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

Abstract

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.

Hippocampal Atrophy in Major Depression: a Function of Childhood Maltreatment Rather than Diagnosis?

“…First, our finding of reduced hippocampal volumes in depressed patients compared with healthy controls is well in line with numerous imaging studies showing similar effects, including meta-analyses (Arnone et al, 2012a;Cole et al, 2011;MacQueen and Frodl, 2011). Second, the results of our study suggest a strong impact of childhood maltreatment on hippocampal morphometry in both, patients and healthy subjects, with comparable effect sizes in both samples (accounting for B8-9% variance of hippocampal volume), which is also in accordance with several previous studies reporting similar effects and effect sizes (Dannlowski et al, 2012;Edmiston et al, 2011;Teicher et al, 2012) but contradicts a study by Lenze et al (2008) that found childhood adversity to be associated with earlier onset of MDD but not with reduced hippocampal volume.…”

“…In fact, reduced hippocampal volume is probably the most frequently reported finding in neuroimaging studies comparing MDD patients with healthy controls (Cole et al, 2011). Recent meta-analyses underlined this notion, but the debate on its underpinnings prevails (MacQueen and Frodl, 2011). Alterations in this structure have been found to be associated with various clinical and demographic characteristics in patient samples (McKinnon et al, 2009).…”

SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex

“…1,8 The frontal-cortical limbic networks of which the hippocampus is part 9,10 have been shown to underlie the regulation of emotional behaviour, 11,12 with the hippocampus specifically having a role in the dysfunctional cognitive impairments associated with depressive episodes. 13 The hippocampus has previously been shown to be modulated by chronic antidepressant drug action in animals, 14 and thus our results may indicate its importance for also the early effects of SSRIs on the emotional modulation of cognition. Such early effects have also been seen in healthy volunteers after 7 days SSRI treatment.…”

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

“…These observations of the increased immunoreactivity using two distinct markers for each glial cell substantiate both microglial activation and astrocytic activation in the hippocampus of Gunn rats. In this study, we intensively analyzed the hippocampus as the region of interest, based on the evidence that hippocampal dysregulation along with its small volume is strictly associated with major depression and stress (Kino, 2015; MacQueen & Frodl, 2011). Activated microglia and astrocytes may contribute to neuronal cell death in the hippocampus and result in hippocampal atrophy, as the activation of both types of glial cells has been demonstrated to cause neurotoxicity in vitro (Hashioka, Klegeris, & McGeer, 2011, 2012; Hashioka, Klegeris, Schwab, & McGeer, 2009).…”