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Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies
Journal of Affective Disorders 134 (2011) 483–487
Contents lists available at ScienceDirect
Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Brief report
Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies James Cole, Sergi G. Costafreda ⁎, Peter McGuffin, Cynthia H.Y. Fu Institute of Psychiatry, King's College London, London, UK
a r t i c l e
i n f o
Article history: Received 28 March 2011 Received in revised form 30 May 2011 Accepted 30 May 2011 Available online 13 July 2011 Keywords: Depression Structural magnetic resonance imaging Hippocampus Meta-analysis
a b s t r a c t Background: Reduced hippocampal volume has been consistently observed in major depressive disorder. Hippocampal volume loss is particularly evident in patients with recurrent and chronic depression. However, the reports in first episode depression have been mixed. Methods: We performed a random effects meta-analysis to establish whether hippocampal atrophy exists from disease onset. We included magnetic resonance imaging studies of hippocampal volume in patients with first episode major depressive disorder and matched healthy controls. Results: A total of 7 studies met our inclusion and exclusion criteria, representing independent observations in a total sample of 191 patients and 282 healthy controls. The cumulative analysis revealed hippocampal volume loss in patients with first episode depression relative to controls in both the left (standardised mean difference, SMD = −0.41, 95% Confidence Interval: [− 0.78;−0.03], z = − 2.14, p = 0.0321) and right (SMD = − 0.53[− 0.98;−0.09], z = − 2.38, p = 0.0173) hippocampi. The average volume reduction was − 4.0% in the left and − 4.5% in the right hippocampus. Conclusions: Hippocampal volume loss in first episode depression is consistent with a neurodevelopmental model of depression, advocating hippocampal structure as a potential diagnostic neurobiomarker for depression. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Initial reports of hippocampal volume in depression suffered from limited resolution of early neuroimaging methods leading to poor separation of the hippocampus and adjacent structures (reviewed in: Fu et al., 2003). More recent meta-analyses have convincingly established that reduced hippocampal volume is a neurobiological feature of major depressive disorder, particularly in illnesses characterised by recurrent episodes and in chronic depression (Campbell and MacQueen, 2004; McKinnon et al., 2009; Videbech and
⁎ Corresponding author at: Institute of Psychiatry, King's College London De Crespigny Park, PO Box 68, London SE5 8AF, UK. Tel.: + 44 203 228 3052; fax: + 44 203 228 2016. E-mail address: [email protected] (S.G. Costafreda). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.05.057
Ravnkilde, 2004). However, the stage at which hippocampal atrophy begins in depression is unclear. In first episode depression, the evidence has been equivocal, with some studies observing decreased hippocampal volume (Cole et al., 2010; Frodl et al., 2002), while others have reported no significant difference (Eker et al., 2010; Kronmüller et al., 2009). The presence of hippocampal atrophy from disease onset would have significant etiological and clinical implications as it would support a model of depression in which structural abnormalities appear earlier than previously believed with potentially deleterious effects on clinical outcome and response to antidepressant therapy (MacQueen and Frodl, 2010). In the present study, we sought to establish whether hippocampal atrophy exists from disease onset. We performed a random effects meta-analysis of magnetic resonance imaging studies of hippocampal volume in first episode depression.
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2. Methods 2.1. Literature search MEDLINE, EMBASE, Scopus and PsychINFO electronic databases were queried with the following search terms: “depression”, “major depressive disorder”, “magnetic resonance imaging”, “hippocampus”, and abbreviations “MDD”, “MRI”, “unipolar” for papers published between January 1990 and February 2011. References from the retrieved papers and reviews of hippocampal and regional brain volumes in major depressive disorder (MDD) were also inspected for relevant articles. Inclusion criteria were: 1) patients with a primary diagnosis of first-episode major depressive disorder (MDD) assessed using international diagnostic criteria; 2) a healthy comparison group; 3) clinical samples were comprised of patients with first and/or recurrent MDD; 4) participants were screened for neurological and medical disorders that could affect brain structure, including alcohol and substance abuse; 5) magnetic resonance imaging (MRI) was the primary measurement tool; 6) a continuous measure of hippocampal volume as the dependent variable; 7) distinct measures of the hippocampus, rather than combined measures with adjacent regions such as the amygdala. In samples from which more than one publication from the same research group and overlaps between samples were not explicitly described, authors were contacted to establish whether these samples could be considered independent. In cases in which an overlap was established, the most extensive sample was included. If papers did not report sufficient data, but satisfied all other inclusion criteria, requests for the requisite data were made. The literature search identified 8 published research reports meeting inclusion and exclusion criteria (Cole et al., 2010; Eker et al., 2010; Frodl et al., 2002; Kaymak et al., 2010; Kronmüller et al., 2009; MacQueen et al., 2003; Meisenzahl et al., 2010; van Eijndhoven et al., 2009). We confirmed with the authors of two of the studies (Frodl et al., 2002; Meisenzahl et al., 2010) an overlap in their samples and therefore included only the most recent one, presenting the largest number of subjects. This strategy led to a total of 7 independent studies. 2.2. Data extraction and analysis For each study, the following data were extracted for the patients and controls samples: number of participants, mean hippocampal volumes and their standard deviations, mean patient age at scanning, mean disease duration, gender distribution and medication status of the patient sample. Left and right volumes were assessed separately and Hedges' adjusted g was calculated for each study as the effect size estimator (Hedges, 1981). One major source of inconsistency across studies could be the divergent protocols used to define hippocampal boundaries. The main point of contention between protocols is the inclusion of white matter areas (i.e. the alveus and fimbria) adjacent to the hippocampus proper. Based on Konrad et al.'s (2009) assessment, each of the current studies was categorised as including white matter or not (Supplementary Table A). Where studies were not explicitly considered by Konrad et al. (2009), the history of the tracing protocol was examined. All studies were found to
derive their protocol from one assessed by Konrad et al. (2009). Effect sizes were combined using the DerSimonian–Laird method for random effects models (DerSimonian and Laird, 1986) to generate a pooled standardised mean difference (SMD), and 95% confidence intervals (95% CI). For the studies which reported a number of findings from more than one experimental group with first episode depression (Kronmüller et al., 2009; van Eijndhoven et al., 2009), separate measurements were aggregated into one overall summary effect size to ensure independence of study estimates, by taking the weighted mean and pooled variance of all within-study measurements, with the weight being the sample size in each experimental group. The random effects model for metaanalysis was selected over the fixed effects approach as previous analyses have indicated considerable between-study heterogeneity. The investigation of the effects of categorical moderators was also performed by using random effects metaregression (Thompson and Higgins, 2002). Where possible potential moderators were kept as continuous variables: patient age, percentage of males in the sample and disease duration; while medication status was investigated as a categorical variable: unmedicated versus medicated patient samples, as well as whether the delineation protocol was inclusive of white matter in the hippocampal definition. One of the studies was identified as reporting outlier results (Kaymak et al., 2010), and we therefore conducted a sensitivity analysis by recomputing the random effects estimates after exclusion of that study to ensure that the findings were not biased by such outlier measurements. Analyses were conducted using standard packages for meta-analysis of the R statistical software (http://www.r-project.org/). 3. Results A total of 7 independent studies (Cole et al., 2010; Eker et al., 2010; Kaymak et al., 2010; Kronmüller et al., 2009; MacQueen et al., 2003; Meisenzahl et al., 2010; van Eijndhoven et al., 2009) met our inclusion and exclusion criteria, reporting measurements of 191 patients with a first episode of depression (Table 1, additional methodological study characteristics in Supplementary Tables A and B). Briefly, all studies had recruited adult patients (mean age: 37.6 years, weighted by sample size; 64.3% females). Patients suffered from moderate depression (mean HRSD score 21.0) with average illness duration of 14.4 months (range of 4.7–25.2 months). Approximately half of the patients were either drug naïve (n=33) or drug free (n= 65), while the remainder were taking antidepressant medication. All control samples were matched by age and gender, with the exception of one study in which controls were matched only by gender (Meisenzahl et al., 2010). One study employed a 3 Tesla scanner (Kaymak et al., 2010), while all others were conducted on 1.5 Tesla systems, and image slice thickness equal or less than 2 mm in all cases. Manual segmentation protocols with high intra and intra and inter-rater reliability (N0.90 in most cases) were employed throughout. There was substantial heterogeneity in hippocampal volume measurements (Fig. 1), justifying the use of a random-effects analysis approach. The cumulative analysis showed atrophy in first episode MDD patients relative to controls for both left (standardised mean difference, SMD=−0.41, 95% Confidence Interval: [−0.78;
J. Cole et al. / Journal of Affective Disorders 134 (2011) 483–487
485
Table 1 Demographic and clinical characteristics of first episode depression studies included in meta-analysis. Study
Year
Participants
Age, years
% female
Mood at scan
MacQueen
2003 2009
Kronmuller
2009
Eker
2010
Kaymak
2010
Cole
2010
Meisenzahl
2010
28.4 28.4 34.1 35.8 37.3 38.1 41.5 42.0 42.7 32.1 29.7 32.0 29.3 38.1 42.2 41.8 33.3
65% 65% 65% 70% 65% 0% 100% 0% 100% 72% 77% 100% 100% 85% 76% 55% 43%
n/s
van Eijndhoven
20 1st episode MDD 20 matched controls 20 depressed 1st episode 20 remitted 1st episode 20 controls 13 1st episode MDD male 13 1st episode MDD female 11 male controls 19 female controls 25 1st episode MDD 22 controls 20 1st episode MDD 15 controls 13 1st episode MDD 37 controls 47 1st episode MDD 138 controls
(11.8) (11.5) (11.6) (11.7) (12.7) (11.9) (16.7) (11.3) (14.0) (9.3) (6.4) (8.5) (5.8) (7.9) (9.0) (13.5) (12.2)
Mood measure
HDRS; BDI Depressed/remitted HDRS
Disease duration, months
Medication status
Dx
25.2 (n/s)
Some 1st episode patients taking ADM Medication naïve/medication free All taking ADM
SCID
13 drug naïve, all 4 weeks drug free All drug naïve
SCID
All 2 weeks drug free Most on ADM.
SCID
7.1 (5.5) 33.7 (17.3)
Depressed
HDRS
10.6 (13.7) 10.6 (13.7)
Depressed
HDRS
7.1 (7.0)
Depressed
HDRS
4.7 (3.6)
Depressed
HDRS
n/s
Depressed
HDRS
19.2 (37.2)
SCID; MINI
SCID
SCID
SCID
MDD = patients with Major Depressive Disorder; HDRS = Hamilton Depression Rating Scale; BDI = Beck Depression Inventory; SCID = Structured Clinical Interview for DSM-IV; MINI = Mini-International Neuropsychiatric Interview; ADM = anti-depressant medication; n/s = data not stated.
− 0.03], z = − 2.14, p = 0.0321) and right (SMD = − 0.53 [− 0.98 ; − 0.09], z =− 2.38, p = 0.0173) hippocampi (Fig. 1). The average volume reduction in first episode depression relative to healthy controls, weighted by each study sample size, was −4.0% in the left and −4.5% in the right hippocampus. None of the clinical or methodological moderating values demonstrated statistically significant effects, although unmedicated patient samples tended to report larger right hippocampal volume reductions than medicated ones (z=1.72,p=0.0849). Given the relatively small number of studies available for this meta-analysis and the presence of a study with outlier results of extreme atrophy (Kaymak et al., 2010, reporting −19.0% and −20.0% atrophy for left and right hippocampi, respectively), we conducted an additional sensitivity analysis to investigate whether the summary findings were unduly determined by this particular study. Following its exclusion, the magnitude of atrophy was reduced bilaterally (weighted volume reduction, left: −2.2%, right: −2.6%), but these differences remained statistically significant (SMD = − 0.23[− 0.42 ; − 0.02], z = −2.17,p=0.0295) and right (SMD =−0.30[−0.56;−0.04],
z=−2.24,p=0.0248). In this sensitivity analysis the association between medication status and hippocampal volume reduction was not significant (z=1.14,p=0.2547).
4. Discussion The present meta-analysis establishes that hippocampal volume loss is not only a feature of recurrent and chronic depression but is also evident in adult patients with a first episode of the illness. Hippocampal volume reduction in first episode patients has also been recently demonstrated using whole-brain voxel-based morphometry (Zou et al., 2010). These findings can be linked with recent studies reporting smaller hippocampal volume in subjects at high risk for depression due to a family history of depression or early childhood adversity (Chen et al., 2010; Rao et al., 2010) and in adolescents with early-onset depression (MacMaster and Kusumakar, 2004). Taken together, these results are consistent with a neurobiological model whereby volume loss is not
Fig. 1. Cumulative analysis of hippocampal volume differences between patients with a first episode of depression and healthy controls. For each study, the forest plot presents the standardised mean difference in hippocampal volume between patients and controls, along with its 95% confidence interval (horizontal line). Negative SMD represents volume loss in patients relative to controls. The diamond-shape random effects summary shows that bilateral hippocampal atrophy is present for first episode patients bilaterally (left p = 0.0321; right p = 0.0173).
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just a “scar” of depression, but may be a marker of risk preceding and possibly predisposing to depression. The existence of hippocampal atrophy from disease onset has significant clinical implications. Deficits in autobiographical (Williams and Scott, 1988) and episodic memory (Ilsley et al., 1995), are a common feature of depression, and the volume loss in the hippocampus may parallel the memory impairment experienced by patients. Depression is also associated with greater than a 50% increased risk for dementia (Saczynski et al., 2010), which may reflect a progression of the hippocampal atrophy with onset in first episode depression and is also apparent with subsequent episodes (McKinnon et al., 2009). Disturbed hypothalamic pituitary adrenal (HPA) axis function is a feature of depression, and it has been proposed that adrenal hypersecretion of glucocorticoids, in particular cortisol, is linked to hippocampal atrophy in depression (Sapolsky, 2001) as cortisol leads to neural atrophy and inhibition of neurogenesis in the hippocampus (McEwen, 1999). Hippocampal volumetric reductions may therefore be a key marker of the HPA disturbances linking early adversity, stress and depression (Frodl et al., 2008b). A key prediction from the proposed neurodevelopmental model of depression is that hippocampal atrophy should also exist in patients with a first episode of adolescent depression. As all of the studies identified by our strategy were composed of adult patients, we were unable in the present meta-analysis to test this prediction which would be an important hypothesis for future research. Hippocampal atrophy has also been shown to predict poor treatment response and increased risk of relapse of depression (Frodl et al., 2008a; MacQueen and Frodl, 2010). The first episode of this illness may thus be a critical point for assertive intervention in which effective treatments may palliate or reverse structural changes, resulting in improved long-term clinical outcomes. Hippocampal atrophy, alongside other structural or functional abnormalities, may contribute to generate new clinical biomarkers for diagnosis and prognostic prediction in depression (Costafreda et al., 2011; Nouretdinov et al., 2010). Three-dimensional shape analysis may identify the initial development of subregional volumetric losses and establish whether there is diagnostic specificity of abnormalities in depression (Cole et al., 2010) that are distinct from other disorders with hippocampal abnormalities, such as schizophrenia (Narr et al., 2004). One of the studies identified by the meta-analysis reported findings that were an outlier, with up to 20% reduction between patients and controls in hippocampal volume, more than double than those reported by the other studies (Kaymak et al., 2010). Further examination of the patient sample indicated that these subjects had a similar severity of illness of a moderate to severe range (Hamilton Depression Rating Scale mean score of 23.10 ±4.20), but the patients had marked neuropsychological impairments over a range of tasks in executive function, memory and language, which may be linked to their marked hippocampal atrophy. We thus repeated the analysis, excluding this report, and demonstrated that the findings of hippocampal volume reduction were robust to the inclusion or exclusion of this study. Potential moderating effects of age, gender, or disease duration did not show any significant effects on hippocampal volume. The range of mean ages of the patients included in the meta-analysis though was limited (range of 28.4 to 42.7 years),
reducing the ability to detect effects that may be apparent in older patients. Significant effects of gender and disease duration have been demonstrated in some individual studies with first episode patients (Frodl et al., 2002; van Eijndhoven et al., 2009), but not all (Cole et al., 2010). Age and disease duration have also been shown to have significant effects in a recent meta-analysis involving samples of both recurrent and first episode depression patients (McKinnon et al., 2009). While all the studies in the present meta-analysis employed manual segmentation to measure the hippocampal volume, studies differed with regard to their definition of the hippocampus. In particular, three studies (Eker et al., 2010; Kaymak et al., 2010; van Eijndhoven et al., 2009) included white matter areas (i.e. the alveus and fimbria) in their computation of volume. While these methodological differences are likely to have contributed to the heterogeneity of results across studies, we did not find a significant effect on hippocampal volume. There was a marginally significant effect of medication, in which unmedicated samples tended to report larger right hippocampal volume reduction consistent with reports of a neurotrophic benefit of antidepressants on the hippocampus (Boldrini et al., 2009; Duman et al., 2001). As more studies in first episode patients become available, it would be interesting to revisit potential moderating effects in first episode depression with increased statistical power. In summary, significant hippocampal volume loss is evident in the first episode of depression. The findings from the present meta-analysis are consistent with a neurodevelopmental model of depression and indicate the utility of the hippocampal structure as a biomarker for depression. The clinical implications underline the importance of early interventions to help to reduce the deleterious effects of recurrent episodes. Supplementary materials related to this article can be found online at doi:10.1016/j.jad.2011.05.057. Role of funding source Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Conflict of interest All authors declare that they have no conflicts of interests.
Acknowledgements JC was supported by a Medical Research Council PhD studentship. SGC was supported by the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London.
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Contents lists available at ScienceDirect
Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Brief report
Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies James Cole, Sergi G. Costafreda ⁎, Peter McGuffin, Cynthia H.Y. Fu Institute of Psychiatry, King's College London, London, UK
a r t i c l e
i n f o
Article history: Received 28 March 2011 Received in revised form 30 May 2011 Accepted 30 May 2011 Available online 13 July 2011 Keywords: Depression Structural magnetic resonance imaging Hippocampus Meta-analysis
a b s t r a c t Background: Reduced hippocampal volume has been consistently observed in major depressive disorder. Hippocampal volume loss is particularly evident in patients with recurrent and chronic depression. However, the reports in first episode depression have been mixed. Methods: We performed a random effects meta-analysis to establish whether hippocampal atrophy exists from disease onset. We included magnetic resonance imaging studies of hippocampal volume in patients with first episode major depressive disorder and matched healthy controls. Results: A total of 7 studies met our inclusion and exclusion criteria, representing independent observations in a total sample of 191 patients and 282 healthy controls. The cumulative analysis revealed hippocampal volume loss in patients with first episode depression relative to controls in both the left (standardised mean difference, SMD = −0.41, 95% Confidence Interval: [− 0.78;−0.03], z = − 2.14, p = 0.0321) and right (SMD = − 0.53[− 0.98;−0.09], z = − 2.38, p = 0.0173) hippocampi. The average volume reduction was − 4.0% in the left and − 4.5% in the right hippocampus. Conclusions: Hippocampal volume loss in first episode depression is consistent with a neurodevelopmental model of depression, advocating hippocampal structure as a potential diagnostic neurobiomarker for depression. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Initial reports of hippocampal volume in depression suffered from limited resolution of early neuroimaging methods leading to poor separation of the hippocampus and adjacent structures (reviewed in: Fu et al., 2003). More recent meta-analyses have convincingly established that reduced hippocampal volume is a neurobiological feature of major depressive disorder, particularly in illnesses characterised by recurrent episodes and in chronic depression (Campbell and MacQueen, 2004; McKinnon et al., 2009; Videbech and
⁎ Corresponding author at: Institute of Psychiatry, King's College London De Crespigny Park, PO Box 68, London SE5 8AF, UK. Tel.: + 44 203 228 3052; fax: + 44 203 228 2016. E-mail address: [email protected] (S.G. Costafreda). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.05.057
Ravnkilde, 2004). However, the stage at which hippocampal atrophy begins in depression is unclear. In first episode depression, the evidence has been equivocal, with some studies observing decreased hippocampal volume (Cole et al., 2010; Frodl et al., 2002), while others have reported no significant difference (Eker et al., 2010; Kronmüller et al., 2009). The presence of hippocampal atrophy from disease onset would have significant etiological and clinical implications as it would support a model of depression in which structural abnormalities appear earlier than previously believed with potentially deleterious effects on clinical outcome and response to antidepressant therapy (MacQueen and Frodl, 2010). In the present study, we sought to establish whether hippocampal atrophy exists from disease onset. We performed a random effects meta-analysis of magnetic resonance imaging studies of hippocampal volume in first episode depression.
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2. Methods 2.1. Literature search MEDLINE, EMBASE, Scopus and PsychINFO electronic databases were queried with the following search terms: “depression”, “major depressive disorder”, “magnetic resonance imaging”, “hippocampus”, and abbreviations “MDD”, “MRI”, “unipolar” for papers published between January 1990 and February 2011. References from the retrieved papers and reviews of hippocampal and regional brain volumes in major depressive disorder (MDD) were also inspected for relevant articles. Inclusion criteria were: 1) patients with a primary diagnosis of first-episode major depressive disorder (MDD) assessed using international diagnostic criteria; 2) a healthy comparison group; 3) clinical samples were comprised of patients with first and/or recurrent MDD; 4) participants were screened for neurological and medical disorders that could affect brain structure, including alcohol and substance abuse; 5) magnetic resonance imaging (MRI) was the primary measurement tool; 6) a continuous measure of hippocampal volume as the dependent variable; 7) distinct measures of the hippocampus, rather than combined measures with adjacent regions such as the amygdala. In samples from which more than one publication from the same research group and overlaps between samples were not explicitly described, authors were contacted to establish whether these samples could be considered independent. In cases in which an overlap was established, the most extensive sample was included. If papers did not report sufficient data, but satisfied all other inclusion criteria, requests for the requisite data were made. The literature search identified 8 published research reports meeting inclusion and exclusion criteria (Cole et al., 2010; Eker et al., 2010; Frodl et al., 2002; Kaymak et al., 2010; Kronmüller et al., 2009; MacQueen et al., 2003; Meisenzahl et al., 2010; van Eijndhoven et al., 2009). We confirmed with the authors of two of the studies (Frodl et al., 2002; Meisenzahl et al., 2010) an overlap in their samples and therefore included only the most recent one, presenting the largest number of subjects. This strategy led to a total of 7 independent studies. 2.2. Data extraction and analysis For each study, the following data were extracted for the patients and controls samples: number of participants, mean hippocampal volumes and their standard deviations, mean patient age at scanning, mean disease duration, gender distribution and medication status of the patient sample. Left and right volumes were assessed separately and Hedges' adjusted g was calculated for each study as the effect size estimator (Hedges, 1981). One major source of inconsistency across studies could be the divergent protocols used to define hippocampal boundaries. The main point of contention between protocols is the inclusion of white matter areas (i.e. the alveus and fimbria) adjacent to the hippocampus proper. Based on Konrad et al.'s (2009) assessment, each of the current studies was categorised as including white matter or not (Supplementary Table A). Where studies were not explicitly considered by Konrad et al. (2009), the history of the tracing protocol was examined. All studies were found to
derive their protocol from one assessed by Konrad et al. (2009). Effect sizes were combined using the DerSimonian–Laird method for random effects models (DerSimonian and Laird, 1986) to generate a pooled standardised mean difference (SMD), and 95% confidence intervals (95% CI). For the studies which reported a number of findings from more than one experimental group with first episode depression (Kronmüller et al., 2009; van Eijndhoven et al., 2009), separate measurements were aggregated into one overall summary effect size to ensure independence of study estimates, by taking the weighted mean and pooled variance of all within-study measurements, with the weight being the sample size in each experimental group. The random effects model for metaanalysis was selected over the fixed effects approach as previous analyses have indicated considerable between-study heterogeneity. The investigation of the effects of categorical moderators was also performed by using random effects metaregression (Thompson and Higgins, 2002). Where possible potential moderators were kept as continuous variables: patient age, percentage of males in the sample and disease duration; while medication status was investigated as a categorical variable: unmedicated versus medicated patient samples, as well as whether the delineation protocol was inclusive of white matter in the hippocampal definition. One of the studies was identified as reporting outlier results (Kaymak et al., 2010), and we therefore conducted a sensitivity analysis by recomputing the random effects estimates after exclusion of that study to ensure that the findings were not biased by such outlier measurements. Analyses were conducted using standard packages for meta-analysis of the R statistical software (http://www.r-project.org/). 3. Results A total of 7 independent studies (Cole et al., 2010; Eker et al., 2010; Kaymak et al., 2010; Kronmüller et al., 2009; MacQueen et al., 2003; Meisenzahl et al., 2010; van Eijndhoven et al., 2009) met our inclusion and exclusion criteria, reporting measurements of 191 patients with a first episode of depression (Table 1, additional methodological study characteristics in Supplementary Tables A and B). Briefly, all studies had recruited adult patients (mean age: 37.6 years, weighted by sample size; 64.3% females). Patients suffered from moderate depression (mean HRSD score 21.0) with average illness duration of 14.4 months (range of 4.7–25.2 months). Approximately half of the patients were either drug naïve (n=33) or drug free (n= 65), while the remainder were taking antidepressant medication. All control samples were matched by age and gender, with the exception of one study in which controls were matched only by gender (Meisenzahl et al., 2010). One study employed a 3 Tesla scanner (Kaymak et al., 2010), while all others were conducted on 1.5 Tesla systems, and image slice thickness equal or less than 2 mm in all cases. Manual segmentation protocols with high intra and intra and inter-rater reliability (N0.90 in most cases) were employed throughout. There was substantial heterogeneity in hippocampal volume measurements (Fig. 1), justifying the use of a random-effects analysis approach. The cumulative analysis showed atrophy in first episode MDD patients relative to controls for both left (standardised mean difference, SMD=−0.41, 95% Confidence Interval: [−0.78;
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Table 1 Demographic and clinical characteristics of first episode depression studies included in meta-analysis. Study
Year
Participants
Age, years
% female
Mood at scan
MacQueen
2003 2009
Kronmuller
2009
Eker
2010
Kaymak
2010
Cole
2010
Meisenzahl
2010
28.4 28.4 34.1 35.8 37.3 38.1 41.5 42.0 42.7 32.1 29.7 32.0 29.3 38.1 42.2 41.8 33.3
65% 65% 65% 70% 65% 0% 100% 0% 100% 72% 77% 100% 100% 85% 76% 55% 43%
n/s
van Eijndhoven
20 1st episode MDD 20 matched controls 20 depressed 1st episode 20 remitted 1st episode 20 controls 13 1st episode MDD male 13 1st episode MDD female 11 male controls 19 female controls 25 1st episode MDD 22 controls 20 1st episode MDD 15 controls 13 1st episode MDD 37 controls 47 1st episode MDD 138 controls
(11.8) (11.5) (11.6) (11.7) (12.7) (11.9) (16.7) (11.3) (14.0) (9.3) (6.4) (8.5) (5.8) (7.9) (9.0) (13.5) (12.2)
Mood measure
HDRS; BDI Depressed/remitted HDRS
Disease duration, months
Medication status
Dx
25.2 (n/s)
Some 1st episode patients taking ADM Medication naïve/medication free All taking ADM
SCID
13 drug naïve, all 4 weeks drug free All drug naïve
SCID
All 2 weeks drug free Most on ADM.
SCID
7.1 (5.5) 33.7 (17.3)
Depressed
HDRS
10.6 (13.7) 10.6 (13.7)
Depressed
HDRS
7.1 (7.0)
Depressed
HDRS
4.7 (3.6)
Depressed
HDRS
n/s
Depressed
HDRS
19.2 (37.2)
SCID; MINI
SCID
SCID
SCID
MDD = patients with Major Depressive Disorder; HDRS = Hamilton Depression Rating Scale; BDI = Beck Depression Inventory; SCID = Structured Clinical Interview for DSM-IV; MINI = Mini-International Neuropsychiatric Interview; ADM = anti-depressant medication; n/s = data not stated.
− 0.03], z = − 2.14, p = 0.0321) and right (SMD = − 0.53 [− 0.98 ; − 0.09], z =− 2.38, p = 0.0173) hippocampi (Fig. 1). The average volume reduction in first episode depression relative to healthy controls, weighted by each study sample size, was −4.0% in the left and −4.5% in the right hippocampus. None of the clinical or methodological moderating values demonstrated statistically significant effects, although unmedicated patient samples tended to report larger right hippocampal volume reductions than medicated ones (z=1.72,p=0.0849). Given the relatively small number of studies available for this meta-analysis and the presence of a study with outlier results of extreme atrophy (Kaymak et al., 2010, reporting −19.0% and −20.0% atrophy for left and right hippocampi, respectively), we conducted an additional sensitivity analysis to investigate whether the summary findings were unduly determined by this particular study. Following its exclusion, the magnitude of atrophy was reduced bilaterally (weighted volume reduction, left: −2.2%, right: −2.6%), but these differences remained statistically significant (SMD = − 0.23[− 0.42 ; − 0.02], z = −2.17,p=0.0295) and right (SMD =−0.30[−0.56;−0.04],
z=−2.24,p=0.0248). In this sensitivity analysis the association between medication status and hippocampal volume reduction was not significant (z=1.14,p=0.2547).
4. Discussion The present meta-analysis establishes that hippocampal volume loss is not only a feature of recurrent and chronic depression but is also evident in adult patients with a first episode of the illness. Hippocampal volume reduction in first episode patients has also been recently demonstrated using whole-brain voxel-based morphometry (Zou et al., 2010). These findings can be linked with recent studies reporting smaller hippocampal volume in subjects at high risk for depression due to a family history of depression or early childhood adversity (Chen et al., 2010; Rao et al., 2010) and in adolescents with early-onset depression (MacMaster and Kusumakar, 2004). Taken together, these results are consistent with a neurobiological model whereby volume loss is not
Fig. 1. Cumulative analysis of hippocampal volume differences between patients with a first episode of depression and healthy controls. For each study, the forest plot presents the standardised mean difference in hippocampal volume between patients and controls, along with its 95% confidence interval (horizontal line). Negative SMD represents volume loss in patients relative to controls. The diamond-shape random effects summary shows that bilateral hippocampal atrophy is present for first episode patients bilaterally (left p = 0.0321; right p = 0.0173).
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just a “scar” of depression, but may be a marker of risk preceding and possibly predisposing to depression. The existence of hippocampal atrophy from disease onset has significant clinical implications. Deficits in autobiographical (Williams and Scott, 1988) and episodic memory (Ilsley et al., 1995), are a common feature of depression, and the volume loss in the hippocampus may parallel the memory impairment experienced by patients. Depression is also associated with greater than a 50% increased risk for dementia (Saczynski et al., 2010), which may reflect a progression of the hippocampal atrophy with onset in first episode depression and is also apparent with subsequent episodes (McKinnon et al., 2009). Disturbed hypothalamic pituitary adrenal (HPA) axis function is a feature of depression, and it has been proposed that adrenal hypersecretion of glucocorticoids, in particular cortisol, is linked to hippocampal atrophy in depression (Sapolsky, 2001) as cortisol leads to neural atrophy and inhibition of neurogenesis in the hippocampus (McEwen, 1999). Hippocampal volumetric reductions may therefore be a key marker of the HPA disturbances linking early adversity, stress and depression (Frodl et al., 2008b). A key prediction from the proposed neurodevelopmental model of depression is that hippocampal atrophy should also exist in patients with a first episode of adolescent depression. As all of the studies identified by our strategy were composed of adult patients, we were unable in the present meta-analysis to test this prediction which would be an important hypothesis for future research. Hippocampal atrophy has also been shown to predict poor treatment response and increased risk of relapse of depression (Frodl et al., 2008a; MacQueen and Frodl, 2010). The first episode of this illness may thus be a critical point for assertive intervention in which effective treatments may palliate or reverse structural changes, resulting in improved long-term clinical outcomes. Hippocampal atrophy, alongside other structural or functional abnormalities, may contribute to generate new clinical biomarkers for diagnosis and prognostic prediction in depression (Costafreda et al., 2011; Nouretdinov et al., 2010). Three-dimensional shape analysis may identify the initial development of subregional volumetric losses and establish whether there is diagnostic specificity of abnormalities in depression (Cole et al., 2010) that are distinct from other disorders with hippocampal abnormalities, such as schizophrenia (Narr et al., 2004). One of the studies identified by the meta-analysis reported findings that were an outlier, with up to 20% reduction between patients and controls in hippocampal volume, more than double than those reported by the other studies (Kaymak et al., 2010). Further examination of the patient sample indicated that these subjects had a similar severity of illness of a moderate to severe range (Hamilton Depression Rating Scale mean score of 23.10 ±4.20), but the patients had marked neuropsychological impairments over a range of tasks in executive function, memory and language, which may be linked to their marked hippocampal atrophy. We thus repeated the analysis, excluding this report, and demonstrated that the findings of hippocampal volume reduction were robust to the inclusion or exclusion of this study. Potential moderating effects of age, gender, or disease duration did not show any significant effects on hippocampal volume. The range of mean ages of the patients included in the meta-analysis though was limited (range of 28.4 to 42.7 years),
reducing the ability to detect effects that may be apparent in older patients. Significant effects of gender and disease duration have been demonstrated in some individual studies with first episode patients (Frodl et al., 2002; van Eijndhoven et al., 2009), but not all (Cole et al., 2010). Age and disease duration have also been shown to have significant effects in a recent meta-analysis involving samples of both recurrent and first episode depression patients (McKinnon et al., 2009). While all the studies in the present meta-analysis employed manual segmentation to measure the hippocampal volume, studies differed with regard to their definition of the hippocampus. In particular, three studies (Eker et al., 2010; Kaymak et al., 2010; van Eijndhoven et al., 2009) included white matter areas (i.e. the alveus and fimbria) in their computation of volume. While these methodological differences are likely to have contributed to the heterogeneity of results across studies, we did not find a significant effect on hippocampal volume. There was a marginally significant effect of medication, in which unmedicated samples tended to report larger right hippocampal volume reduction consistent with reports of a neurotrophic benefit of antidepressants on the hippocampus (Boldrini et al., 2009; Duman et al., 2001). As more studies in first episode patients become available, it would be interesting to revisit potential moderating effects in first episode depression with increased statistical power. In summary, significant hippocampal volume loss is evident in the first episode of depression. The findings from the present meta-analysis are consistent with a neurodevelopmental model of depression and indicate the utility of the hippocampal structure as a biomarker for depression. The clinical implications underline the importance of early interventions to help to reduce the deleterious effects of recurrent episodes. Supplementary materials related to this article can be found online at doi:10.1016/j.jad.2011.05.057. Role of funding source Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Conflict of interest All authors declare that they have no conflicts of interests.
Acknowledgements JC was supported by a Medical Research Council PhD studentship. SGC was supported by the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London.
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