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Reviews and Overviews   |    
Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies
Poul Videbech, M.D.; Barbara Ravnkilde, Ph.D.
Am J Psychiatry 2004;161:1957-1966. doi:10.1176/appi.ajp.161.11.1957
Abstract

OBJECTIVE: Several studies have found reduced hippocampal volume in patients with unipolar depression, but discrepancies exist. The authors performed a systematic review and meta-analysis of volumetric studies of the hippocampus in patients with mood disorders. METHOD: Studies of hippocampal volume in unipolar and bipolar patients were identified. A meta-analysis of the 12 studies of unipolar depression fulfilling specific criteria was performed. The sample comprised 351 patients and 279 healthy subjects. RESULTS: The studies were highly heterogeneous regarding age and gender distribution, age at onset of the disorder, average number of episodes, and responsiveness to treatment, but the pooled effect size of depression was significant in both hemispheres for the unipolar patients. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side. The causes of the heterogeneity were analyzed, and a meta-regression showed that the total number of depressive episodes was significantly correlated to right but not left hippocampal volume reduction. CONCLUSIONS: Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.

Abstract Teaser
Figures in this Article

Increasing evidence has shown structural cerebral abnormalities in patients with unipolar and bipolar depression. Several studies have thus indicated an increased ventricle/brain ratio and other signs of both generalized and localized cerebral atrophy of the prefrontal cortex, cingulate gyrus, caudate nucleus, cerebellum, and hippocampus (for reviews see references 1–4). Often this atrophy is found to correlate with poor treatment response and shorter time to recurrence of the disease. Functional neuroimaging has also pointed to widespread abnormalities in the brain during depression (5).

The hippocampus is one of the areas in the brain that has been extensively studied in patients with mood disorders. This interest rests on a large body of neuropsychological and neuroimaging studies. The hippocampus is involved in episodic, declarative, contextual, and spatial learning and memory (6, 7), deficits which often accompany depression (8, 9). Furthermore, extensive rodent and human research has shown that its mnemonic functions and its neuroplasticity are highly sensitive to stress, i.e., increased cortisol levels (see reference 10 for an excellent review), which is found in a large proportion of patients with major depression (11).

In a Danish positron emission tomography (PET) study that included 42 acutely depressed patients and 47 matched healthy volunteers, one of the main findings was increased blood flow to the right hippocampus (12, 13). Accordingly, several other PET studies have found abnormalities in this structure in depression under various scanning conditions (1419).

The hippocampus of patients with unipolar depression has been studied since 1993 using magnetic resonance imaging (MRI) techniques to reveal changes in volume, density, and water contents. Some volumetric studies have found significant bilateral volume deficits in depression (2022). Others have found significantly lower volume in the right hemisphere (23, 24) or in the left hemisphere (2527), but several studies have failed to find any differences (2834).

Likewise, the picture is inconsistent regarding the correlation between measurements of hippocampal volume and clinical characteristics of the patient groups. One study found a correlation between age at onset of depression and hippocampal volume, namely that patients with late onset tended to have smaller hippocampi, especially in the right hemisphere (24). Other studies found the opposite to be the case (23) or could not confirm any relationship at all (33). Several authors have also tried to correlate the accumulated duration of episodes of depression to the volume of hippocampus and found that longer total duration of the disease or more episodes was correlated to smaller volumes (2022). Important discrepancies do, however, still exist (26, 28, 33, 34). Finally, responsiveness to treatment has been correlated to volume reduction, which is often most pronounced in the right hippocampus (27, 32, 35).

Because of these discrepancies, which make it very difficult to reach a conclusion by simple summation of previous results, we decided to perform a meta-analysis of the effect of depression on hippocampal volume, hypothesizing that at least some of the discrepancies can be explained by between-group differences in number of recurrences.

The MEDLINE and EMBASE electronic databases were searched using the following medical subject heading (MeSH): "Mood disorders" and "Magnetic Resonance Imaging" and "Hippocampus." To make sure no study was missed, a free-text search was performed on the words "depression" and "MRI" and "hippocampus." The search covered the years from 1966 through 2003. Furthermore, all reference lists of the obtained papers were scrutinized for studies not indexed in the electronic databases.

If not otherwise stated, all the studies reviewed herein fulfill the following criteria: 1) thorough clinical characterization of the patients with DSM-IV, ICD-10, or an equivalent system used as a diagnostic tool; 2) a comparison group of nearly the same size or larger than that of the probands, with approximately the same average age; 3) exclusion of patients and comparison subjects with neurological disorders or medical diseases that could affect brain function; 4) exclusion of subjects with alcohol or drug dependency/abuse; and 5) comparison groups screened for psychiatric disorders. Since the first studies used scanners with low resolution unable to distinguish between the hippocampus and the adjacent amygdala, these studies were not considered.

In the present report all relevant studies were scrutinized, but only studies stating the mean and standard deviation of the hippocampal volume in each hemisphere separately were included in the meta-analysis. We converted all volumes to mm3 before entering them into the meta-analysis. Furthermore, this analysis was only carried out for studies of patients with unipolar depression and not for bipolar disorder patients, since these studies were few and very heterogeneous regarding the scanning techniques and actual measurements of hippocampal volume compared with the studies of unipolar depression patients.

The calculations were performed by using STATA, version 8 (Stata Corp., College Station, Tex.) by means of the Metan, Metareg, Metainf, and Metabias programs. The meta-analyses were performed by using a random effects model weighting the studies by the inverse variance and calculating the Dersimonian-Laird effect size. The random effects model was chosen because it is considered more conservative than a fixed effects model, since it takes into account the variability between studies leading to wider confidence intervals (CIs). Furthermore, the analyses were repeated excluding one study at a time to ensure that the results were not skewed by a single outlier. Heterogeneity, i.e., whether the differences between studies were greater than would be expected by chance alone, was assessed by the Q test and further analyzed by so-called meta-regression, a linear regression of the effect sizes against selected covariates. Meta-regression using the Metareg program was conducted to evaluate factors that could affect results between studies, such as differences in gender distribution or average age. A variable called RECUR was defined for each study and assigned a value of 1 if the study comprised patients with first-episode depression only and a value of 3 if all the patients participating in the study had recurrent depression. In three studies a value of 2 was assigned because the patient group was considered to consist of both types of patients (t1). This variable was also used in a meta-regression.

Begg’s and Egger’s tests were used to test for publication bias, i.e., the phenomenon in which for instance studies with negative results are not published.

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Unipolar Depression

Twelve studies comprising 351 patients and 279 healthy subjects fulfilled the aforementioned criteria and were entered into the meta-analysis (t1). The studies deviate markedly on several demographic characteristics of the study groups: the mean age varies from 28 to 74 years and the percentage of male subjects in each group varies from 0 to 63. Clinically, some of the studies comprise patients with first-episode depression (20, 29, 31) or treatment-resistant depression (25). Furthermore, the average volumes measured varied somewhat, with one study deviating especially noticeably (26).

The Q test of heterogeneity (df=11) was highly significant as expected (left side: p<0.003; right side: p<0.01). For this reason the effect size was calculated under the assumption of a random effects model. The Derimonian-Laird pooled effect size revealed bilateral statistical significance: –0.38 (95% CI=–0.65 to –0.11) for the left hippocampus (F1) and –0.32 (95% CI=–0.56 to –0.08) for the right hippocampus (F2). The average volume reduction weighted by sample size was 8% in the left hemisphere and 10% in the right.

Begg’s and Egger’s tests for publication bias were both far from significant (smallest p=0.135), confirmed graphically by a funnel plot (F3). The meta-analysis was repeated omitting one study at a time to ensure that the result was not skewed by a single study. This procedure did not change the random-effect estimate notably, as it in all cases continued to be statistically significant.

The significant heterogeneity was then analyzed using meta-regression. A priori we assumed that interstudy differences in age and gender distribution could explain some of the variation. Analyzed separately and together these variables were, however, not significantly correlated with the random effect estimate in either hemisphere (data available upon request). Meta-regression using the variable RECUR (t1) as covariate showed a significant negative correlation with the random-effect estimate in the right hemisphere (r=–0.30; z=–2.36, p<0.02) and nonsignificant correlation in the left (r=–0.20; z=–1.18, p<0.24). This means that the higher the proportion of patients with recurrent depression, the smaller the volume of the right hippocampus.

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Bipolar Patients

Studies of the hippocampus in bipolar disorder patients are shown in t2. Most of the studies except one (36) showed no significant differences between patients and comparison subjects (3742). Several of the studies did, however, use a very crude slice thickness to calculate the volumes, which increased the variation. Furthermore, one of the studies reports very deviating volumes of the hippocampus. Despite such methodological shortcomings the results are rather uniform, indicating that the volume of hippocampus is not changed in bipolar disorder. However, in an uncontrolled study Ali et al. (43, 44) found that larger right hippocampal volume was associated with longer duration of the illness and poorer neuropsychological functioning.

The question whether depression is associated with shrinkage of the hippocampus is indeed important for our understanding of the disease. From t1 it is seen that two studies found significant bilateral volume deficits, one found significantly reduced volume in the right hemisphere, and two found reduction in the left, whereas seven studies failed to find any differences. In contrast, the meta-analysis of the 12 studies included showed a significant effect size of depression on the volume of hippocampus in both hemispheres, most pronounced in the right. Furthermore, the volume reduction in the right hippocampus was significantly correlated to the number of episodes. Tests for publication bias both fell out negatively.

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Heterogeneity of Studies

The marked differences among patient groups regarding age and gender distribution, age at first depression, average number of episodes, and responsiveness to treatment were a priori expected to increase the variation of hippocampal volume. Further increase in variation was expected considering differences in scanning protocols and delineation of the structures in question. Meta-analysis plays an important role precisely because of these possible serious confounders, since it is most likely that some of the confounding effects are diluted or even cancel each other out in the large number of patients analyzed. This increases the extendibility of the results to the general population of depressed patients (45). The risk, of course, is that the results of the studies point in so many directions that they too cancel each other out and obscure important links between volume and depression in certain subpopulations of patients.

It is therefore important to analyze the causes of the significant heterogeneity found among the studies included. The studies of unipolar depression patients are comparable regarding the MRI scanner used and spatial resolution applied in contrast to the studies of bipolar disorder patients. None of the studies showed any statistical differences in total intracranial volume between patients and healthy subjects, but all authors corrected for this, either by using relative measurements or by using total intracranial volume as a covariate in the statistical analysis.

Differences in scanning protocols and the delineation of the hippocampal boundaries on the MRI scans are thus important sources of variation between the measurements (46, 47). The meta-analysis is, however, relatively robust against this, since the effect of such moderators in the individual studies were the same in both patients and comparison subjects, and studies using protocols that cause large variance have less influence on the summarized effect size in the meta-analysis because of the weighting of studies. One study especially stood out with very deviating measurements (26) but did not skew the analysis, since stepwise exclusion of one study at a time did not change the effect sizes significantly. The results of the meta-analysis thus cannot be attributed to any single study with extreme results. Clinical and demographical variables can, however, play an important role and were therefore controlled.

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Age and Gender

The hippocampus is generally larger in men than in women, a fact accounted for in the selection of comparison subjects or, in a few of the included studies, by statistical means. Furthermore, decreased hippocampal volume has been reported with increasing age in male but not female healthy volunteers (48). Moreover, significant interaction between hippocampal size, depression, and gender was observed in at least one study of patients with first-episode depression (29). In this study, the volume of the left hippocampus was smaller in male patients, whereas the right was larger in female patients. If correct, this could confound the results of the studies mentioned in t1 as the female-to-male ratio varies considerably (from 0% to 63% male). Generally it is also problematic to draw any conclusions from a study of predominantly male participants to the predominantly female population of depressed patients. Using linear meta-regression we were, however, unable to demonstrate any significant confounding of age and gender on the summarized effect size.

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Treatment Response

The ratio between treatment response and treatment resistance in the study populations may also influence the results. In three studies smaller volume in right hippocampus (32, 35) or reduced density in the left (27) was linked to poor response to antidepressant medication. It is difficult to account for the importance of this fact, since the frequency of refractory depression is practically never stated in the studies. If this result is confirmed, it is clinically very interesting as a potential predictor of treatment response.

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Cumulative Time Being Depressed

Several studies (20, 23) have found a negative correlation between total lifetime duration of depression and volume of the hippocampus since Sheline et al. (21, 22) reported this in women. However, others did not find any relationship between duration of depression or number of episodes and hippocampal volume (26, 28, 33). One study in fact even found nearly the opposite to be the case: smaller hippocampal volumes in late-onset depression (24), supporting the notion that late-onset depression has a different etiology and pathophysiology compared with early-onset depression (1, 49). Omitting this study from the present analysis does not, however, change the results significantly.

Two studies of first-episode patients found no differences in hippocampal volume (20, 29). Accordingly, a meta-regression with the variable RECUR designating the proportion of first-episode patients versus patients with recurrent depression showed a highly significant correlation with the estimate of effect size in the right hemisphere. This means that the number of depressed episodes was correlated with lower volume of right but not left hippocampus, and that some of the heterogeneity can be explained by this variable. The RECUR variable is indeed a very crude measurement of recurrences and probably only loosely correlated to the accumulated time of depression. This crudeness will increase the risk of type II error, thus making our conclusion even stronger. Sheline et al. extended their original data using a much more precise estimate, namely the number of days of untreated depression, and correlated it with hippocampal volume. Their results (R2=0.28, p=0.0006) revealed that 28% of the variation in volume can be explained by this variable (50).

Other studies have used statistical parametric mapping to estimate hippocampal size and found significantly smaller right hippocampi in depressed patients, particularly in patients with a longer course of illness (23). Others found that subjects with chronic depression showed reduced gray matter density in the left temporal cortex, including the hippocampus, and a tendency toward reduction in the right hippocampus (27).

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Limitations of the Study

In principle, cross-sectional studies such as those included in the present analyses cannot conclude about causality. Does the depression cause shrinkage of the hippocampus or are subjects with small hippocampi susceptible to depression? It is tempting to conclude the former on the basis of our meta-regression and the data of Sheline et al. (50), but longitudinal follow-up studies are necessary. We have therefore initiated a study along these lines at our department.

A confounding effect of posttraumatic stress disorder and early lifetime stress, which both are often followed by depression, cannot be completely excluded. In some studies, but not all, these conditions have been associated with reduced hippocampal size (51, 52). Hence, it is important in future studies to account for such factors.

Other factors can also act as confounders, such as adolescent-onset alcohol abuse, which has been connected to smaller hippocampi (53), but this has been accounted for in the studies.

We abstained from performing a meta-analysis of the data on bipolar disorder patients because of the small number of studies and because some of the studies used scanning techniques that today must be considered suboptimal. The conclusions on this topic are therefore tentative.

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Depression, Hippocampal Shrinkage, Cognitive Deficits, Dementia?

Volume reduction of the hippocampus offers an explanation of recent epidemiological and clinical findings of depression being a risk factor for dementia. A large register study showing that affective patients had an increased risk of developing dementia compared with the general Danish population (54) has recently been confirmed by meta-analyses (55, 56). Moreover, cognitive impairment has been demonstrated even in the euthymic phase in patients with unipolar depression and bipolar disorder (57, 58), and severity of the deficits has been shown to correlate with the number of affective episodes (59).

A few MRI studies have supported a connection between hippocampal abnormalities in depressed patients and cognitive deficits. In a study of patients with chronic depression, reduced gray matter density was found in the left temporal cortex, including the hippocampus, as well as a tendency toward reduction in the right hippocampus. Left hippocampal gray matter density was correlated with verbal recognition memory: the higher the density, the better the performance (27). Relative to matched comparison subjects, euthymic women with recurrent depression showed smaller bilateral hippocampal volumes and a lower score in verbal memory, which is a neuropsychological measure of hippocampal function. In contrast, no difference in overall brain size or general intellectual performance was found (22). Concurrently, another study found impairments on hippocampus-dependent verbal memory tests in both patients with first-episode depression and those with multiple episodes. However, only the latter group had hippocampal volume reductions, which suggests that dysfunctions of the hippocampus predate detectable structural changes (20).

Two studies of geriatric depression found correlations between the brief assessment of memory and attention from the Mini-Mental State Examination and volume deficits in the left (24) and bilateral (33) hippocampus, although one study did not find any associations (23). It is of interest that having a small left hippocampus has been found to predict dementia at 5-year follow-up in a group of 115 older nondemented depressed individuals (60).

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What Is the Mechanism Behind the Decreased Hippocampal Volume?

The nature of the volume reduction of hippocampus is not known. The elevated glucocorticoid levels often seen in severely depressed patients (11) along with the decreased hippocampal volume suggest a mechanism for putative neuronal loss seen within depressive patients either by apoptosis (programmed cell death) or inhibition of neurogenesis (6163). Other mechanisms are, however, also possible, such as reduction of the volume of individual neurons or reduction of glia tissue (64, 65). Numerous animal studies have shown that glucocorticoids are toxic to the hippocampus, analogous to what is seen in Cushing’s syndrome, in which the patients exhibit cognitive dysfunction, depression, and reduced hippocampal volume in addition to the other symptoms characteristic for this disease (66). It is thus well established that approximately half of depressed patients have hypothalamic-pituitary-adrenal (HPA) axis hyperactivity (11, 67, 68). This abnormality could implicate hippocampal dysfunction because of its inhibitory influence on the HPA axis (6971). In a PET study of relatively acutely depressed patients, we found markedly increased blood flow to the hippocampus (12), whereas others have found decreased activity in the parahippocampal area in a study of patients with treatment-resistant depression with a very long depression history (72). It is therefore tempting to hypothesize that in some types of depression, stressful life events may initiate a vicious circle in which increased cortisol levels gradually overstimulate the hippocampal cells, leading to their death and further decreasing the inhibitory regulation of the HPA axis (7376). However, only one volumetric study of depression has been performed where the authors also measured cortisol after a dexamethasone suppression test, but unfortunately their MRI technique did not allow separation of amygdala from the hippocampus (77). In future research the combination of measuring HPA activity together with hippocampal volume in longitudinal studies is important.

It is not known whether the reduction in volume is reversible. Several studies have, however, suggested that treatment of depression can stop hippocampal atrophy or even reduce it (7880), and a recent study has suggested that the behavioral effects of chronic antidepressant treatment may be mediated by the stimulation of neurogenesis in the hippocampus (81). Furthermore, neuropathological evidence from postmortem studies of patients with major depressive disorder or bipolar disorder suggests that depression is a disorder of neuroplasticity and cellular resilience and not a neurodegenerative disease (65, 82). The aforementioned connection between depression, stress, cortisol, and reduced hippocampal volume is intriguing. It is tempting to speculate that the hippocampus in patients with bipolar disorder being of normal size points to differences in pathogenesis between unipolar depression and bipolar disorder, but this requires further research because of the small number of volumetric studies of bipolar disorder patients.

In the present meta-analysis we found an average reduction of hippocampal volume of 8% in the left hemisphere and 10% in the right hemisphere in depressed patients relative to comparison subjects. It is interesting that a recent PET study of acutely depressed patients also found abnormalities in the right hippocampus (12). Reduced hippocampal volume is, however, not specific for depression, since it is also seen to a much larger degree in Alzheimer’s disease (83).

The present findings of reduced hippocampal volume in unipolar depression and a correlation with the number of episodes are clinically interesting and in accordance with the predictions of the so-called glucocorticoid cascade hypothesis, although other explanations are also possible. If hippocampal volume reduction is a consequence of untreated depression, secondary prophylaxis to prevent the damage to the hippocampus becomes extremely important, especially since several studies suggest that treatment can stop the shrinkage or even reduce it. To test these hypotheses, longitudinal studies are necessary.

   

Received Aug. 29, 2003; revision received Dec. 9, 2003; accepted Jan. 9, 2004. From the Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital, Aarhus University Hospital. Address reprint requests to Dr. Videbech, Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital, Aarhus University Hospital, DK-8240 Risskov, Denmark; videbech@dadlnet.dk (e-mail).

 
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Figure 1.

Standardized Mean Difference of Left Hippocampal Volume in Patients With Depression Relative to Comparison Subjects From a Meta-Analysis of 12 MRI Studiesa

aOverall difference represents the Derimonian-Laird pooled effect size, calculated under the assumption of a random effects model. Studies are grouped by their RECUR variable, a value assigned on the basis of patient group type (1=first-episode patients, 2=mixed group, 3=patients with recurrent depression).

 
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Figure 2.

Standardized Mean Difference of Right Hippocampal Volume in Patients With Depression Relative to Comparison Subjects From a Meta-Analysis of 12 MRI Studiesa

aOverall difference represents the Derimonian-Laird pooled effect size, calculated under the assumption of a random effects model. Studies are grouped by their RECUR variable, a value assigned on the basis of patient group type (1=first-episode patients, 2=mixed group, 3=patients with recurrent depression).

 
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Figure 3.

Publication Bias Test of Meta-Analysis Resultsa

aFor the 12 studies that showed an overall statistically significant difference in hippocampal volume between depressed patients and healthy subjects, the Begg’s funnel plot confirms no obvious signs of publication bias.

Videbech P: MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatr Scand  1997; 96:157–168
[PubMed]
[CrossRef]
 
Strakowski SM, Adler CM, DelBello MP: Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord  2002; 4:80–88
[PubMed]
[CrossRef]
 
Soares JC, Mann JJ: The anatomy of mood disorders—review of structural neuroimaging studies. Biol Psychiatry  1997; 41:86–106
[PubMed]
[CrossRef]
 
Beyer JL, Krishnan KR: Volumetric brain imaging findings in mood disorders. Bipolar Disord  2002; 4:89–104
[PubMed]
 
Videbech P: PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand  2000; 101:11–20
[PubMed]
 
Fanselow MS: Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res  2000; 110:73–81
[PubMed]
[CrossRef]
 
Burgess N, Maguire EA, O’Keefe J: The human hippocampus and spatial and episodic memory. Neuron  2002; 35:625–641
[PubMed]
[CrossRef]
 
Veiel HO: A preliminary profile of neuropsychological deficits associated with major depression. J Clin Exp Neuropsychol  1997; 19:587–603
[PubMed]
[CrossRef]
 
Ravnkilde B, Videbech P, Clemmensen K, Egander A, Rasmussen NA, Rosenberg R: Cognitive deficits in major depression. Scand J Psychol  2002; 43:239–251
[PubMed]
[CrossRef]
 
Kim JJ, Diamond DM: The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci  2002; 3:453–462
[PubMed]
[CrossRef]
 
Checkley S: The neuroendocrinology of depression. Int Rev Psychiatry  1996; 8:373–378
[CrossRef]
 
Videbech P, Ravnkilde B, Pedersen AR, Egander A, Landbo B, Rasmussen NA, Andersen F, Stødkilde-Jørgensen H, Gjedde A, Rosenberg R: The Danish PET/Depression Project: PET findings in patients with major depression. Psychol Med  2001; 31:1147–1158
[PubMed]
 
Videbech P, Ravnkilde B, Pedersen TH, Hartvig H, Egander A, Clemmensen K, Rasmussen NA, Andersen F, Gjedde A, Rosenberg R: The Danish PET/Depression Project: clinical symptoms and cerebral blood flow: a regions-of-interest analysis. Acta Psychiatr Scand  2002; 106:35–44
[PubMed]
[CrossRef]
 
Saxena S, Brody AL, Ho ML, Alborzian S, Ho MK, Maidment KM, Huang SC, Wu HM, Au SC, Baxter LR Jr: Cerebral metabolism in major depression and obsessive-compulsive disorder occurring separately and concurrently. Biol Psychiatry  2001; 50:159–170
[PubMed]
[CrossRef]
 
Sheline YI, Mittler BL, Mintun MA: The hippocampus and depression. Eur Psychiatry  2002; 17:300–305
 
de Asis JM, Stern E, Alexopoulos GS, Pan H, Van Gorp W, Blumberg H, Kalayam B, Eidelberg D, Kiosses D, Silbersweig DA: Hippocampal and anterior cingulate activation deficits in patients with geriatric depression. Am J Psychiatry  2001; 158:1321–1323
[PubMed]
[CrossRef]
 
Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ: Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry  2001; 158:899–905
[PubMed]
 
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry  2000; 48:830–843
[PubMed]
[CrossRef]
 
Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA: The functional neuroanatomy of the placebo effect. Am J Psychiatry  2002; 159:728–737
[PubMed]
[CrossRef]
 
MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT: Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA  2003; 100:1387–1392
[PubMed]
[CrossRef]
 
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA  1996; 93:3908–3913
[PubMed]
[CrossRef]
 
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; 19:5034–5043
[PubMed]
 
Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF III, Becker JT: Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. Am J Psychiatry  2002; 159:1424–1427
[PubMed]
[CrossRef]
 
Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, MacFall JR, Krishnan KR: Hippocampal volume in geriatric depression. Biol Psychiatry  2000; 48:301–309
[PubMed]
[CrossRef]
 
Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J: Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med  2000; 30:117–125
[PubMed]
[CrossRef]
 
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS: Hippocampal volume reduction in major depression. Am J Psychiatry  2000; 157:115–117
[PubMed]
 
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; 172:527–532
[PubMed]
[CrossRef]
 
Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, Babb CM, Csernansky JG: High-dimensional mapping of the hippocampus in depression. Am J Psychiatry  2003; 160:83–89
[PubMed]
[CrossRef]
 
Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jäger M, Leinsinger G, Bottlender R, Hahn K, Möller H-J: Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry  2002; 159:1112–1118
[PubMed]
[CrossRef]
 
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; 50:960–964
[PubMed]
[CrossRef]
 
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; 12:493–498
[PubMed]
[CrossRef]
 
Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA: Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry  2000; 47:1087–1090
[PubMed]
[CrossRef]
 
Ashtari M, Greenwald BS, Kramer-Ginsberg E, Hu J, Wu H, Patel M, Aupperle P, Pollack S: Hippocampal/amygdala volumes in geriatric depression. Psychol Med  1999; 29:629–638
[PubMed]
[CrossRef]
 
Pantel J, Schroder J, Essig M, Popp D, Dech H, Knopp MV, Schad LR, Eysenbach K, Backenstrass M, Friedlinger M: Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia. J Affect Disord  1997; 42:69–83
[PubMed]
[CrossRef]
 
Hsieh MH, McQuoid DR, Levy RM, Payne ME, MacFall JR, Steffens DC: Hippocampal volume and antidepressant response in geriatric depression. Int J Geriatr Psychiatry  2002; 17:519–525
[PubMed]
[CrossRef]
 
Swayze VW II, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC: Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry  1992; 31:221–240
[PubMed]
 
Pearlson GD, Barta PE, Powers RE, Menon RR, Richards SS, Aylward EH, Federman EB, Chase GA, Petty RG, Tien AY: Ziskind-Somerfeld Research Award 1996: medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry  1997; 41:1–14
[PubMed]
[CrossRef]
 
Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J: Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry  1998; 55:663–664
[PubMed]
[CrossRef]
 
Hirayasu Y, Shenton ME, Salisbury DF, Dickey CC, Fischer IA, Mazzoni P, Kisler T, Arakaki H, Kwon JS, Anderson JE, Yurgelun-Todd D, Tohen M, McCarley RW: Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry  1998; 155:1384–1391
[PubMed]
 
Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res  2003; 37:287–295
[PubMed]
[CrossRef]
 
Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X, Post RM: MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord  2000; 60:25–32
[PubMed]
[CrossRef]
 
Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER: Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry  1999; 56:254–260
[PubMed]
[CrossRef]
 
Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Smith-Jackson EE, Leverich GS, Post RM: Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study. Neuropsychiatry Neuropsychol Behav Neurol  2001; 14:227–232
[PubMed]
 
Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Mirsky AF, Smith-Jackson EE, Post RM: A preliminary study of the relation of neuropsychological performance to neuroanatomic structures in bipolar disorder. Neuropsychiatry Neuropsychol Behav Neurol  2000; 13:20–28
[PubMed]
 
Matt GE, Cook TD: Threats to the validity of research syntheses, in The Handbook of Research Synthesis. Edited by Cooper H, Hedges LV. New York, Russell Sage Foundation, 1994, pp 503–520
 
Pantel J, O’Leary DS, Cretsinger K, Bockholt HJ, Keefe H, Magnotta VA, Andreasen NC: A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus  2000; 10:752–758
[PubMed]
[CrossRef]
 
Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL: Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res  1997; 75:31–48
[PubMed]
[CrossRef]
 
Pruessner JC, Collins DL, Pruessner M, Evans AC: Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood. J Neurosci  2001; 21:194–200
[PubMed]
 
Krishnan KR: Biological risk factors in late life depression. Biol Psychiatry  2002; 52:185–192
[PubMed]
[CrossRef]
 
Sheline YI, Gado MH, Kraemer HV: Untreated depression and hippocampal volume loss. Am J Psychiatry  2003; 160:1516–1518
[PubMed]
[CrossRef]
 
Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP, Kim DM: The neurobiological consequences of early stress and childhood maltreatment. Neurosci Biobehav Rev  2003; 27:33–44
[PubMed]
[CrossRef]
 
Tanev K: Neuroimaging and neurocircuitry in post-traumatic stress disorder: what is currently known? Curr Psychiatry Rep  2003; 5:369–383
[PubMed]
[CrossRef]
 
De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS: Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry  2000; 157:737–744
[PubMed]
[CrossRef]
 
Kessing LV, Olsen EW, Mortensen PB, Andersen PK: Dementia in affective disorder: a case-register study. Acta Psychiatr Scand  1999; 100:176–185
[PubMed]
[CrossRef]
 
Jorm AF: History of depression as a risk factor for dementia: an updated review. Aust NZ J Psychiatry  2001; 35:776–781
[CrossRef]
 
Jorm AF: Is depression a risk factor for dementia or cognitive decline? a review. Gerontology  2000; 46:219–227
[PubMed]
[CrossRef]
 
Trichard C, Martinot JL, Alagille M, Masure MC, Hardy P, Ginestet D, Feline A: Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study. Psychol Med  1995; 25:79–85
[PubMed]
[CrossRef]
 
Paradiso S, Lamberty GJ, Garvey MJ, Robinson RG: Cognitive impairment in the euthymic phase of chronic unipolar depression. J Nerv Ment Dis  1997; 185:748–754
[PubMed]
[CrossRef]
 
Kessing LV: Cognitive impairment in the euthymic phase of affective disorder. Psychol Med  1998; 28:1027–1038
[PubMed]
[CrossRef]
 
Steffens DC, Payne ME, Greenberg DL, Byrum CE, Welsh-Bohmer KA, Wagner HR, MacFall JR: Hippocampal volume and incident dementia in geriatric depression. Am J Geriatr Psychiatry  2002; 10:62–71
[PubMed]
 
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med  1998; 4:1313–1317
[PubMed]
[CrossRef]
 
Lee AL, Ogle WO, Sapolsky RM: Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord  2002; 4:117–128
[PubMed]
[CrossRef]
 
Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry  2000; 57:925–935
[PubMed]
[CrossRef]
 
Cotter DR, Pariante CM, Everall IP: Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull  2001; 55:585–595
[PubMed]
[CrossRef]
 
Rajkowska G: Cell pathology in mood disorders. Semin Clin Neuropsychiatry  2002; 7:281–292
[PubMed]
[CrossRef]
 
Starkman MN, Gebarski SS, Berent S, Schteingart DE: Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry  1992; 32:756–765
[PubMed]
[CrossRef]
 
Arana GW, Baldessarini RJ, Ornsteen M: The dexamethasone suppression test for diagnosis and prognosis in psychiatry: commentary and review. Arch Gen Psychiatry  1985; 42:1193–1204
[PubMed]
 
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB: The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol  1999; 160:1–12
[PubMed]
[CrossRef]
 
Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev  1991; 12:118–134
[PubMed]
[CrossRef]
 
Mitchell A: The contribution of hypercortisolaemia to the cognitive decline of geriatric depression. Int J Geriatr Psychiatry  1995; 10:401–409
[CrossRef]
 
Carrasco GA, Van De Kar LD: Neuroendocrine pharmacology of stress. Eur J Pharmacol  2003; 463:235–272
[PubMed]
[CrossRef]
 
Kimbrell TA, Ketter TA, George MS, Little JT, Benson BE, Willis MW, Herscovitch P, Post RM: Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry  2002; 51:237–252
[PubMed]
[CrossRef]
 
McEwen BS: Effects of adverse experiences for brain structure and function. Biol Psychiatry  2000; 48:721–731
[PubMed]
[CrossRef]
 
Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry  2000; 48:755–765
[PubMed]
[CrossRef]
 
Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry  1997; 54:597–606
[PubMed]
 
Holsboer F: Implications of altered limbic-hypothalamic-pituitary-adrenocortical (LHPA)-function for neurobiology of depression. Acta Psychiatr Scand Suppl  1988; 341:72–111
[PubMed]
 
Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH Jr, Krishnan KR: Hypercortisolemia and hippocampal changes in depression. Psychiatry Res  1993; 47:163–173
[PubMed]
[CrossRef]
 
Pariante CM, Miller AH: Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry  2001; 49:391–404
[PubMed]
[CrossRef]
 
McEwen BS, Magarinos AM: Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Hum Psychopharmacol 2001; 16(suppl 1):S7-S19
 
Miguel-Hidalgo JJ, Rajkowska G: Morphological brain changes in depression: can antidepressants reverse them? CNS Drugs  2002; 16:361–372
[PubMed]
[CrossRef]
 
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science  2003; 301:805–809
[PubMed]
[CrossRef]
 
Manji HK, Moore GJ, Rajkowska G, Chen G: Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry  2000; 5:578–593
[PubMed]
[CrossRef]
 
Scheltens P: Early diagnosis of dementia: neuroimaging. J Neurol  1999; 246:16–20
[PubMed]
 

Figure 1.

Standardized Mean Difference of Left Hippocampal Volume in Patients With Depression Relative to Comparison Subjects From a Meta-Analysis of 12 MRI Studiesa

aOverall difference represents the Derimonian-Laird pooled effect size, calculated under the assumption of a random effects model. Studies are grouped by their RECUR variable, a value assigned on the basis of patient group type (1=first-episode patients, 2=mixed group, 3=patients with recurrent depression).

Figure 2.

Standardized Mean Difference of Right Hippocampal Volume in Patients With Depression Relative to Comparison Subjects From a Meta-Analysis of 12 MRI Studiesa

aOverall difference represents the Derimonian-Laird pooled effect size, calculated under the assumption of a random effects model. Studies are grouped by their RECUR variable, a value assigned on the basis of patient group type (1=first-episode patients, 2=mixed group, 3=patients with recurrent depression).

Figure 3.

Publication Bias Test of Meta-Analysis Resultsa

aFor the 12 studies that showed an overall statistically significant difference in hippocampal volume between depressed patients and healthy subjects, the Begg’s funnel plot confirms no obvious signs of publication bias.

+

References

Videbech P: MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatr Scand  1997; 96:157–168
[PubMed]
[CrossRef]
 
Strakowski SM, Adler CM, DelBello MP: Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord  2002; 4:80–88
[PubMed]
[CrossRef]
 
Soares JC, Mann JJ: The anatomy of mood disorders—review of structural neuroimaging studies. Biol Psychiatry  1997; 41:86–106
[PubMed]
[CrossRef]
 
Beyer JL, Krishnan KR: Volumetric brain imaging findings in mood disorders. Bipolar Disord  2002; 4:89–104
[PubMed]
 
Videbech P: PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand  2000; 101:11–20
[PubMed]
 
Fanselow MS: Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res  2000; 110:73–81
[PubMed]
[CrossRef]
 
Burgess N, Maguire EA, O’Keefe J: The human hippocampus and spatial and episodic memory. Neuron  2002; 35:625–641
[PubMed]
[CrossRef]
 
Veiel HO: A preliminary profile of neuropsychological deficits associated with major depression. J Clin Exp Neuropsychol  1997; 19:587–603
[PubMed]
[CrossRef]
 
Ravnkilde B, Videbech P, Clemmensen K, Egander A, Rasmussen NA, Rosenberg R: Cognitive deficits in major depression. Scand J Psychol  2002; 43:239–251
[PubMed]
[CrossRef]
 
Kim JJ, Diamond DM: The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci  2002; 3:453–462
[PubMed]
[CrossRef]
 
Checkley S: The neuroendocrinology of depression. Int Rev Psychiatry  1996; 8:373–378
[CrossRef]
 
Videbech P, Ravnkilde B, Pedersen AR, Egander A, Landbo B, Rasmussen NA, Andersen F, Stødkilde-Jørgensen H, Gjedde A, Rosenberg R: The Danish PET/Depression Project: PET findings in patients with major depression. Psychol Med  2001; 31:1147–1158
[PubMed]
 
Videbech P, Ravnkilde B, Pedersen TH, Hartvig H, Egander A, Clemmensen K, Rasmussen NA, Andersen F, Gjedde A, Rosenberg R: The Danish PET/Depression Project: clinical symptoms and cerebral blood flow: a regions-of-interest analysis. Acta Psychiatr Scand  2002; 106:35–44
[PubMed]
[CrossRef]
 
Saxena S, Brody AL, Ho ML, Alborzian S, Ho MK, Maidment KM, Huang SC, Wu HM, Au SC, Baxter LR Jr: Cerebral metabolism in major depression and obsessive-compulsive disorder occurring separately and concurrently. Biol Psychiatry  2001; 50:159–170
[PubMed]
[CrossRef]
 
Sheline YI, Mittler BL, Mintun MA: The hippocampus and depression. Eur Psychiatry  2002; 17:300–305
 
de Asis JM, Stern E, Alexopoulos GS, Pan H, Van Gorp W, Blumberg H, Kalayam B, Eidelberg D, Kiosses D, Silbersweig DA: Hippocampal and anterior cingulate activation deficits in patients with geriatric depression. Am J Psychiatry  2001; 158:1321–1323
[PubMed]
[CrossRef]
 
Kennedy SH, Evans KR, Krüger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ: Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry  2001; 158:899–905
[PubMed]
 
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry  2000; 48:830–843
[PubMed]
[CrossRef]
 
Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA: The functional neuroanatomy of the placebo effect. Am J Psychiatry  2002; 159:728–737
[PubMed]
[CrossRef]
 
MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT: Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA  2003; 100:1387–1392
[PubMed]
[CrossRef]
 
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW: Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA  1996; 93:3908–3913
[PubMed]
[CrossRef]
 
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; 19:5034–5043
[PubMed]
 
Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF III, Becker JT: Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. Am J Psychiatry  2002; 159:1424–1427
[PubMed]
[CrossRef]
 
Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, MacFall JR, Krishnan KR: Hippocampal volume in geriatric depression. Biol Psychiatry  2000; 48:301–309
[PubMed]
[CrossRef]
 
Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J: Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med  2000; 30:117–125
[PubMed]
[CrossRef]
 
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS: Hippocampal volume reduction in major depression. Am J Psychiatry  2000; 157:115–117
[PubMed]
 
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; 172:527–532
[PubMed]
[CrossRef]
 
Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, Babb CM, Csernansky JG: High-dimensional mapping of the hippocampus in depression. Am J Psychiatry  2003; 160:83–89
[PubMed]
[CrossRef]
 
Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jäger M, Leinsinger G, Bottlender R, Hahn K, Möller H-J: Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry  2002; 159:1112–1118
[PubMed]
[CrossRef]
 
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; 50:960–964
[PubMed]
[CrossRef]
 
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; 12:493–498
[PubMed]
[CrossRef]
 
Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA: Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry  2000; 47:1087–1090
[PubMed]
[CrossRef]
 
Ashtari M, Greenwald BS, Kramer-Ginsberg E, Hu J, Wu H, Patel M, Aupperle P, Pollack S: Hippocampal/amygdala volumes in geriatric depression. Psychol Med  1999; 29:629–638
[PubMed]
[CrossRef]
 
Pantel J, Schroder J, Essig M, Popp D, Dech H, Knopp MV, Schad LR, Eysenbach K, Backenstrass M, Friedlinger M: Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia. J Affect Disord  1997; 42:69–83
[PubMed]
[CrossRef]
 
Hsieh MH, McQuoid DR, Levy RM, Payne ME, MacFall JR, Steffens DC: Hippocampal volume and antidepressant response in geriatric depression. Int J Geriatr Psychiatry  2002; 17:519–525
[PubMed]
[CrossRef]
 
Swayze VW II, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC: Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry  1992; 31:221–240
[PubMed]
 
Pearlson GD, Barta PE, Powers RE, Menon RR, Richards SS, Aylward EH, Federman EB, Chase GA, Petty RG, Tien AY: Ziskind-Somerfeld Research Award 1996: medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry  1997; 41:1–14
[PubMed]
[CrossRef]
 
Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J: Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry  1998; 55:663–664
[PubMed]
[CrossRef]
 
Hirayasu Y, Shenton ME, Salisbury DF, Dickey CC, Fischer IA, Mazzoni P, Kisler T, Arakaki H, Kwon JS, Anderson JE, Yurgelun-Todd D, Tohen M, McCarley RW: Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry  1998; 155:1384–1391
[PubMed]
 
Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res  2003; 37:287–295
[PubMed]
[CrossRef]
 
Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X, Post RM: MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord  2000; 60:25–32
[PubMed]
[CrossRef]
 
Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER: Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry  1999; 56:254–260
[PubMed]
[CrossRef]
 
Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Smith-Jackson EE, Leverich GS, Post RM: Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study. Neuropsychiatry Neuropsychol Behav Neurol  2001; 14:227–232
[PubMed]
 
Ali SO, Denicoff KD, Altshuler LL, Hauser P, Li X, Conrad AJ, Mirsky AF, Smith-Jackson EE, Post RM: A preliminary study of the relation of neuropsychological performance to neuroanatomic structures in bipolar disorder. Neuropsychiatry Neuropsychol Behav Neurol  2000; 13:20–28
[PubMed]
 
Matt GE, Cook TD: Threats to the validity of research syntheses, in The Handbook of Research Synthesis. Edited by Cooper H, Hedges LV. New York, Russell Sage Foundation, 1994, pp 503–520
 
Pantel J, O’Leary DS, Cretsinger K, Bockholt HJ, Keefe H, Magnotta VA, Andreasen NC: A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus  2000; 10:752–758
[PubMed]
[CrossRef]
 
Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL: Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res  1997; 75:31–48
[PubMed]
[CrossRef]
 
Pruessner JC, Collins DL, Pruessner M, Evans AC: Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood. J Neurosci  2001; 21:194–200
[PubMed]
 
Krishnan KR: Biological risk factors in late life depression. Biol Psychiatry  2002; 52:185–192
[PubMed]
[CrossRef]
 
Sheline YI, Gado MH, Kraemer HV: Untreated depression and hippocampal volume loss. Am J Psychiatry  2003; 160:1516–1518
[PubMed]
[CrossRef]
 
Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP, Kim DM: The neurobiological consequences of early stress and childhood maltreatment. Neurosci Biobehav Rev  2003; 27:33–44
[PubMed]
[CrossRef]
 
Tanev K: Neuroimaging and neurocircuitry in post-traumatic stress disorder: what is currently known? Curr Psychiatry Rep  2003; 5:369–383
[PubMed]
[CrossRef]
 
De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS: Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry  2000; 157:737–744
[PubMed]
[CrossRef]
 
Kessing LV, Olsen EW, Mortensen PB, Andersen PK: Dementia in affective disorder: a case-register study. Acta Psychiatr Scand  1999; 100:176–185
[PubMed]
[CrossRef]
 
Jorm AF: History of depression as a risk factor for dementia: an updated review. Aust NZ J Psychiatry  2001; 35:776–781
[CrossRef]
 
Jorm AF: Is depression a risk factor for dementia or cognitive decline? a review. Gerontology  2000; 46:219–227
[PubMed]
[CrossRef]
 
Trichard C, Martinot JL, Alagille M, Masure MC, Hardy P, Ginestet D, Feline A: Time course of prefrontal lobe dysfunction in severely depressed in-patients: a longitudinal neuropsychological study. Psychol Med  1995; 25:79–85
[PubMed]
[CrossRef]
 
Paradiso S, Lamberty GJ, Garvey MJ, Robinson RG: Cognitive impairment in the euthymic phase of chronic unipolar depression. J Nerv Ment Dis  1997; 185:748–754
[PubMed]
[CrossRef]
 
Kessing LV: Cognitive impairment in the euthymic phase of affective disorder. Psychol Med  1998; 28:1027–1038
[PubMed]
[CrossRef]
 
Steffens DC, Payne ME, Greenberg DL, Byrum CE, Welsh-Bohmer KA, Wagner HR, MacFall JR: Hippocampal volume and incident dementia in geriatric depression. Am J Geriatr Psychiatry  2002; 10:62–71
[PubMed]
 
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med  1998; 4:1313–1317
[PubMed]
[CrossRef]
 
Lee AL, Ogle WO, Sapolsky RM: Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord  2002; 4:117–128
[PubMed]
[CrossRef]
 
Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry  2000; 57:925–935
[PubMed]
[CrossRef]
 
Cotter DR, Pariante CM, Everall IP: Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull  2001; 55:585–595
[PubMed]
[CrossRef]
 
Rajkowska G: Cell pathology in mood disorders. Semin Clin Neuropsychiatry  2002; 7:281–292
[PubMed]
[CrossRef]
 
Starkman MN, Gebarski SS, Berent S, Schteingart DE: Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry  1992; 32:756–765
[PubMed]
[CrossRef]
 
Arana GW, Baldessarini RJ, Ornsteen M: The dexamethasone suppression test for diagnosis and prognosis in psychiatry: commentary and review. Arch Gen Psychiatry  1985; 42:1193–1204
[PubMed]
 
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB: The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol  1999; 160:1–12
[PubMed]
[CrossRef]
 
Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev  1991; 12:118–134
[PubMed]
[CrossRef]
 
Mitchell A: The contribution of hypercortisolaemia to the cognitive decline of geriatric depression. Int J Geriatr Psychiatry  1995; 10:401–409
[CrossRef]
 
Carrasco GA, Van De Kar LD: Neuroendocrine pharmacology of stress. Eur J Pharmacol  2003; 463:235–272
[PubMed]
[CrossRef]
 
Kimbrell TA, Ketter TA, George MS, Little JT, Benson BE, Willis MW, Herscovitch P, Post RM: Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry  2002; 51:237–252
[PubMed]
[CrossRef]
 
McEwen BS: Effects of adverse experiences for brain structure and function. Biol Psychiatry  2000; 48:721–731
[PubMed]
[CrossRef]
 
Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry  2000; 48:755–765
[PubMed]
[CrossRef]
 
Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry  1997; 54:597–606
[PubMed]
 
Holsboer F: Implications of altered limbic-hypothalamic-pituitary-adrenocortical (LHPA)-function for neurobiology of depression. Acta Psychiatr Scand Suppl  1988; 341:72–111
[PubMed]
 
Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH Jr, Krishnan KR: Hypercortisolemia and hippocampal changes in depression. Psychiatry Res  1993; 47:163–173
[PubMed]
[CrossRef]
 
Pariante CM, Miller AH: Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry  2001; 49:391–404
[PubMed]
[CrossRef]
 
McEwen BS, Magarinos AM: Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Hum Psychopharmacol 2001; 16(suppl 1):S7-S19
 
Miguel-Hidalgo JJ, Rajkowska G: Morphological brain changes in depression: can antidepressants reverse them? CNS Drugs  2002; 16:361–372
[PubMed]
[CrossRef]
 
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science  2003; 301:805–809
[PubMed]
[CrossRef]
 
Manji HK, Moore GJ, Rajkowska G, Chen G: Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry  2000; 5:578–593
[PubMed]
[CrossRef]
 
Scheltens P: Early diagnosis of dementia: neuroimaging. J Neurol  1999; 246:16–20
[PubMed]
 
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