Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group

Abstract

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen's d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen's d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder

“…Converging evidence suggests neural disturbances occur in a limbic-cortical-striatal-pallidal-thalamic circuit (Drevets et al, 2008). Structural alterations in the prefrontal cortex, particularly the anterior cingulate, and subcortical hippocampal, amygdalar, thalamic, and striatal/ pallidal centers are consistently implicated (Drevets et al, 2008;Lorenzetti et al, 2009;Schmaal et al, 2015). Lesion and functional imaging studies show these regions form networks governing mood regulation, reward sensitivity, and emotion (Koenigs and Grafman, 2009;Ochsner et al, 2012;Hamilton et al, 2013;Korgaonkar et al, 2013).…”

White matter microstructure in boys with persistent depressive disorder

“…Dickstein et al, 2010;Forbes et al, 2006;Hammar & Ardal, 2009;Kovacs, Joormann, & Gotlib, 2008) but may not be unique to the disorder. There is increasing evidence that depression onset during childhood and/or adolescence is associated with alterations in brain structure (Schmaal et al, 2015), greater relapse risk and continuity into adulthood (Garber & Rao, 2014). Given its prolonged maturational trajectory, the UNC may be particularly vulnerable to stressors that have the potential to alter the normal developmental trajectory and contribute to the onset and maintenance of psychopathology.…”

“…Many cases of adult MDD begin in adolescence and risk factors for depression may occur even earlier (Kennard, Emslie, Mayes, & Hughes, 2006;Kovacs & LopezDuran, 2010). Adolescence is marked by continued changes in brain maturation and a rise in depressive symptoms during adolescence has often been associated with these changes (e.g., Davey, Yucel, & Allen, 2008;Foland-Ross et al, 2015;Schmaal et al, 2015).…”

Genetics of the Connectome and the ENIGMA Project

“…In parallel, ENIGMA launched several working groups to identify brain measures that showed the greatest patient vs. control differences in cohorts of patients with schizophrenia (Turner et al 2014;van Erp et al 2015), bipolar illness , depression (Schmaal et al 2014(Schmaal et al , 2015, and ADHD (Hoogman et al 2014). Some of these studies now number 4000-8000 subjects, making them the largest studies ever of their respective disorders.…”