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Reduced Basal Ganglia Volumes After Switching
to Olanzapine in Chronically Treated Patients
With Schizophrenia
Donna J. Lang, Ph.D.
Objective: A follow-up study of patients
Lili C. Kopala, M.D., F.R.C.P.C.
spectively) and did not differ from those of healthy subjects at the follow-up evalua- Robert A. Vandorpe, M.D.,
tion. Akathisia was also reduced. In the pa- F.R.C.P.C.
Method: Thirty-seven patients with schizo-
tients receiving risperidone at baseline, Qing Rui, M.B.
typical antipsychotics (N=10) or risperidone sponse, and no significant volume changes Geoffrey N. Smith, Ph.D.
pine. Patients receiving risperidone and ex- Vina M. Goghari, B.A.
hibiting a good response (N=14) continuedtreatment with risperidone. Caudate, puta- Conclusions: Olanzapine reversed puta-
Jocelyne S. Lapointe, M.D.,
used to assess clinical signs and symptoms.
William G. Honer, M.D.,
Results: At baseline, basal ganglia vol-
umes in patients treated with typical anti-
pallidus: 20.7% larger). After the switch to (Am J Psychiatry 2004; 161:1829–1836)
Antipsychotic medications are known to alter the patients experiencing decreases and responsive patients structure and metabolism of basal ganglia in humans and experiencing no changes in metabolic activity (18). In con- animals (1–7). In patients with schizophrenia, typical anti- trast, a study of clozapine and fluphenazine showed that psychotics induce striatal enlargement, particularly in the both medications decreased striatal and cingulate glucose caudate, putamen, and globus pallidus (7–9). In contrast, metabolism, with female subjects experiencing a greater the majority of studies of patients switched from typical change in glucose utilization than male subjects (19). Ris- antipsychotics to clozapine report decreases in caudate peridone was also reported to decrease striatal glucose volume (6, 10–13). The effects in humans of alternate atyp- metabolism after 6 weeks of treatment (20). Parallel rat ical antipsychotics (risperidone, olanzapine, quetiapine, studies showed that haloperidol has little effect on neu- ziprasidone) are less understood. In one published study, ronal activity levels in the striatum, whereas risperidone long-term administration of risperidone did not induce and clozapine decrease activity in the substantia nigra re- striatal enlargement (7). The effects seen in animal studies ticulata nucleus of the basal ganglia system in a dose-de- are inconsistent. In rats, both increases and decreases in pendent manner, thus differentially affecting the output of striatal volumes occur after administration of either halo- the basal ganglia system (21). Despite their potential for peridol or clozapine (14, 15). In comparison, long-term differential effects, few studies have made direct drug-to- administration of olanzapine in rats decreases striatal We performed two separate studies to examine in chron- The effects of antipsychotic medications on basal gan- ically treated schizophrenia patients the effects on striatal glia metabolism may vary depending on medication type volumes of switching from treatment with either typical an- and patient characteristics (16, 17). Haloperidol does not tipsychotics or risperidone to olanzapine. In the first study, reduce striatal glucose metabolism and differentially re- patients were switched from typical antipsychotic medica- duces cortical glucose metabolism, with nonresponsive tions to olanzapine and compared with healthy volunteers.
Am J Psychiatry 161:10, October 2004 BASAL GANGLIA VOLUME AND OLANZAPINE
TABLE 1. Volumetric Data and Clinical Characteristics of Healthy Volunteers and Patients With Schizophrenia Switched
From Typical Antipsychotic Treatment to Olanzapine

a Mixed regimens of typical antipsychotics.
b Conversions based on the Clinical Handbook of Psychotropic Drugs (31).
Caudate, putamen, and pallidal volumes were expected to come scans were reported previously for 17 of the healthy com- decrease after switching from typical antipsychotics to parison subjects (7). Subjects were recruited through the NovaScotia Early Episode Psychosis Program in Halifax. Approval was olanzapine. The severity of extrapyramidal symptoms was obtained from the Dalhousie University Ethics Committee. In- also expected to decrease after switching. In the second formed written consent was obtained from all subjects. Exclusion study, all subjects were taking risperidone at baseline. Sub- criteria were a history of significant head injury or loss of con- sequently, a subgroup was switched to olanzapine. The de- sciousness exceeding 5 minutes, a history of facial or nasal cision to switch treatments was based on clinical evaluation trauma, a history of DSM-IV substance abuse, a current diagnosisof substance abuse during treatment or at follow-up, a history of of the patients’ overall clinical response to risperidone.
seizure disorder, or a family history of psychotic disorders. Pa- Olanzapine is pharmacologically more similar to clozapine tients were reassessed after a mean interval of 45.6 weeks.
than risperidone (22), suggesting that the effects of olanza-pine on basal ganglia volumes may be similar to those of Treatment and Clinical Measures
clozapine (10, 13, 23). Additionally, olanzapine is less likely Clinical assessments included the Positive and Negative Syn- to induce extrapyramidal symptoms compared with ris- drome Scale (27) and the Extrapyramidal Symptom Rating Scale, peridone at comparable doses, as is clozapine (24–26). In a comprehensive rating of extrapyramidal symptoms and signs(28). Global scores on the Extrapyramidal Symptom Rating Scale the second study, basal ganglia volumes were expected to subscales are reported. Interrater reliability for clinical measures decrease after switching from risperidone to olanzapine, as based on intraclass correlations (ICCs) were high (Positive and Negative Syndrome Scale: ICC=0.85; Extrapyramidal SymptomRating Scale: ICC=0.89). All ratings were performed by trained cli-nicians (L.C.K. and Heather M. Milliken, M.D., F.R.C.P.C.).
The first study investigated the effects of switching from typical antipsychotics (loxapine, trifluoperazine, chlorpromazine, flu- Subjects
phenazine, haloperidol) to olanzapine. Some patients were receiv- Thirty-seven patients with DSM-IV schizophrenia and 23 ing additional anticholinergic medications to ameliorate extra- healthy comparison subjects were included in this study. No sub- pyramidal symptoms at baseline (Table 1). No patients required jects in this study received adjunct treatments for mood disorders anticholinergic agents at follow-up.
during the course of treatment. The baseline scans of 15 patients Both patient groups in the second study were being treated were included in a previous study, and both baseline and out- with low to moderate doses of risperidone at baseline (Table 2).
Am J Psychiatry 161:10, October 2004 LANG, KOPALA, VANDORPE, ET AL.
TABLE 2. Volumetric Data and Clinical Characteristics of Risperidone-Treated Schizophrenia Patients Switched to Olanzapine
or Continuing Treatment With Risperidone

a Conversions based on the Clinical Handbook of Psychotropic Drugs (31).
Thirteen patients were switched to olanzapine treatment, and 14 ments began two slices anterior to and ended two slices posterior continued receiving risperidone. Medications were switched on to the anterior commissure slice to cover a total distance of 25 the basis of a clinical evaluation by a psychiatrist. Those patients mm in the anterior commissure-posterior commissure plane switched from risperidone to olanzapine exhibited more severe (Figure 1). Anatomically, this protocol excluded the anterior-most extrapyramidal symptoms and more severe psychiatric symp- portion of the head of the caudate (5-mm depth), the tail of the toms at baseline compared with those who continued risperi- caudate, and the posterior-most putamen. Similarly, the poste- done treatment (Table 2). Complete follow-up clinical assess- rior-most globus pallidus was excluded. The rater was blind to di- ments were available for 10 of the 14 patients who continued agnosis, treatment, gender, and time of scan. All measures were risperidone and 11 of the 13 patients switched to olanzapine.
repeated four times. Final volumes were calculated on the mean No patients in either study required mood stabilizing or antide- of four repetitions to reduce the possibility of rater error. Volumes were calculated on absolute slice thickness across all five slices.
Total brain volumes were assessed from axial slices. Axial slices Scanning and Measurement Protocols
were obtained with a T2-weighted sequence; TR/TE=4000/90 Subjects were scanned with a Siemens Magnetom Vision 1.5- msec, field of view=220 mm, and matrix=238×256 pixels. Slice Tesla MRI scanner. An inversion recovery sequence in the coronal thickness for all T2-weighted images was 5 mm with a 1-mm in- plane was obtained. The inversion recovery sequence was ob- terslice gap, 22 slices were obtained in each T2-weighted plane.
tained as follows: TR/TE=2000/20 msec, field of view=200 mm, Digitized slices were measured using a Macintosh G4 PowerMac matrix=168×256 pixels. A total of 18 slices, 4 mm thick with a 1- computer. All scans were reviewed by a neuroradiologist (J.S.L.).
mm interslice gap, were available for this sequence. Inversion re- Intrarater reliability for all regions was greater than 0.90 (caudate: covery images were chosen for their superior white-gray tissue ICC=0.98; putamen: ICC=0.96; globus pallidus: ICC=0.97; total in- contrast. The white-to-gray pixel intensity for the images ob- tained with the inversion recovery sequence was 1.42, which Data Analysis: Statistical Methods
compared favorably with three-dimensional volumetric spoiledgradient recall acquisition (pulse sequence) data from the same Initial comparisons of left and right striatal volumes did not re- scanner that had a pixel intensity ratio of only 0.89. A trained rater veal any significant left-right asymmetries, therefore subsequent made manual selections for all regions of interest using interac- analyses were based on total (left plus right) volumes. An initial tive shareware (NIH Image 1.62 pcc) (29). Selections were made ANOVA of total brain volume did not reveal any differences be- based on Duvernoy’s atlas of the human brain (30). Measure- tween groups. Comparisons of the effects of treatment over time Am J Psychiatry 161:10, October 2004 BASAL GANGLIA VOLUME AND OLANZAPINE
FIGURE 1. Sample Set of Manually Selected Striatal Regions for Volumetric Measures
Raw images
Modified images
were made with a repeated measures analysis of variance, with nificant differences in basal ganglia volumes between pa- time (baseline, follow-up) and region (caudate, putamen, globus tients and healthy comparison subjects.
pallidus) as within-subject factors, and group (schizophrenia pa- At baseline, five of 10 patients being treated with typical tients, healthy subjects [first study]; continued with risperidone, antipsychotic agents were receiving adjunct anticholin- switched to olanzapine [second study]) as a between-subject fac-tor. Multivariate analyses of covariance (MANCOVAs) were per- ergic medications (Table 1). While mean Extrapyramidal formed to compare basal ganglia volumes between groups at Symptom Rating Scale scores decreased following the baseline or at follow-up, using the factor group, the covariates in- switch to olanzapine, this was not statistically significant tracranial volume and age at time of scan, and the dependent (t=1.82, df=9, p>0.10). However, at follow-up none of the 10 measures caudate, putamen, and globus pallidus volumes.
patients in this group were being treated with anticholin- For analysis of changes in extrapyramidal symptoms, paired t ergic medications. Examination of individual Extrapyrami- tests were used with the Extrapyramidal Symptom Rating Scale dal Symptom Rating Scale subscores revealed a statistically data, with Bonferroni alpha set at p=0.01 to control for five com- significant decrease in akathisia scores (t=3.59, df=19, p= parisons (total score, parkinsonism, dyskinesia, dystonia, andakathisia). Additional descriptive statistics of anticholinergic us- 0.007) but not in parkinsonism, dystonia, or dyskinesia.
Risperidone Continuation
Versus Switch to Olanzapine

As seen in Figure 3, basal ganglia volumes of risperi- Schizophrenia Patients
done-treated patients subsequently switched to olanza- Versus Healthy Comparison Subjects
pine did not differ at baseline from those continuing treat-ment with risperidone (Wilks’s lambda F=0.55, df=3, 21, p= At baseline, patients treated with typical antipsychotic 0.65). For analysis of changes over time, the MANCOVA in- drugs had overall larger basal ganglia structures than dicated a significant effect of time (F=4.41, df=3, 23, healthy comparison subjects (Wilks’s lambda F=7.68, df= p<0.02) but no statistically significant effects of group 3, 27, p=0.0007). Differences were statistically significant (Wilks’s lambda F=0.25, df=3, 23, p=0.86) or group-by-time for the putamen (7.0% larger, F=9.11, df=1, 29, p=0.005) interaction (F=2.87, df=3, 23, p=0.059). At follow-up, no and the globus pallidus (20.7% larger, F=24.06, df=1, 29, p= statistically significant differences between the groups in 0.0001). For analysis of changes over time in patients after overall basal ganglia volumes were observed ( Wilks’s medication switch relative to comparison subjects, the MANCOVA indicated statistically significant effects of Mean total Extrapyramidal Symptom Rating Scale scores group (Wilks’s lambda F=5.05, df=3, 29, p=0.006), time (F= at baseline in patients switched to olanzapine were higher 4.82, df=3, 29, p=0.008), and a group-by-time interaction than scores in patients continuing risperidone treatment (F=5.61, df=3, 29, p=0.004). As seen in Figure 2, basal gan- (t=2.85, df=21, p=0.01) (Table 2). Extrapyramidal Symptom glia volumes decreased over time in the patients switched Rating Scale total scores at the follow-up evaluation did from typical antipsychotics to olanzapine, while volumes not significantly differ from baseline scores for either the remained steady in healthy comparison subjects. Subse- patients continuing risperidone treatment (t=–1.00, df=9, quent analyses indicated volume decreases in the puta- p>0.34) or those switched to olanzapine (t=–0.37, df=10, men (smaller by 9.8%) and globus pallidus (smaller by p>0.70). Examination of the subscales of the Extrapyra- 10.7%) associated with change from typical antipsychotics midal Symptom Rating Scale did not reveal significant to olanzapine. At follow-up, there were no statistically sig- Am J Psychiatry 161:10, October 2004 LANG, KOPALA, VANDORPE, ET AL.
FIGURE 2. Baseline and Follow-Up Basal Ganglia Volumes
FIGURE 3. Baseline and Follow-Up Basal Ganglia Volumes
of Healthy Volunteers and Patients With Schizophrenia
of Risperidone-Treated Schizophrenia Patients Switched
Switched From Typical Antipsychotic Tre atm ent to
to Olanzapine or Continuing Treatment With Risperidone
Patients Switched
Patients Switched From
Patients Continuing
From Risperidone
Typical Antipsychotics
Risperidone Treatment
to Olanzapine
to Olanzapine
Volume (mm
Volume (mm
a Significant decrease from baseline in putamen volume (F=6.62, df= 1, 31, p<0.02) and globus pallidus volume (F=6.02, df=1, 31, p= Baseline
gional inconsistencies may be a reflection of specific ef-fects of previously administered typical antipsychotics or As expected, treatment with typical antipsychotics was differences in effects of clozapine and olanzapine. The role associated with larger basal ganglia volumes, and switch- of the putamen in both the presentation of schizophrenia- ing to olanzapine was associated with reduction in basal related symptoms and extrapyramidal symptoms is not ganglia volumes. Specifically, the putamen and globus pal- fully understood. An earlier study by Stratta and colleagues lidus volumes were normalized following the switch to (32) demonstrated a significant correlation of performance olanzapine. The pattern of regional changes differs some- on the Wisconsin Card Sorting Test and left-sided putamen what from two earlier reports of the effects of switching volume, suggesting a role in executive functioning, which from typical antipsychotic medications to clozapine. Fol- is known to be affected in schizophrenia (33, 34).
lowing switching, Chakos et al. (3) reported a reduction in Eight out of 10 patients receiving typical medications at caudate volume in adult patients, and Frazier et al. (12) baseline had movement disorders according to the Ex- found reduction in both the caudate and the globus palli- trapyramidal Symptom Rating Scale. This scale covers a dus in childhood-onset schizophrenia patients. The re- full range of potential motor abnormalities and is sensitive Am J Psychiatry 161:10, October 2004 BASAL GANGLIA VOLUME AND OLANZAPINE
to subtle movement disorders (35). The mean total base- tial or poor risperidone response. Additional variance in line Extrapyramidal Symptom Rating Scale scores were the volumetric measures may have been related to MRI likely partially ameliorated by anticholinergic medication.
slice thickness and slice angulation. However, a compari- These are most effective in treating tremors, rigidity, and son of volumes reported in other studies with thinner bradykinesia but have low efficacy for treating antipsy- slices did not reveal any deviation in the volumes reported chotic-induced akathisia (36). The observed reduction in akathisia after the switch to olanzapine may be a true re- Individual atypical antipsychotic agents exhibit specific flection of olanzapine’s low propensity to induce extrapy- neurochemical pathways of activity, and this specificity may contribute to differential volumetric changes in the In our second study, overall basal ganglia volumes did striatum in response to antipsychotic challenge (15, 39). In not differ between patients with good and poor responses a study of striatal volumes in rats, caudate or putamen vol- to risperidone. Subsequent switching to olanzapine in umes were significantly increased by chronic exposure to those with a poor response to risperidone was not associ- haloperidol and clozapine (15). In contrast, this same ated with a significant change in basal ganglia volume.
study found that chronic exposure to risperidone had no This observation suggests the effects of olanzapine on effect on caudate or putamen volumes whereas long-term basal ganglia volume in patients previously treated with exposure to olanzapine resulted in a significant decrease in typical antipsychotics represent normalization rather striatal volumes (15). Additionally, a recent study employ- ing fMRI in patients with schizophrenia demonstrated dif- Neither overall symptom severity nor overall extrapyra- ferential activation of the caudate and putamen during a midal symptom severity changed when patients with a cognitive challenge (40). Signal intensity was reduced in poor response to risperidone were switched to olanza- the putamen and anterior cingulate during testing in pa- pine. However, patients previously receiving typical anti- tients relative to healthy subjects, but not in the caudate.
psychotics did have moderate reductions in dyskinesia These findings are supported by differential responses to and akathisia. The extrapyramidal symptoms present in individual antipsychotic medications (41). These differ- the group of patients poorly responsive to risperidone ences are likely related to different receptor-targeting pro- may be related to a different mechanism, perhaps intrin- files of specific antipsychotic agents (39). While the evi- sic to schizophrenia, that is less responsive to switching to dence for increased striatal volumes in humans or animals olanzapine than are extrapyramidal symptoms related to exposed to typical antipsychotic medications treatment is typical antipsychotic medications. Moreover, relative dos- convincing (1, 3, 4, 6, 7, 10–12, 14, 15, 42), there are no data suggesting that clozapine increases striatal volumes. The from risperidone to olanzapine remained relatively equal, majority of published reports in human subjects indicated thus there would be little expectation for a change in ex- that exposure to clozapine is associated with a reduction in trapyramidal symptom severity (37). The relationships striatal volumes in patients previously exposed to typical among antipsychotic dose, striatal volume, and extrapyra- antipsychotics (12–14, 23). Studies of risperidone’s and midal symptom severity are not clear. Data from this study olanzapine’s effects on striatal volumes after chronic ad- do not demonstrate any relationship of either total dose or ministration are far fewer in number (7, 15). The findingsfrom the current study in conjunction with those from ani- current dose of antipsychotic medication being correlated mal studies suggest that closer examination in subpopula- with striatal volumes, change in striatal volumes, or sever- tions of patients with schizophrenia is required to clarify ity of extrapyramidal symptoms scores (all exploratory re- the true physiological and clinical effects of individual an- gression analyses had r values <0.40 and corresponding p tipsychotic medications in the treatment of schizophrenia.
values >0.05). This suggests that striatal volume, while re-sponsive to specific types of antipsychotic agents, does Received May 30, 2003; revision received Dec. 29, 2003; accepted not affect the presence or severity of extrapyramidal Jan. 9, 2004. From the Departments of Psychiatry and Radiology, Uni- versity of British Columbia, Vancouver; and the Departments of Psy-chiatry and Radiology, Dalhousie University, Halifax, N.S., Canada; Ad- Summary
dress reprint requests to Dr. Lang, VGH Research Pavilion, Centre forComplex Disorders, West 10th Ave., Room 211–828, Vancouver, Brit- The main findings of the present study were significant ish Columbia, Canada V5Z 1L8; (e-mail). reductions in putamen and globus pallidus volumes in pa- Supported by a Canadian Institutes of Health Research Scientist tients switched to olanzapine from typical antipsychotics.
Award to Dr. Honer and by a grant from the Norma Calder Founda-tion for Schizophrenia Research to Dr. Lang. Dr. Kopala was sup- These subregional-specific results may be due to differen- ported by a Clinical Scientist Award from Dalhousie University. Partial tial effects of olanzapine on striatal structures or of an un- funding for MRI scanning was provided by investigator-initiated known sampling bias of the subjects chosen for this study.
grants from Janssen-Ortho of Canada and Eli Lilly Canada. Additionalfunding for scanning was provided by the Queen Elizabeth-II Hospital As well, the results from the risperidone-to-olanzapine Health Science Research Foundation and the Department of Psychi- group may only be valid for those patients who have par- Am J Psychiatry 161:10, October 2004 LANG, KOPALA, VANDORPE, ET AL.
The authors thank Melissa M. Butler, R.T.N.M., C.C.R.C.; Jason O.
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