Hippocampal volume and 2-year outcome in depression

Although the hippocampus has been found to be smaller in peoplewith depression, the clinical relevance of this is unclear.We investigated hippocampal volume (using high-resolution magneticresonance imaging) and 2-year outcome in 57 patients with majordepression. The left and right hippocampal volumes of patientswith a depression relapse were significantly smaller than thoseof healthy controls. Our results support the hypothesis thatthe hippocampus is crucial in the outcome of depression.

INTRODUCTION

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INTRODUCTION

Studies have found abnormalities in hippocampal volumes in patientswith major depression.^1,2 Although the hippocampus has beenfound to be smaller in patients with depression, prospectivelongitudinal studies are necessary to investigate whether asmaller hippocampal volume predicts the course of depression.The only study that investigated the predictive effect in alonger follow-up period reported that patients who had notremitted at the 1-year follow-up investigation showed significantlyreduced left and right hippocampal volumes compared with patientswho had remitted; however, no relapse prediction was done inthis study.³ In recent meta-analysis, gender differences inhippocampal volumes were discussed.¹ The aim of the presentstudy was to examine the relationship between hippocampal volumeand 2-year outcome of depression. The hypothesis was that patientswith recurring depression have smaller hippocampal volumesat the beginning of the study in comparison with patients withstable remission, and healthy controls. Additionally, gendereffects were examined.

Method

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Method

A total of 57 in-patients with DSM–IV major depressiontreated in the Department of Psychiatry of the University inHeidelberg were recruited.⁴ Diagnoses were based on the StructuredClinical Interview for DSM–IV (SCID). The mean age ofthe 33 female and 24 male patients at initial assessment was43.54 years (s.d.=12.82, range 18–64). Twenty-seven (47.37%)were married, 22 (38.6%) had a high and 35 (61.4%) a low levelof school education; 26 (45.61%) patients had a first episodeof major depression whereas 31 (54.39%) had recurrent depression.Mean score on the Hamilton Rating Scale for Depression (HRSD)at admission to treatment was 22.74 (s.d.=6.58). For comparison,30 healthy participants without a history of psychiatric disordersaccording to the SCID were recruited. Patients with major depressiondid not differ significantly from healthy controls regarding age, gender, height, weight, handedness, social class, educationor alcohol consumption.

The main investigations were carried out at the beginning oftreatment, at discharge from hospital as well as 1 and 2 yearsafter discharge. Relapse was defined according to DSM–IVcriteria of major depression. Follow-up criteria of Frank et al⁵ were used in combination with the Longitudinal IntervalFollow-up Evaluation (LIFE).⁶ After a complete descriptionof the study was given to patients and healthy controls, writteninformed consent was obtained. The study protocol was approvedby the local ethics committee and was prepared in accordancewith the Declaration of Helsinki.

Magnetic resonance imaging (MRI) scans of the whole brain wereobtained by using a Siemens 1.5 T magnetic resonance scanner.T₁-weighted three-dimensional magnetisation-prepared rapidgradient echo sequences (3D–MPRAGE) and T₂-weighted imageswere acquired.⁴ Image processing was performed on a computerworkstation using BRAINS (Brain Research: Analysis of Images,Networks, and Systems) software. As part of the segmentationprocedure of BRAINS, intracranial volume and total brain volume were determined semi-automatically. Hippocampal volume wasmeasured by using a reliable and validated method, previouslydescribed in detail.⁷ The hippocampal formation was tracedmanually on the continuous segmented image (stereo image) providedby BRAINS. A detailed description of boundary definition isprovided at http://iowa-mhcrc.psychiatry.uiowa.edu/mhcrc/IPLpages/manual_tracing.htm. The intraclass correlation coefficient (ICC) was 0.97 for theleft hippocampus and 0.98 for the right hippocampus.

Morphometric data were normally distributed. We performed ANOVAswith repeated measurement to examine the relationship betweenbaseline and follow-up variables. The main interaction effectsof the within-participants factor time and the between-participantfactors outcome and gender were assessed by using total cranialvolume and age as the cofactors. Significant interactions wereresolved by univariate ANCOVAs on the hippocampal volumes foreach region and prognostic group, controlling for total cranialvolume and age. Contrasts were performed using the Tukey test.Results were considered statistically significant if at orbelow 5% probability (two-tailed). Analyses were performedwith SAS Version 9.12 for Windows.

Results

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Results

Follow-up data were obtained for all 57 patients. In the follow-upperiod of 2 years, 49 (85.96%) of the 57 patients had remittedfrom index depression: 21 (36.84%) patients suffered a recurrenceafter recovery on average after 47.95 weeks (s.d.=29.13). Becauseof the small number of patients with a chronic course and becausewe do not know whether these patients will recover or haverecurrences in the future, we excluded this group from the analyses.

The hippocampal volumetric data are shown in Table 1. A significantmain effect on hippocampal volume was found for outcome (F=4.93, d.f.=2,71, P=0.01). The main gender effect was not significant (F=3.91, d.f.=1,71, P=0.05), whereas the interaction between outcome and gender was significant (F=3.38, d.f.=2,71, P=0.04).The hemisphere (left–right asymmetry) main effect (F=0.22,d.f.=1,71, P=0.64) and the interaction effect of hemisphereand outcome (F=0.16, d.f.=2,71, P=0.85) were both not significant.The covariates age and intracranial volume were not significanteither. Post hoc univariate ANCOVA revealed that male patientswith a recurrence of depression had significantly smaller left (F=4.91, d.f.=2,24, P=0.02), right (F=4.49, d.f.=2,24, P=0.02)and total (F=5.08, d.f.=2,24, P=0.01) hippocampal volumes thanhealthy male controls. No significant differences of left,right and total hippocampal volumes were found for women. Additionally,there was no significant difference in the total brain volumebetween the groups. Even after controlling for current depression,duration of illness, age at onset, number of episodes, severityof illness and medication using ANCOVA, the differences inhippocampal volumes between the two outcome groups remainedsignificant.

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Table 1 Hippocampal volumes of patients with and without recurrence of depression compared with healthy controls: 2-year follow-up

Discussion
Overall, 37% of patients had a recurrence in the 2-year follow-upperiod, which is in accordance with most follow-up studieson depression. In the present study, it could be shown forthe first time that male patients with a recurrence after recoveryfrom depression had a significantly smaller left and righthippocampal volume in comparison with healthy controls. No significant left–right asymmetry effects for outcome prediction wererevealed. Since no significant differences in total brain volumecould be found between the groups, and intracranial volumeand age were controlled as covariates, the effect of hippocampalvolume change can be regarded as being specific and cannotbe attributed to general brain morphological changes or ageeffects. Thus, we could complement the results of Frodl et al³ who showed a bilateral hippocampal reduction for patientswho had not remitted.

Regarding gender effects, results of past studies are heterogeneous.^1,2 However, it is well known that the hippocampal volume of healthymen is greater than that of healthy women and that it decreasesover the lifespan only in men. Some recent studies found smallerhippocampal volumes more often in men with depression thanin women with depression.⁸ Thus, it can be assumed that hippocampalvolume reduction is a gender-specific factor in the pathophysiologyof depression.

It remains unclear whether smaller hippocampal volumes existbefore the onset of depression or the reductions are the resultof depression or other psychosocial influences. Analysis ofthe prognostic effects of hippocampal volumes is no substitutefor longitudinal structural imaging studies in obtaining moreinformation on the causality of the relationship. Our results strongly point to the clinical relevance of morphological alterationsof the hippocampus by showing that these changes predict relapsein male patients. Moreover, the present findings can also contributeto the reformulation of neuroanatomical models of the pathophysiologyof depression in a more gender-specific conceptualisation.In future studies, the mechanisms behind changes in hippocampalvolume and their relationship to treatment and outcome of depressionshould be addressed.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

Supported by the German Federal Research Ministry within theGerman Research Networks in Medicine promotion as part of theGerman Research Network on Depression project.

REFERENCES

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