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Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD 17 ) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD 17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

Objective: In major depressive disorder (MDD), single nucleotide polymorphisms (SNPs) in monoaminergic genes may impact disease susceptibility, treatment response, and brain volume. The objective of this study was to examine the effect of such polymorphisms on hippocampal volume in patients with treatment-resistant MDD and healthy controls. Candidate gene risk alleles were hypothesised to be associated with reductions in hippocampal volume., Methods: A total of 26 outpatients with treatment-resistant MDD and 27 matched healthy controls underwent magnetic resonance imaging and genotyping for six SNPs in monoaminergic genes [serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), serotonin 1A and 2A receptors (HTR1A and HTR2A), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF)]. Hippocampal volume was estimated using an automated segmentation algorithm (FreeSurfer)., Results: Hippocampal volume did not differ between patients and controls. Within the entire study sample irrespective of diagnosis, C allele-carriers for both the NET-182 T/C [rs2242446] and 5-HT1A-1019C/G [rs6295] polymorphisms had smaller hippocampal volumes relative to other genotypes. For the 5-HTTLPR (rs25531) polymorphism, there was a significant diagnosis by genotype interaction effect on hippocampal volume. Among patients only, homozygosity for the 5-HTTLPR short (S) allele was associated with smaller hippocampal volume. There was no association between the 5-HT2A, COMT, and BDNF SNPs and hippocampal volume., Conclusion: The results indicate that the volume of the hippocampus may be influenced by serotonin- and norepinephrine-related gene polymorphisms. The NET and 5-HT1A polymorphisms appear to have similar effects on hippocampal volume in patients and controls while the 5-HTTLPR polymorphism differentially affects hippocampal volume in the presence of depression.

Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants., (© The Author(s) 2014.)

Electroconvulsive therapy (ECT) is the most potent biological therapy in depression. Animal studies suggest that ECT acts via neuroplasticity effects on limbic structures involved in the pathophysiology of depression but in vivo evidence at the human system level is scarce. Therefore, the aim of the present study was to investigate the effect of ECT on hippocampus and amygdala volume in 15 antidepressant-free patients with treatment refractory depression (seven males, range 42-63 years). ECT treatment was successful as indexed by a significant decrease in depressive symptoms (t14=13.6; p<0.001). Analysis of normalized volumetric data before and after ECT treatment revealed a significant volume increase of both hippocampus and amygdala (minimum p<0.005) with no evidence for a change in global brain volume. Though this change in volume cannot be clearly related to treatment effects, ECT is associated with broader neurotrophic effects other than mere adult neurogenesis in the hippocampus, which has been previously suggested as a core mechanism on the basis of animal data., (© 2013 Published by Elsevier Ireland Ltd.)

Background: A literature review suggested age and cognitive problems to be related to an increased prevalence of small areas of signal variation within the hippocampus observed on MRI, described as hippocampal sulcal cavities (HSCs; (Maller et al., 2011)). The current study aimed to describe the prevalence of HSCs in patients with treatment-resistant depression (TRD) and healthy controls over a large age-range., Methods: 115 TRD patients and 86 controls underwent MRI brain scanning. Right and left HSCs were rated separately for prevalence and length., Results: HSCs were observed in 73.04% of those with TRD, statistically more prevalent (p=0.001) than amongst controls (51.16%). These findings are consistent with our review (66% prevalence in memory disorders and 47% in healthy controls). Furthermore, HSC presence and length was associated with aging., Limitations: The study was cross-sectional so its implications for aging are tentative. A larger sample scanned longitudinally will allow for more sophisticated statistical methods by which to investigate the relationship between HSCs, aging, and TRD., Conclusions: Although their clinical significance remains uncertain, the results of the current study suggest that HSCs are related with age and those with TRD have more aged brains than their peers., (Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.)

Approximately 50% of patients with a major depressive episode fail to achieve remission with first-line antidepressant treatments. Second-line treatment strategies for such patients include lithium augmentation of antidepressants, particularly with tricyclic antidepressants. The neurobiological mechanisms underlying the therapeutic effects of lithium augmentation are not yet fully understood. Unravelling these mechanisms could aid the development of more effective antidepressant drugs. In the present study, we investigated whether chronic treatment with a combination of lithium and the tricyclic antidepressant, desipramine, could produce antidepressant-like behaviour in a mouse strain (BALB/cOLaHsd) that exhibited reduced sensitivity to the behavioural effects of chronic desipramine treatment in the novelty-induced hypophagia test. Since chronic treatment with antidepressant drugs increases the proliferation of newly-born cells in the hippocampus, and hippocampal cell proliferation is required for the behavioural effects of at least some antidepressants in neohypophagia tests, the present study also investigated whether lithium plus desipramine increased cell proliferation in the hippocampus. Chronic treatment with lithium plus desipramine but neither drug alone, induced antidepressant-like behaviour and increased hippocampal cell proliferation, thus suggesting that increased hippocampal cell proliferation may be a mechanism underlying lithium augmentation of antidepressants. Moreover, since BALB/cOLaHsd mice respond to lithium plus desipramine but not to either drug alone, they may become useful in the development of a mouse model of treatment-refractory depression for which there is an unmet need., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Studies of patients with major depressive disorder (MDD) and schizophrenia (SCH) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD, SCH, and healthy subjects, using a strict measurement protocol, to elucidate morphological-specific volumetric differences. Patients with treatment-resistant MDD (N = 182) and treatment-resistant SCH with auditory-verbal hallucinations (N = 52), and healthy controls (N = 76) underwent psychiatric assessments and brain MRI. The findings indicate that (1) MDD and SCH patients have reduced total hippocampal volume which was marked in the tails (more so in patients with MDD), (2) region of interest estimation protocols and sample characteristics may help explain volumetric differences between previous SCH studies., (Copyright © 2010 Wiley Periodicals, Inc., Inc.)

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.