Late-Life Depression, Hippocampal Volumes, and Hypothalamic-Pituitary-Adrenal Axis Regulation: A Systematic Review and Meta-analysis

BACKGROUND: We systematically reviewed and meta-analyzed the association of late-life depression (LLD) with hippocampal volume (HCV) and total brain volume (TBV), and of cortisol levels with HCV, including subgroup analyses of depression characteristics and methodological aspects. METHODS: We searched PubMed and Embase for original studies that examined the cross-sectional relationship between LLD and HCV or TBV, and 46 studies fulfilled the inclusion criteria. Standardized mean differences (Hedges' g) between LLD and control subjects were calculated from crude or adjusted brain volumes using random effects. Standardized Fisher transformations of the correlations between cortisol levels and HCVs were calculated using random effects. RESULTS: We included 2702 LLD patients and 11,165 control subjects from 35 studies examining HCV. Relative to control subjects, patients had significantly smaller HCVs (standardized mean difference = -0.32 [95% confidence interval, -0.44 to -0.19]). Subgroup analyses showed that late-onset depression was more strongly associated with HCV than early-onset depression. In addition, effect sizes were larger for case-control studies, studies with lower quality, and studies with small sample size, and were almost absent in cohort studies and studies with larger sample sizes. For TBV, 2523 patients and 7880 control subjects from 31 studies were included. The standardized mean difference in TBV between LLD and control subjects was -0.10 (95% confidence interval, -0.16 to -0.04). Of the 12 studies included, higher levels of cortisol were associated with smaller HCV (correlation = -0.11 [95% confidence interval, -0.18 to -0.04]). CONCLUSIONS: While an overall measure of LLD may be associated with smaller HCVs, differentiating clinical aspects of LLD and examining methodological issues show that this relationship is not straightforward.