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

Schmaal L1, Veltman DJ1, van Erp TG2, Sämann PG3, Frodl T4,5, Jahanshad N6, Loehrer E7, Tiemeier H7,8, Hofman A7, Niessen WJ9,10, Vernooij MW7,9, Ikram MA7,9,11, Wittfeld K12, Grabe HJ12,13,14, Block A13, Hegenscheid K15, Völzke H16, Hoehn D3, Czisch M3, Lagopoulos J17, Hatton SN17, Hickie IB17, Goya-Maldonado R18, Krämer B18, Gruber O18, Couvy-Duchesne B19,20,21, Rentería ME22, Strike LT19,20,21, Mills NT22,23, de Zubicaray GI20, McMahon KL21, Medland SE24, Martin NG22, Gillespie NA25, Wright MJ19, Hall GB26, MacQueen GM27, Frey EM4, Carballedo A28, van Velzen LS1, van Tol MJ29, van der Wee NJ30,31, Veer IM32, Walter H32, Schnell K33, Schramm E34, Normann C34, Schoepf D35, Konrad C36, Zurowski B37, Nickson T38, McIntosh AM38,39, Papmeyer M38, Whalley HC38, Sussmann JE38, Godlewska BR40, Cowen PJ40, Fischer FH41,42, Rose M41,43, Penninx BW1, Thompson PM6, Hibar DP6.

Author information


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.

PMID: 26122586

Since the introduction of magnetic resonance imaging (MRI) in the 1980’s and functional MRI (fMRI) in the 1990’s in the field of psychiatry, many studies across the world have examined abnormalities in brain structure and function associated with depression. These studies have provided many valuable insights, such as the finding of lower gray matter volumes, on average, in various regions of the depressed brain. For example, one of the most consistent findings to date is a lower hippocampal volume in individuals who meet the criteria for a Major Depressive Disorder (MDD) diagnosis compared to individuals who never experienced depression. However, for other brain regions, results are less consistent. Some studies show decreases in volumes of regions such as the amygdala1-3, while others find no differences in these structures or even increases in volume4.  These inconsistencies can be due to small sample sizes, heterogeneity in methods for acquiring, processing and analyzing the MRI data and differences across samples in clinical characteristics. A clear picture of the pattern of brain abnormalities in MDD is still lacking.


Therefore, three years ago we initiated the Major Depressive Disorder (MDD) working group within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. The ENIGMA consortium is a global alliance of over 700 scientists from over 300 institutions in 35 countries to study brain imaging data worldwide, discovering factors that modulate brain structure, integrity, connectivity, and patterns of brain differences in major brain diseases5.


The aim of the MDD working group within the ENIGMA consortium is to increase statistical power to further elucidate brain abnormalities associated with depression. At this point in time (September 2016), researchers across the world have shared neuroimaging and clinical data from 31 research samples from 14 different countries (Figure 1) and we are continuously welcoming new sites to join.

Figure 1: Overview of research institutes participating in the ENIGMA-Major Depressive Disorder (MDD) Working Group in September 2016, displayed on a world map.


For our first project within ENIGMA MDD we aimed to answer the question: which brain areas that lie deeper in the brain – the so-called subcortical brain regions – show a difference in volume, on average, in individuals with an MDD diagnosis compared to control subjects? This first project was recently published in Molecular Psychiatry and included 3D brain MRI data from 1,728 MDD patients and 7,199 controls from 15 research samples. This study examined the largest sample of MRI data from MDD patients and controls to date and allowed us to identify brain regions that show differences in volume that are robustly associated with depression across many different research samples worldwide.


For this first project, instead of pooling all of the raw MRI data, we used a meta-analysis approach. Using this approach we could include the data from all samples, as not all sites meet legal and ethical requirements to share individual subject data. This means that each participating site processed their structural MRI scans locally. However, in contrast to retrospective meta-analyses that summarize results reported from the existing literature, we provided sites with standardized protocols to segment the MRI scans and perform quality checks. In addition, each site analyzed their data according to harmonized analysis scripts with a priori defined statistical models. We then meta-analyzed the results of all sites at a central site. The advantage of this so-called individual participant data (IPD) based meta-analysis is that it ensures low methodological heterogeneity across sites and is less affected by publication bias.


Only the hippocampus was found to be smaller, on average, in MDD patients compared to controls (Figure 2). Unlike many smaller studies, we found no consistent subcortical brain alterations beyond the hippocampus – even the smaller hippocampus was observed only in specific patient subgroups. A smaller hippocampus was observed in patients with recurrent MDD, so multiple episodes of depression, compared to controls, but we did not see a reduction in hippocampal volume in first episode patients. In addition, patients with an age of onset of depression before or at the age of 21 had a smaller hippocampus and a trend towards smaller amygdala and larger lateral ventricles, but no structural abnormalities were shown in patients who had their first depressive episode after the age of 21.

Our study revealed the profile of subcortical volume alterations in MDD, and some factors that affect it. Of note, the effect size for the smaller hippocampus in MDD patients was small – with a Cohen’s between -0.14 and -0.21. However, our finding is robust: the hippocampus was consistently smaller, on average, across a large number of samples encompassing the broad heterogeneity of MDD. This included patients residing in the community or primary care and patients recruited from specialized mental health services – and many of them had more severe and recurrent MDD. In addition, a smaller hippocampus has been associated with executive function impairments6, learning and memory deficits7, and poorer treatment response8 in MDD, so the hippocampal volume reduction is important despite its small effect size. It is important to note however, that the effects of depression on the brain may be reversible. Studies in rodents have shown that stress-induced hippocampal changes may be reversed by serotonin reuptake inhibitors through enhanced neurogenesis and dendritic plasticity9, and similar mechanisms are have been identified in post-mortem human hippocampus10.


Additional research is needed to track hippocampal volume changes over the disease course and to further elucidate whether hippocampal abnormalities result from prolonged duration of chronic stress associated with depression, represent a vulnerability factor for MDD, or both. Within ENIGMA MDD, we are currently investigating the volumes and shape of individual subregions within the hippocampus, which are each responsible for different cognitive functions11, and their relation with depression.


Our work within the ENIGMA MDD consortium is ongoing and we recently reported the results of our second ENIGMA MDD project in Molecular Psychiatry12 showing abnormalities in thickness and surface area of cortical regions in MDD. Moreover, new projects are currently ongoing or on the way, investigating the role of childhood maltreatment, suicidal thoughts and insomnia on brain abnormalities in MDD, and examining dynamic associations between depression and brain structure across different stages of brain maturation and aging, and different stages of disease. Finally, recently initiated projects also include other neuroimaging modalities such as diffusion tensor imaging (DTI) scans, to assess abnormalities in white matter tracts connecting the subcortical and cortical regions.



  1. van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R et al. Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry 2009; 65(9): 812-818.
  2. Frodl T, Meisenzahl E, Zetzsche T, Bottlender R, Born C, Groll C et al. Enlargement of the Amygdala in Patients with a First Episode of Major Depression. Biol Psychiatry 2002; 51(9): 708-14.
  3. Hamilton JP, Siemer M, Gotlib IH. Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Mol Psychiatry 2008; 13(11): 993-1000.
  4. Kronenberg G, Tebartz van Elst L, Regen F, Deuschle M, Heuser I, Colla M et al. Reduced amygdala volume in newly admitted psychiatric in-patients with unipolar major depression. J Psychiatr Res 2009; 43(13): 1112-1117.
  5. Thompson PM, Andreassen OA, Arias-Vasquez A, Bearden CE, Boedhoe PS, Brouwer RM et al. ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide. Neuroimage 2015; doi: 10.1016/j.neuroimage.2015.11.057. [Epub ahead of print].
  6. Frodl T, Schaub A, Banac S, Charypar M, Jäger M, Kümmler P et al. Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psychiatry Neurosci 2006; 31(5): 316-323.
  7. Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell P et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry 2005; 186: 197-202.
  8. MacQueen GM. Magnetic resonance imaging and prediction of outcome in patients with major depressive disorder. J Psychiatry Neurosci 2009; 34(5): 343-349.
  9. Morais M, Santos PA, Mateus-Pinheiro A, Patrício P, Pinto L, Sousa N, et al. The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition. J Psychopharmacol 2014; 28(12): 1178-83.
  10. Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ, et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 2012; 72(7): 562-71.
  11. Kesner RP, Lee I, Gilbert P. A behavioral assessment of hippocampal function based on a subregional analysis. Rev Neurosci 2004; 15(5): 333-51.
  12. Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry 2016; doi: 10.1038/mp.2016.60. [Epub ahead of print]