Do antipsychotic drugs affect brain structure?
A systematic and critical review of MRI findings
S. Navari1,2* and P. Dazzan1
1Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King’s College London, UK
2Section of Psychiatry, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy
Background. The potential effects of antipsychotic drugs on brain structure represent a key factor in understanding
neuroanatomical changes in psychosis. This review addresses two issues: (1) do antipsychotic medications induce
changes in total or regional human brain volumes and (2) do such effects depend on antipsychotic type?
Method. A systematic review of studies reporting structural brain magnetic resonance imaging (MRI) measures:
(1) directly in association with antipsychotic use; and (2) in patients receiving lifetime treatment with antipsychotics
in comparison with drug-naive patients or healthy controls. We searched Medline and EMBASE databases using
the medical subject heading terms: ‘antipsychotics’ AND ‘brain’ AND (MRI NOT functional). The search included
studies published up to 31 January 2007. Wherever possible, we reported the effect size of the difference observed.
Results. Thirty-three studies met our inclusion criteria. The results suggest that antipsychotics act regionally rather
than globally on the brain. These volumetric changes are of a greater magnitude in association with typical than with
atypical antipsychotic use. Indeed, there is evidence of a specific effect of antipsychotic type on the basal ganglia,
with typicals specifically increasing the volume of these structures. Differential effects of antipsychotic type may also
be present on the thalamus and the cortex, but data on these and other brain areas are more equivocal.
Conclusions. Antipsychotic treatment potentially contributes to the brain structural changes observed in psychosis.
Future research should take into account these potential effects, and use adequate sample sizes, to allow improved
interpretation of neuroimaging findings in these disorders.
Received 21 December 2007; Revised 17 December 2008; Accepted 15 January 2009; First published online 2 April 2009
Key words: Antipsychotic drugs, brain, MRI, psychosis.
Regardless of which causes are involved in the aetio-
pathogenesis of psychoses, antipsychotic drugs are
effective, to some extent, in alleviating the symptoms
of these severe and incapacitating disorders (Seeman,
Antipsychotic drugs mostly target the dopamine
D2 receptors, and specific pharmacodynamic inter-
actions depend on drug class (Seeman, 2002). Typical
‘haloperidol-like’ molecules act as dopamine D2 re-
ceptor antagonists in the mesolimbic and mesostriatal
regions. Atypical ‘clozapine-like’ compounds reduce
dopaminergic activity in the mesolimbic system, by
blocking D1and D2receptors, and have higher affinity
for serotonin 5-hydroxytryptamine type 2 receptors
than for D2 receptors. Despite clinical evidence of
different side-effects profiles of atypical compared to
typical antipsychotics, their mechanisms of action are
not fully understood.
Studies on animals, mostly rodents, suggest that
antipsychotics can affect neuronal structure and func-
tion through neuroplasticity, neurotoxicity, gene ex-
pression and apoptosis (Dean, 2006). Conventional
antipsychotics may be neurotoxic and induce neuronal
loss and gliosis in the striatum, hypothalamus, brain-
stem, limbic system and cortex. Moreover, apoptosis
has been documented with in vivo administration
of haloperidol in the substantia nigra, caudate and
putamen (Dean, 2006). A study of non-human pri-
mates showed that chronic therapeutic-like daily ex-
posure to either the typical antipsychotic haloperidol
or the atypical olanzapine is associated with re-
ductions in both grey and white matter (Dorph-
Petersen et al. 2005).
Morphological changes in brain structures, such as
lateral and third ventricle enlargement and temporal
regions reductions, have been reported in patients
withchronic schizophrenia(Lawrie&Abukmeil, 1998;
* Address for correspondence: S. Navari, M.D., Ph.D., Psychiatrist
and Research Associate, Division of Psychological Medicine and
Psychiatry, PO Box 63, Institute of Psychiatry, De Crespigny Park,
London SE 8AF, UK.
Psychological Medicine (2009), 39, 1763–1777.
f Cambridge University Press 2009
Printed in the United Kingdom
Table 1. Cross-sectional studies presented in chronological ordera
Reference Antipsychotic (type, dose)Main findings
Dazzan et al.
Typicals (32 patients): mean dose in chlorpromazine equivalents=269¡245 mg/
Atypicals (30 patients):
21 on olanzapine, 14 mg/day; 5 on risperidone, 4 mg/day;
2 on quetiapine, 400 mg/day; 1 on sertindole, 16 mg/day; 1 on amisulpiride,
Drug-free (22 patients)
Typical versus drug free: putamen ‹ with typicals and › frontal areas, temporal-insular areas
and precuneus (pf0.002)
Atypical versus drug free: ‹ thalamus with atypicals (p=0.002)
Typical versus atypical: › left middle temporal gyrus with typicals (p=0.002)
Narr et al.
Atypicals (33 patients): either olanzapine or risperidone Patients versus controls: in patients › cortical thickness within cingulate, occipitals and
Chakos et al.
(a) Typicals (17 patients): haloperidol
Atypicals (15 patients): 12 on olanzapine, 3 on risperidone
Typicals and atypicals (1 patient): clozapine and molindone
Unknown (1 patient)
(b) Typicals (5 patients): 3 on haloperidol, 1 on trifluoperazine,
1 on thiothixene
Atypicals (15 patients): 6 on olanzapine, 8 on clozapine, 3 on risperidone
(a) Atypical versus typical: ‹ hippocampal volumes with atypicals (d=1.3, r=0.56)
(b) Atypical versus typical: =hippocampal volumes (F=0.54, p=0.48)
Deicken et al.
Mean dose in chlorpromazine equivalents=613.6¡649.7 mg/day No correlation between thalamic volume and current antipsychotic dose
et al. 2001
Cumulative antipsychotic exposure at the time of the MRI as chlorpromazine
equivalents=mean dose of 40.59¡94.699 mg, range 0–524
If ‹ the antipsychotic exposure then › the midbrain area (r=x0.42, p=0.002)
Gur et al.
Typicals: 24 patients
Atypicals: 6 patients
Typicals followed by atypicals: 11 patients
Naive versus previously treated patients: =prefrontal cortex volume
et al. 1999
Total antipsychotic dose in chlorpromazine equivalents:
– for long-term treated patients: 21018¡16153 mg (mean daily dose:
– for short-term treated patients: 5384¡7983 mg (mean daily dose: 164¡107)
Chronic schizophrenia patients versus controls: › hippocampal volumes in patients
(right side: r=0.5, left side: r=0.4)
First-episode psychosis patients versus controls: › hippocampal volumes in patients
(right side: r=0.4, left side: r=0.5)
Chronic schizophrenia patients: no associations between whole-brain volume (r=0.08) or
hippocampal volumes (right side: 0.02, left side: 0.09) and medication dosage
First-episode psychosis patients: no associations between whole-brain volume (r=x0.15) or
hippocampal volumes (right side: x0.17, left side: 0.04) and medication dosage
S. Navari and P. Dazzan
McCarley et al. 1999; Shenton et al. 2001). Less fre-
quently, volume reductions of frontal and parietal
cortices and of subcortical structures have also been
reported. There is also evidence that some of these
brain changes may progress over time (Ho et al. 2003;
Pantelis et al. 2003; Thompson et al. 2001); this may
occur as part of the disease and its progression or be-
cause of treatment exposure. For example, the seminal
study by Chakos et al. (1995) showed that when in-
dividuals were switched from a typical antipsychotic
to clozapine, the basal ganglia volume decreased.
This suggests that typical antipsychotics have an
effect on the basal ganglia volume that is specific and
also potentially reversible. These findings renewed
interest in the question of whether antipsychotics
affect brain structure, with an increasing number of
reports documenting structural brain changes in as-
sociation with use of antipsychotics. However, it has
remained unclear to what extent current and previous
antipsychotic drug use has influenced imaging find-
This review addresses the following two questions:
(1) is there sufficient evidence that antipsychotic
medications induce changes in total or regional
human brain volumes, and if so, (2) do such effects
depend on antipsychotic type?
We searched Medline and EMBASE databases using
the medical subject heading (MeSH) terms: ‘anti-
psychotics’ AND ‘brain’ AND (MRI NOT functional).
The electronic search was not restricted to English
language papers and included studies published up to
31 January 2007. We also searched published research
with the Science Citation Index.
Articles were selected by the first author (S.N.) and
checked by the last author (P.D.). We included studies
directly reporting structural brain magnetic resonance
imaging (MRI) measures in association with anti-
psychotic treatment, or studies that evaluated these
in patients who had received at least some treatment
with antipsychotics and compared them with drug-
naive patients or controls.
Data were extracted from the studies and, when
records were missing or incomplete, authors were
contacted directly for clarification. For each study
(Tables 1 and 2; see also expanded online versions)
we recorded information on: (a) year of publication;
Gur et al.
Typicals: 44 patientsTypicals+atypicals: 24 patients
Mean dose in chlorpromazine equivalent units/day:
atypicals (clozapine and risperidone): 334.1¡286.3
Long-term treated patients: ‹ putamen (F=4.86, p=0.03) and globus pallidus (F=12.58,
p=0.0005) compared with controls and naive patients
Patients on typicals: if ‹ dose of typicals then ‹ caudate (left side: r=0.38, p<0.01; right side:
r=0.34, p<0.05) and thalamus (left side: r=0.55, p<0.01; right side: r=0.36, p<0.05) and
left putamen (r=0.36, p<0.01)
Patients on typicals and atypicals:
(a) if ‹ dose of typicals then ‹ thalamus (left side: r=0.75, p<0.01; right side: r=0.62,
p<0.01), left putamen (r=0.37, p<0.01) and left globus pallidus (r=0.46, p<0.05)
(b) if ‹ dose of atypical then ‹ thalamus (left side: r=0.60, p<0.01; right side: r=0.59,
et al. 1998
Haloperidol for 4 weeks (haloperidol dose was increased until the ‘optimal dose’
13 patients treated with 2 mg/day (‘low-dose group’)13 patients treated with doses of 5, 10 or 20 mg/day (‘higher-dose group’)
The low-dose group had more cortical grey matter than the higher-dose group (t=2.35,
There was a trend in the same direction for the total grey matter volume (t=1.89, p=0.07)
et al. 1998
Antipsychotics (type and dose not known)
Drug-free patients: › caudate than controls (ventral: d=0.8, r=0.37; dorsal: d=0.9, r=0.43
and combined: d=0.8, r=0.39) and than drug-naive patients (ventral: d=0.0, r=0.04;
dorsal: d=0.5, r=0.28 and combined: d=0.2, r=0.12)
Drug-free patients: ‹ dorsal putamen than drug-naive patients (d=0.3, r=0.16) and than
controls (d=0.3, r=0.15)
aAn expanded version of this table is available at the Journal’s website (http:/ /journals.cambridge.org/psm).
Systematic review of antipsychotics and brain structure 1765
Table 2. Follow-up studies presented in chronological ordera
References Antipsychotic (type, dose)Main findings
Girgis et al. 2006Risperidone (mean dose 2.67 mg/day)Patients: ‹ in left superior temporal gyrus and middle temporal gyrus and › in left rectal gyrus
and corpus callosum
Controls: no changes over time
Khorram et al.
Typicals for at least 1 year before the first MRI then atypicals
until the second MRI
If ‹ dosage of typical antipsychotics at baseline then › thalamus after switching to olanzapine
McClure et al.
Placebo versus typicals and atypicals Drug-withdrawal group: both with ROI and VBM, no effect of treatment status and antipsychotic
type on brain volumes
Chronic stable treatment group: both with ROI and VBM, no effect of treatment on brain volumes
Taylor et al. 2005 Haloperidol (2 patients);
risperidone (7 patients), mean dose 4 mg/day;
ziprasidone (2 patients)
Patients: ‹ in striatal tissues (left side: d=0.3, r=0.1; right side: d=0.3, r=0.1)
Garver et al. 2005 First 7 patients assigned to risperidone at 4 mg/day and
subsequent 12 patients randomly assigned to: ziprasidone,
120 mg/day (6 patients); haloperidol, 7 mg/day (6 patients)
Patients on atypicals: diffuse ‹ cortical grey matter without differences between ziprasidone (d=0.3,
r=0.1) and risperidone (d=0.5, r=0.2)
Patients on haloperidol: =cortical grey matter (d=1.1, r=0.5)
Lieberman et al.
Haloperidol (79 patients) 2–20 mg/day;
olanzapine (82 patients) 5–20 mg/day
Olanzapine versus haloperidol:
(a) whole-brain grey matter: › in the haloperidol group (week 12: d=1.6, r=0.6). Frontal grey
matter: › in the haloperidol group (week 52: d=2.6, r=0.79). Temporal and parietal grey matter:
› in the haloperidol group (week 52: d=1.1, r=0.5 and d=1.2, r=0.5 respectively)
(b) caudate volumes: ‹ in the haloperidol group (week 24 d=1.3, r=0.5; week 52: d=2.3, r=0.76;
week 104: d=0.2, r=0.13)
Patients versus controls:
(a) whole-brain grey matter: › in the haloperidol group (week 12: d=3, r=0.1; week 52: d=2.3,
r=0.7) whereas=in the olanzapine group (week 12: d=3, r=0.1; week 52: d=0.17, r=0.0).
Frontal grey matter: › in the haloperidol group (week 12: d=2.1, r=0.7; week 52: d=3.3, r=0.8)
Temporal grey matter: › in the haloperidol group (week 52: d=0.9, r=0.4)
Parietal grey matter: › in the haloperidol group (week 52: d=1.3, r=0.5)
Massana et al.
Risperidone (no fixed dose; mean dose of 6.05 mg/day)
‹ left nucleus accumbens (T=4.26, p=0.00) and the left caudate (T=3.68, p=0.02)
S. Navari and P. Dazzan
Lang et al. 200410 patients under typicals (mean dose/day, chlorpromazine
equivalents 360¡263.7) switched to olanzapine (mean
dose/day, chlorpromazine equivalents 170¡64);
27 patients under risperidone: 13 switched to olanzapine
(mean dose/day, chlorpromazine equivalents
132¡44p150¡10.7) and 14 continuing with risperidone
(mean dose/day, chlorpromazine equivalents
Patients on typicals switched to olanzapine.
(a) at baseline, patients on typicals ‹ basal ganglia than controls (differences were statistically
significant for putamen: d=0.7, r=0.3 and globus pallidus: d=1.4, r=0.5)
(b) at follow-up, basal ganglia volume › in patients (caudate: d=0.04, r=0.02; putamen: d=1.2,
r=0.5; globus pallidus: d=1.06, r=0.4) and
patients versus controls: =basal ganglia (caudate: d=0.2, r=0.1; putamen: d=0.1, r=0.08;
globus pallidus: d=0.5, r=0.2)
Patients on risperidone:
(a) at baseline, risperidone-treated patients subsequently switched to olanzapine versus those
continuing risperidone: =basal ganglia volumes (caudate: d=0.4, r=0.2; putamen: d=0.08,
r=0.04; globus pallidus: d=0.1, r=0.07)
(b) at follow-up, risperidone patients versus olanzapine patients: =basal ganglia volumes
(caudate: d=0.00, r=0.00; putamen: d=0.08, r=0.00; globus pallidus: d=0.4, r=0.2)
Heitmiller et al.
Atypicals (risperidone: mean dose 3.625 mg/day,
olanzapine, quetiapine, clozapine)
Mean dose-years at follow-up, chlorpromazine
Patients versus controls: =amount of change caudate (d=0.00, r=0.001)
However, the female patients had a negative correlation between drug exposure and volume change
(total volume: r=x0.6, p=0.1) whereas the male patients had a positive correlation (total volume:
Christensen et al.
Risperidone (7 patients) at 4 mg/day, ziprasidone
(6 patients) at 120 mg/day, haloperidol (6 patients) at
Risperidone versus ziprasidone versus haloperidol: =change in white matter (paired t: 1.561, p=0.1)
Cahn et al. 2002Typicals (5 patients)
Atypicals (15 patients)
Typicals+atypicals (14 patients)
Cumulative lifetime dose in haloperidol equivalents:
If ‹ cumulative dose of antipsychotic medication (typical or atypical) between T0and T1then › in
global grey matter volume (r=x0.45, p=0.00)
et al. 2002
Typicals (4 patients): haloperidol at mean dose of 2 mg/day
(2 patients); loxapine at mean dose of 10 mg/day
Atypicals (9 patients): clozapine (3 patients)
Typicals+clozapine (2 patients)
At baseline, naive versus treated patients: =caudate (F=0.18, p=0.68)
At follow-up, controls and patients=caudate › of 9% (controls: d=0.6, r=0.3; patients: d=0.5,
r=0.2; clozapine: d=0.4, r=0.2; atypicals: d=0.09, r=0.04; typicals: d=2.1, r=0.7;
clozapine+typicals: d=0.2, r=0.1)
Scheepers et al.
Clozapine: mean dose 346¡61 mg/day
› left caudate at week 24 if on clozapine (left side: F=3.9, p<0.05; right side: F=2.4, p=0.1)
Scheepers et al.
mean dose 345.57¡63.44 mg/day (range 200–600)
› caudate if on clozapine (d=0.2, r=0.1); =whole-brain volume if on clozapine (F=3.85, p=0.6)
Systematic review of antipsychotics and brain structure
Table 2 (cont.)
ReferencesAntipsychotic (type, dose)Main findings
Puri et al. 2001 Still naive (3 patients)
Risperidone (4 patients)
Typicals (27 patients)
Cumulative medication dose in chlorpromazine equivalents:
T0=mean 6677.45 (¡6994.73)
T1=mean 68365.96 (¡53879.50)
Patients versus controls: =ventricular volume at baseline (d=0.4, r=0.2) and follow-up (d=3.2,
r=0.8) and=ventricle brain ratios at baseline (d=0.5, r=0.2) and follow-up (d=0.5, r=0.2)
No correlations between ventricular size at presentation and cumulative medication dose (r=x0.2)
or duration of treatment (r=x0.1)
No correlations between change in ventricular size and total duration of treatment (r=0.2 ) or total
cumulative medication dose (r=0.05)
Lieberman et al.
Open therapy with a standardized treatment algorithm
composed largely of conventional antipsychotic drugs
(used ultimately clozapine for treatment refractory patients)
Patients versus controls: › caudate in patients; › anterior hippocampus and cortical volume in
controls; =ventricles volumes
No association between cumulative dose of antipsychotic treatment in the interscan interval and
ventricular, cortical, hippocampal or caudal volumes
Association between longer duration of treatment with typicals during the interscan interval and
smaller ventricular volumes in patients both at baseline and follow-up scan (F=5.73, p=0.2)
Lang et al. 2001At baseline patients treated with risperidone (dose range
1–6 mg/day, mean 2.7 mg/day). They took risperidone
continuously for o6 months
At follow-up, both patients and controls=basal ganglia than at baseline (for all comparisons p>0.2)
Corson et al. 1999 Typicals: 13 patients; 8 treated only with typicals and
5 minimally exposed also to atypicals. Mean dose years,
Atypicals: 10 patients; 6 treated only with atypicals and
4 minimally exposed also to typicals. Mean dose years,
Patients on typicals: ‹ basal ganglia (t=2.93, p<0.02)
Patients on atypicals: › basal ganglia (t=1.98, p<0.04)
Gur et al. 1998aMainly typicals+atypicals
Follow-up daily dose in chlorpromazine equivalents:
drug-naive: mean dose 259.9¡165.6
drug-free: mean dose 515.3¡224.0
Drug-naive versus drug-free patients: in drug-naive patients more › in left hemispheric frontal lobes
(T=0.17, p=0.02) and in temporal lobes bilaterally (T=0.12, p=0.05)
Drug-free patients: if ‹ medication dose then › in frontal and temporal volumes (r=x0.75 and
x0.66 respectively; p<0.001)
Drug-naive patients: no association between medication dose and › in frontal and temporal volumes
(r=0.03 and 0.16 respectively)
Frazier et al. 1996Patients were under typicals for about 2 years before the first
All patients were under clozapine at the time of the second
MRI (mean dose 400¡128.9 mg/day)
Caudate: › in patients (F=4.96, p=0.02)
Putamen: › in patients (F=2.32, p=0.08)
Globus pallidus: › equally in patients and controls (F=21.74, p=0.00)
Lateral ventricles: ‹ in patients (F=2.38, p=0.07)
S. Navari and P. Dazzan
(b) study design; (c) sample characteristics; (d) dur-
ation of treatment with antipsychotic drugs before the
first MRI and time to follow-up MRI [data on length of
treatment before the first MRI scan were not available
for one study (Corson et al. 1999b), for which plausible
estimates based on length of illness were imputed];
(e) type and dose of antipsychotic drug; (f) brain
region/s evaluated; (g) methods for estimating brain
volumes and slice thickness; and (h) any reported as-
sociation or lack of association between brain volume
and antipsychotic treatment. If information on the
strength of the association (either Pearson’s r, or
Cohen’s d, correlation coefficient) was reported, this
was included in the tables. When this was not the case
but the data were available in the original paper, we
calculated the effect size (d) (Cohen, 1992). When data
were not sufficient to calculate the effect size, we re-
ported the statistical test with the p value quoted in the
As length of exposure to antipsychotic treatment
can be associated with different brain changes, we
classified studies first according to design (cross-
sectional versus longitudinal). Then, within each study
design, studies were classified according to duration
of treatment prior to first MRI scan: (1) studies con-
ducted in drug-naive (never-treated) and drug-free
(not treated for the previous 3 weeks) subjects. These
two groups were considered together according to the
existing literature on antipsychotic washout (Farde
et al. 1986; Miller et al. 1997a,b, 2001); (2) studies con-
ducted in subjects receiving short-term treatment (f12
weeks); and (3) studies conducted in subjects receiv-
ing long-term treatment (>12 weeks). This makes it
easier to discriminate between brain changes that are
potentially due to a specific treatment effect and those
that are related to the illness itself and its progression
(Dazzan & Murray, 1999).
Method of analysis
Published reports did not provide sufficient infor-
mation across studies to allow a meta-analytical
quantitative summary; therefore, data were used for a
systematic review and critical literature analysis.
We identified 33 papers investigating the association
between antipsychotic drug treatment and brain struc-
ture: 10 cross-sectional and 23 longitudinal studies.
We report on the effects on any regional or global brain
volume. For studies with the same design, we first
present findings at a regional level, following brain
anatomy from cortical to subcortical structures (basal
ganglia and thalamus). We then present findings on
Chakos et al.
(a) Patients were under typicals before the first MRI, then
switched to clozapine before the second MRI
(b) Patients were under typicals at the time of the first and
the second MRI
(a) Patients on clozapine: caudate › 10% at second scan (d=0.9, r=0.4)
(b) Patients on typicals: caudate ‹ 8% at second scan (d=0.5, r=0.2)
Chakos et al.
Standardized typical antipsychotics regimens (fluphenazine
up to 20 mg/day for 6 weeks. If not improved, patients progressed through the treatment algorithm receiving full
trials of up to 3 different typical antipsychotics)
Patients: caudate ‹ 5.7% (d=0.3, r=0.1)
Controls: caudate › 1.6% (d=0.09, r=0.04)
A higher daily dose received prior to the first MRI was associated with larger ‹ in caudate (r=0.4,
Keshavan et al.
Typicals: mean maintenance dose in haloperidol equivalents
‹ in right (d=1, r=0.44), left (d=0.68, r=0.32) and total caudate (d=0.86, r=0.39)
None of the other MRI parameters changed
aAn expanded version of this table is available at the Journal’s website (http://journals.cambridge.org/psm).
Systematic review of antipsychotics and brain structure 1769
global volumes (grey and white matter, whole brain,
Cross-sectional studies evaluated brain structure and
its association with concomitant antipsychotic treat-
ment in terms of dosage and type of antipsychotic
used at a single time-point (Table 1).
Studies conducted in drug-naive and drug-free subjects
Such studies are extremely valuable in understanding
brain changes at illness onset and also the possible
effect of previous medication on brain structure. Only
three studies were available on patients either drug-
naive or drug-free at MRI.
A single report compared cortical volumes in drug-
naive patients, long-term treated patients, and controls
(Gur et al. 2000). Both patient groups showed reduced
prefrontal cortex volume, particularly in the dorso-
lateral sector. The authors concluded that reduced
prefrontal volume is not a by-product of treatment and
might representa neuroanatomical
already present at illness onset.
Nopoulos et al. (2001) studied a sample of male
patients at their first episode of psychosis; all 45 drug-
free patients had previous exposure to typicals and
four of these had been additionally exposed to atypi-
cals. The cumulative dose of antipsychotic medication
was negatively correlated with the size of the mid-
brain, indicating that the greater the antipsychotic
exposure, the smaller the midbrain area. When the
authors compared subjects naive (n=5) and with
minimal antipsychotic exposure (n=9) to those medi-
cated, they found that the medicated group had
a smaller midbrain area. Treatment with typicals
seemed to induce a reduction in the midbrain area that
was still present 3 weeks after withdrawal.
Shihabuddin et al. (1998) looked at volume of stri-
atum in a small sample of naive and drug-free
schizophrenia patients in comparison to healthy in-
dividuals. They found a significant group (drug-naive
versus drug-free versus controls) by level (ventral ver-
sus dorsal side) by structure (putamen versus caudate)
interaction. The largest difference was a larger dorsal
putamen volume in drug-free patients versus controls
and, to a minor extent, versus drug-naive patients.
Findings on the caudate size were in the opposite
direction, with drug-free patients showing a smaller
caudate volume than both drug-naive patients and
controls. The authors suggested that the post-
treatment enlargement might last longer after treat-
ment discontinuation for the putamen than for the
caudate, possibly because of a higher density of D2
receptors in the putamen. The difference between the
drug-naive and drug-free subjects in putamen and
caudate volumes might be more likely to reflect the
effect of never-medicated versus previously medicated
status than that of age or illness severity.
More investigations on drug-naive and drug-free
patients are required to clarify the timing of brain
changes and the possible relationship between caus-
ality and antipsychotic treatment.
Studies conducted in subjects receiving short-term
treatment (f12 weeks)
Studies on patients at the initial stages of psychosis,
when treatment would have occurred only for a short
time, can provide information on the occurrence and
timing of structural brain changes; such studies can
help to disentangle changes caused by a specific class
of antipsychotics from those due to the illness and its
Our group (Dazzan et al. 2005) has evaluated a
sample of first-episode psychosis patients treated
with typical or atypical antipsychotics for a relatively
short period of time (mean 8.5 weeks). Patients who
received typicals, but not those on atypicals, compared
to drug-free patients showed cortical grey matter
reduction in frontal areas, temporal-insular areas
and precuneus. As there were no clinical differences
between the groups that could explain the brain
morphological differences, these results support the
hypothesis that these brain changes could be at least
in part explained by the different treatment received.
A potential effect of haloperidol on cortical volume
has also been suggested by another study (Zipursky
et al. 1998). Here, first-episode psychosis patients
treated with higher doses of haloperidol had signifi-
cantly smaller total cortical grey matter volumes than
subjects on lower doses. Therefore, more marked brain
structural changes may represent a dose-dependent
effect of haloperidol on cortical grey matter. Alterna-
tively, individuals with more marked structural ab-
normalities may also be those less responsive to
treatment, and hence receiving higher antipsychotic
Narr et al. (2005) reported that both patients receiv-
ing short-term treatment (mean length 8 days) with
atypical antipsychotics and drug-naive patients, when
compared to controls, had significant cortical thin-
ning of cingulate, occipitals and frontopolar cortices,
suggesting that brain changes at this level predate
illness onset. This is an important issue to consider
when evaluating potential medication effects, and it
may be at least partially addressed by comparing
patients on treatment with those who are drug free,
the approach used by our group (Dazzan et al. 2005).
1770 S. Navari and P. Dazzan
Most of the differences found in our study were be-
tween the group on typicals and the drug-free group.
This suggests a different effect of antipsychotic type,
which could not be estimated in the report by Narr
et al. (2005), where all patients were taking atypicals. It
remains unclear whether medications act on cortical
volume or on cortical thickness. Changes in cortical
thickness may reflect cytoarchitectural abnormalities
more closely related to illness onset than volumetric
abnormalities (Thompson et al. 2003).
Data on the basal ganglia in patients on short-
term treatment are limited to a single report from
our group (Dazzan et al. 2005). Typical antipsychotics
were found to be specifically associated with increased
putamen volume in comparison to drug-free status.
Of note, we found no differences in basal ganglia
volumes when patients on typicals and atypicals were
compared directly. This suggests that atypicals also
act on these structures, although to a lesser extent.
This finding may also reflect a lack of statistical
power, and a larger sample size could have clarified if
indeed basal ganglia enlargement is an effect specific
to typical antipsychotics. Our study is also the only
report on thalamus volume in patients on short-term
treatment (Dazzan et al. 2005). We found that only
patients treated with atypicals showed an enlarge-
ment of the thalami in comparison with drug-free
Finally, one study (Velakoulis et al. 1999) specifically
evaluated the relationship between hippocampal
volume and antipsychotics, albeit indirectly. Here, the
smaller hippocampal volume identified in patients
at their first episode of psychosis in comparison to
controls was not related to the cumulative dose of
antipsychotics received prior to MRI.
Studies conducted in subjects receiving long-term
treatment (>12 weeks)
Findings from these studies are difficult to interpret
because subjects may have been treated with different
antipsychotics at different doses for many years.
Therefore, brain modifications due to medication are
difficult to distinguish from those due to illness
We identified four studies that included patients
treated for >12 weeks, and most have evaluated the
effect of antipsychotics on the basal ganglia and
thalamus. Data from a sample of males with schizo-
phrenia found no differences in thalamic volumes
between patients and controls and no association be-
tween thalamic volume and antipsychotic dose at time
of MRI (Deicken et al. 2002). By contrast, Gur et al.
(1998b) found that a total higher lifetime dose of typi-
cals was associated with larger caudate, putamen and
thalamus volumes whereas a higher dose of atypicals
was associated only with larger thalamic volume.
These data on chronic patients are consistent with
the findings from Dazzan et al. (2005), who described
thalami enlargement following short-term treatment
with atypicals, and enlargement of the putamen in
relation to use of typicals.
In the study by Velakoulis et al. (1999) on long-term
patients with schizophrenia, hippocampal volume
was found to be significantly smaller than in controls.
Similar to their findings in subjects on short-term
treatment, they found no correlation between hippo-
campal volume and cumulative antipsychotic dose.
Only one study evaluated hippocampal volume in
relation to type of antipsychotic used, with negative
findings (Chakos et al. 2005). However, patients had
received long-term treatment with both typical and
atypical antipsychotics, and it could have been diffi-
cult to distinguish specific effects of drug type. To
better investigate the effects of different antipsychotics
on hippocampal volume, Chakos et al. (2005) ran-
domly assigned male patients to treatment with either
an atypical (olanzapine or risperidone) or a typical
(haloperidol) antipsychotic. They found a larger hip-
pocampal volume in patients treated with atypicals
than in those taking haloperidol, suggesting that
male patients, treated early in the course of illness
with atypicals rather than typicals, might be protected
against hippocampal volume reduction. Despite the
randomized design, the sample evaluated was rela-
The cross-sectional studies reviewed used different
designs to test the relationship between antipsychotics
and brain structure (Table 1): three are drug-type
(typicals and/or atypicals); five are dose-correlation
(chlorpromazine equivalents range: from 40.59¡
94.96 mg for drug-naive and drug-free patients to
21018¡16153 mg for long-term treated patients); and
one is dose-correlation for drug-type (chlorpromazine
equivalents for typicals: 407.1¡25.3 mg and for
atypicals: 334.1¡286.3 mg). Finally, two are compari-
sons between drug-free and drug-naive patients
versus controls (for one of them neither the type nor
the dose of antipsychotic used was reported, and for
the other one only the number of patients taking
which type of antipsychotic was reported). Indeed, as
cross-sectional studies evaluate brain structure at a
single time-point, it is difficult to understand the role
of antipsychotics in determining brain changes if type
and dose used are not reported systematically, as
either could be responsible for any effect observed.
Even taking into account these limitations, the cross-
sectional studies reviewed suggest that antipsy-
chotics, typicals in particular, affect the basal ganglia
even after short-term treatment. They also provide
Systematic review of antipsychotics and brain structure1771
preliminary evidence of an early action at cortical
level that may be drug specific.
A longitudinal design allows a better understanding
of the timing and progression of changes in brain
structures and of the effects of antipsychotics on these
changes, making it possible to speculate on causality.
Studies conducted in drug-naive and drug-free patients
We identified eight longitudinal studies on drug-naive
and drug-free patients. Keshavan et al. (1994), in naive
first-episode psychosis patients, found that the pre-
frontal cortex did not change significantly over 1 year
of treatment with typicals. By contrast, Gur et al.
(1998a,b) found, over approximately 2 years, a more
pronounced reduction in frontal and temporal lobes in
drug-naive patients at their first psychotic episode
than in drug-free patients treated previously for more
than 12 weeks (mainly with typicals). The differences
between these studies might be related to the slightly
different brain areas investigated, and to the subjects
receiving different antipsychotics at different doses.
Indeed, Garver et al. (2005) found that, even after a
short period (28 days) of antipsychotic use, patients
treated with haloperidol did not show any change in
cortical grey matter volume whereas patients treated
with atypicals showed an increase in cortical grey
matter volume. These data support a different effect
of typical versus atypical antipsychotics, even after a
short period of treatment.
Regarding the basal ganglia, Heitmiller et al. (2004)
followed up naive patients treated with different
atypical antipsychotics for 2 years. They found that
patients had a very small increase in caudate volume,
almost identical to that of the controls. This replicates
findings from cross-sectional studies suggesting that
exposure to atypicals affects the caudate volume
less than exposure to typicals. By contrast, a study by
Massana et al. (2005) on naive schizophrenia patients
treated with risperidone reported an increase in left
caudate and left accumbens volumes, with a positive
correlation between dose and volume. Considering
the large body of evidence of an increase in caudate
volumes after treatment with typicals (Chakos et al.
1994, 1995; Keshavan et al. 1994; Corson et al. 1999a,b;
Lang et al. 2001; Scheepers et al. 2001a,b), it is possible
that the increase in caudate volume seen at higher
doses of risperidone reflects an action more like that
of a typical antipsychotic (Nyberg et al. 1999). Finally,
Taylor et al. (2005) found an increase of striatal
volumes following 4 weeks of treatment with either
atypicals or typicals in schizophrenia patients but
not in healthy controls. The small sample size did not
allow an evaluation of antipsychotic-type differences
on striatal volume.
In the study by Christensen et al. (2004), white
matter did not change significantly following 4 weeks
of treatment (typicals or atypicals) in schizophrenia
subjects. Indeed, Keshavan et al. (1994) reported no
change in brain volume even after 1 year of treatment
with typicals in drug-naive patients at their first psy-
chotic episode. By contrast, Girgis et al. (2006) found,
in naive first-episode psychosis patients, a decrease in
white matter and an increase in grey matter volumes
after 6 weeks of treatment with the atypical risperi-
done. Differences between studies might be related to
the characteristics of the subjects and to the different
treatment received (type and dose of antipsychotics).
In conclusion, studies on drug-naive and drug-free
subjects have been mostly conducted on small samples
(between 11 and 19), and this may have affected the
power of such studies to identify significant differ-
ences. Studies on larger samples would allow testing
the hypothesis of an antipsychotic-type effect not only
on basal ganglia but also on cortical grey and white
Studies conducted in subjects receiving short-term
treatment (f12 weeks)
These studies take into account the treatment re-
ceived prior to, and in between, MRI scans. Chakos
et al. (1994) studied drug-naive and short-term treated
patients with first-episode schizophrenia and did not
find any cortical volume change following treatment
with typical antipsychotics. These findings are con-
sistent with two other studies that also found no
longitudinal changes in total cortical and prefrontal
cortex volumes over a period of 2.5 years (Lieberman
et al. 2001) and 1 year (Keshavan et al. 1994) respect-
ively. It is possible that treatment may prevent the
volume loss potentially associated with disease pro-
gression. However, a later study with a randomized
design (Lieberman et al. 2005) reported a drug-type
effect of antipsychotics on cortical grey matter over
2 years. Subjects treated with haloperidol, but not
with olanzapine, lost frontal grey matter between
weeks 12 and 24, suggesting that typical and atypical
antipsychotics have differential effects also at the
have found increased basal ganglia volumes follow-
ing short-term treatment with typicals (Chakos et al.
1994; Lieberman et al. 2001). By contrast, Tauscher-
Wisniewski et al. (2002) reported a 9% reduction in
caudate volumes over 5 years in first-episode schizo-
phrenia patients mostly treated with atypicals and
1772S. Navari and P. Dazzan
low-dose typicals (about one-tenth of the doses re-
ceived in the study by Chakos et al. 1994). This would
suggest an effect related to both dose and type of
antipsychotic. A drug-type effect of antipsychotics
on basal ganglia was also reported by Lieberman
et al. (2005), who found a caudate volume increase
in haloperidol-treated but not in olanzapine-treated
subjects. Similarly, Corson et al. (1999b) found an in-
crease in basal ganglia volumes in patients receiving
mostly typicals, whereas the opposite was observed
in patients receiving mostly atypicals. Of interest, the
use of the atypical risperidone at low doses has been
associated with no basal ganglia volume change over
time (Lang et al. 2001), in contrast with the volume
increase observed when risperidone is administered
at higher doses (Massana et al. 2005), when is thought
to have a more typical-like action.
Only one study specifically examined hippocampal
volume, in patients mostly treated with typicals
(Lieberman et al. 2001). Anterior hippocampal volume
remained unchanged in patients, independently from
cumulative antipsychotic dose, whereas it decreased
over time in controls.
Regarding total grey matter, Cahn et al. (2002)
found a 3% volume decrease over 1 year, positively
correlated with cumulative antipsychotic dose. These
authors did not find any association between grey
matter decrease and antipsychotic type. The small size
of the typical antipsychotic group could limit this
conclusion, which contrasts with evidence from
Lieberman et al. (2005) that subjects treated with
haloperidol, but not with olanzapine, lose grey matter
over 2 years.
As far as ventricular volumes are concerned, Puri
et al. (2001) found that patients on antipsychotic
treatment (mostly with typicals) did not show any
significant change in ventricular volume over time in
comparison with controls. These results are consistent
with data from short- and long-term treated patients
showing no significant changes in lateral and third
ventricular volume over time (Frazier et al. 1996;
Lieberman et al. 2001).
This evidence is in accordance with data from
studies on drug-free and drug-naive patients, sug-
gesting that even after short-term treatment, typical
and atypical antipsychotics differentially affect brain
structure not only at the subcortical but also at the
Studies conducted in subjects receiving long-term
treatment (>12 weeks)
The existing literature on chronically treated patients
mostly evaluated basal ganglia volume and the re-
versibility of volume changes in these structures.
Most studies consistently suggest that switching
from long-term treatment with typical antipsychotics
to clozapine results in a significant decrease in basal
ganglia volume (Chakos et al. 1995; Frazier et al. 1996;
Scheepers et al. 2001a). This has been most often
shown for the caudate (Chakos et al. 1995; Frazier
et al. 1996; Scheepers et al. 2001a), and to a lesser extent
for the putamen (Frazier et al. 1996). The volume of
the globus pallidus has also been reported as de-
creasing over time both in patients switching from
typicals to atypicals and in healthy individuals
(Frazier et al. 1996). Switching from haloperidol to
olanzapine is also reported to be associated with pu-
tamen and globus pallidus volume reduction (Lang
et al. 2004). By contrast, switching from risperidone to
olanzapine (pharmacologically more similar to cloza-
pine than risperidone) is not associated with a de-
crease in basal ganglia volume (Lang et al. 2004). This
suggests that atypical antipsychotics could induce
basal ganglia volume normalization, rather than re-
duction, in patients previously treated with typicals,
and supports the notion that atypical antipsychotics
also act on basal ganglia, albeit differently from typi-
cals (Heitmiller et al. 2004). Indeed, Khorram et al.
(2006) found that switching from typicals to olanza-
pine also resulted in a reduction in thalamic volumes,
with higher baseline dosage being associated with a
greater reduction over time. These changes would
therefore represent a normalization of previously
larger volumes associated with the dosage of typicals
administered. These findings are in contrast to data
from cross-sectional studies suggesting an association
between increased thalamic volume and atypical
antipsychotic treatment (Gur et al. 1998b; Dazzan
et al. 2005). These inconsistencies could be due to
methodological issues and differences in sample
McClure et al. (2006) explored whole-brain volume
changes with both region of interest (ROI) and voxel-
based morphometry (VBM) methods in subjects
scanned before and after antipsychotic withdrawal,
and in subjects scanned at two time-points during
stable antipsychotic treatment. Both methods found
no volume changes in either group. The authors con-
cluded that these findings may be explained by the
small sample size, the low statistical power, and the
brief follow-up period.
Finally, only one study looked at lateral ventri-
cular volume changes, following switch to clozapine
(Frazier et al. 1996), and found a trend for an increase
in lateral ventricle volume compared to controls.
In conclusion, findings from studies on long-
term treated patients, already exposed to different
antipsychotics at baseline, are limited by the im-
plicit difficulties in interpreting the nature of the
Systematic review of antipsychotics and brain structure1773
relationship between brain structure and antipsy-
The studies reviewed suggest that antipsychotic drugs
act regionally rather than globally on the brain, with
different effects on different brain structures. An esti-
mate of the effect sizes of these volumetric changes
suggests that they are of a greater magnitude in
association with typical than with atypical anti-
The studies reviewed also suggest an early action of
antipsychotics on the basal ganglia, and possibly on
the thalamus, with typicals specifically increasing the
volume of the basal ganglia and atypicals increasing
the volume of the thalamus. Moreover, they suggest
that antipsychotics also affect cortical grey matter,
with typicals reducing global grey matter volume,
possibly with a dose-dependent effect, and atypicals
potentially retaining/increasing cortical grey matter
Whether there are progressive brain changes
after the onset of schizophrenia remains debatable
(Mathalon et al. 2001; Ho et al. 2003). Some changes
could precede illness onset and may progress in the
course of the disease. Should this be the case, we might
expect these changes to be associated with measures
of illness severity but this association remains contro-
versial (Hulshoff Pol & Kahn, 2008). It is also possible
that antipsychotic treatment interacts with the under-
lying pathophysiology of the illness, co-determining
structural brain changes or playing a protective
role against the progression of the illness itself (Ho
et al. 2003). Indeed, in this perspective, the potential
reversibility of antipsychotic effects has to be con-
sidered, as observed, for example, for the caudate
enlargement induced by typicals and reversed by
clozapine (Chakos et al. 1995; Frazier et al. 1996).
The potentially different effects of typical and
atypical antipsychotics on brain structures could be
due to different mechanisms of action (Lieberman et al.
2005; Scherk & Falkai, 2006). Atypical drugs, such
as clozapine and olanzapine, could increase cellular
resilience and therefore act on the pathophysiology
of psychosis through an agonistic effect on N-methyl-
D-aspartate (NMDA) receptors (Duncan et al. 1999;
Millan, 2005), increasing the expression of trophic
factors (Fumagalli et al. 2004; Angelucci et al. 2005) and
stimulating neurogenesis (Halim et al. 2004; Wang
et al. 2004). Moreover, typical antipsychotics such as
haloperidol may have a potentially toxic effect, and
induce oxidative stress and excitatory neurotoxicity
(Post et al. 1998; Wright et al. 1998). The potential
confounding effect of dose also has to be considered.
For example, low doses of typicals may produce
effects similar to those of atypicals (Oosthuizen et al.
2004), although the data reviewed did not support
Changes in MRI volume measurements can also be
produced by alterations in neuronal and non-neuronal
tissue compartments, in addition to physiological
alterations in brain tissue (e.g. changes in tissue per-
fusion, fat and water content) and in body weight,
alcohol intake, steroid administration and hormonal
status (Weinberger & McClure, 2002). An additional
issue, implicit to all MRI studies, is that measurements
can be affected by differences in image acquisition and
analysis techniques. The studies reviewed certainly
used several different parameters, which made com-
parability of findings difficult.
The interpretation of findings can be difficult
when these are negative, and when the raw data are
not presented. The significance of the p value is often
overestimated, and a critical interpretation of the data
in terms of effect size would be more informative
and improve comparability. Indeed, it would be useful
if authors systematically reported the median of the
dose of antipsychotic used, and also the type of anti-
psychotic, to allow more meaningful comparisons
on the association between typical and atypical anti-
psychotics and changes in brain structures. These
issues make it difficult to discern to what extent find-
ings are comparable, and to interpret the meaning of
volume changes at a neuroanatomical, clinical and
Implications for future research
This is, to our knowledge, the first systematic review
on the effects of past and current antipsychotic drug
use on brain structure. The evidence reviewed sup-
ports the notion that treatment represents one of the
factors among those potentially contributing to the
wide range of brain structural modifications in psy-
chosis, and it should be considered in the interpret-
ation of neuroimaging findings.
Studies accounting for structural brain changes
over time, in first-episode psychotic patients, possibly
drug-naive or short-term treated, with randomized
assignment of medications and dose, would be desir-
able. Finally, evaluating measures such as the shape
of brain structures could provide a complementary
approach to volumetric methods. In fact, volume
changes may not be uniform over a specific structure
but rather localized to specific parts.
Declaration of Interest
1774 S. Navari and P. Dazzan
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