Pharmacogenomic Testing in Psychiatry: Ready for Primetime?

Pharmacogenomic testing in clinical psychiatry has grown at an accelerated pace in the last few years and is poised to grow even further. Despite robust evidence lacking regarding efficacy in clinical use, there continues to be growing interest to use it to make treatment decisions. We intend this article to be a primer for a clinician wishing to understand the biological bases, evidence for benefits, and pitfalls in clinical decision-making. Using clinical vignettes, we elucidate these headings in addition to providing a perspective on current relevance, what can be communicated to patients, and future research directions. Overall, the evidence for pharmacogenomic testing in psychiatry demonstrates strong analytical validity, modest clinical validity, and virtually no evidence to support clinical use. There is definitely a need for more double-blinded randomized controlled trials to assess the use of pharmacogenomic testing in clinical decision-making and care, and until this is done, they could perhaps have an adjunct role in clinical decision-making but minimal use in leading the initial treatment plan.

Treatment of vasomotor symptoms in the menopausal transition and postmenopausally: psychiatric comorbidity.

This article aims to educate the nonpsychiatric as well as the psychiatric clinician on the impact of vasomotor symptoms in women with comorbid psychiatric problems and the challenges of treating vasomotor symptoms in these women. The pathophysiology, prevalence and common risk factors associated with disturbing hot flashes in the menopausal transition are reviewed. Hormonal, nonhormonal and behavioral treatment options of vasomotor symptoms for these women are discussed. Special pharmacokinetic implications for hormonal treatment of those women on anticonvulsant medications for the treatment of their mood disorders, on tamoxifen and/or with high or low sex hormone-binding globulin are examined. An in-depth discussion of mood and the menopausal transition, theoretical mechanisms for mood problems with the symptomatic menopause and the impact of stress on the symptomatic menopause are found elsewhere in this clinical review series on psychiatric illness, stress and the symptomatic menopause.

Assessment and treatment for insomnia and fatigue in the symptomatic menopausal woman with psychiatric comorbidity.

Studies and treatments for the symptomatic menopausal woman with sleep complaints have been reviewed elsewhere. This article, as part of the clinical review series on the comorbid symptomatic menopausal woman, aims to examine the evidence for diagnosis and treatment of women who present with distressing sleep symptoms that they attribute to menopause. The etiology of these symptoms may be a psychiatric disorder, a pre- or co-existing problem with sleep, or a dynamic interaction among one of these and/or a symptomatic menopause. The relationship between sleep disturbance and cognitive complaints, mood problems, fatigue and low energy will be reviewed. The new research on sleep, clinical consequences of insomnia of various types, the impact of sleep disturbance on morbidity and functioning--in the context of the midlife woman in the menopausal transition--will be explored along with the evidence for different treatment strategies for these sleep problems.

Arthralgias, bodily aches and pains and somatic complaints in midlife women: etiology, pathophysiology and differential diagnosis.

Somatic symptoms characterized by arthralgias, bodily aches and pains, musculoskeletal pain and joint pain have been investigated in a number of menopause and depression studies. Although depression is one of the most common causes of bodily aches and pains, and arthralgias, these same symptoms are also commonly associated with a natural menopause, surgical menopause and menopause induced by chemotherapy in breast cancer treatment. Somatic symptoms in the absence of definitive medical diagnoses result in these patients receiving various diagnoses and labels--'medically unexplained symptoms', 'worried well', as well as various Diagnostic and Statistical Manual of Mental Disorders (4th edition) somatoform diagnoses. Osteoarthritis and joint pain increase in prevalence from premenopausal- to menopausal-aged women with hormonal change implicated in their etiology. The current research on the relationships among menopause, depression, nociceptive mechanisms, perception and pain in the distressed midlife patient is discussed. The amelioration and management of pain symptoms in the menopausal and postmenopausal woman, with or without comorbid depression, have been elusive and difficult problems for clinicians. Familiarity with the differential diagnosis, pathophysiology and evidence-based treatment for such patients is crucial to their proper care.

Impact of clinician and patient attitudes on clinical decision making for the symptomatic menopausal woman with or without comorbidity.

Culture, individual health beliefs and distressing symptoms frequently determine women's perceptions of their menopausal transitions. Women's perceptions of mental health problems and the acceptability of different interventions greatly affect if and what a woman is willing to try as a treatment option and whether or not she will accept the possibility that her menopausal symptoms represent a comorbidity with a diagnosis, such as depression or anxiety. These perceptions have a significant impact on women's choices with regard to health practices, as well as on whether or not they will seek out medical care for their distressing symptom(s). Working with a woman's beliefs, sharing decision making, and empowering her through health education are all critical aspects of the treatment of the patient with comorbid perimenopausal symptoms, regardless of their etiology.

Role of psychiatric comorbidity on cognitive function during and after the menopausal transition.

While cognitive complaints are common during the menopausal transition, measurable cognitive decline occurs infrequently, often due to underlying psychiatric or neurological disease. To clarify the nature, etiology and evidence for cognitive and memory complaints during midlife, at the time of the menopausal transition, we have critically reviewed the evidence for impairments in memory and cognition associated with common comorbid psychiatric conditions, focusing on mood and anxiety disorders, attention-deficit disorder, prolonged stress and decreased quantity or quality of sleep. Both the evidence for a primary effect of menopause on cognitive function and contrarily the effect of cognition on the menopausal transition are examined. Impairment in specific aspects of executive function is explored. Evaluation and treatment strategies for the symptomatic menopausal woman distressed by changes in her day-to-day cognitive function with or without psychiatric comorbidity are presented.

Nomenclature and endocrinology of menopause and perimenopause.

The early and late perimenopausal transition is characterized by changing cycle length as well as by menopausal symptoms in some women, including increasing hot flashes and night sweats. Breast tenderness decreases as women enter the late transition. This review, as part of the clinical reviews on the menopausal woman with comorbidity, covers the endocrine phenomena of perimenopause, terminology and the observed clinical characteristics of the transition. It should be noted that the definitions covering this period vary between publications. The average duration of perimenopause is approximately 5A years. The earliest detectable hormonal change is a fall in ovarian secretion of inhibinA B, with a subsequent rise in follicle-stimulating hormone and maintained or increased levels of estradiol. As women transit the perimenopause, cycle irregularity increases, with the more frequent occurrence of prolonged ovulatory and anovulatory cycles. Levels of follicle-stimulating hormone and estradiol fluctuate increasingly and luteal function declines. Vasomotor symptoms tend to be most frequent around the time of final menses. The perimenopause is thus a time of cycle and hormone variability and single hormone measurements provide little useful information, with the clinical history being the most appropriate method of assessing menopausal status. This information will be very helpful to the clinician treating the concerned and symptomatic patient. It will also aid clinicians to avoid unnecessary laboratory testing and help them educate their patients about their perimenopause.

Series overview and introduction.

Studies and treatments for the symptomatic menopausal woman have been reviewed elsewhere. The aim of this clinical review series is to examine the evidence for the diagnosis and treatment of the woman who presents with distressing symptoms that she attributes to menopause, whose actual etiology may be a psychiatric disorder, a pre- or co-existing problem such as sleep or cognitive problems, or a dynamic interaction among one of these and a symptomatic menopause. This series of articles will review new research on somatic symptoms of depression, the depression continuum and its impact on morbidity and functioning, treatment issues related to remission of depression, cognitive decline or impairment secondary to a mood disorder, sleep problems in women and their impact on well-being and functioning, and attention and working memory problems in women. These will all be reviewed in the context of the vulnerable female patient and her experience of increased or new distressing symptoms during her menopausal transition. Recommendations for the diagnosis and management of women with psychiatric comorbidity and a symptomatic menopause are discussed.

Women, anxiety and mood: a review of nomenclature, comorbidity and epidemiology.

Women experience a high prevalence of mood and anxiety disorders, and comorbidity of mood and anxiety disorders is highly prevalent. Both mood and anxiety disorders disturb sleep, attention and, thereby, cognitive function. They result in a variety of somatic complaints. The mood disorder continuum includes minor depression, dysthymia, major depression and bipolar disorder. Chronobiological disorders, such as seasonal affective disorder as well as premenstrual dysphoric disorder, occur in some women, with comorbid seasonal affective disorder and premenstrual dysphoric disorder in just under half of these individuals [1] . Early life experience, heritability, gender, other psychiatric illness, stress and trauma all interact dynamically in the development of mood and anxiety disorders. The epidemiology, nomenclature and clinical diagnostic issues of these illnesses in midlife woman are reviewed.

Collaborative depression care, screening, diagnosis and specificity of depression treatments in the primary care setting.

The identification, referral and specific treatment of midlife patients in primary care who are distressed by mood, anxiety, sleep and stress-related symptoms, with or without clinically confirmed menopausal symptoms, are confounded by many structural issues in the delivery of women's healthcare. Diagnosis, care delivery, affordability of treatment, time commitment for treatment, treatment specificity for a particular patient's symptoms and patient receptiveness to diagnosis and treatment all play roles in the successful amelioration of symptoms in this patient population. The value of screening for depression in primary care, the limitations of commonly used screening instruments relative to culture and ethnicity, and which clinical care systems make best use of diagnostic screening programs will be discussed in the context of the midlife woman. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) program illustrates the relatively high rate of unremitted patients, regardless of clinical setting, who are receiving antidepressants. Nonmedication treatment approaches, referred to in the literature as 'nonsomatic treatments', for depression, anxiety and stress, include different forms of cognitive-behavioral therapy, interpersonal therapy, structured daily activities, mindfulness therapies, relaxation treatment protocols and exercise. The specificity of these treatments, their mechanisms of action, the motivation and time commitment required of patients, and the availability of trained practitioners to deliver them are reviewed. Midlife women with menopausal symptoms and depression/anxiety comorbidity represent a challenging patient population for whom an individualized treatment plan is often necessary. Treatment for depression comorbid with distressing menopausal symptoms would be facilitated by the implementation of a collaborative care program for depression in the primary care setting.

Neurobehavioral impact of menopause on mood.

The menopausal transition is a time of risk for mood change ranging from distress to minor depression to major depressive disorder in a vulnerable subpopulation of women in the menopausal transition. Somatic symptoms have been implicated as a risk factor for mood problems, although these mood problems have also been shown to occur independently of somatic symptoms. Mood problems have been found to increase in those with a history of mood continuum disorders, but can also occur de novo as a consequence of the transition. Stress has been implicated in the etiology and the exacerbation of these mood problems. Estrogen and add-back testosterone have both been shown to positively affect mood and well-being. In most cases, the period of vulnerability to mood problems subsides when the woman's hormonal levels stabilize and she enters full menopause.

Role of stressful life events and menopausal stage in wellbeing and health.

Stress plays an essential role in the development, continuation and exacerbation of mood problems throughout a woman's life. It exacerbates somatic symptoms of menopause, increasing the risk of recurrence of mood disorders, as well as of a mood disorder de novo throughout the lifespan and specifically in the menopausal transition. Chronic stress affects the hypothalamic-pituitary axis, hypothalamic-pituitary-ovarian axis, the proinflammatory cytokines and cardiovascular risk. The current evidence for the potential interactions between acute stress, chronic stress, childhood stress and victimization, and individual susceptibility to the development of depression and/or anxiety in response to stressful life events, are reviewed in the context of the increasing data on the association of these and a symptomatic menopausal transition. Strategies for the optimal approach for clinicians to evaluate and treat the symptomatic perimenopausal patient with stressful life events and comorbid mood disorders are presented.

A symptomatic approach to understanding women's health experiences: a cross-cultural comparison of women aged 20 to 70 years.

OBJECTIVES: To determine patterns of symptoms across age groups, identify symptom groups associated with ovarian hormonal depletion or other variables, and develop a prediction model for each symptom. DESIGN: This was a cross-sectional survey of 4,517 women ages 20 to 70 years recruited from market research panels in the United States, United Kingdom, Germany, France, and Italy using a self-report questionnaire that included general health information and a checklist of 36 symptoms. Stepwise regression was used to determine for each symptom how prevalence varied with age, indicators of menopausal hormonal changes, and the effects of other explanatory variables, including body mass index, morbidity, and country. Hierarchical clustering was used to group symptoms. RESULTS: Six groups of symptoms were found, of which two groups, with seven symptoms in total, were related to markers of menopausal hormonal change: a group consisting of hot flashes and night sweats and a second group including poor memory; difficulty sleeping; aches in the neck, head, and shoulders; vaginal dryness; and difficulty with sexual arousal. Physical and mental morbidity affected estimates of the prevalence of all symptoms. Psychological symptoms declined with age from a maximum prevalence before age 40. Certain physical symptoms increased with age and body mass index. Clustering identified three country groups: (1) US and UK women; (2) French and Italian women; and (3) German women. There were marked differences in prevalence between countries for certain physical and psychological symptoms. CONCLUSIONS: The seven symptoms most linked to menopausal hormonal change should form part of any future menopause symptom list. Physical and mental morbidity affect symptom prevalence and should be measured.

Quest for timely detection and treatment of women with depression.

BACKGROUND: Women are at risk for a wide range of depressive and anxiety disorders and particularly for mood disorders associated with their menstrual cycle, with seasonality, and during the menopausal transition. OBJECTIVE: To review the presentation of depression, the importance of timely and effective treatment, and some of the research surrounding increased prevalence of depression in women, and the times and conditions--such as the perimenopausal transition, pregnancy, postpartum period, and comorbidities--of this increased risk in women. SUMMARY: Dynamic interactions of both biological and environmental factors contribute to the development of major depression. These include, but are not limited to, predisposing genetic influences, gender, environmental stressors, poor social support, childhood sexual abuse, other psychiatric illness, and trauma. Timely and effective treatment of each episode of depression to remission is critically important. Barriers to instituting collaborative care of depressive illness are numerous. The lack of adequate collaborative care along with the consequent failure to adequately diagnose and treat depression reflects some of the deficiencies in the current organization and delivery of health services. CONCLUSION: The prevalence of depression, its psychosocial and medical consequences, and the worsening course of depression without treatment highlight the public health importance of early detection and improved strategies for the treatment of depression in modern health care settings.

Estrogen and androgen hormone therapy and well-being in surgically postmenopausal women.

BACKGROUND: Women undergoing surgical menopause experience an abrupt drop in gonadal hormones and are more likely to have symptoms that negatively impact well-being, including hot flashes, sexual dysfunction, psychological problems, and testosterone deficiency. The purpose of this review was to examine the effects of hormone therapies on well-being among surgically menopausal women. METHODS: Studies were retrieved using both Cochrane and PubMed searches. A systematic literature review was performed to identify double-blind randomized controlled trials of the effects of menopausal hormone therapies on quality of life and well-being among women who have undergone hysterectomy with bilateral oophorectomy. Two studies meeting these criteria were included for review. RESULTS: For each study reviewed, the following aspects were examined: type of hormonal therapies used, inclusion/exclusion criteria, overall changes, and changes in specific parameters of well-being. General well-being improved from baseline with certain types and doses of estrogen or estrogen plus testosterone therapy, with no serious adverse events. CONCLUSIONS: Estrogen with or without testosterone may improve general well-being in some groups of surgically menopausal women. Levels of serum estrogen achieved in these studies were within a normal range for premenopausal women. Adding testosterone to estrogen therapy may provide additional improvements in well-being in some women, but only at supraphysiological levels of total testosterone and physiological levels of free testosterone. It is recommended that the clinician discuss the potential benefits and risks with each woman and devise an individualized plan based on shared decision making.

Practical aspects in the management of vaginal atrophy and sexual dysfunction in perimenopausal and postmenopausal women.

INTRODUCTION: The decline in circulating estrogen levels in peri- and postmenopause has a wide range of physiological effects, including atrophy of tissues in the urogenital tract. Vaginal atrophy is an important contributor to postmenopausal sexual dysfunction. AIM: To provide a framework for clinical evaluation and clinical management of sexual dysfunction secondary to vaginal atrophy. METHOD: Conduct a brief overview of literature on evaluation and treatment of vaginal atrophy, augmented with the authors' clinical observations and experience. RESULTS: Estrogen decline disrupts many physiological responses characteristic of sexual arousal, including smooth muscle relaxation, vasocongestion, and vaginal lubrication; genital tissues depend on continued estrogen and androgen stimulation for normal function. An upward shift in vaginal pH as the result of vaginal atrophy alters the normal vaginal flora. Reduced lubrication capability and reduced tissue elasticity, in addition to shortening and narrowing of the vaginal vault, can lead to painful and/or unpleasant intercourse. At the same time, diminished sensory response may reduce orgasmic intensity. Other contributors to peri- and postmenopausal sexual dysfunction include reduced androgen levels, aging of multiple body systems, and side-effects of medications. Workup of sexual health problems starts by taking a comprehensive sexual, medical, and psychosocial history, followed by complete physical examination and laboratory evaluation. Clinical management includes measures to preserve and enhance overall health, adjustment of medication regimes to reduce or avoid side-effects, and topical or systemic hormone supplementation with estrogens and/or androgens. CONCLUSIONS: No single therapeutic approach is appropriate for every woman with peri- or postmenopausal sexual dysfunction; instead, treatment should be based on a comprehensive evaluation and consideration of medical and psychosocial contributors to the individual's dysfunction. Further research is required to establish optimal regimens of hormonal and nonhormonal agents, including dosages/dosage forms and duration of treatment, for specific subtypes of sexual dysfunction.

The effects of postmenopausal hormone therapies on female sexual functioning: a review of double-blind, randomized controlled trials.

Double-blind randomized controlled trials of estrogen and/or testosterone on sexual function among natural or surgical menopause in women are reviewed. Power, validity, hormone levels, and methodological issues were examined. Certain types of estrogen therapy were associated with increased frequency of sexual activity, enjoyment, desire, arousal, fantasies, satisfaction, vaginal lubrication, and feeling physically attractive, and reduced dyspareunia, vaginal dryness, and sexual problems. Certain types of testosterone therapy (combined with estrogen) were associated with higher frequency of sexual activity, satisfaction with that frequency of sexual activity, interest, enjoyment, desire, thoughts and fantasies, arousal, responsiveness, and pleasure. Whether specific serum hormone levels are related to sexual functioning and how these group effects apply to individual women are unclear. Other unknowns include long-term safety, optimal types, doses and routes of therapy, which women will be more likely to benefit from (or be put at risk), and the precise interplay between the two sex hormones.