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Research Roundtable: Heterogeneity in Child and Adolescent Depression

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Meeting Summary
Washington, DC

Sponsored by:
National Institute of Mental Health
Division of Developmental Translational Research (DDTR)

Overview

Juvenile depression rarely exists in isolation, and children and adolescents with depression exhibit great variability in clinical characteristics (e.g., age of onset, course, severity), patterns of neurobiological correlates, and social profiles of risk. In addition, treatment response varies considerably among depressed youth. The purpose of this workshop was to discuss empirical evidence for sources of heterogeneity in child and adolescent depression, evaluate the significance of known heterogeneity, and identify promising research directions in this area. The specific goals of this workshop were:

  1. To evaluate the validity and utility of clinical subtypes of depression as a source of heterogeneity for defining etiology and informing treatment among youth
  2. To review findings on diversity in clinical course of and divergent etiologic pathways to depression in childhood and adolescence
  3. To identify dimensions and sources of heterogeneity in child and adolescent depression that may contribute to refining etiological models and intervention approaches
  4. To discuss the integration of sources of heterogeneity

Heterogeneity in Presentation: Phenotypes

Research has suggested numerous potential subtypes of pediatric depression based on differences in phenotypic symptom patterns; however, few have been evaluated systematically. With the exceptions of bipolar depression and possibly double depression (i.e., major depression and dysthymia) and child-onset depression, the workshop participants generally agreed that few of the proposed subtypes have been shown to be distinct and valid subtypes of depression among youth. Current evidence supports a focus on heterogeneity in pathways to depression rather than on heterogeneity of the manifestations of this disorder. Participants discussed the utility of subtyping for clinical versus research purposes and fruitful approaches to identifying and refining phenotypes to guide etiological models. There was general agreement that the application of the spectrum concept of depression would provide a more valid approach to defining depression in youth for research purposes. Systematic studies of the validity of the threshold and boundaries of depression may benefit from a range of powerful methods, including population-based, prospective studies, genetic epidemiologic study designs, and treatment outcome studies. Participants also debated the pros and cons of incorporating genetic and biological factors into clinical phenotypes to minimize heterogeneity.

Heterogeneity in Course: Maturational and Cultural Influences

One of the most consistent findings in the pediatric depression literature is the emergence of gender differences during the transition to adolescence (ages 12-14 years), notably, the increase in rates of depression among girls. Although this increase suggests that maturational change (e.g., puberty) at adolescence may be a critical piece of the causal typology of depression among females, earlier influences on this sex-defined difference should also be considered. Moreover, brain development during this period may differentially influence the development of depression among females and males. Little is known, however, about how brain development trajectories interact with behavioral changes that are associated with the emergence of depression and with other developmental processes (e.g., neuroendocrine changes associated with puberty).

Evidence for racial and ethnic heterogeneity in risk for depressive disorders suggests a lower lifetime risk for depression among African Americans and Hispanics compared to Caucasians, in contrast to other health outcomes. Focusing on protective factors (e.g., race/ethnic identity, coping strategies) may facilitate the identification both of factors involved in risk for depression and of effective prevention strategies.

Heterogeneity in Presentation and Course: Comorbidity

A second robust finding in child and adolescent depression is the substantial rate of comorbidity with other psychiatric disorders. The presence of comorbidity is consistently associated with greater depression severity and overall functional impairment. The effects of comorbidity on course of depression and treatment response, however, are less clear due to conflicting findings and/or lack of data. Some evidence suggests that particular temporal sequences of comorbid conditions may signal heterogeneity in developmental pathways among depressed youth. For example, early anxiety compared to oppositional defiant disorder preceding depression may mark separate developmental pathways. Whether comorbidity is a meaningful source of heterogeneity depends in part on the processes responsible for the comorbidity (e.g., distinct versus common etiologies). Research explicitly seeking to elucidate causes of comorbidity may help address this issue. In addition, these questions will be informed by studies that evaluate comorbidity with specific disorders (as opposed to higher-order groups) and distinguish between concurrent and successive comorbid diagnoses when evaluating pathways.

Heterogeneity in Etiology and Risk

Participants reviewed current findings on biological, genetic, social, and cultural risk for depression. Most known risk factors for depression appear to be non-specific and are not correlated with one another. Additionally, most associations are small to moderate in magnitude and many do not replicate across studies. Many other factors complicate etiological examinations. For example, context may influence proximal risk and coping resources and therefore may affect etiology, course, and treatment. Further, measurement issues may impede evaluation of potentially informative factors (e.g., core psychological processes targeted in imaging studies have uncertain relation to clinical disorders). Discussion focused on these issues and on the merits of adopting final common pathway or multiple pathways models of depression. The group generally agreed that sufficient data are not currently available to resolve these issues. Prospective data are needed to examine the complex interrelationships of various systems involved in depression and in within-subject response to treatment.

Integrating Sources of Heterogeneity and Other Challenges

Current approaches may integrate sources of heterogeneity in one or more of the following ways: (a) focus on subgroups of people (e.g., girls with a maternal history of depression, African Americans); (b) evaluate specific symptoms or components of depression (e.g., dysregulated emotion); (c) assess multiple domains of risk and examine the interplay among distinct etiological factors; and (d) examine developmental transitions. Such integrative models present significant challenges in collaboration and methodology (e.g., changing meaning of constructs across development; perception of depression among subgroups), but hold promise to significantly advance knowledge on etiology and intervention approaches.

Finally, sources of etiological heterogeneity were also discussed in terms of their relevance to heterogeneity in treatment response. Limited evidence from both etiological and treatment studies suggests that treatment response may be moderated by factors such as pubertal status, gender, exposure to traumatic events, cognitive distortions, and family history. Multiple research approaches (e.g., risk factor studies to identify mechanisms, studies of biomarkers of treatment response) are necessary to inform this important issue.

Conclusions

  • Prospective studies that begin at or before adrenarche or no older than 8/9 years of age are necessary to capture relevant risk processes for emergence of depression.
  • Large collaborative studies are probably necessary to incorporate the array of methods, address complicating factors such as comorbidity and development, and develop maximally informative, integrative models.
  • Genetic epidemiology methods are needed to evaluate specificity with regard to pathways of risk, identification of endophenotypes, and differentiation of state and trait markers for disorder.
  • Use of innovative and effective mechanisms for recruiting and retaining diverse populations and incorporating multiple levels of risk are necessary to ensure relevance and generalizability of findings.
  • Potential sources (or meta-dimensions) of heterogeneity that require further evaluation include family history, recurrence, gender differences, and unipolar versus bipolar depression, and patterns of comorbidity.
  • Existing data from phenomenology and treatment outcome studies might be mined to explore sources of heterogeneity.
  • Better links must be established between risk and intervention research to increase relevance and translation.

For more information, please contact Dr. Shelli Avenevoli.