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

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

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

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

 

 

Abstract

 

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

 

Introduction

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

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

 

The Menopausal Transition

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

 

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

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

 

Risk of Depression During the Menopausal Transition

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

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

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

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

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

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

 

Risk Factors for Depression During the Menopausal Transition

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

 

Physical Context of the Menopausal Transition

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

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

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

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

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

 

Psychosocial Context of the Menopausal Transition

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

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

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

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

 

Psychiatric Risk Factors for Depression During the Menopausal Transition

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


Genetic Factors

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

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

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

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

 

The Transition Triad: A Biopsychosocial Model of Depression

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

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

 

Evaluating Depression During the Menopausal Transition

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

 

 

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

 

Treating Depression During the Menopausal Transition

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

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

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

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

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

 

Use of Estrogen in Treatment of Menopausal Depression

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

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

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

 

Conclusion

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

 

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

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

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

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

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

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

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

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

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

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

 

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

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

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

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

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

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

 

Detection and Management of Dementia in General Practice

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

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

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

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

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

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

 

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

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

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

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

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

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

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

 

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

 

Estrogen May Ease Schizophrenia in Women

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

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

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

 

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

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

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

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

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

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

 

New Medications May Help Drinkers Battle Alcohol Dependence

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

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

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

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

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

 

Detection and Management of Dementia in General Practice

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

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

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

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

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

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

 

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

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

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

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

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

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

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

 

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

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

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

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

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

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

 

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

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

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

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

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

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

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

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

 

Estrogen May Ease Schizophrenia in Women

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

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

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

 

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

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

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

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

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

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

 

New Medications May Help Drinkers Battle Alcohol Dependence

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

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

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

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

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

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

 

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

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

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

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

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