Association of Initial Antipsychotic Response to Clozapine and Long-Term Weight Gain

This study was a retrospective chart review of 96 patients hospitalized with schizophrenia (per DSM-IV) at the largest psychiatric teaching hospital that offered long-term care to patients with refractory schizophrenia or patients with poor social support. These patients had undergone at least two typical antipsychotic trials of adequate dose and duration with no response. The patients were consecutively started on clozapine regimens between May 1995 and March 1997. All patients were weighed monthly by nurses, and continuous body weight records for the 8-year period were available for review. The initial clinical response for the first 14 months was rated by the psychiatrist-in-charge (Y.M.B.) using the CGI. Patients who received CGI improvement ratings of 1 (very much improved) or 2 (much improved) were considered to have a significant clinical response. Other patients were considered to have a nonsignificant response. Data on age, gender, clozapine dose, and concomitant use of mood stabilizers and other antipsychotics were obtained through retrospective chart review. To examine the relationship between weight gain and clinical response over the 8-year study period, a repeated measures analysis of covariance with baseline body mass index (BMI) was used. Multiple linear regression analysis was performed to investigate the factors associated with 8-year weight change.

The 96 patients (46 women and 50 men) were 38.3 years old (SD=8) at clozapine initiation and had an average baseline BMI of 23.4 (SD=4.5). Fifty-five (57.3%) patients received clozapine for the entire 8-year study period. Forty-one patients were excluded because of incomplete weight records (N=10), unavailable medical records (N=4), discharge (N=4), death (N=4), or switch to other antipsychotics (N=19). Among the 19 patients switched to other antipsychotics, 17 had no response to clozapine and at the time of discontinuation, the average duration of clozapine treatment was 39.6 months (SD=29.3) and average weight gain was 4.5 kg (SD=15.1). The other two patients had responded, but one discontinued because of hypersalivation at the 48th month without weight change. The reason for the other patient’s discontinuation was unknown because the medical records were unavailable. There were no significant demographic differences or differences in initial 14-month weight change or clinical response between the 55 patients included in the analysis and the 41 who were excluded. For the 55 patients included in the study, the average weight gain was 11.7 kg (SD=1.6) over 8 years. Seventeen of these patients (30.9%) had a significant initial antipsychotic response (average CGI improvement rating: 2.0 [SD=0.6]). This group had an average 8-year weight gain of 13.8 kg (SD=8.4). The other 38 patients did not have a significant clinical response (average CGI improvement rating: 3.7 [SD=0.5]), and their average 8-year weight gain was 4.5 kg (SD=12.0). As seen in Figure 1, there was a significant difference in BMI change over the 8-year study period between those with and those without a significant initial antipsychotic response. Multiple linear regression showed that two factors, significant initial clinical response and lower baseline BMI, were associated with greater weight gain. When a supplementary regression analysis was performed that expanded the number of subjects to include those participating in the study at the 6-month mark (N=85), the results still showed that clinical response and baseline BMI were the two factors associated with weight gain ( Table 1 ).

The results show that in this patient group, the initial antipsychotic response to clozapine was associated with subsequent weight gain over an 8-year period. Previous studies have also shown evidence for an association between weight gain and clinical response with other atypical antipsychotic drugs (13) and typical antipsychotics (14, 15) . These results suggest that the relationship found in our study between weight gain and antipsychotic response may be a more generalized phenomenon. The patients in our study who showed significant initial antipsychotic response gained up to 14 kg (30.8 lb), suggesting a morbidity concern for which a weight control program for these patients may be recommended from the start. Our results are consistent with previous reports that patients with a lower baseline BMI demonstrate greater weight gain associated with clozapine treatment (16) as well as with olanzapine treatment (17 – 19) . Our previous study noted the association between weight gain and clinical response in female but not male patients (11) . However, after baseline BMI was controlled, the gender difference no longer existed at 14 months and at 8 years, which indicated that future weight gain studies should control for baseline BMI.

To the best of our knowledge, this is the first study to report that initial antipsychotic response predicts long-term weight gain. However, the study was retrospective in nature and therefore selection bias may exist. But this concern might be alleviated by the similar characteristics between patients included in the study group and those who were excluded. Another concern is that the initial clinical response was determined only by the CGI. However, the ratings were all performed by one experienced psychiatrist-in-charge, who cared for these patients for years, which avoids the concern about interrater reliability. Moreover, the clinical response rate to clozapine was 30.9%, similar to the 30% that Kane et al. reported (20) . Considering the long-term health risks associated with excess weight gain, for patients with lower baseline BMI and a good initial clinical response, weight change and associated metabolic syndrome symptoms should be closely monitored.

Received Sept. 8, 2005; revision received Nov. 15, 2005; accepted Dec. 2, 2005. From the Community Medicine Research Center and Institute of Public Health, National Yang-Ming University; the Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; the Department of Psychiatry, Yu-Li Veterans Hospital, Taiwan; and the Department of Psychiatry, National Yang-Ming University. Address correspondence and reprint requests to Dr. Chou, Community Medicine Research Center and Institute of Public Health, National Yang-Ming University,155 Li-Nong St., Sec. 2, Shihpai, Taipei 112, Taiwan; [email protected] (e-mail).Supported by grants from the National Science Council, Taiwan (NSC94-2314-B-480-002)