Hippocampal volume in first episode and recurrent depression
Klaus-Thomas Kronmüllera,⁎, Johannes Schröderb, Sebastian Köhlera, Bianca Götza, Daniela Victora,
Jörg Ungera, Frederic Gieselc, Vincent Magnottad, Christoph Mundta, Marco Essigc, Johannes Pantele
aDepartment of Psychiatry, University of Heidelberg, Germany
bSection of Geriatric Psychiatry, University of Heidelberg, Germany
cDepartment of Radiology, German Cancer Research Center, Heidelberg, Germany
dMental Health Clinical Research Center, Department of Psychiatry, University of Iowa, Iowa City, IA, USA
eDepartment of Psychiatry and Psychotherapy, University of Frankfurt/Main, Germany
a b s t r a c ta r t i c l ei n f o
Received 9 March 2007
Received in revised form 17 December 2007
Accepted 5 August 2008
Structural brain imaging
Abnormalities in limbic–thalamic–cortical networks are hypothesized to modulate human mood states. In
the present study differences in hippocampal volumes of patients with a first episode of depression,
recurrent major depression and healthy control subjects were examined with high-resolution magnetic
resonance imaging (MRI). Male patients with a first episode of major depression had a significantly smaller
left hippocampal volume than male control subjects. Also, these patients had a significant left–right
asymmetry in hippocampal volume. Female patients showed no significant alterations in hippocampal
volumes. The results support the hypothesis that the hippocampus plays an important role in the
pathophysiology of the early phase of major depression, especially for male patients. Implications for the
neurodevelopmental and the neurodegenerative model of hippocampal change are discussed.
© 2008 Elsevier Ireland Ltd. All rights reserved.
Increasing evidence has shown structural cerebral abnormalities in
limbic–thalamic–cortical networks inpatients with unipolar depression
(Soares and Mann,1997; Campbell and MacQueen, 2003, 2006). A core
and emotional regulation deficits that often accompany depression.
Several structural imaging studies have found abnormalities in hippo-
a smaller volume unilaterally, others founda bilaterallysmallerone, and
(Videbech and Ravnkilde, 2004; Campbell et al., 2004; Campbell and
MacQueen, 2006). In recent studies a smaller hippocampal volume has
been found only in subsamples of depressed patients. It has been
presumed that the inconsistencies inresults cannot solely be ascribed to
the heterogeneity of MRI methods but also to the sampling, which was
inconsistent concerning the proportion of first episode and recurrently
depressed patients as well as the gender ratio (Videbech and Ravnkilde,
2004; Campbell et al., 2004). Frodl et al. (2002) compared depressive
men and women with healthy controls and found a smaller left
hippocampal volume only for men with a first episode of major
depression. MacMaster and Kusumakar (2004) found an even more
pronounced reduction in left hippocampal volume in male adolescent
patients. In contrast, MacQueen et al. (2003) found that patients with
multiple episodes in comparison to first episode patients were more
likely to have smaller hippocampal volumes. To date, only one study
exists, namely that of MacQueen et al. (2003), which systematically
compares first episode and recurrently depressed patients, and also
considers gender effects. The aim of the present study therefore was to
compare thehippocampal formation of male andfemale patients with a
The hypotheses were that depressed patients have a smaller hippocam-
pal volume in comparison to healthy control subjects and that patients
with multiple episodes have a smaller hippocampal volume in
comparison to patients with a first episode of major depression.
Fifty-seven inpatients with major depression according to DSM-IV
(American Psychiatric Association,1994) treated in the Department of
Psychiatry of the University in Heidelberg were recruited. The
diagnoses were made using a structured clinical interview (SCID;
Wittchen et al., 1997). The mean age of the 33 female and 24 male
seven (47.37%) patients were married. Twenty-two (38.60%) had a
high and 35 (61.40%) a low level of school education. Twenty-six
(45.61%) patients had a first episode of major depression. The mean
score in the 17-item Hamilton Depression Rating Scale (HDRS;
Hamilton, 1960) was 22.74 (S.D.=6.58) at admission to treatment.
Psychiatry Research: Neuroimaging 174 (2009) 62–66
⁎ Corresponding author. Department of Psychiatry, University of Heidelberg,
Voßstraße 4, D-69115 Heidelberg, Germany. Tel.: +49 6221 5632747; fax: +49 6221
E-mail address: email@example.com (K.-T. Kronmüller).
0925-4927/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging
journal homepage: www.elsevier.com/locate/psychresns
Mean duration of current depressive episode was 34.79 weeks (S.D.=
47.92) with a median of 15 weeks. Average age of onset of depression
was38.54 years(S.D.=13.27),meandurationof illnesswas5.00years
(S.D.=8.31), and mean number of episodes including the current
episode of depression was 3.09 (S.D.=4.83). Of the consecutively
treated patients fulfilling the inclusioncriteria, eight (11.76%) declined
participation in the studyand three (4.4%) could not take part because
of fulfilling exclusion criteria for the MRI examination. There were no
indications of a systematic selection bias. All patients were receiving
antidepressant medication at the time of the MRI examination: 21
patients (36.84%) were taking serotonin reuptake inhibitors, 12
(21.05%) patients were taking tricyclic antidepressants and 24
(42.11%) patients were taking other new antidepressants. Additionally,
34 patients (59.65%) received some kind of comedication with
benzodiazepines, neuroleptics or mood stabilizers. On average, patients
had been treated with antidepressants for 25.21 weeks (S.D.=53.59)
with a median of 6 weeks. All the participants were screened for
comorbid medical and psychiatric conditions by means of clinical,
physical, and neurological examinations. Exclusion criteria for all
participants were a history of substantial head injury, seizures,
neurological diseases, dementia, impaired thyroid function, corticoid
use or alcohol or substance abuse or dependence. Seventeen of the
patients (29.8%) had a DSM-IV axis I co-morbidity mainly with anxiety
disorders. No patient wasdiagnosed withposttraumatic stress disorder.
Twenty-six of the patients (45.6%) had a personality disorder. For
comparison, 30 healthy subjects (19 female,11 male) without a history
of psychiatric disorder according to the SCID and aged between 18 and
17-item HDRS for the control group was 1.27 (S.D.=1.36).
Patients with a first episode of major depression and recurrent
depression did not differ significantly from healthy comparison
subjects with respect to age, gender, height, weight, handedness,
social class, education and alcohol consumption (see Table 1). There
was a trend for first episode patients to be younger than multiple
episode patients (F=2.17, df=5,81, P=0.12); this effect, however, was
not statistically significant. Therefore, age was included as a covariate in
the volumetric analyses. No statistically significant sex effect was found
between the groups (chi2=1.48, df=2,85, P=0.48). There was a
significant main effect (F=170.0, df=5,81, P=0.001) for severity of
depression (HDRS) with control subjects having lower HDRS scores
compared with depressed patients. No significant difference in severity
of depression was found between first episode patients and patients
with recurrent depression. Patients with a first episode of major
depression and recurrent depression did not differ significantly
regarding age at onset of depression (z=0.19, df=1,56, P=0.85).
Patients with recurrent depression, as would be expected, had a
significantly longer duration of illness compared with first episode
patients (z=−4.74, df=1,56, P=0.001), but no significant differences
P=0.16). Multiple episode patients had suffered 4.84 episodes (S.D.=
6.06) on average. There were neither significant differences between
first episode and multiple episode patients nor between male and
female patients, regarding kind and duration of antidepressant medica-
tion (see Table 1).
After a complete description of the study was given to the patients
and normal control subjects, written informed consent was obtained.
The study protocol was approved by the local ethics committee and
was prepared in accordance with the ethical standards laid down in
the Declaration of Helsinki.
2.2. Magnetic resonance imaging and image analysis
MRI scans of the whole brain were obtained by using a Siemens
1.5-Tesla MR scanner (Siemens Medical Systems, Inc., Erlangen,
Germany). T1-weighted three-dimensional magnetization-prepared
rapid gradient echo sequences (3D-MPRAGE) were acquired with the
following parameters: 124 1.5-mm coronal slices, TR=11.6 ms,
TE=4.9 ms, total acquisition time=9 min, FOV=260 mm, number
of acquisitions=1, matrix=512×512. T2-weighted images were
acquired with the following parameters: 2-mm coronal slices,
TR=7840 ms, TE=54 ms, total acquisition time=4 min, number of
acquisitions=1, FOV=260 mm, matrix=256×192. Image proces-
sing was performed on a computer workstation (Silicon Graphics Inc.,
Mountain View, Calif) using the BRAINS (Brain Research: Analysis of
Images, Networks, and Systems) software package (Andreasen et al.,
1992). As part of the segmentation procedure of BRAINS, intracranial
volume total brainvolumewas determinedsemi-automatically. In this
study, hippocampal volume was measured by using a reliable and
validated method which was previously described in detail by Pantel
et al. (2000). The hippocampal formation was measured according to
Sociodemographical and clinical characteristics of the sample (n=87).
Total sample major
First episode major
S.D. Mean N
Hamilton Depression Rating Scale (HDRS)b
Number of episode
Fourth or more
Age at onsetc
Duration of illnessd
Duration of current episodec
Duration of AD medicationc
in weeks53.59 44.6760.59 NA
For detailed F and P values see text.
NA: not applicable.
aNo significant differences were found between patients and controls or between first episode patients and patients with recurrent depression.
bSignificant differences were found between patients and controls but not between first episode patients and patients with recurrent depression.
cNo significant differences were found between first episode patients and patients with recurrent depression.
dSignificant differences were found between first episode patients and patients with recurrent depression.
K.-T. Kronmüller et al. / Psychiatry Research: Neuroimaging 174 (2009) 62–66
its true anatomical definition based on the concise and extensive
morphological description given by H.M. Duvernoy in his Atlas of
Applied Hippocampal Anatomy (Duvernoy, 1988). The hippocampal
formation was traced manually on the continuous segmented image
(stereo image) provided by BRAINS. This could be accomplished by
relying on the capacity of the used software (BRAINS) of simultaneous
visualization in multiple planes, by the capacity to “telegraph”
tracings or cursor position from one plane to another, and by
simultaneously relying on information from the two different image
modalities (T1 and T2). Once BRAINS had been started, the stereo
image and the realigned and fitted T1 and T2 images were loaded. In
accordance with most previously published methods for the volu-
metric measurement of the hippocampus, the regions of interest were
defined on the coronal plane. However, tracing began with the
generation of the auxiliary guideline traces on the sagittal plane. The
auxiliary traces were necessary to provide a neuroanatomically
correct separation of rostral (head) and caudal (tail) parts of the
hippocampus from adjacent non-hippocampal brain tissue. A detailed
description of boundary definition is provided at: http://iowa-mhcrc.
reliability for two independent raterswascalculatedusingtheintraclass
correlation coefficient (ICC) for volumetric assessments of the hippo-
to diagnosis and other sociodemographical and clinical characteristics of
the patients and control subjects, and images were randomly distributed.
The ICCs were 0.97 for the left hippocampus and 0.98 for the right
2.3. Statistical analyses
Morphometric data were normally distributed. They were sub-
jected to a repeated measurement analysis of covariance (ANCOVA)
assessingthemainandinteraction effectsof thewithin-subjectsfactor
usingtotal cranialvolume andageascofactors. Significantinteractions
of this model were resolved by univariate ANCOVAs on the
hippocampal volumes for each region, and diagnostic group, total
cranial volume and age were used as covariates. Contrasts were
performed using the Tukey test. Dependent Student's t-tests were
used for post hoc analysis of (left–right) hemispheric differences.
Results were considered statistically significant if at or below the 5%
probability level (two-tailed). Analyses were performed with SAS
Version 9.12 (SAS System for Windows, 2002–2003).
The hippocampal volumetric data are shown in Table 2. No
significant main effects on hippocampal volume were found for
diagnosis (F=1.45, df=2,79, P=0.24). The main gender effect was
significant (F=8.12, df=1,79, P=0.006), with male subjects having
a larger hippocampal volume than female subjects. The interaction
between diagnosis and gender, however, was not significant (F=1.53,
df=2,79, P=0.22). Also, the hemisphere (left–right asymmetry)
main effect (F=0.83, df=1,80, P=0.36) was not significant. The
interactions of diagnosis, hemisphere, and gender (F=3.33, df=2,79,
P=0.04) on the other hand were significant, whereas the cofactors
age (F=1.50, df=2,79, P=0.22) and intracranial volume (F=0.01,
df=2,79, P=0.99) were not. Post hoc univariate ANCOVA revealed
thatmale patientswitha firstepisodeof depression hada significantly
smaller left hippocampal volume than healthy male control subjects
(F=5.12, df=2,31, P=0.01). The right hippocampal volume, how-
ever, was not significantly different (F=1.77, df=2,31, P=0.19). For
female patients with a first or recurrent episode, no significant
differences in left (F=0.19, df=2,48, P=0.92) and right (F=0.16,
df=2,48, P=0.85) hippocampal volume in comparison with healthy
female subjects were found. Post hoc analysis revealed a significant
left–right asymmetry in male first episode patients (t=2.34, df=12,
P=0.04), whereas male patients with recurrent depression and
healthy male control subjects did not show significant hemispheric
differences. No significant left–right asymmetry was found for female
patients and control subjects. Additionally, there was no significant
difference in total brain volume between the three groups.
An analysis of the association of hippocampal volumes, duration of
illness and duration of the indexepisode neither revealed a significant
correlation for the whole group of depressed patients nor for the
subgroups of first episode patients and patients with recurrent
depression.Moreover, nosignificant correlationsbetween thenumber
of depressive episodes and hippocampal volume could be found for
the whole group of depressed patients or for the male and female
The present study shows that male patients with a first episode of
compared with male control subjects. The reduction in hippocampal
volumeofnearly 10% foundin meta-analysesondepression(Videbech
episode male patients. Depressed male patients with a first episode of
depression also showed a significant hemispheric asymmetry of
hippocampalvolume. It can be assumedthatthisleft-rightasymmetry
indicates the beginning of volume loss in the area of the left
hippocampus. Thus, our results confirm those of Frodl et al. (2002)
and MacMaster and Kusumakar (2004), who also observed a smaller
hippocampal volume only for male first episode patients and only in
theleft hippocampus. In themeta-analysesonhippocampalvolumein
depression (Videbech and Ravnkilde, 2004; Campbell et al., 2004), it
was shown that more studies found a reduction in left than in right
hippocampal volume. However, in most studies no sex effects in
comparisonwith control groups could be identified, and Videbech and
Ravnkilde (2004) did not find a significant sex effect in their meta-
analysis either. This could be due to the relatively small sizes of the
samples, the differences in gender ratio, and the fact that first and
the non-significant sex effects in their meta-analysis, Videbech and
Ravnkilde (2004) assumed that the heterogeneous findings of
structural imaging studies can perhaps be explained by the high
varietyof the female-to-male ratio in several studies. Thus, differences
disorders but these abnormalities also differ depending on sex and
course of the disorder. These associations are complicated by the fact
that physiological gender differences in hippocampal volume exist in
Hippocampal volumes of patients with first episode depression and recurrent
depression in comparison with healthy comparison subjects.
volume and age
Mean S.D.MeanS.D.Mean S.D.
aPatients with first episode major depressionbhealthy comparison subjects.
K.-T. Kronmüller et al. / Psychiatry Research: Neuroimaging 174 (2009) 62–66
in men (Pruessner et al., 2001; Lupien et al., 2007). In summary, our
first hypothesis that depressed patients have a smaller hippocampal
volume in comparison to healthy control subjects could be confirmed
only for male patients with a first depressive episode. The second
hypothesis that patients with recurrent depression have a smaller
hippocampal volume in comparison to first episode patients could not
be supported. Since no significant differences in total brain volume
could be found between the groups, the effect of hippocampal volume
change can be regarded as being specific and cannot be attributed to
general brain morphological changes or age effects which were
In the present study, no significant differences could be shown
between recurrently depressed patients and healthy controls, a finding
which contradicts that of MacQueen et al. (2003) and Neumeister et al.
(2005) who found smaller hippocampal volumes in patients with
multiple episodes. One explanation for the missing differences in the
present study could be that the patients of the MacQueen et al. (2003)
study were considerably younger than the patients we examined. Early
onset, however, is more frequently associated with traumatization than
later onset is. Vythilingam and Heim (2002) found a smaller
hippocampal volume only in depressed women with prepubertal
abuse whereas postpubertal abuse was not associated with a smaller
volume. Also, a reduction in hippocampal volume could be found in
subjects havingtraumatic experiences without suffering from posttrau-
matic stress disorder (Smith, 2005; Karl et al., 2006; Kitayama et al.,
comparison to multiple episode patients is probably not specific for
depression. Strakowski et al. (2002) found a larger hippocampus,
corresponding to that of healthy controls, in multiple episode bipolar
patients compared with first episode patients. These results could be
triggering than later depressive episodes (Post, 1992; Monroe and
Harkness, 2005). Possibly, this means that a stress and hypercortisolism
related reduction in hippocampal volume is more typical for patients
with first episodes than for patients with multiple past episodes for
whom other biological mechanisms may be more relevant. Another
explanation for this association is the influence pharmacological
treatment has on hippocampal volume. The group of multiple episode
patients included more patients receiving lithium. Yucel et al. (2007)
showed that patients treated with lithium had a significantly larger
hippocampus within a brief treatment period compared to untreated
patients or patients treated with other medications.
These findings could also be relevant for the interpretation of
inconsistent results concerning the association of the duration of
depression and hippocampal volume. Several studies have found a
negative correlation between lifetime duration of depression and
hippocampal volume since Sheline et al. (1999) had first reported this
inwomen.However,in somestudiesthisresultcould notbe replicated
(Bremneret al.,2000; PosenerandWang,2003;Frodletal.,2002).In a
study on early onset depression, duration of illness was significantly
positively correlated with left hippocampal volume (MacMaster and
Kusumakar, 2004). In the meta-analysis of Videbech and Ravnkilde
(2004), the number of depressed episodes correlated with smaller
volume of right but not left hippocampus. However, the number of
depressed episodes was only loosely correlated with the accumulative
volume in depressed outpatient women but no significant association
between duration of treated depression and hippocampal volume. In
the present study, we did not find a significant correlation between
cumulative duration of depression or duration of the index episode
with hippocampal volumes. Also, no significant correlation could be
found between number of depressive episodes and hippocampal
volume. Furthermore, patients with recurrent depression often have
shorter periods of untreated depression which could also account for
larger hippocampal volume since treatment of depression may stop
hippocampal atrophy and stimulate neurogenesis (Lucassen et al.,
2006; Dranovsky and Henn, 2006). Possibly, differences in treatment
gender effects in hippocampus morphometry. Depressive men,
especially in their first episode, seek medical treatment at a later
point in time than depressive women do (Piccinelli and Wilkinson,
2000; Möller-Leimkühler, 2002).
Different models for the explanation of changes in hippocampal
that the reduction in volume increases exponentially with the course of
the disorder (DeLisi et al., 2004), whereas MacQueen et al. (2003)
suggested that, in depressive patients, volume reduction takes place
logarithmically, that is in the early phase of the disorder. Besides this
degenerative-progressive model of volume reduction, a neurodevelop-
mental hypothesis was formulated. This postulates that etiopathoge-
netic factors impair brain development long before the onset of
depression and that structural brain changes observable at the first
appearance of the illness do not progress over time. Some studies have
recently begun to address the hypothesis that structural changes might
predispose to depression, because hippocampal size has been found to
2002; Frodl et al., 2007). A fact not considered in both models is that
hippocampal volume may increase again (Lucassen et al., 2006;
Dranovsky and Henn, 2006; Yucel et al., 2007). Also, findings of recent
associated with several dysfunctions. For example, Petten van (2004)
found that a smaller hippocampus correlated with a better cognitive
schizophrenia,it wasfound that persons witha largerhippocampus are
al., (2006) found no significant differences in hippocampal volume
between depressed patients and ultra high risk persons without
depression. Studies on the amygdala also show that brain structures
change over the course of depression. Here, convergent results exist
showing that the amygdala volume increases in the first depressive
episodes whereas in patients with recurrent depression smaller
volumes are found (Lange and Irle, 2004). Frodl et al. (2003) and
Velakoulis et al. (2006) found abnormalities in the amygdala volume
only in first episode patients but not in multiple episode patients
compared to healthy controls. However, no follow-up studies exist.
The results of the present study do not support the hypothesis of
depression as a neurodegenerative disease and also do not support a
neurodevelopmental model positing that structural brain changes do
not progress over the course of depression. It seems that both models
are not elaborated enough to explain the dynamics of changes in
central nervous system changes may occur during the onset and long-
term course of depression in which gender effects, stress and the
play an important role. This hypothesis of a gender- and illness-phase-
specific dynamic model of hippocampal volume change, however,
be ruled out, particularly in pseudo-longitudinal studies.
The comparison of first episode and recurrently depressed patients
canprovide some information on aspects of the course of the disorder,
patients were all first episode patients in the past but, not all first
episode patients will suffer a relapse or seek in-patient treatment in
case of relapse. Selection bias is a problem of studies that compare
patients in different illness stages. To date, no study exists that could
show a decrease or increase of hippocampal volumes in depression.
The only longitudinal structural imaging study in depression revealed
no significant changes in hippocampal volumes in the 1-year course
(Frodl et al., 2004). However, this study did not differentiate between
K.-T. Kronmüller et al. / Psychiatry Research: Neuroimaging 174 (2009) 62–66
first episode and recurrent depression or between sexes. However, Download full-text
what can only be differentiated by longitudinal data is the question
whether the hippocampus volume decreases or increases over the
course of depression or whether there are different subgroups of first
episode patients that premorbidly differ in hippocampal volume.
The study has several limitations which need to be mentioned.
First of all, the study sample is relatively small and includes only
inpatients. We also did not differentiate between grey and white
matter and did not examine any substructures of the hippocampus.
The study did not include patients not receiving medication. Never-
theless, the results do support the hypothesis that the hippocampus
plays an important role in the pathophysiology of major depression,
especially in the early phase of the disorder and especially in male
patients. The findings also revealed that it is of great importance to
consider sex effects and to differentiate between different phases of
the disorder when studying hippocampal volume in depressive
patients. Thus, the results can contribute to the reformulation of
neuroanatomic models of the pathophysiology of depression in a
more gender-specific conceptualization. In future studies the mechan-
isms behind decreased hippocampal volume and its relevance for
clinical outcome of depression should be addressed.
This study was supported by the German Federal Research
Ministry within the German Research Networks in Medicine promo-
tion as part of the German Research Network on Depression project.
The authors thanks Nancy C. Andreasen and her coworkers for their
help with the program BRAINS.
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