Kathleen Merikangas, Ph.D. - US grants

The Zurich Cohort Study is a prospective longitudinal study of a cohort of young adults from Zurich, Switzerland, who were followed from the ages of 20-40 in order to estimate the prevalence, incidence, impairment, treatment patterns and stability of the major mental disorders. This study assessed a wide range of psychiatric syndromes as well as somatic syndromes including mild manifestations under the conventional diagnostic thresholds. The Zurich cohort study is comprised of a cohort of 4,547 subjects (m=2201; f = 2346) representative of the canton of Zurich in Switzerland, who were screened in 1978 with the Symptom Checklist 90-R. In order to enrich the probability of psychiatric syndromes, a sub-sample of 591 subjects (291 males, 299 females) was selected for interview, with two thirds consisting of high scorers (defined by the 85th percentile or more of the SCL-90) and a random sample of those with scores below the 85th percentile. There have been a total of 6 waves of interviews covering the age period of 20-40 years. Those who had dropped out did not differ significantly in their baseline measures in terms of demographic characteristics, or risk group at study entry. A direct interview, the Structured Psychopathological Interview and Rating of the Social Consequences for Epidemiology (SPIKE), was administered by psychiatric residents and clinical psychologists with extensive clinical training in the subjects' homes. This interview schedule assesses a number of somatic syndromes, including headache, gastrointestinal, cardiovascular, and respiratory syndromes, as well as psychological syndromes, including depression, anxiety, phobia, obsessive-compulsive disorder, and substance abuse. Rather than adhering to a single diagnostic classification system, the entire spectrum of symptoms and correlates were assessed. Other measures included a personal and family history of all syndromes, dimensional measures of impairment and distress, personality traits, and other relevant constructs. Comorbid anxiety and depression tended to be far more persistent than either syndrome alone. Individuals with anxiety states alone tended to develop either depression alone or comorbid anxiety and depression as they progressed through adulthood. In contrast, depression alone and that which was comorbid with anxiety tended to be far more stable than anxiety alone over time.These findings have important implications for classification and treatment of affective disorders. The greater stability of comorbid anxiety and depression than either disorder alone illustrates the importance of further investigation of comorbid states compared to non-comorbid states in etiologic and treatment research. The persistence of subthreshold level depression and anxiety from early- to mid- adulthood suggests the importance of characterizing the continuum of expression of depression and anxiety rather than adhering to strict diagnostic thresholds.

The key objective of this study is to collect the first nationally representative data on prevalences and correlates of DSM-IV MDD from the recently completed National Comorbidity Survey Replication (NCS-R). The study design is a direct interview household survey of a probability household survey of adults ages 18 and over from the 48 contiguous United States. The total number of subjects in the study is 9090, representing a 79% response rate. The diagnostic interview was the WHO Composite International Diagnostic Interview (CIDI), developed to collect diagnostic criteria for the DSM-IV. Clinical re-interviews were carried out with the Structured Clinical Interview for DSM-IV (SCID) to validate CIDI diagnoses. The NCS research program consists of a series of surveys associated with the U.S. National Comorbidity Survey (NCS). The baseline NCS, fielded from the fall of 1990 to the spring of 1992, was the first nationally representative mental health survey in the U.S. to use a fully structured research diagnostic interview too assess the prevalences and correlates of DSM-III-R disorders. The baseline NCS respondents are being reinterviewed in 2001-02 (NCS-2) to study patterns and predictors of the course of mental and substance use disorders and to evaluate the effects of primary mental disorders in predicting the onset and course of secondary substance disorders. In conjunction with this, an NCS Replication survey (NCS-R) is being carried out in a new national sample of 10,000 respondents. The goals of NCS-R are to study trends in a wide range of variables assessed in the baseline NCS and to obtain more information about a number of topics either not covered in the baseline NCS or covered in less depth than we currently desire. A survey of 10,000 adolescents (NCS-A) is being carried out in parallel with the NCS-R and NCS-2 surveys. The goal of NCS-A is to produce nationally representative data on the prevalences and correlates of mental disorders among youth. NCS-R and NCS-A, finally, are being replicated in a number of countries around the world. Centralized cross-national analysis of these surveys is being carried out by the NCS data analysis team under the auspices of the World Health Organization World Mental Health Survey Initiative. During the past year, we have completed the primary analyses of the National Comorbidity Survey-Replication data. The results were presented in the June issue of the Archives of General Psychiatry. There are several major findings from these papers: First, as reported in earlier population-based studies, mental disorders begin in early life and are common and protracted. As suggested in the W.H.O. Burden of Disease study (15), mental illnesses are the chronic diseases of the young. Kessler et al find lifetime history of a mental disorder in 46.4 % of their sample and a 12-month prevalence of 26.2%, with half of all cases reporting onset by age 14 and three-quarters by age 24. Secondly, Kessler et al report that more than half of those diagnosed with a disorder in the previous 12 months were rated as ?serious? (22.3%) or ?moderate? (37.3%) rather than mild. Those rated as ?serious? (5.8% of the population) reported a mean of 88.3 days when they were unable to carry out their normal daily activities because of mental or substance abuse problems. Ratings of ?serious? were most common among bipolar disorder (83%), drug dependence (56.5%), obsessive-compulsive disorder (50.6%), oppositional-defiant disorder (49.6%), and mood disorders (45%). Corroborating the high rates of comorbidity described in earlier studies, 45% of the population met criteria for two or more disorders, with severity strongly related to comorbidity. Finally, mental health care in America is ailing. Over a 12-month period, 60% of those with a disorder (recall that 60% of these are serious or moderate) receive no treatment. While the survey can only crudely estimate adherence to evidence-based standards and adequacy of treatment, the sources of care are informative. Those with a mental or substance use disorder were more likely to receive help from a general medical professional (e.g. primary care physician or nurse) or a complementary-alternative source (e.g. internet support group) than a psychiatrist. Yet, quality of treatment is much higher in mental health specialty care (minimally adequate in 48.0% of specialty mental health vs. 12.8% of general medical and 13.1% for non-healthcare). We have also analyzed data and completed manuscripts on the following topics: migraine and other headaches, the spectrum of bipolar disorder, sex differences in mood disorders, the impact of mental and physical disorders on work disability, and comorbidity between sleep and mood disorders. During the next year, we plan to complete these manuscripts and continue to analyze the data. We will also prepare the data for public access within the next 6 months.

The National Comorbidity Survey - Adolescent (NCS-A) is a survey of 10,000 adolescents being carried out in parallel with the National Comorbidity Survey Replication (NCS-R) and National Comorbidity Survey 2 (NCS-2). The goal of NCS-A is to produce nationally representative data on the prevalences and correlates of mental disorders among youth. SDGE has played a leading role in the development of the diagnostic interview, compilation of a comprehensive battery of risk factors, and conducting the clinical reappraisal of the lay interviewer-based diagnostic assessments using the K-SADS, a clinical diagnostic interview. At NIMH we designed a sub-study to evaluate neuroendocrine hormones in this population-based sample, as described below: There is emerging evidence regarding the importance of the association between neuroendocrine hormones and psychiatric disorders, particularly depression and anxiety; some recent research even suggests that certain hormones such as testosterone and the Dehydroepiandrosterone (DHEA)/cortisol ratio may predict the incidence of depression (Angold et al, 1998; Goodyer et al, 2000). However, most of the information on associations between neuroendocrine parameters and psychopathology is based on non-systematic small samples; moreover, there is a general lack of population baseline data on neuroendocrine or reproductive hormones in a nationally representative sample of the age group spanning childhood and adulthood. The lack of population baseline data has also precluded proper evaluation of the intriguing sex and developmental differences in the associations between testosterone and depression (Angold et al, 1998), cortisol with both anxiety and depression (Dorn et al, 1996; Tout, de Haan, Campbell, & Gunnar, 1998) and the DHEA/cortisol ratio with stress reactivity (Goodyer et al, 1998). The NCS-A, a combined probability and school-based multi-ethnic sample of 10,000 U.S. adolescents, provides an excellent opportunity for the collection of this essential baseline information, as well as information on associations between neuroendocrine parameters and the common mental disorders, particularly mood and anxiety disorders. The primary aims of the NCS-A neuroendocrine hormone study are: o To examine the associations between endocrine measures with anxiety and depression in youth; o To evaluate whether there are differences between hormone levels in youth according to pubertal status; o To assess whether high risk youth without disorders themselves have lower levels of endocrine hormones than those with a history of mood or anxiety disorders; o To examine the influence of gender in moderating the risk and protection conferred by variation in expression of these neuroendocrine measures. In collaboration with Ron Kessler at Harvard University, staff members of the Institute of Survey Research, members of the NMH intramural program, and other external collaborators, Drs. Merikangas and Avenevoli have played an integral role in the National Comorbidity Survey-Adolescent Study (NCS-A). The NCS-A is a nationally representative face-to-face survey of 10,129 adolescents, selected from households and schools, conducted between February 2001 and February 2004. In their homes, participants completed a diagnostic interview (the Composite International Diagnostic Interview (CIDI)) that assessed psychopathology, demographic information, and information on risk and protective factors, and also provided saliva samples before and after the interview. One parent of each participant completed a questionnaire about the participant and his or her family members. Our collaborators at the University of Michigan are currently cleaning the survey data. In the past year, SDGE members have participated in the assessment of validity of the diagnostic interview, consultation of analyses of survey data, and the collection and assay of endocrrine samplles. Many members of SDGE are assessing the validity of the CIDI-A by coding and comparing interviews using the CIDI and the Schedule for Affective Disorders and Schizophrenia-Child Version. Drs. Merikangas and Avenevoli continue to participate in monthly phone calls and annual meetings regarding plans for the cleaning and analyses of adult and adolescent data. With regard to the biomarkers data, Shelli Avenevoli has coordinated the collection of saliva samples from the NIMH intramural (in conjunction with Kathleen West). Drs. Merikangas, Avenevoli, and Brostedt are currently completing plans and an NIMH protocol for the assaying of the saliva samples and analyses of cortisol, DHEA, testosterone and other endocrine data. As part of the clinical reappraisal phase of the National Comorbidity Survey (NCS), our section and clinical interviewing staff are reviewing audiotapes of the child interviews (KSADS; respondent and parent reports) to clarify assigned diagnoses. Fifteen interviewers (i.e., psychiatrists, developmental psychologists, clinical social workers, research psychologists) have reviewed tapes, coded interviews, and written short reports identifying areas where discrepancies in diagnoses may have occurred. Dr. Merikangas and staff meet weekly, via conference call, with the staff at Harvard University to discuss progress and resolve diagnostic dilemmas. Fifty tapes will be completed in their entirety, and to date, thirty cases have been reviewed. We are now beginning to conduct the data analyses of the clinical appraisal data to evaluate the level of agreement between lay and clinical interviews, and between maternal and child informants. During the next year, we will focus on conducting the primary data analyses of this unique survey and will present the findings at professional meetings and as publications.

The chief goal of this study is to identify the endophenotypes of the spectrum of mood disorders using the methods of genetic epidemiology, developmental psychopathology and clinical psychiatry/psychology. The major research questions focus on the specificity of familial transmission of the mood disorder spectrum (i.e., symptoms, symptom clusters, subtypes) and the role of comorbidity with anxiety disorders and migraine syndromes in defining subtypes of mood disorders. This study employs a family study design of probands with mood, anxiety and migraine disorders with nested case control studies of the key study questions described below. We propose to recruit 500 probands with bipolar I, bipolar II, major depression, panic/GAD, phobias, migraine, and unaffected controls, ascertained through both psychiatric and non-psychiatric clinical settings and systematic community samples, in order to enhance generalizability to the population. Approximately 2500 first-degree adult relatives and spouses and 750 child offspring (ages 8-17) will comprise the family study component. Probands and relatives will be evaluated using structured diagnostic interviews and standardized diagnostic criteria followed by clinical validation interviews and diagnostic consensus procedures. Assessment instruments will collect information on the DSM-IV criteria as well as the spectrum of mood disorders and comorbid conditions. This will provide information that will be used to validate the diagnostic thresholds and boundaries of the current diagnostic systems. Families enrolled in this phase of research will be invited to participate in the next phase of research which is designed to identify familial endophenotypes of affective disorders that may comprise intermediate forms of expression of underlying genetic factors. These families will be followed longitudinally to evaluate the development of the mood disorder spectrum, subtypes, and syndromes across the lifespan. Separate protocols will be written concurrently to develop the research on specific endophenotypes and longitudinal evaluation as the identification and characterization of families proceeds. The major contributions of this research will include: (1) Identification of clinical phenotypes that breed true in families and are specific to particular subtypes of mood disorders; (2) Refinement of phenotypes for the diagnostic nomenclature; (3) Resolution of the role of comorbid disorders, particularly anxiety and migraine, as indicators of subtypes of mood disorders or the converse; and (4) Elucidation of age and development-specific patterns of expression of salient components of the mood disorder spectrum across the lifespan. During the past year, we have enrolled 106 families in our NIH Family Study of Affective Spectrum Disorders. Interviews are ongoing with more than 500 relatives and spouses of these probands and the data are now being prepared for data entry. The distribution of probands with known diagnoses is: 32 with Bipolar Disorder; 32 with Major Depression; 12 with Migraine; 3 Controls. In addition, DNA collection from probands and their relatives has commenced. Earlier this year we established recruitment collaboration with the MAP Research Unit in the CRC. Subjects enrolled in studies (inpatient or outpatient) are referred to us by MAP investigators. The subject?s medical chart is reviewed to assess eligibility, and then reviewed by a clinician. After clinician?s approval, we discuss our study and consent the subject. All referral information is entered into our tracking database, an interviewer is assigned, and interviews can take place on the inpatient or outpatient units. SDGE staff now meet daily with Dr. Paulo J. Negro, Suburban Hospital?s Behavioral Health Director, to identify inpatients and attendees of SH?s Day Program (outpatients) who are eligible for the Family Study. From the NIMH/ Mood and Anxiety Disorder Program (MAP) Research Unit in the CRC we have received and screened 30 referrals since July, 2005. Of the 27 referred, 26 patients are either in progress or completed. From Suburban Hospital we have received and screened 65 referrals since February, 2005. Fifty-two were eligible, 30 have been consented, and 24 are in progress or completed. From other sources such as the MAP Referrals List, NIH clinical trials website, and Suburban Newsletter we have consented 32 persons and 6 are now in progress. Thirty-eight adult relatives have consented to the study, and clinical interviewers are continuing to contact family members of the probands. Over the past year, SDGE staff members have modified the Schedule for Affective Disorders and Schizophrenia for Children ? Epidemiologic version (K-SADS-E) for use with child offspring (ages 8-11) of probands and controls in the family study to include DSM-IV criteria. The modifications are now complete and we will employ this interview as we are beginning to recruit the children in the families enrolled in our study. This year we completed the development of a diagnostic interview for headaches including migraine, tension-type, cluster, and post-traumatic. This interview was piloted on participants who were identified through the medical history interview as having headaches. We have completed the development of a diagnostic interview for sleep patterns and problems, and it is currently being piloted and validated in the Stanford Sleep Clinic, as well as the Chevy Chase Center for Sleep and Wake Disorders. The study is being done in collaboration with Dr. Helene Emsellem at the Center for Sleep and Wake Disorders in Chevy Chase and Dr. Emmanuel Mignot at Stanford University. The subjects for the study are recruited from the sleep center in Chevy Chase, and the sleep clinic at Stanford University. Subjects are administered the interview by a trained interviewer who is blind to the subject?s sleep diagnosis. The diagnosis that is formed from the interview is then compared with the diagnosis that was established by the doctor in the sleep clinic to assess the accuracy of the sleep interview. Four papers have been drafted following completion of complex genetic epidemiologic data analyses on the Yale Family Study data. They include: (1) Assortative mating for substance use and anxiety disorders, (2) Familial aggregation of anxiety disorders ascertained from the community versus clinics, (3) Migraine and affective disorders: Familial patterns of comorbidity and coaggregation, and (4) The Familial Aggregation of Cannabis Use Disorders. SDGE staff members primarily contributing to these analytic projects and papers have been the fellows, biostatiscian and the Senior Investigator. These papers will be submitted by the end of September 2005. Plans for next year: During the next year, we will continue to recruit probands and families for this study. We anticipate completion of a total of 300 families by the end of the next project period. We are also beginning to establish a cohort of high-risk youth offspring of the probands included in the endophenotypes protocol to investigate the evolution of the components of these conditions in a prospective manner. In collection of a new community sample, we are collaborating with investigators from the National Institute of Neurologic Disease and Stroke (NINDS) and the National Institute of Aging (NIA) in order to screen for neurologic disorders in the local community as well.

Background: The NHANES is a program of studies designed to assess the health and nutritional status of adults and children in the US. The survey is unique in that it combines interview and physical examinations. It is a continuous program that collects a nationally representative sample of 5000 persons in 15 counties across the country each year. Although symptom rating scales for depression and general well-being have been included in numerous surveys since the 1970s, diagnostic criteria for mental disorders in adults and children were not collected until 1998. Sections on Generalized Anxiety Disorder and Panic Disorder of the NIMH Diagnostic Interview Schedule for Children (DISC) version 2.3 were collected annually in representative samples of respondents aged 8 through 19 years in 1999 through 2004, and sections on eating disorders, elimination disorders, major depression/dysthymia, Attention Deficit Disorder/Hyperactivity, and Conduct Disorders from youth and/or parents were collected since 2000. [unreadable] [unreadable] There is a rich constellation of other correlates of mental disorders including demographics (e.g. age, sex, race/ethnicity, education, family income, country of birth), environmental exposures and risk factors (e.g. heavy metals, dietary pattern, physical activity), physical disorders (e.g. asthma, hypertension, diabetes, anemia, stroke, severe headache, thyroid condition), service patterns (e.g. seen or set up an appointment with a health professional for underlying mental disorder) and various biologic measures in the NHANES survey data such as DNA, lead, mercury, and thyroid hormone.[unreadable] [unreadable] Progress: Our analytic team has prepared merged data sets for demographic characteristics and mental disorders in children across the survey years from 1999-2004. We have completed the preliminary analyses of the prevalence estimates of GAD, panic, elimination, ADHD and conduct disorders, and prevalence estimates by youth, parent, and youth/parent combined for eating and major depressive/dysthymic disorders for the overall sample, by survey year, gender, race/ethnicity, and age. In order to assess the severity of these conditions, we have also calculated prevalence by four alternative impairment algorithms. These data will provide the first population prevalence data on these seven major mental disorders in children ages 8 through 19 in a national probability sample of the US. A second study conducted by our analytic team investigates patterns of mental and physical comorbidity among adults with severe headaches and migraine using merged data from the 1999-2004 survey years. The analyses include a comparison of the sociodemographic characteristics of individuals with versus without headaches as well as a description of the rates of comorbidity of both mental and physical disorders within both headache groups. In order to assess the relative impact of these comorbid conditions, we compared the responses to a series of questions on health care utilization and health perception across five groups (no headache, headache only, headache plus any physical condition, headache plus any mental condition, headache plus a physical and mental condition). These data provide new information on the significant role of comorbid disorders, specifically comorbid mood and anxiety disorders, on the impact of severe headaches or migraine, on health care utilization and health perception. Future analyses will then examine the risk factors and biological correlates of these conditions in the general population. We will prioritize our analyses to address the key study questions that are the focus of our own research.

We have continued to analyze this rich data set at the NIMH where we have also made substantial progress in defining the factors involved in the transmission of these conditions in families, particularly the family studies of Puerto Ricans and African American families. This study examined the familial transmission of anxiety disorders and substance abuse using a combination of the family study/longitudinal high risk paradigms. This study also investigated comorbidity between physical disorders and mood and anxiety disorders. These data have provided a valuable resource for trainees in our laboratory who have learned to analyze data on familial aggregation as we await the results of the ongoing studies in our research group. The results of the recent analyses have been used to refine the research questions and methods of the ongoing NIMH family study. The chief findings reveal specificity of familial aggregation of anxiety disorders in general and the panic and social phobia subtypes in particular. Likewise, there was familial aggregation of substance abuse, with some suggestion of specificity of specific drugs. In contrast, although there was no evidence for vertical transmission of nicotine dependence, there was an increased risk of nicotine dependence among siblings. With respect to physical disorders, it was found that anxiety disorders were most strongly associated with physical disorders in general, and that there was evidence for co-transmission of migraine with anxiety and mood disorders in families. During the past year, we have published two papers on comorbidity of mood and anxiety disorders with substance use disorders. The first paper showed that there was an elevated risk of life-time history of cannabis use disorders among siblings, adult offspring, and spouses of probands with cannabis use disorders. There is a latent familial factor underlying cannabis use disorders that was shared partially with alcohol abuse/dependence. Comorbid mood and anxiety disorders aggregated independently from cannabis use disorders in families. Equal elevation in the magnitude of the association among the first-degree adult relatives and spouses of probands with a cannabis use disorder suggests the probable contribution of both environmental and genetic factors. Our findings suggest that cannabis dependence is both a cause and consequence of anxiety and mood disorders, thereby highlighting the importance of integrating treatment and intervention in the mental health and substance treatment sectors. The second project that examines the familial and societal correlates substance use disorders, with mood and anxiety disorders by comparing Puerto Rican families residing in the mainland USA and Puerto Rico. We found that the rates for alcohol use were greater among San Juan youth than their migrant counterparts. By contrast, US migrant adolescents were more likely to use cannabis. A strong association was observed between parental and child substance use at both sites, particularly for boys, and offspring of probands with drug use disorders were at greatest risk for substance use and related disorders. Familial aggregation patterns did not vary substantially by site. Despite societal influences on the magnitude and patterns of substance use in migrant youth, the consistent influence of parental disorders across sites reveals that the cross-generational transmission of substance use disorders in prior studies extends to Hispanic families and is an important factor to consider in the development of prevention strategies. Public Health Impact: Future research of migrant samples may benefit from integrating family history in understanding the risk and protective factors for the development of substance use disorders. In this regard, the promotion of treatment and prevention programs targeting vulnerable Hispanic populations has been slow. A clear need exists for the expansion of intervention and prevention programs for high-risk Hispanic youth, and in particular prior to the onset of behavioral and substance-related problems.

Family Study of African Americans[unreadable] This project was a five year study of black children ages 8-17 at high and low risk for alcohol-related problems based on a history of parental alcoholism. A prospective design was used to identify the specific disorders for which these children are at heightened vulnerability, and salient risk and protective processes in the development of the various types of childhood disorders. [unreadable] The major goals of the study were:[unreadable] 1. To examine the extent and patterns of psychopathology and behavioral problems among the offspring ages 8-17 of black alcoholic parents;[unreadable] 2. To assess the role of familial transmission of alcohol abuse/dependence and comorbid psychopathology, including substance abuse/dependence, in the pathogenesis of alcohol abuse in children; and[unreadable] 3. To identify multiple risk and protective indices of the pathogenesis of alcohol problems in black youth in order to yield information on the key targets of prevention and intervention.[unreadable] [unreadable] The key features of the study were: the sample of black alcohol abusers with young children about which there are sparse data; the epidemiologic source of the sample, which strengthened the generalizability of the findings and minimizes the bias in ascertainment of minorities from specialty treatment settings; the application of an epidemiologic family study paradigm, which permitted assessment of factors associated with familial transmission of risk factors and the mechanisms thereof; evaluation of the role of comorbidity of anxiety disorders and alcoholism in the transmission of alcohol-related problems; comprehensive assessment of vulnerability factors from broad domains or risk encompassing personal, family, and environmental attributes including community violence; the provision of knowledge essential for prevention through the assessment of protective factors which may inhibit pathogenic processes among children at high risk.[unreadable] [unreadable] Data collection of this study was completed at Yale University before the Principal Investigators relocation to the NIMH. The resources of our section have been devoted to preparation of these data for analysis and subsequent publications. This research provides a model for conducting studies of social epidemiology of mental disorders and substance abuse. During the past year, we have completed data cleaning and coding. The data are now ready for statistical analyses of the key study questions. We are continuing to analyze these data and are submitting manuscripts for publication.[unreadable] [unreadable] Substance abuse and its sequelae, particularly AIDS and interpersonal violence, constitute a contemporary public health crisis of ever-widening impact. The increasing risk of substance abuse in youth, particularly among urban minorities, reveals the need for prevention and early intervention measures. Elucidation of the role of specific familial and sociocultural factors in the development of drug use and abuse would yield targets for primary and secondary prevention of substance abuse and its complications.[unreadable] [unreadable] Vulnerability Factors Among Migrant Puerto Ricans[unreadable] [unreadable] This project proposes to integrate family and migrant study methodology in a five-year prospective epidemiologic study of adolescent offspring of native and migrant Puerto Rican substance abusers and controls. The wave of migration of Puerto Ricans to Connecticut over several decades provides an exceptional opportunity to differentiate cultural, familial, and individual risk and protective factors for adolescent drug use and abuse. Puerto Ricans are an important yet understudied ethnic subgroup characterized by an apparently low prevalence of substance use and abuse on the island of Puerto Rico, yet by a prevalence of AIDS that is among the greatest in the world.[unreadable] [unreadable] Migrant study methodology permits identification of environmental risk factors for substance use/abuse by comparing the disease experience of biologically similar subgroups in their native and adopted environments. The family study method enables the identification of transmissible components of a condition by comparing the rates and risk factors for diseases in relatives of cases with those of controls. Combining these two approaches in a single study to investigate risk factors for substance abuse allows us to: a) identify the relative contribution of family history of substance abuse and psychopathology on drug use and abuse in Puerto Rican adolescents while taking into account the influence of cultural environment, and b) identify the relative contribution of cultural factors on the risk of adolescent substance use and abuse, while taking into account background familial factors. The main aims of the study are:[unreadable] [unreadable] (1) To elucidate familial patterns of substance use and abuse and comorbid psychopathology between island and mainland Puerto Ricans;[unreadable] (2) To investigate the role of specific sociocultural factors in the development of adolescent substance use and abuse;[unreadable] (3) To identify and model the dynamics of the salient risk and protective factors at the individual, familial, and environmental levels for Puerto Rican adolescents at high and low risk for the development of substance abuse by virtue of parental substance abuse, and;[unreadable] (4) To conduct a longitudinal follow-up of the offspring to examine transitions in substance use status, and the association between the early patterns of substance use and comorbid psychopathology (including course and outcomes), as well as examine the stability of the assessments.[unreadable] [unreadable] Data collection of this study was completed at Yale University before the Principal Investigators relocation to the NIMH. The resources of our section have been devoted to developing analytic models for this complex data set comprised of families nested within sites. There are several manuscripts in preparation to report the results of this unique study. This project serves as a model for cross-cultural research that uses the migrant study design to identify specific cultural risk factors that may serve as targets for prevention and intervention.[unreadable] [unreadable] We have continued to analyze the data from this migration study of families in the U.S. and San Juan. We published two papers this past year (Conway et al, 2007) and (Dierker et al, 2006) and have a third that should be submitted in the next few weeks (Gau et al, in preparation). We are also developing a comparable family study here at the NIMH to study Hispanics in the Washington, D.C. area.

Although analyses of these data are ongoing, a number of interesting findings have emerged. Some of this work was completed in the Neuropsychiatry Branch, but much of it has continued in our Section, and we have several promising avenues for future research. When the project was transferred to my group, we invested several months streamlining the database, and creating an exhaustive codebook for the project describing its origins, its source data, the variables in its dataset, and instructions for accessing these data. The first set of analyses demonstrated the substantial burden of first hospitalizations for severe psychiatric illness in the military. Additional data on mortality in this cohort were obtained from the National Death Index. Analyses from the new data were presented at the Society for Epidemiological Research in 2006. All-cause mortality in the 3 groups of military personnel who were hospitalized are substantially increased (hazard ratios from 1.7 for unipolar depression) to 3.5 for schizophrenia). Risk of death was substantially higher for suicides (HR=2.1 for unipolar depression; 8.5 for schizophrenia). This paper has been submitted for publication (Herrell et al, under review). Another paper on "The impact of life events on the development of psychiatric disorders" by Grammer et al, is also under review.

During the past year, 7,500 youth have been enrolled in the study and undergone the clinical and medical interviews, and cognitive testing, and 750 have completed the neuroimaging component of the project. The NIMH and U Penn teams have worked closely in the development of the diagnostic measures, and in developing algorithms for identification of youth at risk for emotional and behavioral disorders, as well as a range of medical conditions. Cross validation of this assessment with more extensive diagnostic interviews at the NIMH site is now underway. Public Health Impact: The proposed comprehensive phenotyping will benefit medicine across diseases and include neurobehavioral measures, which will help elucidate both specific effects of neuropsychiatric disorders and the impact of other medical disorders on brain function. Future Plans: Enrollment of the study should be completed by the end of 2011, and the NIMH team will work with the U Penn and CHOP collaborators to develop plans for analyses of the data. In addition, NIMH is planning some nested case control studies of youth with mood disorders and migraine in the sample.

The collection of data from this cohort has now been completed and analyses of the data are now underway. The National Institute of Mental Health (NIMH) Family Study of Affective Spectrum Disorders has included numerous comparable measures of psychiatric and cardiovascular phenotypes that can be analyzed to develop hypotheses for COLAUS and conversely. The major papers on familial aggregation of mood disorder subtypes have both been published during the past year. We showed that mania and depression are strongly familial, but are transmitted independently in families (Merikangas et al, 2014). This finding was replicated by the parallel Lausanne Family Study, which also demonstrated that psychosis was independently transmitted in families (Vandeleur et al, 2013). In terms of cardiovascular disease comorbidity, we recently found an association between atypical depression, alcohol misuse and cardiovascular disease (Glaus et al, 2012). Furthermore, inflammatory processes were associated with mood disorder subtypes (Glaus et al, 2014). Public Health Impact: Cardiovascular diseases, their well-established risk factors and mental disorders have the greatest public health impact of all chronic non-infectious human diseases (Vandeleur et al, 2012). Moreover, a recent World Health Organization (WHO) projection of future population health concluded that by 2030, unipolar depressive disorders and ischemic heart disease (IHD) will be among the three leading causes of disease burden worldwide. Given the major public health impact of both CVD/CVRF and mental disorders, the study of the mechanisms underlying their associations is of high clinical and scientific relevance. Future Plans: The next phase of this project continues joint analysis of the family study data on mood disorder subtypes, hyperthymia, comorbid anxiety, sleep disorders and migraine, and analysis of the biomarker and clinical data in the Lausanne site. We will integrate the family study data and common biomarkers from the NIMH Family Study with those of the COLAUS Study to enhance analytic power and to cross-replicate the findings. We have begun to add the electronic diary and activity measures to the COLAUS study and are currently collaborating with Johns Hopkins to coordinate the new activity measures and analytic methods. Two chief goals continue to be: 1) implementing mobile technologies developed for our studies in the NIMH Intramural Research Program and 2) conducting joint analyzes of NIMH Family Study adults and children. The results will then be used to guide plans for future follow-up and extension of the study samples.

During the past year, 1,736 youth were enrolled in the study and 250 completed the neuroimaging component of the project, resulting in a total number of 9,236 youth who have undergone the clinical and medical interviews, and cognitive testing, and 1,000 who have completed the neuroimaging component of the project. The NIMH and U PENN teams have worked closely in the development of the diagnostic measures, and in developing algorithms for identification of youth at risk for emotional and behavioral disorders, as well as a range of medical conditions. We are currently modifying the diagnostic algorithms of two large population-based studies of youth (i.e., the National Health and Nutritional Examination Survey and the National Comorbidity Survey- Adolescent Supplement) to be consistent with those used in the U PENN Study. In combination with pre-selected sociodemographic factors (i.e., race/ethnicity, parental education, poverty status), comparable diagnostic algorithms will allow examination of potential bias in the U PENN sample. Cross validation of this assessment with more extensive diagnostic interviews at the NIMH site is now underway. The NIMH team is currently working with the U PENN and CHOP collaborators to develop topical workgroups that will facilitate data analysis and manuscript preparation. We have also made formal plans to follow at least 300 youth between the ages of 15 and 25 years who show or are at risk for mood spectrum disorders, acquiring measures of activity, experiential momentary sampling, olfaction, neurocognition, and clinical symptom measures. Public Health Impact: The proposed comprehensive phenotyping will benefit medicine across diseases and include neurobehavioral measures, which will help elucidate both specific effects of neuropsychiatric disorders and the impact of other medical disorders on brain function. Future Plans: The NIMH team will work with the U PENN and CHOP collaborators to prepare and analyze the data, and prepare manuscripts for publication. In addition, the NIMH will collaborate with U PENN to acquire data on the 300 youth who show or are at risk for mood spectrum disorders.

The Genetic Epidemiology Research Branch at the National Institute of Mental Health (NIMH) has partnered with U PENN and CHOP in the design and assessments, as well as the data analysis of this rich resource. The NIMH team has particularly focused on the topics of medical-mental comorbidity, mood disorders, and migraine and other neurologic conditions. Our publication on physical-mental comorbidity (Merikangas et al, 2015) revealed that there was a direct association between the severity of physical conditions and most classes of mental disorders, as well as with functional impairment. We also found that there was specificity of associations between mood disorders with immune/inflammatory conditions, and between behavior disorders and attention deficit hyperactivity disorder with neurologic/central nervous system conditions. Findings demonstrate the strong overlap between physical and mental conditions and its impact on severity and functional impairment in youth. In our analyses of racial-ethnic disparities in sub-threshold psychosis symptoms (Paksarian et al, under review), we found that ethnic minority youth were more likely to manifest sub-threshold psychosis symptoms than were non-Hispanic white youth. However, there was some indication that these associations differed between minority groups and were strongest for non-Hispanic black youth. We have also completed analyses of comorbidity patterns of migraine with other physical and mental conditions that showed specific associations between migraine with anxiety and depressive disorders in youth (Lateef et al, under review). Additionally, we have continued to work with collaborators at Harvard to examine the heritability of behavioral phenotypes in the study (Robinson et al, 2015). This work showed that several components of childhood cognitive abilities, such as reading ability, emotion identification, and verbal memory, are influenced by genetics. These findings further support the need to study the diverse cognitive abilities of children and contribute greatly to the existing research on the subject. Our collaborative efforts have also yielded 2 methodological publications in the past year: 1) a manuscript describing the methodology of the study of youth at risk for psychotic spectrum symptoms (Calkins et al, 2014) and 2) a manuscript providing an overview of PNC recruitment and clinical assessment methods to allow informed use and interpretation of the PNC resource by the scientific community (Calkins et al, 2015). Public Health Impact: This report on physical and mental comorbidity is the first study to investigate the specificity of associations between a broad range of physical and mental conditions using a large, systematically obtained pediatric sample with enriched information from electronic medical records and direct interviews. The findings highlight the importance of capturing the roots of both physical and mental disorders in childhood in order to trace their evolution into chronic diseases causing major public health concerns. Information generated from such a sample may have profound impact on the current clinical practices. Our research on race-ethnicity and psychosis is one of the few studies to document racial-ethnic disparities in sub-threshold psychosis symptoms among U.S. youth, and adds to a growing amount of literature on racial and ethnic health disparities that document the disproportionate health burden of the minorities in the U.S. The study on migraine comorbidity indicates that comorbidity could be an important source of the clinical and etiologic heterogeneity in migraine. Future Plans: The NIMH team will continue to work with the U PENN and CHOP collaborators to conceptualize and analyze the data, prepare manuscripts for publication, and facilitate follow-up of the subsample with mood disorders. The NIMH team will focus analytic effort on 1) using the geographic information system data to examine associations between area-level measures, such as neighborhood socioeconomic deprivation, and mood and other mental disorders; 2) using latent class analysis approach in qualitative phenotype identification; 3) conducting genome-wide complex trait analysis on selected disorders and patterns of disorders in youth; 4) examining the patterns of medical-psychiatric comorbidity in more depth; and 5) defining dimensional measures of psychopathology in the dataset. In addition, the NIMH will continue to collaborate with U PENN to follow-up youth with mood symptoms and disorders to complement the ongoing follow-up of youth at risk for psychosis in order to supplement the clinical and biomarkers research on mood disorder subtypes now underway in the NIMH Family Study of Affective Spectrum Disorders.

There is growing interest in studying the environmental, biologic and genetic correlates of the components of motor activity as well as the relationships between motor activity with sleep, exercise, mood, and cognitive functioning. Aggregation of the findings across these studies is complicated by the substantial differences in both the study goals, procedures and statistical methods. There is a need for greater coordination across studies in the procedures and analytic methods that can take into account advances in analysis of functional data. We have begun to present our preliminary data at scientific meetings and thus have received an increasing number of requests from multiple investigators collecting actigraphy data to join the mMARCH initiative. Although the study was originally centralized by the use of the GENEActiv device, subsequent work suggests that estimates from different devices can be adjusted for common analyses. We are currently comparing several devices and are developing empirical algorithms for calibrating measures across devices. Therefore, we have extended our collaboration to include more than 15 additional sites that are using alternative actigraphy devices, or are studying topics other than mood disorders (e.g., insomnia, ADHD, substance abuse, and cardiovascular disease). We are also including prospective studies of population samples of adults and children in the U.S., Switzerland and Australia that will use these devices to track activity over time. This expansion has led us to establish thematic subgroups that will focus on developing procedures, ancillary data collection and analyses of a range of relevant physical and mental health topics. A subgroup that focuses on genetics was also recently established. Public Health Impact: The formation of the mMarch initiative will enable groups to efficiently share and combine data to learn more about how activity affects different disorders and diseases across many populations, including mood disorders, sleep patterns, circadian rhythms, genetic studies, emotion, eating, etc. This work will also define targets for prevention and intervention studies. Future Plans: We propose to devote substantial effort to implement the goals and progress begun in the mMARCH initiative to address the aims described above. This administrative effort is balanced by the scientific opportunity to sample more than 5,000 people with actigraphy data and up to 1,000 with BPD without greater burden than those associated with our original collaborative network on actigraphy and mood disorders at 5 core sites. Establishing a larger network will also increase our ability to examine clinical and biologic subgroups of people with BPD, examine developmental patterns cross-sectionally across diverse age groups, and prospectively track patterns of activity and clinical correlates over time. The most important goal of the next year will be to develop standard measures of core domains assessed across the sites to facilitate common analyses of the data. We plan to have future publications of mega-analyses and to form topical work groups for mood disorders, sleep patterns, circadian rhythms, developmental trajectories, and genetic studies. One of the most important activities of the mMARCH initiative will be the development of an international team of biostatisticians and mathematicians directed by Drs. Vadim Zipunnikov and Haochang Shou who will identify and develop methods for analyses of the complex data from actigraphy. The joint application of actigraphy and EMA provides powerful measures that track multiple systems simultaneously, but the analytic issues of these multilevel data are quite complex. Therefore, the Analytic Work Group of mMARCH will develop methods that address diverse research questions in the network by reviewing available analytic approaches. This comprehensive approach will simultaneously characterize multiple landmarks in circadian rhythms and will model inter- and intra-day interactions and dynamics in rest/activity and sleep patterns, thereby augmenting the available information and will empower the analytical framework uniformly applied across mMARCH sites.

During the past year we have conducted a number of studies addressing the aims above. Although the NCS-A survey was conducted 10 years ago, it remains the richest source of data on DSM mental disorders and risk factors in a nationally-representative sample of U.S. adolescents. During the past year, we conducted 3 studies of comorbidity in mental disorder. One investigated prior mental disorders as risk factors for transition between stages of alcohol and drug use and abuse/dependence (Conway et al, 2016). We found that both anxiety disorders and behavioral disorders were important predictors of progression, but that they operated at different stages in substance use. We have also investigated comorbidities between mental and physical disorders. We examined physical health comorbidities of ADHD in adolescents and found that allergies, asthma, enuresis, headache/migraine, and serious stomach or bowel problems were more common in those with ADHD (Jameson et al, 2016). We also documented the high burden of adverse social and economic consequences of those who have both migraine and PTSD among adults in the NCS-R (Rao et al, 2015). The Zurich Study is one of only a few longitudinal studies in psychiatric epidemiology that performed multiple diagnostic interviews in a community-based sample from young adulthood into middle age. In collaboration with our colleagues in Zurich, we have recently completed an analysis of the trajectory of mental disorder risk across ages 20 to 50 (Paksarian et al, in press). We found that trajectories differed between men and women. We also found that while very few people had persistent mental disorder across the entire age period studied, one trajectory that was consistently identified indicated high risk from the late 20s until the early 40s. Our collaboration with researchers at UPENN has continued through data analysis of the PNC study. In the past year we have published our findings regarding racial-ethnic disparities in sub-clinical psychosis (Paksarian et al, 2016). We found that ethnic minority youth were more likely to manifest sub-threshold psychosis symptoms than were non-Hispanic white youth. However, there was some indication that these associations differed between minority groups and were strongest for non-Hispanic black youth. In the past year we have continued to collaborate with researchers from the COLAUS study in Switzerland. We found support for the independence of familial aggregation of bipolar disorder from major depressive disorder and the heterogeneity of bipolar disorder based on patterns of onset (Preisig et al, 2016). Additionally, we assessed the associations between serum leptin and adiponectin levels and migraine or migraine subtypes and found that high leptin might be a contributing factor in the role of migraine and migraine with and without aura (Pisanu et al, in press). Public Health Impact: These studies provide valuable insight into the nature of mental disorders and their burden among children, adolescents, and adults across time. The NCS-A study was the first with comprehensive domains of emotional and behavior disorders in a nationally representative sample of U.S. youth, and the results have had significant public health impact. The PNC is also destined to become a high-impact project because it consists of a large, systematically obtained pediatric sample with enriched information from electronic medical records and direct interviews. Our studies of comorbidity in adolescents and youth, such as that between mental and substance use disorders or between sleep patterns and mental disorders, highlight the potential for identification of opportunities for intervention in adolescent mental health. The findings highlight the importance of capturing the roots of both physical and mental disorders in childhood in order to trace their evolution into chronic diseases causing major public health concerns. The Zurich Cohort Study is an extremely valuable data source, as it is the longest community-based longitudinal study in which participants were enrolled at the beginning of adulthood. Data on the frequency and persistence of mental disorders are important for planning interventions and service delivery as well as for research on etiology. Lastly, our work on the COLAUS study has substantial potential for public health impact because it combines information regarding cardiovascular risk factors and mental disorders in a longitudinal study. Given the major public health impact of both, the study of the mechanisms underlying their associations is of high clinical and scientific relevance. Our recent work represents only the beginning of a research program that we hope will help to tease apart the longitudinal relationships between physical and mental health in the population. Future Plans: We plan to continue to analyze these rich data sources, both within our research group and the NIMH, as well as to provide support to investigators outside the National Institutes of Health. We will continue to focus on the aims stated above when generating hypotheses and designing studies. Several important manuscripts are now in progress that will continue to provide knowledge about adolescent and adult mental health in the general population. We are currently focusing on the following areas: 1) mental-physical comorbidities among adolescents; 2) perinatal risk factors for emotional and behavior disorders; 3) the consistency of age-of-onset reports for mental disorders in general population samples; 4) disparities in mental disorder prevalence among adolescents based on race-ethnicity and immigrant status; and 5) psychosocial and health risk factors including sleep, activity and stress for emotional and behavior disorders.