Objective. So far, there have been no attempts to integrate the growing number of all brain volumetric magnetic resonance imaging studies in depression. In this comprehensive meta-analysis the magnitude and extent of brain volume differences between 2,418 patients with major depressive disor- der and 1,974 healthy individuals from 64 studies was determined. Methods. A systematic research was conducted for volumetric magnetic resonance imaging studies of patients with major depressive disorder in relation to healthy control subjects. Studies had to report sufficient data for computation of effect sizes. For each study, the Cohen's d was calculated. All analyses were performed using the ran- dom effects model. Additionally, meta-regression analyses were done to explore the effects of potential sources of heterogeneity. Results. Patients showed large volume reductions in frontal regions, especially in the anterior cingulate and orbitofrontal cortex with smaller reductions in the prefrontal cortex. The hippocampus, the putamen and caudate nucleus showed moderate volume reductions. Conclusions. This is the first comprehensive meta-analysis in major depressive disorder demonstrating structural brain abnormalities, particularly in those brain areas that are involved in emotion processing and stress-regulation. Hum Brain Mapp 30:3719-3735, 2009. V C 2009 Wiley-Liss, Inc.

Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies

Context Although differences in clinical characteristics exist between major depressive disorder (MDD) and bipolar disorder (BD), consistent structural brain abnormalities that distinguish the disorders have not been identified. Objectives To investigate structural brain changes in MDD using meta-analysis of primary studies; assess the effects of medication, demographic, and clinical variables; and compare the findings with those of a meta-analysis of studies on BD. Data Sources The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1980, to February 2, 2010. Study Selection Two hundred twenty-five studies that used magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with MDD with that of controls were included in an online database, and 143 that measured common brain structures were selected for meta-analysis. Data Extraction Twenty-five variables, including demographic and clinical data, were extracted from each study, when available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and the proportion of patients and controls with an abnormality in brain structure was extracted for categorical variables. Data Synthesis Compared with the structure of a healthy brain, MDD was associated with lateral ventricle enlargement; larger cerebrospinal fluid volume; and smaller volumes of the basal ganglia, thalamus, hippocampus, frontal lobe, orbitofrontal cortex, and gyrus rectus. Patients during depressive episodes had significantly smaller hippocampal volume than patients during remission. Compared with BD patients, those with MDD had reduced rates of deep white matter hyperintensities, increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia. Both disorders were associated with increased lateral ventricle volume and increased rates of subcortical gray matter hyperintensities compared with healthy controls. Conclusions The meta-analyses revealed structural brain abnormalities in MDD that are distinct from those observed in BD. These findings may aid investigators attempting to discriminate mood disorders using structural magnetic resonance imaging data.

Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder

Background
Some, although not all, studies report small hippocampal volume in patients with major depressive disorder (MDD) relative to healthy controls. Here, we explore the contribution of key demographic and clinical variables to this difference.

A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder.

Major depressive disorder (MDD) has until recently been conceptualized as an episodic disorder associated with 'chemical imbalances' but no permanent brain changes. Evidence has emerged in the past decade that MDD is associated with small hippocampal volumes. This paper reviews the clinical and biological correlates of small hippocampal volumes based on literature searches of PubMed and EMBASE and discusses the ways in which these data force a re-conceptualization of MDD. Preclinical data describe the molecular and cellular effects of chronic stress and antidepressant treatment on the hippocampus, providing plausible mechanisms through which MDD might be associated with small hippocampal volumes. Small hippocampal volumes are associated with poor clinical outcome and may be a mechanism through which MDD appears to be a risk factor for Alzheimer's disease. The pathways through which stress may be linked to MDD, the emergence of chronicity or treatment resistance in MDD and the association between MDD and memory problems may be at least partially understood by dissecting the association with depression and changes in the hippocampus. MDD must be re-conceived as a complex illness, associated with persistent morphological brain changes that are detectable before illness onset and which may be modified by clinical and treatment variables.

The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research?

Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies

A number of studies have used magnetic resonance imaging to examine the volumetric differences in temporal lobe structures especially the hippocampus in patients suffering from major depressive disorder (MDD). Although some studies reported lower hippocampal volume, others did not. It is proposed that the inconsistency among studies may be due to the heterogeneity of patients and antidepressant treatment during scanning. In this study, we aimed to evaluate the hippocampus in drug-free patients. Twenty-four patients (6 males and 18 females) diagnosed as having MDD according to the DSM-IV criteria and 24 healthy controls (6 males and 18 females) were included in the study. Eleven of the patients had their first mood episode and were drug-naive. Other patients were drug-free for at least 4 weeks. The Hamilton depression rating scale (HAM-D) assessed the severity of depression. Magnetic resonance imaging was performed on a 1.5-T MR unit. The Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal volume. The data were evaluated by a repeated measure of ANOVA and the intracranial volume was taken as a covariate. A significant hippocampal volume difference was observed between the patients and healthy controls (F=4.43, df=1.45, P 0.05). The left hippocampus of patients was significantly lower than those of controls (t=1.98, df=46, P<0.05). Correlation analysis showed a correlation between HAM-D scores and the right hippocampal volume. The results of this study indicate that hippocampus volume is reduced in depressed patients especially in the left side. This finding in the drug-free depressed outpatients without a history of alcohol dependence supports previous studies that have reported lower hippocampal volume.

Reduced hippocampal volume in drug-free depressed patients.

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Reduced hippocampal volume in drug-free depressed patients.