Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia

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Schizophrenia Research

Increase in gray matter and decrease in white matter volumes in the

cortex during treatment with atypical neuroleptics in schizophrenia

Vicente Molina a,*, Santiago Reig b, Javier Sanz c, Tomas Palomo c, Carlos Benito d,

Javier Sanchez b, Fernando Sarramea e, Javier Pascau b, Manuel Desco b

a Department of Psychiatry, Hospital Clınico Universitario, P8 S. Vicente, 58-182. Salamanca 37007, Spainb Department of Experimental Medicine, Hospital Gregorio Maranon, Madrid, Spain

c Department of Psychiatry, Hospital Doce de Octubre, Madrid, Spaind Department of Neuroradiology, Hospital Gregorio Maranon, Madrid, Spain

e Department of Psychiatry, Hospital Reina Sofıa, Cordoba, Spain

Received 7 May 2005; received in revised form 27 June 2005; accepted 6 July 2005

Available online 16 September 2005

Abstract

The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly

understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic

resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients

were analyzed: treatment-naıve patients (n =17) and chronic treatment-resistant patients (n =12). Treatment-naıve patients

received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white

matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups

of patients presented GM increases and WM decreases in the parietal and occipital lobes ( p b .005). Frontal GM also increased

in the chronic group with clozapine. There was a significant ( p b .001) inverse relationship between the baseline volumes (GM

deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus,

treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs

further exploration.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Schizophrenia; MRI; Atypical neuroleptics; DLPF cortex atrophy; Clozapine

0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.schres.2005.07.031

* Corresponding author. Fax: +34 923 291 383.

E-mail address: [email protected] (V. Molina).

1. Introduction

Cortical volume deficit is present in schizophrenia

(Shenton et al., 2001), and it is possible that antipsy-

chotic treatments could have an effect on this volume

deficit (Harrison, 1999); however, the direction of that

80 (2005) 61–71

V. Molina et al. / Schizophrenia Research 80 (2005) 61–7162

effect is unclear. On the one hand, it has been reported

that typical antipsychotics can induce neuronal apop-

tosis (Noh et al., 2000) or reduce synaptic density

(Kelley et al., 1997), which suggests they play a role

in producing volume deficits. A decrease in brain-

derived neurotrophic factor has also been reported in

association with neuroleptic treatment (Angelucci et

al., 2000). Moreover, a recent study performed in

monkeys suggests that chronic exposure to haloper-

idol and olanzapine may decrease brain weight and

volume (Dorph-Petersen et al., 2005).

On the other hand, it has been reported that higher

cumulative exposure to conventional neuroleptics is

associated with lower ventricular enlargement (DeLisi

et al., 1997; Lieberman et al., 2001) and that, in first

psychotic episodes, the volume deficit in the superior

temporal gyrus may resolve with treatment (Keshavan

et al., 1998). In addition, another primate study has

shown that treatment with antipsychotics, whether

typical or atypical, can induce an increase in cortical

volume (Selemon et al., 1999). These data suggest

that some antipsychotics can compensate for certain

structural effects associated with mental illness.

When it comes to determining the possible effect

of neuroleptics on alterations in cortical volume, it is

necessary to distinguish between conventional and

atypical drugs. It has been reported that clozapine

has an effect of reversing the increases in basal gang-

lia volume induced by typical antipsychotics (Chakos

et al., 1995). It has also been found that atypical drugs

do not produce an increase in basal ganglia volume in

treatment-naıve patients (Heitmiller et al., 2004) and

that atypical drugs have a greater capacity for increas-

ing NAA levels in the prefrontal (PF) cortex (Berto-

lino et al., 2001).

Table 1

Demographic and clinical data on patients and controls, expressed as the

Chronic (n =12)

Pre Post

Age (years) 31.0 (5.9)

Duration (years) 7.6 (4.0)

Time bet. scans (months) 28.7 (11.8)

Positive dimension 33.5 (16.3) 9.6 (12.5)

Negative dimension 34.5 (15.4) 28.5 (11.8)

Disorganization 19.3 (12.3) 3.7 (4.0)

Parental socioec. level 2.3 (0.9)

Education (years) 8.7 (8.9)

To our knowledge, no longitudinal studies have

been conducted on structural changes in adult schizo-

phrenia patients during exclusive treatment with aty-

pical drugs. Therefore, we performed a longitudinal

analysis of changes in cortical volume in schizophre-

nia patients treated with atypical neuroleptics. We

enrolled two groups of patients, one consisting of

treatment-naıve patients receiving risperidone during

the follow-up period, and the other of chronic patients

previously treated with typical neuroleptics, who were

switched to clozapine during the follow-up period. We

also analyzed a group of healthy subjects of similar

age as a reference control for longitudinal changes in

the brain in the absence of disease.

2. Methods

2.1. Subjects

Twenty-nine schizophrenia patients (20 males) and

11 controls (6 males), all right-handed Caucasians,

were enrolled. The patients were assigned to two

groups: neuroleptic-naıve (NN) and chronic-resistant

(CR) (Table 1).

The NN group included 17 subjects diagnosed with

paranoid schizophrenia (DSM-IV criteria). Twelve

cases were first psychotic episodes, followed prospec-

tively to confirm the diagnosis after one year. The

other five cases already met the above criteria on

enrollment. These 17 patients belonged to a sample

of 49 first-episode cases, the rest of whom were not

included in the longitudinal study for various reasons

(diagnosis other than schizophrenia in 15 cases, loss

to follow-up in 8 cases, administration of a different

mean (SD)

N. naıve (n =17) Controls (n =11)

Pre Post

25.6 (4.0) 28.4 (6.2)

2.3 (1.4)

25.6 (9.9) 27.5 (14.0)

25.9 (14.0) 5.0 (4.5)

35.4 (19.4) 47.5 (26.0)

18.8 (9.4) 9.4 (11.5)

2.5 (0.7) 2.4 (0.8)

10.8 (6.1) 11.2 (9.1)

V. Molina et al. / Schizophrenia Research 80 (2005) 61–71 63

treatment in 4 cases, and refusal of a repeat MRI in 3

cases). In the NN group of patients, the baseline MRI

was done at initiation of treatment, within two weeks

following diagnosis of the first psychotic episode. The

second MRI was done a mean of 26 months (range:

20–30) later. During this follow-up period, treatment

was maintained with risperidone at dosages adjusted

according to clinical criteria (mean final dosage: 5F2

mg/day). None of the patients received any other

treatment, except for one patient who received biper-

iden, two who received propanolol for extrapyramidal

effects, and three who briefly received benzodiaze-

pines for insomnia.

The CR patient group comprised 12 cases (8

males), all chronic and refractory to conventional

treatment. This group included 7 cases of paranoid

schizophrenia and 5 of the undifferentiated subtype

(DSM-IV criteria). It was part of a sample of 29

chronic treatment-resistant patients, the rest of whom

were not included in this study for the following

reasons: loss to follow-up in 10 cases, treatment

other than clozapine in 5 cases, and refusal of a repeat

imaging study in 2 cases.

In the CR group of patients, the baseline MRI was

done after maintaining prior haloperidol treatment

(dosage: 10 mg/day) for one month, in order to con-

firm treatment resistance. After the baseline MRI, the

treatment was converted to clozapine (initial dosages

after escalation: 410F339 mg/day; final dosages

260F211 mg/day), until a second imaging study

was done a mean of 26 months (range: 20–31) later.

No patient received any other antipsychotics, antide-

pressants, or mood stabilizers, except for one patient

who received benzodiazepines for insomnia.

In all patients, diagnosis was confirmed using a

semi-structured interview (SCID, patient version) and

information from families and clinical staff.

Symptoms were assessed using the SANS

(Andreasen, 1983a) and SAPS (Andreasen, 1983b).

Scores were calculated for positive, negative, and

disorganization dimensions. Changes in weight

between the first and second MRI were also mea-

sured. Data regarding clinical and demographic char-

acteristics at inclusion are shown in Table 1.

A sample of 11 healthy volunteers (6 males) was

studied as a reference control for longitudinal changes

in a healthy population. These controls had a below

college educational level in order to properly match

them with the patient group, and received minor

compensation for their participation. No differences

in parental socioeconomic status (Hollingshead and

Frederick, 1953) were detected between groups. As in

the patient groups, each subject underwent MRI stu-

dies over a similar period (mean interval between

studies: 27 months; range: 19–36) (Table 1). There

were no significant differences between the age of the

controls and the patients.

Exclusion criteria for patients and controls were

neurological illness, MRI findings judged clinically

relevant from a neurological perspective by a radiolo-

gist blind to diagnosis, history of cranial trauma with

loss of consciousness, substance dependence criteria

during the last 3 years (except for caffeine or nicotine),

substance abuse during the last 6 months (a urinalysis

at intake was used to rule out current consumption),

history of axis I psychiatric processes or treatment

(except schizophrenia in the case of patients), or any

current treatment having known CNS action in addi-

tion to neuroleptics and benzodiazepines for insomnia.

After receiving full information, the patients and

their relatives signed an informed consent form. The

independent ethics committee approved the study.

2.2. MRI acquisition and processing

MRI scans were acquired with the same Philips

Gyroscan 1.5T scanner and the same acquisition pro-

tocol at baseline and follow-up, a T1-weighted 3D

gradient echo sequence with the following parameters:

matrix size 256�256, pixel size 0.9�0.9 mm (FOV

256 mm), flip angle 308, echo time 4.6 ms, slice

thickness ranging from 1.1 to 1.5 mm. T2-weighted

sequences were also acquired for verification of CSF

segmentations and for other clinical purposes (Turbo-

Spin Echo, turbo factor 15, echo time 120 ms, matrix

size 256�256, slice thickness 5.5 mm).

2.2.1. Segmentation and ROI definition

The MRI processing and volumetric quantifica-

tion have been described in detail elsewhere (Desco

et al., 2001; Molina et al., 2003b). Briefly, to obtain

volume measurements of the main brain lobes, we

used a method for semi-automated segmentation of

the brain based on the Talairach reference system

(Fig. 1), similar to the method described in Andrea-

sen et al. (1996) and Kates et al. (1999). This

Fig. 1. An example of a Talairach grid built upon an MRI scan. Regions of interest are defined by adding grid cells, according to the Talairach

Atlas.


method has also been used in similar studies mea-

suring longitudinal volume changes in brain regions

(Ho et al., 2003). Basically, it is a two step proce-

dure. The first step involved editing the MRI to

remove skull and extracranial tissue using the T2-

weighted image, and an initial segmentation of cere-

bral tissues into gray matter (GM), white matter

(WM), and cerebrospinal fluid (CSF) of the T1-

weighted image. Segmentation of cerebral tissue

was performed using an automated method included

in the SPM2 (Statistical Parametric Mapping) pro-

gram (Ashburner and Friston, 1997). The method

performs a cluster analysis with a modified mixture

model and a priori information about the likelihood

of each MRI voxel being one of 4 tissue types: GM,

WM, CSF, and bother tissues.Q The a priori informa-

tion consists of anatomical templates that represent

an daverageT brain and provides information about

the spatial distribution of the different brain tissues.

The algorithm also removes the effect of radiofre-

quency field inhomogeneities (Ashburner and Fris-

ton, 2000). This segmentation was checked for

inconsistencies and manually corrected whenever

necessary by an experienced radiologist blind to

the diagnosis. In a second stage, we applied the

Talairach reference system (Talairach and Tournoux,

1988) to define regions of interest (ROIs) and to

obtain volume data. MRI processing was performed

using locally developed software that incorporates a

variety of image processing and quantification tools

(Desco et al., 2001). The validity of the Talairach-

based procedure as a suitable automated segmenta-

tion tool in schizophrenia research has been pre-

viously proven (Andreasen et al., 1996; Ho et al.,

2003; Kates et al., 1999). In our study, all manual

procedures were performed by a single operator, thus

avoiding any potential inter-rater variability. Relia-

bility of the method was assessed by repeating the

entire segmentation procedure in a sample of 5

randomly selected cases. ICC values ranged from

0.95 to 0.99 for regional GM and WM measure-

ments, and from 0.89 to 0.99 for CSF data. Again,

all manual procedures were performed by a single

operator, thus avoiding any potential inter-rater varia-

bility. Repeatability of the tissue segmentation pro-

cedure was 99% for total volumes of gray and white

tissue (Chard et al., 2002; Gispert et al., 2004). In

addition to total volumes of GM and WM, the

analysis included the frontal, parietal, temporal and

occipital lobes, defined using the boundaries

described previously for the Talairach method

(Andreasen et al., 1996). ROIs were measured bilat-

erally, adding the left and right sides together. Intra-

cranial volume (ICV) was calculated by adding total


GM, WM, and CSF for each brain (including the

cerebellum).

2.3. Statistical analysis

Improvement in the three symptom dimensions

was studied using Wilcoxon tests for paired samples,

comparing the scores before and after the treatment

period.

2.3.1. Gross change in volume

The longitudinal change in volume was measured

as the difference between the initial and final volume

of each ROI. To avoid bias due to overall differences

in brain size, instead of absolute change values in cc,

we used a quotient for total volume of the correspond-

ing ROI. On the other hand, to control for any poten-

tial difference between the two scans due to updates of

MRI equipment, we calculated a correction factor as a

quotient between the initial (baseline) and final intra-

cranial volume (ICV) (EICV=ICV1 / ICV2), assuming

that the total ICV should be equal in both scans

(Mathalon et al., 2001). Thus, for each ROI, the

magnitude of the relative change in volume between

the baseline (Vol1) and final (Vol2) MRI was calcu-

lated as follows:

Longitudinal change

¼ Vol2� EICVð Þ � Vol1ð Þ=Vol1½ � � 100

The significance of the differences in the long-

itudinal change in GM and WM between the patient

groups and the controls was analyzed for each ROI

using a Mann–Whitney test. The total GM and WM

volume was also analyzed, but we did not include data

on changes in CSF volume, since those are secondary

to the changes in GM or WM volume.

2.3.2. Measurement of baseline atrophy / hypertrophy

To evaluate the hypothesis of a relationship

between the degree of initial volume alteration and

the magnitude of longitudinal change, we converted

the volume values to directly indicate a condition of

atrophy/hypertrophy as compared to healthy subjects,

independent of factors such as age and ICV.

Since age and total cranial size are known factors

affecting regional cerebral volumes, their effect was

removed by using the residuals from the regression

models obtained from a group of healthy individuals

(n =31, 17 males), following the procedure of Pfeffer-

baum et al. (1992). After this correction, volume vari-

ables were expressed as deviations from the expected

volumes in healthy individuals of the same age as the

patient. Thus, negative residuals represent a quantita-

tive measurement of atrophy and vice versa. The re-

gression parameters used for this transformation were

obtained from a previous study (Molina et al., 2003b).

To analyze the relationship between baseline

alterations and longitudinal changes, we calculated

the coefficient of correlation (Spearman’s q) betweenthe converted baseline and final GM and WM volume

change in the regions with significant longitudinal

changes in volume.

2.3.3. Sources of error

Of the possible sources of error that potentially

affected our results, we found that gender did not

affect the measurement of longitudinal changes,

since there were no significant differences between

men and women in the Mann–Whitney test. Nor did

we find any relationship between longitudinal changes

in weight and volume, using a Spearman correlation.

This relationship was not significant whether each

group of patients was analyzed separately or together.

Statistical analysis was done using the SPSS software

package (version 11).

3. Results

3.1. Change in symptoms

The group of NN patients presented a significant

improvement in positive symptoms (z =2.9, n =17,

p =.002). There were no significant differences in the dis-

organization or negative dimensions. The weight of these

patients increased significantly (mean 8.5 kg, SD 9.0, t =2.8,

p =.02). In the CR group, the positive dimension (z =2.3,

n =12, p =.01) and the disorganization dimension (z =2.1,

n =12, p =.02) improved significantly, but the negative

dimension did not. The weight of this group of patients

also increased significantly (mean 3.1 kg, SD 4.3, t =2.0,

n =12, p =.05).

3.2. Gross longitudinal changes

There was no significant change in total brain volume

(GM plus WM total volume; Table 2) in either group.

Table 2

Regional volumes in the three groups and their corresponding longitudinal changes

Chronic patients (n =12) N. naive patients (n =17) Controls (n =11)

Baseline (cc) % change from

baseline


baseline


baseline

ICV 1463.8 (113.8) 1.3 (1.9) 1509.9 (117.6) 0.3 (1.6) 1458.2 (123.5) �2.3 (1.8)

Total brain 1021.7 (63.2) �1.0 (4.1) 1086.4 (96.7) �1.3 (3.2) 1038.6 (109.9) 0.5 (3.8)

Total GM 733.0 (61.2)*** 4.2 (5.7)* 816.7 (56.8) 1.0 (2.6) 798.9 (71.9) �0.5 (2.5)

Total WM 455.7 (41.2)* �9.0 (5.9)*** 438.7 (57.6) �3.1 (5.0)** 406.4 (54.3) 2.3 (4.8)

Frontal GM 132.8 (12.2)*** 6.8 (8.5)* 154.3 (12.2)* 2.7 (4.8) 154.9 (17.6) 0.0 (4.0)

Frontal WM 112.2 (12.7) �7.6 (6.6)** 109.6 (15.7) �1.5 (6.6) 104.8 (18.4) 1.7 (6.7)

Parietal GM 107.7 (12.1)*** 7.3 (11.2)** 120.7 (10.9) 1.2 (7.8)* 117.6 (17.0) �3.5 (3.6)

Parietal WM 118.6 (12.1)* �7.6 (7.7)*** 111.7 (16.6) �2.6 (6.9) 110.4 (18.4) 4.0 (7.4)

Temporal GM 138.3 (10.8)** 1.7 (8.3) 149.7 (10.0) 1.6 (4.3) 148.2 (8.4) �1.2 (3.3)

Temporal WM 68.1 (7.5) �6.4 (10.1) 68.0 (10.8) �5.0 (7.3) 59.9 (6.5) �0.2 (6.5)

Occipital GM 61.2 (6.9)*** 14.9 (12.0)*** 68.4 (9.1)* 6.2 (10.1)* 68.3 (9.5) �1.4 (6.1)

Occipital WM 50.8 (5.6)*** �9.0 (7.6)** 46.9 (6.9) �4.1 (8.8)* 43.2 (7.8) 2.9 (8.0)

Baseline data expressed as mean (SD) in cc. Change in each structure is expressed as mean (SD) percent of the initial volume of the structure,

corrected for intracranial volume (see Methods section). Significance of differences in longitudinal changes between each group of patients and

controls and of baseline volume differences relative to expected values from normal populations appear in the corresponding columns of each

patient group (see Methods section) (Mann–Whitney test). *p b0.05; **p b0.01; ***p b .001.


In the control group, there was a small decrease in GM

volume and an increase in WM volume (Table 2, Fig. 2),

which followed the pattern expected in healthy individuals

(Bartzokis et al., 2001; Coffey et al., 1992; Sowell et al.,

2003). This change was not statistically significant (using a t

test for one sample, with the null hypothesis of no change),

except for the change in parietal GM, which decreased

significantly (t =�3.14, p =.01).

The group of NN patients presented a significant

increase in occipital (U =47, z =2.2, p =.02) and parietal

(U =53, z =1.9, p =.05) GM compared to the healthy indi-

viduals. The changes in total GM (U =56, z =1.8, p =.08)

did not achieve statistical significance, but were in the same

direction (Fig. 2). These patients also presented a decrease

in total (U =41, z =2.4, p =.01) and occipital (U =48, z =2.2,

p =.03) WM compared to the control group (Table 2, Fig. 2).

The group of CR patients presented significant increases

in total (U =30, z =2.2, p =.02), frontal (U =33, z =2.0,

p =.04), parietal (U =21, z =2.9, p =.004), and occipital

(U =14, z =3.2, p =.001) GM compared to the controls. In

addition, they presented total (U =3, z =3.9, p b .001), fron-

tal (U =20, z =2.8, p =.004), parietal (U =16, z =3.1,

p =.001), and occipital (U =19, z =2.9, p =.003) WM

decreases compared to the controls (Table 2, Fig. 2).

3.3. Longitudinal changes in degree of baseline alterations

3.3.1. Baseline alterationsCompared to the expected values in a normal population

(see Methods), the NN group presented a statistically sig-

nificant baseline deficit in frontal (U =246, z =�2.2, p =.03)

and occipital (U =247, z =2.1, p =.03) GM, but no altera-

tions in WM (Table 2). At baseline, the CR group presented

a statistically significant deficit in total (U =72, z =�4.1,

p b .001), frontal (U =57, z =�4.4, p b .001), parietal

(U =41, z =�4.7, p b .001), temporal (U =126, z =�3.1,

p =.002), and occipital (U =40, z =�4.7, p b .001) GM,

along with an excess in total (U =125, z =2.2, p =.03),

parietal (U =122, z =2.8, p =.03), and occipital (U =98,

z =3.6, p b .001) WM (Table 2).

3.3.2. Relationship between longitudinal change and degree

of baseline alterationIn the NN patients, there was a significant inverse rela-

tionship (q =� .56, p =.02) between the total increase in GM

and the baseline deficit, using volume data adjusted for age

and ICV. In other words, the greater the initial deficit, the

greater the increase in GM. The relationship between the

baseline deficit in parietal GM and its change was also

significant (q =� .80, p b .001). In addition, in these

patients, there was a significant relationship between initial

WM volume and its change in the total (q =� .77, p b .001)

and occipital (q =� .70, p =.002) regions (the greater the

initial excess, the greater the longitudinal decrease).

In the CR group, there was also a significant relationship

between the baseline alteration and changes in GM in the

occipital region (q =� .57, p =.05). For total, parietal, and

frontal GM, this relationship was not significant. In this

group, there was also a significant inverse relationship

between the baseline volume and changes in WM in all

30

22

14

6

–2

–10Chronics N. Naive Controls

%

Change

GM

Frontal

30

20

10

0

–10


%

Change

GM

Pariet.

30

20

10

0

–10


%

Change

GM

Tempor.

40

28

16

4

–8


%

Change

GM

Occipt.

20

12

4

–4

–12


%

Change

WM

Frontal

30

18

6

-6

-18

-30Chronics N. Naive Controls

%

Change

WM

Pariet.

30

18

6

–6

–18


%

Change

WM

Tempor.

20

10

0

–10

–20


%

Change

WM

Occipt.

Fig. 2. Scatter plots of changes in GM and WM in the four lobes. Values represent percentage of change in the corresponding structure, once

corrected for the change in ICV between the two MRI studies (see Methods). Bars show standard error for each group.


regions. In other words, the greater the baseline volume

excess of WM, the more negative the change (greater

decrease) in the total (q =� .75, p =.005), frontal

(q =� .83, p =.001), parietal (q =� .74, p =.006), and occi-

pital (q =� .84, p =.001) regions.

Analyzing the entire patient sample together, we found

significant correlations between a baseline deficit in GM and

the longitudinal increase in total (q =� .62, n =29, p b .001),

frontal (q =� .45, n =29, p =.01), parietal (q =� .74, n =29,

p b .001), and occipital (q =� .51, n =29, p =.004) volumes.

On the other hand, in the control group, we found no

significant relationship between the baseline volumes and

their longitudinal change.

4. Discussion

In the current study, an increase in gray matter and

decrease in white matter volume occurred in patients

with schizophrenia after treatment with clozapine or

risperidone. These changes were more marked in the

chronic clozapine-treated group. Furthermore, the

increase in gray matter was not statistically associated

with an increase in weight. However, these longitudi-

nal changes in volume were related to the degree of

baseline structural alteration. In other words, the

greater the gray matter (GM) deficit, the greater the

change after treatment with risperidone or clozapine.

The observed longitudinal effect suggests a diffuse

increase in cortical GM volumes with clozapine and

risperidone. In both treatment groups, the most marked

GM gain was observed in the occipital region. The

location of this longitudinal effect is consistent with the

most significant metabolic change observed with posi-

tron emission tomography (PET) in a sample including

most of the patients participating in the present study

(Molina et al., 2005a, 2003a). In these studies, meta-

bolic activity in the visual area (at rest with eyes open)

increased in recent-onset and chronic patients treated

with risperidone or clozapine, respectively.

Similar gains in GM with atypical neuroleptics

have been previously reported. In a study of GM

changes (frontal cortex only) in adolescents with


schizophrenia (n =16, mean age at baseline=18), a

1.9% increase was reported after 2 years of treatment

with atypical drugs (James et al., 2004). That change

did not reach statistical significance, perhaps due to

the small sample size. Another study performed in

first-episode adults described frontal and temporal

GM deficits in patients treated with typical drugs for

8 weeks (n =32) compared to untreated patients

(n=22), while another group of patients treated with

atypical drugs (n =30) presented a thalamic GM

excess with no cortical deficit compared to the same

untreated group (Dazzan et al., 2004).

Longitudinal studies in patients treated exclusively

with typical neuroleptics have reported a significant

decrease in frontal GM volume (Gur et al., 1998;

Mathalon et al., 2001) or hemispheric volume (DeLisi

et al., 1997). However, more recent studies, in which

some patients were treated with atypical and others

with typical neuroleptics, have found no decrease in

GM (Dazzan et al., 2004; DeLisi et al., 2004; Ho et al.,

2003), with the possible exception of juvenile onset

cases (Gogtay et al., 2004). Moreover, our findings are

consistent with a study of first-episode patients, which

reported that haloperidol-treated patients exhibited

significant decreases in GM volume, whereas patients

receiving olanzapine showed no significant volume

changes (Lieberman et al., 2005).

Although the morphologic outcomes were similar

in both groups of patients, the gain in GM was greater

in the CR group during treatment with clozapine

(Table 2, Fig. 2). The relationship between prior

degree of structural alteration and treatment-induced

change suggests that the greater gain in GM with this

drug may be related to the greater initial atrophy in

these patients. Our results suggest that such atrophy

may be reversible, as previously reported in other

ROIs (Keshavan et al., 1998).

In a recent study by Dorph-Petersen et al. (2005),

macaque monkeys were administered haloperidol or

olanzapine for 17 to 27 months to investigate the

macroscopic effects of antipsychotics on the brain.

They found that both treatments produced a slight,

but significant decrease in brain weight and volume,

more pronounced in the frontal and parietal regions.

However, these results can only be partially associated

with our findings because, in their study, both gray and

white matter volumes were reduced in treated mon-

keys compared to controls. This inconsistency may

originate from the higher doses of neuroleptics admi-

nistered to monkeys to achieve plasma levels similar

to those in humans. Moreover, we cannot conclude

that the human brain would show the same changes as

in monkeys, especially in the case of cerebral illness.

In support of this, the association in our patients

between basal GM deficit and volume increase with

clozapine and risperidone suggests that, in the absence

of such a basal deficit, the outcome would have been

different. Finally, different treatments (olanzapine and

haloperidol versus risperidone and clozapine) might

have had different effects on brain morphology.

Even though our data suggest that the GM increase

was due to the atypical treatment, we cannot be

certain of this, since we did not study the outcome

in similar groups of patients not treated with atypical

neuroleptics. Among other limitations of the study,

not all of our chronic patients received the same

treatment prior to enrollment in the study and the

initiation of clozapine, although all received haloper-

idol during the preceding month. Therefore, our

results could be affected by the withdrawal of drugs

received prior to clozapine. However, this problem

does not affect the NN patient sample, which pre-

sented a similar pattern of changes. Another important

limitation was the small sample size, partially offset

by a more statistically powerful longitudinal design.

In particular, the number of controls was small; how-

ever, the observed changes in volume followed the

longitudinal pattern expected in the general popula-

tion (Bartzokis et al., 2001; Coffey et al., 1992;

Sowell et al., 2003).

We can not rule out the possibility that the observed

volumetric differences in this study were not a con-

sequence of treatment and could, instead, be caused by

an as-yet unknown epiphenomenon, either related to

subject metabolic changes or to MRI scanner artifacts

during the longitudinal period of this study. The asser-

tion that atypical neuroleptics have an effect on brain

volume has yet to be definitively demonstrated.

However, even if we are observing true effects of

the medication, we can only speculate about the

potential cellular processes underlying the changes

observed in the cortex. Relying upon histological

data from studies performed in rats and monkeys,

two possible explanations arise: proliferation of neu-

ronal elements or of glial cells. Concerning the first,

formation of new neuronal elements, such as


synapses, seems more likely than neurogenesis in the

adult brain. Synaptogenesis may be indeed an effect

of classical treatment in subcortical regions (Konradi

and Heckers, 2001). However, a huge increase in

connections would be required to explain a GM

volume increase capable of MRI detection. On the

other hand, in primate cortices, there was no increase

of neuronal tissue after treatment with typical or aty-

pical neuroleptics (Selemon et al., 1999). However,

another study showed that clozapine induced cell

division in the hippocampus, though the resulting

neurons did not survive 3 weeks (Halim et al.,

2004). Thus, it seems unlikely that the increase in

GM observed in our patients was caused by the

appearance of new neurons or increased connections.

Regarding changes in the glia, proliferation of

cells, along with cortical hypertrophy, has been

observed in the prefrontal cortex of primates after

treatment with typical and atypical neuroleptics (Sele-

mon et al., 1999). Moreover, olanzapine can increase

the number of dividing glial cells in the frontal cortex

in adult rats (Wang et al., 2004). A similar effect of

atypical neuroleptics on glial cells would also be

consistent with the increased brain metabolic activity

observed in our patients (Molina et al., 2005a; Molina

et al., 2003a), given the role of glial cells in PET data

(Magistretti, 2000). At any rate, more specific data are

needed to demonstrate the histological substrate of the

GM changes observed in our study.

The co-occurrence of GM increase and WM

decrease is consistent with the recent finding of a

decrease in WM after four weeks of typical or

atypical treatment (Christensen et al., 2004). This

WM decrease suggests that GM increase is not due

to the production of new healthy cells, as the WM is

partly formed by the extension of such cells. The

decrease in WM due to atypical treatment could be

explained by a blockade of factors stimulating mye-

lin synthesis, the other WM component. We could

speculate that such a factor could have to do with a

chronic glutamatergic hyperactivation state, since

hyperactivity relates to increased myelination in

other disease states (Adamsbaum et al., 1996; Krish-

nan et al., 1994). Such a hyperactivity state might be

present in schizophrenia (Molina et al., 2005b; Volk

and Lewis, 2002).

In summary, the present study found brain gray

matter increases and white matter decreases following

treatment with atypical drugs such as risperidone and

clozapine in chronic and neuroleptic-naıve patients.

While these changes could be associated with the

effects of these drugs on the brain, this phenomenon

needs further exploration before this conclusion can

be reached. We cannot be sure that the changes

observed in our group were solely due to the atypical

treatment, as we did not have a control group of

patients treated without atypical neuroleptics over

the same period of time.

Acknowledgments

Supported in part by grants from the bFondo de

Investigaciones SanitariasQ (02/3095, Red Tematica

IM3), bG03/185Q and bFundacion La CaixaQ (99/042-00). We thank Angel Santos Briz, pathologist from the

Neuroscience Institute of Castilla y Leon, for his valu-

able assistance in data interpretation.

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Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia