Volume Changes in Gray Matter in First-Episode Neuroleptic-Naive Schizophrenic Patients Treated With Risperidone

Journal of Clinical Psychopharmacology

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Volume Changes in Gray Matter in First-EpisodeNeuroleptic-Naive Schizophrenic Patients

Treated With Risperidone

Guillem Massana, MD, PhD,*y Pilar Salgado-Pineda, PhD,z Carme Junque, PhD,yz Merce Perez, MS,zImmaculada Baeza, MD,* Alexandre Pons, MD, PhD,* Joan Massana, MD, PhD,*

Vıctor Navarro, MD, PhD,* Jordi Blanch, MD, PhD,* Astrid Morer, MD,*

Jose Marıa Mercader, MD, PhD,x and Miquel Bernardo, MD, PhD*y

Abstract: Structural neuroimaging techniques have consistently

shown that treatment of schizophrenic patients with conventional

antipsychotics causes an increase in basal ganglia volume.

However, findings in schizophrenic patients treated with the newer

atypical antipsychotic drugs are less consistently reported. To

explore this issue, the authors used a whole-brain, unbiased, and

automated technique for comparing brain structural features across

scans in schizophrenic patients before and after a treatment with the

atypical antipsychotic risperidone. T1-weighted images from 11

first-episode neuroleptic-naive schizophrenic patients were pro-

cessed and analyzed for regions of interest (basal ganglia) by using

optimized voxel-based morphometry. Scans were repeated after 3

months of continuous treatment with risperidone. ROIAQ1 -based voxel-

based morphometry analyses revealed increases in gray matter

volume for the right and left caudate nuclei and for the left

accumbens after the treatment with risperidone. Hence, in our

sample of schizophrenic patients, treatment with risperidone was

associated, in contrast to the findings for other atypical anti-

psychotics, with an increase in basal ganglia volume. Such

discrepancy could be related to the pharmacodynamics of ris-

peridone (the atypical antipsychotic showing the higher affinity

for D2 receptors) and the rather high mean doses used in our study

(ie, 6.05 mg/d).

(J Clin Psychopharmacol 2005;25:1–7)

Knowledge of the brain mechanisms involved in the

therapeutic effects of antipsychotic drugs (and in the

delay of such therapeutic effects) is crucial for understanding

the neurobiology of schizophrenia and for developing new

treatment strategies. Thus, since the first antipsychotic drug

was discovered in the 1950s, several hypotheses have been

proposed. Some authors (for a review, see Ref. 1) have

speculated that the mechanism of action might involve the

ability of antipsychotic drugs to induce neuroplasticity, a

gradual process by which the brain adapts to changes in the

environment. Neuroplasticity changes involve 2 processes:

neurogenesis and synaptic plasticity.

Whereas neurogenesis has not been clearly demon-

strated for any antipsychotic drug, synaptic plasticity has

been consistently observed in both animal models and

clinical human samples after treatment with the conventional

antipsychotic haloperidol. At the level of macroscopic

measurements, haloperidol has been found to increase

regional brain volume, mainly the striatum.2 This finding

is consistent with the pharmacodynamics of conventional

antipsychotics, that is, dopamine D2 receptor antagonism,

because D2 receptors are abundantly expressed in the

striatum.

The effects of atypical antipsychotic drugs in brain

anatomy are less clear. Interestingly, some studies have

revealed that the increase in caudate volume observed during

treatment with conventional antipsychotic drugs normalizes

after cessation of treatment or when patients are treated with

atypical antipsychotics.3–5 Atypical antipsychotic drugs

affect the dopaminergic system to a lesser extent than do

conventional antipsychotics.6–8 In fact, they are less potent

in the striatum, and anatomical changes are generally more

subtle and difficult to uncover.

To explore this issue, the present study used optimized

voxel-based morphometry (VBM) to examine possible brain

structural changes in schizophrenic patients before and after

treatment with the atypical antipsychotic risperidone. In fact,

Original Contribution

Journal of Clinical Psychopharmacology � Volume 25, Number 2, April 2005 1

*Institut Clınic de Psiquiatria i Psicologia, Corporacio Sanitaria Clınic;

yInstitut d’Investigacions Biomediques August Pi-Sunyer (IDIBAPS),

Area de Neurociencies Clıniques i Experimentals; zDepartament de

Psiquiatria i Psicobiologia Clınica, Universitat de Barcelona and

xCentre de Diagnostic per la Imatge, Corporacio Sanitaria Clınic,

Barcelona, Catalonia, Spain.

Received May 10, 2004; accepted after revision October 1, 2004.

Address correspondence and reprint requests to Guillem Massana, MD, PhD,

Institut Clınic de Psiquiatria i Psicologia, Corporacio Sanitaria Clınic,

Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail: tricosmos1@

yahoo.es.

Copyright n 2005 by Lippincott Williams & Wilkins

ISSN: 0271-0749/05/2502-0000

DOI: 10.1097/01.jcp.0000155818.29091.53

Lang et al9 used volumetric magnetic resonance imaging

(MRI) to determine caudate, putamen, and globus pallidus

volumes in first-episode schizophrenic patients. After a mean

of 1.06 years of exposure to continuous treatment with

risperidone, basal ganglia volumes were unchanged in these

patients. In the present study, we shared similar objectives

but now using a newer methodological approach, VBM.

Voxel-based morphometry is a whole-brain, unbiased, and

automated technique for comparing structural features across

scans. Its main advantage is that it avoids problems of

intraobserver and interobserver bias and sensitivity in

assessing differences in cerebral morphology between

groups of subjects.10 Recent methodological developments

have optimized VBM techniques,11 improving their sensi-

tivity. To date, the optimized version of VBM has been used

in studies of schizophrenic patients12; these authors found

selective regional gray matter (GM) differences in the

mediodorsal thalamus and across cortical regions in non–

neuroleptic-naive schizophrenic patients compared with

healthy matched comparison subjects.

MATERIALS AND METHODS

SubjectsEleven (8 men and 3 women) patients aged 18 to 30

(mean 23 ± 4) years with a Diagnostic and Statistical

Manual of Mental Disorders, Fourth Edition diagnosis of

schizophrenia or schizophreniform disorder were included in

the study. Patients were recruited in the Department of

Psychiatry of the Hospital Clinic of Barcelona (Catalonia,

Spain). All patients were first-episode and neuroleptic-naive

at the time of the first exploration. Consensus diagnoses were

established by both a junior (I.B.) and a senior (M.B.)

psychiatrist after independent assessments. All subjects were

right-handed (according to the Oldfield handedness inventory).13

The assessments were performed at study entry and 1 year

later; those patients with schizophreniform disorder met the

criteria for a diagnosis of schizophrenia after 1 year of

illness. The presence or absence of psychopathology was

established for all patients using the 18-item Brief Psychi-

atric Rating Scale,14 the Scale for the Assessment of

Negative Symptoms,15 and the Scale for the Assessment of

Positive Symptoms.16 All the scales were administered by

the same psychiatrist (I.B.).

The study was carried out in accordance with

Declaration of Helsinki and was approved by the local

research ethics committee of our university hospital. All

patients signed written informed consent agreements follow-

ing detailed explanation of the study and procedure.

MedicationAll 11 patients were treated with unfixed doses of the

atypical antipsychotic risperidone once the first MRI scan

had been performed. The mean daily dose of risperidone was

6.05 mg. The dose of the antipsychotic was adjusted based

on clinical response, and all patients were on their optimal

dose at least 9 weeks. Some patients took lorazepam for

insomnia or anxiety and/or biperiden for extrapyramidal side

effects on an ad libitum basis.

Magnetic Resonance Imaging Acquisitionand Processing

Magnetic resonance imaging was obtained in all

subjects using a 1.5 Signa scanner (General Electric,

Milwaukee, Wis, USA). A strict imaging protocol was used,

including a 3D IR Prep SPGR sequence of the entire brain in

the axial plane and the following parameters: repetition time

= 12; time to echo = 5; delay time = 300 AQ2; 1.5-mm thickness;

FOV = 24 � 24; matrix = 256 � 256; flip angle = 208;1 NEX. During the study, subjects reclined in a supine

position on the bed of the scanner and an RF coil was

placed over their head. Images were visually examined

for artifacts by an expert radiologist (J.M.M). The same

MRI protocol was used at study entry (in which all

patients were neuroleptic-naive) and 3 months later.

A T1 volume was reconstructed for each subject from

the DICOM raw data by means of the MRIcro (Nottingham,

UK) software. Volumes were further saved in ANALYZE

7.5 format compatible with the SPM99 software (Statistical

Parametric Mapping, Wellcome Department of Cognitive

Neurology, University College London, UK).

For the morphological analysis, the authors used

VBM10 with the optimized protocol.11 All the automated

image processing was done using SPM99 running in Matlab

(MathWorks, Natick, Mass). A single investigator performed

the manual step in image preparation (determination of the

anterior commissure and reorienting the images according to

the anterior-posterior commissure line).

First, an anatomical template was created from the 11

subjects, for which each MRI was transformed into a

standardized coordinate system. This was achieved through

registering each of the 22 images to the same template image

(T1 SPM template) by minimizing the residual sum of

squared differences between them.10 The normalized data

were smoothed with a 8-mm full-width at half-maximum

isotropic Gaussian kernel, and a mean image (the T1

template) was created. All the 22 structural images (in

native space) were then transformed to the same stereotactic

space, using the template created. The spatially normalized

images were automatically partitioned into separate images

representing probability maps for GM, white matter, and

cerebrospinal fluid using the combined pixel intensity and

an a priori knowledge approach integrated in SPM99. The

tissue classification method is described in detail else-

where.17 The partitions were completed by the ‘‘lots of inho-

mogeneity correction’’ option.10 The normalized segmented

2 n 2005 Lippincott Williams & Wilkins

Massana and Associates Journal of Clinical Psychopharmacology � Volume 25, Number 2, April 2005

images were smoothed using an 8-mm full-width at half-

maximum isotropic Gaussian kernel. A separate GM tem-

plate was created by averaging all the 22 smoothed

normalized GM images.

All the original images (in native space) were then

segmented into gray and white matter images; this was

followed by a series of fully automated morphological

operations for removing nonbrain voxels from the segmented

images by the evaluated function: for the GM images: GM/

(GM + white matter + cerebrospinal fluid + extrapyramidal

side effects) * BrainMask.

The extracted GM images (‘‘cleaned’’) were normal-

ized to the GM template (preventing any contribution of non

brain voxels and affording optimal spatial normalization of

GM). However, because the initial segmentation is performed

on a nonnormalized image (applying probability maps that

are created for normalized images), the optimized (for GM)

normalization parameters were reapplied to the original

structural images. These normalized (by optimal GM

parameters) images were then segmented again. The GM

images were cleaned following the same procedure described

previously.

To compensate for possible volume changes because

of the spatial normalization procedure, the segmented images

were modulated by the Jacobian determinants derived from

the spatial normalization step.

The processed GM images were smoothed with a 12-

mm full-width at half-maximum kernel and analyzed using

an SPM99 group comparison. A paired t test analysis was

performed, results being thresholded for the study group at P

< 0.001 (uncorrected). Uncorrected P values were calculated

as the software’s correction for multiple comparisons

(originally designed to analyze functional imaging data) is

very strict when applied to the analysis of structural data.

Only clusters longer than 5 contiguous voxels were con-

sidered in the analysis.

ROIs DefinitionAs we focused on possible subcortical increases, the

Marsbar toolbox for SPM9918 was used. Ten ROIs were

drawn: 1 for each caudate nucleus, 1 for each putamen

nucleus, 1 for each pallidus nucleus, 1 for each accumbens

nucleus, and 1 for each thalamic nucleus (see Fig. 1). ROIs

were the same for all images and were defined according to

the following steps:

1. Creation of an average image from all the T1 normalized

images into the MNIAQ4 space images,

2. Definition of coordinates for each structure according to

the Talairach map,

3. Conversion of the Talairach coordinates to MNI coor-

dinates with the following formulas (http://www.mrc-

cbu.cam.ac.uk/Imaging/Common/mnispace.shtml):

� X = (XTalairach + 0.8)/0.88� Y = (YTalairach + 3.32)/0.97� Z = (ZTalairach � 0.05Y + 0.44)/0.88,

4. Manual delimitation of the ROIs using the ‘‘point by

point’’ tool of the Marsbar ROI definition into the T1

average image, and

5. Filtering the ROIs by white matter a priori own template

(created in the VBM steep).

ROI-GM volume increase analyses were performed for

these unilateral Student t analyses, the significance threshold

being set at P (corrected) < 0.1.

RESULTSCorrected P values showed significant GM increases in

the left accumbens and the left caudate nuclei. Additional

GM increases could also be observed using uncorrected P

values < 0.001 for all the basal ganglia (accumbens, caudate,

pallidus, and putamen) bilaterally, as well as for the left

thalamus (see Table 1).

DISCUSSIONWe have used optimized VBM to study a group of

first-episode neuroleptic-naive schizophrenic patients before

and after a treatment with risperidone. Results of ROI-based

analyses indicate an increase of the basal ganglia volume

(left caudate and left accumbens) in our sample of

schizophrenic patients after a 3-month treatment with this

atypical antipsychotic.

Several MRI and postmortem studies observed an

increased basal ganglia size in schizophrenia.2,19–21 Al-

though this increase was initially considered to be a disease-

specific manifestation of schizophrenia, subsequent evidence

has suggested that it is caused by antipsychotic medica-

tion.22,23 Volumetric studies indicate that neuroleptic-naive

schizophrenic patients, compared with healthy subjects, do

not show larger basal ganglia volumes, but rather an absence

of differences9,24,25 or a trend toward smaller volume of such

structures.26–29 Interestingly, many investigations have

documented increases in basal ganglia structures after

treatment with conventional antipsychotic drugs,22,23 a

change which does not seem to occur after treatment with

atypical antipsychotics. In fact, several previous studies have

reported that atypical antipsychotics reverse3–5 or fail to

produce this increase in size.25,30 In a 2-year follow-up study,

mean basal ganglia volume of patients receiving predomi-

nantly conventional antipsychotics increased, whereas the

opposite was observed for patients receiving mostly atypical

antipsychotics.30 In another follow-up study, a higher dose of

a conventional antipsychotic was associated with higher

caudate, putamen, and thalamus volumes, whereas a higher

dose of an atypical antipsychotic was associated only with a

higher thalamic volume.25

AQ3

n 2005 Lippincott Williams & Wilkins 3

Journal of Clinical Psychopharmacology � Volume 25, Number 2, April 2005 Volume Changes in Gray Matter With Risperidone

Thus, our findings of increased caudate and accumbens

volume after treatment with an atypical antipsychotic drug

are inconsistent with this existing literature. It should be

remarked, however, that (1) the studies showing that atypical

antipsychotic drugs normalize increased basal ganglia

volumes caused by conventional antipsychotics3–5 were

carried out in patients switched to clozapine and not to any

other atypical antipsychotic, and (2) the studies reporting that

atypical antipsychotics do not bring about increases in basal

ganglia volumes25,30 were, despite being carried out in larger

samples than that of the present study, rather heterogeneous,

in that they included patients taking different atypical

antipsychotics (ie, some patients were receiving clozapine,

others olanzapine, and others risperidone) or a combination

of conventional and atypical antipsychotics.

As mentioned above, our sample consisted of pa-

tients receiving only 1 atypical antipsychotic drug, namely,

risperidone. Among currently marketed atypical antipsychot-

ic drugs, risperidone shows a higher affinity for D2 receptors,

and this may account for our findings of increased basal

ganglia volume consistent with those observed in schizo-

phrenic patients treated with conventional antipsychotic drugs

(the latter showing a markedly higher dopamine D2 receptor

affinity and occupancy than do atypical antipsychotics).

However, Lang et al9 did not detect significant changes

in basal ganglia volumes in first-episode schizophrenic

patients after a mean of 1.06 years of exposure to

risperidone. Although they used a different technique to

analyze basal ganglia volumes (volumetric MRI) and their

sample consisted in first-episode schizophrenic patients who

FIGURE 1. Average T1-weighted MRI showing ROIs delimitation (bilaterally).



were not neuroleptic-naive at the time of the baseline

exploration, their findings can be considered virtually

opposite to the ones in our study.

One possible explanation for these differences could be

the dose of risperidone used in our study. In fact, our sample

of schizophrenic patients was treated with a mean dose of

risperidone that was rather high (6.05 mg/d), whereas

patients studied in the work of Lang et al9 received a mean

dose of 2.7 mg/d. Nyberg et al31 used positron emission

tomography in schizophrenic patients treated with 2

consecutive fixed doses of risperidone, 6 and 3 mg/d, to

examine the relationships between dose and plasma concen-

trations of risperidone and D2 and 5-hydroxytryptamine (5-

HT)2A receptor occupancy. Results showed that treatment

with risperidone, 6 mg/d, is likely to induce unnecessarily

high D2 receptor occupancy, with a consequent risk of

extrapyramidal side effects. In fact, some of our patients had

to be treated for extrapyramidal side effects with biperiden

on an as-needed basis.

The differences between our data and those of Lang

et al9 could also be accounted for by the different techniques

used to analyze basal ganglia volumes (volumetric MRI vs.

VBM) and also by the acquisition of data. Lang et al used a

coronal inversion recovery sequence with a total of 18 slices

of 4 mm thick with a 1-mm interslice gap. We used a 3D IR

Prep SPGR sequence of the entire brain in the axial plane

and 1.5-mm thickness of continuous slices.

Whatever the case, our results of increased subcortical

volumes after treatment with the atypical antipsychotic

risperidone seem to be indicating a medication-induced

hypertrophy. Although the cellular processes responsible for

basal ganglia volume increase in neuroleptic-treated schizo-

phrenic patients have not been identified, it is believed that

such hypertrophy could reflect structural adaptation to

receptor blockade and may modulate the effects of the

antipsychotic treatment.25 The suggestion that increased

subcortical volume is related to exposure to neuroleptics is

further strengthened by the positive correlation between

medication dose and volumes.25

Research has yet to determine the mechanism by which

basal ganglia volume increases after a neuroleptic treatment.

It has been hypothesized that when neuroleptic medication is

administered, dopamine receptors embedded in the neuronal

membrane are up-regulated as a consequence of chronic

receptor blockade, which in and of itself leads to an upsurge

in metabolic need and therefore increased blood flow to the

area (the mechanism through which the increased metabolic

needs can be met).32

In this regard, brain metabolism and blood flow in

subjects with schizophrenia have been examined by means of

functional neuroimaging techniques. Westmoreland Corson

et al32 found no differences in striatal blood flow between

first-episode neuroleptic-naive schizophrenic patients and

healthy volunteers. Other studies have examined brain

metabolism before and after antipsychotic treatment,33–40

and although the results are mixed, the most consistent

finding is increased metabolism in the basal ganglia during

treatment with conventional antipsychotics. Interestingly,

similar studies have reported neither a significant effect on

blood flow in the basal ganglia41 nor a reduction in

metabolism (related to mean global metabolism) in the

ventral striatum, thalamus, and prefrontal cortex42 during

treatment with the atypical antipsychotic risperidone. If

risperidone does not bring about a significant effect on blood

flow and metabolism in basal ganglia, as shown by the

papers already mentioned,41,42 but it is associated with an

increase of basal ganglia volume, as our findings indicate,

the hypothesis of volume increase being the consequence of

increased blood flow must be put into question.

Another mechanism that could explain an increase in

basal ganglia volume after treatment with an atypical

antipsychotic drug like risperidone is induction of gene

expression. Indeed, atypical antipsychotics have been

consistently found to affect neuroplasticity, as revealed by

their induction of gene expression in several brain

areas.1,43,44 Whatever the case, in the striatum, the effect

of atypical antipsychotics is less than the observed with

conventional antipsychotics and also shows a different

distribution.43–47

An increase of GM volume in the left accumbens AQ5has

also been found in our sample of schizophrenic patients

treated with risperidone. To date, volumetric studies of the

accumbens in schizophrenia have been rather scarce, maybe

because this structure is very difficult to explore using

standard volumetric techniques. ROI-based analyses focus-

ing on the accumbens are now more feasible with VBM, and

that will allow investigators to study this structure, which has

been considered a main ‘target’ for neuropsychiatrists as part

of the frontostriatal circuit more directly involved in

TABLE 1. ROI-Based Analysis for GM Volume Increase

ROI t Statistic Uncorrected P Corrected P

Right accumbens 2.29 0.023 0.203

Left accumbens 4.26 0.001 0.001*

Right caudate 3.07 0.006 0.053

Left caudate 3.68 0.002 0.020*

Right pallidus 1.79 0.052 0.414

Left pallidus 2.32 0.021 0.193

Right putamen 2.25 0.024 0.216

Left putamen 2.06 0.033 0.288

Right thalamus 1.35 0.102 0.661

Left thalamus 2.47 0.016 0.152

*Statistically significant.



psychiatric illnesses, in general, and in schizophrenia, in

particular.48 The accumbens is the target of the afferences

from the anterior cingulate, a structure that has been found to

be directly involved in schizophrenia.49 The positive finding

only in the left hemisphere is consistent with previous

literature on structural neuroimaging that points to the

existence of abnormalities in the left hemisphere in

schizophrenia. Moreover, a lack of the normal structural

asymmetry of the anterior cingulate gyrus and in the

paracingulate sulcus has been described in schizophrenic

patients.50,51 On the other hand, risperidone has been found

to increase D2AQ6 and 5-HT2 in the nucleus accumbens in

laboratory rats.52

A possible limitation of our study is implicit in the VBM

procedures. One should be cautious when using automated

image-processing packages for disease description and

identification. Although the algorithms in SPM are considered

robust, this software was not specifically designed to evaluate

structural abnormalities, and imperfect registration can lead

to inaccuracy.53 We attempted to solve this problem by

creating a customized template as well as prior maps for each

group of subjects.11,54–56 To evaluate gray matter changes, we

used the modulation by the Jacobian determinants derived

from spatial normalization. This procedure attempts to correct

for the effects of volume changes, but it cannot be considered

a direct measure of regional volumes, and one must be

cautious in the interpretation of the results.

Another limitation of the present study is that the

sample size overall is only 11 patients, and there are men and

women included in the mix. If there were sex-related effects

of medication, then this could account for why this report is

substantially different from other studies that included only

men or that included more patients.

In summary, our results indicate that treatment with

risperidone, an atypical antipsychotic drug widely used in

schizophrenic patients, is associated with an increase in basal

ganglia volume (left caudate and left accumbens). Although

our sample consisted of first-episode neuroleptic-naive

schizophrenic patients, these findings should be interpreted

conservatively, especially bearing in mind that the study was

open, comprised only 11 patients, and used rather high doses

of risperidone that were not fixed. Further studies examining

possible anatomical changes in schizophrenic patients

receiving atypical antipsychotic drugs may help to clarify

the mechanism of action of these drugs, to design novel

treatment strategies, and to elucidate the neurobiology of

schizophrenia.

ACKNOWLEDGMENT

This study was supported by a public research grant

(00/0233) from the Fondo de Investigaciones Sanitarias,

Instituto Carlos III, Spain.

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Volume Changes in Gray Matter in First-Episode Neuroleptic-Naive Schizophrenic Patients Treated With Risperidone

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