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Mol Psychiatry. Author manuscript; available in PMC 2009 September 8.

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Published in final edited form as:
Mol Psychiatry. 2008 November ; 13(11): 993–1000. doi:10.1038/mp.2008.57.

Amygdala volume in Major Depressive Disorder: A meta-analysis
of magnetic resonance imaging studies
J. Paul Hamilton, Ph.D.,
Department ofPsychology, Stanford University, Stanford, CA 94305, USA
Matthias Siemer, Ph.D., and
Department of Psychology, University of Miami, Coral Gables, FL 33146, USA
Ian H. Gotlib, Ph.D.
Department of Psychology, Stanford University, Stanford, CA 94305, USA

Abstract
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Major Depressive Disorder has been associated with volumetric abnormality in theamygdala. In this
meta-analysis we examine results from magnetic resonance imaging volumetry studies of the
amygdala in depression in order to assess both the nature of the relationship between depression and
amygdala volume as well as the influence of extra-experimental factors that may account for
significant variability in reported findings. We searched PubMed and ISI Web of Knowledgedatabases for articles published from 1985 to 2008 that used the wildcard terms “Depress*” and
“Amygdal*” in the title, keywords, or abstract. From the 13 studies that met inclusion criteria for
our meta-analysis, we calculated aggregate effect size and heterogeneity estimates from amygdala
volumetric data; we then used meta-regression to determine whether variability in specific extraexperimentalfactors accounted for variability in findings. The lack of a reliable difference in
amygdala volume between depressed and never-depressed individuals was accounted for by a
positive correlation between amygdala volume differences and the proportion of medicated depressed
persons in study samples: whereas the aggregate effect size calculated from studies that included
only medicated individualsindicated that amygdala volume was significantly increased in depressed
relative to healthy persons, studies with only unmedicated depressed individuals showed a reliable
decrease in amygdala volume in depression. These findings are consistent with a formulation in
which an antidepressant-mediated increase in levels of brain derived neurotrophic factor promotes
neurogenesis and protectsagainst glucocorticoid toxicity in the amygdala in medicated but not in
unmedicated depression.

Keywords
major depressive disorder; SSRI; SNRI; MRI volumetry; antidepressant; neurogenesis; BDNF;
glucocorticoid; neurotoxicity

Introduction
Major Depressive Disorder (MDD) is characterized by a constellation of emotional and
behavioral symptoms, and requires sustained sad mood or significantlydiminished enjoyment
of daily activities to yield a DSM-IV diagnosis of depression (1). Given that depression is, in
important ways, a disorder of affective expression, experience, and regulation, attempts to
Correspondence regarding this manuscript should be addressed to: J. Paul Hamilton, Ph.D., email: paul.hamilton@stanford.edu, phone:
650-725-2458, fax: 650-725-5699.

Hamilton et al.Page 2

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understand the neural substrates of this disorder have focused primarily on structures
implicated in the experience of emotion and the processing of affective information and stimuli
(e.g., 2,3). Although anomalies in the structure and function of a number of limbic and
paralimbic structures have been found to be associated with depression — most reliablythe
dorsolateral and ventral prefrontal cortex, hippocampus, and amygdala — the amygdala, a
structure crucial to the perception of and memory for emotional material (e.g., 4,5–7), has,
arguably, been the focus of the most extensive theoretical and empirical examination.
Studies using functional neuroimaging have found both elevated baseline activity in the
amygdala (e.g., 8) and heightened...