Psychiatric Dispatches

Print Friendly 

New Mechanisms of Action Explored in Promising Alzheimer’s Disease Therapies

Two new therapies show promise targeting Alzheimer’s disease at little-explored mechanisms of action, researchers announced at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD). Such treatments may pave the way to safe and effective disease-modifying therapies for Alzheimer’s disease, a goal that has eluded researchers in recent years.

At ICAD, Philip Scheltens, MD, PhD, of the Alzheimer Center of the VU University Medical Centre, Amsterdam, the Netherlands, presented data from a 12-week, randomized, double-blind, placebo-controlled study of Souvenaid, a drink containing the nutrients uridine monophosphate, choline, omega-3 fatty acids, phospholipids, B vitamins, and antioxidants. Souvenaid had been shown to increase synapse formation in preliminary studies by the Massachusetts Institute of Technology. It is believed that the nutrients in Souvenaid impact the synthesis of the membrane phosphatides that compose neural synapses. The provision of these nutrients, it is hypothesized, could promote brain cell outgrowth, synapse formation, and neurotransmitter release, and could also improve cognitive function.

Two hundred twelve subjects with mild Alzheimer’s disease were recruited from the Netherlands, Germany, Belgium, and the United States. Of these, half were assigned to receive 125 ml of Souvenaid per day, and half received a control drink. None of the subjects had received prior treatment for their condition. The primary outcome measures were cognition on the Wechsler Memory Scale-revised and the modified Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). Secondary outcomes included the Mini Mental State Examination (MMSE), the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, Clinician’s Interview Based Impression of Change plus Caregiver Input (CIBIC-plus), the Quality of Life in Alzheimer’s Disease, and the Neuropsychiatric Inventory (NPI). This study also included an optional 12-week extension phase, which 85% of subjects who completed the first phase elected to participate in.

Investigators found a statistically significant benefit on the delayed verbal memory test in the Souvenaid group. There appeared to be no significant effect on the modified ADAS-cog. There was no decline in modified ADAS-cog and verbal memory in the control group during the 12 weeks of the study, however subjects with a higher baseline ADAS-cog score seemed to experience greater cognitive effect with Souvenaid.  Souvenaid was well tolerated and showed a good safety profile.

“We believe that medical foods such as Souvenaid can be a valuable part of Alzheimer’s disease management,” said Dr. Scheltens, and this trial showed proof of concept.

Mitochondrial function is another mechanism of action being explored in potential Alzheimer’s disease treatments. Dimebon, a product of Medivation that improves impaired mitochondrial function, showed efficacy in preserving function among subjects with Alzheimer’s disease in an 18-month extension trial. Initially, 183 subjects were randomized to dimebon or placebo for six months, after which subjects could elect to remain in the study for an additional six months. After the completion of both of these periods, an open-label extension was conducted in which 104 participants received dimebon 20 mg TID. Of these participants, 92 had completed 6 months of prior treatment with dimebon.

Jeffrey L. Cummings, MD, director of the Mary S. Easton Centre for Alzheimer’s Disease at the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues found that subjects who received dimebon through all 18 months of the study showed preservation of function close to their baseline measures. They showed benefit compared to projected placebo decline on the ADAS-cog, CIBIC-plus, ADCS-ADL, NPI, and MMSE. Those who had been randomized to placebo during the first 12 months, then to dimebon for open-label trial showed stabilization of their previous decline on all endpoints. Those who received dimebon for 18 months continued to show benefit over those receiving the agent for only six, suggesting this treatment may have disease-modifying properties. However, Dr. Cummings advised that “open-label extensions are not the same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution.” Phase III clinical trials are currently being planned.

Funding for the clinical trial of Souvenaid was provided by the Danone Research Centre for Specialised Nutrition. Funding for the 18-month extension trial of dimebon was provided by Medivation, Inc. (July 29, 2008. Alzheimer’s Association’s International Conference on Alzheimer’s Disease.) –RZ

High Incidence of Psychiatric Disorders in Youths Transferred to Adult Courts

Legal mandates in all states and the District of Columbia allow them to try juveniles in adult courts based on the type of offense, criminal history, and age of the offender. While the transferred youth population steadily climbs, primary care physicians are likely to encounter them, as these young individuals are at high risk for disorder. Jason J. Washburn, PhD, at Northwestern University Feinberg School of Medicine, and colleagues, compared the occurrence of psychiatric disorders among youths tried in adult court to that of youths processed in juvenile court.

They garnered a stratified random sample of 1,829 youths 10–18 years of age arrested in Chicago. One thousand seven-hundred fifteen of them (1,440 processed in juvenile court; 275 processed in adult criminal court) 13–18 years of age underwent version 2.3 of the Diagnostic Interview Schedule for Children.
Results, even after analyses controlled for felony-level violent crime, found males, African Americans, Hispanics, and older youths more likely to be processed in adult criminal court than females, non-Hispanic whites, and younger youths. Sixty-eight percent of youths processed in adult criminal court presented with ≥1 psychiatric disorder, and 43% had ≥2 types of disorders; such figures and findings were essential the same for those processed in juvenile court. However, the most interesting finding concerned juvenile offenders sentenced to prison in adult criminal court.

“These youths [sentenced to prison in adult court] were not only more likely to have disruptive behavior and substance use disorders, as might be expected from more ‘antisocial’ youths, but they were also more likely to have comorbid affective and anxiety disorders,” Washburn said. “These youths who were tried as adults, found guilty, and sentenced to prison had nearly three times the odds of having comorbid affective and anxiety disorders than youths given a lesser sentence.”

It is important to note the study’s dependence on self-report since parents of the offenders could not be interviewed and a majority of them could not be located. Such dependence possibly underestimates actual rates of certain disorders (ie, disruptive behavioral disorders).

Washburn and colleagues’ study outlines the lack of mental health care available for males coming from racial-ethnic minority groups. Psychiatric services within community and correctional systems for youths processed in adult criminal court, particularly those sentenced to prison, are needed.

“Because many of these youths are unlikely to receive appropriate treatment, primary care physicians can be a critical resource for identifying and connecting this vulnerable population with services,” Washburn added.

Funding for this study was provided by grants from the Division of Services and Intervention Research; Center for Mental Health Research on AIDS of the National Institute of Mental Health; Office of Juvenile Justice and Delinquency Prevention, US Department of Justice; National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH); Center for Mental Health Services, Center for Substance Abuse Prevention, and Center for Substance Abuse Treatment of the Substance Abuse and Mental Health Services Administration; National Center on Injury Prevention and Control and National Center for HIV, Sexually Transmitted Disease, and Tuberculosis Prevention of the Centers for Disease Control and Prevention; NIH Office of Research on Women’s Health; NIH Center on Minority Health and Health Disparities; US Department of Housing and Urban Development; NIH Office on Rare Diseases; US Department of Labor; William T. Grant Foundation; Robert Wood Johnson Foundation; John D. and Catherine T. MacArthur Foundation; Open Society Institute; and Chicago Community Trust. (Psychiatr Serv. 2008;59(9):965-973.) –ML

Acute Stress Disorder Not Effective Predictor of Posttraumatic Stress Disorder

Although prior studies have shown evidence that the presence of acute stress disorder can predict the later onset of posttraumatic stress disorder (PTSD), other studies have shown mixed or conflicting results. Additional studies examining the relationship between PTSD and acute stress disorder have also been limited due to single site study locations and small sample sizes. Recently, researchers at the School of Psychology at the University of New South Wales in Sydney, Australia evaluated any possible relationship between the two disorders with a large-scale, multi-site study in order to reduce limitations found with prior studies.

Richard A. Bryant, PhD, and colleagues examined 597 patients admitted to four major trauma hospitals during a 1-year period for presence of acute stress disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Among patients assessed, 62% suffered injury due to automobile accident, 16% due to fall, 8% due to industrial accident, and 5% due to assault; 9% were admitted to trauma hospitals for other reasons. All patients were randomly selected for screening during hospital admission, which occurred within 1 month of trauma exposure, and reassessed for PTSD at 3 months following the initial assessment (N=507). Among patients who met criteria for PTSD at follow-up, the authors studied how many also presented with acute stress disorder at first assessment to determine predictive rates between the disorders.

Bryant and colleagues found that 33 patients met DSM-IV criteria for acute stress disorder and 49 patients met diagnostic criteria for PTSD at 3-month follow-up. Fifteen patients diagnosed with acute stress disorder and 34 patients who were not diagnosed with acute stress disorder were later diagnosed with PTSD at follow-up. For patients who experienced brain injury in addition to other trauma, presence of acute stress disorder predicted later development of PTSD in 58% of all patients with brain injury as compared to 31% among all patients presenting with trauma.  

Due to the main findings, the authors concluded that the majority of patients who develop chronic PTSD do not initially present with acute stress disorder. The study’s results are similar to results found in other studies and illustrate that presence of acute stress disorder is not an effective tool to predict chronic PTSD. The authors recommend researchers seek to create improved tools for physicians to determine the development of chronic PTSD among trauma patients as acute stress disorder may be more predictive of PTSD in patients whose trauma occurred due to non-accidental incidence, such as physical assault or military combat. Bryant and colleagues added that patient heart rates or mood states following trauma may be better predictors of subsequent chronic PTSD development.

 
Funding for this research was provided by the Australian National Health and Medical Research Council. (J Clin Psychiatry. 2008;69(6):923-929.) –CP

Childhood Abuse May Lead to Adult Obesity

Obesity is a continuously spreading global epidemic. While the disease has been linked to mental disorders such as anxiety and depression, whether these conditions truly lead to mid-life obesity is unknown. In addition, historic and contextual factors have been seldom researched. However, a recent study of 9,310 members of the 1958 British birth cohort by Claudia Thomas, PhD, of the University College of London and colleagues found that physical abuse during childhood served as a precursor to mid-life obesity.

Each member was evaluated for negative experiences (ie, verbal, physical, or sexual abuse, parental depression, authoritarian upbringing, parental separation/divorce) at 7, 11, and 16 years of age. At 45 years of age, subjects underwent a biomedical interview, ascertaining their body mass index (BMI), waist circumference, and glycosylated hemoglobin level. Total obesity was defined by a BMI of ≥30, and a waist circumference of ≥102 cm and ≥88 cm indicated central obesity for men and women, respectively. Any individual with a glycosylated hemoglobin level of ≥6 was considered obese. The researchers used the negative-experience findings and the data gathered from the biomedical interviews to determine whether negative childhood experiences were associated with obesity, specifically at 45 years of age.

Results revealed that mid-life obesity risk increased by 20% to 50% for those who experienced negative childhood events. Adverse childhood events most strongly associated with obesity were indicated in members with glycosylated hemoglobin levels of ≥6. However, most associations were explained by adjustment for adulthood mediators (eg, obesity). Effects of other adversities exhibiting milder emotional neglect and less harsh family environments were mostly due to socioeconomic factors during upbringing.

Though findings indicate childhood adversities increase risk of obesity in adulthood, further research is needed to better understand interrelations among the adversities, social contexts in which they occur, and trajectories from harsh childhood circumstances to adult disease. (Pediatrics. 2008;121(5):e1240-e1249.) –ML

Paternal Age and Risk of Bipolar Disorder

Advanced age of fathers or mothers can increase the risk of bipolar disorder in their offspring, although the effect of paternal age is much more significant, especially in the risk of early-onset bipolar disorder. A large, national, case-control study from Sweden suggests that the risk of developing bipolar disorder is higher in the offspring of older fathers.

Emma M. Frans, M.Med.Sc., at the Karolinska Institutet, in Stockholm, Sweden, and colleagues selected 13,428 people with a bipolar disorder diagnosis from the Swedish national databases Multigeneration Register and the Hospital Discharge Register, each of whom were required to have had a bipolar disorder diagnosis on ≥2 separate hospital admissions. For each person in the bipolar disorder group, the researchers chose five random, age- and sex-matched controls without bipolar disorder.

The researchers controlled for parity, maternal age, socioeconomic status, and family history of psychotic disorders, finding that the offspring of men ≥55 years of age were 1.37 times more likely to be diagnosed with bipolar disorder (CI, 1.02–1.84), compared to the offspring of men 20–24 years of age. Advanced maternal age was less significant. The effect of advanced paternal age was much stronger for early-onset cases of bipolar disorder (odds ratio, 2.63; CI, 1.19–5.81), although there was no link with maternal age. (Arch Gen Psychiatry. 2008;65(9):1034–1040.) –LS

Psychiatric Disturbance in Low Birth Weight Children from Urban and Suburban Communities

According to previous research, children born with low weight (≤5.5 pounds), very low weight (≤3.3 pounds), and extremely low weight infants (≤2.2 pounds) may have higher risk of externalizing (ie, delinquent and aggressive behavior), internalizing (ie, withdrawn behavior, anxiety/depression), and attention (ie, symptoms of attention-deficit/hyperactive disorder) problems. Despite advances in neonatal medicine increasing survivorship of low birth weight infants, Naomi Breslau, PhD, and Kipling M. Bohnert, BA, of Michigan State University in East Lansing investigated the long-term effects of low birth weight on psychiatric problems in both socially disadvantaged children and middle-class children.

The study involved a stratified random sample of 823 urban (n=413) and suburban (n=410) low and normal birth weight children from newborn discharge lists (from 1983 through 1985) in two Detroit, Michigan hospitals.  Mothers and teachers used the Child Behavior Checklist and Teacher’s Report Form to rate children’s attention, externalizing, and internalizing problems at 6, 11, and 17 years of age. Standard cutoffs were used to identify infants with psychiatric disturbances above normal range.

Results found that psychiatric outcomes of low birth weight did not vary across age. However, low birth weight children had moderate excesses of externalizing (adjust odds ratio [AOR]=1.53; P=.001) and internalizing (AOR=1.28; P=.02) disturbances. Children from the urban cohort demonstrated greater risk of attention problems associated with low birth weight, with very low birth weight infants having higher risk than heavier low birth weight infants. Interestingly, the suburban counterparts showed no increased risk for attention problems associated with low birth weight.

The data indicate that low birth weight effects on psychiatric disturbance are relatively stable during the period of school attendance. However, the differential effect of low birth weight on attention problems between the urban and suburban communities suggests a relationship between prenatal adversity and social environment.

Funding for this research was provided by grants from the National Institute of Mental Health and the National Institute on Drug Abuse. (Arch Gen Psychiatry. 2008;65(9):1080-1086.) –ML


Psychiatric dispatches is written by Michelisa Lanche, Carlos Perkins, Jr, Lonnie Stoltzfoos, and Rebecca Zerzan.

 

Needs Assessment: Breast cancer reconstruction is powerful in helping patients recover from breast cancer therapy, but it remains underutilized in the United States healthcare system. It is essential for clinicians involved in the early phases of breast cancer diagnosis to understand factors involved in breast cancer reconstruction and to be able to provide access to information or specialists who can adequately educate patients during their decision-making process.

Learning Objectives:
• Identify the practical, psychological, and clinical factors involved in a woman’s decision to undergo breast cancer reconstruction
• Summarize the types of breast reconstruction and their advantages/disadvantages
• Evaluate the available data regarding the psychological impact of breast cancer reconstruction and determine how this can be helpful in counseling 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):72-80

 

Dr. Ceradini is chief resident at the Institute of Reconstructive Plastic Surgery at New York University (NYU) Langone Medical Center. Dr. Levine is assistant professor of surgery, director of microsurgery, and director of Bellevue Hospital Plastic Surgery at the Institute of Reconstructive Plastic Surgery at NYU Langone Medical Center.

Disclosures: Drs. Ceradini and Levine report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Jamie P. Levine, MD, New York University Langone Medical Center, TH-169, 550 1st Avenue, New York, NY 10016; Tel: 212-263-8452; Fax: 212-263-7002; E-mail: Jamie.Levine@nyumc.org.


Abstract

Breast cancer often leads to significant alteration of body image and disfigurement of the breast. Reconstruction for breast cancer defects can provide the patient with a restored breast contour. The potential benefit of breast cancer reconstructive surgery is to increase the patient’s post-surgical quality of life and alleviate the posttraumatic psychological sequelae of breast cancer surgery. Time of breast cancer diagnosis is an important point of access for patients to receive information on breast reconstruction. Access to this information and plastic surgeons in the early phases of diagnosis is critical to a patient’s decision to undergo reconstructive surgery, but is currently underutilized in the United States. Breast cancer reconstruction is a complex process that should be treated in a multidisciplinary fashion. This process must begin with the identification and treatment of psychological issues preceding or accompanying breast cancer diagnosis. These psychological problems should be addressed immediately and can significantly influence a patient’s decision toward and level of satisfaction with breast cancer reconstruction. Breast reconstruction continues to be an essential element in helping patients recover from the diagnosis and treatment for breast cancer.

Introduction

The evolution of surgical decision making in breast cancer treatment has created a challenging environment for breast cancer reconstruction. Breast cancer is the most common form of cancer diagnosed in women. In 2007, it was the second leading cause of cancer mortality. Current data suggests that one in eight women will be diagnosed with breast cancer in their lifetime. While the incidence of breast cancer has progressively increased in the United States over the past 2 decades, the mortality from breast cancer has declined largely due to better detection and improved therapeutic interventions.1 Unlike the vast majority of cancers, breast cancer is unique in that the treatment often leads to significant alteration of body image2,3 and disfigurement of the breast, which is considered to be a major symbol of femininity and sexuality.4,5 There has been a trend over the past decade toward therapeutic interventions attempting to preserve as much of the native breast as possible to avoid these issues, particularly breast conservation therapy (BCT).

Along with these changes in the approach to breast cancer therapy, the indications, options, and ultimate aesthetic outcomes of breast cancer reconstruction have changed. It is estimated that 57,102 breast reconstructions were performed in 2007 compared to 80,908 performed in 2000.6 This reduction in the rate of breast reconstruction likely reflects the trend toward earlier detection and BCT for smaller tumors. The theoretical advantage of breast cancer reconstruction is to recreate the patient’s breast contour following mastectomy, thereby restoring the feminine form, increasing quality of life (QOL), and alleviating the posttraumatic psychological sequelae of breast cancer surgery. Indeed, while there is tremendous interest in and investigation into the psychological issues of breast cancer, the study of the psychology of breast cancer reconstruction is in its infancy. This article reviews clinical data and specific psychological issues in breast cancer reconstruction to facilitate counseling of these patients during their treatment.

Preoperative Decision Making in Breast Cancer Reconstruction: Psychological Impact of the Breast Cancer Diagnosis

The diagnosis of breast cancer frequently leads to significant psychological problems that can interfere with patients’ course of treatment.7 Patients often learn of their diagnosis from their primary care physician or gynecologist who refers them to a surgical oncologist. Prior to their surgical consultation, >40% of newly diagnosed breast cancer patients rate their psychological distress as clinically significant resulting in practical, family-related, emotional, and physical problems. In addition, rates of major depressive disorder (11%) and posttraumatic stress disorder (10%) in these patients significantly interfere with their activities of daily function.7 Despite these statistics, many women are reluctant to discuss psychological distress8 and few are screened for distress during their surgical work up and treatment.9 These problems can persist over 10 years following treatment,10 indicating that early identification and treatment is critical to long-term psychological well being. Furthermore, early intervention may facilitate a patient’s decision making for breast reconstruction and ultimately influence her satisfaction with the final appearance. Examination of women with higher levels of preoperative affective distress, depression, anxiety, and somatic preoccupation revealed they were significantly less satisfied with both the general and aesthetic outcome of their breast reconstruction.11 This suggests that mental healthcare providers have an integral role in the pre- and postoperative treatment of breast cancer. In most multidisciplinary cancer centers, psychological evaluation and support play an important role in both the initial evaluation and the patient’s long-term care.

Patient Decision Making and Access to Breast Reconstruction

Within 2 weeks following diagnosis, patients may have up to four medical or surgical consultations, including those by radiation oncologists and a reconstructive plastic surgeon, who will outline a treatment plan collectively. The oncologic treatment algorithm is largely driven by data and requires very few choices by the patient; that is, given the imaging findings and clinical stage of breast cancer, the survival of various operative approaches, surgical margins, and adjuvant therapy have been well studied and guide patients’ decision making. However, one of the few critical decisions a patient needs to make regarding oncologic therapy in early breast cancer is whether to have a mastectomy or undergo BCT. This decision is usually reserved for patients with stage I or II disease, and data from multiple studies has established that the long-term survival between these two treatment modalities is equivalent up to 20 years post-therapy.12,13 Furthermore, emerging neoadjuvant treatment protocols may facilitate BCT in select patients who would otherwise require a formal mastectomy. This is usually a discussion between the patient and an oncologic surgeon, and it does not necessarily involve a reconstructive surgery consultation. This is unfortunate, as plastic surgeons utilize numerous approaches to local tumor resection to minimize the aesthetic impact of breast excision frequently overlooked by oncologic surgeons. In fact, early discussion of reconstruction may also allow patients to more comfortably choose mastectomy over BCT. The aesthetic consequences of a lumpectomy excision in a relatively small breast with postoperative radiation (ie, BCT) must be weighed against a total mastectomy with reconstruction (Figure 1). In certain circumstances, the mastectomy with reconstruction will actually provide a better aesthetic outcome. Therefore, involvement of the reconstructive surgeon during the treatment planning process may facilitate decision making by providing patients with a reasonable expectation of aesthetic outcome, regardless of the mode of therapy selected.

 

 

 
Despite the potential advantages offered by BCT, mastectomy remains the treatment of choice for a select number of early cancers and the vast majority of more advanced cancers. The rate of breast reconstruction following mastectomy in the US has increased over the past 3 decades from 3.4% in the mid 1980s, to 8.3% in the early 1990s, to nearly 40% in the 2000s.14,15 Younger age seems to be the most powerful predictive factor for breast cancer reconstruction. Higher income, higher levels of education, race, and tumor stage also play a significant role. The seemingly low global rate of reconstruction following mastectomy may be explained by a failure to adequately inform patients of their reconstructive options at the time of clinical decision making. A population-based study by Morrow and colleagues15 demonstrated that while 78% of breast cancer patients report some discussion of breast reconstruction, <12% could answer three basic questions on breast reconstruction that would be required for informed consent. In addition, more recent data suggest that only 33% of general surgeons discuss breast reconstruction with patients during consultation.18 Patients who understand their reconstructive options were four times more likely to opt for mastectomy with reconstruction than those who were not counseled on reconstruction. The desire to avoid more surgery and the belief that breast reconstruction was not important were the most common reasons to avoid reconstruction.18 This loss of first-line counseling is clearly a major barrier to informed decision making in breast cancer reconstruction. These data become even more interesting when compared to a healthcare system where breast reconstruction is universally proposed during the surgical oncology consultation. Under these conditions, investigators in France report that 81% of breast cancer patients evaluated for mastectomy selected breast reconstruction, more than double the number of US women in the busiest centers.19 These data strongly suggest that one’s being adequately informed about breast cancer reconstruction and having access to reconstructive options significantly impacts a patient’s decision on breast cancer reconstruction.

Immediate versus Delayed Reconstruction

In the majority of cases, immediate breast reconstruction following mastectomy is considered the standard of care and affords a number of psychological benefits compared to delayed reconstruction, including a decrease in post-mastectomy anxiety and depression as well as improved self-esteem and sexual satisfaction.20 In addition, prospective studies suggest that the QOL 1 year following immediate reconstruction approaches that of age-matched control subjects without breast cancer.21 However, after 1 year, there appears to be no difference in the general and aesthetic satisfaction with reconstruction between immediate and delayed reconstruction.22

There is still a significant role for delayed reconstruction, particularly in patients with advanced cancers who will require postoperative radiation therapy. Radiation causes progressive fibrosis and microvascular obliteration that manifests as poor wound healing and scar contracture, compromising the tissue health and the ultimate aesthetic outcome of the breast reconstruction. Due to these potential complications, most surgeons would defer reconstruction in this patient population until after radiotherapy when the rate of complications approaches that of non-irradiated patients (Figure 2).23

 

Autologous Tissue versus Implant-based Reconstruction

There are two broad classifications of breast reconstruction following mastectomy. One is the use of prosthetic implants inserted under the skin and muscle of the mastectomy flaps, and the other is transfer of the patient’s own autologous tissue into the mastectomy defect to recreate the contour of the breast mound (Figures 3 and 4). The choice of reconstructive methodology depends on numerous factors, including patient preferences, surgical expertise, stage of disease, potential for postoperative radiation, availability of donor tissue, and general medical health of the patient preoperatively. The potential advantages and disadvantages of these reconstructive options are summarized in the Table.

 

 

 

 
Implant-based reconstruction has evolved significantly over the past decade and, according to 2007 Americian Society of Plastic Surgeons statistics, accounts for approximately 75% of breast reconstruction performed in 2007.6 Typically, this reconstruction can be performed either as a single immediate procedure with insertion of a long-term prosthesis at the time of mastectomy or more commonly as a two-stage procedure, wherein a temporary tissue expander is inserted at time of mastectomy, expanded in an office setting over 1–2 months, and then replaced with a long-term prosthesis (Figures 5 and 6). Very high levels of patient satisfaction have been reported using these techniques.24 The down side of this approach is that it requires a two-stage approach, as noted above, and the implants need to be exchanged at regular intervals based on the approximate 10-year lifespan of the implant device.

 

 

Autologous breast reconstruction utilizes a patient’s own tissue to recreate the breast shape, most often involving the transfer of excess skin, fat, and sometimes muscle from a patient’s abdomen to the mastectomy defect. Compared to implant-based reconstruction, the operative time and hospital stay following these procedures is significantly longer. While this reconstruction creates a more natural breast, removal of this “donor tissue” from its native location can weaken the abdominal wall. This has not been found to affect health-related and physical QOL using standardized measures, but it may limit more strenuous physical exercise.25 Based on prospective studies, women selecting autologous reconstruction are aesthetically more satisfied with their reconstruction than women who opt for implant-based reconstruction while the levels of general satisfaction were comparable 2 years postoperatively.22,26,27

In either method, the final stage of reconstruction is the re-creation of the nipple-areolar complex (Figure 7). This typically occurs in a staged fashion under minimal anesthetic. Local skin flaps are re-arranged in such a way to create a projecting nipple. Finally, the surrounding skin and reconstructed nipple can be tattooed to match the areolar color of the contralateral side to complete the breast reconstruction.

 

Impact of Post-mastectomy Radiation

Another important preoperative consideration in breast reconstruction relates to the increasing role of post-mastectomy radiation in breast cancer therapy.28 Frequently, the ultimate oncologic stage is uncertain at the time of mastectomy as definitive pathologic analysis is required to determine the involvement of the axillary lymph nodes. This presents several issues with clinical decision making for breast reconstruction. First, and most importantly, the patient will not know the extent of postoperative adjuvant therapy required (ie, radiation and/or chemotherapy). While breast reconstruction has not been shown to impact the administration of postoperative chemotherapy, radiation, or the ability to detect locoregional recurrence,29-33 complications of the reconstruction, including problems with wound healing can delay adjuvant therapy, which is a source of anxiety for both patient and physician.

Second, whether or not the patient will require radiation potentially changes the optimal reconstructive plan. If this is ultimately determined 1 week following mastectomy after the pathology has been finalized, it presents an obvious clinical dilemma. When it is certain that a patient will not require postoperative radiation, all reconstructive options are available to him or her. Alternatively, if it is known that the patient will definitely require postoperative radiation, then most surgeons would alter their reconstructive plan to either delay reconstruction all together or offer a very limited number of options due to the known increase in complications related to reconstruction after radiation therapy. One such option may be the temporary placement of a tissue expander to maximize skin stretch prior to radiation, which is converted to another form of reconstruction after radiation treatment is completed. However, there is no consensus among plastic surgeons on the use of this particular technique.

In patients presenting with intermediate-sized tumors and clinically negative axillary lymph nodes, it is unknown at the time of mastectomy whether the patient will receive postoperative radiation therapy. Sentinel lymph node biopsy has become the standard tool used to detect involvement in the clinically negative axilla. A negative sentinel node in experienced hands has a 5% to 10% false-negative rate on intraoperative evaluation, making the likelihood of postmastectomy radiation very low when the sentinel node is negative.34 Conversely, a positive sentinel node mandates a formal axillary dissection to quantify the number of nodes involved determined by pathologic diagnosis several days later. Currently, ≥4 positive nodes are an indication for radiotherapy. Again, the uncertainty of postoperative radiotherapy in this situation and how reconstruction should be managed has been the topic of much debate.35,36

Psychological Outcomes of Breast Cancer Reconstruction

Breast reconstruction is powerful in helping patients cope with and recover from the sequelae of breast cancer. The most important measures of success in reconstruction are the level of improvement in QOL and patient satisfaction. In studying these outcomes, it is difficult to utilize prospectively randomized trials to evaluate breast cancer reconstruction, as patient decision making is essential and serves as the basis for this elective procedure. As a result, there are a variety of studies with varied designs and endpoints that must be interpreted wholly rather than individually.

Rubino and colleagues37 retrospectively examined QOL, sexual function, anxiety, and depression of healthy women, mastectomy-only patients, and mastectomy with reconstruction patients at 1 year postoperatively in Italy. They found that after one year there was no statistical difference between healthy patients and reconstructed patients using measures of social and sexual relationships as well as overall QOL. Further, they found that indicators of depression were less severe in reconstructed patients compared to mastectomy-only patients, while levels of anxiety remained similar between these groups. Although reporting relatively few numbers, they identified that a pre-existing psychological disorder was an indicator for postoperative dissatisfaction with reconstruction. They did not demonstrate any significant difference between the type and timing of breast reconstruction. While these data suggest a significant benefit to breast reconstruction, it is unclear whether there were baseline psychological differences between the two groups preoperatively (ie, patients with higher QOL standards may opt to undergo breast reconstruction more frequently). Nonetheless, these data provide strong evidence that patients benefit from breast reconstruction.

Elder and colleagues21 prospectively compared QOL in a broad range of categories under the Medical Outcome Study 36-Item short form in Swedish women who underwent immediate implant-based reconstruction compared to a healthy reference population at 1 year. These investigators found that, like others before them, the QOL measures were lower pre-operatively in the breast cancer group than the reference population. However, 1 year following surgery, they found that QOL measures of patients who underwent immediate breast reconstruction returned to levels comparable to that of the reference population with a high rate of reconstruction satisfaction. While this study did not analyze a group that underwent mastectomy-only or breast-conserving surgery, these data seem to support the psychological benefits of immediate breast reconstruction.

Ananian and colleagues19 prospectively examined factors involved in patient decision making for breast cancer reconstruction in a French healthcare system that universally offers reconstruction (without added cost) to mastectomy patients. This is important because reconstruction is not a universally discussed topic during oncologic consultation in the US. They found a strikingly high rate of breast reconstruction following mastectomy (81%). Greater awareness of body image was an important factor in the decision to reconstruct while fears of additional surgery prevented most women who did not choose to have reconstruction from choosing this pathway. Patients selecting reconstruction were more often younger, active, and more educated patients who were with a partner. Furthermore, 83% of patients who chose to have reconstruction selected immediate reconstruction, most often predicted by breast symptoms, greater preoperative appetite loss, lower body mass index, and a more patient-centered doctor-patient relationship. Due to the nature of the healthcare system, this study essentially excluded issues of patient access to reconstruction information and economic restraints, focusing primarily on patient decision making. The higher rate of reconstruction (over twice that observed in the US) indicates the great influence that patient access to reconstruction information has on decision making in breast cancer reconstruction. These data suggest that when patients have access and are offered the option of reconstruction in a multidisciplinary and non-biased fashion, reconstructive rates will be high.

Harcourt and colleagues38 prospectively compared QOL indicators in women in the United Kingdom undergoing mastectomy alone, mastectomy with immediate reconstruction, and mastectomy with delayed reconstruction. Based on their data, they failed to identify a consistent benefit of immediate breast reconstruction in QOL and psychological variables but noted a significant improvement in a small sample of delayed reconstruction patients. However, there was a notable difference in the mean age of the mastectomy-only group compared to the two reconstructed groups (approximately 10 years), and as noted previously, age is the most powerful predictor of the decision to reconstruct. It has been suggested that possible reasons why older women are less likely to undergo reconstruction include the reluctance to undergo multiple additional procedures to complete the reconstruction, decreased importance of body image compared to younger patients, and the bias of surgeon selection of younger healthier patients who would tolerate a prolonged procedure.15

Based on the above studies, although somewhat disparate in terms of study designs and goals, it would seem that women’s attitudes toward breast reconstruction vary according to geographic and cultural differences. Mullan and colleagues39 specifically addressed this question, prospectively comparing the QOL of women from different countries undergoing mastectomy with reconstruction to healthy controls. They also observed an improvement in the psychological profile of women undergoing reconstruction but noted that country of origin and cross-cultural factors do not seem to contribute to the QOL benefit to breast reconstruction in these populations. As with earlier studies, however, there was no comparison to a mastectomy without reconstruction group. It has been reported that breast cancer patients experience some degree of improvement of QOL and psychological measures during the first year following mastectomy.

The Michigan Breast Reconstruction Outcome Study26,40 is a large prospective study underway examining patient satisfaction and QOL outcomes in patients undergoing different types of breast reconstruction. These investigators did not include a mastectomy-only group or a healthy reference population, as their goal was to compare procedure choice. Although still in data collection, patients who underwent autologous tissue reconstruction were more aesthetically satisfied 2 years postoperatively than patients who underwent implant-based reconstruction. The levels of general satisfaction with the reconstructive procedure were comparable at 2 years. It will be interesting to follow the outcome of this study to see if patient preference for autologous reconstruction persists beyond 5 years.

Parker and colleagues41 prospectively compared outcomes in patients with early breast cancer (stage I or II) who underwent mastectomy alone, mastectomy with reconstruction, and breast-conserving therapy. They found no differences in the majority of QOL and psychological outcomes 2 years following treatment. Specifically, they provided evidence that all three groups experience significant improvement in psychological functioning at two years, often returning to preoperative levels (ie, post-cancer diagnosis) but did not find that reconstruction differed from BCT significantly in level and rate of improvement. They found that patients reconstructed with autologous tissue were somewhat more satisfied with the appearance of their abdominal area (Figure 8) and that there was less of a decline in sexual function. While this study seems to conclude that BCT and reconstruction are equivalent in terms of outcomes, it is unclear how each patient was presented with their surgical options and how decision making was influenced by the surgeons. For example, in patients with large breasts, a small peripherally located tumor would likely have good to excellent cosmesis following BCT, and most plastic surgeons would agree that a formal “reconstruction” would not be required. Alternatively, in patients with small breasts for whom a significant percentage of the breast will be taken with the specimen, reconstruction would likely provide a better cosmetic outcome than BCT. The relationship between tumor size and the percent of breast parenchyma required for resection is an important factor that is often overlooked in outcome studies. It is unclear how these factors influenced the results reported in this study.

 

 

 

Conclusion

Breast cancer reconstruction is a complex process that should begin with the identification and treatment of psychological issues preceding or accompanying the diagnosis of breast cancer. Access and delivery of breast cancer reconstruction information to eligible patients remains widely underutilized. The time of breast cancer diagnosis is an important point of access for patients to either receive actual information or to be instructed on where to find information on breast reconstruction. Early consultation with a reconstructive plastic surgeon may facilitate patient decision making, optimizing the aesthetic outcome of breast reconstruction. Thus, a close collaboration between primary providers, oncologic surgeons, and plastic surgeons is essential. Several studies demonstrate positive psychological and QOL outcomes following breast cancer reconstruction and, in some cases, near normalization of these parameters when compared to healthy individuals. Breast cancer reconstruction continues to be an essential element in helping patients recover from breast cancer diagnosis and therapy. PP

References

 

1.    American Cancer Society. Cancer Facts & Figures: 2007. Atlanta, GA: American Cancer Society; 2007.
2.    Bard M, Sutherland AM. Psychological impact of cancer and its treatment. IV. Adaptation to radical mastectomy. Cancer. 1955;8(4):656-672.
3.    Bard M. The sequence of emotional reactions in radical mastectomy patients. Public Health Rep. 1952;67(11):1144-1148.
4.    Goin MK, Goin JM. Psychological reactions to prophylactic mastectomy synchronous with contralateral breast reconstruction. Plast Reconstr Surg. 1982;70(3):355-359.
5.    Steinberg MD, Juliano MA, Wise L. Psychological outcome of lumpectomy versus mastectomy in the treatment of breast cancer. Am J Psychiatry. 1985;142(1):34-39.
6.    American Society of Plastic Surgeons. 2007 Reconstructive Surgery Procedures. Arlington Heights, IL: American Society of Plastic Surgeons; 2007.
7.    Hegel MT, Moore CP, Collins ED, et al. Distress, psychiatric syndromes, and impairment of function in women with newly diagnosed breast cancer. Cancer. 2006;107(12):2924-2931.
8.    Koopman C, Angell K, Turner-Cobb JM, et al. Distress, coping, and social support among rural women recently diagnosed with primary breast cancer. Breast J. 2001;7(1):25-33.
9.    Fallowfield L, Ratcliffe D, Jenkins V, Saul J. Psychiatric morbidity and its recognition by doctors in patients with cancer. Br J Cancer. 2001;84(8):1011-1015.
10.    Kornblith AB, Herndon JE 2nd, Weiss RB, et al. Long-term adjustment of survivors of early-stage breast carcinoma, 20 years after adjuvant chemotherapy. Cancer. 2003;98(4):679-689.
11.    Roth RS, Lowery JC, Davis J, Wilkins EG. Psychological factors predict patient satisfaction with postmastectomy breast reconstruction. Plast Reconstr Surg. 2007;119(7):2008-2015.
12.    Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1995;333(22):1456-1461.
13.    Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227-1232.
14.    Rowland JH, Desmond KA, Meyerowitz BE, Belin TR, Wyatt GE, Ganz PA. Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst. 2000;92(17):1422-1429.
15.    Morrow M, Mujahid M, Lantz PM, et al. Correlates of breast reconstruction: results from a population-based study. Cancer. 2005;104(11):2340-2346.
16.    Morrow M, Scott SK, Menck HR, Mustoe TA, Winchester DP. Factors influencing the use of breast reconstruction postmastectomy: a National Cancer Database study. J Am Coll Surg. 2001;192(1):1-8.
17.    Christian CK, Niland J, Edge SB, et al. A multi-institutional analysis of the socioeconomic determinants of breast reconstruction: a study of the National Comprehensive Cancer Network. Ann Surg. 2006;243(2):241-249.
18.    Alderman AK, Hawley ST, Waljee J, Mujahid M, Morrow M, Katz SJ. Understanding the impact of breast reconstruction on the surgical decision-making process for breast cancer. Cancer. 2008;112(3):489-494.
19.    Ananian P, Houvenaeghel G, Protière C, et al. Determinants of patients’ choice of reconstruction with mastectomy for primary breast cancer. Ann Surg Oncol. 2004;11(8):762-771.
20.    Al-Ghazal SK, Sully L, Fallowfield L, Blamey RW. The psychological impact of immediate rather than delayed breast reconstruction. Eur J Surg Oncol. 2000;26(1):17-19.
21.    Elder EE, Brandberg Y, Bjorklund T, et al. Quality of life and patient satisfaction in breast cancer patients after immediate breast reconstruction: a prospective study. Breast. 2005;14(3):201-208.
22.    Alderman AK, Wilkins EG, Lowery JC, Kim M, Davis JA. Determinants of patient satisfaction in postmastectomy breast reconstruction. Plast Reconstr Surg. 2000;106(4):769-776.
23.    Williams JK, Bostwick J 3rd, Bried JT, Mackay G, Landry J, Benton J. TRAM flap breast reconstruction after radiation treatment. Ann Surg. 1995;221(6):756-764.
24.    Cordeiro PG, McCarthy CM. A single surgeon’s 12-year experience with tissue expander/implant breast reconstruction: part II. An analysis of long-term complications, aesthetic outcomes, and patient satisfaction. Plast Reconstr Surg. 2006;118(4):832-839.
25.    Dian D, Schwenn K, Mylonas I, Janni W, Friese K, Jaenicke F. Quality of life among breast cancer patients undergoing autologous breast reconstruction versus breast conserving therapy. J Cancer Res Clin Oncol. 2007;133(4):247-252.
26.    Alderman AK, Kuhn LE, Lowery JC, Wilkins EG. Does patient satisfaction with breast reconstruction change over time? Two-year results of the Michigan Breast Reconstruction Outcomes Study. J Am Coll Surg. 2007;204(1):7-12.
27.    Cederna PS, Yates WR, Chang P, Cram AE, Ricciardelli EJ. Postmastectomy reconstruction: comparative analysis of the psychosocial, functional, and cosmetic effects of transverse rectus abdominis musculocutaneous flap versus breast implant reconstruction. Ann Plast Surg. 1995;35(5):458-468.
28.    Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19(5):1539-1569.
29.    Kroll SS, Khoo A, Singletary SE, et al. Local recurrence risk after skin-sparing and conventional mastectomy: a 6-year follow-up. Plast Reconstr Surg. 1999;104(2):421-425.
30.    Huang CJ, Hou MF, Lin SD, et al. Comparison of local recurrence and distant metastases between breast cancer patients after postmastectomy radiotherapy with and without immediate TRAM flap reconstruction. Plast Reconstr Surg. 2006;118(5):1079-1086.
31.    Singletary SE. Skin-sparing mastectomy with immediate breast reconstruction: the M. D. Anderson Cancer Center experience. Ann Surg Oncol. 1996;3(4):411-416.
32.    Noone RB, Frazier TG, Noone GC, Blanchet NP, Murphy JB, Rose D. Recurrence of breast carcinoma following immediate reconstruction: a 13-year review. Plast Reconstr Surg. 1994;93(1):96-106.
33.    Eberlein TJ, Crespo LD, Smith BL, Hergrueter CA, Douville L, Eriksson E. Prospective evaluation of immediate reconstruction after mastectomy. Ann Surg. 1993;218(1):29-36.
34.    Cody HS 3rd, Hill AD, Tran KN, Brennan MF, Borgen PI. Credentialing for breast lymphatic mapping: how many cases are enough? Ann Surg. 1999;229(5):723-726.
35.    Pomahac B, Recht A, May JW, Hergrueter CA, Slavin SA. New trends in breast cancer management: is the era of immediate breast reconstruction changing? Ann Surg. 2006;244(2):282-288.
36.    McCarthy CM, Pusic AL, Disa JJ, McCormick BL, Montgomery LL, Cordeiro PG. Unilateral postoperative chest wall radiotherapy in bilateral tissue expander/implant reconstruction patients: a prospective outcomes analysis. Plast Reconstr Surg. 2005;116(6):1642-1647.
37.    Rubino C, Figus A, Lorettu L, Sechi G. Post-mastectomy reconstruction: a comparative analysis on psychosocial and psychopathological outcomes. J Plast Reconstr Aesthet Surg. 2007;60(5):509-518.
38.    Harcourt DM, Rumsey NJ, Ambler NR, et al. The psychological effect of mastectomy with or without breast reconstruction: a prospective, multicenter study. Plast Reconstr Surg. 2003;111(3):1060-1068.
39.    Mullan MH, Wilkins EG, Goldfarb S, et al. Prospective analysis of psychosocial outcomes after breast reconstruction: cross-cultural comparisons of 1-year postoperative results. J Plast Reconstr Aesthet Surg. 2007;60(5):503-508.
40.    Wilkins EG, Cederna PS, Lowery JC, et al. Prospective analysis of psychosocial outcomes in breast reconstruction: one-year postoperative results from the Michigan Breast Reconstruction Outcome Study. Plast Reconstr Surg. 2000;106(5):1014-1025.
41.    Parker PA, Youssef A, Walker S, et al. Short-term and long-term psychosocial adjustment and quality of life in women undergoing different surgical procedures for breast cancer. Ann Surg Oncol. 2007;14(11):3078-3089.

Column

Print Friendly 

Donald S. Robinson, MD

Primary Psychiatry. 2008;15(10):32-34
 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, Epix, Johnson and Johnson, PGxHealth, Pfizer, QRx Pharma, and Schering.


Osteoporosis is a common medical condition among older aged adults in the United States. It is estimated that 50% of women and 20% of men >50 years of age of Caucasian descent are afflicted, and as a result, they carry higher risk for osteoporotic fractures during their lifetime.1 Osteoporosis represents a major public health concern, with an estimated annual cost of $17 billion in the US alone.2,3 Numerous widely prescribed medications may have heightened risk for osteoporotic fractures. A recent example is linkage between popular drugs prescribed for heartburn and acid reflux, the proton pump inhibitors (eg, omeprazole), and hip fracture.4 While the mechanism of this increased risk is unclear, it is speculated that inhibiting stomach acid by proton pump-inhibiting drugs speeds up bone demineralization.

Several psychotropic medications are implicated in increased risk of osteoporotic fracture.5-7 Selective serotonin reuptake inhibitors (SSRIs), in particular, are linked to greater susceptibility to bone fractures. This raises concerns because of the likelihood of long-term exposure to SSRIs at both ends of the age spectrum, ie, children and adolescents as well as older adults. These age groups appear to be more susceptible to potential adverse effects of certain psychotropic agents on skeletal health. A recent large epidemiologic study of residents enrolled in the provincial healthcare system of the Province of Manitoba, Canada implicates psychotropic medications as a cause of bone fragility fractures in older adults.8

Role of Neurotransmitter Systems in Bone Metabolism

There are convincing data that the nervous system exerts a significant physiologic influence on bone and periosteum tissue. These structures have sympathetic nerve fiber and sensory innervation. Studies show that nerve terminals innervating bone contain several neuropeptides, including calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y.9 Current investigations suggest that neurotransmitters play a role in regulating bone metabolism. Studies in rodents with genetically deleted transporter for the neurotransmitter dopamine find reduced cancellous bone mass of vertebrae and tibia and decreased femur length and thickness.10 Impairment of the dopamine transporter appears to affect skeletal structure and integrity during growth periods.

Serotonin (5-HT) receptors have been isolated from osteoblastic cells, the major cell type involved in bone production. The 5-HT transporter (5-HTT) appears to be an important modulator of bone cell activity.10,11 Rodents with genetically deleted 5-HTT transporter have significantly less bone mineral content. Bone mineral content is diminished in normal animals treated chronically with fluoxetine.11 This fluoxetine effect was most prominent at weight-bearing sites of skeletal bone.

Several 5-HT receptor subtypes have been identified in osteoblasts, osteoclasts, and periosteal fibroblasts, including 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors.11,12 Osteoblasts appear to contain a functional 5-HT receptor system intracellularly as well as an intrinsic 5-HT uptake mechanism to modulate the effects of this neurotransmitter on bone metabolism. Abnormalities ascribed to chronic fluoxetine administration are of concern because SSRIs are often prescribed to children and adolescents as well as older adults who are at greater risk for age-related osteoporosis.

Population Studies of SSRI Use and Fragility Fractures

Several prior studies show that SSRI treatment is associated with lower bone mineral density13,14 and increased fracture risk.8,15-18 Utilizing healthcare administrative data, studies15-18 find that SSRI use correlates with incidence of fragility fractures. However, these investigations all suffer the drawback that they failed to adequately control for potential confounding factors, including concomitant medications, lifestyle differences, and health conditions that might affect bone density.

In a recent large population study,7 investigators involved in the Canadian Multicentre Osteoporosis Study examined SSRI use and fracture risk due to bone fragility. They conducted a population-based, randomly selected, prospective cohort study of >5,000 community-dwelling adults ≥50 years of age. Clinical fragility fractures were defined as those due to minimal trauma and documented by radiography. The subjects were participants in a long-term osteoporosis study living near seven regional urban centers in Canada. As part of the osteoporosis study, subjects underwent an in-depth health status interview at entry, and again 5 years later. Data on medication use, dosage, type of drug, and frequency of use were collected. Only data on SSRIs available for prescription at the time of the initial interview were analyzed. Bone-mineral density of the lumbar spine and hip was measured by radiography. Fragility fractures were categorized as those due to minimal trauma, eg, falling from bed, chair, or upright standing position.

The study enrolled 6,005 subjects ≥50 years of age; 997 subjects were excluded for incomplete or missing data. Of the remaining 5,008 subjects, 609 (12.2%) reported depressive symptoms, and 137 (2.7%) were found to be chronic SSRI users. This prevalence of SSRI use was similar to that reported by Canadian and US general populations.7 After adjusting for potential confounding factors documented by the in-depth interview, the findings clearly showed that daily SSRI use is correlated with heightened risk of fragility fracture (hazard ratio, 2.0; 95% confidence interval 1.3–3.1). Anatomic location of fractures sustained by SSRI users were: forearm (40%), foot and ankle (21%), hip (13%), rib (13%), femur (9%), and back (4%). Chronic SSRI use was associated with reduced bone mineral density of the hip and lumbar spine.

Case-Controlled Study of Fracture Risk and Use of Psychotropic Medications

University of Manitoba investigators utilizing provincial healthcare data recently reported the largest, most definitive study to date of psychotropic drug use and osteoporotic fractures.8 This case-controlled study accessed patient population data from the Manitoba Department of Health to assess health status and concurrent medication use of patients with recorded bone fractures. Manitoba Health provides comprehensive coverage for essentially all residents of the province of Manitoba, and claims data and pharmacy records are relatively complete for the provincial population. Patients ≥50 years of age with diagnosis of vertebral, wrist, or hip fractures were selected for study. Each patient was randomly matched to three controls based on year of birth, sex, ethnicity, and comorbidity index calculated from diagnostic codes. Only subjects with continuous coverage for health services from the Manitoba government between the years 1988 and 2004 were included. Exclusions were for incomplete medication data, long-term care facility residency, and exposure to drugs that might affect osteoporosis, eg, parathyroid hormones, estrogens, or biphosphanates.

Of 15,797 fracture cases, 99.5% of cases were successfully matched to three control subjects. There were three categories of medication usage, namely, none, past use, and current use within 3 months preceding bone fracture. Potential confounders adjusted for in the statistical analysis were diagnostic codes recorded during the 3-year pre-fracture period for diabetes, heart disease, epilepsy, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), dementia, schizophrenia, and home health care (as a proxy for fragility). Multivariate statistical analyses were employed to control for demographic variables, including income and place of residence, and confounding medical diagnoses and medication usage.

Osteoporotic Fractures and Psychotropic Drug Use

Analysis of demographic variables showed that fractures were more common among urban dwellers and those with the lowest incomes.8 Fractures were more prevalent in subjects with diagnoses of diabetes; epilepsy; arthritis; COPD; and psychiatric diagnoses for depression, substance abuse, schizophrenia, and dementia. Antidepressant and benzodiazepine usage was significantly higher among the fracture cases (Table).

 

 

Depression, dementia, schizophrenia, and substance abuse disorders all correlated with higher fracture risk. Among psychotropic agents, SSRIs were the medication most strongly associated with fractures, even after adjusting for medical and psychiatric diagnoses and concurrent medications. The odds ratio of 1.45 with chronic SSRI usage observed in this study falls within the range reported previously and provides compelling evidence that SSRIs are a significant risk factor for fragility fractures in older adults. This multivariate statistical analysis found that the dosage of both SSRIs and benzodiazepines correlated with fracture risk, unlike other antidepressants, antipsychotics, and lithium.

Conclusion

Population studies show a relationship between psychotropic drug usage and risk of fractures resulting from bone fragility. The mechanism of this heightened susceptibility to bone fracture is unclear. Bone-mineral metabolism appears to be controlled, in part, by serotonin-modulated systems, which could account for the susceptibility of older individuals taking SSRIs to osteoporotic fractures. Unresolved is the issue of how SSRIs might impact bone-mineral accrual in the growing skeleton during phases of growth and development in younger subjects. PP

References

1.    US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2004.
2.    Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761-1767.
3.    Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465-475.
4.    Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.
5.    Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf. 2007;30(2):171-184.
6.    Howard L, Kirkwood G, Leese M. Risk of hip fracture in patients with a history of schizophrenia. Br J Psychiatry. 2007;190:129-134.
7.    Richards JB, Papaoianna A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Int Med. 2007;167(2):188-194.
8.    Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 2008;28(4):384-391.
9.    Hill EL, Elde R. Distribution of CGRP-, VIP-, DβH-, SP-, and NPY-immunorecative nerves in the periosteum of the rat. Cell Tissue Res. 1991;264(3):469-480.
10.    Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 2001;29:477-486.
11.    Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology. 2005;146(2):685-693.
12.    Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ. Expression of serotonin receptors in bone. J Biol Chem. 2001;276(31):28961-28968.
13.    Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167(12):1240-1245.
14.    Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use. Arch Intern Med. 2007;167(12):1246-1251.
15.    Liu B, Anderson G, Mittmann N, Axcell T, Shear N. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 1998;351(9112):1303-1307.
16.    Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A. Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol. 2003;158(1):77-84.
17.    Schneeweiss S, Wang PS. Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol. 2004;24(6):632-638.
18.    Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 2006;17(6):807-816.

 

Dr. Nakka is fellow in the Hematology/Oncology Division at Maimonides Medical Center in Brooklyn, New York, Dr. Miller is associate director of Continuing Day Treatment Services in the Department of Psychiatry at Maimonides Medical Center, and Dr. Astrow is director of the Division of Hematology/Medical Oncology, all at Maimonides Cancer Center in Brooklyn.

Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Acknowledgments: The authors wish to express their appreciation to Vijay Nakka, MSEE, for technical support.

Please direct all correspondence to: Alan B. Astrow, MD, Maimonides Cancer Center, 6300 8th Ave, Brooklyn, NY, 11220; Tel: 718-765-2653; Fax: 718-765-2654; E-mail: aastrow@maimonidesmed.org.


 

Focus Points

• It is necessary to address patients’ psychosocial health to deliver high-quality cancer care.
• Faith and spirituality are important factors in medical decision making, and if physicians do not account for it, the decision-making process may be unsatisfactory.
• Communication skills training is essential for cancer professionals.

 

Abstract

Numerous physicians find it difficult to relay emotionally charged diagnostic and prognostic information to patients. Poor communication leads patients to misunderstand the status of their disease and goals of treatment, which can both adversely impact their decision making and reduce their quality of life. Despite advances in medical science and technology, physicians find themselves face-to-face with anxiety, sadness, and human tragedy. Delivering information to patients in an understandable way that displays concern for the patient as a person is a difficult yet required assignment demanding study and practice. Informative and empathic communication of prognostic information contributes to enhanced patient satisfaction. The high prevalence of physician burnout in oncology community is worrisome, as patients often rely heavily on their physicians for empathy and support. Communication skills training allowing oncologists to practice giving emotionally charged information and to explore their responses to human suffering and tragedy may enhance both patient and physician satisfaction. The authors of this article discuss how varied personality and coping styles and spiritual/cultural values, play a role in the patient’s response to a cancer diagnosis. They describe tools and strategies that can equip physicians to incorporate their understanding of the patient as a person into clinical practice.

Introduction

Discussing cancer diagnosis and communicating with distressed patients are extremely important yet challenging tasks required of the medical profession. The benefits of good communication skills should be well known, but breaking bad news and dealing with human tragedy are never easy, regardless of how skilled one may be. While the natural response to human tragedy is sadness or compassion, another less desirable response is avoidance. Improved communication and a greater degree of connection between the physician and the seriously ill patient may provide the patient with practical knowledge and emotional support needed for informed decision making and the physician with greater work satisfaction and an enhanced sense of meaning and purpose. The authors of this article have reviewed several articles in the medical literature regarding patients’ and physicians’ perspectives on discussing diagnosis and prognosis as well as how a patient’s personality style and any underlying psychiatric illness may affect physicians’ approach to meeting the patients’ information needs. The proposed approach for discussing prognosis is based on negotiation and patient-centered communication as well as the available research on what patients want to know.1,2

 

Physicians’ Perspectives

The difficulties doctors face when discussing prognosis with their patients include their deciding whether to provide estimates and survival statistics, discussing life expectancy with patients with “poor” prognoses, conveying prognostic information with sensitivity and honesty, deciding whether and how to encourage hope, and meeting the needs of patients from various cultural backgrounds whose prognostic information needs may differ. Clinically, the challenge has been balancing these concerns with the complexities of making prognostic estimates while complying with legal requirements to provide patients with all necessary information. A recent survey3 of 604 Australian cancer physicians found that insufficient time to spend with the patient and patients refusing recommended treatment were perceived by these physicians as the leading barriers to engaging in shared decision-making, while a trusting relationship with the patient was seen as most helpful. Though there is a lack of explicit guidance for clinicians concerning the best way to approach prognostic discussion, an evidence-based literature is underway. Anecdotal reports in the literature document the difficulties that physicians face in this arena. A physician in training, for example, recently described a young patient dying from advanced cancer and the plight of the patient’s father who was distressed about not being told the truth of his son’s impending death.4 She outlines treating physicians’ own fear of death and the “unknown” and, in this case, is critical of physicians’ inability to face the truth.

Communications skills do not automatically improve with increasing physician experience. Formal training in communicating complex and emotionally charged information is needed. Until recently, traditional oncology training programs focused on the skills needed to treat a wide range of cancers but did not prepare oncologists for the responsibility of talking to patients about undesired outcomes. In 1998, at the annual meeting of the American Society of Clinical Oncology (ASCO), among 400 oncologists who attended a session on breaking bad news, 74% indicated that they did not have a specific approach planned for breaking bad news, and >90% felt that the most difficult aspect was handling emotions that arise during the interview.5

The oncology community has responded through workshops, sessions at annual meetings, and innovative communications skills modules incorporated into the curricula of oncology training programs. The strongest evidence for the benefit of communications skills training comes from randomized clinical trials offering face-to-face learning involving communication with the patient or simulated patient coupled with opportunities to practice skills and receive feedback in a learner-focused environment.6,7 A 6-step algorithm for breaking bad news with the acronym SPIKES (setting, perception, invitation, knowledge, emotion, strategy, and summary) has been shown to be easily learned and taught8 and mirrors what patients say they want from their physicians.9,10

SPIKES is a consistent strategy that helps oncologists relate bad news. It encourages them to both assess patient response as it occurs and respond flexibly and constructively. The keys are to allow sufficient time, choose a comfortable setting, minimize distractions and interruptions, avoid jargon and try using the patient’s language, resist the temptation to offer premature reassurance, acknowledge and then validate the patient’s emotional response to bad news, and close with a summary and strategy. This approach will likely leave the patient feeling satisfied and prepared to take the necessary steps following the news.

When the SPIKES strategy was presented at the 1998 ASCO workshop, >99% of the oncologists found it easy to understand and remember.5 At the University of Texas MD Anderson Cancer Center, the SPIKES protocol was used in interactive workshops for oncologists and oncology fellows. As an outcome measure, the researchers used a paper and pencil test before and after the workshop to assess physician confidence in carrying out the various skills associated with SPIKES. They found that SPIKES in combination with experiential techniques (eg, role play) can increase the confidence of faculty and fellows in applying SPIKES.11 Undergraduate teaching experience also showed that the protocol increased medical students’ confidence in formulating a plan for breaking bad news.12 The SPIKES protocol has been tried and accepted in both academic and community settings. It may be a valuable tool for numerous medical specialties.5

Bach and colleagues describe the communication skills program, “Oncotalk,” developed for medical oncology fellows with funding from the National Cancer Institute.13 This program uses educational, evidence-based techniques with content tailored to medical oncology fellows. This structured curriculum includes the SPIKES protocol for breaking bad news, simulated clinical situations, trained actors functioning as patients, and other successful programs. The efficacy of Oncotalk was evaluated by measuring changing observable communication behaviors among participants.8 The primary outcomes were observable participant communication skills. These skills were measured during standardized patient encounters before and after a workshop on bad news and discussing transitions to palliative care. Compared with pre-workshop standardized patient encounters, post-workshop encounters showed that participants acquired a mean of 5.4 bad news skills and a mean of 4.4 transitions skills. This behavioral change leads to increased patient centeredness on the part of the physician and improves patient satisfaction.

Whether training in communication skills enhances professional satisfaction and lessens “burnout” is a ripe area for empirical study. Prevalence of burnout in the oncology community of the United States is >60%. The signs of burn-out are frustration, emotional exhaustion, depersonalization, and a sense of low personal accomplishment, all leading to decreased effectiveness at work.14 Burnout and distress can also lead to cynicism, which undermines physicians’ empathy and their relationships with patients. This erosion of compassion is especially troublesome in the field of oncology, as cancer patients often rely heavily on their physicians for emotional support.15 Recently, various causes for burnout were explored in detail. The prevalence of burnout was approximately 60% in a survey of primarily medical oncologists and hematologists. Number of hours spent on patient care and having colleagues with burnout were among the most critical positive associations with burnout, whereas attendance at educational meetings and number of days away from the office were highly significantly associated with less burnout.16

It is important to understand what makes an oncologist feel successful, what coping strategies help combat burnout, and what adds to the process of renewal. The doctor-patient relationship plays an important role for numerous oncologists in this regard, and communication skills are increasingly recognized for their importance in this arena. Clinical encounters that have shown to be especially stressful for oncologists include breaking bad news, discussing transitions in care, discussing/offering end-of-life care, suggesting participation in investigational studies, disclosing error, suggesting complementary and alternative medicine, addressing spirituality, entering family discussions, and approaching cross-cultural issues.17 Communication skills workshops offer simulated patient encounters wherein physicians can explore their responses to sadness and tragedy in a structured and supportive environment. This might lead to a reduction in oncology physician burnout. One small study supports this hypothesis. In a pilot workshop, medical oncology fellows were invited to present cases including a challenging psychosocial component. The purpose was to highlight both the patients’ psychosocial needs and the fellows’ personal responses to them. The program showed high satisfaction among the participants.18 Additional prospective studies are needed to see if these sorts of programs help in preventing burnout among oncologists in the long run.

Patient’s Perceptions and Preferences

Bad news has a direct impact a patient’s life. Each patient has a unique life history and psychological make-up. Therefore, he or she responds to bad news in a unique manner. Some patients seem to prefer less disclosure or at least a gradual unveiling of troubling prognostic information. Two cases suggesting the range of different perceptions that a medical oncologist must be prepared for are discussed below.

An 86-year-old woman with metastatic cancer of the vulva was referred by her gynecologist for evaluation and treatment recommendations. She underwent initial resection 8 years prior, followed by “re-resection” for disease recurrence 4 years prior, followed by additional surgery and radiation for a new recurrence 1 year prior. When seen at her initial visit to the medical oncologist, she presented with widespread painful abdominal wall skin and subcutaneous metastasis. Her son and daughter accompanied her to the medical oncology consultation and were visibly distressed because of their mother’s suffering. The patient, an intelligent woman living independently, had limited knowledge about the nature of her illness, despite the clearly visible metastases, one of which was open and draining. The son and daughter, also intelligent and concerned about their mother, displayed little understanding regarding their mother’s diagnosis and prognosis, despite her extensive medical history and numerous medical and surgical procedures and visits to physicians. The immediate issues at hand for the oncologist to address at this initial consultation were the patient’s severe pain, her profound psychological distress, and her foul smelling and draining cutaneous ulcer. At the same time, the oncologist needed to explain the diagnosis, prognosis, and reasonable treatment options to a patient and family with whom he had no prior relationship and in whom it appeared that some degree of denial was at play. Where does the physician begin?

A 52-year-old flight attendant had stage-3 ovarian cancer, sub-optimally debulked. She had a good initial response to standard chemotherapy but then had an extensive unresectable intra-abdominal recurrence within 6 months. The disease progressed despite multiple attempts at chemotherapy. Throughout, the patient’s main concern was that she continue working. She expressed a strong desire not to receive treatment that would cause hair loss. She made it clear that she did not want to hear bad news and that she wanted to focus only on the positive. Her sister, who accompanied her to several visits, insisted that the patient not be informed of her grave prognosis. The patient continued to work albeit with occasional absences for treatment and for therapeutic palliative paracentesis. Eventually, her condition worsened; she developed fevers, abdominal bloating, and inability to eat and was hospitalized for terminal care. The patient, though clearly dying, showed no interest in discussing what lay ahead. What is the oncologist’s obligation in this setting?

Empirical studies are beginning to give some evidence-based guidance to these questions. Understanding the patients values appears to help determine how to speak to a patient and what information to provide. Attention to the spiritual needs of patients can be considered an important aspect of health care that is not necessarily based on therapeutic benefit but that instead stems from a commitment to respecting patients as whole people.19 Faith is an important factor in medical decision making and plays an important role in how some patients decide on treatment.20 If physicians do not account for it, the decision-making process may be unsatisfactory to all involved. In a study21 of urban patients’ views about spirituality and health care, patients whose spiritual needs were not met reported lower ratings of quality and satisfaction with care.

Other studies have shown that factors predicting satisfaction among patients included making the environment comfortable, giving the patient adequate time to digest troubling news, and attempting to empathize with the patient’s experiences.9 Patients’ preferences for how they would like to be told news regarding their cancer can be grouped into three categories, namely content (what and how much information is told), facilitation (setting and context variables), and support (emotional support during the interaction). In a study of 351 patients with a variety of cancers, women and patients with higher education had signficantly higher scores on the content scale; women had higher scores on the support scale. In other words, women and patients with more education wanted more detailed information; female patients wanted more emotional support. Younger patients and those with more education had higher scores on the message facilitation scale. Medical variables were not associated with patients’ ratings of the importance of the three categories.10

There is growing evidence that psychological interventions can positively affect quality of life of cancer patients,22 prolong life,23,24 and possibly even affect the immune system.25 Maximizing hope during disclosure of a diagnosis is one way clinicians can contribute to psychological adjustment early in the treatment process. Patients look to their physicians for knowledge, expertise, skill, and human concern. By appearing confident and empathic while still realistic, a physician helps give patients hope. In contrast, being negative and maintaining a distant affect takes hope away.26 In a British survey of 2,331 patients with cancer, 98% indicated that they wished to have “all information” about their cancer.27 A more recent survey of 126 cancer patients found that almost all patients wanted their doctor to be realistic, provide an opportunity to ask questions, and acknowledge them as an individual when discussing prognosis. In addition to physicians’ knowledge on up-to-date treatment about patients’ cancer, they found that “saying that pain will be controlled” is one of the most hope-giving behaviors.28

Depression as a Barrier to Effective Oncologist-Patient Communication

Depression is common in the general population, as well as in adults and children with cancer, frequently coexisting with anxiety and pain. Unsuspected depression and/or anxiety can frustrate the oncologist’s efforts to communicate effectively with patients.29 The Psychosocial Collaborative Oncology Group determined that approximately 47% of hospitalized and ambulatory adult cancer patients had clinically apparent psychiatric disorders and 68% with depressed or anxious mood. A higher percentage of patients with a psychiatric diagnosis experienced significant pain compared to those who did not receive a psychiatric diagnosis.30 Cancer types highly associated with depression include oropharyngeal (22%–57%), pancreatic (33%–50%), breast (1.5%–46%), and lung (11%–44%).29 Depression is less prevalant in patients with cancers, such as colon (13%–25%), gynecologic (12%–23%), and lymphoma (8%–19%).29 It is important to note that the prevalence of depression varies with age, gender, where the individual stands in the course treatment, geographic location,31 and the presence of pain. It is difficult for the clinician to reliably predict the potential for depressed affect in an individual patient. Perhaps a more effective predictor of clinical depression is physical performance as measured by the Karnofsky scale.32 In one study, among patients with a Karnofsky score of ≤40, 77% met the criteria for major depressive disorder (MDD). Of those with scores >60, only 23% met the criteria for MDD.29

In addition, there was variance in screening and referral for depression based on the location. A study reported from New York City33 found that 44% of patients scoring ≥13 on Hospital Anxiety and Depression Scale were referred for evaluation. Another study34 from South Africa found that only 14% of patients identified as depressed had been identified and treated for depression. Pascoe and colleagues34 found that the majority of cancer patients with psychological distress were not receiving counseling or psychological treatment.

Hoffman and Weiner35 described strategies to enhance the oncologists’ ability to detect and diagnose depression in his or her patients. First, oncologists should expand their differential diagnosis of somatic symptoms to include depression. Second, the observatoins of people close to the patient should be obtained. Third, oncologists should follow the patient’s mood longitudinally. Fourth, the patient’s responses should be compared with normative responses. Lastly, the oncologists should be aware of disease phases associated with patient distress. The oncologist is typically under much time pressure during an average visit. If a patient has mild-to-moderate symptoms sugggestive of depression, the oncologist can space his or her evaluation over two meetings (Figure 1).36   

 

 

Coping Style and Prognostic Disclosure

Personality, spirituality/culture, and adaptation style collectively play a role in the patient’s response to a cancer diagnosis. The physician who knows his or her patient and acknowledges these key variables can most effectively engage in guiding the patient throughout the illness cycle (Figure 2).37,38

 

 

Personality

To be most thoroughly informed, the physician must begin by examining the building blocks38 informing the patient’s view of himself, others, and the world. These are formed early in childhood, and initially introduced by one’s parents. They are elaborated on through one’s learning and contact with other individuals, including teachers, clergy, friends, and family. With a sense of community and embedded national belief systems, the templates an individual utilizes to interpret events in his or her life are established.

Spirituality/Culture

It is essential to elucidate the patient’s spiritual/cultural beliefs with respect to a higher power and death/dying. While physicians are best informed of these by asking the patient formally and directly, informal conversation with and observation of the patient and his or her family are just as useful in informing physicians of the patient’s views.

Adaptation Style

Watson and Greer37 offer a practical and illuminating way to perceive the manner in which patients approach coping with serious medical conditions. A summary of a sample of those views is illustrated in Table 1,37 where an attempt is made to categorize them as they inform the physician of the patient’s likely adaptation style. Through an elucidation of the patient’s adaptation style, it is possible to anticipate and predict the specific coping strategies most likely to be employed throughout the illness cycle. Numerous studies have examined these coping strategies, concluding that active coping styles are much more effective in minimizing the emotional distress associated with serious medical illnesses.39 Approaching serious illness with a sense of helplessness/hopelessness has yielded depressive disorders while anxious preoccupation is likely to result in anxiety-related illnesses.

 

 

 

Synthesis: The Informed Physician

The physician who utilizes these building blocks develops insight into the patient’s likely adaptation style and is in the best position to establish a treatment approach best suited to his patient. For example, those who believe their fate is in God’s hands and have a fatalistic adaptation approach are less likely to ask questions or seek a great deal of attention/assistance from family/friends. However, those with a more hopeless or preoccupied approach may require the intervention of a psychiatric consult to help them cope with their emotional pain. Overall, the physician is now most thoroughly and appropriately informed with respect to the best manner in which to communicate/intervene with his patient.

Practical Application

Recalling the two case scenarios presented earlier, the emerging evidence base offers practical suggestions. For the 86-year-old woman with advanced vulvar cancer, the key initial issues include ascertaining patient and family’s understanding of the nature of her illness. Given her severe pain and distress at the foul smell of her metastatic lesions, offering a practical strategy to address these would be crucial at an initial visit. Confronting the patient and family’s denial would likely prove counter-productive. At subsequent visits, the physician would want to explore the patient and family’s wishes regarding how they want information to be related, try to get a sense of what the patient’s “coping style” might be and how her spiritual beliefs and values might influence attitudes toward continued treatment, explore the patient’s emotional reaction to the presence of visible and disfiguring metastases and offer empathic support. Once a trusting relationship has been established, the physician could move on to discussion of realistic treatment alternatives, including hospice referral. If there was evidence of underlying depression or anxiety, a psychiatric referral or pharmacologic treatment might be offered.

Regarding the second patient with advanced ovarian cancer who only wanted to hear good news and whose sister insisted that she not be told of her grave prognosis, patients may choose to allow others to be the primary recipients of diagnostic and prognostic information. This patient’s coping style appears to best fit the category of “avoidance/denial,” and attempts to engage in realistic discussion are likely to be rejected by the patient. However, it would be important to explore the patient’s reasons for not wishing to participate in crucial decisions about her care, offer her opportunites over the course of the relationship to change her approach, and explore the sister’s reasons for wishing to keep the patient uninformed. Requests for non-disclosure are common. Table 2 summarizes the priniciples of a suggested approach to such a scenario.40

 

Conclusion

Communication skills do not necessarily improve solely with years of medical practice.41 In recent years a variety of resources have emerged, highlighting the importance of communication skills training for cancer professionals. Evidence for the efficacy of formal training in communicating diagnosis and prognosis is beginning to emerge. Recognition of co-existing psychiatric illness and elucidation of each patient’s unique coping style may facilitate oncologist-patient communication. Additional studies of the impact of improved communication on patient and professional satisfaction need to be conducted. PP

References

1.    Back AL, Arnold RM. Discussing prognosis: “how much do you want to know?”: talking to patients who do not want information or who are ambivalent. J Clin Oncol. 2006;24(25):4214-4217.
2.    Back AL, Arnold RM. Discussing prognosis: “how much do you want to know?”: talking to patients who are prepared for explicit information. J Clin Oncol. 2006;24(25):4209-4213.
3.    Shepherd HL, Tattersall MH, Butow PN.  Physician-identified factors affecting patient participation in reaching treatment decisions. J Clin Oncol. 2008;26(10):1724-1731.
4.    Rockwell LE. Truthtelling. J Clin of Oncol. 2007;25(4):454-455.
5.    Buckman RA. Breaking bad news: the S-P-I-K-E-S strategy. Community Oncology. 2005;2(2):138-142.
6.    Fallowfield L, Jenkins V, Farewell V, et al. Efficacy of Cancer Res UK communication skills training model for oncologists: a randomized controlled study. Lancet. 2002;359(9307):650-656.
7.    Razavi D, Delvaux N, Marchal S, et al. Does training increase the use of more emotionally laden words by nurses when talking with cancer patients? A randomized study. Br J Cancer. 2002;87(1):1-7.
8.    Back AL, Arnold RM, Baile WF, et al. Efficacy of communication skills training for giving bad news and discussing transitions to palliative care. Arch Int Med. 2007;167(5):453-460.
9.    Ptacek JT, Ptacek JJ. Patients’ perceptions of receiving bad news about cancer. J Clin Oncol. 2001;19(21):4160-4164.
10.    Parker PA, Baile WF, de Moor C, Lenzi R, Kudelka AP, Cohen L. Breaking bad news about cancer: patients’ preferences for communication. J Clin Oncol. 2001;19(7):2049-2056.
11.    Baile WF, Lenzi R, Kudelka AP, et al. Improving physician-patient communication in cancer care: outcome of a workshop for oncologists. J Cancer Educ. 1997;12(3):166-173.
12.    Garg A, Buckman R, Kason Y. Teaching medical students how to break bad news. CMAJ. 1997;156(8):1159-1164.
13.    Back AL, Arnold RM, Tulsky JA, Baile WF, Fryer-Edwards KA. Teaching communication skills to medical oncology fellows. J Clin Oncol. 2003;21(12):2422-2426.
14.    Whippen DA, Cannelos GP. Burnout syndrome in the practice of oncology: results of a random survey of 1,000 oncologists. J Clin Oncol. 1991;9(10):1916-1920.
15.    Shanafelt T, Chung H, White H, Lyckholm LJ. Shaping your career to maximize personal satisfaction in the practice of oncology. J Clin Oncol. 2006;24(24):4020-4026.
16.    Allegra CJ, Hall R, Yothers G. Prevalence of burnout in the U.S. oncology community: results of a 2003 survey. J Oncol Pract. 2005;1(4):140-147.
17.    Armstrong J, Holland J. Surviving the stresses of clinical oncology by improving communication. Oncology (Williston Park). 2004;18(3):363-368.
18.    Armstrong J, Lederberg M, Holland J. Fellows’ forum: a workshop on the stresses of being an oncologist. J Cancer Educ. 2004;19(2):88-90.
19.    The Joint Commission. Spiritual assessment. Available at: www.jointcommission.org/AccreditationPrograms/HomeCare/Standards/FAQs/Provision+of+Care/Assessment/Spiritual_Assessment.htm. Accessed September 5, 2008.
20.    Silvestri G, Knittig S, Zoller J, Nietert PJ. Importance of faith on medical decisions regarding cancer care. J Clin Oncol. 2003;21(7):1379-1382.
21. Astrow AB, Wexler A, Texeira K, He MK, Sulmasy DP. Is failure to meet spiritual needs associated with cancer patients’ perceptions of quality of care and their satisfaction with care? J Clin Oncol. 2007;25(36):5753-5757.
22. Anderson BL. Psychological interventions for cancer patients to enhance the quality of life. J Consult Clin Psychol. 1992;60(4):552-558.
23. Spiegel D, Bloom Jr, Draemer HC, et al. Effect of psychosocial treatment on survia of patients with metastatic breast cancer. Lancet. 1989;2(8868):888-891.
24. Spiegel D. Can psychotherapy prolong cancer survival? Psychosomatics. 1990;31(4):361-366.
25. Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology: can psychologic interventions modulate immunity? J Consult Clin Psychol. 1992;60(4):569-575.
26. Sardel AN, Trierweiler SJ. Disclosing the cancer diagnosis. Cancer. 1993;72(11):3355-3365.
27. Jenkins V, Fallowfield l, Saul J. Information needs of patients with cancer: results from a large study in UK cancer centers. Br J Cancer. 2001;84(1):48-51.
28.    Hagerty RG, Butow PN, Ellis PM, et al. Communicating with realism and hope: incurable cancer patients’ views on the disclosure of prognosis. J Clin Oncol. 2005;23(6):1278-1288.
29.    Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004;(32):57-71.
30.    Derogatis LR, Morrow GR, Fetting J. The prevalence of psychiatric disorders among cancer patients. JAMA. 1983;249(6):751-757.
31. Berard RMF, Boermeester F, Viljoen G. Depressive disorders in an out-patient oncology setting: prevalence, assessment and management. Psychooncology. 1998;7(2):112-120.
32.    Bukberg J, Penman D, Holland JC. Depression in hospitalized cancer patients. Psychosom Med. 1984;46(3):199-212.
33. Payne DK, Hoffman RG, Theodoulou M, Dosik M, Massie MJ. Screening for anxiety and depression in women with breast cancer. Psychosomatics. 1999;40(1):64-69.
34. Pascoe S, Edelman S, Kidman A. Prevalence of psychological distress and use of support services by cancer patients at Sydney hospitals. Aust N Z J Psychiatry. 2000;34(5):785-791.
35. Hoffman MA, Weiner JS. Is Mrs S depressed? Diagnosing depression in the cancer patient. J Clin Oncol. 2007;25(19):2853-2856.
36. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
37. Watson M, Greer S. Personality and coping. In: Holland JC, Breitbart W, Jacobsen PB, Lederberg MS, Loscalzo M, Massie MJ, McCorkle R, eds., ed. Psycho-oncology. 1st ed. New York, NY: Oxford University Press; 1998.
38. Young JE. Cognitive Therapy for Personality Disorders: A Schema–Focused Approach. 3rd ed. Sarasota, FL: Professional Resources Exchange, Inc.; 1990.
39.    Spencer SM, Carver CS, Price AA. Psychological and Social Factors in Adaptation. In: Holland JC, Breitbart W, Jacobsen PB, et al, eds. Psycho-oncology. 1st ed. New York, NY: Oxford University Press; 1998.
40. Hallenbeck J, Arnold R. A request for nondisclosure: don’t tell mother. J Clin Oncol. 2007;25(31):5030-5034.
41. Cantwell BM, Ramirez AJ. Doctor-patient communication: a study of junior house officers. Med Educ. 1997;31(1):17-21.

 

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

1.    Falby A. The modern confessional: Anglo-American religious groups and the emergence of lay psychotherapy. J Hist Behav Sci. 2003;39(3):251-267.
2.    Fuller RC. American psychology and the religious imagination. J Hist Behav Sci. 2006;42(3):221-235.
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. 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

 

 

 

 

References

1.    McDowell D. MDMA, Ketamine, GHB, and the “Club Drug” scene. In: Galanter M, Kleber HD, eds. Textbook of Substance Abuse Treatment. 3rd ed. Arlington, VA: American Psychiatric Association; 2004:321-333.
2.    Krupitsky E. Kolp E. Ketamine psychedelic psychotherapy. In: Winkelman MJ, Roberts TB, eds. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments. Westport, CT: Greenwood Publishing Group, Inc.; 2007:67-85.
3.    Domino EF, Chodoff P, Corssen G. Pharmacologic effects of Ci-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279-291.
4.    Siegal RK. Phencyclidine and ketamine intoxication: a study of four populations of recreational users. NIDA Res Monogr. 1978;21:119-147.
5.    Adler CM, Malhotra AK, Elman I, et al. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry. 1999;156(10):1646-1649.
6.    Carpenter WT. The schizophrenia ketamine challenge study debate. Biol Psychiatry. 1999;46(8):1081-1091.
7.    Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25(4):455-467.
8.    Khorramzadeh E, Lotfy AO. The use of ketamine in psychiatry. Psychosomatics. 1973;14(6):344-346.
9.    Fontana A. Antidepressant therapy with ketamine [Spanish]. Acta Psiquiat Psicol Amer Lat. 1974;20:32.
10. Roquet S. Operacion Mazateca: Estudio de hongos y otras plantas allucinoganas Mexicanastratamiento psicotherpapeutico de psicosintesis [Spanish]. Mexico City: Asociacion Albert Schweitzer; 1974.
11. Kiefer R, Rohr P, Unertl K, Altemeyer K, Grothusen J, Schwartzman RJ. Recovery from intractable complex regional pain syndrome type I (RSD) under high dose intravenous ketamine-midazolam sedation. Neurology. 2002;58A:475.
12. Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004:5(3):263-275.
13. Goldberg ME, Domsky R, Scaringe D et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. 2005;8(2):175-179.
14. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. 2004;108(1-2):17-27.
15. Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl). 2003;169(3-4):215-233.
16. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.
17. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
18. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
19. Valentine G, Mason GF, Krystal JH, Sanacora G. The acute effects of ketamine on mood and occipital cortex amino acid neurotransmitter content. Biol Psychiatry. 2007;61(suppl 1):233.
20. Jansen KL. A review of the nonmedical uses of ketamine: use, users, and consequences. J Psychoactive Drugs. 1993;32(4):419-433.
21. Wolff K, Winstock AR. Ketamine: from medicine to misuse. CNS Drugs. 2006:20(3):199-218.
22. Lee SJ, Galanter M, Dermatis H, McDowell D. Circuit parties and patterns of drug use in a subset of gay men. J Addict Dis. 2003;22(4):47-60.
23. Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res. 2000;34(1):35-43.
24. Smith GS, Schloesser R, Brodie JD, et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology. 1998;18(1):18-25.
25. Beardsley PM, Balster RL. Behavioral dependence upon phencyclidine and ketamine in the rat. J Pharmacol Exp Ther. 1987;242(1):203-212.
26. Klein M, Calderon S, Hayes B. Abuse liability assessment of neuro-protectants. Ann NY Acad Sci. 1999;890:515-525.
27. Leccese AP, Marquis KL, Mattia A, Moreton JE. The anticonvulsant and behavioral effects of phencyclidine and ketamine following chronic treatment in rats. Behav Brain Res. 1986;22(3):257-264.
28. Benthuysen JL, Hance AJ, Quam DD, Winters WD. Comparison of isomers of ketamine on catalepsy in the rat and electrical activity of the brain and behavior in the cat. Neuropharmacology. 1989;28(10):1003-1009.
29. Jansen KL. Ketamine: can chronic use impair memory. Int J Addict. 1990;25(2):133-139.
30. Moore NN, Bostwick JM. Ketamine dependence in anesthesia providers. Psychosomatics. 1999;40(4):356-359.
31. Hampton RY, Medzihradsky F, Woods JH, Dahlstrom PJ. Stereospecific binding of 3H-phencyclidine in brain membranes. Life Sci. 1982;30(25):2147-2154.
32. Kornhuber J, Mack-Burkhardt F, Kornhuber ME, Riederer P. MK-801 binding sites in post-mortem human frontal cortex. Eur J Pharmacol. 1989;162(3):483-490.
33. Krystal JH et al. Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry. 1998;55(4):354-360.
34. Smith DJ, Azzaro AJ, Zaldivar SB, Palmer S, Lee HS. Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology. 1981;20(4):391-396.
35. Leary T, Sirius RU. Design for Dying. New York, NY: HarperCollins Publishers; 1998.
36. Volkow ND, Wang GJ, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386(6627):830-833.
37. Martin-Soelch C, Chevalley AF, Künig G. Changes in reward-induced brain activation in opiate addicts. Eur J Neurosci. 2001;14(8):1360-1368.
38. Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403-1413.
39. Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol. 1998;341(1):45-56.
40. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998;281(5381):1349-1352.
41. Hoffer A, Osmond H. New Hope For Alcoholics. New Hyde Park, NY: University Books; 1968.
42. Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacology. 1996;14(4):285-298.
43. O’Brien CP, Jones RT. Methodological Issues In the evaluation of a medication for its potential benefits in enhancing psychotherapy. In: Pletscher A, Ladewig D, eds. Fifty Years of LSD: Current Status and Perspectives of Hallucinogens (A Symposium of the Swiss Academy of Medical Sciences). Nashville, TN: Parthenon Publishing; 1994.
44. Greyson B. Varieties of near-death experience. Psychiatry. 1993;56(4):390-399.
45. Karasu TB. Spiritual psychotherapy. Am J Psychother. 1999;53(2):143-162.
46. Brady MJ, Peterman AH, Fitchett G, Mo M, Cella D. A case of including spirituality in quality of life measurement in oncology. Psychooncology. 1999;8(5):417-428.
47. Breitbart W. Spirituality and meaning in supportive care: spirituality- and meaning-centered group psychotherapy interventions in advanced cancer. Support Care Cancer. 2002;10(4):272-280.
48.    Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29(2):165-183.
49. Krupitsky E, Burakov A, Romanova T, Dunaevsky I, Strassman R, Grinenko A. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Substance Abuse Treat. 2002;23(4):273-283.
50. Collins ED, Ward AS, McDowell DM, Foltin RW, Fischman MW. The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans. Behav Pharmacol. 1998;9(7):587-598.
51.    Bisaga A, Evans SM. Acute effects of memantine in combination with alcohol in moderate drinkers. Psychopharmacology (Berl). 2004;172(1):16-24.
52. Krupitsky EM, Neznanova O, Masalov D, et al. Effect of memantine on cue-induced alcohol craving in recovering alcohol-dependent patients. Am J Psychiatry. 2007;164(3):519-523.
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

 

References

1.    Falby A. The modern confessional: Anglo-American religious groups and the emergence of lay psychotherapy. J Hist Behav Sci. 2003;39(3):251-267.
2.    Fuller RC. American psychology and the religious imagination. J Hist Behav Sci. 2006;42(3):221-235.
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.

Return

 
 

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.

 

 

 

This interview took place on August 6, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

 

Disclosure: Dr. Gandy is on the scientific advisory boards of and receives honoraria from Diagenic, Epix Pharmaceuticals, and SMART Pharmaceuticals; is on the Data and Safety Monitoring Board of  and receives honoraria from Elan/Wyeth; and receives grant support from Forest Research Institute.

 

Samuel Gandy, MD, PhD, is Mount Sinai Professor of Alzheimer’s Disease Research, professor of neurology and psychiatry, associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City, and past chair of the National Medical and Scientific Advisory Council of the Alzheimer’s Association. As an international expert in the metabolism of amyloid that clogs the brain in patients with Alzheimer’s disease, Dr. Gandy has written over 150 original papers, chapters, and reviews on this topic. In 1989, he and his colleagues discovered medications that could lower the formation of amyloid. He has received continuous National Institutes of Health funding for his research on amyloid metabolism since 1986.

 

 

 

What is Alzheimer’s disease?

Alzheimer’s disease is the most common cause of dementia, which is the loss of one’s ability to think. It involves changes in memory, executive function, ability to locate oneself in space, and personality. As a neurodegenerative disease, it is clearly related to aging. It is responsible for approximately 66% of all dementia.

 

Is there a way to distinguish age-related cognitive impairment from early Alzheimer’s disease?

Though there are other technologically advanced methods available, the best way to make a diagnosis of Alzheimer’s disease is to conduct a battery of neuropsychological tests. They can take several hours to administer, but they are the most sensitive way for physicians to diagnosis the condition.

While it is known that Alzheimer’s disease is associated with aging, it is also known that it is possible to live to 120 years of age and still be cognitively intact. Therefore, distinguishing age-associated cognitive impairment from early Alzheimer’s disease may be slightly artificial beyond that age. Since we know that it is possible to live to ≥100 years of age with completely intact cognition, we have taken that as our working definition of “successful aging,” and that is our goal.

 

Are imaging studies clinically useful?

Neuroimaging is important for excluding reversible causes of dementia, including hydrocephalous, brain tumors, and chronic neurologic infection. Currently, magnetic resonance imaging is the most popular imaging tool used for that purpose. The fluoride-oxyglucose positron emission tomography (PET) scan is useful in excluding the possibility of frontotemporal dementia (FTD), a rare disease formerly referred to as Pick’s disease and associated with approximately 15% to 33% of dementia. (Alzheimer’s disease is associated with the remaining percentage of all forms of dementia.) The fluoride-oxyglucose PET scan may help distinguish Alzheimer’s disease from FTD.

 

What is the clinical difference in presentation between Alzheimer’s disease and FTD?

FTD tends to occur earlier in life than Alzheimer’s disease. It is said to be the most common cause of new-onset psychosis between 40 and 60 years of age and may rival Alzheimer’s disease as the more common cause of dementia in that same young age group. The distinguishing features of FTD include disinhibition and development of especially inappropriate affect, sexual activity, and criminal activity. Further, prominent speech disturbance can lead to primary progressive aphasia. However, the underlying disease for speech disturbance is often FTD, as it affects the frontal and temporal poles of the brain wherein the personality and speech areas are prominent. PET scans have shown that Alzheimer’s disease tends to affect the occipital/posterior temporal and parietal lobes, which are involved in orientation in space, memory, and cognitive reasoning.

 

Are there genetic markers indicating Alzheimer’s disease and FTD?

The genetics of the rarer forms of these conditions are well configured. Approximately 3% of Alzheimer’s disease in early onset form usually occuring at ≤65 years of age is attributed to genetic makeup. In those cases, there are identified mutations causing a dominant, completely penetrant disease; that is, if a patient has a mutated gene, he or she is guaranteed to get the disease. The genes in which those mutations are located concern mistakes in amyloid metabolism, which are the strongest indicators available for identifying Alzheimer’s disease. Genetic tests predictive of early onset familial forms of Alzheimer’s disease can be conducted even from the time of conception.

FTD mutations are also identified in early onset forms of the disease. Unlike early onset Alzheimer’s disease wherein the mutations are in the amyloid protein, mutations in genetic makeup indicating FTD are in the tau protein that forms the tangles. The involvement of different proteins distinguishes Alzheimer’s disease from FTD pathologically. Alzheimer’s disease is an “amyloid plaque and tangle disease” while FTD is a “tangle-only” disease.

 

What is the prevalence of Alzheimer’s disease according to age group?

The prevalence of Alzheimer’s disease at 65 years of age is approximately 10%. At ≥85 years of age, the probability increases to  approximately 50%. On a physical basis, individuals ≥85 years of age have a dementia that is often categorized as Alzheimer’s disease. Statistically, it is a very common disease.

 

How effective are current treatments for Alzheimer’s disease?

Currently available medications fall into two classes. The first class consists of donepezil hydrochloride, rivastigmine tartrate, and galantamine hydrobromide. Though each medication has a slightly different dosing schedule than the others, all of them act on acetyl cholinesterase, an enzyme found in the synapses between nerve cells. Its job is to degrade excess acetylcholine after synapses have occurred and acetylcholine has been released. From the presynaptic neuron, acetylcholine diffuses across the synaptic cleft to the postsynaptic neurons and bound receptors where it leaves an excess. Acetyl cholinesterase helps degrade this excess to terminate neurotransmission. In Alzheimer’s disease, the presynaptic neurons making the acetylcholine eventually become sick and die. (The reasons for this occurrence have yet to be determined.) Once those presynaptic nerve cells are no longer able to make the acetylcholine, the treatment effects dissipate, as the acetylcholinesterase inhibitors require the integrity of the presynaptic neuron to create acetylcholine. In essence, the medications in the first class block the breakdown of the acetylcholine, offering patients modest, temporary relief that invariably wears off as time passes.

The second class of drugs is solely represented by memantine. While it is approved for moderate stages of Alzheimer’s disease, it is currently being tested in earlier stages of the disease and may eventually be tested for slowing the conversion of mild cognitive impairment to Alzheimer’s disease. Memantine blocks the receptor from glutamate, the most widely used neurotransmitter, particularly in the brain. However, excess amounts of glutamate can kill postsynaptic nerve cells. It has been shown in model systems, including nerve cells from a dish and animal models, that whenever amyloid plaques are present, nerve cells are more sensitive to glutamate than usual. Once amyloid plaque sufficiently accumulates, it begins exerting toxins on nerve cells. Memantine helps to block glutamate receptors (eg, N-methyl-d-aspartic acid), preventing them from their becoming too sensitive. The treatment helps preserve and protect the surviving nerve cells.

 

For how long does the treatment hinder the usual progression of the disease?

Cholinesterase inhibitors (ChEIs) “turn back the clock” (in terms of regaining lost function) for approximately 3–6 months, but “the clock keeps ticking” so that the rate of decline is unchanged with these drugs. The National Institute for Clinical Excellence study1 from the United Kingdom indicated that, after 18 months, patients treated with ChEIs and those who go untreated have roughly equivalent functional status. In other words, there is a brief improvement in functional status but since the ChEIs are not disease modifying, the benefit wears off after 1.5–2 years.

Are anti-inflammatory drugs helpful in treating Alzheimer’s disease?
The association of non-steroidal anti-inflammatory drugs (NSAIDs) has an interesting history. Pathologists noticed that people with chronic arthritis taking NSAIDs seemed to have lower burdens of plaque pathology in their brains. This observation formed the basis of numerous trials recently initiated on certain compounds. For example, a class of classical anti-inflammatories involving the enzyme cyclooxygenase-2 (COX-2) was tested and failed, as there was excess mortality in subjects taking the NSAIDs. Conventional NSAIDs seemed to have no place in slowing the progression of Alzheimer’s disease.

Approximately 5 years ago, an unusual property was discovered indicating certain subtypes of NSAIDs could modify the production of amyloid. On that basis, flurbiprofen, a fluoride derivative of ibuprofen, was synthesized to maximize anti-amyloid activity and completely ablate COX-2 activity, which is responsible for side effects accompanying NSAIDs such as gastrointestinal distress and hemorrhage. Flurbiprofen recently underwent a phase-3 trial to see if it would slow the progression of Alzheimer’s disease. It failed with no clear explanation for this failure despite new modalities of neuroimaging that make visualizing plaque build-up during life possible. For example, chemists and physicians at the University of Pittsburgh developed a compound called Pittsburgh Compound-B (PIB) that can show plaque burden when used in PET scans. When flurbiprofen was tested, PET scans using PIB were not employed, so we do not now know whether the flurbiprofen was ineffective in changing amyloid burden or whether amyloid burden was relieved but cognitive function remained poor.

Current knowledge of genetic forms notes amyloid build-up as one of the earliest indicators of Alzheimer’s disease. It is known from pathologic studies, and now from these PIB scans, that plaque begins to accumulate ≥10 years before the first clinical symptom or sign. Therefore, it is possible that patients suffering from mild Alzheimer’s disease may already have such a heavy plaque burden that it is basically too late for an anti-amyloid agent to have a meaningful impact. Another possibility is that there are several stages to the disease’s progression. First, there is the amyloid build-up. Second, the build-up triggers the formation of neurofibrillary tangles and an inflammatory response around the amyloid plaque. Once the amyloid build-up triggers these secondary effects, even the removal of the amyloid cannot stop the progression of the disease. The knowledge concerning genetic forms has been especially important in modeling the disease’s pathology in animals. However, much research must be conducted in order to translate those models  into meaningful therapy.

 

Do exercising and mental stimulation help prevent shrinkage in the brain?

The aforementioned cases were epidemiologic studies, and it is very difficult to show causality in these types of studies. However, it seems that the factors associated with cardiac health are also associated with brain health and dementia. For example, controlling body weight, blood sugar, cholesterol, blood pressure, and other activities associated with heart health are relevant for brain health as well.

Health risks applying to the heart (eg, diabetes, hypertension, hypercholesterolemia, obesity) also apply to Alzheimer’s disease. In terms of factors modulating the risk for Alzheimer’s disease, issues of fitness and mental stimulation are robust clinical associations. It is difficult to reduce an individual’s mental stimulation to a drug. It is difficult to both write patients prescriptions and tell them what to do so that they improve their condition. The challenge now is to determine whether it is possible to specify good physical and mental activities. It is important to test them the same way in which medications are tested; that is, the effects of physical and mental activity on the development and progression of Alzheimer’s disease should be evaluated in randomized clinical trials. That a patient’s starting a regimen of physical and mental activity will protect or delay him or her from onset of Alzheimer’s disease should be definitively determined, not supposed. Epidemiologic studies come with risk, as they may result in associations arising due to a possibility that was not initially considered. For example, there may be people who have better access to professional care or who take better care of themselves. These participants may be the ones who confound a study’s results. For this possibility, randomized clinical trials are the gold standard. However, maintaining a heart-healthy lifestyle and mental stimulation is beneficial to an individual. Physicians recommend them, as they are obviously good for the heart and do no harm to the brain. Though it is believed that such activities are helpful in the prevention of Alzheimer’s disease, such a belief cannot be completely proven that prescribing will be effective with the usual level of scientific rigor.

[Additional information on the topic of Alzheimer’s disease can be found by consulting references 2–15]. PP

 

References

1.    Loveman E, Green C, Kirby J, et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease. Health Technol Assess. 2006;10(1):iii-iv,ix-xi,1-160.
2.    Qin W, Chachich M, Lane M, et al. Calorie restriction attenuates Alzheimer’s disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis. 2006;10(4):417-422.
3.    Greenberg SM, Rosand J, Schneider AT, et al. A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Alzheimer Dis Assoc Disord. 2006;20(4):269-274.
4.    Small SA, Gandy S. Sorting through the cell biology of Alzheimer’s disease: intracellular pathways to pathogenesis. Neuron. 2006;52(1):15-31.
5.    Martins IJ, Hone E, Foster JK, et al. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry. 2006;11(8):721-736.
6.    Gandy S, Heppner FL. Breaking up (amyloid) is hard to do. PLoS Med. 2005;2(12):e417.
7.    Balakrishnan K, Verdile G, Mehta PD, et al. Plasma Abeta42 correlates positively with increased body fat in healthy individuals. J Alzheimers Dis. 2005;8(3):269-282.
8.    Lautenschlager NT, Wu JS, Laws SM, et al. Neurological soft signs are associated with APOE genotype, age and cognitive performance. J Alzheimers Dis. 2005 Aug;7(4):325-330.
9.    Gandy S, Heppner FL. Alzheimer’s amyloid immunotherapy: quo vadis? Lancet Neurol. 2005;4(8):452-453.
10.    Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease.J Clin Invest. 2005;115(5):1121-9.
11.    Walker LC, Ibegbu CC, Todd CW, et al. Emerging prospects for the disease-modifying treatment of Alzheimer’s disease. Biochem Pharmacol. 2005;69(7):1001-1008.
12.    Gandy S, Walker L. Toward modeling hemorrhagic and encephalitic complications of Alzheimer amyloid-beta vaccination in nonhuman primates. Curr Opin Immunol. 2004;16(5):607-615.
13.    Heppner FL, Gandy S, McLaurin J. Current concepts and future prospects for Alzheimer disease vaccines. Alzheimer Dis Assoc Disord. 2004;18(1):38-43.
14.    Gandy S. Cerebral Abeta amyloidosis and postmenopausal hormone deficiency: roles in the genesis of Alzheimer’s disease. Hum Pathol. 2004;35(3):271-274.
15.    Gandy S, DeMattos RB, Lemere CA, et al. Alzheimer’s Abeta vaccination of rhesus monkeys (Macaca mulatta). Mech Ageing Dev. 2004;125(2):149-151.

 

Dr. Rao is associate professor and vice-chair in the Department of Psychiatry and Behavioral Neurosciences at Loyola University Medical Center in Maywood, Illinois.

Disclosures: Dr. Rao is on the speaker’s bureau of Forest.

Acknowledgments: The author thanks Maria Theodorou for her assistance in compiling the references used in this manuscript.

Please direct all correspondence to: Murali Rao, MD, DFAPA, FAPM, Associate Professor and Vice-Chair, Department of Psychiatry and Behavioral Neurosciences, Loyola University Medical Center, Maywood, IL 60153; Tel: 708-216-3276; Fax: 708-216-5885; E-mail: mrao1@lumc.edu.

 


 

Focus Points

• Depression should not be discounted as an inevitable natural consequence  to a serious medical illness.
• The utility of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, in diagnosing depression in the medially ill is limited.
• Aggressive treatment of depression utilizing all available modalities along with the treatment of comorbid medical illnesses is important as it affects not only the patient’s improved participation in the treatment but also decreased morbidity.
• The overall effect on the course of the disease itself and mortality needs to be further studied.

 

Abstract

As depression is strongly associated with physical illness, it can be a complex and challenging condition for the medically ill. Approximately 33% of physically ill patients have depressive symptoms, many of which are regarded as understandable responses or reactions to the physical illness. Depressive illness is often under-diagnosed and under-treated, particularly in those with coexisting physical illnesses. The assessment of both conditions and the interaction between them is critical in managing these patients. Studies have clearly established that these depressive disorders are amenable to psychological or pharmacologic treatments.

 

Introduction

Depressed patients are more likely than non-depressed patients to have longer hospital stays and more outpatient visits, suffer greater disability, suffer from poorer quality of life, and experience suicidal thoughts and even commit suicide.

Major depression is at least twice as common in hospitalized medical patients compared to depression in the general population. The prevalence of major depressive disorder (MDD) in patients with comorbid medical illness can be as high as 30% in the hospital setting.1 Presence of comorbid depression is predictive of worse outcomes of medical illness and increased mortality.2 It may be better to risk over diagnosing depression than to leave depression untreated. Studies have shown that treatment of even minor or sub-syndromal depression has beneficial effects on the overall functioning of the physically ill individual and enhances treatment compliance for the co-existing medical illness and the recovery and rehabilitation process. It has been well established that in patients with type-2 diabetes, MDD is both a precursor as well as a comorbid illness. This is also the case in cerebrovascular and cardiovascular diseases.

 

The Association of Depression and Physical Illness

The association of depression and physical illness can be best understood as follows. First, depression can be caused by an underlying physical illness or be an exacerbated response3 or a reaction to the illness. Second, depression can be a consequence of treatment of physical illness with medications (eg, antihypertensives, corticosteroids, and other immunosuppressants) or cancer treatments, especially with interferons.4 Third, depression may be a consequence of various medical illnesses. Depression occurs in approximately 30% to 40% of patients with acute stroke or myocardial infarction, and has been linked to poorer cognitive and physical recovery. Fourth, depression can be a complication.3 Depression should be considered a new strong risk factor among other pre-existing risk factors, especially anxiety or panic states, through increased sympathetic activity; mobilization of free fatty acid from adipose tissue; thrombogenicity and platelet activation, agglutination; thrombus formation; and inflammation, particularly in coronary and cerebrovascular disorders; and possibly in other conditions. Fifth, depression may be a co-existant, pre-existant, or coincidental association3 to a physical illness. Sixth, depression can be contextual; it may be an effect of illness and its impact on life situations (eg, personal, job, relationships, finances) or in the context of metabolic disturbances (eg, hypoactive delirium presenting as depression). Seventh, depression may be a cue or clue to an underlying illness or a prelude to yet to be diagnosed major illness, especially in those who have the first onset of depression in mid-life or later. Approximately 33% of Alzheimer’s patients experience depression in the prodromal and early stages of dementia.5 Last, depression may be a contributing factor to the prolongation of the distress of a physical illness.

 

Detection of Depression

Detection of depression in the medically ill can be difficult for the following reasons.6 First, it may be regarded as a “normal: reaction to physical illness. Second, common vegetative symptoms include weight loss, fatigue, weakness, and anorexia often due to the medical illness. Third, it is difficult to distinguish onset of a depressive syndrome from psychological reactions to life-threatening illness. Last, the effects of impaired cognitive functioning secondary to the medical illness itself may detract from the detection of depression. As a result, the symptom pattern cannot be relied upon to a make a definitive diagnosis.7

To quote Dr. Elizabeth Scott8:

The reason for these disorders largely being unrecognized is fairly complex. But, certainly the conventional classification systems that we use in psychiatry contribute to this. Those classification systems are often not helpful in patients with physical illness. That’s because these systems largely depend on vegetative symptoms, as part of their diagnostic criteria. Symptoms such as sleep or appetite disturbance, changes in weight, changes in neuro-cognitive status, short-term memory or concentration, or changes in energy level also are symptoms of the underlying physical illness itself and then it becomes hard to tease out what’s the underlying physical illness or the disease process and what’s the contribution of depression or anxiety and also it makes it hard to gauge the severity of depressive or anxiety symptoms. Psychiatrists generally have a lack of agreement or consensus about the appropriate diagnostic criteria or classification systems to use in these patients…Physicians and patients themselves often assume that these symptoms are a reaction to the underlying physical illness, or…part of the disease process itself, so they often feel that they don’t merit separate identification assessment or intervention.

Screening instruments such as the Beck Depression Inventory cannot replace clinical assessment. When usual resilience to illness is replaced by pervasive low mood, depression characterized by lack of interest in life should be strongly suspected; empirical trial of treatment should be considered, especially in view of newer, safer antidepressants and psychological treatments.4 Although depression associated with medical illness has been shown to increase mortality, the benefits of treating depression on medical morbidity and mortality have yet to be established.9

 

Alternative Approaches to Help Detect Comorbid Depression

The Inclusive Approach

Instead of excluding symptoms appearing to be caused by a medical condition (eg, fatigue), the inclusive approach considers all symptoms describing depression. The inclusive approach is easy to use and sensitive to functional impairment.10

 

Substituting the “Classic” Vegetative Symptoms

Classic vegetative symptoms include change in appetite and sleep, fatigue and loss of energy, diminished ability to think or concentrate, indecisiveness, psychomotor slowing, tearfulness, depressed appearance, social withdrawal and decreased talkativeness, brooding, self-pity, pessimism, lack of reactivity to environmental events, and latency in responses.11

 

Modifying DSM-IV Criteria

One alternative approach to help detect comorbid depression is to modify the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,12 to include the criteria in Table 1.13

 

 

Eliciting Positive Answers

Eliciting positive answers to the questions in Table 2 should raise awareness of the possibility of depression.

 

 

Asking Useful Questions

It is important to ask prime medical questions eliciting emotion and cognitive symptoms (Table 3).14 For example, during the past month, has the patient been frequently bothered by feeling down, depressed, or hopeless? During the past month, has he or she held little interest or experienced meager pleasure from certain activities? More simply, the patient could be directly asked if he or she felt sad or depressed, which seems to be the simplest and most yielding research question.

 

 

 

Prevalence Rates of Depression in Various Medical Conditions

As per the United States Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, the prevalence rates of depression in various medical conditions are listed in Table 4 and Figure 1.15-27

 

 

 

Cardiovascular System

According to Ginzburg, “the damage to the heart, with its symbolic meaning as the essence of the human being may shatter the patient’s sense of wholeness and safety.”28

Figure 2 shows cumulative mortality for depressed and non-depressed patients following a heart attack.29

 

As first reported by Frasure-Smith and colleagues,29 MDD in patients hospitalized following a myocardial infarction is an independent risk factor for mortality at 6 months and increases mortality 3–5 fold. Its impact is at least equivalent to that of left ventricular dysfunction and history of previous myocardial infarction.

A prospective cohort study by Surtees and colleagues30 found that MDD was associated with an increased risk of ischemic heart disease mortality. This association was independent of established risk factors for ischemic heart disease and remained undiminished several years after the original assessment.

One study31 has shown that, after acute coronary syndromes, depressed patients have elevated levels of inflammatory markers, thus suggesting chronic endothelial activation among these patients.

Depression may itself predispose to vascular disease. Mechanisms proposed for the linkage between depression and cardiovascular disease include the effects of hypercortisolemia (glucocorticoids inhibiting inflammation processes38 or by reducing glucocorticoid signaling leading to abnormal brain functioning32-24), immune activation, depression-related platelet aggregation leading to increased thrombosis, depression-induced impairment of arterial endothelial functioning, and abnormal folate or homocysteine metabolism. Although these mechanisms have been proposed to relate depression to cardiovascular diseases, depression could also be linked to cerebrovascular disease.32

 

Cerebrovascular System

Depression occurs in approximately 40% of patients with acute stroke and has been linked to poorer cognitive and physical recovery. An association between depressive symptoms and stroke mortality was reported by Morris and colleagues,35 who found that stroke patients with in-hospital depression were 3.5 times more likely to die during 10 years of follow up than patients without depression.

Treatment with fluoxetine or nortriptyline for 12 weeks during the first 6 months poststroke significantly increased the survival of both depressed and nondepressed patients. This finding suggests that the pathophysiologic processes determining the increased mortality risk associated with poststroke depression last longer than the depression itself and can be modified by antidepressants.36

Based on the above, one could wonder if depression is a “contributor or a consequence” of both cardiovascular and cerebrovasular pathologies (Figure 3).37,38 It remains possible that the high rate of depression in both conditions represents a common vascular mechanism.39

 

 

 

Cancer

The prevalence of depression among cancer patients ranges between 23% and 60%. Acute stress and anxiety and/or dysphoric states following discovery of cancer (a traumatic life event) are poorly understood in traditional medical settings. Pain and depression are the most common neuropsychiatric presentations, and they are followed by fatigue, distress, and various disabilities. As the disease progresses, immunologic changes and the effect of treatment could be an additional burden contributing to MDD. Increased levels of cytokines, (eg, interleukin) secreted by the immune system to fight cancer or infections could also result in “sickness behavior syndrome,” characterized by a depressed mood, sleepiness, and poor concentration (Figure 4).40 Higher than normal plasma IL-6 concentrations were associated with a diagnosis of MDD in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with MDD.41

 

While helping to bolster the immunologic response, it is equally important to acknowledge the patient’s symptoms and treat them vigorously with cognitive-behavioral therapy, stress management, and antidepressant drug therapy.

 

Diabetes Mellitus

Depression as a precursor and as a consequence to type 2 diabetes has been studied. Prevalence of depression in adult diabetics is 3–5 times compared to prevalence in general population. Fourteen percent to 15% of patients diagnosed with type-2 diabetes have MDD. Thirty-three percent of all patients with neuropathy, retinopathy, and nephropathy are depressed. MDD in diabetes indicates poorer prognosis, worse glucose control, increased symptoms, decreased adherence to prescription plans, increased complications, decreased overall functional well being, and occasionally suicidality with complications.

Following a large population-based study in Norway, Engum and colleagues21 concluded that diabetes did not predict symptoms of depression or anxiety. Rather, symptoms of depression and anxiety emerged as significant risk factors for onset of type-2 diabetes independent of established risk factors for diabetes, such as socioeconomic factors, lifestyle factors, and markers of the metabolic syndrome.

The studies, presented at the meeting of the European Association for the Study of Diabetes,42 add to a growing body of evidence linking depression and other mental disorders to diabetes risk. Symptoms of depression or psychological stress were associated with increased risk of type-2 diabetes in men, but not in women, as per Swedish researchers.42 “People with diabetes had a higher prevalence of all mental illnesses compared with people without diabetes,” according to researchers from Canada.43 In particular, they noted that the rate of affective and anxiety disorders was >30% higher in people with diabetes who were <50 years of age. Other researchers have found hippocampal changes in patients with juvenile onset diabetes.

 

Neurologic Illnesses

Table 5 provides the rates of depression in neurologic illnesses.44

 

 

 

Aging, Frailty, and Alzheimer’s Disease

Physical frailty and need for assistance in daily living often causes dysphoria. However, depression should not be accepted as a normal part of aging, as untreated depression in the elderly causes needless suffering. Depression can render mild cognitive impairment to appear like dementia, thus confounding diagnosis and prognostication. A history of early onset depression increases the risk for Alzheimer’s disease compared to those with no history.45

 

HIV/AIDS

In addition to social stigma in the early stages, even when physically well, drug issues, HIV’s later physical effects of nausea and fatigue with anti-retro virals, HIV-related apathy, mood disorders, and cognitive impairments are seldom recognized early in the course of the disease. The cerebral events may remain compartmentalized and not necessarily reflected in the routine assessment of peripheral markers such as viral loads or T-cell counts.

 

Musculoskeletal Rehabilitation

See Table 6 for the prevalence of psychiatric disorders in musculoskeletal rehabilitation.46

 

 

 

Conclusion

In addition to the knowledge that depression contributes both to disability and diminished survival among medically ill, it is increasingly evident that MDD is a multi-systemic disorder that affects both brain and bodily functions.40

The inter-relationship between the two is rather complex. Inflammation could be the common link through neuro-immuno-endocrine mechanisms contributing to both psychological and somatic symptoms such as depression and cardiovascular diseases.27,47,48 As more evidence accumulates, it seems clear that late-onset depression in particular is not just a mood disorder but could be a warning signal of an impending major or catastrophic physical illness. It is well known that depression is a heralding symptom of undiagnosed medical conditions including multiple sclerosis, Parkinson’s disease, hypo- or hyperthyroidism, Cushing’s disease, and pancreatic cancer. The assessment of both conditions and the interaction between them is critical in managing these patients.1 When the medical illness is treated, the depression often gets better. While the importance of recognition and treatment of comorbid depression in helping reduce disability and suffering is very clear, the effect of treatment on the course of the comorbid illnesses themselves and the overall effect on survival need to be further studied. Also in need of further investigation are yet-to-be-discovered, non-antidepressant, disease-modifying effects of selective serotonin reuptake inhibitors or other newer agents on diabetes, stroke, multiple sclerosis, and Alzheimer’s disease (among other diseases).

Considering the available evidence, it is clearly prudent to include aggressive treatment of comorbid depression, utilizing all available modalities—including psychopharmacologic agents—in the management of all physical illnesses. PP

 

References

1.     Heidenreich A, Aus CC, Abbou M, et al. EAU guidelines on prostate cancer. Eur Urol. 2005:53(1):68-80.
2.    Goodnick PJ, Hernandez M. Treatment of depression in comorbid medical illness. Expert Opin Pharmacother. 2000;1(7):1367-1384.
3.    Peveler R, Carson A, Rodin G. Depression in medical patients. BMJ. 2002;325(7356):149-152.
4.    Rapp MA, Schnaider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry. 2006;63(2):161-167.
5.    Wyszynski AA, Wyszynski B. Manual of Psychiatric Care for the Medically Ill. 1st ed. Washington, DC: American Psychiatric Publishing, Inc.; 2004.
6.    Hickie IB, Davenport TA, Naismith SL, Scott EM. SPHERE: a national depression project. SPHERE National Secretariat. Med J Aust. 2001;175(suppl):S4-S5.
7.    Royal College of Physicians of London and Royal College of Psychiatrists. The Psychological Care of Medical Patients: A Practical Guide. Wiltshire, England: Sarum ColourView Group; 2003.
8.    Scott E. Depression and Anxiety in the Medically Ill. SPHERE: A National Depression Project. Available at: www.spheregp.com.au. Accessed August 5, 2008.
9.    Kroenke K. Patients presenting with somatic complaints: epidemiology, psychiatric comorbidity and management. Int J Methods Psychiatr Res. 2003;12(1):34-43.
10.    Koenig HG, George LK, Peterson BL, et al. Depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. Am J Psychiatry. 1997;154:1376-1383.
11.    Endicott J. Measurement of depression in patients with cancer. Cancer. 1984;53(10 suppl):2243-2248.
12.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
13.    Cavanaugh S, Clark DC, Gibbons RD. Diagnosing depression in the hospitalized medically ill. Psychosomatics. 1983;24(9):809-815.
14.    Arroll B, Khin N, Kerse N. Screening for depression in primary care with two verbally asked questions: cross sectional study. BMJ. 2003;327(7424):1144-6.
15.    Folks DG. The interface of psychiatry and irritable bowel syndrome. Curr Psychiatry Rep. 2004;6(3):210-215.
16.    Mikkelsen RL, Middelboe T, Pisinger C, Stage KB. Anxiety and depression in patients with chronic obstructive pulmonary disease (COPD). A review. Nord J Psychiatry. 2004;58(1):65-70.
17.    Krueger RF, Tackett JL, Markon KE. Structural models of comorbidity among common mental disor¬ders: connections to chronic pain. Adv Psychosom Med. 2004;25:63-77.
18.    Cruess DG, Petitto JM, Leserman J, et al. Depression and HIV infection: impact on immune function and disease progression. CNS Spectr. 2003;8(1):52-58.
19.    Iosifescu DV, Bankier B, Fava M. Impact of medical comorbid disease on antidepressant treatment of major depressive disorder. Curr Psychiatry Rep. 2004;6(3):193-201.
20.    Parker JC, Wright GE. The implications of depression for pain and disability in rheumatoid arthritis. Arthritis Care Res. 1995;8(4):279-283.
21.    Engum A, Mykletun A, Midthjell K, Holen A, Dahl AA. Depression and diabetes: a large population-based study of sociodemographic, lifestyle, and clinical factors associated with depression in type 1 and type 2 diabetes. Diabetes Care. 2005;28(8):1904-1909.
22.    Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the national comorbidity survey. I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29(2-3):85-96.
23.    Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA. 2003;289(23):3095-3105.
24.    Evans DL, Staab JP, Petitto JM, et al. Depression in the medical setting: biopsychological interactions and treatment considerations. J Clin Psychiatry. 1999;60(suppl 4):40-55.
25.    Astrom M, Adolfsson R, Asplund K. Major depression in stroke patients. A 3-year longitudinal study. Stroke. 1993;24(7):976-982.
26.    Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. Rockville, MD: US Department of Health; 1993.
27.    Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. Rockville, MD: US Dept of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research; 1993: no. 93-0550.
28.    Porter V. Depression and Stress Hit Hard on the Heart. Medscape Cardiology. 2003: 7(1). Available at: www.medscape.com/viewarticle/449909. Accessed August 7, 2008.
29.    Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA. 1993;270(15):1819-1825.
30.    Surtees PG, Wainwright NW, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Depression and isch¬emic heart disease mortality: evidence from the EPIC-norfolk United Kingdom prospective cohort study. Am J Psychiatry. 2008;165(4):515-523.
31.    Lesperance F, Frasure-Smith N, Theroux P, Irwin M. The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. Am J Psychiatry. 2004;161(2):271-277.
32.    Kales HC, Maixner DF, Mellow AM. Cerebrovascular disease and late-life depression. Am J Geriatr Psychiatry. 2005;13(2):88-98.
33.    Pace TW, Hu F, Miller AH. Cytokine effects on glucocorticoid receptor function. Brain Behav Immun. 2007;21(1):9-19.
34.    Andrea Danese, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults. Arch Gen Psychiatry. 2008;65(4):409-416.
35.    Morris PL, Robinson RG, Andrzejewski P, Samuels J, Price TR. Association of depression with 10-year poststroke mortality. Am J Psychiatry. 1993;150(1):124-129.
36.    Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.
37.    Hays JC, Krishnan KR, George LK, Blazer DG. Age of first onset of bipolar disorder: demographic, family history, and psychosocial correlates. Depress Anxiety. 1998;7(2):76-82.
38.    Frasure-Smith N, Lesperance F. Depression and other psychological risks following myocardial infarction. Arch Gen Psychiatry. 2003;60(6):627-636.
39.    Aben I, Verhey F, Strik J, Lousberg R, Lodder J, Honig A. A comparative study into the one year cumula¬tive incidence of depression after stroke and myocardial infarction. J Neurol Neurosurg Psychiatry. 2003;74(5):581-585.
40.    Insel TR, Charney DS. Research on major depression: strategies and priorities. JAMA. 2003;289(23):3167-3168.
41.    Musselman DL, Miller AH, Porter MR, et al. Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry. 2001;158(8):1252-1257.
42.    Östenson CG, Eriksson AK, Granath F, Hilding A, Efendic S, Ekbom A. Depressive symptoms and risk of type 2 diabetes and pre-diabetes in a prospective study of middle aged Swedish men and women. Paper presented at: 43rd Annual Meeting of the European Association for the Study of Diabetes; September 20, 2007; Amsterdam, Netherlands.
43.    Osterweil, N. Studies Link Depression and Type 2 Diabetes. EASD: European Association for the Study of Diabetes Meeting. MedPage Today. Reviewed by Agus, Z. Sept 21, 2007. Available at: www.medpagetoday.com/MeetingCoverage/EASD/tb/6752. Accessed August 7, 2008.
44.    Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MM. History of Depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology. 2008:70(15):1258-1264.
45.    Schiffer RB. Goldman consensus statement on depression in MS. Goldman Consensus Group. Multiple Sclerosis. 2005;11:328-337.
46.    Harter M, Reuter K, Weisser B, Schretzmann B, Aschenbrenner A, Bengel J. A descriptive study of psychiatric disorders and psychosocial burden in rehabilitation patients with musculoskeletal diseases. Arch Phys Med Rehabil. 2002;83(4):461-468.
47.    Evans DL, Charney DS, Lewis L, et al. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry. 2005;58(3):175-189.
48.    Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the enhancing recovery in coronary heart disease patients (ENRICHD) randomized trial. JAMA. 2003;289(23):3106-3116.