Hippocampal volume change in schizophrenia.

Abstract

Patients with schizophrenia show reductions in hippocampal volume. However, the time course of these changes is still unresolved. The aim of this study is to examine the extent to which hippocampal volume change in patients with schizophrenia is confounded by effects of age and/or antipsychotic medication.
Between 1995 and 2003, two structural magnetic resonance imaging brain scans were acquired from 96 patients with DSM-IV-diagnosed schizophrenia and 113 healthy subjects within an interval of approximately 5 years. Hippocampal volume change was measured and related to age and cumulative medication intake during the scan interval.
Patients with schizophrenia and healthy controls demonstrated significantly different age-related trajectories of hippocampal volume change. Before the age of 26 years, patients with schizophrenia showed increased volume loss relative to controls. In contrast, after the age of 40 years, controls showed larger volume loss than patients with schizophrenia. Higher exposure to atypical antipsychotic medication was related to a smaller decrease in hippocampal volume over time.
Our findings suggest progressive hippocampal volume loss in the early course of the illness in patients with schizophrenia but not in the more chronic stages of the illness. The relationship between larger exposure to atypical antipsychotic medication and smaller hippocampal volume loss during the interval may suggest neuroprotective effects of these agents on hippocampal volume.

Full text

Page 1

Koolschijn et al
737 J Clin Psychiatry 71:6, June 2010
Hippocampal Volume Change in Schizophrenia
P. Cédric M. P. Koolschijn, PhD; Neeltje E. M. van Haren, PhD;
Wiepke Cahn, MD, PhD; Hugo G. Schnack, PhD; Joost Janssen, PhD;
Floris Klumpers, MS; Hilleke E. Hulshoff Pol, PhD; and René S. Kahn, MD, PhD
Objective: Patients with schizophrenia show
reductions in hippocampal volume. However, the
time course of these changes is still unresolved.
The aim of this study is to examine the extent to
which hippocampal volume change in patients
with schizophrenia is confounded by effects of
age and/or antipsychotic medication.
Method: Between 1995 and 2003, two structural
magnetic resonance imaging brain scans were ac-
quired from 96 patients with DSM-IV–diagnosed
schizophrenia and 113 healthy subjects within an
interval of approximately 5 years. Hippocampal
volume change was measured and related to age
and cumulative medication intake during the
scan interval.
Results: Patients with schizophrenia and
healthy controls demonstrated significantly dif-
ferent age-related trajectories of hippocampal
volume change. Before the age of 26 years, patients
with schizophrenia showed increased volume loss
relative to controls. In contrast, after the age of
40 years, controls showed larger volume loss than
patients with schizophrenia. Higher exposure to
atypical antipsychotic medication was related to a
smaller decrease in hippocampal volume over time.
Conclusion: Our findings suggest progressive
hippocampal volume loss in the early course of the
illness in patients with schizophrenia but not in the
more chronic stages of the illness. The relationship
between larger exposure to atypical antipsychotic
medication and smaller hippocampal volume loss
during the interval may suggest neuroprotective
effects of these agents on hippocampal volume.
J Clin Psychiatry 2010;71(6):737–744
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: July 28, 2008; accepted January 30, 2009.
Online ahead of print: January 12, 2010 (doi:10.4088/JCP.08m04574yel).
Corresponding author: P. Cédric M. P. Koolschijn, PhD, Rudolf Magnus
Institute of Neuroscience, Department of Psychiatry, A.01.126, University
Medical Center Utrecht, PO Box 85060, 3584 CX Utrecht, The Netherlands
(koolschijnpcmp@fsw.leidenuniv.nl).
P
meta-analyses, see references 1–3). This is of interest since
decreased hippocampal volumes have been associated with
decreased memory and poorer executive function4 and
aberrant cognitive function is one of the key features of
schizophrenia.5 Despite the volume differences reported
in cross-sectional studies, longitudinal brain imaging stud-
ies6–8 have failed to find hippocampal volume change over
time in patients with schizophrenia as compared to healthy
controls. However, these studies6–8 examined first-episode
atients with schizophrenia show reductions in hip-
pocampal volume relative to healthy subjects (for
patients and patients with chronic schizophrenia within a
limited age range (20–35 years), making it difficult to dis-
entangle the influence of age-related and illness-related
changes on hippocampal volume. In addition, it is unclear
to what extent hippocampal volume loss is affected by an-
tipsychotic medication. Indeed, treatment with olanzapine
and risperidone has been associated with larger hippocam-
pal volumes in patients with schizophrenia as compared to
those treated with haloperidol in a cross-sectional study,9
but this finding was not replicated in another study with
chronically ill patients.10 In addition, 2 follow-up studies
with short scan intervals (both less than a year) found no
relationship between type of antipsychotic medication and
hippocampal volume change.11,12
Earlier, we reported on excessive global brain volume
change in patients with schizophrenia relative to healthy in-
dividuals.13 In the current study, we used the same data set to
compare age-related hippocampal volume change between
96 patients with schizophrenia and 113 healthy individuals.
Furthermore, the relationship between cumulative dose of
antipsychotic medication during the scan interval and hip-
pocampal volume change in patients was investigated.
METHOD
Subjects
A 5-year follow-up magnetic resonance imaging (MRI)
study was carried out between 1995 and 2003, including
patients with schizophrenia and healthy comparison sub-
jects. At baseline (T0), 159 patients with schizophrenia (112
male/47 female) and 158 healthy individuals (106 male/52
female) were included.14 A total of 96 patients with schizo-
phrenia (70 male/26 female) and 113 healthy comparison
subjects (76 male/37 female) completed the longitudinal
study and were rescanned after an interval of 5 years (T5).13,15
The study was approved by the Human Ethics Committee
of the University Medical Center Utrecht. Written informed
consent was obtained from all subjects.
Criteria for inclusion in the study and clinical assess-
ment were discussed previously13–15 and will be described
only briefly. At baseline measurement, subjects with a major
medical or neurologic illness, including migraine, epilepsy,
hypertension, cardiac disease, diabetes mellitus, endocrine
disorders, cerebrovascular disease, alcohol abuse, or other
drug dependence in the 6 months before entry in the study;
head trauma in the past; or an IQ below 80 were excluded
from this study. Both at baseline and at follow-up, the pres-
ence or absence of psychopathology was established using
the Comprehensive Assessment of Symptoms and History

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Hippocampal Volume Change in Schizophrenia
J Clin Psychiatry 71:6, June 2010738
(CASH)16 and was assessed by 2 independent raters. Pa-
tients gave permission to contact their treating physician
or nurse for further information, and medical records were
used when necessary. In the instance that the information
provided by the patient, medical records, treating physician,
or nurse was not reliable, the patient was excluded from the
analysis.
Diagnostic consensus was achieved in the presence of
a psychiatrist. All patients met Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV)
criteria for schizophrenia or schizophreniform disorder at
time of first measurement; those with schizophreniform
disorder were reassessed and met the criteria for a diagnosis
of schizophrenia after 1 year of illness. At follow-up, all pa-
tients met criteria for schizophrenia except 4 who received
a diagnosis of schizoaffective disorder. Severity of illness
was measured using the Positive and Negative Syndrome
Scale (PANSS).17 Outcome at follow-up was measured us-
ing the Camberwell Assessment of Need (CAN; sum of all
relevant needs as rated by the treating physician divided
by the number of relevant needs)18 and Global Assessment
of Functioning (GAF)19 scales. Age at onset of illness was
defined as the first time the patients experienced psychotic
symptoms, as obtained from the CASH interview.16 Dura-
tion of illness was defined as the time between age at onset
of illness and age at first MRI scan. Information on num-
ber of hospitalizations and total duration of hospitalization
during the scan interval was obtained from the CASH in-
terview16 and the patient’s medical records.
To calculate the cumulative dosage of typical antipsy-
chotics during the scan interval, a table from the Dutch
National Health Service20 was used to derive the haloperidol
equivalents (similar to the guidelines from the American
Psychiatric Association).21 For atypical antipsychotics, the
respective pharmaceutical companies suggested conversion
rates into haloperidol equivalents (clozapine, 40:1; olanza-
pine, 2.5:1; risperidone, 1:1; sulpiride, 170:1; quetiapine, 50:1;
and sertindole, 2:1). No reliable information on medication
intake during the scan interval was available for 6 patients.
Ten patients had been taking typical antipsychotic medica-
tion exclusively, and 27 patients had been taking atypical
antipsychotic medication exclusively over the entire 5-year
period. Forty-three patients switched between typical and
atypical medication during the scan interval. Thirty of these
43 patients switched from typical to atypical antipsychotic
medication, 1 patient from atypical to typical antipsychotic
medication, and 12 patients changed several times between
the 2 types of drugs during the 5-year interval. Clozapine
and olanzapine were the types of atypical antipsychotics
most often prescribed.
All healthy comparison subjects met Structured Inter-
view for DSM-IV Personality22 criteria for “never mentally
ill” and had no first-degree family members with a psychotic
illness. The comparison subjects were matched for age, sex,
handedness, height, socioeconomic status of their parents
(expressed as the highest level of education completed by 1
of the parents), and scan interval.
Brain Imaging
Magnetic resonance imaging brain scans at baseline and
follow-up were acquired on a Philips NT scanner operating
at 1.5T (Philips Medical Systems, Best, The Netherlands)
using the identical scanning protocol for all subjects on both
measurements. Details of the MRI acquisition protocol and
processing of the images have been presented before.23–25
Briefly summarized, quantitative assessments of intracra-
nial, cerebrum (gray and white matter of the cerebrum,
excluding the cerebellum and brainstem), lateral and third
ventricles, and peripheral cerebrospinal fluid volumes were
performed on the basis of histogram analyses and series
of mathematical morphological operators to connect all
voxels of interest. The hippocampus was manually seg-
mented using Display imaging software (http://www.bic.
mni.mcgill.ca/software/Display/) according to a fixed set
of rules. This hippocampus segmentation procedure has
been published previously.26–28 In short, the hippocampus
is part of the parahippocampal gyrus, but it is segmented
separately. Segmentation is done in coronal slices, from an-
terior to posterior (Table 1). Every segment was checked in
all dimensions after the initial segmentation. To be certain
that there were no voxels in the hippocampal segment that
were actually part of the cerebrospinal fluid in the tempo-
ral horns, the segment was multiplied with the cerebrum
segment.
The interrater reliability of the volume measurements
between 3 trained raters (P.C.M.P.K., F.K., and J.J.), deter-
mined by the intraclass correlation coefficient (ICC)29 in
13 brains for the left and right hippocampus, was at least
0.85 or higher (range, 0.85–0.95). Intrarater reliabilities
for left and right hippocampus were 0.85 or higher (range,
0.85–0.96).
Due to poor quality of the scans, no hippocampal
segmentations were obtained from 6 patients with schizo-
phrenia (5 at baseline) and 2 healthy controls (both at
baseline), resulting in hippocampal volumes for 153 patients
with schizophrenia and 156 healthy controls at baseline, of
which 95 patients with schizophrenia and 113 healthy con-
trols had a follow-up measurement.
Statistical Analysis
Data were checked for outliers, extreme values, and
the normality of the distribution. Except for the different
medication variables, all variables were normally distrib-
uted. Nonparametric testing was used in the instance that
Table 1. Segmentation Procedure of the Hippocampus
Border
AnteriorThe first coronal slice in which the characteristic oval
shape of the mamillary bodies is visible.
PosteriorThe last slice to be segmented; the slice before the slice
in which the fornix forms a continuous tract for the
first time.
SuperiorThe inferior horn of the lateral ventricle.
Inferior/Medial The surrounding white matter; the subicular complex
and the uncal sulcus are included in this segment.

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Koolschijn et al
739 J Clin Psychiatry 71:6, June 2010
the medication variables were included into the analysis.
All analyses were performed for left, right, and total hip-
pocampal volume (change).
Hippocampal volume change per year was calculated by
subtracting baseline volume from follow-up volume, divid-
ing it by the duration of the scan interval in years ([T5 − T0]/
interval) and is thus expressed as milliliter change per
year.
Correlation analyses showed that hippocampal volume
change was significantly associated with hippocampal
volume at baseline (r = −0.335, P < .0001) and change in
cerebral brain volume (r = 0.305, P < .0001). Linear regres-
sion was used to correct hippocampal volume change per
year for hippocampal volume at baseline, change in cerebral
brain volume per year, and sex and age at baseline, and un-
standardized residuals were saved (ie, further referred to as
corrected hippocampal volume change). In addition, lin-
ear regression was used to correct hippocampal volume at
baseline for age at baseline, and sex and cerebral brain vol-
ume at baseline, and unstandardized residuals were saved
(ie, further referred to as corrected baseline hippocampal
volume).
Group Differences
First, we used a general linear model univariate analy-
sis to detect cross-sectional group differences, using age at
baseline, sex, and cerebral brain volume as covariates. This
analysis was performed on the total baseline sample (Npt = 153
patients with schizophrenia and Nnc = 158 controls) and on
the subsample of only those subjects that participated at
follow-up (npt = 95 patients with schizophrenia and nnc = 113
controls). Moreover, corrected hippocampal volume change
was compared between the groups.
Because we were particularly interested in the relation-
ship between age and hippocampal volume change in both
groups in this study, a regression analysis in the form of
a locally weighted running-line smoother30,31 was used to
obtain the dependence of volume changes on age (see also
reference 13). Software for these analyses was developed
in-house (available from the authors on request). Fits with
different df were calculated for each group to find the one
that described the data best. Standard error bands were cal-
culated to show the age at which volume change differed
significantly between patients with schizophrenia and
healthy subjects.
The analyses were done on corrected and uncorrected
hippocampal volume change, both with and without cor-
recting for sex. The results from these analyses were similar;
therefore, the findings of the uncorrected volume changes
per year are reported here.
Relationship With Clinical Variables
In the patients with schizophrenia group only, Pearson
and Spearman rank correlations were calculated between
corrected hippocampal volume change and (1) medication
intake (cumulative intake of typical antipsychotic medi-
cation in haloperidol equivalents, atypical antipsychotic
medication in haloperidol equivalents per year during the
scan interval [haloperidol equivalents/scan interval], and
clozapine and olanzapine in milligrams per year during the
scan interval [milligrams/scan interval]) and (2) outcome (ie,
GAF score at follow-up, CAN score [a square-root transfor-
mation was performed to create a normal distribution of the
data] at follow-up, number of hospitalizations and total dura-
tion of hospitalization during the scan interval, and scores
on the positive, negative, and general symptom scales of the
PANSS at follow-up).
A 2-tailed α level of .05 was used to determine significance
of the effect.
Selection Bias at Follow-Up
At baseline, the patients with schizophrenia included at
follow-up were younger and had a shorter duration of illness,
fewer negative symptoms, and larger volumes of cerebral
(gray) matter than those who did not complete the follow-up
(for further details, see reference 15). Moreover, the number
of years of education was significantly lower in patients with
schizophrenia who participated only at baseline compared
with those included at follow-up. A linear regression analysis
was performed to compare corrected baseline hippocampal
volume between patients with schizophrenia who partici-
pated at follow-up and patients with schizophrenia who did
not. This analysis was repeated to investigate the confound-
ing effects of negative symptoms, duration of illness, or years
of education.
RESULTS
Group Differences
For demographic information at baseline and follow-up,
see Table 2. Mean and SD hippocampal volumes at baseline
and follow-up are presented in Table 3.
In the total baseline sample (Npt = 153; Nnc = 156), pa-
tients with schizophrenia had significantly smaller bilateral
hippocampus volumes compared to healthy controls after
correction for age, sex, and cerebral brain volume (left:
F = 8.205, P = .004; right: F = 5.49, P = .02; total: F = 7.81,
P = .006). However, when including only those subjects who
participated at follow-up, the difference in baseline hip-
pocampus volume between patients and controls was no
longer significant (left: F = 0.665, P = .416; right: F = 1.863,
P = .174; total: F = 1.386, P = .24). Moreover, at follow-up, no
significant difference in hippocampal volume between the
groups was present (left: F = 0.071, P = .79; right: F = 1.21,
P = .291; total: F = 0.182, P = .67)
Finally, no differences were found in the rate of volume
change in the patients with schizophrenia group compared
to the control group (left: F = 1.131, P = .289; right: F = 0.143,
P = .705; total: F = 0.229, P = .633).
Our main interest concerned the association between
age and hippocampal volume change and possible differenc-
es in this relationship between patients with schizophrenia
and healthy individuals. Healthy controls showed a linear
relationship between hippocampal volume change and

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Hippocampal Volume Change in Schizophrenia
J Clin Psychiatry 71:6, June 2010740
Table 2. Demographic and Clinical Variables of All Subjects at Baseline and Follow-Up
Variable
Sex, male/female, n/n
Age, mean (SD), y
Range, y
Height, mean (SD), cm
Handedness, right-handed/left-handed/both, n/n/n
Level of education, mean (SD), yb
Parental level of education, yc
Follow-up duration, mean (SD), y
Range
Age at onset of illness, mean (SD), y
Range
Duration of illness at baseline, mean (SD), y
Range (n = 152)d
< 1 y
1–2 y
2–5 y
5–10 y
10–20 y
> 20 y
Positive and Negative Syndrome Scale score, mean (SD)
Negative symptoms
Positive symptoms
General psychopathology
Global Assessment of Functioning score at follow-up,
mean (SD)
Range (n = 93)
Cumulative medication intake per year during the scan
interval, mean (SD)e
Only typical antipsychotic medication
(n = 10, HEQ)
Only atypical antipsychotic medication
(n = 27, HEQ)
Patients who switched and used among othersf
Typical (n = 43, HEQ)
Atypical (n = 36, HEQ)
aHippocampal volume was not obtained from 1 patient due to poor scan quality.
bLevel of education was significantly lower in patients than in comparison subjects (F = 15.511; P < .001). Level of education was also significantly lower in
patients who participated only at baseline compared with patients included at follow-up (F = 4.292; P = .04).
cUsed to determine socioeconomic status; the highest level of education completed by 1 parent.
dDuration of illness was significantly longer in patients who participated only at baseline compared with patients included at follow-up
(F = 17.736; P < .001). Information not available for 1 patient.
eCumulative typical and atypical antipsychotic medication intakes are in haloperidol equivalents per year during the scan interval. Cumulative
olanzapine intake is in milligrams per year during the scan interval.
fDuring the scan interval, 52 patients switched between at least 2 of typical antipsychotics and atypical antipsychotics. For example, 43 of these patients
used typical antipsychotic medication at some point during the scan interval, but have also been taking atypical antipsychotics.
Abbreviation: HEQ = haloperidol equivalent.
Patients With Schizophrenia
Patients Included at
Follow-Up (n = 95a)
Baseline
108/4569/26
34.82 (12.31) 32.16 (11.14)
16.88–67.5316.88–56.25
176.27 (9.30)176.69 (9.5)
131/19/382/10/3
10.81 (2.95)12.03 (2.77)
10.67 (3.29)11.08 (3.08)
Healthy Comparison Subjects
Patients Included at
Follow-Up (n = 113)
Baseline
105/5176/37
37.33 (13.87)35.28 (12.25)
16.75–67.7916.75–56.27
178.05 (8.7)178.4 (8.4)
131/23/296/15/2
12.07 (2.97)12.81 (2.57)
10.66 (2.87) 10.92 (2.69)
Total Baseline
(n = 153)
Total Baseline
(n= 156)Follow-Up
69/26
36.98 (11.25)
21.32–61.25
Follow-Up
76/37
40.22 (12.21)
21.97–61.54
4.83 (0.55)
3.48–6.34
4.94 (0.32)
4.15–5.71
20.97 (5.36)
9–36
13.94 (12.28)
0.40–51.53
10
16
31
18
29
48
21.29 (5.43)
9–36
10.86 (10.25)
0.40–36.25
10
9
23
15
18
20
18.47 (5.65)
17.04 (5.61)
36.24 (9.33)
17.78 (5.52)
16.87 (5.83)
35.74 (8.36)
13.22 (6.03)
13.74 (5.23)
26.75 (8.32)
52.62 (17.20)
11–90
1828 (1238)
1403 (1031)
366 (451)
789 (693)
age, representing a larger decrease of hippocampal volume
with increasing age (df = 2; Figure 1 in black). Around the
age of 20 years, very little hippocampal volume change was
present, while around the age of 45 years, the decrease was
0.1 mL/y), showing a further decrease to approximately 0.15
mL/y around the age of 55 years. In contrast, hippocampal
volume loss in patients with schizophrenia remained stable
across the entire age range (df = 1; Figure 1 in gray), decreas-
ing approximately 0.05 mL/y. The slopes of patients with
schizophrenia and healthy controls were significantly dif-
ferent before the age of 26 years (nonoverlapping SE bands),
showing increased volume loss in patients with schizophre-
nia relative to controls; conversely, after the age of 40 years,
the slopes showed significant progressive volume loss in
controls relative to patients with schizophrenia.
Results for age-related volume change in the left and
right hippocampus were similar to those found for total
hippocampal volume change.
Relationship With Clinical Variables
Correlations between unstandardized residuals of cor-
rected hippocampal volume change (corrected for baseline
hippocampal volume, change in cerebral volume, sex,
and age at baseline) and cumulative dose of antipsychotic
medication per year were calculated. A significant positive
association was found between hippocampal volume change
and cumulative intake of atypical antipsychotics per year
during the scan interval (n = 49, ρ = 0.31, P = .028; Figure
2A); higher exposure to atypical antipsychotics was associ-
ated with less decrease in hippocampal volume. Olanzapine,

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Koolschijn et al
741 J Clin Psychiatry 71:6, June 2010
in particular, showed a positive association between atypical
antipsychotic exposure and hippocampal volume change
that reached trend-level significance (n = 37, ρ = 0.32,
P = .056). Moreover, a negative correlation between cu-
mulative intake of typical antipsychotics and hippocampal
volume change (n = 51, ρ = −0.27, P = .058; Figure 2B) was
significant at trend level, indicating that a larger dose of typ-
ical antipsychotics during the scan interval was correlated
with a larger decrease in hippocampal volume. One patient,
who was prescribed a larger dose of typical antipsychotics
compared to all other patients, was excluded from the cor-
relation analysis. This did not change our findings (n = 52,
ρ = –0.26, P = .062). After Bonferroni correction for multiple
comparisons, our findings were no longer significant.
No significant differences were found between “good”
and “poor” outcome patients with schizophrenia (as defined
by GAF19 score at follow-up). In addition, no significant
correlations were found between scores on the negative,
positive, or general symptom scales of the PANSS,17 CAN18
scores at follow-up, number and total duration of hospi-
talizations during the interval, and corrected hippocampal
volume change at the .05 significance level.
Selection Bias at Follow-Up
No significant differences were found between corrected
baseline hippocampal volumes between patients with schizo-
phrenia who participated at follow-up and those who did
not (F = 2.062, P = .153). Moreover, adding level of negative
symptoms (F = 1.359; P = .246), duration of illness (F = 1.002;
P = .318), or years of education of parent (F = 1.684; P = .196)
as covariates did not change this finding.
DISCUSSION
This 5-year follow-up study compared age-related hip-
pocampal volume change in 95 patients with schizophrenia
relative to 113 healthy control subjects. The main find-
ing is that the trajectory of hippocampal volume change
over time differs between patients with schizophrenia and
healthy individuals. Before the age of 26 years, patients with
schizophrenia demonstrated a pattern of larger hippocam-
pal volume loss relative to healthy controls, but thereafter,
patients with schizophrenia did not show excessive volume
loss when compared with healthy controls. In fact, after the
age of 40 years, healthy individuals showed a larger volume
loss relative to the patients with schizophrenia, suggesting
that progressive brain abnormalities are present (only) in
the early course of the disease.
Our results are consistent with those of cross-sectional
studies reporting decreased hippocampal volumes in pa-
tients with first-episode schizophrenia,32 with effect sizes
twice as large as those found in chronically ill patients.1
One may speculate that this early volume loss is the result
of increased (psychological) stress that accompanies the
onset of psychosis, since it has been demonstrated that in-
creased levels of circulating cortisol have been associated
with atrophy and loss of neurons in the hippocampus.33–36
Table 3. Hippocampal Volumes at Baseline and Follow-Up of Patients With Schizophrenia and Comparison Subjectsa
Patients With Schizophrenia
Patients Included at
Follow-Up (n = 95b)
Baseline
Left hippocampus3.57 (0.57)c
3.66 (0.52)
Right hippocampus 3.57 (0.58)d
3.61 (0.58)
Total hippocampus 7.15 (1.09)e
7.27 (1.04)
aPatients in the total baseline sample showed bilateral smaller corrected baseline hippocampal volumes compared to healthy comparison subjects at
baseline.
bHippocampal volume was not obtained from 1 patient due to poor scan quality.
cF = 8.205; P = .004.
dF = 5.49; P = .02.
eF = 7.81; P = .006.
Volume, mean (SD), mL
Healthy Comparison Subjects
Total Baseline
(n = 153)
Total Baseline
(n = 156)
3.77 (0.57)c
3.76 (0.59)d
7.53 (1.09)e
Patients Included at
Follow-Up (n = 113)
Baseline
3.75 (0.57)
3.77 (0.60)
7.51 (1.11)
Follow-Up
3.54 (0.55)
3.50 (0.55)
7.05 (1.03)
Follow-Up
3.57 (0.58)
3.63 (0.62)
7.20 (1.14)
Figure 1. Age-Related Trajectory of Hippocampal Volume
Change in Patients With Schizophrenia and Healthy
Comparison Subjectsa,b
aCorrection for change in cerebral brain volume, hippocampal volume at
baseline, and sex did not change the results.
bThe bars in the figure represent the standard error bands determined by
the regression analysis in the form of a locally weighted running-line
smoother. Nonoverlapping standard error bands indicate a significant
difference in the slopes of patients with schizophrenia and healthy
individuals.
cLinear df = 1.
dLinear df = 2.
eThe y-axis represents the mean volume change per year during the
interval that started at this particular age.
0.4
0.2
0
–0.2
–0.4
Mean Hippocampal Volume Change, mL/ye
0102030 4060
Age at Baseline, y
50
Patients With Schizophreniac
Healthy Comparison Subjectsd

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J Clin Psychiatry 71:6, June 2010742
Interestingly, individuals at high risk for psychosis who sub-
sequently developed frank psychosis display higher levels of
anxiety and depressive symptoms than those who do not go
on to develop psychosis.37 However, brain changes during
the period of transition to illness are inconsistent.38 Because
depressive symptoms and depression are highly prevalent
in schizophrenia39 and have been related to decreased
hippocampal volume,40,41 these factors could be potential
confounders. Although in our sample a small number of
patients showed minor depressive symptoms (as measured
with the depressive scale of the PANSS) and were treated
with antidepressants, no significantly different hippocam-
pal volume (change) was found compared to those solely
treated with antipsychotic medication.
In contrast to the progressive hippocampal volume loss
before the age of 26 years in patients with schizophrenia,
healthy individuals demonstrated a progressive volume loss
after the age of 40 years relative to the patients with schizo-
phrenia group. The linearly increasing hippocampal volume
loss as age increases is in line with earlier findings in normal
aging demonstrating accelerated hippocampal volume loss
in later life.42,43
Antipsychotic medication intake appears to be an impor-
tant confounder when investigating hippocampal volume
over time. A significant positive association was found
between cumulative intake of atypical antipsychotics, olan-
zapine in particular, and hippocampal volume change.
Patients with schizophrenia who were exposed for a longer
period or received a higher dose of atypical antipsychotics
over time showed less decrease or even small increases in
hippocampal volume. In contrast, a negative correlation (al-
though only significant at trend level) was found between
cumulative intake of typical antipsychotics and hippocampal
volume change, suggesting that patients who received more
typical antipsychotic medication during the scan interval
showed larger decreases in hippocampal volume. Although
our findings indicate a positive association between atypical
antipsychotic medication intake and hippocampal volume
change, suggesting possible neuroprotective properties of
atypical antipsychotics similar to those found in previous
reports,44,45 these findings should be interpreted with cau-
tion, since many of the patients currently receiving atypical
medication may have been prescribed typical medication at
an earlier stage of their illness.
Evidence from animal studies indicates that atypical
antipsychotics, such as quetiapine and olanzapine, increase
neurogenesis in the hippocampus46–48 (but see Schmitt
et al49). Moreover, olanzapine and quetiapine have been
associated with increased hippocampal cell prolifera-
tion and prevention of brain-derived neurotrophic factor
(BDNF) decrease compared to typical antipsychotics such
as haloperidol.50–52 Interestingly, BDNF regulates neuronal
cell survival, differentiation, synaptic strength, and mor-
phology,53 and emerging evidence suggests that several
polymorphisms of the BDNF gene play a role in several
neuropsychiatric disorders, including schizophrenia.54
Although hippocampal volume was significantly smaller
in the (larger) baseline schizophrenia sample than in the
controls, the difference no longer reached significance after
including only those subjects who participated at follow-up.
Inspection of Table 3 indeed indicates that hippocampus
volume in the total sample of controls and the subsample
of control subjects who participated at follow-up is almost
similar, while for the patients with schizophrenia, it is not.
Patients with schizophrenia who participated at follow-up
showed a larger baseline hippocampal volume than patients
Figure 2. Association Between Corrected Hippocampal Volume Change and Cumulative Dose of Atypical and Typical Antipsychoticsa
aOne patient who was prescribed a large dose of typical antipsychotics compared to all other patients was excluded from the analysis.
bHaloperidol equivalents.
cHigher exposure to atypical antipsychotic medication was related to smaller decrease or even small increase of hippocampal volume over time.
dHigher cumulative dose of typical antipsychotic medication was related to larger decrease of hippocampal volume over time (at trend level).
0.4
0.2
–0.2
–0.4
0
Cumulative Dose per Year of Atypical Antipsychotics
(haloperidol equivalents)
Corrected Hippocampal Volume Change, mL
01000200030004000
A. Atypical Antipsychoticsb,c
0.4
0.2
–0.2
–0.4
0
Cumulative Dose per Year of Typical Antipsychotics
(haloperidol equivalents)
Corrected Hippocampal Volume Change, mL
0 1000 20003000 4000
B. Typical Antipsychoticsb,d

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Koolschijn et al
743 J Clin Psychiatry 71:6, June 2010
who participated only at baseline; although this difference
was not significant, this might suggest a selection bias in our
follow-up sample. Indeed, as was presented earlier,15 those
patients that were lost for follow-up were older, hence had
a longer illness duration, showed more negative symptoms,
and had smaller cerebral gray matter volume at baseline.
Moreover, those patients included at follow-up had a high-
er level of education compared to those lost for follow-up.
However, these dissimilarities could not explain the lack
of difference in baseline hippocampal volume between in-
cluded and excluded patients with schizophrenia.
Several other limitations have to be taken into consider-
ation when interpreting these findings. Most patients with
schizophrenia changed medication during the scan inter-
val, making it difficult to reliably investigate the specific
effects of different types of antipsychotics. Only 10 patients
were exclusively taking olanzapine during the scan interval;
therefore, it cannot be ruled out that the protective effect
can be explained by the release of exposure to typical anti-
psychotics. Moreover, it should be noted that patients with
schizophrenia differed in the amount of medication they
had used prior to inclusion in the study, while reliable in-
formation on their lifetime cumulative medication use was
not available.
Similar to Whitworth et al,8 we found no association be-
tween hippocampal volume change and clinical variables
such as symptom and outcome measurements at follow-up.
However, it must be noted that CAN and GAF scores were
not available at baseline. Therefore, whether improvement
in daily life functioning between baseline and follow-up was
associated with hippocampal volume change could not be
assessed.
In summary, the age-related trajectories of hippocampal
volume change differ significantly between patients with
schizophrenia and healthy control subjects, with patients
with schizophrenia showing an excessive volume decrease
in the early course of the illness. In contrast, after the age of
40 years, the control group showed a progressive decrease
of hippocampal volume with increasing age relative to the
patients with schizophrenia. Speculatively, these differences
could be taken to suggest that the high levels of stress that
accompany the onset of psychosis result in decreases in
hippocampal volumes. Moreover, our findings suggest a
differential influence of typical and atypical antipsychotic
medication, since a larger dose of atypical antipsychotic
medication during the interval was related to a smaller
decrease of hippocampal volume, suggestive of neuropro-
tective effects of atypical antipsychotic medication.
Drug names: clozapine (FazaClo, Clozaril, and others), haloperidol
(Haldol and others), olanzapine (Zyprexa), quetiapine (Seroquel),
risperidone (Risperdal and others).
Author affiliations: Rudolf Magnus Institute of Neuroscience,
Department of Psychiatry, University Medical Center Utrecht, The
Netherlands (Mr Koolschijn and Drs van Haren, Cahn, Schnack, Pol,
and Kahn); Laboratorio de Imagen Medica, Department of Experimental
Medicine and Surgery, Hospital Universitario Gregorio Marañon,
Madrid, Spain (Dr Janssen); and Departments of Experimental
Psychology and Psychopharmacology, Utrecht University,
The Netherlands (Mr Klumpers).
Potential conflicts of interest: None reported.
Funding/support: None reported.
Previous presentation: Presented as a poster at the International
Congress on Schizophrenia Research, March 28–April 1, 2007,
Colorado Springs, Colorado, and at the Human Brain Mapping
conference, June 10–14, 2007, Chicago, Illinois.
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