Society on Alcoholism president Raymond Anton, MD, disclosed results from the initial 6-week active treatment phase of a 14-week double-blind, placebo-controlled study involving 60 alcohol-dependent patients as characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, who took part in the Prometa Protocol. Participant level of alcohol withdrawal was assessed via the 67-point Clinical Institute of Withdrawal Assessment (CIWA). Based on their CIWA scores, patients were placed in either the higher (scores ≥7; n=18) or lower (scores <7; n=42) alcohol withdrawal group. That the patients were not required to maintain alcohol abstinence prior to research should be noted.

Eight patients in the higher CIWA group and 25 patients in the lower CIWA group received the pharmacologic aspect (ie, a combination of generic medications) of the treatment program while the remaining members of each division received placebo. During the first 6 weeks of active treatment, all participants received standardized behavioral counseling sessions and were evaluated weekly for drinking, craving, mood, sleep, and adverse effects from treatment.

Patients reported reduced cravings and alcohol withdrawal symptoms, more consistent abstinence, and improved mood and sleep. However, the full 14-week study is still underway, as the results represent patient response during the first 6 weeks of active treatment. (Arch Intern Med. 2008;168(11):1188-1199) –ML

 

Sildenafil Effective in the Treatment of Antidepressant-related Female Sexual Dysfunction

Women taking antidepressants may experience treatment-related sexual dysfunction, often causing them to prematurely discontinue treatment. Sexual dysfunction is particularly associated with  the most commonly prescribed antidepressants for outpatients 18–65 years of age, selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. Antidepressant-associated sexual dysfunction occurs in an estimated 30% to 70% of men and women treated for major depressive disorder (MDD) with first- or second-generation agents. There is a three-fold increased risk of nonadherence that leads to increased relapse and recurrence.

A study of sildenafil by H. George Nurnberg, MD, of the University of New Mexico School of Medicine in Albuquerque, and colleagues, proved promising for the reduction in adverse sexual effects of SSRIs in women. In an 8-week, prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 2003 and January 2007 at seven United States research centers, sildenafil was compared to placebo in 98 women (mean age=approximatetly 37 years) with in-remission MDD. Participants were randomly assigned to sildenafil (n=49) at a flexible dose starting at 50 mg and adjustable to 100 mg, approximately 1–2 hours before sexual activity, or placebo (n=49). Seventy-three percent of women taking placebo, compared to 28% taking sildenafil, reported no improvement with treatment. Scales used in the study included the Clinical Gloabal Impression sexual function scale, the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale–female version, the University of New Mexico Sexual Function Inventory–female version, a sexual activity event log, and the Hamilton Rating Scale for Depression. Women in the sildenafil group showed greater improvement in sexual function compared to women in the placebo group. Adverse effects included headache, flushing, and dyspepsia, but none of the patients withdrew due to serious adverse events.

The study established that selective phosphodiesterase type 5 inhibitors, such as sildanefil, are effective for women for the treatment of antidepressant-related sexual dysfunction. Thus, patients being treated for depression can continue with antidepressant treatment without the worry of adverse sexual effects. (JAMA. 2008;300(4):395-404). –DC

Posters were drawn from the Annual Meeting of the Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD; July 26-31, 2008, Chicago, Illinois). Psychiatric dispatches is written by Dena Croog, Michelisa Lanche, Carlos Perkins, Jr,, José R. Ralat, Lonnie Stoltzfoos, and Rebecca Zerzan.

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Latest Clinical Trial Data On Disease-Modifying Therapies from the 2008 International Conference on Alzheimer’s Disease

Clinical trial results examining a diversity of promising Alzheimer’s disease therapies were presented at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease in Chicago. The therapies presented targeted a wide variety of possible mechanisms of action and revealed both advancements and setbacks in the larger effort to develop disease-modifying treatments for Alzheimer’s disease.

Data from the Phase III trials of tarenflurbil, formerly considered one of the more promising potential treatments, were discouraging. Robert C. Green, MD, MPH, of Boston University School of Medicine, reported on the randomized, double-blind, placebo-controlled trials of tarenflurbil, a selective amyloid-lowering compound that was shown in non-clinical trials to modulate gamma secretase activity. Over 1,649 subjects with mild Alzheimer’s disease were given tarenflurbil 800 mg  BID or placebo BID for 18 months. Primary outcome measures were defined as standard measures of cognition on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and activities of daily living on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. The results showed no difference between groups: both declined approximately 7 points on the ADAS-cog and 10 points the ADCS-ADL. While tarenflurbil was generally well tolerated, it showed slightly higher incidences of anemia, infections, and gastrointestinal ulcers than placebo.

“It is definitive that there is no efficacy,” said Dr. Green. Myriad Genetics has discontinued its development of tarenflurbil for Alzheimer’s disease.

Other therapeutic targets showed more promise. PBT2, a metal-protein-attenuating compound, is being explored by Prana Biotechnology for its effect on the toxicity of amyloid-β (Aβ) toxicity on the brain. PBT2 is thought to reduce the toxicity of Aβ by preventing the interaction of Aβ with copper and zinc. A Phase IIa trial of PBT2 was conducted to determine its safety and tolerability and to observe the preliminary efficacy of the compound on memory and thinking. In the randomized, double-blind, placebo-controlled 12-week trial, 29 subjects with mild Alzheimer’s disease received placebo, 20 received PBT2 50 mg/day, and 29 received PBT2 250 mg/day.

Jeffrey L. Cummings, MD, director of the Mary S. Easton Centre for Alzheimer’s Disease at the David Geffen School of Medicine at the University of California, Los Angeles, reported the findings: The 250 mg group showed statistically significant improvement in two of the four executive function tests after 12 weeks. No significant trends were observed on the safety of the compound, no serious adverse events were reported, and tolerability was comparable to placebo. The trial also examined the effect of the compound on Alzheimer’s disease biomarkers, and found that subjects receiving 250 mg of PBT2 produced statistically less cerebrospinal Ab protein than subjects on placebo. 

“There is great interest in finding a biomarker,” said Dr. Cummings. “I think we have shown that.”

Another promising therapy departed from the theory of an amyloid protein mechanism of action, instead targeting tau, the neurofibrillary protein “tangles” originally described by Alois Alzheimer. Claud Wischik, chairman of TauRX Therapeutics, Singapore, and professor of Mental Health at the University of Aberdeen in Scotland, presented Phase IIb data on a methylthioninium chloride (MTC), which had been previously shown to dissolve tau tangles in test tube studies.

A double-blind, randomized, placebo-controlled study of MCT was conducted in 321 subjects with mild or moderate Alzheimer’s disease, with results taken at 24 weeks and 84 weeks. Subjects received oral MTC 30 mg, 60 mg, or 100 mg TID, or placebo. (The 100 mg capsule shell later proved defective.) Primary outcome measures were effects on cognition as measured by the ADAS-cog at 24 weeks. Secondary outcome measures were the effects of MTC on molecular brain imaging at 25 weeks, safety and tolerability, and disease modifying potential at 50 and 84 weeks. At 24 weeks, MTC produced a 5.5-unit improvement on the ADAS-cog in subjects with moderate Alzheimer’s disease receiving 60 mg tid compared to controls. By 50 weeks, MTC subjects showed an 81% reduced rate of decline compared to controls, a 6.8-unit difference on the ADAS-cog. MTC subjects’ ADAS-cog scores at 84 weeks were not significantly different from their scores at baseline. Single photon emission computed tomography and positron emission tomography showed that subjects on 60 mg MTC experienced less regional cerebral blood flow decline than control subjects. This effect was greatest in regions of the brain with the most severe tau accumulation: the hippocampus and entorhinal cortex. Phase III studies of MTC are planned for 2009.

Funding for the Phase III clinical trial on tarenflurbil was provided by Myriad Genetics. Dr. Green received no personal funding from the company. Funding for the Phase IIa trial of PBT2 was provided by Prana Biotechnology. Funding for the Phase IIb trial on MTC was provided by TauRx Therapeutics. (July 29, 2008. Alzheimer’s Association’s International Conference on Alzheimer’s Disease.) –RZ

 

FDA Approves Methlyphenidate HCI for the Treatment of ADHD in Adults 18–65 Years of Age

The United States Food and Drug Administration announced it has approved methlyphenidate HCI (Concerta extended-release, Johnson & Johnson) tablets for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults 18–65 years of age.  The approved dose range is 18–72 mg/day, with a recommended starting dose of 18 or 36 mg/day. Methylphenidate is already indicated for use in children and adolescents with ADHD.

The approval is based on the results of clinical trials in adults 18–65 years of age. Two double-blind, placebo-controlled studies were conducted in 627 adults 18–65 years of age.  The first study was a multicenter, parallel-group trial comparing methlyphenidate 36–108 mg/day with placebo during 7 weeks of dose titration. The second trial was a 5-week multicenter, parallel-group fixed-dose study during which participants received methlyphenidate 18, 36, and 72 mg/day.

The former study demonstrated the treatment effectiveness based on the change to final study visit on the Adult ADHD Investigator Rating Scale. In the latter trial, all three doses of methlyphenidate were, according to results, significantly more effective than placebo in improving Conners’ Adult Scale total scores at double-blind endpoint in adult subjects with ADHD.

The most common adverse reaction (>5%) reported in children and adolescents is upper abdominal pain. The most common adverse reactions (>10%) reported in adults are dry mouth, nausea, decreased appetite, headache, and insomnia.

For more information, please consult the medication’s full prescribing information (http://www.concerta.net/concerta/pages/full.jsp). –JRR

 

Detection and Management of Dementia in General Practice

Depression occurs in approximately 57% of dementia patients, demonstrating a high comorbidity in the conditions. Guidelines from the Royal Australian College of General Practitioners (RACGP) suggest using paper and pencil cognitive evaluations to assess crucial items, such as the possibility of other diagnoses and pathology, for the detection and management of dementia. Dimity Pond, PhD, FRACGP, Dip SSc, MBBS, at the University of Newcastle in Australia, and colleagues, compared findings from both general practitioner audits and the General Practitioner Assessment of Cognition (GPCOG) with that of the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly (CAMCOG) in terms of dementia detection. They also compared geriatric depression scale (GDS) findings to the clinical perspective with respect to concomitant depression.

The researchers sent letters to approximately 160 general practitioners and 2,000 of their patients ≥75 years of age from four Australian cities (Adelaide, Melbourne, Newcastle, and Sydney). Responding practitioners were assigned to either the intervention group or the control group. Their task was to audit patients; identify whether they had “possible,” “probable,” “definite,” or no dementia; and note the methods to their investigation (ie, pathology, radiology, pencil and paper tests, specialist order tests, services, and identification of other diagnoses) for those who answered with any of the first three responses. After the general practitioner’s audit, a research nurse conducted a battery of cognitive assessments, including the CAMCOG and GDS. The GPCOG was administered to each patient by general practitioners trained in intervention.

The general practitioner’s data from the CAMCOG found that 27% of patients scored <81, meaning they suffer from dementia. The GDS characterized 9% of this dementia group as depressed but not cognitively impaired, indicating a different diagnosis of depression than that of the general practitioners. Further, the general practitioners identified three patients with concomitant dementia and depression, one of whom fit the CAMCOG definition for dementia. In actuality, however, none of the three individuals fit the criteria for depression.

These results indicate that general practitioners struggle to make accurate diagnoses between dementia and depression. In addition, that the researchers found obvious patterns of investigation following RACGP guidelines, with radiology and pathology assessments as the most commonly used, suggests a need for improvement in the detection and management of dementia in general practice.

To increase accurate depression and dementia detection rates, the researchers recommend an approach that both acknowledges the need to minimize unnecessary patient anxiety and facilitates the benefits of early diagnosis with complementary services (ie, mobilizing support services, support for families and caretakers). The combination of clinical judgment and appropriate methods of investigation should lead to optimal detection and improved differential diagnoses. Pond and colleagues are further exploring paper and pencil tests with respect to general practitioner’s diagnostic accuracy in cognitive impairment.

Funding for this research was provided by the Australian National Health and Medical Research Council and the Dementia Collaborative Research Center. (ICAD 2008; Poster P1-280). –ML

 

Anosognosia: Assessment Tools for Its Epidemiologic Study in Geriatric Populations with Dementia

Anosognosia, a common feature of dementia that is associated with increased behavioral disturbance and reduced treatment compliance, is difficult to assess in elderly populations with dementia. There are limited methods or clinical tools available for the assessment of anosognosia, but many existing methods may be too lengthy and otherwise difficult to apply to epidemiologic research.

Trevor Buckley, MA, at Utah State University in Logan, and colleagues, tested a 7-item “metacognition questionnaire.” Modified Mini-Mental State Exam (3MS) results were collected at baseline. At 3-year follow-up, the 3MS was administered again, and subjects and informed caregivers both completed the self-report questionnaire. Questionnaire results were compared with two external criteria: change in 3MS scores over the 3-year period, and informed caregiver report using the Informant Questionnaire of Cognitive Decline in the Elderly.

Six hundred eighty-seven adults comprised the study population, of which 157 were classified with dementia. The mean age of all subjects was approximately 82 years of age. Of those with dementia, 61.1% (n=99) were male, and 34.9% (n=53) were female. In subjects without dementia, metacognitive ratings of decline were in alignment with a decline in 3MS ratings (t=2.21, P=.027) and informant ratings (OR=4.0, 95% CI=1.16, 13.85, P=.029). In subjects with dementia, however, metacognitive ratings were inversely associated with a decline in 3MS ratings (t=-1.923, P=.056) but not with informant ratings (OR=1.8, 95% CI=.56, 5.83, P=.32).

As expected, the results indicate that self-perception of cognitive and functional decline in subjects with dementia are likely to run counter to the informed caregivers’ perceptions and to 3MS scores. In contrast, those without dementia reported much more accurate perceptions of their own cognitive and functional decline.

“These findings promote the use of a brief questionnaire of metcognition in conjunction with either informant report or cognitive test performance to assess anosognosia,” said JoAnn Tschanz, PhD, a co-author of the study. “The brevity of each of the measures is a particularly appealing feature that lends itself for use in clinical and research settings.”

Funding for this research was provided by the National Institute on Aging. (ICAD 2008; Poster P2-241). –LS

 

Cognitive Benefits of Hormone Therapy Use in Women Matched for Cardiovascular Risk Factors

According to data from the Women’s Health Initiative study and its Memory Study (WHIMS), there are increased rates of cardiovascular risk, cognitive decline, and dementia in women using hormone therapy during menopause. Further, prior research has reported cardiovascular and cognitive benefits and reduced risk for dementia with menopausal hormone therapy as a result of a “healthy-user” bias. This theory states that women choosing to use hormone therapy during menopausal transition are healthier than women who do not, and as a result, the healthier women experience hormone treatment advantages. However, Carey Gleason, PhD, at the University of Wisconsin in Madison, and colleagues, found that more current findings support both reduced risk of Alzheimer’s disease and beneficial neurobiologic and cognitive effects of menopausal hormonal therapy independent of health-related factors.

To investigate the “healthy-user” bias, the researchers sent questionnaires to 237 women who were part of the Midwest Initiative for Dementia Screening. The surveys assessed one’s health history, menopausal status, and hormone use. One-hundred ninety of 213 patients who responded were stratified into two groups of either users (previous or current; n=95) or non-users (n=95) and were matched for cardiovascular conditions, health-related behaviors, age, and education. Clinical screening involved a neuropsychological set of evaluations, including the Mini Mental State Examination, Cognistat, Trail Making Test A and B, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List, Animal Fluency, the Stroop Color Word Test, and the Geriatric Depression Scale to audit mood.

Participants’ scores were compared using a series of t-tests and adjusted using an overall α=.10 and a Sidak-Holm sequential formula. Results found that the between-group means were statistically different for Cognistat similarities, CERAD delayed recall, and CERAD retention. These findings imply that the “healthy-user” bias does not explain differences in cognitive performance between the two cohorts.

The researchers suggest that it is more likely that developing theories discussing time of hormonal therapy initiation as a factor conducive to neuropsychological benefits and reduced Alzheimer’s disease risk (eg, “critical period” theory) explain data discrepancies among previous research, WHIMS, and current research.

Funding for this research was provided by grants from the National Institute on Aging; the Extendicare Foundation; and the Geriatric Research, Education, and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. (ICAD 2008; Poster P2-393). –ML

 

Condensed Informational Counseling for Potential Genetic Alzheimer’s Disease Risk Effective Communication Tool for Patients

Researchers studying Alzheimer’s disease have identified apolipoprotein E (APOE) as a genetic factor that, if present in asymptomatic patients, may increase the risk of the later development of the neurodegenerative disease. Despite the potential effectiveness of APOE as a genetic marker for Alzheimer’s disease, researchers have cautioned its clinical use until further study is conducted into the impact of susceptibility genotyping and communicating such information to patients.

Currently, studies have shown that APOE genotype information can only be safely communicated to first-degree relatives of Alzheimer’s disease patients following traditional genetic counseling procedures. These procedures include in-person appointments between patients and genetic counselors, which can be time and resource consuming for genetic counselors. Recently, researchers investigated the use of a condensed genetic informational session, which may be more feasible for counselors, and its potential impact for patients. 

J. Scott Roberts, PhD, of the Department of Health Behavior and Health Education at the University of Michigan School of Public Health in Ann Arbor, and colleagues, studied the psychosocial and behavioral impact of condensed APOE genotype disclosure among 352 patients in The Risk Evaluation and Education for Alzheimer’s Disease study, a multi-center, randomized trial. Patients in the study were divided into two groups. one group (n=120) received the extended informational protocol, which included an in-person education session and counseling. The second group (n=232) received the condensed protocol, which included education brochures sent by mail and a question-and-answer session with a counselor. Study outcome measures included clinical cut-off rates on various screening tools, such as the Center for Epidemiologic Studies Depression Scale and the Beck Anxiety Inventory, among others. Patients received follow-up assessments at 6-week, 6-month, and 12-month intervals.

Both groups received neuropsychological and psychiatric screening, and all patients were asymptomatic adult children or siblings of patients with Alzheimer’s disease. Among all study patients, 280 continued to Alzheimer’s disease risk assessment with APOE disclosure (condensed protocol, n=187; extended protocol, n=93).

Roberts and colleagues found that there were few significant differences between the condensed and extended protocol groups in rates of depression or anxiety as well as in self-report health measures. Patients in the condensed protocol group reported higher levels of distress at the 6-week follow-up, however, that difference was not found at the 12-month follow-up. Patients in either group also changed their behavior at similar rates, with the percentage of patients in both groups making any health-related changes following APOE assessment being the same (54%).

In addition, more patients in the condensed protocol group reported understanding of genotype information (60% vs. 59%) and recall of lifetime risk of Alzheimer’s disease (61% vs. 51%) than those in the extended protocol group. The authors concluded that patients in the condensed genotype information protocol group had mean anxiety and depression levels far below cut-off measures and there were no differences in understanding among the two groups. As time demands for counselors in the condensed protocol group were significantly lower than demands for those in the extended protocol group (33 minutes vs. 76 minutes), the authors recommend that further research be conducted to explore the feasibility and effectiveness of alternative models for genetic counseling protocols for Alzheimer’s disease.

Funding for this research was provided by the National Institutes of Health. (ICAD 2008; Poster P2-282). –CP

 

Estrogen May Ease Schizophrenia in Women

According to the National Institute of Mental Health, schizophrenia affects approximately 1.1% of the population ≥18 years of age in any given year. It is usually diagnosed in late adolescence or early adulthood. According to a randomized, double-blind study by Jayashri Kulkarni, MD, of the Alfred and Monash University in Melbourne, Australia, and colleagues, estrogen may have therapeutic effects in women with severe mental illnesses, including schizophrenia.

With the goal of comparing the efficacy of adjunctive transdermal estradiol (a form of estrogen) with that of adjunctive placebo in the treatment of acute psychotic symptoms, female patients were recruited from inpatient acute hospital wards and outpatient clinics of two metropolitan Melbourne general hospitals. Participants included 102 schizophrenic women of childbearing age (73 of whom were outpatients) who were in an acute or chronic stage of their illness. Over the course of 28 days, patients were randomized to receive 100 microg of transdermal estradiol (n=56) or transdermal placebo (n=46). All patients continued to take their regular medications, which most commonly included atypical antipsychotics such as olanzapine. Using the Positive and Negative Syndrome Scale, psychopathalogic symptoms were assessed weekly. Results found that compared to women receiving antipsychotics alone, the addition of 100 microg of transdermal estradiol reduced positive (P<.05) and general psychopathalogic (P<.05) symptoms significantly.

Estrogen therapy may prove useful in schizophrenic women after childbirth and during menopause (when they are more prone to relapse) as well as during low-estrogen phases of a woman’s menstrual cycle. (Arch Gen Psychiatry. 2008;65(8):955-960). –DC

 

Family Meals May Increase Parental Communication and Decrease Substance Abuse for Teenage Girls

Studies have shown that meals between parents and adolescents provide an environment for communication as well as parental monitoring of mood or behavioral changes among adolescents and teenagers. Researchers in the Division of Adolescent Health and Medicine at the University of Minnesota in Minneapolis sought to examine if family meals with adolescents could deter later incidence of substance abuse.

Marla Eisenberg, ScD, MPH, and colleagues studied 806 adolescents (mean age=12.8 years) attending public schools between 1998–1999 to determine how often participants ate meals with parents and if family meals deterred later substance abuse. Adolescents were asked how often their families ate meals together in the past week as well as the presence or frequency of smoking and/or alcohol and marijuana use.

A second survey was conducted by mail 5 years later (2003–2004) which investigated the presence or frequency of family meals and substance abuse among teenagers. Among all participants, 45.4% were male and 54.6% were female, and the mean age at follow-up was 17.2 years.

According to the first survey, approximately 60% of adolescents ate >5 family meals each week, which was the expected result. Rates of family meals were lower for teenagers at the 5-year follow-up evaluation. Regarding substance abuse, the authors found significantly lower rates of smoking and marijuana or alcohol use among female participants who reported >5 family meals per week (approximately 50% lower rates of substance abuse when compared to female teenagers who reported <5 family meals per week). This finding was not significant for male participants.

The authors concluded that frequent family meals may provide increased parental/child communication, which may lead to lower rates of substance abuse. They also found that these lower abuse rates may not be significant for male teenagers due to societal expectations and differences in parental interaction with male children. (J Adolesc Health. 2008;43(2):151-156.) –CP

 

New Medications May Help Drinkers Battle Alcohol Dependence

Alcohol-dependent individuals suffer from destructive symptoms affecting their physicality, mentality, and interpersonal relationships. However, a study by Bankole A. Johnson, DSc, MD, PhD, MPhil, FRCPsych, and colleagues from the Medical University of South Carolina suggest that certain medications may help alcoholics moderate their alcohol consumption and prevent relapse.

Johnson and colleagues studied the effects of topiramate in 371 alcohol-dependent patients during a 14-week, double-blind, randomized controlled trial. While receiving weekly adherence-enhancement therapy, the participants were either given topiramate (≤300 mg/day) or placebo. The researchers compared the physical, mental, and psychosocial effects of topiramate to that of placebo and found that the former was more effective in reducing body mass index (mean difference, 1.08), liver enzyme levels (P<.01 for all), plasma cholesterol level (mean difference, 13.3 mg/dL), and systolic (mean difference, 9.7 mm Hg) and diastolic (mean difference, 6.74 mm Hg) blood pressure. Such reductions may lower risk of fatty liver degeneration, in turn, decreased risk of cirrhosis and cardiovascular disease.

Though the topiramate cohort reported more side effects (eg, paresthesia, taste perversion, anorexia, difficulty with concentration) than those in the placebo group, its members experienced significantly decreased psychological compulsion and improved psychosocial health and quality of life. These benefits reduce risk of relapse and long-term negative outcomes.

Research Society on Alcoholism president Raymond Anton, MD, disclosed results from the initial 6-week active treatment phase of a 14-week double-blind, placebo-controlled study involving 60 alcohol-dependent patients as characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, who took part in the Prometa Protocol. Participant level of alcohol withdrawal was assessed via the 67-point Clinical Institute of Withdrawal Assessment (CIWA). Based on their CIWA scores, patients were placed in either the higher (scores ≥7; n=18) or lower (scores <7; n=42) alcohol withdrawal group. That the patients were not required to maintain alcohol abstinence prior to research should be noted.

Eight patients in the higher CIWA group and 25 patients in the lower CIWA group received the pharmacologic aspect (ie, a combination of generic medications) of the treatment program while the remaining members of each division received placebo. During the first 6 weeks of active treatment, all participants received standardized behavioral counseling sessions and were evaluated weekly for drinking, craving, mood, sleep, and adverse effects from treatment.

Patients reported reduced cravings and alcohol withdrawal symptoms, more consistent abstinence, and improved mood and sleep. However, the full 14-week study is still underway, as the results represent patient response during the first 6 weeks of active treatment. (Arch Intern Med. 2008;168(11):1188-1199) –ML

 

Sildenafil Effective in the Treatment of Antidepressant-related Female Sexual Dysfunction

Women taking antidepressants may experience treatment-related sexual dysfunction, often causing them to prematurely discontinue treatment. Sexual dysfunction is particularly associated with  the most commonly prescribed antidepressants for outpatients 18–65 years of age, selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. Antidepressant-associated sexual dysfunction occurs in an estimated 30% to 70% of men and women treated for major depressive disorder (MDD) with first- or second-generation agents. There is a three-fold increased risk of nonadherence that leads to increased relapse and recurrence.

A study of sildenafil by H. George Nurnberg, MD, of the University of New Mexico School of Medicine in Albuquerque, and colleagues, proved promising for the reduction in adverse sexual effects of SSRIs in women. In an 8-week, prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 2003 and January 2007 at seven United States research centers, sildenafil was compared to placebo in 98 women (mean age=approximatetly 37 years) with in-remission MDD. Participants were randomly assigned to sildenafil (n=49) at a flexible dose starting at 50 mg and adjustable to 100 mg, approximately 1–2 hours before sexual activity, or placebo (n=49). Seventy-three percent of women taking placebo, compared to 28% taking sildenafil, reported no improvement with treatment. Scales used in the study included the Clinical Gloabal Impression sexual function scale, the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale–female version, the University of New Mexico Sexual Function Inventory–female version, a sexual activity event log, and the Hamilton Rating Scale for Depression. Women in the sildenafil group showed greater improvement in sexual function compared to women in the placebo group. Adverse effects included headache, flushing, and dyspepsia, but none of the patients withdrew due to serious adverse events.

The study established that selective phosphodiesterase type 5 inhibitors, such as sildanefil, are effective for women for the treatment of antidepressant-related sexual dysfunction. Thus, patients being treated for depression can continue with antidepressant treatment without the worry of adverse sexual effects. (JAMA. 2008;300(4):395-404). –DC

Posters were drawn from the Annual Meeting of the Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD; July 26-31, 2008, Chicago, Illinois). Psychiatric dispatches is written by Dena Croog, Michelisa Lanche, Carlos Perkins, Jr,, José R. Ralat, Lonnie Stoltzfoos, and Rebecca Zerzan.

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy is consultant to Myriad; on the speaker’s bureau of Pfizer; and has received grant support from Forest, Janssen, Myriad, Novartis, Pfizer, and Takeda.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.

 


 

The influence of depressive disorders on cardiac morbidity and mortality is widely accepted and bolstered by an array of established mechanisms through which mood disorders might be the antecedent or aftermath of heart disease. However, interventions to reduce the influence have not had dramatic impact. A close examination of recent studies may explain why.

William Harvey, MD, the physician most responsible for the development of modern cardiology, described the heart as a sense organ.

 

Every passion of the mind which troubles men’s spirits, either with grief, joy, hope, or anxiety and gets access to the heart, there makes it to change from its natural constitution, by distemperment, pulsation, and the rest…1

Numerous efforts to reduce the heart’s vulnerability to emotion have shown mixed results.2 Despite remarkable advances in clinical cardiology, the leading cause of death in the United Sates remains cardiovascular disease. Approximately 6 million Americans have symptomatic coronary heart disease.3 The combined morbidity and mortality of heart disease among older Americans remains a major public health problem. This column discusses suggestions for a new perspective on the mood and minds of heart patients.

 

Personality and Behavioral Style

Although unhealthy behaviors such as smoking, lack of exercise, excessive alcohol intake, poor diet, and medication non-adherence are clearly related to disease through direct biologic mechanisms, personality traits and behavioral styles that may have psychologically induced cardiotoxic effects have received considerable attention over the last 50 years. The type A behavior pattern of impatience, hostility, and anger was thought to predispose persons to atherosclerosis. However, large clinical trials failed to support this relationship.2 More recently, the type D personality, characterized by social inhibition and tendency toward negative affect, has been found to be a stable trait4 in post-myocardial infarction patients. Unlike depression, it is not confounded by the severity of somatic disease.5 Type D personality is a risk factor for adverse prognosis following the onset of heart disease but, unlike depression, is not considered an antecedent to disease. Therefore, interventions promoting a healthy lifestyle and optimizing adherence to treatment after the development of heart disease might counter the limitations of type D personality.

 

Social Support and Psychotherapy With or Without Antidepressants

Cannon6 postulated a sympthoadrenal mechanism whereby overwhelming stress of hopelessness and social ostracism might lead to cardiac collapse. Elevations in stress hormones cortisol and the catecholamines promote both atherosclerosis and cardiomyopathy.6 Further, it is the perception of inadequate emotional social support rather than the frequency of contact or size of the social network that is associated with illness. The Enhancing Recovery in Coronary Heart Disease (ENRICHD) study employed a psychosocial intervention to increase social support and alleviate depression among 1,503 adults following acute myocardial infarction.7 The ENRICHD study’s social support intervention utilized behavioral, cognitive, and network interventions to enhance perceived emotional support. Over an average 29-month follow up, the combined endpoint of either death or myocardial infarction was 10% in the non-depressed comparison group and 23% in the ENRICHD patients with lower perceived social support. However, improvement in perceived social support did not predict subsequent survival. Lower perceived baseline social support predicted death or recurrent infarction independent of treatment assignment. Post hoc analyses indicated a partner surrogacy role for the interventionist and the need for a moderate level of baseline support for the intervention to be effective. Although the intervention did not reduce recurrent myocardial infarction or mortality despite reducing depression and improving support, it is important to add that all study participants received enhanced “routine” care as evidenced by increased access to depression monitoring, antidepressants, and psychiatric consultation. One cannot exclude the possibility that the supportive nature of study participation, whether in the routine or intervention groups, was beneficial.

A similar caveat seems appropriate for the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE).8 In CREATE, 284 coronary artery disease patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,9 criteria for diagnosis of major depressive disorder (MDD) of 4 weeks duration or longer were randomized to receive 12 weekly sessions of interpersonal psychotherapy in addition to clinical management or with clinical management only. All were subsequently randomized to receive either 12 weeks of citalopram or placebo. Citalopram was superior to placebo in achieving 12-week Hamilton Rating Scale for Depression response (52.8% vs. 40.1%; P=.03) and remission rates (35.9% vs. 22.5%; P=.01). However, the effect size was small. There was no evidence of benefit from interpersonal psychotherapy compared to clinical management. This trial documents the efficacy of citalopram administered in conjunction with weekly clinical management for coronary patients with MDD. Clinical management provided weekly cannot be considered routine any more than weekly interpersonal psychotherapy.

Linden and colleagues’10 2007 meta-analysis of 23 psychological treatment trials among >9,000 cardiac patients revealed inconsistent results. Mortality was reduced only among men (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.57–1.00 for men; OR 1.01; 95% CI 0.87–1.72 for women). Interventions initiated ≥2 months after a cardiac event showed greater mortality reduction than those initiated immediately after the event. Mortality reductions associated with the psychological interventions were achieved despite small reductions in negative affect. Linden and colleagues10 concluded that psychological treatments reduce mortality and recurrent cardiac events, but the mortality benefits appeared only in men even after controlling for age differences. The timing of treatment initiation may be a critical variable mediating mortality.

 

Antidepressants with or without Psychotherapy

Taylor and colleagues11 performed secondary analyses of the ENRICHD database from patients prescribed any antidepressant either before or during the study. Over a mean follow up of 29 months, the risk of death or recurrent myocardial infarction was significantly lower among those taking a selective serotonin reuptake inhibitor (SSRI; adjusted hazard ratio [HR], 0.57; 95% CI 0.38–0.84) compared to those not using an SSRI. The risk of mortality from any cause was also reduced in association with an SSRI (adjusted HR, 0.59; 95% CI, 0.37–0.96). Though risks of recurrent myocardial infarction and mortality were also reduced in association with other antidepressants, the reduction was not substantial. Missing from the analyses are data on the adequacy of dosing and the efficacy of the antidepressants.

Glassman and colleagues12 randomized 369 MDD patients with either an acute myocardial infarction or unstable angina to 24 weeks of sertraline ≤200 mg or placebo. All participants received a 2-week placebo run-in prior to administration of sertraline. Neither sertraline nor placebo had a significant effect on left ventricular ejection fraction, runs of ventricular premature complexes, or QTc interval >450 milliseconds. The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo but not statistically significant. The responder rates as determined by the Clinician Global Impression of Improvement were significantly higher for sertraline than for placebo in the total sample (67% vs. 53%; P=.01). However, in the group with at least one prior episode of depression and in the more severely depressed group, the superiority of sertraline to placebo was more impressive 72% versus 51% (P=.003) and 78% versus 45% (P=.001), respectively. These results indicate that sertraline was safe and effective for the treatment of depression in patients with recent myocardial or unstable angina. However, the 2-week delay in treatment, which ensured that all participants met DMS-IV-TR criteria for depression, may have delayed the response rates and blunted the impact of sertraline on subsequent cardiac events. When depressive symptoms are severe or have recurred following a prior depressive episode, one would not delay the initiation of treatment on the basis of this study. In addition, the placebo responder rates across the sample may be indicative of the benefit of study participation alone.

 

Executive Dysfunction and the Vascular Depression Hypothesis

Two groups by Krishnan and colleagues13 and Alexopoulos and colleagues14 have described major depressive episodes (MDEs) occurring after 55 years of age as associated white matter changes on magnetic response imaging (MRI) of the brain and executive dysfunction on measures of neuropsychological performance. Approximately 50% of older adults experiencing an MDE may have subcortical white matter changes.15 These patients are also more likely to have heart disease, hypertension, and diabetes. More importantly, executive dysfunction predicts delayed or absent response to antidepressants16 and accelerates development of dementia.17 Executive deficits may prevent the recovery of independence even when the mood disorder of an MDE has fully remitted.18

More recently, Alexopoulos and colleagues16 used diffusion tensor imaging to test the hypothesis that depressed elders failing to achieve remission have microstructural white matter abnormalities in cortico-striato-limbic networks. Diffusion tensor imaging is an MRI technique that displays the integrity of neural tracts connecting cortical and subcortical structures. The greater the diffusion tensor anisotropy, the greater the tact integrity and connectivity. Lesser anisotropy is thought to represent disconnection between distributed cerebral networks. Among 23 older patients who did not achieve remission of depressive symptoms despite adequate dose and duration of antidepressant treatment, Alexopoulos and colleagues16 found lower fractional anisotropy in multiple frontal limbic brain areas, including the anterior cingulate, prefrontal cortex, corpus callosum, and white matter adjacent to the hippocampus, than those who achieved remission (N=25). In addition, lower fractional anisotropy was detected in the multiple posterior cingulate cortex, insular white matter, neostriatum, and midbrain as well as select temporal and parietal regions. The authors16 concluded that lower fractional anisotropy is associated with poor antidepressant response and may represent a neuroanatomical substrate that predisposes to geriatric depression.

However, the white matter changes, and anisotropy associated with depression may convey other risks as well. In the Longitudinal Aging Study of Amsterdam,19 2,965 adults with a mean of 70 years of age and without a history of stroke were followed for 9 years or until the occurrence of a stroke. In participants with prior heart disease, but not in those without, clinically relevant depressive symptoms at baseline (HR, 2.18; 95% CI 1.17–4.09) and the severity (range, 0–60; HR 1.08; 95% CI 1.02–1.13) and chronicity (HR 3.51; 95% CI 1.13–10.93) of symptoms during follow up were associated with stroke. The investigators17 concluded that symptoms of depression at baseline as well as their severity and persistence were associated with subsequent stroke.

 

Conclusion

As noted above, depression predisposes the individual to acute coronary events, but it is not entirely clear that antidepressants reduce the likelihood of recurrent acute events. This may be due to the methodologic limitations of study designs in which assignment to the “routine care” arm of the protocol conveys genuinely enhanced care. As a result, the superiority of the experimental intervention over “routine care” is modest since both groups received enhanced care. When the protocols used an antidepressant there was no formal provision for early detection of poor responders and switching or augmenting their care with different antidepressants. In addition, the investigators did not have the advantage of knowing which patients exhibited executive dysfunction or subcortical white matter changes that would have impeded their response to antidepressants as well as psychotherapy. With depression being prevalent among patients with congestive heart failure, which is one of the leading causes of hospitalization in older adults,20,21 one might argue for different start- and endpoints for studies seeking to show the benefits of behavioral health interventions for depressed heart patients. For example, would patients with congestive heart failure and executive dysfunction experience lesser rates of hospitalization if they received a prophylactic antidepressant? Would a more aggressive antidepressant protocol combining switch and augmentation steps for poor responders reduce hospitalization rates among depressed congestive heart failure patients with executive dysfunction? It is known that executive dysfunction is prevalent among depressed older adults, but how prevalent is it among older patients with coronary artery disease or congestive heart failure? Does executive dysfunction magnify the disability or worsen the course of congestive heart failure? Although efforts to reduce cardiac morbidity and mortality through treatment of depression have not shown dramatic benefits, new insights into the reciprocity of depression and heart disease suggest additional avenues for intervention. PP

 

References

1. Harvey WL. Exercitatio Anatomica de Motu Cordis et Sanguinis Animalibus. London, England: Bailliere, Tindall and Cox; 1928.
2. Razzini C, Bianchi F, Leo R, Fortuna E, Siracusano A, Romeo F. Correlations between personality factors and coronary artery disease: from type A behaviour pattern to type D personality. J Cardiovasc Med (Hagerstown). 2008;9(8):761-768.
3. McGovern PG, Pankow JS, Shahar E, et al. Recent trends in acute coronary heart disease–mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators. N Engl J Med. 1996;334(14):884-890.
4. Martens EJ, Kupper N, Pedersen SS, Aquarius AE, Denollet J. Type-D personality is a stable taxonomy in post-MI patients over an 18-month period. J Psychosom Res. 2007;63(5):545-550.
5. De Jonge P, Denollet J, van Melle JP, et al. Associations of type-D personality and depression with somatic health in myocardial infarction patients. J Psychosom Res. 2007;63(5):477-482.
6. Cannon WB. Voodoo death. Psychosom Med. 1957;19(3):182-190.
7. Burg MM, Barefoot J, Berkman L, et al. Low perceived social support and post–myocardial infarction prognosis in the enhancing recovery in coronary heart disease clinical trial: the effects of treatment. Psychosom Med. 2005;67(6):879-888.
8. Lesperance F, Frasure-Smith N, Koszycki D, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007;297(4):367-379.
9. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 1994.
10. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J. 2007;28(24):2972-2984.
11. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry. 2005;62(7):792-798.
12. Glassman AH, O’Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288(6):701-709.
13. Krishnan KR, Doraiswamy PM, Clary CM. Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(2):347-361.
14. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D, Charlson M. Clinically defined vascular depression. Am J Psychiatry. 1997;154(4):562-565.
15. Krishnan KR, Taylor WD, McQuoid DR, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry. 2004;55(4):390-397.
16. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, et al. Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry. 2008;165(2):238-244.
17. Alexopoulos GS, Kiosses DN, Heo M, Murphy CF, Shanmugham B, Gunning-Dixon F. Executive dysfunction and the course of geriatric depression. Biol Psychiatry. 2005;58(3):204-210.
18. Alexopoulos GS, Meyers BS, Young RC, et al. Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psyciatry. 2000;57(3):285-290.
19. Wouts L, Oude Voshaar RC, Bremmer MA, Buitelaar JK, Penninx BW, Beekman AT. Cardiac disease, depressive symptoms, and incident stroke in an elderly population. Arch Gen Psychiatry. 2008;65(5):596-602.
20. Freedland KE, Rich MW, Skala JA, et al. Prevalence of depression in hospitalized patients with congestive heart failure. Psychosom Med. 2003;65(1):119-128.
21. Fullop G, Strain JJ, Stettin G. Congestive heart failure and depression in older adults: clinical course and health services use 6 months after hospitalization. Psychosomatics. 2003;44(5):367-373.

 

Dr. Butcher is chief resident in the Department of Obstetrics and Gynecology at the University of Alabama at Birmingham. Dr. Ling is clinical professor in the Department of Obstetrics and Gynecology at Vanderbilt University School of Medicine in Nashville, Tennessee, and partner at Women’s Health Specialists, PLLC, in Germantown, Tennessee.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Sharon Butcher, MD, Chief Resident, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 619 19th St S, Birmingham, AL 35249-7333; Tel: 205-934-5631; Fax: 205-975-6411; E-mail: sbutcher@whsobgyn.com.

 


 

 

Abstract

According to the National Health and Social Life Survey, the prevalence of sexual dysfunction among women in the United States is 43%. Despite findings that nearly 50% of all female patients have complaints related to sexuality, only 18% of practitioners report routinely obtaining a sexual history. To further complicate this issue, when sexual dysfunction is present, patients are often unwilling to address the subject with their respective physicians. As primary reasons for avoiding the subject of sexual dysfunction, patients cite fear that the clinician will dismiss their concerns, the clinician will be uncomfortable discussing sexuality, or no effective treatment will be available to treat the problem. Over the past decade, significant strides have been made in the field of sexual dysfunction. Clinicians have developed a better understanding of the psychological and physical mechanisms contributing to this array of disorders. Effective pharmacologic therapy for the treatment of male sexual dysfunction is readily available. Development of comparable therapy for women is under investigation. Given the recent dynamic nature of the field, as well as the large number of affected patients, it behooves the astute practitioner to be well versed in understanding disease mechanisms related to sexual dysfunction, their diagnosis, and possible treatment modalities.

Introduction

Sexual dysfunction is characterized by a disturbance of the normal sexual response cycle or by pain associated with sexual intercourse. Four classifications of sexual dysfunction exist, as set forth by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.1 This article provides an in-depth exploration of one of the four DSM-IV sexual dysfunction classifications, ie, sexual pain disorders.

 

Sexual Pain Disorders

Population-based survey studies suggest a 17% to 19% overall lifetime prevalence of sexual pain disorders.2 Sexual pain disorders, as defined by the DSM-IV, are classified as either vaginismus or dyspareunia.1 Significant risk factors include peri-menopausal age, postmenopausal age, anxiety, depression, and history of sexual assault or pelvic inflammatory disease (PID).

Pain can be related either to the normal physiology of the sexual response cycle or a pathologic condition that triggers a painful sensation for a woman when sex is attempted. In a normal patient, vaginal lubrication is known to be a manifestation of arousal, thereby reducing discomfort upon penetration. Should arousal not occur (ie, the vagina does not lubricate as it normally does by means of transudation through the vaginal wall as a result of vasocongestion), the patient will experience dyspareunia associated with penetration and a sense of dryness. Alternatively, even in the face of adequate lubrication, a painful condition may exist which results in painful sex when penetration is attempted. Over time, if the pain is persistent, the woman will no longer become aroused (ie, will not moisten, even when adequately stimulated), as the body “learns” that coitus is an unpleasant experience. The management of sexual pain disorders requires investigation of both biologic as well as psychogenic etiologies.

 

Vaginismus

Vaginismus is characterized by recurrent or persistent involuntary contractions of the perineal muscles surrounding the outer third of the vagina. Involuntary contractions are associated with attempted vaginal penetration with any object. Penetration is, thereby, impaired or even impossible. Such a disruption in the normal sexual functioning of the woman causes marked distress and/or interpersonal difficulty and is not better accounted for by another Axis I disorder. The disturbance is also not due exclusively to the direct psychological effects of a general medical condition.

In the evaluation of a woman thought to have vaginismus, it is important to distinguish between primary and secondary forms as well as generalized and situational variants. Primary vaginismus is related to psychosocial stressors, while secondary vaginismus is typically associated with a conditioned response to pain. Generalized vaginismus occurs with each sexual encounter, while situational forms tend to occur only under a certain set of circumstances or with a specific partner.

Vaginismus, in its primary form, is treated with techniques designed to assist the affected female in controlling the relaxation of pelvic floor musculature. Activities include Kegel exercises as well as instructing patients to insert dilators of graduated size in and out of the vagina. Such insertion techniques enable the patient to learn that control of introital musculature can be voluntary, thereby resulting in a painless sexual encounter. Other therapeutic approaches include sex therapy, hypnosis, and utilization of medications such as benzodiazepines and botulinum toxin. Additionally, physical therapy and biofeedback methods have been used in the treatment of pelvic floor motor instability.

The treatment of secondary vaginismus is similar to that of primary vaginismus, although in these cases previous experience with successful penetration can assist in more rapid therapeutic success.

 

Dyspareunia

Dyspareunia is a condition characterized by recurrent, unexplained genital discomfort before, during, or after sexual intercourse. The disturbance may affect the male or female partner and causes marked distress or interpersonal difficulty. The disturbance must not be caused exclusively by vaginismus or lack of adequate lubrication, may not be accounted for by another Axis I disorder, and may not be due exclusively to the direct physiologic effects of a medication or drug of abuse. Clinically, it is often difficult to distinguish between dyspareunia and the above defined, vaginismus. Such difficulty results from the inherent phenomenon in which vaginismus may occur secondary to dyspareunia, as well as that in which even mild vaginismus results in significant dyspareunia.

As with vaginismus, it is imperative to determine if dyspareunia is primary, secondary, generalized, or situational. Primary dyspareunia is most frequently associated with psychosocial issues or congenital anomalies, while secondary dyspareunia tends to result from an acquired physical cause. Additionally, the clinician should investigate whether the pain occurs superficially at the introitus, within the vaginal barrel, or deep with penile thrusting. Such localization of pain will enable the clinician to narrow the differential diagnosis from a vast number of potential etiologies of dyspareunia, as discussed below.

Potential etiologies of dyspareunia are numerous. In women >50 years of age, vulvovaginal atrophy is the leading cause of sexual dysfunction. The leading cause of dyspareunia in women <50 years of age is vulvar vestibulodynia. Other common causes of dyspareunia experienced at the introitus include inadequate lubrication, anatomic abnormalities of the introitus (eg, imperforate hymen), vulvovaginal atrophy, infection, urethral disorders (eg, urethral diverticulum), and vulvar dystrophies. Pain associated with deep penetration is most commonly related to anatomic positioning of the uterus, impaired mobility of pelvic organs as a result of scarring from endometriosis or pelvic inflammatory disease, urologic disorders such as cystitis and interstitial cystitis, adnexal pathology, and bowel pathology.

 

Vulvodynia

Vulvodynia is defined by the International Society of the Study of Vulvovaginal Disorders as “chronic vulvar discomfort with feelings of rawness, burning, stinging, and irritation.”3 Two subtypes have been described: vulvar vestibulitis (vestibulodynia) and essential dysesthetic vulvodynia (generalized vulvodynia).

Vulvar vestibulodynia is characterized by severe pain upon vestibular touch or attempted vaginal entry. Also referred to in the past as vulvar vestibulitis, it may be asymptomatic unless the vestibule is touched. It may also manifest by constant burning. Physical findings are typically limited to focal vestibular tenderness as elicited by palpation with a cotton-tipped swab. This is most easily found at the openings of the Skene’s and Bartholin’s gland ducts. Sometimes erythema is found, which is attributable to sympathetic response. Features of vestibulodynia should be present at least 3–6 months in duration to diagnose a patient with the disorder.

The prevalence of vulvar vestibulodynia is approximately 10% to 15% of women seeking gynecologic care.4 A 2003 population-based assessment of unexplained vulvar pain found that 16% of approximately 4,900 female participants reported experiencing symptoms diagnostic of vulvar vestibulodynia.5 This assessment also demonstrated that Caucasian and African-American women reported similar lifetime rates of vulvar pain. Interestingly, Hispanic women were found to be 80% more likely to experience chronic vulvar pain than their Caucasian and African-American counterparts.

To date, there has been no single etiology identified as being responsible for the majority of vulvar vestibulodynia cases. Current thoughts regarding specific etiology revolve around a theory of chronic inflammation in which one of a variety of insults to the mucous membrane of the vestibule results in neuroinflammatory or nociceptive pain. An in-depth discussion of the neuropathology involved in vestibulodynia is beyond the scope of this article. Briefly, it is theorized that sensitization of vestibular nerve fibers may occur following events such as subclinical human papillomavirus infection, chronic candidiasis, or recurrent bacterial vaginosis. Ongoing release of cytokines and neurokines precipitates prolonged neuronal firing such that sensitization of neurons located in the dorsal horn of the spinal cord occurs. Sensitized neurons subsequently participate in transmitting an incorrect signal of pain, rather than light touch, to the brain.

Diagnosis of vulvar vestibulodynia can often be made by history alone. Women with primary vestibulodynia present a history consistent with pain upon first attempt at sexual intercourse. Those with primary vestibulodynia may also report inability to utilize tampons or tolerate a vaginal speculum. Secondary vestibulodynia, developing after a period of comfortable sexual relations or vaginal examinations, may appear after childbirth, repeated infection, long-term dermatosis, or previous vulvar treatment with laser or chemicals. A subset of women diagnosed with vestibulodynia is sensitized to seminal fluid, with an allergic reaction to such serving as the etiology of their symptoms.6 Upon physical examination, the vulva should be evaluated to confirm normal anatomy and exclude dermatoses. Erythema may be present diffusely, in patches, in focal red spots near the minor vestibular gland openings, or not at all. A Q-tip evaluation of the vestibule is then utilized to evaluate whether there is pain with pressure at any point around the vestibule just external to the hymen.

Treatment of vestibulodynia is largely anecdotal. Successful therapy often necessitates more than one type of therapeutic approach. Attention to vulvar care is essential. Dyes, fragrances, or chemicals should be avoided. Clothing should be comfortable and loose. Cotton undergarments should be recommended to the patient. The use of sanitary napkins should be discouraged. Some women may find relief of symptoms with warm Sitz baths. Diets eliminating foods high in oxalate content have been reported to improve symptoms in some patients; however, such anecdotal improvement has never been demonstrated in randomized, controlled trials. Daily use of topical anesthetics such as 5% lidocaine in ointment form should be recommended for pain relief and may be used just prior to intercourse to reduce dyspareunia.7 Occasionally, male partners may complain of penile burning or numbness when they come in contact with the lidocaine. The use of condoms may eliminate this problem. Tricyclic antidepressants (TCAs) can be useful as treatment of the presumed neuropathic pain. Nortriptyline 10 mg TID, increasing by 10 mg increments to a maximum dose of 150 mg/day is the least sedating TCA with the fewest anticholinergic side effects. If one TCA is not successful, other medications within the class may be utilized. Patients must be counseled that effects of TCAs may not be observed for several weeks. Anticonvulsants are typically initiated in women who have failed TCAs. Gabapentin is the most frequently used anticonvulsant, popular for its low side-effect profile.8 Gradual increase in dosage of gabapentin, to a maximum dosage of 3,000 mg/day, will aid patients in avoiding transient sedation, dizziness, and ataxia, side effects occasionally occurring with the drug’s usage. Other medications that may be used when gabapentin is unsuccessful or poorly tolerated may include pregabalin, topiramate, levetiracetam, and tiagabine hydrochloride. Other less frequently utilized therapeutic approaches include the injection of botulinum toxin A,9-11 capsaicin,12-14 and interferon.15 Physical therapy with biofeedback is successful in some women with vestibulodynia when the muscular component of pain appears to be significant. The effectiveness of physical therapy modalities demonstrates the difficulty encountered when the clinician is trying to differentiate vaginismus from other sources of sexual pain.

Vulvar vestibulodynia was once commonly treated with surgery in which the vestibule was either surgically excised or treated with laser. As vestibulodynia came to be looked upon as a possible neuropathic condition, surgery has been relegated to a secondary role. Although medical management should be considered the primary therapeutic approach, surgery in selected cases remains appropriate. In one recent report, vestibulectomy demonstrated efficacy up to 2.5 years postoperative, while also demonstrating superiority to biofeedback and cognitive-behavioral therapy (CBT).16

In contrast to vulvar vestibulodynia, the symptoms of vulvodynia may be present anywhere on the vulva. Symptoms include chronic vulvar burning, stinging, rawness, soreness, or pain in the absence of gross anatomic or neurologic findings. Vulvar pain is often experienced by women with vulvodynia both during and after sexual intercourse. Other factors such as bicycle riding, tampon insertion, prolonged sitting, or wearing tight clothing may exacerbate the symptoms associated with vulvodynia, thus, its classification under “other sexual pain disorders.”17

The prevalence of vulvodynia is similar to that of vestibulodynia, as is the age group affected. Although research in the field remains ongoing, little is understood regarding the etiology of vulvodynia. Several studies have identified minor immunologic changes in women with vulvodynia.17,18 The changes may result in decreased ability to downregulate an inflammatory immune response, which may in turn be associated with the neuropathic changes of vulvodynia. The role of neuropathic pain in vulvodynia is yet to be clearly defined; however, it is supported by the excellent response rate noted by patients treated for neuropathic pain.

The diagnosis of vulvodynia is made upon eliciting an extensive history, followed by a confirmatory physical examination. The history should include information regarding the onset and character of the pain, location of the pain, aggravating and alleviating factors, medical evaluations to date, and attempted treatments and the subsequent effects on pain. Physical examination should be initiated with an inspection of the vulva. The vulva of a vulvodynia patient may be erythematous, but the presence of a rash is not a necessity to make the diagnosis. A cotton swab should be used to palpate the affected area of the vulva. This pressure will elicit generalized discomfort. Although the posterior introitus and hymenal remnants are common sites of increased sensitivity, patients with vulvodynia will also have discomfort on the labia minora and majora. Having a more diffuse pain is what differentiates vulvodynia from vestibulodynia.18

Therapy for vulvodynia is similar to the neuropathic approach taken for vestibulodynia. CBT has also been shown to be associated with a 30% decrease in vulvar pain with intercourse. Sexual, individual, and marital counseling may also be effective in patients with prevalent psychosocial stressors.19 Physical therapy with or without biofeedback may also contribute to overall improved symptoms. Because of its diffuse nature, vulvodynia is not amenable to surgery or injections.20

 

Vulvovaginal Atrophy

Vulvovaginal atrophy is the most common cause of dyspareunia in menopausal women. Vulvar, vaginal, and urinary tract epithelium express a relatively large number of estrogen receptors and, thus, are susceptible to the decreased levels of circulating estrogen associated with menopause. Symptoms of hypoestrogenism manifest as lack of adequate vaginal lubrication, vaginal soreness, positcoital spotting, postcoital burning, and dyspareunia.

A diagnosis of vulvovaginal atrophy is usually made by mere physical examination. The vaginal mucosa is thin with diffuse erythema, occasional petechiae, occasional ecchymoses, and few or no vaginal rugae. Patients may also note a watery, serosanginous vaginal discharge. If vaginal pH is evaluated, pH will be abnormal with values ranging from 5.0–7.0, which is higher than in the normal premenopausal patient.

Atrophy is easily corrected with the regular uses of vaginal estrogen cream. Vaginal cream or tablets may be used once daily for 2–4 weeks, after which time the frequency can be reduced to one to two times weekly. At such doses, the systemic effects are negligible.

 

Inadequate Lubrication

Inadequate lubrication is an important cause of dyspareunia. While inadequate lubrication resulting from hypoestrogenism is frequently encountered in the postmenopausal population, younger women may experience dyspareunia as a result of inadequate lubrication for a multitude of reasons. Typically, in younger women, inadequate lubrication is associated with inhibited arousal. Such lack of sufficient arousal may be a result of inadequate foreplay technique, as well as relationship and interpersonal conflict. Commonly used medications such as some antihypertensive agents and antidepressants may contribute to inhibited arousal and lubrication. Other medications associated with significant vaginal dryness include low estrogen dose oral contraceptives, first-generation histamine-1 blockers, tamoxifen, and anticholinergic agents, such as diphenhydramine hydrochloride.

The diagnosis of inadequate lubrication, as well as identifying the etiology, is based on history alone. Treatment consists mainly of managing the underlying causes. If a history of relational difficulties is elicited, referral for counseling is appropriate and may be sufficient. Medication-related arousal inhibition may be treated with discontinuing the offending agent. It is important to be cognizant of the need to taper antidepressants, even if they are thought to be the sole factor in a woman’s sexual difficulty. Failure to do so may result in significant emotional lability and other undesirable withdrawal symptoms. Simple suggestions such as increased amount of foreplay as well as use of over-the-counter vaginal lubricants can be helpful in selected patients.

 

Abnormalities of the Hymen

Women experiencing dyspareunia resulting from anatomic abnormalities of the hymen typically complain of superficial pain with intercourse. It is rare that patients will have a complete imperforate hymen, as women with this condition will typically present at the time of menarche. Patients with an imperforate hymen will experience significant pain due to hematocolpos following the onset of menses. This pain will be relieved upon surgical incision of the hymenal ring.

While an imperforate hymen is an uncommon cause of dyspareunia, it is not uncommon for patients to have hymenal remnants that cause pain upon initiation of sexual activity. Women with a rare cribriform hymen, characterized by many small holes, will present with dyspareunia. This type of hymen lets menstrual and other fluids out with no problem, but sexual activity and the insertion of tampons can be problematic. Other variations of hymen anatomy which tend to be associated with dyspareunia include the denticular hymen, the fimbriated hymen, and the septate hymen. Treatment for hymen abnormalities typically involves surgical intervention.

 

Vulvovaginitis

Vulvovaginitis resulting from a candidal infection or trichimonas vaginalis may cause superficial genital pain during intercourse. This pain is a direct result of local inflammation and edema. Bacterial vaginosis and colonization with Group B streptococcus do not typically serve as etiologies of dyspareunia. Physical examination, including wet mount of vaginal secretions, will serve to assist in the diagnosis of vulvovaginits. It is important to recognize that findings on wet mount may be negative, despite patient infection. Culture is essential when there is an increased clinical suspicion of infection, but negative objective data upon performing the wet smear. Treatment is with appropriate antibacterial and antifungal agents.

 

Urinary Tract Disease: Urethral Diverticulum

Urethral diverticula are a relatively common finding among women presenting with chronic genitourinary conditions, such as recurrent infections, postvoid dribbling, and dyspareunia. Dyspareunia associated with urethral diverticula is most frequently of a superficial nature. A urethral diverticulum can be described as an outpouching of tissue from the urethra into the urethrovaginal potential space. The lining of the diverticulum is identical to the urethral mucosa. Most urethral diverticula are derived from dilated paraurethral ducts or gland. While the etiology of urethral diverticula continues to be debated, the pathophysiology appears to revolve around obstruction of and infection within the paraurethral glands. The glands are thought to become enlarged and inflamed, eventually forming a retention cyst and then an abscess, which ruptures back into the urethra. The clinical presentation of urethral diverticula varies considerably from patient to patient and may also vary depending on when during the natural history of the disorder the diagnosis is made. Early in the natural history, when the periurethral gland initially becomes infected, the predominant symptoms may be related to urination. At this stage, dysuria, frequency, and postmicturition dribbling may bring the patient to clinical attention. Later, as chronic and recurrent inflammation develops around the diverticulum, low pelvic pain and dyspareunia may be reported as well. Clinical signs such as pyuria, a palpable suburethral mass, suburethral induration, and tenderness may be present. Treatment is surgical excision and/or drainage. Contraindications for surgical treatment of urethral diverticula are few and generally involve medical disorders that render surgery of any kind unsafe. In cases of active abscess, definitive surgical treatment should probably be postponed. Temporizing measures include treatment with broad-spectrum, tissue-penetrating antibiotics and drainage either by vaginal incision or by urethral dilation and massage.

 

Urinary Tract Disease: Interstitial Cystitis

Interstitial cystitis is an inflammatory condition of unknown etiology leading to urgency, frequency, dysuria, and pelvic pain. Up to 60% of women diagnosed with interstitial cystitis report significant dyspareunia occurring with superficial penile insertion or deep vaginal thrusting.21 Pain may also occur upon completion of sexual intercourse. It may last for several hours following coitus; however, symptoms are often relieved upon voiding. The character of symptoms may vary from one day to the next in a single patient. Exacerbation of interstitial cystitis symptoms may occur after intake of certain foods or drinks such as strawberries, oranges, beer or coffee. Symptoms may also worsen during the luteal phase of the menstrual cycle, stressful times, or after activities such as exercise or being seated for long periods of time. Population-based studies report prevalence rates of 10 to 865 cases per 100,000 women.21 The mean age of diagnosis is approximately 42–45 years of age, although symptoms have been recognized in children.22,23 A greater concordance of interstitial cystitis among monozygotic than dizygotic twin pairs suggests a genetic susceptibility to interstitial cystitis.24

The clinical diagnosis of interstitial cystitis is based upon the presence of characteristic symptoms after other conditions with similar symptoms are excluded. Physical examination is often remarkable for widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs, pelvic floor, bladder base, and urethra. Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection. Cystoscopy, hydrodistension, bladder biopsy, and potassium sensitivity testing are unnecessary but frequently utilized in the diagnosis of interstitial cystitis. The diagnosis is typically made when, following hydrodistention of the bladder, glomerulations appearing as small petechiae, small subucosal hemorrhages, fissures, or ulcers are visualized in three of four quadrants of the bladder. The hydrodistention process involved in diagnosis may reduce symptoms in 30% to 60% of afflicted patients.

Interstitial cystitis causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Pentosan polysulfate sodium is the only oral treatment for interstitial cystitis approved by the Food and Drug Administration. Uncontrolled studies25 suggest modest benefit in a minority of patients, but a randomized controlled trial26 suggested no benefit over placebo. Intravesical therapy with dimethyl sulfoxide is also approved by the FDA, but is not common in clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine, and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. Amitriptyline has clinical utility, most likely acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies,27 but is expensive and is not approved by the FDA for this indication. Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training.

 

Endometriosis

Endometriosis is defined as the presence of endometrial glands and stroma outside the endometrial cavity and uterine musculature. These ectopic endometrial implants are usually located in the pelvis, but can occur nearly anywhere in the body. Endometriosis can be associated with many distressing and debilitating symptoms. Common symptoms of endometriosis include pelvic pain, which may be chronic but is often more severe during menses or at ovulation; dysmenorrhea; infertility; deep dyspareunia; cyclical bowel or bladder symptoms; abnormal menstrual bleeding; and chronic fatigue. A history in which a patient describes years of painless menstrual cycles with gradual onset of progressive worsening of dysmenorrhea is suggestive of endometriosis. Physical findings in women with endometriosis are variable and depend upon the location and size of the implants. Often, no abnormal findings are present on physical examination. When findings are present, the most common is tenderness when palpating the posterior fornix. Other frequent findings include localized tenderness in the cul-de-sac or uterosacral ligaments; palpable tender nodules in the cul-de-sac, uterosacral ligaments, or rectovaginal septum; pain with uterine movement; tender, enlarged adnexal masses; fixation of adnexa; or findings consistent with a retroverted uterus. Standardized, objective criteria for the diagnosis of endometriosis do not exist because of the variable clinical presentation of the disease. The diagnosis must be made by laparoscopy or laparotomy, ideally with histologic confirmation.

The prevalence of endometriosis in the general population is difficult to interpret because of the lack of standardized criteria described above. Best estimates are that endometriosis is present in 5% to 10% of women of reproductive age and in 25% to 30% of patients with infertility.28

Numerous theories regarding the pathogenesis and etiology of endometriosis have been proposed. Three theories for the histogenesis of endometriosis exist. Sampson’s theory refers to the transplantation of endometrial tissue via retrograde menstruation. It has been shown that 75% to 90% of women have patent tubes with retrograde flow.29 Because such a large number of women experience retrograde flow, with only a small percentage of them demonstrating the disease, it is difficult to completely attribute endometriosis to the theory of retrograde flow. Another potential etiology of endometriosis is the transformation of totipotential cells into endometrial cells outside of the uterus. Lymphatic and vascular transport of endometrial fragments to other areas of the abdomen, pelvis, and even remote areas of the body have also been cited as a potential etiology. Yet another theory proposes that women suffering from endometriosis actually have decreased cellular immunity, thereby “allowing” endometrial cells to implant and proliferate in ectopic sites. Genetic predisposition also seems to contribute to the overall disease development. A woman whose sibling is found to have endometriosis has a six-fold increased risk for developing the disorder, while the daughter of a woman with endometriosis has a 10-fold increased risk as compared with the general population.30

Clinical manifestations of endometriosis fall into three general categories, namely, pelvic pain including dyspareunia, infertility, and pelvic mass. The goal of therapy is to relieve symptoms. There is no high-quality evidence that one medical therapy is superior to another for managing pelvic pain due to endometriosis, or that any type of medical treatment will affect future fertility. Therefore, treatment decisions are individualized, taking into account the severity of symptoms, the extent and location of disease, whether there is a desire for pregnancy, the age of the patient, medication side effects, surgical complication rates, and cost. Treatment options are vast. The spectrum varies from expectant management, to medical management, to surgical intervention. Hormonal medical therapies include combination oral contraceptive pills, gonadotropin-releasing hormone agonists, progestins, danazol, and aromatase inhibitors. It is important to note that these ovulation suppressive agents will improve pelvic pain associated with endometriosis, but will not improve fecundity. Surgical intervention, which may be conservative or definitive with complete removal of the uterus and ovaries, is also employed in the treatment of endometriosis. If conservative surgical treatment is opted for, patients are often placed on hormonal suppressive agents postoperatively.

 

Pelvic Inflammatory Disease

PID refers to acute infection of the upper genital tract structures in women, involving any or all of the uterus, oviducts, and ovaries. This is often accompanied by involvement of the neighboring pelvic organs. Involvement of these structures results in endometritis, salpingitis, oophoritis, and possibly peritonitis, perihepatitis and tubo-ovarian abscesses. PID is more commonly a community-acquired infection initiated by a sexually transmitted agent, and less commonly caused by medical procedures or other primary abdominal processes. According to a National Hospital Ambulatory Medical Care Survey, the estimated number of cases of PID in women 15–44 years of age in the United States decreased from 189,662 in 2002 to 168,837 in 2003.31 This decline is primarily due to aggressive chlamydia screening and treatment programs nationwide.32 Lower abdominal pain is the cardinal presenting symptom in women with PID. The recent onset of pain that worsens during coitus or with jarring movement is also suggestive of PID, as is the onset of pain during or shortly after menses. Abdominal pain is usually bilateral and rarely of more than 2 weeks’ duration. New vaginal discharge, urethritis, proctitis, fever, and chills can be associated signs but are neither sensitive nor specific for the diagnosis. The presence of PID is less likely if symptoms referable to the bowel or urinary tract predominate.33 In addition to acute symptoms, PID can have long-term sequelae including chronic pelvic pain and dyspareunia. Approximately 30% of women with PID will develop dyspareunia and/or chronic pelvic pain.34 The severity of adhesive disease and tubal damage after acute infection often correlates with the likelihood of developing pain and dyspareunia.

 

Uterine Retroversion

Although uterine retroversion is a normal anatomic variant, some women will experience dyspareunia, particularly with deep vaginal penetration. It is thought that the bony structure of the pelvis, in such women, may not provide enough room posteriorly to accommodate the retroverted uterus. No specific complaint or history is associated with this anatomic finding. Diagnosis is typically made upon bimanual examination. Recommendations for improvement of symptoms include coital positional changes in which vaginal penetration is not deep or positions in which the female partner actively controls the depth of penetration. The use of pessary and/or surgery has been reported to relieve symptoms of dyspareunia in these cases.

 

Leiomyomata

Uterine leiomyomas are benign monoclonal tumors arising from the smooth muscle cells of the myometrium. They contain a large amount of collagen, proteoglycan, and fibronectin and are surrounded by a thin pseudocapsule of areolar tissue and compressed muscle fibers. Myomas are clinically apparent in approximately 25% of reproductive aged women and noted on pathologic examination in approximately 80% of surgically excised uteri.35 The relative risk of fibroids is two- to three-fold greater in African-American women than Caucasian women. The myomatous uterus is irregularly shaped and can cause specific symptoms due to pressure from myomas in particular locations. Leiomyomata resulting in pain with sexual intercourse are typically located in the posterior portion of the uterus. The usual posterior location is predictable in that during intercourse, the penis is directed in a posterior fashion upon vaginal entry. The bony pelvis of women with significantly large posterior fibroids does not accommodate the additional posterior displacement of the uterus with intercourse; therefore, the patient experiences pain. Therapeutic options begin with positional changes. If the patient continues to experience significant discomfort, such options as uterine artery embolization to reduce the size of the myoma or complete excision of the myoma (myomectomy) or uterus (hysterectomy) should be explored to eliminate the source of pain.

 

Adnexal Pathology

Thorough discussion of adnexal pathology is beyond the scope of this article; however, it is important to recognize that adnexal masses are a common source of pelvic pain. Adnexal pathology, such as an ovarian cyst, can contribute significantly to deep dyspareunia. Commonly, those women experiencing pain associated with an adnexal mass will have a benign diagnosis. Typically, malignant masses do not cause pelvic pain until they are in the most advanced stages. Adnexal masses are best evaluated by transvaginal ultrasonography. Based on ultrasound findings, a management plan can be made regarding need for medical therapy or surgical intervention.

 

Pelvic Adhesions

Pelvic adhesions may result from surgery, infection, or endometriosis. Such adhesions may result in pelvic pain, including dyspareunia, in some patients. If dyspareunia is experienced, it is often with deep penetration. Diagnosis of pelvic adhesive disease may be made only be visualization by laparotomy or laparoscopy. Treatment consists of lysis of adhesions.

 

Conclusion

Coital pain is the leading symptom of two major sexual disorders, dyspareunia and vaginismus. According to the new International Classification on Female Sexual Disorders,36 they are included under the category of “sexual pain disorders.” In addition to a psychogenic etiology, dyspareunia also has a biologic basis. Biologic factors include hormonal, inflammatory, muscular, iatrogenic, neurologic, vascular, connective, and immune causes. Vaginismus, with its associated contraction of paravaginal muscles at the time of attempted intercourse, is thought to be the pelvic expression of a variable phobic attitude toward coital intimacy. However, more recent thought, as in the case of dyspareunia, alludes to a physical component. Vaginismus may prevent intercourse in the most severe degrees, while in the milder ones it becomes a cause of dyspareunia. The clinical approach to treating patients affected by sexual pain disorders should aim at diagnosing biologic, psychosexual, and context-dependent etiologies. It is such an approach that will serve to completely address the complex nature of sexual dysfunction. PP

 

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2.    Paik A, Laumann EO. Prevalence of women’s sexual problems in the USA. In: Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction. London, England: Taylor and Francis; 2005:299-305.
3.    Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med. 2004;49(10):772-777.
4.    Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol. 1991;164(6 pt 1):1609-1614.
5.    Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58(2):82-88.
6.    Babula O, Bongiovanni AM, Ledger WJ, Witkin SS. Immunoglobulin E antibodies to seminal fluid in women with vulvar vestibulitis syndrome: relation to onset and timing of symptoms. Am J Obstet Gynecol. 2004;190(3):663-667.
7.    Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol. 2003;102(1):84-87.
8.    Harris G, Hotrowitz B, Borgida A. Evalation of gabapentin in the treatment of generalized vulvodynia, unprovoked. J Reprod Med. 2007;52(2):103-106.
9.    Yoon H, Chung WS, Shim BS. Botulinum toxin A for the management of vulvodynia. Int J Impot Res. 2007;19(1):84-87.
10.    Gunter J, Brewer A, Tawfik O. Botulinum toxin A for vulvodynia: a case report. J Pain. 2004;5(4):238-240.
11.    Dykstre DD, Presthus J. Botulinum toxin type A for the treatment of provoked vetibulodynia: an open-label, pilot study. J Reprod Med. 2006;51(6);467.
12.    Bergeron S, Binik YM, Khalifé S, Pagidas K. Vulvar vestibulitis syndrome: a critical review. Clin J Pain. 1997;13(1);27-42.
13. Steinberg AC, Oyama IA, Rejba AE, et al. Capsaicin and the treatment of vulvar vestibulitis. Am J Obstet Gynecol. 2005;192(5):1549-1553.
14. Murina F, Radici G, Bianco V. Capsaicin and the treatment of vulvar vestibulitis syndrome: a valuable alternative? MedGenMed. 2004;6(4):48.
15. Marinoff SC, Turner ML, Hirsch RP, Richard G. Intralesional alpha interferon. Cost effective therapy vulvar vestibulitis syndrome. J Reprod Med. 1993;38(1):19-24.
16. Bergeron S, Khalife S, Glazer HI, Binik YM. Surgical and behavioral treatments for vestibulodynia: two-and-one-half year follow and predictors of of outcome. Obstet Gynecol. 2008;111(1):159-166.
17. Bachmann GA, Rosen R, Arnold LD, et al. Chronic vulvar and other gynecologic pain: prevalence and characteristics in a self reported survey. J Reprod Med. 2006;51(1):3-9.
18. Haefner HK, Collins ME, Davis GD, et al. The vulvodynia guideline. J Lower Genit Tract Dis. 2005;9(1):40-51.
19. Arnold LD, Bachmann GA, Rosen R, et al. Vulvodynia: characteristics and associations with Ccomorbidities and quality of life. Obstet Gynecol. 2006;107(3):617-624.
20. Updike GM, Wisenfeld HC. Insight into the treatment of vulvar pain: a survey of clinicians. Am J Obstet Gynecol. 2005;193(4):1404-1409.
21. Wein AJ, Hanno PM, Gillenwater JY. Interstitial cystitis: an introduction to the problem. In: Hanno PM, Staskin DR, Krane RJ, Wein AJ, eds. Interstitial Cystitis. New York, NY: Springer-Verlag; 1990:145-167.
22. van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53(1):60-67.
23.    Clemens JQ, Meenan RT, Rosetti MC, Gao SY, Calhoun EA. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol. 2005;173(1):98-102.
24.    Parsons JK, Kurth K, Sant GR. Epidemiologic issues in interstitial cystitis. Urology. 2007;69(4 suppl):5-8.
25.    Dimitrakov J, Kroenke K, Steers WD, et al. Pharmacologic management of painful bladder syndrome/interstitial cystitis: a systematic review. Arch Intern Med. 2007;167(18):1922-1929.
26.    Davis EL, Elkhoundary SR, Talbott EO, Davis J, Regan LJ. Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial. J Urol. 2008;179(1):177-185
27.    Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodríguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553-557.
28.    Missmer SA, Hankinson SE, Spiegelman D, et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160(8):784-796.
29. Olive DL, Schwartz LB. Endometriosis. N Engl J Med. 1993;328(2):1759-1769.
30. Bischoff FZ, Simpson JL. Heritability and molecular genetic studies of endometriosis. Hum Reprod Update. 2000;6(1):37-44.
31.    Huppert JS, Goodman E, Khoury J, Slap G. Sexually transmitted infection testing and screening in hospital-based primary care visits by women. Obstet Gynecol. 2005;105(2):390-396.
32. U.S. Department of Health and Human Services Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance, 2004. Atlanta, GA. U.S. Department of Health and Human Services, September 2005. Available at: www.cdc.gov/std/stats/default.htm. Accessed on August 11, 2008.
33. Peipert JF, Ness RB, Blume J, et al. Clinical predictors of endometriosis in women with symptoms and signs of pelvic inflammatory disease. Am J Obstet Gynecol. 2001;184(1):856-863.
34. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55:1-94.
35.    Moore AB, Flake GP, Swartz CD, et al. Association of race, age and body mass index with gross pathology of uterine fibroids. J Reprod Med. 2008;53(2):90-96.

36.    International Statistical Classification of Diseases and Related Health Problems-10 (ICD-10). 2nd ed. Geneva, Switzerland: World Health Organization; 2004.

 

Dr. Galanter is professor of psychiatry and director, Dr. Glickman is assistant clinical professor, Dr. Dermatis is research associate professor, Dr. Tracy is assistant professor, and Ms. McMahon is research assistant, all at the Division of Alcoholism and Drug Abuse of New York University School of Medicine and Bellevue Hospital Center in New York City. Drs. Galanter, Dermatis, and Glickman are also research scientists at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York.

Disclosures: Drs. Galanter and Dermatis receive research support from the John Templeton Foundation. Dr. Glickman and Ms. McMahon report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Tracy receives grant support from the National Institute on Alcohol Abuse and Alcoholism.

Acknowledgments: The authors thank Hannah Barbash, BA, New York University Divisional research assistant, for assistance in the preparation of this article. The authors also thank Lynda Curtis, Drs. Eric Manheimer and Marc Gourevitch, and Irene Torres.

Please direct all correspondence to: Marc Galanter, MD, Professor of Psychiatry, NYU School of Medicine, 550 First Ave, Room NBV20N28, New York, NY 10016; Tel: 212-263-6960, Fax: 212-263-8285;
E-mail: marcgalanter@nyu.edu.

 


 

 

Focus Points

• Many patients have strong spiritually grounded feelings related to their ability to cope with illness.
• Addressing patients’ spiritual needs in the general medical setting can improve their satisfaction with caregivers and their adherence to treatment plans.
• There are emerging approaches to address this issue in the clinical setting.

Abstract

Medical care has long been associated with religion and spirituality, but in recent years a trend has arisen to introduce diverse spiritually oriented approaches in the context of empirically grounded practice. This article reviews the application of these approaches in contemporary medical practice. It highlights the relative utility of such applications, the use of spiritual assessment of the patient, and the role of the clergy and nursing in introducing spirituality into the clinical setting. It then presents findings from a program developed by the authors to employ spiritual support groups in the general hospital in order to aid patients in coping with illness, and to develop among them a more positive identification with their treatment providers.

Introduction

In the Western tradition, medicine and religion have always been linked—sometimes closely and sometimes farther apart—and religious influences on medical practice and on the profession’s ethics are longstanding.1-3 The growth of interest in the interaction of medical practitioners with religion and spirituality over recent years has paralleled similar developments in the larger society, as many healthcare providers with a strong spiritual orientation have sought to bring this spiritual aspect of their personal lives more into their clinical work. A major aspect of this movement has involved legitimating the positive relationship between religious involvement, spirituality, and health in many publications in the professional literature.4 Of comparable importance has been the growing recognition that spirituality and religion permeate the lives of patients as well as many medical encounters. A question to be considered has become not only how to deal with the religious and spiritual aspects of health care, but how they can be introduced into the treatment context. This article focuses on recent attempts to establish the utility of such interventions, and provides by way of illustration such a program that the authors have developed and implemented in the general hospital setting.

The distinction between religion and spirituality is important to this work, though it is not without controversy. Spiritual or religious choices often reflect a very personal and private aspect of a person’s life, which makes any definition subject to intense scrutiny. It is counterproductive to the purposes of research to settle on a definition of spirituality that is either too broad and vague or too individualized.5 There is, however, general agreement on a fundamental level that both religion and spirituality are related to a search for the sacred or transcendental.6,7 This commonality has led to divergent notions of how spirituality and religion are related. According to the theoretical framework posited by Pargament,8 spirituality and religion are inextricably intertwined. Spirituality is viewed as a core component of the more “broadband concept” of religion.8 However, an increasingly widely held view is more in line with Koenig and colleagues’4 contrasting definitions. He casts religion as “an organized system of beliefs, practices, rituals, and symbols” in relation to the sacred, as opposed to the “personal quest for understanding” of spirituality.5 These conceptualizations of religion and spirituality allow for the option of being religious but not spiritual, spiritual but not religious, both, or neither. In this article, spirituality is defined as that which gives people meaning and purpose in life.9 It can be achieved through participation in a religion but can be much broader than that, such as involvement in family, humanism, or the arts.10 In much of the literature and in American culture, spirituality has come to be seen as a human dimension particularly useful in bridging sectarian divisions common to religion.

 

The Spiritual Assessment

A key technique for addressing spirituality in clinical practice is the spiritual assessment.9 Spiritual assessments focus on learning whether the patient is part of a supportive faith community, ascertaining unmet spiritual needs that should be addressed in the course of treatment, identifying religious beliefs that might influence medical treatment decisions, and identifying potentially harmful spiritual practices such as spiritual struggles that patients associate with their illness. Spiritual struggles are defined as “efforts to conserve or transform a spirituality that has been threatened or harmed” and are expressed in terms of conflict and questioning of one’s spiritual/religious convictions.11 With a patient who professes neither to be religious nor spiritual, the physician can still inquire into what they are doing to cope with their illness. Puchalski9 has developed an approach adapted to general clinical settings she terms FICA, involving inquiry into “F”aith and healing, “I”mportance of faith in the patient’s life, “C”ommunities of faith and healing they may be part of, and “A”ddressing unmet needs.

Practitioners developing long-term relationships with dying patients have developed questions probing deeper into their sense of how their illnesses relate to “what it all means” to aid patients in identifying spiritual interventions that might benefit them.10 Spiritual interventions refer to therapeutic strategies that are designed with a spiritual or religious dimension as their central component12 and include but are not limited to spiritual assessments.

Kristeller and colleagues13 designed an intervention to improve patients’ well being and adjustment to cancer and showed that a 5–7-minute patient-centered intervention by an oncologist made a small contribution in patient well being. Patients included in the intervention were recruited at random from the waiting rooms of oncologists’ offices, as were controls who received usual care. The short intervention introduced the topic of spiritual or religious beliefs and encouraged patients to identify ways they used spiritual or religious resources. Questioned after 3 weeks, 33% said they thought the intervention would influence how they coped with cancer, while >40% thought it made them more satisfied with their overall care. Improvement after 3 weeks in quality-of-life measures among patients in the study group compared to those in the control group reached levels associated with clinically meaningful impacts in drug or other behavioral trials. Improvements were most pronounced among those scoring low on a spiritual well-being scale at baseline. Spiritual well being was assessed by the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being Scale. This scale consists of two subscales, namely, meaning/peace and faith.14 The spiritual well-being composite score combining both subscale scores was moderately correlated with measures of emotional and functional well being (r=.58 for each) suggesting that it was an empirically distinct dimension. This study provides support for the benefit of a short, nondenominational empathic intervention in physicians’ offices, even absent a physician’s incorporating the acquired information into treatment. Attention, however, should be paid to whether any aspect of the intervention produces distress in the patient and/or clinician. How often spiritual interventions are conducted, and to what effect, remains unknown.

 

The Clergy

Approximately 85% of all United States hospitals employ chaplains, while an estimated 20% of all hospitalized patients receive a chaplain’s visit.15 The growing professionalization of chaplains within a medical model, however, has contributed to their acceptance as members of a supportive care and palliative medicine team in the intensive care unit of a large trauma hospital, a team including physicians, advanced practice nurses specializing in pain, intensive care unit and palliative care, social workers, pharmacists, and music therapists. Chaplains provide spiritual support to patients who are dealing with issues related to finding meaning in life and coping with suffering, and help patients utilize their beliefs in coping with illness.9

Major barriers identified by chaplains included inadequate staffing, inability of healthcare providers to identify patients’ spiritual needs, and being called in too late to provide proper care to families.16 Physicians are often advised to refer serious spiritually-related problems to clergy or a chaplain affiliated with their hospital; some advocates of greater inclusion of spiritual matters within medicine consider the lack of such appropriate referrals to be a form of negligence.17 Shadowing a chaplain can be a key component of the spiritual education program for many palliative care fellows.

More recently, at Memorial Sloan-Kettering Cancer Center in New York City, approximately 20% of all chaplain interventions came as a result of a referral, mostly from nurses; 33% of the interventions involved working with family and friends.18 A similar survey at a suburban community hospital found that nurses made >50% of referrals to chaplains; 75% of all referrals were to see patients and the remainder were to see friends and family.19 Although referrals by nurses to chaplains most often come in times of crisis, some nursing leaders see a need to develop more ongoing collaboration to address a wider range of situations.20,21 Patients are frequent sources of requests for pastoral care—more frequent than nursing referrals in a study of adolescent inpatients in a pediatric tertiary care hospital.20

 

Nursing

Studies of self-reported spiritual nursing interventions and ideal, complex spiritual nursing competencies shed some light on the vast range of activities nurses see as falling under this rubric to address the spiritual needs of their patients.22,23 Such research stems from the desire to capture the considerable spiritual care delivered by nurses that goes undocumented. Prayer and active listening are the most commonly reported nursing interventions.24 Other commonly reported interventions include conveying acceptance, being present with a patient, therapeutic touch, and instilling hope. Presence as an intervention refers to both being physically present without expecting interactional responses and a psychological component wherein the nurse is attentive and demonstrates an understanding of the patient’s experiences.24

Narayanasamy and Owens25 identified different patterns of nurses’ responses to critical incidents they regard as involving spirituality. In the personal approach, nurses, using counseling, become involved in a mutual sharing of spiritual concerns, usually framed in nonreligious terms. In the procedural approach, the nurse sticks to standard routines, often referring to the expert, the chaplain, or colluding with the patient’s relatives, often without the patient’s involvement. In the evangelical approach, nurses, often sharing the same religious background with patients, attempt to rekindle the patient’s faith. Ethical concerns that arise relate to the potential for nursing staff to impose their specific spiritual/religious beliefs on the patient and/or family and to blur the boundary between nurse professional and clergy.9

 

Incorporating Spirituality in Psychosocial Treatment

One approach to incorporating spirituality in treatment involves integrating a spirituality dimension into an established treatment modality such as psychotherapy. Various attempts have been made to develop psychotherapeutic approaches to accommodate Christian values, including prayer and religious materials. Results of an early study26 showed that although cognitive-behavioral therapy (CBT) and a modified CBT with religious content resulted in improvement among depressed patients, improvement was greatest among depressed patients in the religiously modified program. A small meta-analysis, however, found that religion-accommodative approaches to counseling depressed patients had essentially the same overall efficacy as non-religious approaches.27

Another approach involves integrating spirituality in an existing psychosocial rehabilitation program. A small study among patients with serious psychiatric disabilities in an inner-city community program found that all participants receiving a spiritually oriented support group intervention to improve program functioning met their treatment goals related to symptom management, community integration, and improvement in overall quality of life as opposed to only 50% in the standard rehabilitation program.28 A study by Worthington and Sandage29 included patients with depression who were assigned either to a Beck-oriented CBT program or a Christian accommodative one. Both approaches were found to be equally effective in reducing depression, while the religiously oriented program was associated with greater improvement in spiritual well being.

A recent review12 of the worldwide literature on spiritually modified cognitive therapy in the Islamic, Taoist, and Christian traditions classified these treatments as experimental for anxiety disorder, neurosis, obsessive-compulsive disorder, and other conditions except for depression, which was considered to meet American Psychological Association criteria for a well-established intervention.

 

Models for Intervention

Pargament and colleagues30 and McConnell and colleagues31 have conducted a substantial body of research supporting the view that some forms of spiritual struggles are linked to psychopathology, and that a spiritually integrated psychotherapy can effectively address this problem and others. They have developed interventions based on these ideas, including a short intervention with an individual therapist for female survivors of sexual abuse with spiritual struggles designed to improve spiritual well being.32 A group intervention for people with serious mental illness following Pargament’s theory of positive and negative implications of religious coping33 incorporated issues such as spiritual striving, spiritual struggles, and hope.

Cole and Pargament34 also developed a group psychotherapy program for cancer patients, “Re-Creating Your Life: During and After Cancer,” combining concern with core existential issues and positive religious coping. Numerous models of group psychotherapy have been developed for work with cancer patients.35,36 Although most such groups focus on providing education, a forum for emotional expression, and strengthening coping skills as elements of overall support, spiritual and religious issues are often raised as well directed at reducing spiritual suffering and distress at end of life.

The field of palliative medicine, with its focus on end-of-life care, has been a source of considerable innovation in connecting spiritual issues to its form of medical practice. One such program developed by Breitbart35 at Memorial Sloan-Kettering Cancer Center employs a meaning-centered approach, drawing on the logotherapy developed by Frankl, to develop an eight-session program that explicitly addresses issues of meaning, peace, and ultimate purpose.35,37 Participants, all with advanced cancer and a limited prognosis, are given assigned readings and homework related to group session topics such as “Meaning and Historical Context of Life,” “Cancer and Meaning,” and “Limitations and Finiteness of Life.” The goal here is to help strengthen patients’ sense of being at peace with themselves in the face of the spiritual suffering and hopelessness they often experience.

A more extensive three-level program to enhance patients’ level of spirituality, mood, and self-efficacy for patients with a range of cancer diagnoses and severity was implemented in a metropolitan cancer hospital in Toronto, Canada.38 Level 1 consists of four group sessions dealing with cancer stress; level 2 is comprised of eight group sessions on skills for coping by drawing on the “Inner Healer” through meditation and other modalities. Meditative techniques are not the core of the intervention. Rather, meditative chanting is done for the first few minutes of all the sessions before the main topics are covered. The third level consists of eight sessions on spiritual healing, with a follow-up program of twice-monthly groups available to all who complete the program. This multi-staged model allows patients to decide for themselves which level of spiritual involvement is comfortable for them. In an exploratory study to assess the efficacy of this program, a battery of psychometric tests was administered at entry, 8 weeks, and 6 months, and written homework assignments were completed by study participants. Ninety-seven patients completing the third level showed significant improvement in mood, self-efficacy, and spirituality over the 8-week intervention period. After 6 months, only improvement in spirituality remained significant. Based on the written assignments which showed patients struggling with their spiritual issues, the investigator suggested that this model can provide advanced spiritual training to highly motivated individuals within a resource-constrained environment.

Randomized controlled trials can help assess the relative value of spiritually oriented interventions compared to standard interventions and can also help identify subgroups for which they may be most helpful. A recent clinical trial39 conducted at the Mayo Clinic points in a direction this area is likely to go, namely, integrating spiritual concerns into multidimensional and multidisciplinary interventions with the goal being to improve the overall quality of life of cancer patients. In this trial, advanced cancer patients set to undergo radiation therapy participated in a manualized 3-week program consisting of eight sessions each with a cognitive, emotional, physical, social, and spiritual interventional component. Sessions were lead by a psychiatrist or psychologist, with a chaplain, social worker, and advanced practice nurse as co-facilitator, depending on the session’s content. Quality of life at 4 weeks and 6 months following the intervention was compared with patients receiving standard care supervised by their radiation oncologist. Compared to the controls, the intervention group experienced a significantly better quality of life at 4 weeks; however, at 6 months this difference largely disappeared. The major benefit of the intervention appeared to be averting the sharp decline in quality of life during and shortly after the radiation treatment.

Stefanik and colleagues40 caution against concluding that religion and spirituality affect treatment outcomes in cancer due to methodologic weaknesses in much of the research, including the preponderance of cross-sectional studies, use of small samples sizes and samples of convenience, lack of correction for multiple statistical comparisons, failure to control for confounding variables, and questionable reliability and validity of study instruments.

 

HIV/AIDS

Efforts to include spiritual and religious concerns in the treatment of HIV/AIDS take many forms, but most of them have not been evaluated. Community health workers in one innovative outpatient HIV Palliative Care Program in the Bronx, New York, provided material resources and a dialogic partner in the search for meaning for patients undergoing the process of dying and bereavement and their families.41 In another study, Pargament and colleagues42 developed an eight-session nondenominational group program tailored for urban black women with HIV/AIDS. The program uses exercises such as writing a letter to God about guilt and shame, and identifying dreams still possible despite their illness, to encourage participants to acquire spiritual resources that may contribute to their health and well being while living with illness.

Another intervention designed to improve quality of life is exemplified in a randomized controlled pilot study43 of patients at an AIDS-dedicated skilled nursing facility. The independent and additive effects of meditation and massage on spirituality and quality of life were examined. Patients in a program that combined both modalities showed substantially greater improvement on measures of overall and spiritual quality of life than patients receiving either a meditation or a massage intervention alone or patients receiving standard care. Interventions designed to reduce HIV/AIDS risk combining spirituality and cognitively-based approaches include a nontheistic Buddhist-based program targeting risk behaviors among inner city methadone patients and a spiritual coping group for patients with HIV.44-46

A recent study47 which has implications for the value of spirituality based interventions among people receiving a potentially life-altering diagnosis examined whether changes in spirituality occur after receiving an HIV diagnosis and whether changes are related to disease progression as reflected in CD4 cell counts and viral load. People who had an increase in spirituality/religiousness showed less disease progression on both measures even after controlling for church attendance and initial disease status. These findings support continued efforts to develop spirituality based interventions for people diagnosed with HIV.

Numerous concerns have been reported regarding implementing spiritual interventions in medical and psychiatric treatment settings. Healthcare professionals may feel they lack sufficient expertise to discuss spirituality, are uncertain as to what their role is in relation to that of the chaplain, or construe such inquiries as intruding into the patient’s private life.17 When patient spirituality is addressed within the physician-patient relationship there is the possibility that certain beliefs held by the patient may undermine the physician’s treatment plan resulting in treatment refusal or futile requests for treatment.17 Another issue relates to whether the spirituality intervention is designed to meet the needs of the patients. Healthcare professionals and patients may not agree on what dimensions of spirituality are needed in the care of patients. In a review of nursing research papers published on spiritual care, Ross21 reported that there appears to be a discrepancy between provider and patient understanding of spirituality and the nature of spiritual care desired by patients.

 

A Program for Spiritually Oriented Support Groups

Despite impressive advances in the technology of acute care in general hospitals, the limited adherence by many patients to medical treatment plans regularly compromises their clinical outcome. This results in recidivism, increased morbidity, and undue cost to the healthcare system. In relation to primary care, for example, the World Health Organization has estimated that no more than 50% of patients with hypertension adhere to their prescribed medication regimens.48 Much of this is due to a limited sense of mutuality and trust felt by patients toward their caregivers as well as the impersonal quality perceived in their medical encounters.49

This need has been operationalized by the Joint Commission of Accreditation of Health Care Organizations, the principal certifying body for American hospitals. Its requirements stipulate that, “spiritual and cultural values [should] be gathered during the initial assessment of patients,” and that “Each patient has the right to have his or her . . . spiritual and personal values and beliefs, and preferences respected.”50 Importantly, however, there is little if any programmatic experience published on how spiritually grounded values and beliefs can be effectively addressed in hospital settings.

In order to address this need, the authors of this article conducted focus groups with patients at Bellevue Hospital Center, New York University’s principal teaching hospital, and found that one issue that contributes to this problem is that many patients feel that their core personal and spiritual beliefs are neither recognized nor addressed by hospital personnel. In previous research, staff and patients rated the importance of spiritually related resources relative to medical and material ones in addiction recovery.51,52 Staff rated the spiritual resources lowest, while patients rated them highest. Furthermore, when staff gave ratings to how they thought the patients would respond, they erroneously scored spiritual resources lowest, not recognizing the importance of spirituality to patients’ understanding of how they achieve recovery from their illness.53 Staff underestimated the importance patients placed on spirituality focused groups in the recovery process.51,52 Given this experience, the authors developed a pilot clinical program to determine if patients would discuss how they can draw on their spiritual resources and strengths to enhance their recovery and rehabilitation with support of hospital staff. The authors drew on experience54-56 in related clinical and research projects on the feasibility of such discussion groups in diverse clinical settings, and established groups for patients in a primary care clinic setting and on units dedicated to the treatment of comorbid general psychiatric disorders and substance abuse.

All groups were facilitated by volunteer medical or allied professional staff who have given their time because of their appreciation of the value of this effort, with the goal being to elicit feedback from all participants concerning how their spiritual attitudes, beliefs, and behaviors can help to promote health and cope with illness. The tone of the groups has reflected a mutual respect for each other’s religious (or non-religious) orientations. It would emerge that an underlying spiritual orientation was the primary focus of exchanges. The format of the group meetings is outlined in Table 1.

 

 

The groups were established in a primary care clinic setting in which 221 patients participated in one or more group meetings. The authors chose the primary care clinic to ascertain the applicability of this approach in a general medical population. They were also established in three inpatient (131 participants) and two outpatient (48 participants) psychiatry units. There were six different facilitators, each dedicated to his or her respective unit. The psychiatric patients were chosen to compare singly diagnosed psychiatric patients to those with comorbid substance use disorder; a report on the psychiatric patients will appear elsewhere. In the primary care clinic reception area, posters were prominently displayed and flyers were distributed to patients containing information concerning the group meetings and inviting all patients to attend. On the psychiatry units all patients were invited to attend the discussion groups by staff. This would usually occur at the beginning of the weekly community meeting. Participation in the spirituality discussion groups was completely voluntary and did not in any way affect the medical or psychiatric services received by patients. For purposes of the present report, only participant data collected in the medical outpatient setting will be presented.

In the medical outpatient setting a survey assessing spiritual orientation to life using the Spirituality Self-Rating Scale (SSRS)53 was administered to 52 consecutive patients at their first group session. These patients had as high a mean SSRS score, as did the addiction inpatients, but significantly higher than medical students. In a subsequent survey again administered to consecutive attendees at their first group session, 113 participants were asked items assessing their spiritual and religious views and practices concerning worship service participation. These items had been used in previous national probability surveys.57 The sample was predominantly female (64%) with a mean age of 53 (SD 14). Ethnicity included 27% African-American, 25% Hispanic, 25% White, and 23% other designation which was mainly multiracial. Patients varied with regard to religious preference with 31% Catholic, 15% Protestant, 10% Muslim, 6% Jewish, 28% other religious preference such as “higher power,” and 10% no preference. The results indicated that a greater percentage of the medical outpatients described themselves as being both religious and spiritual and report a higher frequency of spiritual-related practices involving worship service attendance compared to national samples (Table 2).57 These findings suggest that primary care patients perceive spirituality to be important to them and are as active, if not more so, than the general population.

 

 

Feedback from patients attending the group indicate that they value the opportunity to discuss their spiritual experiences with professional healthcare staff in the primary care setting, they feel more positively connected to treatment, and they endorse treatment’s integration in the formal healthcare system. In order to document themes that were discussed during the group sessions, a project assistant had recorded the comments made by the medical outpatients. Patient responses over the course of the sessions have been categorized, and numerous themes emerge prominently.

 

The Meaning of Spirituality

When participants were asked whether they considered themselves to be spiritual, the most common response was belief in a higher power which embodied a connection to God or a higher power. The diversity of the participants’ backgrounds was reflected in the different forms of this higher power, eg, Christian participants spoke of praying to Jesus and God; others, for example, self-identified as Buddhists, believed that this higher power was present in everyday objects.

 

Comparing Spirituality and Religion

Some participants discussed certain aspects of their spirituality in terms of their specific religious practices (eg, prayer, reading of scriptures, rituals) but also articulated distinctions between religion and spirituality.

 

Resources They Draw On

Participants described numerous aspects of their spirituality that reinforced their belief in a higher power, including prayer, recitation of religious or personal mantras, direct communication with the external force (eg, singing), scripture reading, and meditation. These served to calm them, combat depression or discontent, and alleviate physical pain or emotional suffering.

 

Some Personal Experiences

Some participants described their spirituality in terms of internal processes that served to instill hope, empowerment, and general well being. They referred to transformative experiences including revelations, miracles, or rebirth.

 

Quest for Spiritual Fulfillment

Some participants described themselves as emotionally drained and in search of a spiritual connection. Many of these individuals recalled being more spiritual when they were younger, but due to their illness and the physical changes accompanying aging, they became more cynical and spiritually detached.

 

Alienation from the Bellevue Physicians

Some patients were disenchanted with the medical staff. As one said, “All they do is give you pills, and when they do not work they just give you more pills.” Some spoke of “student doctors,” who “do not have time to listen to my story.”

 

Relationship to Treatment and Recovery

Participants discussed various aspects of their spirituality relating to connections with others based on trust, as with a family physician, or a group such as a 12-step fellowship. Many shared their spiritual experiences as a means of helping others to cope with their illness and better adhere to treatment. To a lesser extent, patients expressed the view that their spiritual beliefs could provide a means to a cure for their physical ailments not available through modern medicine, although they rarely endorsed refusal of all medical recommendations.

 

Conclusion

This article highlights progress that has been made in translating a growing interest in the medical field in spirituality and religion into interventions that may be effective and possibly become part of standard medical care. One notable aspect of this development is how spiritually and religiously based interventions have been adapted to diverse forms of clinical practice. Uncontrolled clinical trials have provided most of the information required to describe the complex dynamics involved in the relationship between spiritual interventions and medical care. One approach, developed at New York University and Bellevue Hospital in New York City, illustrates some of the particulars of helping patients to draw on their spiritual resources in order to cope with illness.

Spiritually oriented programs may pose ethical issues like those that have been raised regarding interventions that are specifically religiously oriented. By broadening the scope of discussion to include the many interests subsumed under the rubric of spirituality, however, concerns over sectarianism and religiously grounded bias are mitigated. Given this, diversity of commitment and affiliation among participants in spiritually oriented groups should be accepted and respected. With this proviso in mind, such interventions may be effective in improving patients’ outlook on their medical care as well as their ability to identify with the mission of hospital staff, thereby promoting greater compliance with the treatment regimens proposed. PP

 

References

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20.    Chapman TR, Grossoehme DH. Adolescent patient and nurse referrals for pastoral care: a comparison of psychiatric vs. medical-surgical populations. J Child Adolesc Psychiatr Nurs. 2002:15(3):118-123.
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Dr. Ross is assistant professor of psychiatry and director of the Division of Alcoholism and Drug Abuse at Bellevue Hospital, and associate director for education at New York University School of Medicine in New York City.

Disclosures: Dr. Ross reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Stephen Ross, MD, 104 E 40th St, Suite 802, New York, NY, 10016; Tel: 212-562-4097; Fax: 212-562-2041; E-mail: stephen.ross@nyumc.org.

 

 
 

Abstract

Ketamine is a schedule III drug with a well-established safety profile that has been used extensively as an anesthetic for close to 4 decades. It has long been described as a drug of abuse and has become known as one of the “club drugs,” used by adolescents and young adults in rave and circuit party settings. Ketamine is a congener of phencyclidine and acts as a noncompetitive N-methyl-d-aspartate (NMDA) antagonist. Through a complicated and not completely understood process, NMDA antagonism increases dopamine levels in reward-related areas such as the ventral tegmental area and the nucleus accumbens. In addition to its addictive liability, there is also evidence to suggest that ketamine might have anti-addictive properties when used as an adjunct to psychotherapy that takes advantage of its ability to produce spiritually oriented altered states of consciousness. This technique has been applied to patients with alcohol and opiate use disorders. Ketamine’s potential anti-addictive properties can be understood by looking at biologic and psycho-spiritual models.

 

Introduction

Ketamine is a commonly used, safe, effective and well-known anesthetic agent that has been available as a schedule III agent for close to 4 decades. It has been known as a drug of abuse since its discovery and introduction as a medicine and has most recently become associated as a “club drug” used primarily by adolescents, young adults, and gay men at “raves” and “circuit parties.”1 It is primarily thought of as a drug of abuse; however, it is also starting to find its way into the pharmacopoeia of agents used to treat addictive disorders by taking advantage of its ability to be used as an adjunct to psychotherapy, where its ability to produce psychedelic and spiritual states of consciousness has been successfully applied to induce sobriety in addicted individuals, mostly in Russia.2 It is worth trying to understand this contradictory phenomenon. This can be addressed by looking at biologic and psycho-spiritual etiologic models. This article includes a brief historic review of research and use of ketamine for a variety of medical and psychiatric conditions, addictive liability of ketamine including biologic mechanisms, and potential anti-addictive properties of ketamine with an exploration of biologic and psycho-spiritual mechanisms of action.

 

History of Research and Current Use Practices of Ketamine

Ketamine was synthesized by the American chemist Calvin Stevens in 1962 at the University of Michigan for use as a novel anesthetic agent after phencyclidine (PCP) was discovered to be too psychotigenic when used as an anesthetic.1 In 1965, Domino coined the term “dissociative anesthetic”3 to describe its properties of disconnecting mind from body unlike conventional anesthetics that completely suppressed consciousness. It was patented in 1966 by Parke-Davis and in 1970 the Food and Drug Administration approved its use for anesthesia in children, adults, and the elderly. Since then, it has been used extensively for this purpose as a result of the properties of rapid onset, rapid patient recovery, and its ability to suppress conscious experience without altering respiratory and circulatory functioning. It has a well-established biologic safety profile based on >7,000 published reports. There is some evidence it may prevent neurotoxicity from strokes, head trauma, and seizures, likely a result of its antagonist properties at the N-methyl-d-aspartate (NMDA) receptor.2 In addition, there is no evidence of long-term neurotoxicity or prolonged adverse psychological effects when used in controlled environments.4-7

In the 1970s and 1980s, ketamine was used and studied as an adjunct to psychotherapy in patients with depressive, anxiety, and psychosomatic spectrum disorders with anecdotal reports suggesting an effect on reducing symptom distress.8-10 Current research with ketamine has strongly suggested a role in treating refractory pain syndromes such as complex regional pain syndrome,11-13 and breakthrough pain in chronic pain syndromes such as that related to advanced cancer.14 Krystal15 has successfully used ketamine as a research tool for over a decade in normal volunteers and schizophrenics to explore the NMDA antagonist hypothesis of schizophrenia. As a serendipitous finding in Krystal’s research, subjects reported acute reductions in depressive symptomatology after ketamine administration.16 This laid the foundation for subsequent work by several investigators where ketamine was found to be the first known agent to effect acute antidepressant properties in patients with major depressive disorder (MDD) in randomized, placebo-controlled trials.17-19 Further research into this effect is actively being pursued at several centers in the country.

 

Addictive Liability

Illicit use and abuse of ketamine started soon after its introduction in 1970. Soldiers returning from Vietnam who received ketamine as an anesthetic reported vivid hallucinogenic experiences. It became linked with “intellectual hedonism” in the 1970s and 1980s, particularly in the United States, and the first reports of abuse by healthcare workers began to appear.20 Over the past decade, an increase in non-medical use of ketamine in Australia, Great Britain, Sweden, and the US (particularly in New York City) has been reported, with diversion from veterinary supplies a major source of obtaining the drug.1,21 There are two main groups of users, namely those who use in a solitary fashion seeking transcendental, psychedelic experiences and seeking spiritual growth, and those who use ketamine as a ‘“club drug” as part of the rave and circuit party scene. It is difficult to establish the true prevalence of ketamine use disorders as the users remain a mostly hidden group. One study21 in Britain reported that close to 30% of club-goers surveyed reported a lifetime use of ketamine. Another survey22 of mostly gay, Caucasian men who attended a “circuit party” in the New York City area in 1998 found that 86% of the 173 subjects reported drug or alcohol use at the party with ketamine being the second most common drug used (53%) after methylenedioxymethamphetamine (“ecstasy”; 71%). Several converging pieces of data point to ketamine having real addictive liability. These include positron emission tomography studies demonstrating that ketamine leads to increases in dopamine in the ventral tegmental area (VTA) in humans correlating with elevated mood23; ketamine induces increases in dopamine in the nucleus accumbens in humans24; ketamine induces self-administration in animal models25,26; repeated ketamine administration causes behavioral tolerance in animals27,28 and humans21; and heavy, habitual use of ketamine has been described in humans, including in anesthesiologists.29,30

Understanding ketamine’s addictive properties involves considering its mechanism of action. Ketamine is an arylcyclohexylamine and is part of the class of dissociative anesthetics, which also includes PCP (“angel dust”) and dextromethorphan. Its main receptor action is antagonism at the NMDA glutamate receptor complex at the same site as PCP, located inside the calcium channel leading to blockade of calcium influx through the channel.31 This action underlies its analgesic, dissociative, psychotigenic, psycho-spiritual, and neuroprotective properties. Ketamine mainly acts at the pre-frontal cortex (PFC) and limbic system, with the highest density of NMDA receptors being in the PFC and hippocampus.32 Alcohol, as one of its several mechanisms of action, also antagonizes the NMDA receptor, and ketamine produces alcohol-like subjective effects in humans.33 In addition, ketamine has opioidergic effects (mu and sigma opiate agonism)16 contributing to its analgesic properties and stimulant-like properties by enhancing monoaminergic transmission (dopamine, norepinephrine, serotonin) through inhibition of re-uptake pumps.34 The above effects have led some to describe ketamine’s subjective state as “alcohol-like intoxication, cocaine-like stimulation, opiate-like calming, and cannabis-like imagery.”35

Next, it is first important to look at the biologic underpinning of the addicted state. Two effects that likely contribute significantly to the addicted state are changes in midbrain dopamine as well as PFC dopamine and glutamate function. Damage to the dopamine system leads to decreased dopamine receptor density and release in the nucleus accumbens and PFC, diminishing the ability of dopamine to signal novel salient events, leading to under-excitability to biologically relevant stimuli.36,37 As addiction progresses, the neurocircuity of the reward pathway becomes corrupted, re-organized, and dysregulated whereby the behavioral system changes from a dopamine-oriented one in the nucleus accumbens (involved in the acute high and the initiation of learning and conditioned responses) to a glutamate-based system in the PFC (especially the anterior cingulate and orbitofrontal cortex) marked by altered glutamatergic transmission in projections from the PFC to the nucleus accumbens.38 Specifically, the system becomes hyperexcitable to drug-conditioned cues and under-excitable to biologically oriented ones. As part of these dopaminergic and glutamatergic changes, pharmacotherapy development of anti-addictive agents is currently focusing on agents that can strengthen the saliency of natural reinforcers, such as enhancing dopamine function, and agents that can alter the dysfunctional response to conditioned cues (either drug related or biologically relevant) by altering glutamatergic transmission.

Along the lines of hyperglutamatergic states being associated with addiction, it is key to consider that subanesthetic doses of NMDA antagonists (ie, ketamine) may actually enhance glutamatergic transmission by disinhibiting glutamate release, shunting glutamate to the other glutamatergic receptors other than NMDA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], kainite, and the metabotropic G protein coupled glutamate receptor) and causing a hyperglutamatergic state.15 One may ask how this is possible and what is its significance. There is some evidence to suggest that NMDA receptor blockers may antagonize γ-aminobutyric acid (GABA) neurons with a greater potency than their inhibition at the NMDA receptor. The NMDA antagonism may therefore diminish activation of GABA inhibitory neurons, with a diminution of cortical extracellular GABA levels,39 which in turn would decrease GABA’s normal inhibition of glutamate neurons, causing a net disinhibition of glutamate neurons and an increase in glutamatergic transmission in non-NMDA glutamate receptors.40 In turn, cortical glutamatergic activation stimulates monoaminergic terminals within the cortex, limbic system, midbrain, and brainstem.15 As part of this, extracellular dopamine levels are increased in reward-related areas (ie, VTA and nucleus accumbens) thereby likely explaining ketamine’s addictive liability. Given this, one can ask how we can understand a possible explanation—biologic or otherwise—for ketamine’s putative anti-addictive properties.

 

Anti-Addictive Properties

Brief History of the Use of Hallucinogens to Treat Addictive Disorders

Ketamine is not the first psychedelic agent to be tested to treat addictive disorders. In the 1950s and 1960s, serotonergic hallucinogens (predominantly d-lysergic acid diethylamide [LSD]; “acid”) were applied to patients with addictive disorders, mostly alcohol dependence and to a lesser degree opiate dependence. The most prominent researcher who studied this application was Humphrey Osmond, MD. He, in conjunction with Abram Hoffer, MD,41 treated >1,000 alcoholics using high-dose LSD. Their initial mechanistic hypothesis was based on aversive counterconditioning where they likened the intense LSD experience to the frightening altered state seen in the delirium tremens, which, in their experience, often served as a transformative, near-death (“bottoming out”) state that led to a sober conversion. However, soon after treating alcoholic patients with LSD in highly controlled environments paying careful attention to set and setting, they changed to a more positivist paradigm where they described that such agents had the capacity to produce a transcendental feeling of unity with the world, personal insights, self-understanding, increased sense of responsibility to self and others, and spiritual enlightenment.41 They reported high success rates including improved rates of abstinence, but the research was methodologically flawed with no randomization, no placebo controls, lack of blind raters, the use of unsophisticated severity measures, inadequate diagnostic specificity, inclusion of co-occurring psychiatric and substance use disorders (SUDs) other than alcohol, inadequate informed consent, and inadequate follow up.

Other studies looking at LSDs effect in alcoholism varied widely from astonishingly positive results to worsening of the alcoholism, depending on the design of the study and the set and setting. Unfortunately, almost all studies were methodologically flawed, leaving others unable to determine what if any effect might have existed.42 However, this has laid the groundwork for current studies using these and similar agents (ie, ketamine) to determine if there is a true treatment efficacy signal. The correct methodology would have to include randomization, placebo control, use of specific diagnoses using validated measures (ie, Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), inclusion of severity measures, standardized psychotherapy dose, objective “blind” raters, and having adequate follow up.43

 

Current Use of Ketamine to Treat Addictive Disorders   

The first psychiatrist to rigorously study the potential of ketamine to treat addictive disorders was Evgeny Krupitsky, MD, PhD. In 1985, he developed a technique using ketamine—ketamine psychedelic psychotherapy (KPT)—to treat patients with alcohol use disorders.2 Similar to Osmond, he first conceptualized an aversive counter-conditioning model utilizing preparation and suggestion in combination with the altered state of consciousness induced by ketamine to induce and amplify a negative psychological state paired with the continued negative consequences of alcoholism. It is worth considering a model of a pharmacologically initiated, precipitated or enhanced “hitting of rock bottom.” In the addiction field, we often hear the adage of needing to hit “rock bottom” before the initiation of sobriety. This event may be similar to near-death experiences, which have been described as triggering transformative and positive life changes,44 and may serve to initiate a rapid change to a sober state. In Alcoholics Anonymous (AA), it is taught that this is what is needed before the individual can really get sober. Although this may be true for some, “rock bottom” for other addicts may be death. Rather than disengaging from the patient and waiting for this to happen, one may wonder if it could be possible to chemically induce or enhance this phenomenon, thereby speeding up the process to recovery initiation.

From an adverse psychiatric perspective, ketamine can induce frank psychotic states (with both positive and negative symptoms), dissociation, and cognitive impairment (including impaired attention, memory, and performance).21 However, this does not capture the phenomenology of the profound psychological, mystical, and spiritually oriented altered state of consciousness induced by ketamine. It is useful to define what is meant by “spirituality,” a broad construct that encompasses both faith and meaning.45,46 Faith can be defined as the belief in and relationship with a transcendent higher power, which does not have to be identified as “God” and does not have to occur through participation in traditional organized religion, while meaning can include feeling that one has a unique purpose in life and can achieve a sense of fulfillment and “even transcendence through connectedness with something greater than one’s self.”47 The spiritual types of experiences induced by ketamine, separate from its dissociative properties (ie, out of body experiences) and perhaps overlapping with and traditionally understood as psychotic phenomenon, can include feelings of ego dissolution and loss of identity; experience of psychological death and re-birth; emotionally intense visions and dream-like states; enhanced insight/self-reflection and meaning in life; and feelings of unity with humanity, nature, the universe and God.2 These effects led Krupitsky to change his model from an aversive one to an existential, spiritual model within a positivist framework with the goal of inducing peak/transcendental states to effect conversion to a sober state in addicted patients. He extended his research to include patients with opiate addiction, and from 1985 until 2002 treated >1,000 patients with addictive disorders using KPT.2 KPT includes three stages, namely, preparation, administration, and integration. The preparatory phase includes 5–10 hours of suggestive psychotherapy where the patient is told the ketamine experience may induce important insights related to personal problems, value systems, and the meaning of their lives and that these insights may lead to changes associated with sobriety. During administration, the patients receive 2–2.5 mg/kg intramuscular (IM) of ketamine with onset of action in 10 minutes and the duration of the experience lasting approximately 1 hour. Patients are told they will enter an altered state and to surrender to the experience. They lie supine with eyeshades and headphones, hearing pre-selected music. In the integration phase, a combination of individual and group psychotherapy is administered over time to help subjects interpret and integrate the ketamine experience with the goal of leveraging the experience to effect behavioral changes associated with abstinence. The therapist assists in the integration of the spiritual transformation.2

In a controlled trial48 of patients with alcohol dependence, a one-time dose of ketamine as part of KPT (added to standard psychosocial care for patients with alcohol dependence in Krupitsky’s treatment center) added considerable benefit to the standard treatment. Total abstinence from alcohol for >1 year was reported in approximately 66% (73 out of 111) of alcoholic subjects in the KPT group compared to 24% (24 out of 100) in the conventional treatment control group (P<.01). In addition, based on psychological measures administered in the study, the group receiving KPT had positive changes in their emotions and perception of themselves and others, positive changes in life values and purposes, important insights into the meaning of life, and increased spiritual development compared to the placebo group. Krupitsky further tested the use of KPT in patients with heroin dependence in a double-blind placebo-controlled, randomized trial49 where 70 detoxified heroin-dependent subjects were randomly assigned to two groups—one with a one-time hallucinogenic dose of ketamine (2 mg/kg IM), versus one group with a control, non-hallucinogenic dose (0.2 mg/kg IM). All patients received the same standardized dose of psychotherapy during the preparatory and integration phases. The experimental group had significantly higher rates of abstinence at multiple prospective points in time out until 2 years follow-up, compared to the active placebo group (Table 1).49 As with the above alcohol studies, compared to the control group, the experimental group also displayed improvements in other dimensions of psychological well being including decreased levels of anxiety/depression, enhanced understanding of the meaning and purpose of life, and increased spiritual development. In this study,49 there were no significant adverse physiologic or psychological events and no subjects became addicted to ketamine.

 

 

In these studies, it is unclear as to the exact nature of the pharmacologic or psychosocial component of substance abuse treatment before receiving KPT and especially following the administration stage. For example, in the above study with heroin dependent subjects,49 the integration phase appears to only consist of 5 hours of psychotherapy “carried out within several days after the KPT session” to help “integrate the insights from the ketamine session into everyday life.”49 It is not clear as to exactly what this entails and how such a brief “existentially oriented psychotherapy” intervention could promote long-term abstinence up to 2 years follow up. The follow-up treatment is not described in any detail and it is unknown if these patients received standard evidence-based addiction pharmacologic treatments, such as naltrexone (opiate agonist or partial agonist treatment is banned in Russia), or psychosocial ones, such as motivational interviewing, relapse prevention, contingency management, community reinforcement, or coercion. Furthermore, this was described as a double-blind study. However, there is no description of the integrity of the blinding procedures in terms of any reporting of the percentage of accurate identification, by either subjects or experimenters, of whether the experimental or placebo dose of ketamine was administered. A complete hallucinogenic or psychedelic ketamine experience would seem easily discernible from one that is sub-hallucinogenic given the pronounced phenomenology of the experience. Without data on the blinding integrity, it is unknown how much of the treatment effect could be influenced by either subject or experimenter expectancy biases.

 

Potential Biologic Anti-addictive Mechanisms of Ketamine

Ketamine, Alcohol Dependence, and the NMDA Receptor
In addition to ketamine, there are other examples of NMDA antagonists that have been associated with anti-addictive effects in humans. One such example is memantine, although the studies have had small sample sizes and the efficacy data has been mixed. For example, in a study50 of frequent cocaine smokers, memantine failed to attenuate the subjective or reinforcing properties of cocaine use and was even associated with significant increases in the subjective effects of smoked cocaine. Regarding alcohol use in humans, memantine has been associated with a reduction in the level of alcohol craving preceding alcohol consumption in moderate drinkers but without diminishing the increase in craving following alcohol use.51

In a study52 of abstinent subjects with alcohol dependence, memantine diminished alcohol cue-induced craving in a dose-dependent manner. Finally, in a study53 of heroin dependent subjects, memantine was associated with modest reductions in the subjective but not reinforcing effects of heroin administration. It should be noted that memantine does not cause the pronounced altered states of consciousness seen with ketamine and so its anti-addictive properties can likely only be explained by its biologic mechanism. Other examples of anti-glutamatergic agents that have anti-addictive potential in humans include acamprosate (weak direct NMDA antagonism and direct interaction with the metabotropic glutamate receptor type 5, thereby indirectly acting as an inhibitory modulator at the NMDA receptor) for alcoholism,54 ibogaine (NMDA antagonism as one of its many receptor actions, although its exact anti-addictive mechanism remains unknown as 18-methoxycoronaridine, a congener of ibogaine, has anti-addictive properties without appreciably antagonizing the NMDA receptor) for opiate withdrawal,55 lamotrigine (a glutamate release inhibitor) for alcoholism,56 and topiramate (AMPA/kainite receptor inhibitor) for alcoholism.57

Regarding alcohol use disorders in particular, ketamine’s action as an NMDA antagonist might be helpful at various stages of the illness. For one, we know that neurotoxicity associated with alcohol withdrawal such as seizures and the delirium tremens, are likely mediated by hyperglutamatergic states from both upregulation at the NMDA receptor and increase glutamate release.58,59 Theoretically, it would make sense that administering an NMDA antagonist would suppress withdrawal by replacing the NMDA antagonist effect previously provided by alcohol, and acting like a replacement therapy. There is a growing literature to support the use of anti-glutamatergic agents to treat acute alcohol withdrawal.60 Protracted withdrawal is another stage of illness that might benefit from modulation at the NMDA receptor. Acamprosate is an example of a pharmacotherapy for alcoholism that weakly suppresses acute alcohol withdrawal in humans61 but seems more effective when given in the time period initially following the cessation of acute withdrawal.62

Another strategy in alcoholism pharmacotherapy is prevention of disease progression, such as preventing the expression of ethanol abuse or dependence in those at high risk (ie, strongly positive family history); preventing the transition from alcohol abuse (ie, heavy social drinkers) to alcohol dependence, or preventing relapse in newly abstinent patients. There is evidence to suggest that alcohol’s NMDA antagonist properties mediate negative physiologic, subjective, and cognitive effects associated with high-dose ethanol intoxication that would normally relay an inhibitory feedback signal to stop drinking.60 Furthermore, there is some evidence to suggest that healthy, at-risk individuals for alcoholism with positive family histories63 and alcoholics in early recovery64 demonstrate diminished sensitivity to biologic markers of heavy alcohol ingestion, which may constitute a deficit in the inhibitory feedback signal that would normally halt the progression to heavy drinking. Thus, an NMDA antagonist might theoretically be used to substitute, restore, or maintain the deficient inhibitory feedback signal.60 Ketamine administration to patients with alcohol dependence has been associated with pronounced cognitive impairment and sedation similar subjectively to heavy (ie, ≥8 standard drinks) alcohol ingestion and without causing craving for alcohol.65,66 Taken together, this suggests that the intoxicated state from ketamine’s NMDA antagonism might serve as an inhibitory feedback signal on drinking behavior in humans. This may serve as an aversive stimuli for preventing alcohol use disorders in vulnerable, at-risk populations; interrupting the transition from abuse to dependence; and preventing relapse in those in early recovery.

Ketamine, the NMDA Receptor, and Other Drugs of Abuse
Regarding the above data suggesting the efficacy of ketamine in an opiate-dependent patient population, it is worth considering ketamine’s action as a mu opiate agonist, even though its affinity for the receptor is only 20% compared to its affinity for the NMDA receptor.67 Furthermore, ketamine, like d-methadone (NMDA antagonist properties) can inhibit the development of opiate tolerance and dependence in animals.68 How this translates clinically in humans is unclear. It is possible that this effect might prevent the expression of opiate dependence in vulnerable individuals and those with opiate abuse. However, it is unclear how this might constitute an anti-addictive effect in actively using opiate-dependent patients or how a one-time dose of ketamine (as in the above-mentioned ketamine study in heroin addicts49 could lead to higher abstinence rates relative to placebo up to 2 years follow up.

To try and understand more broadly how ketamine might have anti-addictive properties, one possibility is to consider the level of the reward system activated. For example, NMDA antagonists are reinforcing when injected into the PFC and nucleus accumbens in lab animals but not the VTA where they block the rewarding effects of direct electrical stimulation.69 Thus, the relative degree and variability by which ketamine might be acting in the critical neuroanatomic reward substrates in a given individual might make the difference in determining its relative addictive liability. Another factor might relate to dose. It may be that there is an optimal dose range that confers anti-addictive properties and, above this, the addictive properties start to predominate. Those who become addicted to ketamine tend to continue to escalate their dose and in general use higher doses than those who use it intermittently (ie, occasional use for spiritual enhancement). It may be that higher doses of ketamine lead to a greater relative increase in glutamate transmission compared to lower doses and as stated previously enhanced cortical glutamatergic activation causes dopamine elevation in the VTA and nucleus accumbens, a property associated with addictive liability. One simplistic heuristic divide might be that antagonist effects at the NMDA receptor might confer the relative anti-addictive properties of ketamine and its hyperglutamatergic effects may confer its addictive liability. Thus, the relative balance or ratio of NMDA blockade to enhanced glutamate transmission (which may be a function of dose, route of administration, relative potency at the NMDA receptor, and pharmacokinetic/pharmacodynamic inter-individual variation) may explain why some NMDA antagonists are more reinforcing than others and why some may have greater anti-addictive properties.


Indirect Mechanism: Antidepressant Effects of Ketamine

Rather than a direct anti-addictive effect of ketamine on substance abuse behavior, it may be that ketamine indirectly diminishes addiction by its acute antidepressant properties. As described above, ketamine is emerging as a promising and novel treatment for depressive spectrum disorders.17-19 In the above study49 utilizing KPT in heroin-dependent patients, both high- and low-dose ketamine groups reported significant reductions in depressive symptomatology. There is some evidence to suggest that in patients with depression and co-occurring SUDs, improvements in depression with anti-depressant treatment can be associated with decreased substance abuse. For example, in a 12-week, placebo-controlled trial of imipramine treatment in a cohort of actively drinking patients with alcohol dependence and comorbid depression, McGrath and colleagues70 reported that although imipramine did not have a direct effect on drinking behavior, it was associated with a decrease in depressive symptoms, and the patients with improved mood demonstrated a more pronounced reduction in alcohol intake. In addition, it has been reported that elevated depressive symptoms in patients with heroin dependence may serve as a trigger for relapse in abstinent individuals.71 Further research would be necessary to discern if ketamine’s effects on addictive behavior is independent of its effects on depression.

 

Putative Psycho-Spiritual Anti-Addictive Mechanisms

Perhaps ketamine’s anti-addictive properties have little or nothing to do with its biologic properties and everything to do with its pronounced psychological and spiritual (psycho-spiritual) effects. Alternatively, it may be that its biologic reinforcing properties may be countered by anti-addictive psycho-spiritual effects.

In Krupitsky’s work he lists several psycho-spiritual effects, induced by ketamine’s altered state, that might underlie its anti-addictive properties including…

…important insights into existential problems and the meaning of life, transformation of one’s life value system, a change of view of one’s self and the world around, insight into life and death, enhancing personal growth and self-awareness, increase in creative activities, stabilizing positive psychological changes, broadening of spiritual horizons, and harmonization of a person’s relationship with the world and other people.2

Although this is highly speculative, several aspects here are worth exploring in some detail. For one, the added capacity for insight, self reflection, and learning as it relates to changing addictive behavior are important because these are factors we seek to change in addiction psychotherapy especially in addressing resistance and denial. Another potential factor relates to the phenomenon of ego dissolution or death and then re-birth. There are similarities to this substance-induced state and reports of “near death” experiences, which can be frightening but are usually marked by feelings of calm and peace; transcendent spiritual states are common in these experiences, with past memories often organized into a life review, including important figures from one’s past, and archetypal images of God often experienced as an “ocean of luminescent white light.”2 As mentioned above, these near-death experiences often trigger transformative and positive life changes.44 This death-re-birth experience in the context of enhanced spirituality has some parallels to the core treatment philosophy inherent in AA and other 12-step treatments whereby addicts undergo a spiritual conversion with a concomitant and rapid transformation in identity from an “addict” to one in “recovery.” In fact, Bill Wilson, one of the founders of AA, underwent several sessions of LSD psychotherapy in the 1950s and likened the experience to his spiritually redemptive experiences that led him to sobriety and to form AA.72 He felt so strongly about this, he attempted to introduce LSD use into the bylaws of AA, an attempt rejected by the board at the time. Predating this, both James and Jung recognized the importance of spiritual factors in treating addiction. James famously commented, “the best cure for dipsomania is religiomania” and Jung stated “Spiritus contra spiritum” (ie, spirituality combats alcoholism).72

The idea that spirituality can be a useful anti-addictive tool, as seen in AA, is worth considering in the two instances in the US where a particular religious group is legally allowed to use a schedule I serotonergic hallucinogen or sacrament—the use of peyote in the Native American Church (NAC) and the use of ayahuasca (dimethyltryptamine as the psychoactive compound) in the Brazilian syncretic religion, the Uniao do Vegetal (UDV). These religious groups have similarities to AA (although in AA the spiritual state is not drug induced), where spirituality is combined with social factors such as group cohesion and coercion to effect sobriety.73 There are anecdotal reports of low rates of addiction in the NAC and UDV, where substances (ie, alcohol, nicotine, illicit drugs), other than their respective sacramental hallucinogens, are prohibited.74 Formal epidemiologic study of the prevalence of substance use disorders in these two groups would be an important starting point. If the NAC and UDV were found to have significantly lower rates of addiction compared to the general population or some appropriate comparison group (ie, the NAC versus other Native American groups), one could then speculate on possible etiologies such as biologic effects of the prescribed sacramental hallucinogens; psychosocial factors, such as group cohort effects (ie, proscribed alcohol/drug abuse, cohesion, shared sober identity formation/maintenance, enhanced spiritual or religious affiliation); or some combination of factors.
It would be naïve to think that a one-time experience with ketamine, however profound, could effect long-term sobriety, especially without linkage to after-care and psychosocial treatment. For some addicts, a spiritual conversion experience can last a lifetime. However, for the vast majority, they need multiple repeated attempts included with 12-step treatment. Thus, it may be that repeated dosing is necessary, similar to an electroconvulsive therapy type model. Biologically, it would seem that if ketamine can truly have anti-addictive properties by optimally modulating or re-altering glutamatergic imbalance in the addicted state, it would need to be dosed repeatedly. It may be that in the use of ketamine to treat addictive disorders, multiple sessions are needed, especially for treatment refractory patients. There is some evidence to support this. In a randomized trial of 59 detoxified heroin dependent subjects, subjects who received three sessions of ketamine administration as part of KPT, at monthly intervals had higher abstinence rates at 1-year follow up compared to those who only had one initial ketamine experience, this amounting to 50% versus 22% (P<.05).75 It has been reported that after the use of certain hallucinogens (both serotonergic and NMDA antagonist types), there is a “psychedelic afterglow” inducing positive psychological changes that can last for days to weeks.76 It may be necessary to repeat the experience in a controlled carefully prepared environment to consolidate the new changes/learning. Furthermore, the dose of the experience needs to be sufficiently intense or of a “peak” quality to have a higher likelihood of effecting change. Prior and current research with serotonergic hallucinogens has shown a clear relationship between attaining “peak” or “transcendental mystical” states and resulting in positive and lasting changes.77,78

 

Conclusion

In the US, ketamine administration in humans has almost exclusively been used in psychiatric research as a psychopharmacologic probe to understand the neurobiology of psychiatric disorders, in particular the glutamate hypothesis of schizophrenia, and the effects of drugs of abuse, in particular alcohol. A unique aspect of ketamine, unlike all of the serotonergic hallucinogens, is that it is a schedule III drug, currently available for off-label purposes other than for anesthesia (Table 2). As such, it is currently available in the US for legal use in the treatment of addiction, pain syndromes, and MDD where its ability to induce immediate antidepressant effects seems most promising and may constitute a truly novel psychopharmacologic property.79 However, the data to support the use of ketamine to treat addictive disorders does not currently rise to the level of unequivocally justifying its use as off-label treatment in clinical settings. More research would be needed, ultimately with phase III trials, demonstrating a clear and sufficient treatment effect. Its use would be similar to the current use of g-hydroxybutyrate, another schedule III “club drug” with addictive liability but one with therapeutic utility—treatment of cataplexy associated with narcolepsy and other sleep disorders in this case.1 If the application of ketamine, in conjunction with addiction psychotherapy, turns out to be an effective and reliable treatment for SUDs, it would constitute a novel psychopharmacologic/psychosocial paradigm of care for addicted individuals, although one where the risks of addiction to the substance itself would have to be carefully considered. PP

 

 

 

 

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53. Comer SD, Sullivan MA. Memantine produces modest reductions in heroin-induced subjective responses in human research volunteers. Psychopharmacology (Berl). 2007;193(2):235-245.
54. Littleton JM. Acamprosate in alcohol dependence: implications of a unique mechanism of action. J Addict Med. 2007;1(3):115-125.
55. Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute opioid withdrawal with ibogaine. Am J Addict. 1999;8(3):234-242.
56. Krupitsky EM, Rudenko AA, Burakov AM. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res. 2007;31(4):604-611.
57. Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA. 2007;10;298(14):1641-1651.
58. Hoffman PL, Rabe CS, Grant KA, Valverius P, Hudspith M, Tabakoff B. Ethanol and the NMDA receptor. Alcohol. 1990;7(3):229-231.
59. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry. 1998;155(6):726-732.
60.    Krystal JH, Petrakis IL, Krupitsky E, Schutz C, Trevisan L, D’Souza DC. NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann NY Acad Sci. 2003;1003:176-184.
61. Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol. 2001;36(5):413-418.
62. Hopkins JS, Garbutt JC, Poole CL, West SL, Carey TS. Naltrexone and acamprosate: meta-analysis of two medical treatments for alcoholism. Alcohol Clin Exp Res. 2002;26(suppl):130.
63.    Petrakis IL, Limoncelli D, Gueorguieva R, et al. Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry. 2004;161(10):1776-1782.
64.    Krystal JH, Petrakis IL, Limoncelli D, et al. Altered NMDA glutamate receptor antagonist response in recovering ethanol dependent patients. Neuropsychopharmacology. 2003;28(11):2020-2028.
65. Krystal JH, Petrakis IL, Webb E, et al. Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry. 1998;55(4):354-360.
66. Krupitsky EM, Burakov AM, Romanova TN. Attenuation of ketamine effects by nimodipine in recently detoxified ethanol dependent men: psychopharmacologic implications of the interaction of the NMDA and L-type calcium channel antagonists. Neuropsychopharmacology. 2001;25(6):936-947.
67. Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG. Sterioselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology. 1999;90(1):174-182.
68. Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223(1):5-8.
69. Wise RA. Brain reward circuitry: insights from unsensed incentives. In: Graham AW, Schultz TK, Mayo-Smith MF, eds. Principles of Addiction Medicine. 3rd ed. Chevy Chase, MD: American Society of Addiction Medicine, Inc.; 2003:57-71.
70. McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry. 1996;53(3):232-240.
71.    Nunes EV, Quitkin FM, Donovan SJ, et al. Imipramine treatment of opiate-dependent patients with depressive disorders. Arch of Gen Psychiatry. 1998;55(2):153-160.
72. Grof S. Spirituality, addiction, and western science. ReVision. 1987;10(2):5-21.
73. Galanter M. Spirituality and the Healthy Mind: Science, Therapy, and the Need for Personal Meaning. New York, NY: Oxford University Press; 2005.
74. de Rios MD, Grob CS, Baker JR. Hallucinogens and redemption. J Psychoactive Drugs. 2002;34(3):239-248.
75. Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN, Slavina TY, Grinenko AY. Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence. J Psychoactive Drugs. 2007;39(1):13-19.
76. Grinspoon L, Bakalar JB. Psychedelic Drugs Reconsidered. New York, NY: Basic Books Inc.; 1979.
77. Pahnke WN. The psychedelic mystical experience in the human encounter with death. Harv Theol Rev. 1969;62(1):1-21.
78. Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008. Epub ahead of print.
79. Rot M, Charney DS, Mathew SJ. Intravenous ketamine for treatment-resistant major depressive disorder. Primary Psychiatry. 2008;15(4):39-47.

 

Dr. Galanter is professor of psychiatry and director, Dr. Glickman is assistant clinical professor, Dr. Dermatis is research associate professor, Dr. Tracy is assistant professor, and Ms. McMahon is research assistant, all at the Division of Alcoholism and Drug Abuse of New York University School of Medicine and Bellevue Hospital Center in New York City. Drs. Galanter, Dermatis, and Glickman are also research scientists at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York.

Disclosures: Drs. Galanter and Dermatis receive research support from the John Templeton Foundation. Dr. Glickman and Ms. McMahon report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Tracy receives grant support from the National Institute on Alcohol Abuse and Alcoholism.

Acknowledgments: The authors thank Hannah Barbash, BA, New York University Divisional research assistant, for assistance in the preparation of this article. The authors also thank Lynda Curtis, Drs. Eric Manheimer and Marc Gourevitch, and Irene Torres.

Please direct all correspondence to: Marc Galanter, MD, Professor of Psychiatry, NYU School of Medicine, 550 First Ave, Room NBV20N28, New York, NY 10016; Tel: 212-263-6960, Fax: 212-263-8285;
E-mail: marcgalanter@nyu.edu.

 


 

 

Focus Points

• Many patients have strong spiritually grounded feelings related to their ability to cope with illness.
• Addressing patients’ spiritual needs in the general medical setting can improve their satisfaction with caregivers and their adherence to treatment plans.
• There are emerging approaches to address this issue in the clinical setting.

Abstract

Medical care has long been associated with religion and spirituality, but in recent years a trend has arisen to introduce diverse spiritually oriented approaches in the context of empirically grounded practice. This article reviews the application of these approaches in contemporary medical practice. It highlights the relative utility of such applications, the use of spiritual assessment of the patient, and the role of the clergy and nursing in introducing spirituality into the clinical setting. It then presents findings from a program developed by the authors to employ spiritual support groups in the general hospital in order to aid patients in coping with illness, and to develop among them a more positive identification with their treatment providers.

Introduction

In the Western tradition, medicine and religion have always been linked—sometimes closely and sometimes farther apart—and religious influences on medical practice and on the profession’s ethics are longstanding.1-3 The growth of interest in the interaction of medical practitioners with religion and spirituality over recent years has paralleled similar developments in the larger society, as many healthcare providers with a strong spiritual orientation have sought to bring this spiritual aspect of their personal lives more into their clinical work. A major aspect of this movement has involved legitimating the positive relationship between religious involvement, spirituality, and health in many publications in the professional literature.4 Of comparable importance has been the growing recognition that spirituality and religion permeate the lives of patients as well as many medical encounters. A question to be considered has become not only how to deal with the religious and spiritual aspects of health care, but how they can be introduced into the treatment context. This article focuses on recent attempts to establish the utility of such interventions, and provides by way of illustration such a program that the authors have developed and implemented in the general hospital setting.

The distinction between religion and spirituality is important to this work, though it is not without controversy. Spiritual or religious choices often reflect a very personal and private aspect of a person’s life, which makes any definition subject to intense scrutiny. It is counterproductive to the purposes of research to settle on a definition of spirituality that is either too broad and vague or too individualized.5 There is, however, general agreement on a fundamental level that both religion and spirituality are related to a search for the sacred or transcendental.6,7 This commonality has led to divergent notions of how spirituality and religion are related. According to the theoretical framework posited by Pargament,8 spirituality and religion are inextricably intertwined. Spirituality is viewed as a core component of the more “broadband concept” of religion.8 However, an increasingly widely held view is more in line with Koenig and colleagues’4 contrasting definitions. He casts religion as “an organized system of beliefs, practices, rituals, and symbols” in relation to the sacred, as opposed to the “personal quest for understanding” of spirituality.5 These conceptualizations of religion and spirituality allow for the option of being religious but not spiritual, spiritual but not religious, both, or neither. In this article, spirituality is defined as that which gives people meaning and purpose in life.9 It can be achieved through participation in a religion but can be much broader than that, such as involvement in family, humanism, or the arts.10 In much of the literature and in American culture, spirituality has come to be seen as a human dimension particularly useful in bridging sectarian divisions common to religion.

 

The Spiritual Assessment

A key technique for addressing spirituality in clinical practice is the spiritual assessment.9 Spiritual assessments focus on learning whether the patient is part of a supportive faith community, ascertaining unmet spiritual needs that should be addressed in the course of treatment, identifying religious beliefs that might influence medical treatment decisions, and identifying potentially harmful spiritual practices such as spiritual struggles that patients associate with their illness. Spiritual struggles are defined as “efforts to conserve or transform a spirituality that has been threatened or harmed” and are expressed in terms of conflict and questioning of one’s spiritual/religious convictions.11 With a patient who professes neither to be religious nor spiritual, the physician can still inquire into what they are doing to cope with their illness. Puchalski9 has developed an approach adapted to general clinical settings she terms FICA, involving inquiry into “F”aith and healing, “I”mportance of faith in the patient’s life, “C”ommunities of faith and healing they may be part of, and “A”ddressing unmet needs.

Practitioners developing long-term relationships with dying patients have developed questions probing deeper into their sense of how their illnesses relate to “what it all means” to aid patients in identifying spiritual interventions that might benefit them.10 Spiritual interventions refer to therapeutic strategies that are designed with a spiritual or religious dimension as their central component12 and include but are not limited to spiritual assessments.

Kristeller and colleagues13 designed an intervention to improve patients’ well being and adjustment to cancer and showed that a 5–7-minute patient-centered intervention by an oncologist made a small contribution in patient well being. Patients included in the intervention were recruited at random from the waiting rooms of oncologists’ offices, as were controls who received usual care. The short intervention introduced the topic of spiritual or religious beliefs and encouraged patients to identify ways they used spiritual or religious resources. Questioned after 3 weeks, 33% said they thought the intervention would influence how they coped with cancer, while >40% thought it made them more satisfied with their overall care. Improvement after 3 weeks in quality-of-life measures among patients in the study group compared to those in the control group reached levels associated with clinically meaningful impacts in drug or other behavioral trials. Improvements were most pronounced among those scoring low on a spiritual well-being scale at baseline. Spiritual well being was assessed by the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being Scale. This scale consists of two subscales, namely, meaning/peace and faith.14 The spiritual well-being composite score combining both subscale scores was moderately correlated with measures of emotional and functional well being (r=.58 for each) suggesting that it was an empirically distinct dimension. This study provides support for the benefit of a short, nondenominational empathic intervention in physicians’ offices, even absent a physician’s incorporating the acquired information into treatment. Attention, however, should be paid to whether any aspect of the intervention produces distress in the patient and/or clinician. How often spiritual interventions are conducted, and to what effect, remains unknown.

 

The Clergy

Approximately 85% of all United States hospitals employ chaplains, while an estimated 20% of all hospitalized patients receive a chaplain’s visit.15 The growing professionalization of chaplains within a medical model, however, has contributed to their acceptance as members of a supportive care and palliative medicine team in the intensive care unit of a large trauma hospital, a team including physicians, advanced practice nurses specializing in pain, intensive care unit and palliative care, social workers, pharmacists, and music therapists. Chaplains provide spiritual support to patients who are dealing with issues related to finding meaning in life and coping with suffering, and help patients utilize their beliefs in coping with illness.9

Major barriers identified by chaplains included inadequate staffing, inability of healthcare providers to identify patients’ spiritual needs, and being called in too late to provide proper care to families.16 Physicians are often advised to refer serious spiritually-related problems to clergy or a chaplain affiliated with their hospital; some advocates of greater inclusion of spiritual matters within medicine consider the lack of such appropriate referrals to be a form of negligence.17 Shadowing a chaplain can be a key component of the spiritual education program for many palliative care fellows.

More recently, at Memorial Sloan-Kettering Cancer Center in New York City, approximately 20% of all chaplain interventions came as a result of a referral, mostly from nurses; 33% of the interventions involved working with family and friends.18 A similar survey at a suburban community hospital found that nurses made >50% of referrals to chaplains; 75% of all referrals were to see patients and the remainder were to see friends and family.19 Although referrals by nurses to chaplains most often come in times of crisis, some nursing leaders see a need to develop more ongoing collaboration to address a wider range of situations.20,21 Patients are frequent sources of requests for pastoral care—more frequent than nursing referrals in a study of adolescent inpatients in a pediatric tertiary care hospital.20

 

Nursing

Studies of self-reported spiritual nursing interventions and ideal, complex spiritual nursing competencies shed some light on the vast range of activities nurses see as falling under this rubric to address the spiritual needs of their patients.22,23 Such research stems from the desire to capture the considerable spiritual care delivered by nurses that goes undocumented. Prayer and active listening are the most commonly reported nursing interventions.24 Other commonly reported interventions include conveying acceptance, being present with a patient, therapeutic touch, and instilling hope. Presence as an intervention refers to both being physically present without expecting interactional responses and a psychological component wherein the nurse is attentive and demonstrates an understanding of the patient’s experiences.24

Narayanasamy and Owens25 identified different patterns of nurses’ responses to critical incidents they regard as involving spirituality. In the personal approach, nurses, using counseling, become involved in a mutual sharing of spiritual concerns, usually framed in nonreligious terms. In the procedural approach, the nurse sticks to standard routines, often referring to the expert, the chaplain, or colluding with the patient’s relatives, often without the patient’s involvement. In the evangelical approach, nurses, often sharing the same religious background with patients, attempt to rekindle the patient’s faith. Ethical concerns that arise relate to the potential for nursing staff to impose their specific spiritual/religious beliefs on the patient and/or family and to blur the boundary between nurse professional and clergy.9

 

Incorporating Spirituality in Psychosocial Treatment

One approach to incorporating spirituality in treatment involves integrating a spirituality dimension into an established treatment modality such as psychotherapy. Various attempts have been made to develop psychotherapeutic approaches to accommodate Christian values, including prayer and religious materials. Results of an early study26 showed that although cognitive-behavioral therapy (CBT) and a modified CBT with religious content resulted in improvement among depressed patients, improvement was greatest among depressed patients in the religiously modified program. A small meta-analysis, however, found that religion-accommodative approaches to counseling depressed patients had essentially the same overall efficacy as non-religious approaches.27

Another approach involves integrating spirituality in an existing psychosocial rehabilitation program. A small study among patients with serious psychiatric disabilities in an inner-city community program found that all participants receiving a spiritually oriented support group intervention to improve program functioning met their treatment goals related to symptom management, community integration, and improvement in overall quality of life as opposed to only 50% in the standard rehabilitation program.28 A study by Worthington and Sandage29 included patients with depression who were assigned either to a Beck-oriented CBT program or a Christian accommodative one. Both approaches were found to be equally effective in reducing depression, while the religiously oriented program was associated with greater improvement in spiritual well being.

A recent review12 of the worldwide literature on spiritually modified cognitive therapy in the Islamic, Taoist, and Christian traditions classified these treatments as experimental for anxiety disorder, neurosis, obsessive-compulsive disorder, and other conditions except for depression, which was considered to meet American Psychological Association criteria for a well-established intervention.

 

Models for Intervention

Pargament and colleagues30 and McConnell and colleagues31 have conducted a substantial body of research supporting the view that some forms of spiritual struggles are linked to psychopathology, and that a spiritually integrated psychotherapy can effectively address this problem and others. They have developed interventions based on these ideas, including a short intervention with an individual therapist for female survivors of sexual abuse with spiritual struggles designed to improve spiritual well being.32 A group intervention for people with serious mental illness following Pargament’s theory of positive and negative implications of religious coping33 incorporated issues such as spiritual striving, spiritual struggles, and hope.

Cole and Pargament34 also developed a group psychotherapy program for cancer patients, “Re-Creating Your Life: During and After Cancer,” combining concern with core existential issues and positive religious coping. Numerous models of group psychotherapy have been developed for work with cancer patients.35,36 Although most such groups focus on providing education, a forum for emotional expression, and strengthening coping skills as elements of overall support, spiritual and religious issues are often raised as well directed at reducing spiritual suffering and distress at end of life.

The field of palliative medicine, with its focus on end-of-life care, has been a source of considerable innovation in connecting spiritual issues to its form of medical practice. One such program developed by Breitbart35 at Memorial Sloan-Kettering Cancer Center employs a meaning-centered approach, drawing on the logotherapy developed by Frankl, to develop an eight-session program that explicitly addresses issues of meaning, peace, and ultimate purpose.35,37 Participants, all with advanced cancer and a limited prognosis, are given assigned readings and homework related to group session topics such as “Meaning and Historical Context of Life,” “Cancer and Meaning,” and “Limitations and Finiteness of Life.” The goal here is to help strengthen patients’ sense of being at peace with themselves in the face of the spiritual suffering and hopelessness they often experience.

A more extensive three-level program to enhance patients’ level of spirituality, mood, and self-efficacy for patients with a range of cancer diagnoses and severity was implemented in a metropolitan cancer hospital in Toronto, Canada.38 Level 1 consists of four group sessions dealing with cancer stress; level 2 is comprised of eight group sessions on skills for coping by drawing on the “Inner Healer” through meditation and other modalities. Meditative techniques are not the core of the intervention. Rather, meditative chanting is done for the first few minutes of all the sessions before the main topics are covered. The third level consists of eight sessions on spiritual healing, with a follow-up program of twice-monthly groups available to all who complete the program. This multi-staged model allows patients to decide for themselves which level of spiritual involvement is comfortable for them. In an exploratory study to assess the efficacy of this program, a battery of psychometric tests was administered at entry, 8 weeks, and 6 months, and written homework assignments were completed by study participants. Ninety-seven patients completing the third level showed significant improvement in mood, self-efficacy, and spirituality over the 8-week intervention period. After 6 months, only improvement in spirituality remained significant. Based on the written assignments which showed patients struggling with their spiritual issues, the investigator suggested that this model can provide advanced spiritual training to highly motivated individuals within a resource-constrained environment.

Randomized controlled trials can help assess the relative value of spiritually oriented interventions compared to standard interventions and can also help identify subgroups for which they may be most helpful. A recent clinical trial39 conducted at the Mayo Clinic points in a direction this area is likely to go, namely, integrating spiritual concerns into multidimensional and multidisciplinary interventions with the goal being to improve the overall quality of life of cancer patients. In this trial, advanced cancer patients set to undergo radiation therapy participated in a manualized 3-week program consisting of eight sessions each with a cognitive, emotional, physical, social, and spiritual interventional component. Sessions were lead by a psychiatrist or psychologist, with a chaplain, social worker, and advanced practice nurse as co-facilitator, depending on the session’s content. Quality of life at 4 weeks and 6 months following the intervention was compared with patients receiving standard care supervised by their radiation oncologist. Compared to the controls, the intervention group experienced a significantly better quality of life at 4 weeks; however, at 6 months this difference largely disappeared. The major benefit of the intervention appeared to be averting the sharp decline in quality of life during and shortly after the radiation treatment.

Stefanik and colleagues40 caution against concluding that religion and spirituality affect treatment outcomes in cancer due to methodologic weaknesses in much of the research, including the preponderance of cross-sectional studies, use of small samples sizes and samples of convenience, lack of correction for multiple statistical comparisons, failure to control for confounding variables, and questionable reliability and validity of study instruments.

 

HIV/AIDS

Efforts to include spiritual and religious concerns in the treatment of HIV/AIDS take many forms, but most of them have not been evaluated. Community health workers in one innovative outpatient HIV Palliative Care Program in the Bronx, New York, provided material resources and a dialogic partner in the search for meaning for patients undergoing the process of dying and bereavement and their families.41 In another study, Pargament and colleagues42 developed an eight-session nondenominational group program tailored for urban black women with HIV/AIDS. The program uses exercises such as writing a letter to God about guilt and shame, and identifying dreams still possible despite their illness, to encourage participants to acquire spiritual resources that may contribute to their health and well being while living with illness.

Another intervention designed to improve quality of life is exemplified in a randomized controlled pilot study43 of patients at an AIDS-dedicated skilled nursing facility. The independent and additive effects of meditation and massage on spirituality and quality of life were examined. Patients in a program that combined both modalities showed substantially greater improvement on measures of overall and spiritual quality of life than patients receiving either a meditation or a massage intervention alone or patients receiving standard care. Interventions designed to reduce HIV/AIDS risk combining spirituality and cognitively-based approaches include a nontheistic Buddhist-based program targeting risk behaviors among inner city methadone patients and a spiritual coping group for patients with HIV.44-46

A recent study47 which has implications for the value of spirituality based interventions among people receiving a potentially life-altering diagnosis examined whether changes in spirituality occur after receiving an HIV diagnosis and whether changes are related to disease progression as reflected in CD4 cell counts and viral load. People who had an increase in spirituality/religiousness showed less disease progression on both measures even after controlling for church attendance and initial disease status. These findings support continued efforts to develop spirituality based interventions for people diagnosed with HIV.

Numerous concerns have been reported regarding implementing spiritual interventions in medical and psychiatric treatment settings. Healthcare professionals may feel they lack sufficient expertise to discuss spirituality, are uncertain as to what their role is in relation to that of the chaplain, or construe such inquiries as intruding into the patient’s private life.17 When patient spirituality is addressed within the physician-patient relationship there is the possibility that certain beliefs held by the patient may undermine the physician’s treatment plan resulting in treatment refusal or futile requests for treatment.17 Another issue relates to whether the spirituality intervention is designed to meet the needs of the patients. Healthcare professionals and patients may not agree on what dimensions of spirituality are needed in the care of patients. In a review of nursing research papers published on spiritual care, Ross21 reported that there appears to be a discrepancy between provider and patient understanding of spirituality and the nature of spiritual care desired by patients.

 

A Program for Spiritually Oriented Support Groups

Despite impressive advances in the technology of acute care in general hospitals, the limited adherence by many patients to medical treatment plans regularly compromises their clinical outcome. This results in recidivism, increased morbidity, and undue cost to the healthcare system. In relation to primary care, for example, the World Health Organization has estimated that no more than 50% of patients with hypertension adhere to their prescribed medication regimens.48 Much of this is due to a limited sense of mutuality and trust felt by patients toward their caregivers as well as the impersonal quality perceived in their medical encounters.49

This need has been operationalized by the Joint Commission of Accreditation of Health Care Organizations, the principal certifying body for American hospitals. Its requirements stipulate that, “spiritual and cultural values [should] be gathered during the initial assessment of patients,” and that “Each patient has the right to have his or her . . . spiritual and personal values and beliefs, and preferences respected.”50 Importantly, however, there is little if any programmatic experience published on how spiritually grounded values and beliefs can be effectively addressed in hospital settings.

In order to address this need, the authors of this article conducted focus groups with patients at Bellevue Hospital Center, New York University’s principal teaching hospital, and found that one issue that contributes to this problem is that many patients feel that their core personal and spiritual beliefs are neither recognized nor addressed by hospital personnel. In previous research, staff and patients rated the importance of spiritually related resources relative to medical and material ones in addiction recovery.51,52 Staff rated the spiritual resources lowest, while patients rated them highest. Furthermore, when staff gave ratings to how they thought the patients would respond, they erroneously scored spiritual resources lowest, not recognizing the importance of spirituality to patients’ understanding of how they achieve recovery from their illness.53 Staff underestimated the importance patients placed on spirituality focused groups in the recovery process.51,52 Given this experience, the authors developed a pilot clinical program to determine if patients would discuss how they can draw on their spiritual resources and strengths to enhance their recovery and rehabilitation with support of hospital staff. The authors drew on experience54-56 in related clinical and research projects on the feasibility of such discussion groups in diverse clinical settings, and established groups for patients in a primary care clinic setting and on units dedicated to the treatment of comorbid general psychiatric disorders and substance abuse.

All groups were facilitated by volunteer medical or allied professional staff who have given their time because of their appreciation of the value of this effort, with the goal being to elicit feedback from all participants concerning how their spiritual attitudes, beliefs, and behaviors can help to promote health and cope with illness. The tone of the groups has reflected a mutual respect for each other’s religious (or non-religious) orientations. It would emerge that an underlying spiritual orientation was the primary focus of exchanges. The format of the group meetings is outlined in Table 1.

 

 

The groups were established in a primary care clinic setting in which 221 patients participated in one or more group meetings. The authors chose the primary care clinic to ascertain the applicability of this approach in a general medical population. They were also established in three inpatient (131 participants) and two outpatient (48 participants) psychiatry units. There were six different facilitators, each dedicated to his or her respective unit. The psychiatric patients were chosen to compare singly diagnosed psychiatric patients to those with comorbid substance use disorder; a report on the psychiatric patients will appear elsewhere. In the primary care clinic reception area, posters were prominently displayed and flyers were distributed to patients containing information concerning the group meetings and inviting all patients to attend. On the psychiatry units all patients were invited to attend the discussion groups by staff. This would usually occur at the beginning of the weekly community meeting. Participation in the spirituality discussion groups was completely voluntary and did not in any way affect the medical or psychiatric services received by patients. For purposes of the present report, only participant data collected in the medical outpatient setting will be presented.

In the medical outpatient setting a survey assessing spiritual orientation to life using the Spirituality Self-Rating Scale (SSRS)53 was administered to 52 consecutive patients at their first group session. These patients had as high a mean SSRS score, as did the addiction inpatients, but significantly higher than medical students. In a subsequent survey again administered to consecutive attendees at their first group session, 113 participants were asked items assessing their spiritual and religious views and practices concerning worship service participation. These items had been used in previous national probability surveys.57 The sample was predominantly female (64%) with a mean age of 53 (SD 14). Ethnicity included 27% African-American, 25% Hispanic, 25% White, and 23% other designation which was mainly multiracial. Patients varied with regard to religious preference with 31% Catholic, 15% Protestant, 10% Muslim, 6% Jewish, 28% other religious preference such as “higher power,” and 10% no preference. The results indicated that a greater percentage of the medical outpatients described themselves as being both religious and spiritual and report a higher frequency of spiritual-related practices involving worship service attendance compared to national samples (Table 2).57 These findings suggest that primary care patients perceive spirituality to be important to them and are as active, if not more so, than the general population.

 

 

Feedback from patients attending the group indicate that they value the opportunity to discuss their spiritual experiences with professional healthcare staff in the primary care setting, they feel more positively connected to treatment, and they endorse treatment’s integration in the formal healthcare system. In order to document themes that were discussed during the group sessions, a project assistant had recorded the comments made by the medical outpatients. Patient responses over the course of the sessions have been categorized, and numerous themes emerge prominently.

 

The Meaning of Spirituality

When participants were asked whether they considered themselves to be spiritual, the most common response was belief in a higher power which embodied a connection to God or a higher power. The diversity of the participants’ backgrounds was reflected in the different forms of this higher power, eg, Christian participants spoke of praying to Jesus and God; others, for example, self-identified as Buddhists, believed that this higher power was present in everyday objects.

 

Comparing Spirituality and Religion

Some participants discussed certain aspects of their spirituality in terms of their specific religious practices (eg, prayer, reading of scriptures, rituals) but also articulated distinctions between religion and spirituality.

 

Resources They Draw On

Participants described numerous aspects of their spirituality that reinforced their belief in a higher power, including prayer, recitation of religious or personal mantras, direct communication with the external force (eg, singing), scripture reading, and meditation. These served to calm them, combat depression or discontent, and alleviate physical pain or emotional suffering.

 

Some Personal Experiences

Some participants described their spirituality in terms of internal processes that served to instill hope, empowerment, and general well being. They referred to transformative experiences including revelations, miracles, or rebirth.

 

Quest for Spiritual Fulfillment

Some participants described themselves as emotionally drained and in search of a spiritual connection. Many of these individuals recalled being more spiritual when they were younger, but due to their illness and the physical changes accompanying aging, they became more cynical and spiritually detached.

 

Alienation from the Bellevue Physicians

Some patients were disenchanted with the medical staff. As one said, “All they do is give you pills, and when they do not work they just give you more pills.” Some spoke of “student doctors,” who “do not have time to listen to my story.”

 

Relationship to Treatment and Recovery

Participants discussed various aspects of their spirituality relating to connections with others based on trust, as with a family physician, or a group such as a 12-step fellowship. Many shared their spiritual experiences as a means of helping others to cope with their illness and better adhere to treatment. To a lesser extent, patients expressed the view that their spiritual beliefs could provide a means to a cure for their physical ailments not available through modern medicine, although they rarely endorsed refusal of all medical recommendations.

 

Conclusion

This article highlights progress that has been made in translating a growing interest in the medical field in spirituality and religion into interventions that may be effective and possibly become part of standard medical care. One notable aspect of this development is how spiritually and religiously based interventions have been adapted to diverse forms of clinical practice. Uncontrolled clinical trials have provided most of the information required to describe the complex dynamics involved in the relationship between spiritual interventions and medical care. One approach, developed at New York University and Bellevue Hospital in New York City, illustrates some of the particulars of helping patients to draw on their spiritual resources in order to cope with illness.

Spiritually oriented programs may pose ethical issues like those that have been raised regarding interventions that are specifically religiously oriented. By broadening the scope of discussion to include the many interests subsumed under the rubric of spirituality, however, concerns over sectarianism and religiously grounded bias are mitigated. Given this, diversity of commitment and affiliation among participants in spiritually oriented groups should be accepted and respected. With this proviso in mind, such interventions may be effective in improving patients’ outlook on their medical care as well as their ability to identify with the mission of hospital staff, thereby promoting greater compliance with the treatment regimens proposed. PP

 

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3.    Lazaro J. Doctors’ status: changes in the past millennium. Lancet. 1999;354(suppl):SIV17.
4.    Koenig HG, McCullough ME, Larson DB. Handbook of Religion and Health. New York, NY: Oxford University Press; 2000.
5.    Moreira-Almeida A, Koenig HG. Retaining the meaning of the words religiousness and spirituality: a commentary on the WHOQOL SRPB group’s “A cross-cultural study of spirituality, religion, and personal beliefs as components of quality of life” (62: 6, 2005, 1486-1497). Soc Sci Med. 2006;63(4):843-845.
6.    Hill PC, Pargament KI. Advances in the conceptualization and measurement of religion and spirituality. Am Psychol. 2003;58(1):64-74.
7.    Galanter M. Spirituality and the Healthy Mind: Science, Therapy, and the Need for Personal Meaning. New York, NY: Oxford University Press; 2005.
8.     Pargament KI. The psychology of religion and spirituality? Yes and no. Int J Psychol Relig. 1999;9(1):3-16.
9.     Puchalski CM. Spirituality and health: the art of compassionate medicine. Hosp Physician. 2001;37(3):30-36.
10. Lo B, Ruston D, Kates LW, et al. Discussing religious and spiritual issues at the end of life: a practical guide for physicians. JAMA. 2002;287(6):749-754.
11.    Pargament KI, Murray-Swank NA, Magyar GM, Ano G. Spiritual struggles: a phenomenon of interest to psychology and religion. In: Miller WR, Delaney HD, eds. Judeo-Christian Perspectives on Psychology: Human Nature, Motivation, and Change. 1st ed. Washington, DC: American Psychological Association; 2005:245-268.
12.    Hodge DR. Spiritually modified cognitive therapy: a review of the literature. Soc Work. 2006;51(2):157-166.
13. Kristeller JL, Rhodes M, Cripe LD, Sheets V. Oncologist assisted spiritual intervention study (OASIS): patient acceptability and initial evidence of effects. Int J Psychiatry Med. 2005;35(4):329-347.
14. Peterman AH, Fitchett G, Brady MJ, Hernandez L, Cella D. Measuring spiritual well-being in people with cancer: the functional assessment of chronic illness therapy–Spiritual Well-being Scale (FACIT-Sp). Ann Behav Med. 2002;24(1):49-58.
15.    Flannelly KJ, Galek K, Handzo GF. To what extent are the spiritual needs of hospital patients being met? Int J Psychiatr Med. 2005;35(3):319-323.
16. Feudtner C, Haney J, Dimmers MA. Spiritual care needs of hospitalized children and their families: a national survey of pastoral care providers’ perceptions. Pediatrics. 2003;111(1):e67-e72.
17.    Post SG, Puchalski CM, Larson DB. Physicians and patient spirituality: professional boundaries, competency, and ethics. Ann Intern Med. 2000;132(7):578-583.
18.    Flannelly KJ, Weaver AJ, Handzo GF. A three-year study of chaplains’ professional activities at Memorial Sloan-Kettering Cancer Center in New York City. Psychooncology. 2003;12(8):760-768.
19.    Fogg SL, Weaver AJ, Flannelly KJ, Handzo GF. An analysis of referrals to chaplains in a community hospital in New York over a seven year period. J Pastoral Care Counsel. 2004;58(3):225-235.
20.    Chapman TR, Grossoehme DH. Adolescent patient and nurse referrals for pastoral care: a comparison of psychiatric vs. medical-surgical populations. J Child Adolesc Psychiatr Nurs. 2002:15(3):118-123.
21.    Ross L. Spiritual care in nursing: an overview of the research to date. J Clin Nurs. 2006;15(7):852-862.
22.    Van Leeuwen R, Cusveller B. Nursing competencies for spiritual care. J Adv Nurs. 2004;48(3):234-246.
23.    Cavendish R, Konecny L, Mitzeliotis C, et al. Spiritual care activities of nurses using Nursing Interventions Classification (NIC) labels. Int J Nurs Terminol Classif. 2003;14(4):113-124.
24. Sellers SC, Haag BA. Spiritual nursing interventions. J Holist Nurs. 1998;16(3):338-354.
25.    Narayanasamy A, Owens J. A critical incident study of nurses’ responses to the spiritual needs of their patients. J Adv Nurs. 2001;33(4):446-455.
26. Propst LR, Ostrom R, Watkins P, Dean T, Mashburn D. Comparative efficacy of religious and nonreligious cognitive-behavioral therapy for the treatment of clinical depression in religious individuals. J Consult Clin Psychol. 1992;60(1):94-103.
27.    McCullough ME. Research on religion-accommodative counseling: review and meta-analysis. J Couns Psychol. 1999;46(1):92-98.
28.    Wong-McDonald A. Spirituality and psychosocial rehabilitation: empowering persons with serious psychiatric disabilities at an inner-city community program. Psychiatr Rehabil J. 2007;30(4):295-300.
29.    Worthington EL, Sandage SJ. Religion and spirituality. Psychotherapy: Theory, Research, Practice, Training. 2001;38(4):473-478.
30. Pargament KI, Murray-Swank NA, Tarakeshwar N. An empirically-based rationale for a spiritually-integrated psychotherapy. Ment Health Relig Cult. 2005;8(3):155-165.
31.    McConnell KM, Pargament KI, Ellison CG, Glannelly KJ. Examining the links between spiritual struggles and symptoms of psychopathology in a national sample. J Clin Psychology. 2006;62(12):1469-1484.
32. Murray-Swank NA, Pargament KI. God, where are you? Evaluating a spiritually-integrated intervention for sexual abuse. Ment Health Relig Cult. 2005;8(3):191-203.
33.    Pargament KI. The Psychology of Religion and Coping: Theory, Research, Practice. New York, NY: Guilford Press; 1997.
34.    Cole BS, Pargament KI. Re-creating your life: a spiritual psychotherapeutic intervention for people diagnosed with cancer. Psychooncology. 1999;8(5):395-407.
35. Breitbart WS. Spirituality and meaning in supportive care: Spirituality and meaning-centered group psychotherapy interventions in advanced cancer. Support Care Cancer. 2002;10:272-280.
36. Fawzy FI, Fawzy NW. Group therapy in the cancer setting. J Psychosom Res. 1998;45(3):191-200.
37. Greenstein M, Breitbart W. Cancer and the experience of meaning: a group psychotherapy program for people with cancer. Am J Psychother. 2000;54(4):486-500.
38.    Cunningham AJ. Integrating spirituality into a group psychological therapy program for cancer patients. Integr Cancer Ther. 2005;4(2):178-186.
39.    Lapid MI, Rummans TA, Brown PD, et al. Improving the quality of life of geriatric cancer patients with a structured multidisciplinary intervention: a randomized controlled trial. Palliat Support Care. 2007;5(2):107-114.
40.    Stefanek M, McDonald PG, Hess SA. Religion, spirituality and cancer: current status and methodological challenges. Psychooncology. 2005;14(6):450-463.
41.    La Fosse H, Schwartz CE, Caraballo RJ, Goeren W, Selwyn PA. Community outreach to patient with AIDS at the end of life in the inner city: reflections from the trenches. Palliat Support Care. 2004;2(3):305-314.
42.    Pargament KI, McCarthy S, Shah P, et al. Religion and HIV: a review of the literature and clinical implications. South Med J. 2004;97(12):1201-1209.
43.    Williams AL, Selwyn PA, Liberti L, et al. A randomized controlled trial of meditation and massage effects on quality of life in people with late-stage disease: a pilot study. J Palliat Med. 2005;8(5):939-952.
44.    Beitel M, Genova M, Schuman-Olivier Z, Arnold R, Avants SK, Margolin A. Reflections by inner-city drug users on a Buddhist-based spirituality-focused therapy: a qualitative study. Am J Orthopsychiatry. 2007;77(1):1-9.
45.    Margolin A, Beitel M, Schuman-Olivier Z, Avants SK. A controlled study of a spirituality-focused intervention for increasing motivation for HIV prevention among drug users. AIDS Educ Prev. 2006;18(4):311-322.
46.    Tarakeshwar N, Pearce MJ, Sikkema KJ. Development and implementation of a spiritual coping group intervention for adults living with HIV/AIDS: a pilot study. Ment Health Relig Cult. 2005;8:179-190.
47.    Ironson G, Stuetzle R, Fletcher MA. An increase in religiousness/spirituality occurs after HIV diagnosis and predicts slower disease progression over 4 years in people with HIV. J Gen Intern Med. 2006;21(suppl 5):62-68.
48.    Sabate E, ed. The magnitude of  the problem of poor adherence. In: Sabate E, ed. Adherence To Long-term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003:15.
49.    Makoul G, Curry RH. The value of assessing and addressing communication skills. JAMA. 2007;298(9):1057-1059.
50. The Joint Commission on Accreditation of Hospital Organizations: Division of Standards and Survey Methods, 2007. Available at: www.jointcommission.org. Accessed August 5, 2008.
51.    McDowell D, Galanter M, Goldfarb L, Lifshutz H. Spirituality and the treatment of the dually diagnosed: an investigation of patient and staff attitudes. J Addictive Dis. 1996;15(2):55-68.
52.    Goldfarb L, Galanter M, McDowell D, Lifshutz H, Dermatis H. Medical student and patient attitudes toward religion and spirituality in the recovery process. Am J Drug Alcohol Abuse. 1996;22(4):549-561.
53. Galanter M, Dermatis H, Bunt G, Williams C, Trujillo M, Steinke P. Asessment of spirituality and its relevance to addiction treatment. J Subst Abuse Treat. 2007;33(3):257-264.
54.    Galanter M. Self-help treatment for combined addiction and mental illness. Psychiatr Serv. 2000;51(8):977-979.
55. Dermatis H, Galanter M, Trujillo M, Rahman-Dujarric C, Ramaglia K, LaGressa D. Evaluation of a model for the treatment of combined mental illness and substance abuse: the Bellevue model for peer-led treatment in systems change. J Addict Dis. 2006;25(3):69-77.
56.    Galanter M. Innovations: alcohol & drug abuse: spirituality in Alcoholics Anonymous: a valuable adjunct to psychiatric services. Psychiatr Serv. 2006;57(3):307-309.
57. Adler J. In search of the spiritual. Newsweek. 2005;146:46-64.

 
 

Dr. Basson is clinical professor and director of the Sexual Medicine Program in the Department of Psychiatry at the University of British Columbia in Vancouver, Canada.

Disclosures: Dr. Basson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Rosemary Basson, MD, British Columbia Centre for Sexual Medicine, General Hospital, 855 W 12th Ave, Vancouver, BC, Canada, V5Z 1M9; Tel: 604-875-8254; Fax: 604-875-8249; E-mail: bassonrees@telus.net.

 

 
 

Abstract

Current conceptualization of women’s sexual response recognizes overlapping phases of variable order. Even without their sensing sexual desire at a particular moment, women initiate or agree to a sexual encounter for numerous reasons. Provided there is adequate attention to appropriate sexual stimulation and an ability to remain focused, subjective arousal follows. That arousal is often poorly correlated with typically prompt reflexive genital congestion. If this complex state of arousal is accompanied by positive emotions and thoughts, then sexual desire, along with further arousal, is triggered. Positive sexual experiences provide further motivation to be sexual again. Understanding this cycle allows patients and clinicians to identify points of interruption, guiding traditional and recently adopted forms of psychosexual therapy for problematic desire and arousal. Given the strong correlation between women’s sexual function and their mental and relationship health, it is necessary to first address these parameters. Recommendations to change official definitions of women’s sexual disorders have been published. Pharmacologic and hormonal therapies for sexual disorders are currently under investigation. There are numerous gaps in present knowledge regarding the need and safety of any testosterone supplementation.

 

Introduction

Problematic low sexual desire and arousal is reported by approximately 33% of women.1-3 Sexual dissatisfaction or distress does not necessarily follow,1,4 but when it does and is ongoing, the diagnoses of sexual desire and arousal disorders are considered. Prevalence figures from recent nationally representative surveys of women in the United States suggest a prevalence of desire disorder of 8.3% and 9.5% with minimal variation across ages until a drop in women >60 years of age.2,5 Prevalence may generally reach 12.5% for surgically menopausal women, and 19.9% for women <45 years of age.5 Of women living in the US, the prevalence of dysfunction was higher in those of Japanese and Chinese backgrounds and lower in African-American women.6

 

Currently recommended definitions of disorder reflect the complexities of desire and arousal. Importantly, desire (ie, “drive,” “lust,” “sexual need”) may not be present initially, but it can be triggered during the sexual encounter along with arousal. Secondly, arousal itself includes numerous aspects, notably subjective excitement/sexual pleasure and physical genital and non-genital changes. That the mental and physical aspects are frequently poorly correlated has been repeatedly documented. Therefore, currently recommended definitions of disorder identify the different dysfunctional components of arousal.

This article describes current conceptualization and supporting evidence of women’s sexual response as well as recently recommended definitions of disorder. The main correlates of desire and arousal that guide the assessment and treatment of desire arousal disorders are outlined. Standard and recent additions to psychosexual therapy are clarified prior to mention of investigational medical treatments, including testosterone supplementation.

 

Current Conceptualization of Women’s Sexual Response

A variety of reasons prompt women (and men) to initiate or agree to sex. A recent study identified 235 discrete reasons that were divided into four domains, namely love and intimacy, physical pleasure and stress relief, goal attainment, and protection of the relationship/“mate guarding.” Evaluating 1,500 undergraduate psychology students, the majority of both men and women were mostly motivated for reasons related to attraction, pleasure, affection, love, romance, and emotional closeness. However, women exceeded men in their reporting emotional motivations.7 Although these motivations were not mutually exclusive, the results support the concept that even if drive is initially absent, there are numerous other reasons to engage in sexual activity.8 That women’s desire can be triggered subsequently during the sexual encounter also has empirical support. Data from 125 women 20–70 years of age showed that regardless of their reporting or not reporting sexual dysfunction, all women identified triggers of sexual desire.9 These triggers were in the domains of emotional bonding, erotica, romance and physical proximity. An absence of any initial desire was shown in the baseline Study of Women Across the Nation (SWAN), wherein the majority of 3,250 multi-ethnic middle-aged women in North America indicated that while they were moderately or extremely satisfied with their physical sexual pleasure, they never or very infrequently sensed desire.6 The highest figures were for Chinese and Japanese women (61.4% and 67.8%). If further equally large multi-ethnic studies confirm these findings, it can be concluded that beginning a rewarding sexual experience without desire is at least as common for mid-life women as beginning one with a definite sense of desire.

Consistent anticipatory sexual desire is more typical of new relationships, and it may be a major reason for sexual engagement. However, that phase may be brief; one study suggests it may last only 1 year for some women.10 Current conceptualization of women’s sexual response allows for the possibility that initially there is a willingness to become aroused and sense desire subsequently (Figure 1).8,11 Though the potential absence of initial desire in sexually satisfied women is now documented, the validated questionnaires used to assess sexual function are based on models of sexual response wherein desire was taken as necessary to the outset of engagement. This is unfortunately acknowledged as a serious limitation.12

 

 

It is important to note that qualitative research has shown that numerous women cannot clearly distinguish between desire and arousal.13 Some women refer to genital and non-genital physical sensations as components of their desire, which is especially true of younger women. The discrepancy between subjective sexual arousal and any measurement of the genital congestion has been frequently identified (Table 1).14-19

 

 

The genital response appears to be a reflex automatic entity that can be elicited in response to a stimulus deemed sexual but not erotic or potentially arousing (eg, viewing a video of primates mating).18,19 Moreover, women’s assessment of their genital congestion is inaccurate. Thus, it is clear that women’s arousal cannot be measured by their “report of genital swelling lubrication response.”20 Recently recommended definitions of disordered arousal include the different components of arousal, particularly genital and subjective excitement.21,22

To summarize the current understanding of sexual response, desire may or may not be present at outset.6,7,8 Even when desire is absent, the woman can choose to deliberately attend to sexual stimulation and remain focused for a sufficient amount of time to allow subjective arousal. The type of stimulation, the context, her ability to attend, the number of distractions, and the expected outcome influence the likelihood of her becoming aroused. When arousal follows and the stimulation continues sufficiently long, its intensity can increase and trigger desire. At that point, her focus becomes her need for sexual satisfaction. The latter may or may not include orgasm(s) but usually requires freedom from any pain or partner dysfunction or negative emotional conclusion. Positive experiences reinforce subsequent sexual motivation. The cycle shown in Figure 1 may be cycled many times during one encounter. This cyclicity and phase overlap predicts the well-documented comorbidity of desire and arousal disorders.2,3 This conceptualization includes and expands on those of Masters and Johnson23 and Kaplan.24 The latter described the phase of desire, mentioning both “intrinsic/ biologic” and “extrinsic/responsive” types, that add to the linear sequence of arousal/excitement, orgasm and resolution described by Masters and Johnson.23 Although after the publication of Human Sex Response Cycle by Masters and Johnson,23 the arousal phase in women often became equated to genital events (lubrication and swelling); the original description included both genital and subjective arousal. The focus on the mind’s processing of stimuli is derived from Janssen and colleagues’25 information processing model in addition to the concept of sexual excitation versus sexual inhibition as explored by Sanders and Graham.26 The circular model depicted in Figure 1 is composite, but it allows for the marked variability of response among women who consider their sexual lives as rewarding and functional.

  

Current Recommendations for Definitions of Disorder

Women’s sexual function is highly contextual, and when that context is problematic such that she reports sexual dysfunction it is questionable whether the term “sexual disorder” is truly appropriate. Frequently there is no evidence of innate disruption of her sexual response. Rather, a problematic sexual environment, including lack of emotional closeness or inadequate stimuli, underlies her problematic experiences. Therefore, current contextual factors, factors from the developmental or medical history, should be documented with any diagnosis of sexual disorder/dysfunction.21 Management of “her dysfunction” may well focus on correcting an unhealthy sexual context. It is important to note that women rate relationship difficulties as a major cause of sexual dysfunction.27

Table 28,20-22,28 outlines the recently recommended definitions of dysfunction from an international consensus committee organized by the American Urological Association Foundation.21 Subsequent to this consensus document, other colleagues made further recommendations that uphold the basic principles, including that desire may normally be limited to a “triggered” type, that subjective arousal must be addressed, that the entity of genital sexual arousal disorder should be included, and that the degree of distress must be assessed.22 These definitions have not been accepted by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision20 or International Classification of Diseases, Tenth Edition29 committees. However, the former is currently beginning extensive research in order to provide official revisions in 2010.

 

 

Psychological Factors Predisposing Arousal and Desire Dysfunction

The major risk factor documented in the literature is poor mental health.1,4 Even a history of major depressive disorder (MDD) without current depression or antidepressant therapy proved a risk factor for low arousal and physical pleasure in the SWAN study.30 In a recent study,31 successful antidepressant therapy improved sexual dysfunction that was initially present in 80% of 445 women with MDD, whereas dysfunction worsened if the depression continued. Even when clinical depression is formally excluded, women complaining of low desire still have lower self-esteem, more mood variability, and more anxious and depressed thoughts than control women.32

The second robust correlation with sexual arousal and desire disorders is relationship difficulties and negative feelings toward the current partner. Indeed, positive past sexual experiences and positive feelings for the partner appear to protect middle-aged women from dysfunction associated with their marked hormonal changes.33 Major factors protecting women from sexual distress have been found to be positive feelings for the partner generally and specifically at the time of sexual engagement.4 Even when medical factors are pertinent (eg, among breast cancer survivors), important predictors of their sexual satisfaction include relationship quality and mental health.34 Partner sexual dysfunction is also a major risk factor for a woman’s subsequent dysfunctions that typically improve with successful treatment of her partner.35

 

Biologic Risk Factors

The importance of biologic factors is less clear. Regarding estrogen, the vast majority of untreated postmenopausal women will show signs of vulvovaginal atrophy36 that can reduce sexual motivation, but dyspareunia is by no means universal and most epidemiologic studies show little increase in dyspareunia with age. The (albeit diminishing) intracellular production of estrogen from adrenal and ovarian prohormones, including dihydroepiandrosterone (DHEA) and DHEA sulphate, may be sufficient for some women. Rather than amounts of substrate (ie, prohormones), the activity of the various steroidogenic enzymes including aromatase in the different peripheral tissues may be the key factor. Variations in estrogen receptor numbers and sensitivities may also be relevant.

Regarding lack of androgen, this too is far from straightforward. Surgical menopause has been cited as an example of an androgen-deplete state. However, the prevalence of subsequent desire or arousal dysfunction is unknown. Elective bilateral oophorectomy along with required simple hysterectomy apparently may not lead to sexual dysfunction. This has been confirmed recently in three different studies.37-39 This seems to be in conflict with cross-sectional studies of women with surgical menopause who appear to have more distressing low desire and low satisfaction than naturally post-menopausal women.2,3 However, these latter studies give no details on the degree of choice the women had regarding the bilateral oophorectomy.

The complexities of the intracellular production of sex hormones is an area of active research.40 Adrenal production of precursors is said to decrease by 66% between late 30s and early 60s, but the amount of variation among individual women is unknown. Moreover, the decreased production may still be sufficient if the necessary enzymes in the cells to convert the precursors to testosterone and estrogen remain active.40 However, there are other complexities, including sensitivity of androgen receptors and availability and numbers of cofactors. Moreover, the brain can synthesize sex hormones from the basic building block of cholesterol.41 There is early evidence that with menopause this intracerebral production of neurosteroids increases.42 There is little research into how that production might be modulated with exogenous sex hormone supplementation.

There is consensus43 that the large studies exploring any correlation between (physiologic) serum levels of testosterone and women’s sexual function have been negative.44,45 Though studies are in process, whether a measure of total androgen production via androgen metabolites will show any such correlation remains to be seen. Benefit has been shown in the recent transdermal testosterone supplementation randomized controlled trials (RCTs),8 but the evidence of benefit is limited. This may be partially due to the fact that the women recruited for these studies were already having on average of three sexually satisfying events per month at baseline. In view of recently recommended definitions of disorder, it is questionable whether these women had any sexual disorder. Nevertheless, their arousal and orgasm scores on the questionnaires used in the study improved with testosterone compared to placebo. An important question is, would benefit have been greater if women unable to have any sexually satisfying events had been recruited?46 There is need to study benefits of testosterone supplementation for loss of response and, therefore, absence of triggered desire.

 

Assessment of Desire and Arousal Disorders

Assessment involves evaluating the stages in the woman’s sex response cycle (Figure 1). Involving both partners and seeing them both together and separately are advocated. The woman’s reasons or motivations to be sexual are assessed along with the suitability of the context (ie, circumstances, timing, interpersonal context). Further, her intrapersonal context, in terms of self-image, past sexual experiences, and mood, require careful examination. The variety and usefulness of the stimuli are assessed as is her proneness to distract. The nature of any distractions is clarified. These distractions might concern the sexual experience and the outcome or, more commonly, non-sexual issues. The actual sexual details are then assessed such as the extent to which intercourse is the focus, its timing, her need or experience of orgasm, any discomfort with sexual stimulation or intercourse, and any partner dysfunction. In addition, the emotional outcome both immediately and over the next few hours or days are noted.

While the couple is together, the evolution of their sexual difficulties and each partner’s reaction to them can be evaluated. Then, when the couple is separated, inquiry as to the woman’s own sexual experience with self-stimulation and further details she would like to add is possible now that she is alone. Her past sexual experiences, developmental history, and past and present medical details are also needed. The same information can be obtained from the partner when he or she is seen alone.

The rather simplistic “A–G” guide to sexual assessment is offered at least to screen and decide whether referral or care within one’s own practice is most appropriate (Table 3).47,48

 

 

 

Laboratory Investigations

Laboratory investigations are of limited use for sexual assessment. When there are other symptoms of, for example, thyroid disease or hyperprolactinemia (eg, galactorrhea, irregular menses, infertility), appropriate testing is conducted.

 

Physical Examination

The physical examination is of major importance when there is comorbid dyspareunia. In the context of chronic medical disease (eg, neurologic disease where there may be sensory loss in the genitalia, renal disease where there may be anemia and vulvovaginal atrophy, states of hyperprolactinemia where there may be galactorrhea and in hypoadrenal states where there may be loss of pubic hair), an examination is necessary. Genital examination is necessary when there is lost genital sexual sensitivity to exclude conditions such as lichen sclerosis. In addition, genital and pelvic examination is often used for reasons of reassurance and as a means to encourage the woman to consider what is going in her mind when she is sexual rather than believing the etiology of her arousal dysfunction is confined to her genitalia. In these situations, a psychiatrist not focusing his or her practice on sexual medicine may consider it more appropriate to have a colleague perform the physical examination.

 

Validated Questionnaires

Validated questionnaires are available but are best considered as survey instruments, for example in epidemiologic studies, since they provide only a cursory picture of sexual functioning and are not intended for use to make diagnoses. The algorithms in Figure 2 show how the diagnostic label stems from the assessment questions.28,48

 

 

 

Management of Disordered Sexual Arousal and Desire

The approach is to address the problematic areas in a woman’s sex response cycle that have been identified during the detailed assessment. It is guided by the documented robust correlations between women’s sexual satisfaction and their mental health, including self-image and their emotional intimacy with their partner. It is important to note that assessment typically continues throughout treatment as new information emerges.

 

Psychosexual Therapy

Figure 3 outlines the progression through psychosexual therapy options, initially addressing any mood disorder or interpersonal difficulties.48 Psychosexual education is often therapeutic. The couple is informed about women’s (and men’s) sexual response cycles, clarifying that suitable context and sexual stimuli are needed by all women to trigger desire on many, if not all, occasions. Cognitive-behavioral therapy (CBT) techniques clarify and challenge inaccurate thoughts, beliefs, and myths about the woman’s sexual response, herself, and frequently, misunderstandings about her partner. Behavioral therapy includes sensate focus treatment that targets anticipatory anxiety and performance anxiety about sexual activity. Briefly, these exercises involve the partners taking turns in providing pleasurable low-key sensual and then sexual stimulation to each other, with the recipient guiding as to the type of stimulation they would like. Once the couple has practiced with the low-key types of stimulation, more areas of the body are included, but intercourse itself is still “off-limits.” Focusing on the moment, guiding the partner, finding the pace at which she is more comfortable to progress with sexual activity, and realizing that sexual times can be planned in advance are all potential benefits of sensate focus therapy. When distractions are a difficulty, discussion of the mindfulness technique is warranted. Relevant literature or preferably classes can be suggested. Initially, mindfulness practice in non-sexual everyday life is encouraged and only later guidance on how to specifically use this skill during sexual activity is given.

 

Psychotherapy can include either psychodynamic treatment or psychoanalysis. The latter would be prescribed when there was belief that the sexual dysfunction is at least partially due to pathologic processes in personality development. To help the woman relate intimately to her partner, she works through conflicts from the past that were present in non-sexual relationships. While psychotherapy is supported by the clinical literature, there is minimal empirical support.49

In practice, commonly these methods are mixed. For example, “psychoeducational therapy” can involve CBT techniques, sexual information, sex therapy, and mindfulness practice. It has proven beneficial for women with desire and arousal disorders particularly if they have a history of sexual abuse50 as well as for women with genital sexual arousal disorder due to gynecologic cancer.51 Larger studies with wait-list controls are in process.

 

Hormonal Therapy

Estrogen-related dryness and dyspareunia improve with topical/local or systemic estrogen supplementation. Indirectly, sexual motivation may be improved. Although less well studied, genital sexual sensitivity may also respond to estrogen in the postmenopausal woman.

Supplemental testosterone for postmenopausal women is not approved in the US, but it has been prescribed since the 1930s, off-label, using formulations approved for men or using compounded creams. The previously mentioned recent RCTs8 of transdermal testosterone to surgically (four studies) and naturally (one study) menopausal estrogen supplemented women all by the same sponsor and using the same protocol showed modest benefit from the 300 mcg/day but not the 450 mcg/day dose. At recruitment, the women on average reported three sexually satisfying events each month and these increased to approximately five with active drug and to four with placebo.8 On the basis of this documented benefit, transdermal testosterone has been approved by the European Union for surgically menopausal women. More recently, minimal or no benefit was seen from transdermal testosterone in estrogen-deficient women.52 In pre-menopausal women only one of three doses aimed to increase pre-testosterone levels to the high normal range proved beneficial, and that benefit was in the order of 0.8 more sexually satisfying events per month and was not associated with any improvements beyond placebo as measured by a validated sexual function and satisfaction questionnaire.53 However, consistently, the focus has been on increasing the sexual frequency, recruiting women with satisfactory sexual experiences.

Numerous unresolved issues are shown in Table 4.8,37-39,52,53 A major concern is lack of long-term safety data. Recent reviews of potentially increased risk of breast cancer,54 metabolic syndrome,55 and cardiovascular disease clarify the current clinical dilemma. Testosterone supplementation requires co-administration of estrogen, which presents further difficulty. Despite cardiovascular benefit identified in non-randomized prospective trials of systemic estrogen initiated at menopause, women are currently advised against on-going systemic estrogen on the basis of cardiovascular harm shown in RCTs of women beginning estrogen supplementation many years post menopause.56 A 2006 guideline42 reviews some of these complexities underlying the American Endocrine Society’s advising against testosterone supplementation.

 

 

Identification of Women with “Androgen Deficiency”

Identifying women with “androgen deficiency” is currently not possible.43 The hypopituitary state would be a clear indication of androgen deficiency, but there is little clarity beyond that. Intracellular production of testosterone continues indefinitely as some supply of prohormones from adrenal glands (and ovaries in some women) continues indefinitely. Loss of ovarian androgens from surgery may not amount to androgen deficiency; note the studies showing elective bilateral oophorectomy at the time of perimenopausal hysterectomy does not lead to sexual dysfunction.37-39 As previously mentioned, serum levels of testosterone do not correlate with sexual function and androgen metabolites have not yet been shown to correlate with sexual function.

 

Investigational Therapy

Table 5 outlines some investigational drugs.57-68 The ongoing interest in addressing deficient genital congestion with various drugs, including phosphodiesterase inhibitors, alpha blockers, selective estrogen receptor modulators, and peptidase inhibitors is somewhat puzzling given the documented lack of correlation between women’s sexual symptoms and any measurable deficit in genital congestion. However, these drugs might benefit women with deficient congestion due to, for example, non-nerve-sparing radical hysterectomies.

 

 

 

Conclusion

Current understanding of women’s sex response cycle allows patients and clinicians to consider the points of interruption when difficulties with arousal and desire are reported. Women’s sexual motivation is broad such that interpersonal or personal psychological issues can readily deter women from instigating or accepting sex. Sexual stimuli in appropriate contexts are needed for the sexual response to unfold and trigger arousal and desire. Commonly, these are lacking or problematic. Distractions, low self-image, and difficulties with trust may preclude sufficient arousal to allow pleasure and more intense arousal along with desire. Concern about a negative outcome physically or emotionally may similarly lessen arousal. Having first addressed any mental health or interpersonal issues, combinations of psychoeducation, CBT, and sex therapy are the mainstay of therapy. Teaching mindfulness techniques appears to be a promising addition. Identifying women whose sexual disorder is based on deficiency of sex hormone activity remains challenging. Testosterone supplementation for loss of both initial and triggered desire requires investigation. Pharmacologic adjuncts are being investigated and may have a role especially for genital sexual arousal disorder. PP

 

References

1.    Lutfey KE, Link CL, Rosen RC, Wiegel M, McKinlay JB. Prevalence and correlates of sexual activity and function in women: results from the Boston Area Community Health (BACH) survey. Arch Sex Behav. 2008. Epub ahead of print.
2.    Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women’s International Study of Health and Sexuality (WISHeS). Menopause. 2006;13(1):46-56.
3.    Dennerstein L, Koochaki P, Barton I, et al. Hypoactive sexual desire disorder in menopausal women: a survey of western European women. J Sex Med. 2006;3(2):212-222. 
4.    Bancroft J, Loftus J, Long JS. Distress about sex: a national survey of women in heterosexual relationships. Arch Sex Behav. 2003;32(3):193-211.
5.    West SL, D’Aloisio AA, Agans RP, et al. The prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Int Med. In press.
6. Cain VS, Johannes CB, Avis NE, et al. Sexual functioning and practices in a multi-ethnic study of midlife woman: baseline results from SWAN. J Sex Res. 2003;40(3):266-276
7.     Meston CM, Buss DM. Why humans have sex. Arch Sex Behav. 2007;36(4):477-507.
8.    Basson R. Clinical Practice. Sexual desire and arousal disorders in women. N Engl J Med. 2006;354(14):1497-1506.
9.     McCall K, Meston C. Differences between pre- and postmenopausal women in cues for sexual desire. J Sex Med. 2007;4(2):364-371.
10. Klusmann D. Sexual motivation and the duration of partnership. Arch Sex Behav. 2002;31(3):275-287.
11. Basson R. Female sexual response: the role of drugs in the management of sexual dysfunction. Obstet Gynecol. 2001;98(2):350-353.
12. Althof SE, Dean J, Derogates LR, et al. Current perspectives on the clinical assessment and diagnosis of female sexual dysfunction and clinical studies of potential therapies: statement of concern. J Sex Med. 2005;2(suppl 3):146-153.
13. Graham CA, Sanders SA, Milhausen RR, McBride KR. Turning on and turning off: a focus group study of the factors that affect women’s sexual arousal. Arch Sex Behav. 2004;33(6):527-538.
14. Karama S, Lecours AR, Leroux JM, et al. Areas of brain activation in males and females during viewing of erotic film excerpts. Hum Brain Mapp. 2002;16(1):1-13.
15. Georgiadis JR, Kortekaas R, Kuipers R, et al. Regional cerebral flood flow changes associated with clitorally-induced orgasm in healthy women. Eur J Neurosci. 2006;24(11):3305-3316.
16. van Lunsen RHW, Laan E. Genital vascular responsiveness and sexual feelings in midlife women: psychophysiologic, brain, and genital imaging studies. Menopause. 2004;11(6 pt 2):741-748.
17. Maravilla KR, Cao Y, Heiman JR, et al. Serial MR imaging with MS-325 for evaluating female sexual arousal response: determination of intrasubject reproducibility. J Magn Reson Imaging. 2003;18(2):216-224.
18. Chivers ML, Bailey JM. A sex difference in features that elicit genital response. Biol Psychol. 2005;70(2):115-120.
19. Laan E, Everaerd W, van der Velde J, Geer JH. Determinants of subjective arousal in women: feedback from genital arousal and erotic stimulus content. Psychophysiology. 1995;32(5):444-451.
20. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2003.
21. Basson R, Leiblum S, Brotto L, et al. Definitions of women’s sexual dysfunctions reconsidered: advocating expansion and revision. J Psychosom Obstet Gynaecol. 2003;24(4):221-229.
22. Segraves R, Balon R, Clayton A. Proposal for changes in diagnostic criteria for sexual dysfunctions. J Sex Med. 2007;4(3):567-580.
23.    Masters WH, Johnson V. Human Sex Response Cycle. Boston, MA: Little Brown; 1966.
24.    Kaplan HS. Hypoactive sexual desire. J Sex Marital Ther. 1979;3:3-9.
25. Janssen E, Evereard W, Spiering M, Janssen J. Automatic processes and the appraisal of sexual stimuli: toward an information processing model of sexual arousal. J Sex Res. 2000;37:8-23.
26. Graham CA, Sanders SA, Milhausen R. The sexual excitation and sexual inhibition inventory for women: psychometric properties. Arch Sex Behav. 2006;35(4):397-410.
27. King M, Holt V, Nazareth I. Women’s views of their sexual difficulties: agreement and disagreement with clinical diagnoses. Arch Sex Behav. 2007;36(2):281-288.
28. Basson R, Leiblum S, Brotto L, et al. Revised definitions of women’s sexual dysfunction. J Sex Med. 2004;1(1):40-48.
29.    The International Statistical Classification of Diseases and Related Health Problems. 10th rev. Geneva, Switzerland: World Health Organization; 1992.
30. Cyranowski JM, Bromberge J, Youk A, Matthews K, Kravitz HM, Powell LH. Lifetime depression history and sexual function in women at midlife. Arch Sex Behav. 2004;33(6):539-548.
31. Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med. 2007;4(4):917-929.
32. Hartmann U, Philippsohn S, Heiser K, Rüffer-Hesse C. Low desire in mid life and older women: personality factors, psychosocial development, present sexuality. Menopause. 2004;11(6):726-740.
33. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during mid-life due to aging or menopause. Fertil Steril. 2001;76(3):456-460.
34. Ganz PA, Desmond KA, Belin TR, Meyerowitz BE, Rowland JH. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol. 1999;17(8):2371-2380.
35. Cayan S, Bozlu M, Canpolat B, Akbay E. The assessment of sexual functions in women with male partners complaining of erectile dysfunction: does treatment of male sexual dysfunction improve female partner’s sexual functions? J Sex Marital Ther. 2004;30(5):333-341.
36. Freedman MA. Estrogen, vaginal pH, and genital atrophy. Menopause. 2006;13(6):987.
37. Aziz A, Brannstrom M, Bergquist C, et al. Perimenopausal androgen decline after oophorectomy does not influence sexuality or psychological well-being. Fertil Steril. 2005;83(4):1021-1028.
38. Farquar CM, Harvey SA, Yu Y, et al. A prospective study of three years of outcomes after hysterectomy with and without oophorectomy. Am J Obstet Gynecol. 2006;194(3):714-717.
39. Teplin V, Vittinghoff E, Lin F, et al. Oophorectomy in premenopausal women: health-related quality of life and sexual functioning. Obstet Gynecol. 2007;109(2 pt 1):347-354.
40. Labrie F, Bélanger A, Bélanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol. 2006;99(4-5):182-188.
41. Melcangi RC, Panzica GC. Neuroactive steroids: old players in a new game. Neuroscience. 2006;138(3):733-739.
42. Ishunina TA, Swaab DF. Alterations in the human brain in menopause. Maturitas. 2007;57(1):20-22.
43. Wierman ME, Basson R, Davis SR, et al. Androgen therapy in women: an Endocrine Society Clinical Practice Guideline. J Clin Enocrinol Metab. 2006;91(10):3697-3710.
44. Davis SR, Davison SL, Donath S, Bell RJ. Circulating androgen levels in self-reported sexual function in women. JAMA. 2005;294(1):91-96.
45. Santoro A, Torrens J, Crawford S, et al. Correlates of circulating androgens in midlife women: the study of women’s health across the nation. J Clin Endocrinol Metab. 2005;90(8):2004-2063.
46. Basson R. Testosterone supplementation to improve women’s sexual satisfaction: complexities and unknowns. Ann Intern Med. 2008;148(8):620-621.
47. Basson R. Recent conceptualization of women’s sexual response. Menopause. 2007;16(3):16-28.
48. Young C, Tovey D, Martin A, et al. Congestive heart failure. BMJ. Point-of-Care. 2008. Available at: www.pointofcare.bmj.com. Accessed August 7, 2008.
49. Brotto LA. Psychologic-based desire and arousal disorders: treatment strategies and outcome results. In: Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction: Study, Diagnosis, and Treatment. 1 ed. London, UK: Informa Healthcare; 2005:441-448.
50. Brotto LA, Basson R, Luria M. A mindfulness-based group psychoeducational intervention targeting sexual arousal disorder in women. J Sex Med. 2008;5(7):1646-1659.
51. Brotto LA, Heiman JR, Goff B, et al. A psychoeducational intervention for sexual dysfunction in women with gynecologic cancer. Arch Sex Behav. 2008;37(2):317-329.
52. Barton DL, Wender DB, Sloan JA, et al. Randomized controlled trial to evaluate transdermal testosterone in female cancer survivors with decreased libido; North Central Cancer Treatment Group Protocol N02C3. J Natl Cancer Inst. 2007;999(9):672-679.
53. Davis S, Papalia MA, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treatment of decreased sexual satisfaction in premenopausal women: a placebo-controlled randomized, dose ranging study. Annals Int Med. 2008;148(8):569-577.
54. Schover LR. Androgen therapy for loss of desire in women: is the benefit worth the breast cancer risk? Fertil Steril. 2008;90(1):129-140.
55. Wild RA. Endogenous androgens and cardiovascular risk. Menopause. 2007;14(4):609-610.
56. Stevenson JC. HRT and the primary prevention of cardiovascular disease. Maturitas. 2007;57(1):31-34.
57. Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, Harning R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006;3(4):626-683.
58. Safarinejad MR. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study. J Sex Med. 2008;5(4):887-897.
59. Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S. Pharmacology of flibanserin. CNS Drug Rev. 2002;8(2):117-142.
60. Kolasa T, Matulenko MA, Hakeem AA, et al. 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction. J Med Chem. 2006;49(17):5093-5109.
61. Clayton AH, Warnock JK, Kornstein SG, et al. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin re-uptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 2004;65(1):62-67.
62. Segraves RT, Clayton A, Croft H, Wolf A, Warnock J. Bupropion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women. J Clin Psychopharmacol. 2004;24(3):339-342.
63. Caruso S, Rugolo S, Agnello C, et al. Sildenafil improves sexual functioning in premenopausal women with Type I diabetes who are affected by sexual arousal disorder: double-blind, crossover, placebo-controlled pilot study. Fertil Steril. 2006;85(5):1496-1501.
64. Dasgupta R, Wiseman OJ, Kanabar G, et al. Efficacy of sildenafil in the treatment of female sexual dysfunction due to multiple sclerosis. J Urol. 2004;171(3):1189-1193.
65. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal. J Women’s Health Gend Based Med. 2002;11(4):367-377.
66. Maw GN, Stobie A, Planken S, et al. The structure of small molecule inhibitors of neutral endopeptidase: structure-activity studies on functionalised glutaramides. Chem Biol Drug Des. 2006;67(1):74-77.
67. Ito TY, Polan ML, Whipple B, et al. The enhancement of female sexual function with ArginMax, a nutritional supplement, among women differing in menopausal status. J Sex Marital Ther. 2006;32(5):369-378.
68. Basson R. Women’s sexual function and dysfunction; current uncertainties future directions. Int J Impot Res. 2008. Epub ahead of print.

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Dr. Basson is clinical professor and director of the Sexual Medicine Program in the Department of Psychiatry at the University of British Columbia in Vancouver, Canada.

Disclosures: Dr. Basson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Rosemary Basson, MD, British Columbia Centre for Sexual Medicine, General Hospital, 855 W 12th Ave, Vancouver, BC, Canada, V5Z 1M9; Tel: 604-875-8254; Fax: 604-875-8249; E-mail: bassonrees@telus.net.

 

 
 

Abstract

Current conceptualization of women’s sexual response recognizes overlapping phases of variable order. Even without their sensing sexual desire at a particular moment, women initiate or agree to a sexual encounter for numerous reasons. Provided there is adequate attention to appropriate sexual stimulation and an ability to remain focused, subjective arousal follows. That arousal is often poorly correlated with typically prompt reflexive genital congestion. If this complex state of arousal is accompanied by positive emotions and thoughts, then sexual desire, along with further arousal, is triggered. Positive sexual experiences provide further motivation to be sexual again. Understanding this cycle allows patients and clinicians to identify points of interruption, guiding traditional and recently adopted forms of psychosexual therapy for problematic desire and arousal. Given the strong correlation between women’s sexual function and their mental and relationship health, it is necessary to first address these parameters. Recommendations to change official definitions of women’s sexual disorders have been published. Pharmacologic and hormonal therapies for sexual disorders are currently under investigation. There are numerous gaps in present knowledge regarding the need and safety of any testosterone supplementation.

 

Introduction

Problematic low sexual desire and arousal is reported by approximately 33% of women.1-3 Sexual dissatisfaction or distress does not necessarily follow,1,4 but when it does and is ongoing, the diagnoses of sexual desire and arousal disorders are considered. Prevalence figures from recent nationally representative surveys of women in the United States suggest a prevalence of desire disorder of 8.3% and 9.5% with minimal variation across ages until a drop in women >60 years of age.2,5 Prevalence may generally reach 12.5% for surgically menopausal women, and 19.9% for women <45 years of age.5 Of women living in the US, the prevalence of dysfunction was higher in those of Japanese and Chinese backgrounds and lower in African-American women.6

 

Currently recommended definitions of disorder reflect the complexities of desire and arousal. Importantly, desire (ie, “drive,” “lust,” “sexual need”) may not be present initially, but it can be triggered during the sexual encounter along with arousal. Secondly, arousal itself includes numerous aspects, notably subjective excitement/sexual pleasure and physical genital and non-genital changes. That the mental and physical aspects are frequently poorly correlated has been repeatedly documented. Therefore, currently recommended definitions of disorder identify the different dysfunctional components of arousal.

This article describes current conceptualization and supporting evidence of women’s sexual response as well as recently recommended definitions of disorder. The main correlates of desire and arousal that guide the assessment and treatment of desire arousal disorders are outlined. Standard and recent additions to psychosexual therapy are clarified prior to mention of investigational medical treatments, including testosterone supplementation.

 

Current Conceptualization of Women’s Sexual Response

A variety of reasons prompt women (and men) to initiate or agree to sex. A recent study identified 235 discrete reasons that were divided into four domains, namely love and intimacy, physical pleasure and stress relief, goal attainment, and protection of the relationship/“mate guarding.” Evaluating 1,500 undergraduate psychology students, the majority of both men and women were mostly motivated for reasons related to attraction, pleasure, affection, love, romance, and emotional closeness. However, women exceeded men in their reporting emotional motivations.7 Although these motivations were not mutually exclusive, the results support the concept that even if drive is initially absent, there are numerous other reasons to engage in sexual activity.8 That women’s desire can be triggered subsequently during the sexual encounter also has empirical support. Data from 125 women 20–70 years of age showed that regardless of their reporting or not reporting sexual dysfunction, all women identified triggers of sexual desire.9 These triggers were in the domains of emotional bonding, erotica, romance and physical proximity. An absence of any initial desire was shown in the baseline Study of Women Across the Nation (SWAN), wherein the majority of 3,250 multi-ethnic middle-aged women in North America indicated that while they were moderately or extremely satisfied with their physical sexual pleasure, they never or very infrequently sensed desire.6 The highest figures were for Chinese and Japanese women (61.4% and 67.8%). If further equally large multi-ethnic studies confirm these findings, it can be concluded that beginning a rewarding sexual experience without desire is at least as common for mid-life women as beginning one with a definite sense of desire.

Consistent anticipatory sexual desire is more typical of new relationships, and it may be a major reason for sexual engagement. However, that phase may be brief; one study suggests it may last only 1 year for some women.10 Current conceptualization of women’s sexual response allows for the possibility that initially there is a willingness to become aroused and sense desire subsequently (Figure 1).8,11 Though the potential absence of initial desire in sexually satisfied women is now documented, the validated questionnaires used to assess sexual function are based on models of sexual response wherein desire was taken as necessary to the outset of engagement. This is unfortunately acknowledged as a serious limitation.12

 

 

It is important to note that qualitative research has shown that numerous women cannot clearly distinguish between desire and arousal.13 Some women refer to genital and non-genital physical sensations as components of their desire, which is especially true of younger women. The discrepancy between subjective sexual arousal and any measurement of the genital congestion has been frequently identified (Table 1).14-19

 

 

The genital response appears to be a reflex automatic entity that can be elicited in response to a stimulus deemed sexual but not erotic or potentially arousing (eg, viewing a video of primates mating).18,19 Moreover, women’s assessment of their genital congestion is inaccurate. Thus, it is clear that women’s arousal cannot be measured by their “report of genital swelling lubrication response.”20 Recently recommended definitions of disordered arousal include the different components of arousal, particularly genital and subjective excitement.21,22

To summarize the current understanding of sexual response, desire may or may not be present at outset.6,7,8 Even when desire is absent, the woman can choose to deliberately attend to sexual stimulation and remain focused for a sufficient amount of time to allow subjective arousal. The type of stimulation, the context, her ability to attend, the number of distractions, and the expected outcome influence the likelihood of her becoming aroused. When arousal follows and the stimulation continues sufficiently long, its intensity can increase and trigger desire. At that point, her focus becomes her need for sexual satisfaction. The latter may or may not include orgasm(s) but usually requires freedom from any pain or partner dysfunction or negative emotional conclusion. Positive experiences reinforce subsequent sexual motivation. The cycle shown in Figure 1 may be cycled many times during one encounter. This cyclicity and phase overlap predicts the well-documented comorbidity of desire and arousal disorders.2,3 This conceptualization includes and expands on those of Masters and Johnson23 and Kaplan.24 The latter described the phase of desire, mentioning both “intrinsic/ biologic” and “extrinsic/responsive” types, that add to the linear sequence of arousal/excitement, orgasm and resolution described by Masters and Johnson.23 Although after the publication of Human Sex Response Cycle by Masters and Johnson,23 the arousal phase in women often became equated to genital events (lubrication and swelling); the original description included both genital and subjective arousal. The focus on the mind’s processing of stimuli is derived from Janssen and colleagues’25 information processing model in addition to the concept of sexual excitation versus sexual inhibition as explored by Sanders and Graham.26 The circular model depicted in Figure 1 is composite, but it allows for the marked variability of response among women who consider their sexual lives as rewarding and functional.

  

Current Recommendations for Definitions of Disorder

Women’s sexual function is highly contextual, and when that context is problematic such that she reports sexual dysfunction it is questionable whether the term “sexual disorder” is truly appropriate. Frequently there is no evidence of innate disruption of her sexual response. Rather, a problematic sexual environment, including lack of emotional closeness or inadequate stimuli, underlies her problematic experiences. Therefore, current contextual factors, factors from the developmental or medical history, should be documented with any diagnosis of sexual disorder/dysfunction.21 Management of “her dysfunction” may well focus on correcting an unhealthy sexual context. It is important to note that women rate relationship difficulties as a major cause of sexual dysfunction.27

Table 28,20-22,28 outlines the recently recommended definitions of dysfunction from an international consensus committee organized by the American Urological Association Foundation.21 Subsequent to this consensus document, other colleagues made further recommendations that uphold the basic principles, including that desire may normally be limited to a “triggered” type, that subjective arousal must be addressed, that the entity of genital sexual arousal disorder should be included, and that the degree of distress must be assessed.22 These definitions have not been accepted by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision20 or International Classification of Diseases, Tenth Edition29 committees. However, the former is currently beginning extensive research in order to provide official revisions in 2010.

 

 

Psychological Factors Predisposing Arousal and Desire Dysfunction

The major risk factor documented in the literature is poor mental health.1,4 Even a history of major depressive disorder (MDD) without current depression or antidepressant therapy proved a risk factor for low arousal and physical pleasure in the SWAN study.30 In a recent study,31 successful antidepressant therapy improved sexual dysfunction that was initially present in 80% of 445 women with MDD, whereas dysfunction worsened if the depression continued. Even when clinical depression is formally excluded, women complaining of low desire still have lower self-esteem, more mood variability, and more anxious and depressed thoughts than control women.32

The second robust correlation with sexual arousal and desire disorders is relationship difficulties and negative feelings toward the current partner. Indeed, positive past sexual experiences and positive feelings for the partner appear to protect middle-aged women from dysfunction associated with their marked hormonal changes.33 Major factors protecting women from sexual distress have been found to be positive feelings for the partner generally and specifically at the time of sexual engagement.4 Even when medical factors are pertinent (eg, among breast cancer survivors), important predictors of their sexual satisfaction include relationship quality and mental health.34 Partner sexual dysfunction is also a major risk factor for a woman’s subsequent dysfunctions that typically improve with successful treatment of her partner.35

 

Biologic Risk Factors

The importance of biologic factors is less clear. Regarding estrogen, the vast majority of untreated postmenopausal women will show signs of vulvovaginal atrophy36 that can reduce sexual motivation, but dyspareunia is by no means universal and most epidemiologic studies show little increase in dyspareunia with age. The (albeit diminishing) intracellular production of estrogen from adrenal and ovarian prohormones, including dihydroepiandrosterone (DHEA) and DHEA sulphate, may be sufficient for some women. Rather than amounts of substrate (ie, prohormones), the activity of the various steroidogenic enzymes including aromatase in the different peripheral tissues may be the key factor. Variations in estrogen receptor numbers and sensitivities may also be relevant.

Regarding lack of androgen, this too is far from straightforward. Surgical menopause has been cited as an example of an androgen-deplete state. However, the prevalence of subsequent desire or arousal dysfunction is unknown. Elective bilateral oophorectomy along with required simple hysterectomy apparently may not lead to sexual dysfunction. This has been confirmed recently in three different studies.37-39 This seems to be in conflict with cross-sectional studies of women with surgical menopause who appear to have more distressing low desire and low satisfaction than naturally post-menopausal women.2,3 However, these latter studies give no details on the degree of choice the women had regarding the bilateral oophorectomy.

The complexities of the intracellular production of sex hormones is an area of active research.40 Adrenal production of precursors is said to decrease by 66% between late 30s and early 60s, but the amount of variation among individual women is unknown. Moreover, the decreased production may still be sufficient if the necessary enzymes in the cells to convert the precursors to testosterone and estrogen remain active.40 However, there are other complexities, including sensitivity of androgen receptors and availability and numbers of cofactors. Moreover, the brain can synthesize sex hormones from the basic building block of cholesterol.41 There is early evidence that with menopause this intracerebral production of neurosteroids increases.42 There is little research into how that production might be modulated with exogenous sex hormone supplementation.

There is consensus43 that the large studies exploring any correlation between (physiologic) serum levels of testosterone and women’s sexual function have been negative.44,45 Though studies are in process, whether a measure of total androgen production via androgen metabolites will show any such correlation remains to be seen. Benefit has been shown in the recent transdermal testosterone supplementation randomized controlled trials (RCTs),8 but the evidence of benefit is limited. This may be partially due to the fact that the women recruited for these studies were already having on average of three sexually satisfying events per month at baseline. In view of recently recommended definitions of disorder, it is questionable whether these women had any sexual disorder. Nevertheless, their arousal and orgasm scores on the questionnaires used in the study improved with testosterone compared to placebo. An important question is, would benefit have been greater if women unable to have any sexually satisfying events had been recruited?46 There is need to study benefits of testosterone supplementation for loss of response and, therefore, absence of triggered desire.

 

Assessment of Desire and Arousal Disorders

Assessment involves evaluating the stages in the woman’s sex response cycle (Figure 1). Involving both partners and seeing them both together and separately are advocated. The woman’s reasons or motivations to be sexual are assessed along with the suitability of the context (ie, circumstances, timing, interpersonal context). Further, her intrapersonal context, in terms of self-image, past sexual experiences, and mood, require careful examination. The variety and usefulness of the stimuli are assessed as is her proneness to distract. The nature of any distractions is clarified. These distractions might concern the sexual experience and the outcome or, more commonly, non-sexual issues. The actual sexual details are then assessed such as the extent to which intercourse is the focus, its timing, her need or experience of orgasm, any discomfort with sexual stimulation or intercourse, and any partner dysfunction. In addition, the emotional outcome both immediately and over the next few hours or days are noted.

While the couple is together, the evolution of their sexual difficulties and each partner’s reaction to them can be evaluated. Then, when the couple is separated, inquiry as to the woman’s own sexual experience with self-stimulation and further details she would like to add is possible now that she is alone. Her past sexual experiences, developmental history, and past and present medical details are also needed. The same information can be obtained from the partner when he or she is seen alone.

The rather simplistic “A–G” guide to sexual assessment is offered at least to screen and decide whether referral or care within one’s own practice is most appropriate (Table 3).47,48

 

 

 

Laboratory Investigations

Laboratory investigations are of limited use for sexual assessment. When there are other symptoms of, for example, thyroid disease or hyperprolactinemia (eg, galactorrhea, irregular menses, infertility), appropriate testing is conducted.

 

Physical Examination

The physical examination is of major importance when there is comorbid dyspareunia. In the context of chronic medical disease (eg, neurologic disease where there may be sensory loss in the genitalia, renal disease where there may be anemia and vulvovaginal atrophy, states of hyperprolactinemia where there may be galactorrhea and in hypoadrenal states where there may be loss of pubic hair), an examination is necessary. Genital examination is necessary when there is lost genital sexual sensitivity to exclude conditions such as lichen sclerosis. In addition, genital and pelvic examination is often used for reasons of reassurance and as a means to encourage the woman to consider what is going in her mind when she is sexual rather than believing the etiology of her arousal dysfunction is confined to her genitalia. In these situations, a psychiatrist not focusing his or her practice on sexual medicine may consider it more appropriate to have a colleague perform the physical examination.

 

Validated Questionnaires

Validated questionnaires are available but are best considered as survey instruments, for example in epidemiologic studies, since they provide only a cursory picture of sexual functioning and are not intended for use to make diagnoses. The algorithms in Figure 2 show how the diagnostic label stems from the assessment questions.28,48

 

 

 

Management of Disordered Sexual Arousal and Desire

The approach is to address the problematic areas in a woman’s sex response cycle that have been identified during the detailed assessment. It is guided by the documented robust correlations between women’s sexual satisfaction and their mental health, including self-image and their emotional intimacy with their partner. It is important to note that assessment typically continues throughout treatment as new information emerges.

 

Psychosexual Therapy

Figure 3 outlines the progression through psychosexual therapy options, initially addressing any mood disorder or interpersonal difficulties.48 Psychosexual education is often therapeutic. The couple is informed about women’s (and men’s) sexual response cycles, clarifying that suitable context and sexual stimuli are needed by all women to trigger desire on many, if not all, occasions. Cognitive-behavioral therapy (CBT) techniques clarify and challenge inaccurate thoughts, beliefs, and myths about the woman’s sexual response, herself, and frequently, misunderstandings about her partner. Behavioral therapy includes sensate focus treatment that targets anticipatory anxiety and performance anxiety about sexual activity. Briefly, these exercises involve the partners taking turns in providing pleasurable low-key sensual and then sexual stimulation to each other, with the recipient guiding as to the type of stimulation they would like. Once the couple has practiced with the low-key types of stimulation, more areas of the body are included, but intercourse itself is still “off-limits.” Focusing on the moment, guiding the partner, finding the pace at which she is more comfortable to progress with sexual activity, and realizing that sexual times can be planned in advance are all potential benefits of sensate focus therapy. When distractions are a difficulty, discussion of the mindfulness technique is warranted. Relevant literature or preferably classes can be suggested. Initially, mindfulness practice in non-sexual everyday life is encouraged and only later guidance on how to specifically use this skill during sexual activity is given.

 

Psychotherapy can include either psychodynamic treatment or psychoanalysis. The latter would be prescribed when there was belief that the sexual dysfunction is at least partially due to pathologic processes in personality development. To help the woman relate intimately to her partner, she works through conflicts from the past that were present in non-sexual relationships. While psychotherapy is supported by the clinical literature, there is minimal empirical support.49

In practice, commonly these methods are mixed. For example, “psychoeducational therapy” can involve CBT techniques, sexual information, sex therapy, and mindfulness practice. It has proven beneficial for women with desire and arousal disorders particularly if they have a history of sexual abuse50 as well as for women with genital sexual arousal disorder due to gynecologic cancer.51 Larger studies with wait-list controls are in process.

 

Hormonal Therapy

Estrogen-related dryness and dyspareunia improve with topical/local or systemic estrogen supplementation. Indirectly, sexual motivation may be improved. Although less well studied, genital sexual sensitivity may also respond to estrogen in the postmenopausal woman.

Supplemental testosterone for postmenopausal women is not approved in the US, but it has been prescribed since the 1930s, off-label, using formulations approved for men or using compounded creams. The previously mentioned recent RCTs8 of transdermal testosterone to surgically (four studies) and naturally (one study) menopausal estrogen supplemented women all by the same sponsor and using the same protocol showed modest benefit from the 300 mcg/day but not the 450 mcg/day dose. At recruitment, the women on average reported three sexually satisfying events each month and these increased to approximately five with active drug and to four with placebo.8 On the basis of this documented benefit, transdermal testosterone has been approved by the European Union for surgically menopausal women. More recently, minimal or no benefit was seen from transdermal testosterone in estrogen-deficient women.52 In pre-menopausal women only one of three doses aimed to increase pre-testosterone levels to the high normal range proved beneficial, and that benefit was in the order of 0.8 more sexually satisfying events per month and was not associated with any improvements beyond placebo as measured by a validated sexual function and satisfaction questionnaire.53 However, consistently, the focus has been on increasing the sexual frequency, recruiting women with satisfactory sexual experiences.

Numerous unresolved issues are shown in Table 4.8,37-39,52,53 A major concern is lack of long-term safety data. Recent reviews of potentially increased risk of breast cancer,54 metabolic syndrome,55 and cardiovascular disease clarify the current clinical dilemma. Testosterone supplementation requires co-administration of estrogen, which presents further difficulty. Despite cardiovascular benefit identified in non-randomized prospective trials of systemic estrogen initiated at menopause, women are currently advised against on-going systemic estrogen on the basis of cardiovascular harm shown in RCTs of women beginning estrogen supplementation many years post menopause.56 A 2006 guideline42 reviews some of these complexities underlying the American Endocrine Society’s advising against testosterone supplementation.

 

 

Identification of Women with “Androgen Deficiency”

Identifying women with “androgen deficiency” is currently not possible.43 The hypopituitary state would be a clear indication of androgen deficiency, but there is little clarity beyond that. Intracellular production of testosterone continues indefinitely as some supply of prohormones from adrenal glands (and ovaries in some women) continues indefinitely. Loss of ovarian androgens from surgery may not amount to androgen deficiency; note the studies showing elective bilateral oophorectomy at the time of perimenopausal hysterectomy does not lead to sexual dysfunction.37-39 As previously mentioned, serum levels of testosterone do not correlate with sexual function and androgen metabolites have not yet been shown to correlate with sexual function.

 

Investigational Therapy

Table 5 outlines some investigational drugs.57-68 The ongoing interest in addressing deficient genital congestion with various drugs, including phosphodiesterase inhibitors, alpha blockers, selective estrogen receptor modulators, and peptidase inhibitors is somewhat puzzling given the documented lack of correlation between women’s sexual symptoms and any measurable deficit in genital congestion. However, these drugs might benefit women with deficient congestion due to, for example, non-nerve-sparing radical hysterectomies.

 

 

 

Conclusion

Current understanding of women’s sex response cycle allows patients and clinicians to consider the points of interruption when difficulties with arousal and desire are reported. Women’s sexual motivation is broad such that interpersonal or personal psychological issues can readily deter women from instigating or accepting sex. Sexual stimuli in appropriate contexts are needed for the sexual response to unfold and trigger arousal and desire. Commonly, these are lacking or problematic. Distractions, low self-image, and difficulties with trust may preclude sufficient arousal to allow pleasure and more intense arousal along with desire. Concern about a negative outcome physically or emotionally may similarly lessen arousal. Having first addressed any mental health or interpersonal issues, combinations of psychoeducation, CBT, and sex therapy are the mainstay of therapy. Teaching mindfulness techniques appears to be a promising addition. Identifying women whose sexual disorder is based on deficiency of sex hormone activity remains challenging. Testosterone supplementation for loss of both initial and triggered desire requires investigation. Pharmacologic adjuncts are being investigated and may have a role especially for genital sexual arousal disorder. PP

 

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