Reduced Thalamic Volume in Patients With Chronic Schizophrenia After Switching From Typical Antipsychotic Medications to Olanzapine

The subjects with chronic schizophrenia (N=10) were treated with typical antipsychotic medications continuously for at least 12 months before the baseline scan, switched to olanzapine, and rescanned approximately 1 year later. A comparison group of healthy volunteers was scanned in parallel.

The subjects were scanned with a Magnaton Vision 1.5-T MRI scanner (Siemens, Malvern, Pa.) by using a coronal inversion recovery sequence (4-mm slice thickness plus a 1-mm interslice gap). All images were assessed for motion artifacts. Measurements were made after a manual selection of regions of interest by using interactive shareware (NIH Image, version 1.62, developed at the National Institutes of Health and available at http://rsb.info.nih.gov/nih-image) (12) and a reference atlas (13) . A single rater (B.K.) performed volumetric measures, blind to diagnosis, gender, and time of scan. Measurement of the thalamus began two slices posterior to the anterior commissure and included a total of four slices. Final area measurements were the mean of four independent trials. The white-to-gray pixel intensity of the inversion recovery sequence scans was 1.42, which was significantly better than the 0.89 white-to-gray pixel intensity of the three-dimensional volumetric spoiled gradient-recall acquisition data obtained from the same scanner. Total intracranial volume was ascertained (D.J.L. and V.M.G.) from T ₂ -weighted axial images. Interrater reliability was high (N=10, intraclass correlation coefficient [ICC] whole volume thalamus=0.96, ICC total intracranial volume=0.99).

Repeated-measures analysis of variance was performed, with time (baseline or follow up) and side (left or right) as within-subject factors, group (schizophrenia or healthy) as between-subject factors, and age as covariate. To compare thalamic volumes between groups at baseline and at follow-up, we performed repeated-measures analyses of variance with side (left or right) as a within-subject factor, group (schizophrenia or healthy) as a between-subject factor, and age as a covariate. Correlational analyses were performed to assess the relationship between thalamic volume and antipsychotic medication dosage.

Detailed demographic data has appeared elsewhere (14) . Briefly, healthy volunteers (N=20, 10 men, mean age=23.5, SD=7.7 years) were a subset (20 of 23) of those reported previously. The mean age of the subjects with schizophrenia (N=10, seven men, mean age=35.3, SD=8.8) was significantly greater than that of the volunteers (comparison subjects) (t=3.94, df=28, p=0.0005), and the interscan interval (schizophrenia: mean=56.0 weeks, SD=17.1, volunteers: 60.1 week, SD=12.7) was shorter (t=2.13, df=28, p=0.04). Initial analyses with all subjects used age as a covariate. Secondary analyses used the older 10 of the 20 volunteers. For this subsample (six men and four women), mean age did not differ between groups (t=1.79, df=18, p=0.09) nor did intracranial volume (t=0.22, df=18, p=0.83).

No main effects of diagnosis (Wilks’s λ=1.85, df=2, 26, p=0.18) or time (Wilks’s λ=0.67, df=2, 26, p=0.52) were observed. A time-by-diagnosis interaction (Wilks’s λ=9.75, df=2, 26, p=0.001) was noted. This interaction was also present in the age-matched subgroup (Wilks’s λ=8.80, df=2, 16, p=0.003). On both the left and right sides, thalamic volume was reduced after the switch to olanzapine ( Figure 1 ).

Mean baseline total thalamic volume was 5.8% larger in schizophrenia patients than in volunteers (F=4.96, df=1, 27, p=0.03). A similar difference was present in the age-matched subgroup (F=6.88, df=1, 17, p=0.02). Conversely, at the follow-up scan, no difference related to diagnostic group was detected in the total group (F=0.54, df=1, 27, p=0.47) or in the subgroup (F=0.52, df=1, 17, p=0.48). One subject was briefly treated with an antidepressant near the time of the baseline scan, and one subject was similarly treated near the time of the follow-up scan. Neither subject had results that were different from the pattern of the others.

A positive correlation between baseline thalamic volume and chlorpromazine-equivalent dosage of medication was observed (r=0.77, p=0.009) ( Figure 1 ). A significant correlation between change in thalamic volume (follow-up minus baseline) and baseline dosage of typical antipsychotic medication was also observed (r=0.76, p=0.01). A higher baseline dose was associated with a greater reduction of total thalamic volume between baseline and follow-up scans ( Figure 1 ).

The main finding of this study was that switching patients from typical antipsychotic medications to olanzapine resulted in reductions in thalamic volume. These changes represented normalization of previously larger volumes, which were associated with the dosage of typical antipsychotic medication administered.

A previous study reported a tendency toward larger thalamic volumes in patients with schizophrenia who were treated with typical antipsychotic medications and a strong positive correlation between dosage and baseline thalamic volume (11) . This correlation was much stronger than correlations between the dose of typical antipsychotic medication and the volumes of basal ganglia structures. The present study is the first to report a reduction in thalamic volume after switching from typical to atypical antipsychotic medications. The results suggest that the hypertrophic effects of typical antipsychotic medications extend beyond the basal ganglia.

There are several limitations to the present study. The findings may have been influenced by MRI acquisition protocol, slice thickness, the presence of interslice gaps, and the white-to-gray tissue contrast. Slice thickness and the presence of interslice gaps, in particular, prevented us from segmenting the thalamus into its major nuclei. However, our thalamic volumes fell well within the range of those reported in the postmortem and MRI literature (9) . In addition, there was high interrater reliability for thalamic volume.

In summary, treatment with typical antipsychotic medications was associated with enlargement of the thalamus in patients with chronic schizophrenia. Switching to olanzapine reduced thalamic volume to a size slightly smaller than that of healthy volunteers. Antipsychotic medications could contribute to the wide range of thalamic volumes reported in schizophrenia.

Presented in part at the 12th International Congress on Schizophrenia Research, Savannah, Ga., April 2–6, 2005. Received April 15, 2005; revision received Aug. 19, 2005; accepted Sept. 19, 2005. From the Department of Psychiatry, University of British Columbia; and the Department of Psychiatry and Department of Radiology, Dalhousie University, Halifax, N.S., Canada. Address correspondence and reprint requests to Dr. Honer, Centre for Complex Disorders, VGH Research Pavilion, Rm. 203-828 West 10th Ave., Vancouver, BC, Canada V5Z 1L8; [email protected] (e-mail).Dr. Honer is supported by grant NET-54013 from the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, the National Alliance for Research on Schizophrenia and Depression, the Stanley Medical Research Institute, and the Norma Calder Foundation. Dr. Kopala is supported by a Clinical Scientist Award from Dalhousie University. The remaining authors report no competing interests. Partial funding for MRI scanning was provided by investigator-initiated grants from Janssen-Ortho Canada and Eli Lilly Canada. The Queen Elizabeth II Hospital Health Science Research Foundation and the Department of Psychiatry, Dalhousie University, provided additional funding for scanning.