Compared to the general population, patients with major depressive disorder (MDD) have volumetric differences in the hippocampus and other brain structures associated with exposure to stressful experiences, according to a study in Human Brain Mapping. In this study, differences in structure thickness and surface area were also observed between patients with first-episode MDD and those with recurrent MDD.

Meta-analytic models were applied on effect sizes from 10 study cohorts that participated in the international ENIGMA consortium’s MDD Working Group. Anatomical T1-weighted MRI brain scans were collected by all sites who participated in the consortium. Individual measures of shape metrics, including thickness and surface area, on 7 bilateral subcortical structures were compared between patients with MDD (n=1781) and healthy controls (n=2953). Structures assessed in this study included the amygdala, caudate, hippocampus, nucleus accumbens, pallidum, putamen, and thalamus. Each site performed harmonized data processing and statistical analyses. Findings from these analyses were pooled into a meta-analysis.

Patients with MDD were categorized as those with earlier or adolescent onset MDD (first episode ≥21 years of age) and those with later or adult onset MDD (first episode after 21 years of age). Recurrent-episode MDD was defined as >1 major depressive episode. Compared to healthy controls, patients with early or adolescent onset MDD exhibited lower thickness of the cornu ammonis (CA) 1 of the hippocampus (Cohen d, −0.172; percent affected, 4.51%; I2, 1.41) and basolateral amygdala (Cohen d, −0.164; percent affected, 4.23%; I2, 0.04).

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Additionally, patients with early onset MDD exhibited lower surface area of the CA 1 of the hippocampus (Cohen d, −0.180; percent affected, 22.52%; I2, 2.79) and amygdala (Cohen d, −0.168; percent affected, 6.01%; I2, 1.36) compared to healthy controls. Compared to first-episode MDD, patients with recurrent MDD had lower thickness of the CA1 of the hippocampus (Cohen d, −0.173; percent affected, 1.61%; I2, 6.27) and the basolateral amygdala (Cohen d, −0.174; percent affected, 3.45%; I2, 7.21), as well as lower surface area in the CA1 of the hippocampus (Cohen d, −0.174; percent affected, 1.94%; I2, 0.47) and the basolateral amygdala (Cohen d, −0.183; percent affected, 0.52%; I2, 0).

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Limitations of the study included the lack of harmonization for data collection across samples as well as the use of an automated segmentation tool, which the researchers suggest may have overestimated the size of the subcortical and cortical structures.

The investigators wrote in their conclusion that examination of nuances in subcortical shape and volume may “provide the ability to detect fine-grained changes that show promise in the context of monitoring intervention targets with more specificity.”

Disclosure: Multiple study authors reported financial relationships with pharmaceutical entities. See paper for a full list.


Ho TC, Gutman B, Pozzi E, et al. Subcortical shape alterations in major depressive disorder: findings from the ENIGMA major depressive disorder working group [published online March 21, 2020]. Hum Brain Mapp. doi: 10.1002/hbm.24988.