Kathleen R. Merikangas

The Future of Genetic Studies of Complex Human Diseases

The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult. In their Perspective, Risch and Merikangas propose that we can best accomplish this goal by combining the power of the human genome project with association studies, a method for determining the basis of a genetic disease.

Lifetime Prevalence of Mental Disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication- Adolescent Supplement (NCS-A)

OBJECTIVE To present estimates of the lifetime prevalence of DSM-IV mental disorders with and without severe impairment, their comorbidity across broad classes of disorder, and their sociodemographic correlates. METHOD The National Comorbidity Survey-Adolescent Supplement NCS-A is a nationally representative face-to-face survey of 10,123 adolescents aged 13 to 18 years in the continental United States. DSM-IV mental disorders were assessed using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. RESULTS Anxiety disorders were the most common condition (31.9%), followed by behavior disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%), with approximately 40% of participants with one class of disorder also meeting criteria for another class of lifetime disorder. The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders. CONCLUSIONS These findings provide the first prevalence data on a broad range of mental disorders in a nationally representative sample of U.S. adolescents. Approximately one in every four to five youth in the U.S. meets criteria for a mental disorder with severe impairment across their lifetime. The likelihood that common mental disorders in adults first emerge in childhood and adolescence highlights the need for a transition from the common focus on treatment of U.S. youth to that of prevention and early intervention.

New researchLifetime Prevalence of Mental Disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A)

OBJECTIVE To present estimates of the lifetime prevalence of DSM-IV mental disorders with and without severe impairment, their comorbidity across broad classes of disorder, and their sociodemographic correlates. METHOD The National Comorbidity Survey-Adolescent Supplement NCS-A is a nationally representative face-to-face survey of 10,123 adolescents aged 13 to 18 years in the continental United States. DSM-IV mental disorders were assessed using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. RESULTS Anxiety disorders were the most common condition (31.9%), followed by behavior disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%), with approximately 40% of participants with one class of disorder also meeting criteria for another class of lifetime disorder. The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders. CONCLUSIONS These findings provide the first prevalence data on a broad range of mental disorders in a nationally representative sample of U.S. adolescents. Approximately one in every four to five youth in the U.S. meets criteria for a mental disorder with severe impairment across their lifetime. The likelihood that common mental disorders in adults first emerge in childhood and adolescence highlights the need for a transition from the common focus on treatment of U.S. youth to that of prevention and early intervention.

Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

CONTEXT Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

Replicating genotype-phenotype associations.

What constitutes replication of a genotype–phenotype association, and how best can it be achieved?

Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative

CONTEXT There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. OBJECTIVES To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional, face-to-face, household surveys of 61,392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. MAIN OUTCOME MEASURES Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. RESULTS The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. CONCLUSIONS Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.

Mood disorders in children and adolescents: an epidemiologic perspective

Epidemiologic studies show that major depression is comparatively rare among children, but common among adolescents, with up to a 25% lifetime prevalence by the end of adolescence. Mania is much less common, with no more than a 2% lifetime prevalence by the end of adolescence. Developmental studies that include assessments of both hormonal changes and social changes through the pubertal transition are needed to investigate joint biological and environmental influences on the emergence of the gender difference in depression in puberty. Although subthreshold mood disorder symptoms are common, controversy exists about their clinical significance. This controversy is made more complex by methodologic uncertainties regarding inconsistent symptom reports obtained from parents, teachers, and children and by the pervasive existence of comorbidity. Retrospective reports about age of onset in adult studies suggest that at least 50% of youngsters with major depression and 90% of those with mania continue to have adult recurrences. These recurrences are mediated by adverse role transitions, such as truncated educational attainment and teenage childbearing, that typically occur before the time of initial treatment. Aggressive outreach and early treatment aimed at preventing the occurrence of adverse role effects might help decrease the persistence of child and adolescent mood disorders. Long-term follow-up studies are needed to resolve current uncertainties regarding nosology, methodology, and long-term treatment effects. Innovative epidemiologic research designs aimed at more quickly providing provisional information are also needed to advance understanding of long-term developmental processes.

Prevalence and Correlates of Eating Disorders in Adolescents: Results From the National Comorbidity Survey Replication Adolescent Supplement

CONTEXT Eating disorders are severe conditions, but little is known about the prevalence or correlates of these disorders from population-based surveys of adolescents. OBJECTIVES To examine the prevalence and correlates of eating disorders in a large, reprefentative sample of US adolescents. DESIGN Cross-sectional survey of adolescents with face-to-face interviews using a modified version of the Composite International Diagnostic Interview. SETTING Combined household and school adolescent samples. PARTICIPANTS Nationally representative sample of 10,123 adolescents aged 13 to 18 years. MAIN OUTCOME MEASURES Prevalence and correlates of eating disorders and subthreshold conditions. RESULTS Lifetime prevalence estimates of anorexia nervosa, bulimia nervosa, and binge-eating disorder were 0.3%, 0.9%, and 1.6%, respectively. Important differences were observed between eating disorder subtypes concerning sociodemographic correlates, psychiatric comorbidity, role impairment, and suicidality. Although the majority of adolescents with an eating disorder sought some form of treatment, only a minority received treatment specifically for their eating or weight problems. Analyses of 2 related subthreshold conditions suggest that these conditions are often clinically significant. CONCLUSIONS Eating disorders and subthreshold eating conditions are prevalent in the general adolescent population. Their impact is demonstrated by generally strong associations with other psychiatric disorders, role impairment, and suicidality. The unmet treatment needs in the adolescent population place these disorders as important public health concerns.

Prevalence and Treatment of Mental Disorders Among US Children in the 2001–2004 NHANES

OBJECTIVE: This article presents the 12-month prevalence estimates of specific mental disorders, their social and demographic correlates, and service use patterns in children and adolescents from the National Health and Nutrition Examination Survey, a nationally representative probability sample of noninstitutionalized US civilians. METHODS: The sample includes 3042 participants 8 to 15 years of age from cross-sectional surveys conducted from 2001 to 2004. Data on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for mental disorders were derived from administration of selected modules of the National Institute of Mental Health Diagnostic Interview Schedule for Children, version IV, a structured diagnostic interview administered by lay interviewers to assess psychiatric diagnoses of children and adolescents. RESULTS: Twelve-month prevalence rates of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–defined disorders in this sample were 8.6% for attention-deficit/hyperactivity disorder, 3.7% for mood disorders, 2.1% for conduct disorder, 0.7% for panic disorder or generalized anxiety disorder, and 0.1% for eating disorders. Boys had 2.1 times greater prevalence of attention-deficit/hyperactivity disorder than girls, girls had twofold higher rates of mood disorders than boys, and there were no gender differences in the rates of anxiety disorders or conduct disorder. Only approximately one half of those with one of the disorders assessed had sought treatment with a mental health professional. CONCLUSION: These data constitute a first step in building a national database on mental health in children and adolescents.

Comorbidity of substance use disorders with mood and anxiety disorders: Results of the international consortium in psychiatric epidemiology

This article reports the results of a cross-national investigation of patterns of comorbidity between substance use and psychiatric disorders in six studies participating in the International Consortium in Psychiatric Epidemiology. In general, there was a strong association between mood and anxiety disorders as well as conduct and antisocial personality disorder with substance disorders at all sites. The results also suggest that there is a continuum in the magnitude of comorbidity as a function of the spectrum of substance use category (use, problems, dependence), as well as a direct relationship between the number of comorbid disorders and increasing levels of severity of substance use disorders (which was particularly pronounced for drugs). Finally, whereas there was no specific temporal pattern of onset for mood disorders in relation to substance disorders, the onset of anxiety disorders was more likely to precede that of substance disorders in all countries. These results illustrate the contribution of cross-national data to understanding the patterns and risk factors for psychopathology and substance use disorders.