Family Study of Affective and Anxiety Spectrum Disorders

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

To date, over 600 probands and nearly 1200 of their relatives have completed the study, including 200 children between the ages of 7-17 years. Approximately 600 individuals have also been evaluated at the NIH Clinical Center. Probands represent not only a large range of psychiatric disorders including mood and anxiety spectrum but also substantial medical comorbidity related to sleep, migraine, pain, and cardiovascular conditions, as well as controls with minimal to no pathology. We are focusing on remotely collecting measures including mobile assessments and saliva for extracting genetics data, and recontacting relatives for updated information. During the past year, we have shifted our emphasis to to validating and streamlining research operations. We have devoted research effort to collect follow-up data from families to maximize our ability to study causes, correlates, and consequences of these interrelated conditions. This involved repeating diagnostic interviews and self-report clinical and psychosocial measures, in order to test the stability of these measures over time and track their relationship with emerging mental and medical disorders in probands and family members. To streamline data entry, management, and analyses, we have shifted to administering many of the assessments electronically to permit remote data collection. We are continuing to work with experts to develop efficient platforms to visualize multilevel data in R and to develop a platform that combines data acquisition with data management and analysis. We are also developing computer programs to exploit the item-level data from diagnostic interviews and related measures, including algorithms for subthreshold syndromes, clinical phenomena, and self-report measures. We are also completing collection of DNA samples for both probands and relatives and conducted preliminary analyses of the first phase of the study. We have devoted substantial effort to the refinement and publication of prior preliminary findings, in addition to pursuing promising new work. During the past year, our work focused on: 1) analyses of the familial aggregation and coaggregation of core clinical phenotypes in the family study including mood and anxiety disorder subtypes with attention-deficit hyperactivity disorder (ADHD) and substance use disorders, as well as sleep disorders, pain-related conditions, migraine, and other chronic medical conditions; 2) investigation of the associations between mood and anxiety disorder subtypes and familial transmission of the core domains underlying mood and anxiety disorders including sleep patterns and chronotype, cardiovascular risk factors, hyperthymia and anxiety-related temperaments, and startle and autonomic reactivity; 3) data harmonization and confirmation of findings from our family study with those of a parallel family study in Lausanne, Switzerland, as well as synthesizing high-risk family environment linked to bipolar disorder (BD); and 4) beginning to exploit larger datasets available from the Psychiatric Genomics Consortium to create polygenic risk scores for our own data. Recent publications from our research team have focused on familial aggregation of mood and anxiety disorders in probands and first-degree relatives from our family study sample. With collaborators from Australia, we examined the familial aggregation/coaggregation of anxiety disorder subtypes and anxiety-related temperamental traits, and their association with mood disorders. Our findings suggested that anxiety-related temperamental traits may indicate a vulnerability for mood and anxiety disorders or a potential consequence of these conditions (Iorfino et al, 2020). We also studied the familial aggregation of ADHD and its cross-transmission with BD. Results indicated specificity of familial aggregation of both bipolar I disorder (BP1) and bipolar II disorder (BP2), and no evidence for ADHD and BD cross-transmission in first-degree relatives. Future research is warranted to reconcile the discrepant findings with respect to the common versus independent familial diatheses underlying BD and ADHD (Walsh et al, 2020). Continuing our work to examine mood disorder subtypes from childhood to adulthood, in collaboration with researchers in our parallel family study in Lausanne, we aimed to identify differences in patterns of psychopatholgical precursors among youth with (hypo)mania compared to major depressive disorder (MDD), and whether these patterns differ by subtypes of parental mood disorders. Our findings point to distinct pathways to the development of BD and unipolar mood disorders, and that these precursors differed by mood subtype in offspring. High-risk offspring with these precursors should be closely monitored to prevent further development of MDD or conversion to BD (Rudaz et al, 2020). We continue to devote major effort toward methods development and dissemination and analyses of dynamic phenotypes derived from actigraphy and electronic diaries, which permit investigation of fluctuations in core domains of mood disorders in the context of daily life. This work has been conducted in conjunction with collaborators across multiple sites including Lausanne, Switzerland; Sydney, Australia; Amsterdam, Netherlands; and Hong Kong, China. We continue to conduct methodological work, with collaborators at Johns Hopkins University, focused on educating our peer researchers about the knowledge that can be gained by conducting analyses that respect time of day rather than averaging across days and weeks. Such methodological collaborations highlight opportunities for discovery in psychiatric research afforded by mobile technologies. We previously studied mood dynamics and reactivity and differential patterns of reactivity for those with BP1 compared to those with BP2, MDD, and anxiety disorders, providing phenomenological support for distinguishing BP1 from other affective disorders. In contrast, groups did not differ in their degree of mood variability or instability compared to controls. These findings contribute to our understanding of the underlying bases of mood and anxiety disorders, consistent with the overall objectives of our research program. Finally, expanding upon these findings as well as our prior findings on the role of activity in mood regulation, we have established a workgroup which will conduct follow-up analyses to examine the influence of other factors such as substance use/disorders, exercise, and eating in these relationships. Public Health Impact: Integration of the clinical, neuropsychological, and psychophysiological measures within families will render an in-depth analysis of the mechanisms crucial to mood and anxiety disorders and their underlying diatheses. This will not only lead to a better fundamental, etiologic understanding of these conditions, but also may inform the development of novel treatment options, possible strategies for early intervention, and potential prevention in those with elevated risk for these conditions. Future Plans: During the next year, we plan to shift our efforts from data collection to data analysis in order to exploit the rich and comprehensive clinical, biologic and genetic data from the study. Substantively, our focus will remain centered on the causes, correlates, and consequences of mood spectrum disorders, guided by our growing body of findings related to energy, motor activity, and other biorhythms linked to homeostasis; mental-medical comorbidity and the mechanistic association thereof; and psychiatric endophenotypes and risk processes associated with BD ranging from anxiety disorders to substance use disorders to suicide. These analyses will further discern subgroups in whom more intensive follow-up will examine key clinical and biological questions addressed by this protocol.