Maria Kovacs, PhD - US grants

This is a continuation and extension of our longitudinal prospective investigation of childhood depression (diagnosed according to the DSM-III) with youngsters 8-13 years of age. The objectives include: a) the nosological study of the depressive disorders in juveniles with respect to clinical presentation, course (including recovery rates and later affective and nonaffective disorder sequelae), and anamnestic, demographic, parental, and familial psychiatric history variables, (b) preliminary study of the prognostic value of the childhoood depressive disorders for late adolescent and early adulthood adjustment, and (c) testing of the explanatory power and pragmatic value of cognitive-development and pubertal stage vis-a-vis depressive symptom expression and depressive-disorder parameters. The study entails sequential S recruitment and a repeated measures design in the context of a naturalistic follow-up. The target cohort of 120 depressed Ss will be youngsters referred to child psychiatric- and medical-outpatient clinics who meet the study's inclusionary criteria. They will be followed for a minimum of four and a maximum of ten years. The target Ss' characteristics, and their clinical course for the first five years will be compared with data from an age-matched psychiatric comparison group of 49 Ss. The comparison Ss represent a consecutive series of child psychiatric outpatient referrals with various nondepressive conditions who will be followed for five years. Both cohorts will be assessed repeatedly via a comprehensive battery that includes a semi-structured psychiatric interview, standardized parent- and child-rated scales, pediatric examination, cognitive-stage determination, and evaluation of familial psychiatric history. Pertinent variables (e.g. clinical psychometric, and medical data) will be assessed independent of each other. This study will contribute to a more valid nosology of the childhood depressions; to the field of developmental psychopathology; and to the integration of the areas of "child" and "adult" affective disorders. By documenting the existence and course of the depressions in juveniles, the findings will stimulate the development and testing of efficacious treatment and intervention methods for depressed youth. The longitudinal study of cases may also provide a further perspective on the affective disorders of adulthood which constitute a "number one" mental health problem.

This is a three year prospective study of 100 newly diagnosed juvenile diabetics, aged 8 to 13. It will reliably assess and systematically document the extent of depression in the child to: medical status at the time of hospital admission, adequacy of diabetic control over time, depression and anxiety in the mother (mothering one), and familial history of affective disorders. It is hypothesized that in the child capable of abstract operational thought, a brief depressive reaction may represent a "mourning" for the pre-illness self and may be a good prognosticator of subsequent psychiatric/medical status. On the other hand, familial history of affective disorders and/or concurrent clinical depression in the parent may correlate with clinical depression in the parent may correlate with clinical depression in the child. A structured Clinical Interview Schedule and rating scales are used to assess depressive and related symptoms. Initial assessment is two weeks after discharge from the Metabolic Unit of Children's Hospital. Clinical and medical indices which serve as independent variables are assessed independently of the child's depression. Follow-up interviews at 1-, 4-, 8-, 12-, 18-, and 24-months serve to gather data, and to test the hypothesis made explicit and are contrasted with data from a "psychiatric" child sample. Since clinical depression may be a special problem in the medical management of the diabetic child, its proper identification will enhance appropriate referral for psychological/pharmacological treatment, and will have a positive effect on the child's illness and his/her overall quality of life.

This longitudinal follow-up study of childhood-onset depressive disorders, currently in its 9th year, is entering a phase during which all Ss will have reached adolescence; it will thus be possible to observe the transition of a large subgroup of them into adulthood. Given the findings to date, the class of bipolar disorders is also being investigated. The study's developmental scope will be extended to include social competence and other areas of interest in late adolescence and young adulthood. Ss were 8-to-13 years old at intake. Recruitment is complete and includes 142 Ss with affective disorders and 49 age-matched comparisons with non-affective disorders. Drop-out rates have been low (11% for the affective-disorder Ss; 6% for the comparisons). Specific aims include contributions to nosology and developmental psychopathology, with a particular focus on the practical consequences of early-onset disorders. Nosologic goals entail the delineation of the long-term clinical course of childhood-onset depressive and bipolar disorders (e.g., recovery, chronicity, comorbidity); the predictive validity of these diagnoses; and the patterning of episodes and their associated features (including suicidal behaviors). In the sphere of developmental psychopathology, the developmental mediation of clinical course will be examined (e.g., transitions between juvenile and adult disorders, changes in comorbid conditions), and the effects of disorders on the progression of abilities (e.g., social competence, educational and vocational achievement). Other consequences will be examined in terms of rates of hospitalizations, institutionalizations, and incarcerations. A repeated-measures design will be used, with a comprehensive multiperspective assessment battery, including a semistructured psychiatric interview. Diagnoses will be based on the DSM-III. Ss will be evaluated biannually. Salient variables will be assessed independently of each other, and outcomes will be examined in the context of important covariates. This study is the first of its kind to follow children with affective disorders into their adulthood. Thereby, it will contribute to an improved nosology of these disorders a better understanding of the continuities and discontinuities between them and their "adult" counterparts; and will shed further light on the developmental consequences of early-onset pathology, all of which have relevance to early-identification, prevention, and treatment or remediation of these conditions.

This longitudinal follow-up study of childhood-onset depressive disorders, currently in its 9th year, is entering a phase during which all Ss will have reached adolescence; it will thus be possible to observe the transition of a large subgroup of them into adulthood. Given the findings to date, the class of bipolar disorders is also being investigated. The study's developmental scope will be extended to include social competence and other areas of interest in late adolescence and young adulthood. Ss were 8-to-13 years old at intake. Recruitment is complete and includes 142 Ss with affective disorders and 49 age-matched comparisons with non-affective disorders. Drop-out rates have been low (11% for the affective-disorder Ss; 6% for the comparisons). Specific aims include contributions to nosology and developmental psychopathology, with a particular focus on the practical consequences of early-onset disorders. Nosologic goals entail the delineation of the long-term clinical course of childhood-onset depressive and bipolar disorders (e.g., recovery, chronicity, comorbidity); the predictive validity of these diagnoses; and the patterning of episodes and their associated features (including suicidal behaviors). In the sphere of developmental psychopathology, the developmental mediation of clinical course will be examined (e.g., transitions between juvenile and adult disorders, changes in comorbid conditions), and the effects of disorders on the progression of abilities (e.g., social competence, educational and vocational achievement). Other consequences will be examined in terms of rates of hospitalizations, institutionalizations, and incarcerations. A repeated-measures design will be used, with a comprehensive multiperspective assessment battery, including a semistructured psychiatric interview. Diagnoses will be based on the DSM-III. Ss will be evaluated biannually. Salient variables will be assessed independently of each other, and outcomes will be examined in the context of important covariates. This study is the first of its kind to follow children with affective disorders into their adulthood. Thereby, it will contribute to an improved nosology of these disorders a better understanding of the continuities and discontinuities between them and their "adult" counterparts; and will shed further light on the developmental consequences of early-onset pathology, all of which have relevance to early-identification, prevention, and treatment or remediation of these conditions.

This longitudinal follow-up study of childhood-onset depressive disorders, currently in its 9th year, is entering a phase during which all Ss will have reached adolescence; it will thus be possible to observe the transition of a large subgroup of them into adulthood. Given the findings to date, the class of bipolar disorders is also being investigated. The study's developmental scope will be extended to include social competence and other areas of interest in late adolescence and young adulthood. Ss were 8-to-13 years old at intake. Recruitment is complete and includes 142 Ss with affective disorders and 49 age-matched comparisons with non-affective disorders. Drop-out rates have been low (11% for the affective-disorder Ss; 6% for the comparisons). Specific aims include contributions to nosology and developmental psychopathology, with a particular focus on the practical consequences of early-onset disorders. Nosologic goals entail the delineation of the long-term clinical course of childhood-onset depressive and bipolar disorders (e.g., recovery, chronicity, comorbidity); the predictive validity of these diagnoses; and the patterning of episodes and their associated features (including suicidal behaviors). In the sphere of developmental psychopathology, the developmental mediation of clinical course will be examined (e.g., transitions between juvenile and adult disorders, changes in comorbid conditions), and the effects of disorders on the progression of abilities (e.g., social competence, educational and vocational achievement). Other consequences will be examined in terms of rates of hospitalizations, institutionalizations, and incarcerations. A repeated-measures design will be used, with a comprehensive multiperspective assessment battery, including a semistructured psychiatric interview. Diagnoses will be based on the DSM-III. Ss will be evaluated biannually. Salient variables will be assessed independently of each other, and outcomes will be examined in the context of important covariates. This study is the first of its kind to follow children with affective disorders into their adulthood. Thereby, it will contribute to an improved nosology of these disorders a better understanding of the continuities and discontinuities between them and their "adult" counterparts; and will shed further light on the developmental consequences of early-onset pathology, all of which have relevance to early-identification, prevention, and treatment or remediation of these conditions.

DESCRIPTION (adapted from investigators' abstract): This revised application is for a research grant to expand the goals of the parent grant which has involved a longitudinal, controlled investigation of the presentation, clinical course and long-term outcome of various depressive disorders (as compared to one another and non-depressive disorders) among school-age psychiatrically referred children. Under the FIRCA application the investigators plan to assess 450 outpatients (8 to 17 years of age), accessed through three psychiatric facilities in Budapest, Hungary, as Phase I of an eventual and more extensive diagnostically oriented longitudinal investigation of childhood-onset effective disorders among Hungarian youth. This FIRCA study will entail a cross-sectional, single assessment design, and use of an already developed standardized clinical interview schedule that has a comprehensive coverage of psychiatric symptoms, psychosocial characteristics and background variables. Cases will be recruited over an appropriately 30- month period from among eligible, sequentially referred new patients according to a predetermined sampling procedure. Given the lack of information about the characteristics of child psychiatric outpatients in Hungary, the FIRCA study will provide crucial descriptive data on the rates of depressive and nondepressive symptoms and suicidal behaviors across multiple clinic sites in Budapest and about pertinent clinical developmental, life stress, family related and demographic variables. These data will be the foundation for designing the later Phase II study. In this FIRCA study, psychiatric criterion- based symptom clusters will be used to estimate the sample specific point prevalence of depressive and nondepressive disorders. The association between depression, suicidal behaviors, and non- psychiatric factors will be determined. Attempts will be made to identify variables that increase the odds of depressive versus other conditions, as well as suicidality. While providing useful information about Hungarian clinic-referred youths, the findings will serve primarily to identify the best subpatient population targets for subject selection and the most feasible control group for the Phase II diagnostically-oriented, longitudinal study of childhood-onset affective disorders in Hungary along the lines of the parent grant.

DESCRIPTION (Adapted from applicant's abstract): The present application is in response to Program Announcement (PA) 93-093 for Exploratory/Development Grants (R21) for Psychosocial Treatment Research. As the first step in an eventual controlled treatment trial for children with chronic depression, we propose to: (a) test, refine, and finalize a psychotherapy manual for dysthymic children (ages 7 to 12) and construct a measure of therapist adherence, (b) standardized the final manual and assess the reliability of the measure of therapist adherence, and (c) arrive at a final protocol for the psychotherapy of dysthymia in children. The framework integrates a cognitive-behavioral perspective on depressive symptoms with the broader relational concept of stress and coping, and accommodates the importance of parents in the lives of their offsprings. The treatment will focus on reducing the child's affective symptoms and distress; alleviating other symptoms of depression, behavioral dysregulation, and dysfunction; as well as the teaching of coping skills and the reinforcing of reasonable parent-child interactions. To achieve these goals, the mother (parent) will be enlisted as co-therapist; the family's problems and diffi-culties (including the patient's symptoms) will be reframed from the broad perspective of stress and coping; and a variety of cognitive, behavioral, and related treatment techniques will be used, including emotion-focused or palliative and problem-focused coping strategies. The psychotherapy manual will be refined and finalized using a protocol that consists of three phases: intense treatment, tapering, and a booster phase, with a total of 30-sessions over a 10-month period. Follow-ups will be conducted at 6- and 12-months after termination. Patients will be recruited in 2 Waves. We will use a step-by-step interactive procedure with Wave 1 patients (30 child-mother/ mother surrogate pairs) to finalize our manual and construct the therapist adherence measure. Wave 2 patients (15 child-mother pairs) will serve to standardize the final manual and examine the reliability of the adherence measure. Dysthymic disorder in childhood is a chronic condition, with an average duration of about 4 years. It is associated with a high risk of subsequent episodes of affective disorder as well as functional impairment. Because of the risk of chronicity and long term disability, this mood disorder requires early and effective treatment. The present application will facilitate comparative treatment outcome studies by finalizing a psychotherapy manual and protocol for children with these conditions.

To identify genetic risk factors for childhood-onset affective disorders. We plan to identify genes that contribute to the development of childhood- onset depression using a strategy that combines affected relative pairs (ARP) and association studies that employ family based controls which we call haplotype relative risk (HRR) methods. The research plan is to collect DNA from childhood-onset unipolar depression probands, their parents, and their affected relatives. DNA will be extracted from blood or buccal mucosa taken from the probands, affected relatives, parents and when available, from connecting family members in the pedigree. DNA's will be typed from the ARP sample and the HRR sample for evaluation of candidate genes. Probands and parents will be screened for the presence of expanded trinucleotide repeats as some evidence for genetic anticipation has been documented for affective disorders.

clinical depression; psychological tests; child psychology; biomedical facility; psychotherapy; mental disorder diagnosis; behavioral /social science research tag; clinical research; human subject;

DESCRIPTION: Depression is the most common psychiatric morbidity in youths with insulin dependent diabetes mellitus (IDDM), is often protracted, and is a risk factor for medical complications. However, there are no psychosocial interventions of proven effectiveness for this mental disorder in juveniles with IDDM. Thus, the goals of this project are to: (a) modify an existing manual for treatment of depression in childhood called contextual psychotherapy (CP) to accommodate the IDDM, (b) test and refine the resultant manual with depressed diabetic youth (n=5), conduct a small scale efficacy trial with depressed 8-16 year old diabetic youths (n=40) using a randomized design and "treatment as usual" control group, and (d) arrive at a final psychotherapy protocol suitable for depressed youths with IDDM. Potential subjects will be recruited through the diabetes clinic of the Children's Hospital of Pittsburgh and will be randomized into one of the two treatment cells. CP will include 3 months (16 sessions) of active intervention and a 3 month (3 sessions) "booster" phase. All subjects will receive repeated assessments during the first 6 months of the protocol, and two follow-up evaluations at 9 and 12 months after study entry. A multi perspective assessment battery will be used to quantify psychiatric, functional and familial outcomes. Medical outcomes, determined separately from the treatment study, will be determined as well. Independent clinical evaluation will serve to establish treatment response. Quality care for depression comorbid with IDDM will reduce personal distress, enhance young patients' functioning, may have specific short- and long-term medical benefits, and should result in reduced utilization of health care services.

We will investigate genetic predisposition and problems in the regulation of dysphoric emotions as risk factors for childhood- onset depression, a serious and familial affective illness. We hypothesize that disruption in the early development of emotion regulation in multiple regulatory domains (biologic/social/cognitive) is necessary for the expression of childhood depression and that it occurs within a broad genetic predisposition to depressive illness. We will study high-risk families, i.e., those containing a clinically referred child proband who had a depressive disorder by age 14, and two control groups (as appropriate): referred probands who had childhood-onset anxiety disorder and probands who were free of childhood psychiatric illness. Three unique and valuable cohorts will be merged who were ascertained (as part of separate NIMH grants) while they were youngsters, are now young adults, and have offspring. Study 1 will seek to identify genes in childhood-onset depressive illness by using a strategy that combines affected relative pair and haplotype relative risk methods, screen probands and parents for expanded trinucleotide repeats and perform a genome scan; Study 2 will examine patterning of frontal EEG, autonomic nervous system reactivity, and facial expression as markers of emotion dysregulation in probands, juvenile offspring and adult siblings, of probands; Study 3 will use observational method to explore emotion, regulation in the young, offspring of grown probands and interactions, and related parent-child interactions, and their developmental unfolding: The studies will be supported by the Administrative, Scheduling & Psychiatric Evaluation, and Data Management & Statistical Cores and external consultants. By eventually integrating results of the 3 studies, we will derive a multifaceted characterization of risk factors in depressive illness and identify processes that may be protective. Such findings will facilitate primary prevention with our target population.

DESCRIPTION (Provided by applicant): This is a competing continuation application for our multidisciplinary, multigenerational Program Project (PP) on risk for childhood-onset depression (COD). COD is a recurrent and familial affective illness with serious developmental and functional consequences. The PP?s guiding hypothesis is that COD occurs in the context of a genetic predisposition and that disrupted early development of emotion regulation in multiple (biological, social, cognitive, behavioral) regulatory domains is necessary for the expression of the disorder. Studies 1, 2, and 3 (conducted in the USA) and Study 4 (conducted in Hungary) use converging multidisciplinary approaches to examine molecular genetic, psychophysiologic, psychosocial, and behavioral indices of risk associated with COD. We target two types of families: those containing a grown young adult with a documented history of COD (Studies 1, 2, 3), and those containing a depressed child and his/her affected or unaffected sibling (Study 4). As relevant, COD subjects are compared to young adults who had childhood-onset bipolar disorder, or to normal controls. Study I uses molecular genetic technology to examine genes that may be implicated in COD and related psychophysiologic phenotypes (defined by Study 2). Study 2 uses electroencephalographic, electrocardiographic, and electromyographic techniques to examine domains of emotion regulation in adult probands, juvenile offspring, and adult siblings of probands. Study 3 uses behavioral observations of parent-child interactions to explore the developmental unfolding of emotion regulation in the child and the proband parent. Study 4 uses a high-risk paradigm in a Hungarian national sample to investigate genetic liability and selected indexes of emotion regulation among juvenile depressed probands, their affected and unaffected juvenile siblings, and parents. The Administrative, Scheduling and Psychiatric Evaluation, Information Technology, and Statistics Cores support the studies. Testing specific hypotheses and integrating results across studies will provide a multifaceted characterization of risk for COD and related juvenile onset mood disorder. The results will contribute to our understanding of how depression develops and how it may be prevented.

genetic susceptibility; family genetics; clinical depression; child (0-11); disease /disorder proneness /risk; oral mucosa; siblings; parents; nucleic acid repetitive sequence; clinical research; human subject; blood tests;

DESCRIPTION (provided by applicant): In this second revision of our application, we addressed the reviewers'questions about our comparison condition and several other design issues, and propose a 5-year study of the efficacy of Contextual Emotion Regulation Therapy (CERT), a novel intervention for childhood depression. CERT is an empirically based, developmentally sensitive treatment that targets emotion regulation response skills in depressed children, and deploys parents as co-therapists;parents are taught to effectively coach their children in various tasks, including developmentally appropriate use of emotion regulatory strategies in response to experiencing distress/dysphoria. Altogether 100 children, aged 7-12, with a DSM-IV depressive disorder, will be randomly assigned to CERT or Child-Centered Therapy (CCT), a psychotherapy based on Rogerian principles. Both treatments entail 22 sessions, conducted jointly with the parent and child: weekly sessions across the first 4 months are followed by biweekly sessions (across a two month period) to consolidate treatment gains. Both groups will be followed for 1 year after the end of treatment to evaluate the longer-term effects of the interventions. A multi-perspective assessment battery (clinical interviews and ratings, and parent- and child-self rated inventories) will provide the data to test our hypotheses. We hypothesize that CERT will result in more rapid, complete, and sustained recovery from depression than CCT;that symptomatic improvement will be mediated by improvement in children's and parents'self-regulation of dysphoric affect and by improved parent-child relationship;and that treatment outcome will be moderated by baseline clinical characteristics of the child and parental depressive symptoms. An open treatment trial of CERT with 20 children with dysthymic and/or major depressive disorder showed that a high proportion achieved remission, which was sustained across an additional 12 months of follow-up. Our proposed project has great public health significance because childhood depression is a gateway to adult depression, one of the leading causes of disability worldwide, and there are currently no published, empirically validated treatments for clinical depression for referred children aged 12 years and younger. Public Health Relevance: We plan to test the efficacy of Contextual Emotion Regulation Therapy (CERT), a novel psychosocial treatment for childhood depression, among 7 to 12-year olds. This project has great public health significance because childhood depression is a gateway into adult depression, one of the leading causes of disability worldwide, and there are currently no empirically validated treatments for clinical depression in this age group. CERT translates years of observational and experimental evidence in developmental psychopathology and identifies emotion regulation as the key deficit in depression. As a psychosocial treatment, CERT is 1) flexible, insofar as it can be tailored to the emotion regulatory needs and abilities of the child and family, 2) ecologically valid, as it actively involves the parent as a co-therapist, and 3) likely to result in more complete and enduring treatment response.

DESCRIPTION (provided by applicant): In this revised application, which focuses on bio-behavioral inflexibility as a framework to identify risk factors for juvenile-onset depression (JOD), we responded to each of the IRG's concerns. In particular, we: a) offer more explicit formulations of our model, hypotheses, and statistical approaches, b) address possible environmental moderators, and c) present the results of new pilot studies, which show our ability to induce and remediate dysphoric mood in Hungarian subjects and support the use of somatic probes of cardiac vagal control in youths. In this application, we propose to study the relation between current and prospective JOD risk and two functionally important bio-behavioral systems: cardiac vagal control (CVC) and mood repair. To characterize CVC inflexibility, we will assess CVC functioning across different experimental challenges (somatic vs. psychological);within versions of one type of challenge (e.g., alternative psychological tasks);and across different facets of CVC (resting vs. CVC reactivity and recovery). To characterize inflexible mood repair, we will assess subjects'ability to attenuate dysphoric mood subsequent to negative mood challenges by implementing 2 different mood repair strategies (positive autobiographical recall vs. distraction) and across different mood repair opportunities (experimentally controlled vs. unstructured). Our sample (11-18 years old at entry) will include 200 probands with JOD, 200 of their at-risk siblings not yet affected by JOD, and 100 never-ill controls. Probands (and siblings) will be recruited from a carefully diagnosed and well-characterized sample of 700+ young patients with JOD (each with at least one sibling), representing a national, clinical sample in Hungary, who participated in a recent Program Project. The design includes cross-sectional assessment of CVC, mood repair, psychiatric status, and psychosocial functioning, and longitudinal clinical follow-up. We propose that: (1) physiological inflexibility (operationalized as indices of impaired CVC) and behavioral inflexibility (operationalized as indices of impaired mood repair), and their combinations (global bio- behavioral inflexibility indices), will cross-sectionally distinguish probands, at-risk siblings, and control peers and that (2) global bio-behavioral inflexibility indices will prospectively predict clinical course (elevated depressive symptoms, recurrent depressive episodes in JOD probands, onset of first depressive episode in previously unaffected siblings). We also will test elements of our global inflexibility models in the presence of environmental moderators. Our study is significant because depression is a leading cause of disability worldwide. Moreover, JOD is a severe and recurrent form of depression that accounts for about 50% of the cases of depression in young adults. Our study is innovative because it: (a) integrates biological and behavioral indices relevant to depression that have ready translational potential, (b) uses alternate probes of CVC and mood repair across multiple stimulus conditions to obtain a richer characterization of these constructs, and (c) its bio-behavioral targets can inform improved efforts to detect, prevent, and treat depression. PUBLIC HEALTH RELEVANCE: In this application, we conceptualize depression as a condition of bio-behavioral inflexibility and apply this framework to juvenile-onset depression (JOD)--a particularly serious form of mood disorder. By comparing depressed youths, non-depressed siblings, and never-depressed peers, we will identify biological and behavioral aspects of inflexibility that increase a youngsters'risk of developing JOD and hinder recovery from this condition. The public health significance of this project derives from the fact that it will yield knowledge that can improve efforts to detect, prevent, and treat JOD.

DESCRIPTION (provided by applicant): In this revised re-submission of our study of children at familial risk for depression (and controls), we have responded to the concerns of the IRG and revised our protocol accordingly. As we explicate, cognitive flexibility has been regarded as one component of executive function, which can be indexed as the ability to re- focus/shift attention and rapidly change cognitive sets in response to environmental demands. We now link our index of cognitive (in)flexibility to traditional cognitive risk factors for depression, and also incorporate an index of physiological flexibility, namely cardiac vagal control (CVC). Parental depression is a significant risk factor for major depressive disorder (MDD) in juveniles and also increases the odds of comorbid non-affective disorders. In the tradition of psychiatric high-risk family studies, we propose to examine combinations of selected personal characteristics as predictors of MDD and conduct and/or substance use-related disorders in juveniles at familial risk for depression. The personal characteristics include parental clinical (e.g., severity of mood disorder history) and child neurocognitive attributes (impaired cognitive flexibility). Cognitive flexibility as an executive function will be assessed both by traditional neuropsychological tests and their novel modifications which incorporate emotionally distracting features. As our Primary Aims, we will test hypotheses about the how the confluence of child and parent factors affect risk of MDD and non-affective disorders in offspring. Our sample will consist of n= 250 youths, including offspring of proband parents (who themselves had childhood-onset mood disorder) and offspring of control parents with no history of major psychiatric disorders. As our Secondary Aims, we will explore the relations of 2 traditional cognitive risk factors (ruminative response style and negative attributional style) to cognitive inflexibility, and the extent to which physiologic inflexibility (reflected in dysfunctional CVC) adds incremental information to our predictive model involving neurocognitive-clinical variables. Offspring will be 8-to-16-years old at initial assessment and 10-to- 18-years old at follow-up; this age range covers the transition into and across adolescence, which is the high risk period for MDD incident (new onset) cases and conduct/substance use related disorders. The feasibility of this study is underscored by the fact that we have access to a unique and well-maintained sample of families that had been ascertained as part of a prior Program Project on depression. Our study: a) is innovative because it integrates developmental and neurocognitive perspectives in the context of a high-risk family design and targets a cognitive process that may underlie a range of information processing biases in depression, b) has great public health significance because depression is both a personally devastating condition and a leading cause of disability worldwide, which may possibly be prevented or forestalled based on a better understanding of person-specific risk factors/mechanisms, and c) is timely because it reflects several components of NIMH's Strategic Objectives for research on mental disorders.

DESCRIPTION (provided by applicant): This application responds to PAR-14-008 for secondary analyses of existing clinical research datasets in order to assess the validity of the [Research Domain Criteria] RDoC constructs, and to test novel hypotheses using the RDoC framework. RDoC was introduced in 2009 as a new classification framework for mental disorders. It is based on a matrix of 5 domains (systems) of functioning, each of which includes lower order constructs, and each construct is defined across multiple units of analyses (UAs) (e.g., neural circuits, genes, physiology, actual behavior, and self-report). Given that RDoC is still a moving target (Cuthbert & Insel, 2013), we propose to help refine it by examining the construct and predictive validity of selected constituents. Our archival data derive from a 10-year Program Project on risk factors for juvenile- onset depression (P01-MH-056193), which included (a) adults and juveniles, ranging from minimally symptomatic controls to those with multiple co-morbid psychiatric syndromes and (b) studies of emotional reactivity and regulation in the context of various gradations of familial and personal risk for depression. Thus, the data are well suited to examine facets of RDoC's Negative/Positive Valence Systems. Relevant to the Negative Valence System, we have experimental analogues probing physiological, neural, and psychological responses to Loss, Frustrative Non-reward, and Potential Threat. Relevant to the Positive Valence System, we have probes of Initial Response to Positive Reinforcement and Reward Expectancy. Our neural index is frontal lateralization of EEG alpha waves (EEG asymmetry); one physiological index is respiratory sinus arrhythmia (RSA), an indicator of autonomic nervous system functioning related to affect experience and adaptive functioning. Our behavioral indexes include self-, clinician-, and observer-based ratings of affect, symptoms, and functioning. We have follow-up assessments of key Constructs and outcomes. We propose two Aims. Specific Aim 1. Examine the construct validity of the Negative/Positive Valence Systems in adults and juveniles using neural, physiological, and behavioral UAs. This Aim will be guided by 4 Hypotheses (that include developmental and familial analyses) concerning the relations of UAs and Constructs within and across the Positive and Negative Valence Systems. Specific Aim 2. Examine the predictive validity of Negative and Positive Valence System Constructs in relation to distress (depression/anxiety symptoms), trait negative and positive affect, and adaptive functioning. This Aim will be guided by 2 Hypotheses concerning the concurrent and longitudinal predictive power of Positive/Negative Valence systems and related UAs and constructs. While implementing standard psychometric approaches to validity testing, our study is unique owing to its longitudinal aspect and its developmental & familial emphases: it includes child samples and proposes that Constructs run in the family. Our findings will help pave the way for next steps in the refinement of the RDoC matrix.

DESCRIPTION (provided by applicant): In this revised application, we addressed the IRG's concerns: we clarified the number/type of assessments on the 3 subject groups; proposed a further Hypothesis that mirrors better the use of childhood archival data about probands and their sibs; added ICAM-1 to our biological markers; and responded to various other concerns. Our study focuses on depression and coronary heart disease (CHD), which are enormous public health problems across the world. Depression not only predicts new onset CHD, and morbidity, and mortality in those with existing CHD but also is associated with behavioral risk factors (e.g. smoking, being sedentary) for eventual CHD. Although the depression-CHD link is well established, the causal role of depression is still being debated, and its most cardiotoxic features are yet to be confirmed. Notably, although both depression and CHD often originate in the pre-adult years, few studies have examined their association with behavioral CHD risk factors in a developmental context. We propose to assess 3 established samples of young adults in Hungary: a) probands (n=325), whom we have followed since childhood, when they had their first episode of major depression around the mean age of 9 years, b) never-depressed siblings of probands (n=325), and c) normal peer controls (n=155). We recently reported that: a) proband families have elevated rates of parental CV disease, b) by adolescence (mean age=17 years), being a proband predicted increased rates of behavioral risk factors for CHD (e.g., smoking, being sedentary), and c) rates of behavioral risk factors were highest among probands, lowest among controls, and intermediate among never depressed siblings of probands. The goal of the proposed study is to assess, for the first time, traditional biological risk factors (e.g., LDL cholesterol, blood pressure), along with behavioral risk factors, and several markers of CHD risk: pulse wave velocity, interleukin-6 and C-reactive protein (inflammation), ICAM-1 (endothelial function), and the metabolic syndrome. Our hypotheses address the levels of CHD risk markers as a function of subject group, the role of behavioral risk factors in adolescence in the link between depression and preclinical physiological outcomes, the impact of developmental trajectories of stress and risk variables on physiological outcomes among probands-sibs, and the most cardiotoxic clinical features of depression. Our extensive archival data on subjects' psychiatric history, family stress events, parental history of cardiovascular disease, socio-demographic variables, and various behavioral risk factors for CHD will yield a unique characterization of the unfolding relationships among depression, behavioral risk factors, and early markers of CHD risk. The sibling design will help isolate the contribution of depression to early markers of CHD risk by controlling for the adverse health impact of several family-based variables. Given the public health burden posed by depression and CHD, their study in young adults is particularly warranted, because risk factors and/or preclinical signs of CHD risk may be easier to modify earlier, rather than later, in the lifespan.

Abstract This application responds to RFA-MH-17-405 Adult Maturational Changes and Dysfunctions in Emotion Regulation. As the RFA notes, aging is associated (for most people) with increasing emotional well-being, emotional stability, and a positivity bias. While these maturational changes are believed to reflect improved emotion regulation skills (like better ways of attenuating sad mood), the literature on emotion regulation strategies and age is decidedly equivocal. Further, little is known about when maturational changes may occur given the scarcity of longitudinal studies and the use of designs, which contrast highly divergent age groups. And it is not known how psychopathology affects presumed adult maturational changes in affect-related skills. We propose to build on a unique sample of Ss, heterogeneous with respect to risk of depressive disorder, who (in prior research studies) repeatedly reported during ages 18-35+ on their emotional well-being and how they attenuate sadness/distress (mood repair); their autonomic nervous system (ANS) functioning associated with affect processing was also assessed via peripheral measures. We propose to re-assess n=225 with histories of diagnosed depression and n=200 with no histories of depression once more, and thus extend the data base up to age 59 years, covering middle-age. We will identify latent trajectories of trait mood repair from ages 18 to 59 years and determine its correlates and the effects of personality, treatment exposure and ANS physiologic functioning on class membership. We also will examine the ability to repair mood in the laboratory via two adaptive cognitive regulation strategies: attention-refocusing and neutral reappraisal. Finally, we will use a novel experimental procedure (the Cognitive Effort Discounting Paradigm or COG-ED), which quantifies the subjective cost of cognitive effort (involved in cost-benefit computations to perform a task), to examine the impact of affective load on effort-based decision making. We will test several clearly articulated hypotheses about : i) the effects of depressive illness history and sex on positive maturational effects in mood repair with age, ii) the predictive/moderating values of personality and treatment exposure on age-related mood repair changes, iii) the relations of latent-class mood repair trajectories to sex and shifts in ANS functioning over time; iv) the predictive value of latent-class mood repair trajectories for mood repair success in the laboratory; v) ever-depressed and never-depressed group-related differences on the COG-ED, and vi) the relations of COG- ED performance to mood repair trajectory membership and lab-based mood repair performance via attention refocusing. Our study will fill several gaps in the literature on emotion regulation and aging. It also represents the first step to assess the extent to which a neuro-economic approach to decision making reflects a mechanism that may explain mood repair choices. Findings on mood repair trajectories and COG-ED outcomes have public health implications in the areas of depression prevention and treatment.

Project Summary We are requesting an administrative supplement to make up for the loss of subject enrollment into the study during more than six months of state-mandated closure of our lab due to Covid-19 (while project staff continued to receive salaries). We need to finish recruitment of the proposed sample in order to fulfill the aims of the study and have the statistical power to test key hypotheses. The goals of this study remain as originally proposed. We were to build on a unique sample of Ss, heterogeneous with respect to risk of depressive disorder, who (in prior research studies) repeatedly reported during ages 18-35+ on their emotional well-being and how they attenuate sadness/distress (mood repair); their autonomic nervous system (ANS) functioning associated with affect processing was also assessed via peripheral measures. We propose to re-assess n=225 with histories of diagnosed depression and n=200 with no histories of depression once more, and thus extend the data base up to age 59 years, covering middle-age. We will identify latent trajectories of trait mood repair from ages 18 to 59 years and determine its correlates and the effects of personality, treatment exposure and ANS physiologic functioning on class membership; will examine the ability to repair mood in the laboratory; we will use a novel experimental procedure (the Cognitive Effort Discounting Paradigm or COG-ED), which quantifies the subjective cost of cognitive effort (involved in cost-benefit computations to perform a task), to examine the impact of affective load on effort-based decision making. We will test several clearly articulated hypotheses about : i) the effects of depressive illness history and sex on positive maturational effects in mood repair with age, ii) the predictive/moderating values of personality and treatment exposure on age-related mood repair changes, iii) the relations of latent-class mood repair trajectories to sex and shifts in ANS functioning over time; iv) the predictive value of latent-class mood repair trajectories for mood repair success in the laboratory; v) ever-depressed and never-depressed group-related differences on the COG-ED, and vi) the relations of COG-ED performance to mood repair trajectory membership and lab-based mood repair performance via attention refocusing. Our study will fill several gaps in the literature on emotion regulation and aging and represents the first step to assess the extent to which a neuro-economic approach to decision making reflects a mechanism that may explain mood repair choices.