Jonathan A. Rottenberg, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Depression is among the most prevalent of all psychiatric disorders, accounting for over 20% of economic costs for all mental illness. An important public health priority is the identification of factors that both increase individuals' vulnerability to depression and hinder recovery from this disorder. Abnormalities in cardiac vagal control may confer vulnerability to depression. More specifically, two distinct abnormalities in cardiac vagal control may confer vulnerability: low vagal level (VL) usually measured in a resting state, and low vagal fluctuation (VF), usually measured in response to environmental demands. VL and VF are increasingly understood as independent predictors of physical and mental health outcomes. To date, mood disorders research has focused almost exclusively on VL, with results largely inconclusive as to its etiological and prognostic value. Early data from our laboratory suggests that depression is characterized by low VF and that VF may predict the subsequent course of clinically significant depression. The broad objective of this R21 exploratory research project is to investigate VF as a liability marker for depression. We will use a battery of previously-validated laboratory tasks to elicit VF in 60 outpatients diagnosed with current unipolar depression, 30 participants with a past diagnosis of unipolar depression, and 30 healthy non-psychiatric participants. VL and VF will be assessed via high-frequency heart period variability derived from the electrocardiogram. Participants will be followed longitudinally and reassessed at six months. The specific aims of this project are to examine: (1) whether depression vulnerability is associated cross-sectionally with reduced VF during and after experimental stressors; and (2) whether those depressed individuals who preserve dynamic VF during and after experimental stressors are more likely to recover from their disorder six months later. The investigators intend to use these R21 data as the foundation for a larger R01 research grant project that will examine VF with respect to: (a) psychiatric disorders other than MDD; (b) predicting outcome over longer periods (~3 years); (c) predicting outcome in a controlled treatment modality; and (d) potential antidepressant effects of VF modification. From a public health perspective, the hypothesis that depression risk is related to low VF is exciting because it suggests that easily acquired and potentially manipulable measures of heart rate variability could be used to assist in the early assessment of depression risk, and perhaps to develop interventions that operate directly upon the vagal pathway itself. PUBLIC HEALTH RELEVANCE: An important public health priority is the identification of factors that both increase individuals' vulnerability to depression and hinder recovery from this disorder. Abnormalities in cardiac vagal control may confer vulnerability to depression. This project will examine the hypothesis that depression risk is related to a lack of dynamic cardiac vagal control, which is potentially important because it suggests that easily acquired and potentially manipulable measures of heart rate variability could be used to assist in the early assessment of depression risk, and perhaps to develop interventions that operate directly upon the vagal pathway itself. [unreadable] [unreadable] [unreadable]

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.