The focus of this article is on internalizing problems that are experienced by children and adolescents. We provide an historical perspective, selectively examine the current state of knowledge, consider advances and gaps in what is known, and identify new research directions. Diagnosis, epidemiology, theory, and research first are considered separately for anxiety and depressive disorders. These internalizing problems, however, whether clinical or subclinical, share many common features and show high comorbidity rates. We emphasize the importance of systematic analysis of comorbid anxiety and depression, including their comorbidity with externalizing problems. This could lead to more valid classification of subtypes of internalizing problems and further an understanding of the diverse conditions that constitute internalized distress. We highlight the need to study anxiety and depression within a developmental psychopathology framework, as well as to include both categorical and dimensional assessments of these problems in the same research designs. This will be essential for understanding the complex interplay of biological and environmental processes that contribute to the emergence, progression, and amelioration of internalizing problems over time.

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12–88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen’s d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen’s d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Major depressive disorder (MDD) is a leading cause of disability and global disease burden¹ and frequently emerges during adolescence.² Many adolescents do not respond to evidence-based treatments,^3,4 highlighting the need to better understand the underlying brain mechanisms. Current theory^5,6 holds that frontolimbic neural networks underlying emotion processing are abnormal in MDD. However, neurobiological research in adolescents has lagged behind that in adults. Because of the significant brain maturational changes that occur during adolescence,⁷ the brain abnormalities in adolescent MDD could be different from those in adults. Developmental changes may contribute to the increased risk of disease onset during adolescence, while also providing a potential window for intervention to restore developmental trajectories. These considerations underscore the importance of advancing the understanding of the neurobiology of adolescent MDD.

The purpose of this study was to examine adrenocortical activity (basal, diurnal variation, and responses to social stressors) in adolescents at risk for psychopathology. Salivary cortisol levels were examined in normally developing and at-risk youth with internalizing and externalizing symptoms ranging from subclinical to clinical levels. Adolescents showed expected patterns of diurnal variation, with high early morning cortisol levels and a pattern of decline throughout the day. Females showed higher midday and late afternoon levels than males, and these patterns interacted with risk status. Internalizing problems sometimes were associated with gradual rather than steep declines in basal cortisol production. Both immediate and delayed cortisol reactivity to a social performance stressor were associated with internalizing symptoms. There was no evidence of relations between externalizing problems and underarousal of the hypothalamic–pituitary–adrenal (HPA) system. These and other results suggest that gender is an important moderating factor linking psychopathology, development, and context with HPA axis functioning in adolescence.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.