Global hippocampal atrophy in major depressive disorder: a meta-analysis of magnetic resonance imaging studies

Santos, Marcelo Antônio Oliveira; Bezerra, Lucas Soares; Carvalho, Ana Rita Marinho Ribeiro; Brainer-Lima, Alessandra Mertens

doi:10.1590/2237-6089-2017-0130

Abstract

Introduction:

Major depressive disorder (MDD), an incapacitating mental disorder, is characterized by episodes of at least 2 weeks of apparent changes in mood, cognition, and neurovegetative functions. Many neuroimaging studies using magnetic resonance imaging (MRI) have examined morphometric changes in patients with MDD, but the results are not conclusive. This study aims to review the literature and perform a meta-analysis on hippocampal volume (HcV) in patients with MDD.

Methods:

Studies on HcV in patients with MDD diagnosis were identified from major databases (MEDLINE, EMBASE, The Cochrane Library, Scopus, PsycINFO, and SciELO) using the search terms depression, major depressive disorder, MDD, unipolar, magnetic resonance imaging, MRI, and hippocampus.

Results:

A meta-analysis of 29 studies fulfilling specific criteria was performed. The sample included 1327 patients and 1004 healthy participants. The studies were highly heterogeneous with respect to age, sex, age of onset, and average illness duration. However, the pooled effect size of depression was significant in both hippocampi. MDD was associated with right (-0.43; 95% confidence interval [95%CI] −0.66 to −0.21) and left (-0.40; 95%CI −0.66 to −0.15) hippocampal atrophy.

Conclusions:

MDD seems to be associated with global HcV atrophy. Larger longitudinal follow-up studies designed to analyze the influence of sociodemographic variables on this relationship are required to yield better evidence about this topic.

Keywords:
Hippocampal volume; major depressive disorder; MRI; depression

Resumo

Introdução:

O transtorno depressivo maior (TDM) é uma doença mental incapacitante caracterizada por episódios de pelo menos 2 semanas de mudanças claras no afeto, cognição e funções neurovegetativas. Vários estudos de neuroimagem, realizados através de imagem de ressonância magnética (IRM), examinaram mudanças morfométricas em pacientes com TDM, com resultados não conclusivos. Este estudo tem como objetivo revisar a literatura e realizar uma metanálise sobre o volume do hipocampo (VHc) em pacientes com TDM.

Métodos:

Estudos de VHc em pacientes com TDM foram identificados a partir dos principais bancos de dados (MEDLINE, EMBASE, The Cochrane Library, Scopus, PsycINFO e SciELO) usando os seguintes termos: depression, major depressive disorder, MDD, unipolar, magnetic resonance imaging, MRI e hippocampus.

Resultados:

Foi realizada uma metanálise de 29 estudos que preencheram os critérios específicos. A amostra foi composta por 1327 pacientes e 1004 indivíduos saudáveis. Os estudos foram altamente heterogêneos em relação a idade, gênero, idade do primeiro episódio e duração média da doença, mas o efeito combinado da depressão foi significativo em ambos os hipocampos. O TDM foi associado à atrofia do hipocampo à direita [-0,43; intervalo de confiança de 95% (IC95%) −0,66 a −0,21] e à esquerda (-0,40; IC95% −0,66 a −0,15).

Conclusões:

O TDM parece estar associado à atrofia global do VHc. Estudos longitudinais com maior tempo de seguimento, projetados para analisar a influência dos fatores sociodemográficos nessa relação, são necessários para obter evidências mais robustas.

Descritores:
Volume hipocampal; transtorno depressivo maior; RM; depressão

Introduction

Major depressive disorder (MDD) is an incapacitating mental disorder characterized by episodes of at least 2 weeks of apparent changes in affection, cognition, and neurovegetative functions. ¹1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder. 5th ed. Washington: American Psychiatric Publishing; 2013. Patients with MDD present a lower quality of life and higher prevalence of medical conditions. The global prevalence of MDD is approximately 5%. According to the World Health Organization, MDD is estimated to become the second most disabling condition by 2020. ²2. Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90.

Several neurobiological models have been proposed to explain the pathogenesis of MDD. Because MDD is primarily related to lower affection and humor, many authors have studied and emphasized the role of dysfunctional cortico-limbic networks in MDD. ³3. Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183-206. Postmortem and animal model studies have reported lower hippocampal volume (HcV) in participants with depressive disorders. The hippocampus is involved in episodic and declarative memory, as well as in learning, areas that often present deficits in patients with depression. ⁴4. Schwert C, Aschenbrenner S, Weisbrod M, Schröder A. Cognitive impairments in unipolar depression: the impact of rumination. Psychopathology. 2017;50:347-54. The suggestion that HcV is lower because of depression has been influential in guiding neuroimaging studies on the analysis of the hippocampus. ⁵5. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry. 2000;48:766-77.

Many neuroimaging studies using magnetic resonance imaging (MRI) have examined morphometric changes in patients with MDD, but the results are not conclusive. Some studies have reported bilateral, ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13. unilateral right, ⁷7. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. Hippocampal volume in geriatric depression. Biol Psychiatry. 2017;48:301-9. or unilateral left hippocampal hypotrophy in these patients compared with healthy participants, ⁸8. Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117-25.^,⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8. whereas others have reported no changes. ¹⁰10. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2017;47:1087-90.^,¹¹11. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493-8. Furthermore, some systematic reviews and meta-analyses have examined studies on HcV in the first depressive episode or in specific groups, such as the elderly (aged ≥ 60 years) with depression. ⁷7. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. Hippocampal volume in geriatric depression. Biol Psychiatry. 2017;48:301-9.^,¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.^–¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37. However, to date, no reviews have systematically examined the macro influence of depression on HcV.

This study aims to examine whether patients with MDD present hippocampal atrophy compared with non-depressive participants. We considered HcV reduction as the primary outcome.

Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Details of the study protocol were registered on the International Prospective Register of Systematic Reviews (PROSPERO) and can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018086196 .

The electronic databases MEDLINE, EMBASE, The Cochrane Library, Scopus, PsycINFO, and SciELO were searched for papers published between January 1960 and October 2017. The search terminology included the terms depression, major depressive disorder, MDD, unipolar, magnetic resonance imaging, MRI, and hippocampus. Only studies written in English, Portuguese, or Spanish were reviewed. At least two of the authors performed each search. Furthermore, all reference lists of the obtained papers were checked for studies not indexed in electronic databases. The complete search strategy was as follows: Depression; Major depressive disorder; MAJOR DEPRESSIVE DISORDER (MeSH); MDD; (unipolar) AND (depression); Magnetic resonance imaging; MAGNETIC RESONANCE IMAGING (MeSH); MRI; Hippocampus; HIPPOCAMPUS (MeSH); (hippocampal) AND (volume); (1 OR 2 OR 3 OR 4 OR 5) AND (6 OR 7 OR 8) AND (9 OR 10 OR 11).

All observational studies and clinical trials that evaluated the relationship between MDD and HcV measured through MRI were included in this review. Studies with sample groups in which patients presented any other associated neuropsychiatric or metabolic condition were excluded. Inclusion criteria were as follows: patients with a primary diagnosis of MDD assessed using international diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]); a healthy comparison group; participants screened for neurological, psychiatric, and other medical disorders that could affect brain structure, including alcohol and substance abuse; MRI as the primary measurement tool; and a continuous measure of HcV as the dependent variable.

Two authors examined the abstracts of the articles retrieved against the defined inclusion criteria. All potentially relevant full-text articles were retrieved for quality and satisfaction assessment of inclusion criteria. Figure 1 summarizes the study inclusion process.

Figure 1
PRISMA flow diagram for the meta-analysis of hippocampal volume in major depressive disorder. Adapted from Moher et al. ¹⁵15. Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:e1000097.

For each data criterion, a data extraction table was pilot-tested on five randomly-selected studies and adjusted accordingly. Two independent reviewers assessed the following data from the patient and control samples: number of participants, HcV means and standard deviations, and mean disease duration. A third author double-checked the extracted data. Disagreements were resolved by consensus between the authors; if no consensus could be reached, a third author made a decision. All volumes were converted to mm³ before being entered into the meta-analysis.

To certify the quality and validity of the eligible studies, pairs of reviewers working independently assessed each study using the Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) checklist. ¹⁶16. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-9.

Calculations were performed using the STATA software version 13.0 SE. The meta-analyses were performed using a random effects model weighting the studies by the inverse variance and calculating the Hedges' g effect size. The random effects model using the DerSimonian-Laird method was selected over the fixed effects approach because previous analyses have indicated considerable between-study heterogeneity.

To assess for between-study heterogeneity, the Cochran Q test was performed and I² statistic was recorded and further analyzed by meta-regression. Begg's and Egger's tests were used to determine publication bias.

Results

Twenty-nine studies comprising 1327 patients and 1004 healthy participants fulfilled both inclusion and exclusion criteria and were included in this meta-analysis. ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13.^–⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8.^,¹¹11. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493-8.^–¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37.^,¹⁷17. Cole J, Toga AW, Hojatkashani C, Thompson P, Costafreda SG, Cleare AJ, et al. Subregional hippocampal deformations in major depressive disorder. J Affect Disord. 2010;126:272-7.^–³⁷37. Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, et al. Altered hippocampal morphology in unmedicated patients with major depressive illness. ASN Neuro. 2009;1:AN20090026. One study that found lower left HcV was excluded because volume measurements were unavailable. ³⁸38. Shah PJ, Ebmeier KP, Glabus MF, Goodwin GM. Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. Br J Psychiatry. 1998;172:527-32. A report by Andreescu et al. ³⁹39. Andreescu C, Butters MA, Begley A, Rajji T, Wu M, Meltzer CC, et al. Gray matter changes in late life depression –– a structural MRI analysis. Neuropsychopharmacology. 2008;33:2566-72. was also excluded because only global HcV measurements were available. Pantel et al. ⁴⁰40. Pantel J, Schröder J, Essig M, Schad LR, Popp D, Eysenbach K, et al. [Volumetric brain findings in late depression. A study with quantified magnetic resonance tomography]. Nervenarzt. 1998;69:968-74. reported a study in German that was excluded from the analysis because of language limitations.

All studies selected for this review were cross-sectional studies published in English, except one cohort study. ³⁰30. Sawyer K, Corsentino E, Sachs-Ericsson N, Steffens DC. Depression, Hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. Aging Ment Health. 2012;16:753-62. The main inclusion criteria entailed adults (≥18 years). The Hamilton Depression Scale was the main instrument used to assess the severity of depressive symptoms. Mean age of participants in the study groups varied from 16 to 74 years, and the percentage of male participants in each group varied from 0 to 63. The average HcV measured showed slight variations, and two of these measurements markedly deviated from the mean. ⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8.^,¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37. Sample characteristics of the included studies are presented in Table 1 . Some of the studies included patients with recurrent depression, ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13. first-episode depression, ¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.^,¹⁷17. Cole J, Toga AW, Hojatkashani C, Thompson P, Costafreda SG, Cleare AJ, et al. Subregional hippocampal deformations in major depressive disorder. J Affect Disord. 2010;126:272-7.^,²⁶26. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-92. and late-onset depression. ⁷7. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. Hippocampal volume in geriatric depression. Biol Psychiatry. 2017;48:301-9.^,¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.^,²¹21. Janssen J, Pol HEH, de Leeuw F, Schnack HG, Lampe IK, Kok RM, et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J Neurol Neurosurg Psychiatry. 2007;78:638-40. Eight studies evaluated illness duration, which varied from 7 to 57 months. ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13.^,¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.^,¹⁸18. Eker C, Kitis O, Taneli F, Eker OD, Ozan E, Yucel K, et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci. 2010;260:527-33.^,²⁵25. MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med. 2004;2:2.^,²⁷27. Meisenzahl EM, Seifert D, Bottlender R, Teipel S, Zetzsche T, Jäger M, et al. Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study. Eur Arch Psychiatry Clin Neurosci. 2010;260:127-37.^,²⁸28. Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, et al. High-dimensional mapping of the hippocampus in depression. Am J Psychiatry. 2003;160:83-9.^,³³33. van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R, et al. Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry. 2009;65:812-8.^,³⁵35. Xia J, Chen J, Zhou Y, Zhang J, Yang B, Xia L, et al. Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technolog Med Sci. 2004;24:500-2, 506. Table 2 shows a summary of the included studies.

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Table 1
Studies of hippocampal volume in patients with major depressive disorder

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Table 2
Summary of included studies evaluating hippocampal atrophy in MDD

Because the study performed by MacQueen et al. ²⁶26. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-92. analyzed two samples (first-episode versus multiple episodes of depression) that did not overlap, it was considered as having two distinct samples for statistical calculation. Therefore, the degrees of freedom (df), which is typically the number of studies minus 1, was 29 instead of 28.

The Q test of heterogeneity (df = 29) was highly significant, as expected (both right and left hippocampus: p < 0.00001). The percentage of heterogeneity given by the I ²2. Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90. statistic was 84% (95% confidence interval [95%CI] 77.8 to 88.1, p < 0.00001) for the right hippocampus and 88% (95%CI 83.4 to 90.7, p < 0.00001) for the left hippocampus, which provides high evidence of between-study heterogeneity. Therefore, the effect size was calculated under the assumption of a random effects model. The DerSimonian-Laird pooled effect size revealed bilateral statistical significance: −0.43 (95%CI −0.66 to −0.21) for the right hippocampus ( Figure 2 ) and −0.40 (95%CI −0.66 to −0.15) for the left hippocampus ( Figure 3 ).

Figure 2
Standardized mean difference of right hippocampal volume in patients with depression relative to comparison subjects from a meta-analysis of 29 magnetic resonance imaging studies. 95%CI = 95% confidence interval; Std = standard.

Figure 3
Standardized mean difference of left hippocampal volume in patients with depression relative to comparison subjects from a meta-analysis of 29 magnetic resonance imaging studies. 95%CI = 95% confidence interval; Std = standard.

Begg's and Egger's tests were performed and showed no evident signs of publication bias ( Figure 4 ). The meta-analysis was repeated, omitting one study at a time, to ensure that the result was not skewed by a single study. This analysis did not change the random-effects estimate, and the results continued to be statistically significant.

Figure 4
A, B) Begg's funnel plots, and C, D) Egger's funnel plots showing no obvious signs of publication bias for the meta-analysis results.

Because the studies had significant heterogeneity, the data were analyzed using meta-regression. We assumed that differences in age, sex, duration of illness, and year of publication could explain some of the variation. These variables were analyzed separately and together, but were not significantly correlated with the random-effects estimate in either the right or left hippocampus.

Discussion

The studies included in the analysis yielded highly heterogeneous results. Notably, this heterogeneity was expected because there were marked differences among the patient groups with respect to age and sex distribution, type of MDD (e.g., first episode, dysthymia, refractory, late onset), illness duration, age at the first episode, and factors related to treatment. Moreover, an increase in HcV variation was expected considering various protocols for the scanning and delineation of hippocampal structures.

However, a meta-analysis plays an important role in the analysis of scientific evidence because these possible confounding factors are diluted or neutralize each other based on the large number of participants analyzed. Meta-analyses are conducted to determine whether an effect is present, and summarize the data to determine if this effect is positive or negative. This process increases the external validity of the studies as well as the extendibility of results to the general population of patients with MDD.

It is established that HcV losses are expected as a natural process of aging ⁴¹41. Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM, Baumgartner RN, et al. The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex. 2003;13:1344-51. ; however, Sheline et al. ⁴²42. Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034-43. demonstrated that illness duration, not age, predicted hippocampal loss in women with recurrent MDD. Only eight studies included in our analysis presented information about depression duration. However, in the meta-regression, neither illness duration nor age were significantly correlated with the random-effects estimate.

Seven studies failed to find significant HcV differences in patients with depression compared with healthy participants. ¹¹11. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493-8.^,¹⁸18. Eker C, Kitis O, Taneli F, Eker OD, Ozan E, Yucel K, et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci. 2010;260:527-33.^,¹⁹19. Frodl T, Jäger M, Smajstrlova I, Born C, Bottlender R, Palladino T, et al. Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study. J Psychiatry Neurosci. 2008;33:423-30.^,²⁸28. Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, et al. High-dimensional mapping of the hippocampus in depression. Am J Psychiatry. 2003;160:83-9.^,²⁹29. Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol Psychiatry. 2001;50:960-4.^,³²32. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2000;47:1087-90.^,³³33. van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R, et al. Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry. 2009;65:812-8. Six studies demonstrated significant reduction only in the right hippocampus. ⁷7. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. Hippocampal volume in geriatric depression. Biol Psychiatry. 2017;48:301-9.^,²⁰20. Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell P, et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005;186:197-202.^,²¹21. Janssen J, Pol HEH, de Leeuw F, Schnack HG, Lampe IK, Kok RM, et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J Neurol Neurosurg Psychiatry. 2007;78:638-40.^,³⁰30. Sawyer K, Corsentino E, Sachs-Ericsson N, Steffens DC. Depression, Hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. Aging Ment Health. 2012;16:753-62.^,³¹31. Taylor WD, Steffens DC, Payne ME, MacFall JR, Marchuk DA, Svenson IK, et al. Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry. 2005;62:537.^,³⁵35. Xia J, Chen J, Zhou Y, Zhang J, Yang B, Xia L, et al. Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technolog Med Sci. 2004;24:500-2, 506. Six other studies showed similar findings in the lower left hippocampus. ⁸8. Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117-25.^,⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8.^,¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.^,¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.^,³⁶36. Avila R, Ribeiz S, Duran FLS, Arrais JPJ, Moscoso MAA, Bezerra DM, et al. Effect of temporal lobe structure volume on memory in elderly depressed patients. Neurobiol Aging. 2011;32:1857-67.^,³⁷37. Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, et al. Altered hippocampal morphology in unmedicated patients with major depressive illness. ASN Neuro. 2009;1:AN20090026. Bilateral hippocampal atrophy was reported in 10 studies. ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13.^,¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37.^,²²22. Kaymak SU, Demir B, Şentürk S, Tatar I, Aldur MM, Uluğ B. Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders. Eur Arch Psychiatry Clin Neurosci. 2010;260:217-23.^–²⁷27. Meisenzahl EM, Seifert D, Bottlender R, Teipel S, Zetzsche T, Jäger M, et al. Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study. Eur Arch Psychiatry Clin Neurosci. 2010;260:127-37.^,³⁴34. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072-80.

MacQueen et al. ²⁶26. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-92. evaluated one group of patients during their first depressive episode and another during multiple episodes and compared them to healthy matched participants. After the first episode, there were no differences between the depression and comparison groups. However, in the group with multiple depressive episodes, there was bilateral hippocampal atrophy compared with healthy participants.

Vythilingam et al. ³⁴34. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072-80. theorize that HcV is bilaterally reduced in patients with depression who experienced sexual abuse in childhood compared with participants with depression but with no similar experience. Those authors reported 18% smaller volumes for the left hippocampus and 15% smaller ones for the right hippocampus.

According to the results of Vakili et al., ³²32. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2000;47:1087-90. a smaller volume of the right hippocampus was associated with poor responses to antidepressants. This result is incipient, as investigating this association was not the primary objective of the study. However, if confirmed, that finding would be clinically interesting as a potential predictor of treatment response.

The pathophysiological pathways that explain HcV reduction in MDD remain unclear. Some authors theorize that HcV reduction is associated with disturbed hypothalamic pituitary adrenal axis function and adrenal hypersecretion of glucocorticoids, particularly cortisol. According to this hypothesis, cortisol leads to neural atrophy and the inhibition of neurogenesis in the hippocampus. ⁴³43. Sapolsky RM. Depression, antidepressants, and the shrinking hippocampus. Proc Natl Acad Sci U S A. 2001;98:12320-2. Another important supporting mechanism is the glutamate N-methyl-D-aspartate (NMDA) channel present in inhibitory neurons that comprise this pathway. Subiculum neurons make a synapse with a hypothalamic neuron, inhibiting it through NMDA receptors. The hypothalamic neuron modulates the corticotropic cell, stimulating it through gamma-aminobutyric acid (GAMA) liberation, which culminates in the production and release of the adrenocorticotropic hormone (ACTH). Serum cortisol concentration increases as a product of ACTH, released from the adrenal gland. ⁴⁴44. Radley JJ. Toward a limbic cortical inhibitory network: implications for hypothalamic-pituitary-adrenal responses following chronic stress. Front Behav Neurosci. 2012;6:7.^–⁴⁶46. Ardalan M, Wegener G, Rafati AH, Nyengaard JR. S-ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression. Int J Neuropsychopharmacol. 2016;20:247-56.

It is important to address the potential protective properties of selective serotonin reuptake inhibitors (SSRIs) in patients with MDD. As demonstrated by Frodl et al., ¹⁹19. Frodl T, Jäger M, Smajstrlova I, Born C, Bottlender R, Palladino T, et al. Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study. J Psychiatry Neurosci. 2008;33:423-30. after a follow-up of 3 years, patients with MDD who used SSRI antidepressants showed protective effects against hippocampal atrophy as well as an increase in the left HcV. Although this is the only study to demonstrate this association, many studies have indicated that SSRIs reduce functional deficits in inflammatory and ischemic events. ⁴⁷47. Liechti FD, Grandgirard D, Leib SL. The antidepressant fluoxetine protects the hippocampus from brain damage in experimental pneumococcal meningitis. Neuroscience. 2015;297:89-94.

Study limitations

In principle, cross-sectional studies such as those included in the present analysis do not allow conclusions about causality to be drawn.

Further, socioeconomic and lifestyle characteristics from specific population groups can act as confounders. For example, the habit of regular exercise training is a protective factor against hippocampal atrophy and may be responsible for hippocampus hypertrophy in healthy participants. ⁴⁸48. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108:3017-22.

Other factors can also act as confounders, such as the comorbidity of MDD and anxiety disorders, ⁴⁹49. Hirschfeld RMA. The comorbidity of major depression and anxiety disorders: recognition and management in primary care. Prim Care Companion J Clin Psychiatry. 2001;3:244-54. which was not assessed in any of the studies.

Longitudinal follow-up studies with large samples are the best design to allow the drawing of conclusions about the association between hippocampal atrophy and MDD.

Conclusions

Although the studies available in the literature are quite heterogeneous, MDD seems to be associated with global HcV atrophy. Many confounding factors may have influenced the divergence between studies, in particular sociocultural variables, which are responsible for the construction of social identity and affect the way in which stressful and depressive situations may contribute to changes in hippocampal neuronal circuits. Nevertheless, idiosyncratic biological factors may influence neuronal circuitry development and plasticity and play a role in the fine adjustment of hippocampal dynamics.

Larger longitudinal follow-up studies that consider these aspects are needed to yield better evidence about this topic.

This study was conducted at Departamento de Medicina, Centro Universitário Maurício de Nassau, Recife, PE, Brazil.

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Publication Dates

Publication in this collection
17 Sept 2018
Date of issue
Oct-Dec 2018

History

Received
24 Oct 2017
Accepted
06 May 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] This study was conducted at Departamento de Medicina, Centro Universitário Maurício de Nassau, Recife, PE, Brazil.

	Patients with depression					Healthy controls
Author and year	Age	Right volume	Left volume	N	Age	Right volume	Left volume	N
Meisenzhal 2010 ²⁷27. Meisenzahl EM, Seifert D, Bottlender R, Teipel S, Zetzsche T, Jäger M, et al. Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study. Eur Arch Psychiatry Clin Neurosci. 2010;260:127-37.	44 (12.3)	3770 (420)	3670 (410)	92	33.3 (12.2)	3940 (410)	3830 (410)	138
Posener 2003 ²⁸28. Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, et al. High-dimensional mapping of the hippocampus in depression. Am J Psychiatry. 2003;160:83-9.	33 (10.7)	2948.4 (446.7)	2546.00 (392.7)	27	33.2 (10.8)	2993.9 (414.2)	2475 (359.4)	42
Xia 2004 ³⁵35. Xia J, Chen J, Zhou Y, Zhang J, Yang B, Xia L, et al. Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technolog Med Sci. 2004;24:500-2, 506.	39.5 (12)	3487.2 (62.9)	3109.8 (83.5)	22	35.4 (8.8)	3710.3 (36.6)	3352 (43.5)	13
Sheline 1996 ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13.	68.5 (10.4)	2283 (324)	2159 (301)	10	68.5 (9.5)	2577 (259)	2544 (333)	10
MacMaster 2004 ²⁵25. MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med. 2004;2:2.	16.6 (1.8)	2540 (120)	2530 (90)	17	16.2 (1.6)	2880 (110)	3050 (110)	17
Eijndhoven 2009 ³³33. van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R, et al. Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry. 2009;65:812-8.	34.9 (11.5)	3848 (444)	3610 (372.5)	40	37.3 (12.7)	3881 (429)	3716 (364)	20
Saylam 2006 ¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.	33.4 (9.3)	2696.4 (194.4)	2638.7 (249.2)	24	30.1 (6.1)	2806.3 (256.8)	2786.7 (249.2)	24
Eker 2010 ¹⁸18. Eker C, Kitis O, Taneli F, Eker OD, Ozan E, Yucel K, et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci. 2010;260:527-33.	32.1 (9.3)	3310 (420)	3380 (350)	25	29.7 (6.4)	3110 (260)	3330 (300)	22
Vythilingam 2002 ³⁴34. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072-80.	33.5 (7)	2884 (120.5)	3235.5 (111)	32	27 (5)	3037 (134)	3179 (123)	14
MacQueen 2003 ²⁶26. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-92.	28.4 (11.8)	2793 (303.8)	2738 (301.1)	20	28.4 (11.5)	2784 (342.2)	2761 (368.4)	20
	35.9 (11.1)	2392 (256.7)	2381 (273.5)	17	36.2 (11.9)	2692 (190.1)	2703 (249)	17
Kaymak 2010 ²²22. Kaymak SU, Demir B, Şentürk S, Tatar I, Aldur MM, Uluğ B. Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders. Eur Arch Psychiatry Clin Neurosci. 2010;260:217-23.	32 (8.5)	2720 (320)	2850 (330)	20	29.3 (5.8)	3400 (250)	3520 (330)	15
Lange 2004 ²³23. Lange C, Irle E. Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med. 2004;34:1059-64.	34 (10)	2670 (500)	2790 (410)	17	32 (6)	3190 (370)	2990 (460)	17
Bearden 2009 ³⁷37. Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, et al. Altered hippocampal morphology in unmedicated patients with major depressive illness. ASN Neuro. 2009;1:AN20090026.	32.9 (11.9)	1911.1 (280.1)	1885.4 (230.8)	31	36.7 (10.7)	1828.9 (284.2)	1851.9 (326.8)	31
Rusch 2001 ²⁹29. Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol Psychiatry. 2001;50:960-4.	33.2 (9.5)	2290 (300)	2170 (260)	25	37.4 (14.4)	2200 (240)	2130 (270)	15
Vakili 2000 ¹⁰10. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2017;47:1087-90.	38.5 (10)	2610 (580)	2640 (550)	38	40.3 (10.4)	2600 (510)	2460 (380)	20
Mervaala 2000 ⁸8. Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117-25.	42.2 (12.2)	3462 (405)	3104 (391)	34	42.1 (14.6)	3700 (467)	3441 (436)	17
Cole 2010 ¹⁷17. Cole J, Toga AW, Hojatkashani C, Thompson P, Costafreda SG, Cleare AJ, et al. Subregional hippocampal deformations in major depressive disorder. J Affect Disord. 2010;126:272-7.	41.9 (8.9)	1860 (220)	1770 (260)	37	42.2 (9)	2080 (280)	1980 (290)	37
Bremner 2000 ⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8.	43 (8)	982 (269)	940 (208)	16	45 (10)	1113 (194)	1166 (248)	16
Frodl 2008 ¹⁹19. Frodl T, Jäger M, Smajstrlova I, Born C, Bottlender R, Palladino T, et al. Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study. J Psychiatry Neurosci. 2008;33:423-30.	45 (11.1)	3850 (330)	3780 (380)	30	46.3 (13.1)	3830 (420)	3760 (400)	30
Hickie 2005 ²⁰20. Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell P, et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005;186:197-202.	53.5 (13.5)	3000 (400)	2900 (400)	66	55.8 (10)	3300 (600)	3300 (500)	20
von Gunten 2000 ¹¹11. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493-8.	57.6 (13.9)	2597.9 (244)	2498.6 (294.8)	14	58.1 (11.4)	2699.5 (312.7)	2644.4 (409.9)	14
Janssen 2004 ²¹21. Janssen J, Pol HEH, de Leeuw F, Schnack HG, Lampe IK, Kok RM, et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J Neurol Neurosurg Psychiatry. 2007;78:638-40.	64 (10.9)	2840 (390)	3100 (370)	28	62.37 (11.3)	3120 (450)	3200 (520)	41
Steffens 2000 ¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.	71.4 (8.4)	3300 (440)	3170 (440)	66	67.1 (5)	2980 (390)	2920 (360)	18
Zhao 2008 ¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.	66 (5.5)	3660 (560)	3435 (550)	61	69 (5.5)	3720 (590)	3510 (620)	43
Taylor 2005 ³¹31. Taylor WD, Steffens DC, Payne ME, MacFall JR, Marchuk DA, Svenson IK, et al. Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry. 2005;62:537.	70 (7.3)	3090 (420)	2950 (430)	135	69.4 (6.3)	3120 (440)	2960 (450)	83
Avila 2011 ³⁶36. Avila R, Ribeiz S, Duran FLS, Arrais JPJ, Moscoso MAA, Bezerra DM, et al. Effect of temporal lobe structure volume on memory in elderly depressed patients. Neurobiol Aging. 2011;32:1857-67.	70 (6.67)	3099.3 (489.9)	3439.7 (405.3)	48	70.2 (7.2)	3099.8 (271.6)	3446.5 (334.2)	31
Ballmaier 2008 ¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37.	71.1 (7.6)	1127.5 (231.1)	1116.1 (222)	46	72.3 (6.9)	1308.4 (245.6)	1272.7 (275.6)	34
Lloyd 2004 ²⁴24. Lloyd AJ, Ferrier IN, Barber R, Gholkar A, Young AH, O'Brien JT. Hippocampal volume change in depression: late- and early-onset illness compared. Br J Psychiatry. 2004;184:488-95.	74 (6.3)	2800 (500)	2700 (400)	51	73.1 (6.7)	3000 (400)	2800 (400)	39
Sawyer 2013 ³⁰30. Sawyer K, Corsentino E, Sachs-Ericsson N, Steffens DC. Depression, Hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. Aging Ment Health. 2012;16:753-62.	70 (7.5)	3070 (420)	2930 (410)	238	70,4 (6.2)	3110 (430)	2950 (420)	146

Study	MRI tracing method	Condition	Follow-up	Hippocampal atrophy	Symptom assessment	Females in the sample (%)
Meisenzhal 2010 ²⁷27. Meisenzahl EM, Seifert D, Bottlender R, Teipel S, Zetzsche T, Jäger M, et al. Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study. Eur Arch Psychiatry Clin Neurosci. 2010;260:127-37.	Software	FE, RMD	No	Bilateral	HAM-D	58.3
Posener 2003 ²⁸28. Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, et al. High-dimensional mapping of the hippocampus in depression. Am J Psychiatry. 2003;160:83-9.	Manual	MDD	No	No	HAM-D, CGI	55.8
Xia 2004 ³⁵35. Xia J, Chen J, Zhou Y, Zhang J, Yang B, Xia L, et al. Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technolog Med Sci. 2004;24:500-2, 506.	Manual	MDD	No	Bilateral	HAM-D	51.4
Sheline 1996 ⁶6. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93:3908-13.	Manual	RMD	No	Bilateral	HAM-D	100.0
MacMaster 2004 ²⁵25. MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med. 2004;2:2.	Semi-auto	MDD	No	Bilateral	CDRS	52.9
Eijndhoven 2009 ³³33. van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R, et al. Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry. 2009;65:812-8.	Software	FE	No	No	HAM-D	50.0
Saylam 2006 ¹²12. Saylam C, Üçerler H, Kitiş Ö, Ozand E, Gönül AS. Reduced hippocampal volume in drug-free depressed patients. Surg Radiol Anat. 2006;28:82-7.	Manual	DF MDD	No	Left	HAM-D	75.0
Eker 2010 ¹⁸18. Eker C, Kitis O, Taneli F, Eker OD, Ozan E, Yucel K, et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci. 2010;260:527-33.	Software	FE	No	No	HAM-D	74.4
Vythilingam 2002 ³⁴34. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159:2072-80.	Manual	MDD	No	Left	HAM-D, ZDS	100.0
MacQueen 2003 ²⁶26. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-92.	Manual	FE, RMD	No	Bilateral	HAM-D, CGI, BDI-II	51.9
Kaymak 2010 ²²22. Kaymak SU, Demir B, Şentürk S, Tatar I, Aldur MM, Uluğ B. Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders. Eur Arch Psychiatry Clin Neurosci. 2010;260:217-23.	Software	MDD	No	Bilateral	HAM-D	100.0
Lange 2004 ²³23. Lange C, Irle E. Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med. 2004;34:1059-64.	Not clear	MDD	No	Not clear	HAM-D, BDI-II	100.0
Bearden 2009 ³⁷37. Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, et al. Altered hippocampal morphology in unmedicated patients with major depressive illness. ASN Neuro. 2009;1:AN20090026.	Manual	MDD	No	Left	HAM-D	77.0
Rusch 2001 ²⁹29. Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol Psychiatry. 2001;50:960-4.	Software	MDD	No	No	HAM-D	57.5
Vakili 2000 ¹⁰10. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2017;47:1087-90.	Manual	MDD	No	No	HAM-D	55.3
Mervaala 2000 ⁸8. Mervaala E, Föhr J, Könönen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med. 2000;30:117-25.	Manual	DR MDD	No	Left	HAM-D	56.9
Cole 2010 ¹⁷17. Cole J, Toga AW, Hojatkashani C, Thompson P, Costafreda SG, Cleare AJ, et al. Subregional hippocampal deformations in major depressive disorder. J Affect Disord. 2010;126:272-7.	Software	MDD	No	Bilateral	HAM-D	75.7
Bremner 2000 ⁹9. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157:115-8.	Not clear	MDD	No	Left	Not Clear	37.5
Frodl 2008 ¹⁹19. Frodl T, Jäger M, Smajstrlova I, Born C, Bottlender R, Palladino T, et al. Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study. J Psychiatry Neurosci. 2008;33:423-30.	Software	MDD	3 years	Left increase ^* * Left hippocampal volume increased after a 3-year follow-up in use of antidepressants.	HAM-D	66.0
Hickie 2005 ²⁰20. Hickie I, Naismith S, Ward PB, Turner K, Scott E, Mitchell P, et al. Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression. Br J Psychiatry. 2005;186:197-202.	Manual	LOS, EOS	No	Bilateral	HAM-D	64.0
von Gunten 2000 ¹¹11. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci. 2000;12:493-8.	Manual	MDD	No	No	HADS	57.1
Janssen 2004 ²¹21. Janssen J, Pol HEH, de Leeuw F, Schnack HG, Lampe IK, Kok RM, et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J Neurol Neurosurg Psychiatry. 2007;78:638-40.	Software	MDD	No	Right	MADRS	100.0
Steffens 2000 ¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.	Software	GD	No	Right	CESD, DDES	71.4
Zhao 2008 ¹³13. Zhao Z, Taylor WD, Styner M, Steffens DC, Krishnan KRR, MacFall JR. Hippocampus shape analysis and late-life depression. PLoS One. 2008;3:e1837.	Software	MDD	No	No	MADRS	53.7
Taylor 2005 ³¹31. Taylor WD, Steffens DC, Payne ME, MacFall JR, Marchuk DA, Svenson IK, et al. Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression. Arch Gen Psychiatry. 2005;62:537.	Software	LOS, EOS	No	Right	DDES	70.6
Avila 2011 ³⁶36. Avila R, Ribeiz S, Duran FLS, Arrais JPJ, Moscoso MAA, Bezerra DM, et al. Effect of temporal lobe structure volume on memory in elderly depressed patients. Neurobiol Aging. 2011;32:1857-67.	Manual	LOS, EOS	No	Left	MADRS, HAM-D	72.2
Ballmaier 2008 ¹⁴14. Ballmaier M, Narr KL, Toga AW, Elderkin-Thompson V, Thompson PM, Hamilton L, et al. Hippocampal morphology and sistinguishing late-onset from early-onset elderly depression. Am J Psychiatry. 2008;165:229-37.	Manual	LOS, EOS	No	Bilateral	HAM-D	66.3
Lloyd 2004 ²⁴24. Lloyd AJ, Ferrier IN, Barber R, Gholkar A, Young AH, O'Brien JT. Hippocampal volume change in depression: late- and early-onset illness compared. Br J Psychiatry. 2004;184:488-95.	Software	LOS, EOS	No	Bilateral	MADRS, GDS	75.0
Sawyer 2013 ³⁰30. Sawyer K, Corsentino E, Sachs-Ericsson N, Steffens DC. Depression, Hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. Aging Ment Health. 2012;16:753-62.	Software	MDD	10 years COHORT	Right	DDES, CESD	69.0

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