Clozapine-Induced Weight Gain: Is It Dependent on Dose?

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CASE VIGNETTE 

“Mrs Green” is a 55-year-old African American woman with a history of chronic schizoaffective disorder, bipolar type. She experienced the onset of her psychosis at age 40 years. At 45 years, after several inpatient psychiatric hospitalizations, she was started on clozapine. During that admission, Mrs Green’s clozapine was titrated to a dose of 300 mg/day. When she visited the outpatient clinic 1 week after hospital discharge, her weight was largely unchanged from her pre-clozapine baseline.

When she returned for another outpatient visit 6 weeks later, Mrs Green had gained 40 lb. Through improved nutrition and exercise, she achieved and sustained a loss of 25 lb from her highest recorded weight. However, at age 52 years, she was diagnosed with type 2 diabetes mellitus. Although Mrs Green has been psychiatrically stable on clozapine 300 mg for 10 years, she asks about her risk of weight gain if she were to need a higher dose of clozapine in the future. As her psychiatrist, how would you counsel her regarding this risk?

Clozapine is the gold-standard antipsychotic for treatment-resistant psychosis; however, it is associated with considerable risk of cardiometabolic adverse effects.¹ It is unclear whether clozapine’s adverse effects are dose-dependent,² and findings regarding its effects on weight,^3-5 glucose, and lipids^6-8 are mixed.

The Current Study

Piras and colleagues⁹ analyzed the effects of clozapine dose on weight, blood pressure, and metabolic parameters in a prospective cohort of psychiatric patients in Switzerland. Data were obtained from the PsyMetab and PsyClin cohorts, which included patients who had started clozapine between 2007 and 2020 and had at least 2 weight observations and 3 weeks of clinical follow-up. Data on weight, waist circumference, blood pressure, glucose, and lipids were obtained at baseline, 3 months, and 12 months. Weight was also available at 2 and 6 months. Data on clozapine dose and comedications were also obtained. The study included 115 participants.

The authors compared clinical variables between patients who were taking at least 200 mg and patients who were taking less than 200 mg of clozapine (median dose). Dose effects on weight change were evaluated using linear mixed-effects models, adjusting for age, sex, baseline weight, treatment duration and setting (inpatient vs outpatient), tobacco use, diagnosis, and treatment. Logistic regression was used to detect whether dose was associated with substantial weight gain (≥ 5% at 1 month and ≥ 7% during follow-up).

Patients taking 200 mg of clozapine or more were more likely to be younger, to be smokers, to have a diagnosis of schizophrenia/schizoaffective disorder, and to have a higher baseline weight. Treatment duration and dose were significantly associated with weight change over 1 year, with a 0.5% increase in weight for each additional month and a 0.5% increase in weight for each additional 100-mg dose over 1 year of treatment. Weight increase was greater for treatment duration 3 months or less versus greater than 3 months (+0.84% and +0.47% per month, respectively).

Dose increments of 100 mg were associated with weight increases in adults (+0.71%), the elderly (+1.91%), and men (+1.32%) but not in women. There were no significant effects of clozapine dose on blood pressure, glucose, or lipids. Furthermore, baseline weight was not a predictor of weight change with clozapine.

Study Conclusions

Using a 1-year naturalistic design, the authors found a positive association between clozapine dose and weight change, independent of baseline weight. They also found that the percentage of weight increase after each 100-mg increase in clozapine dose was predictable.

Study strengths include the fact that the influence of multiple covariates could be integrated into the model. Study limitations include the modest sample size and absence of data on diet and physical activity. History of previous psychotropic medications, which could have included clozapine, was also unavailable.

The Bottom Line

There is evidence for a modest effect over 1 year of clozapine dose on weight but not on other metabolic parameters, with differences based on age and sex.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the editorial board of Psychiatric Times® and serves as schizophrenia section chief. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

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2. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review. J Clin Psychiatry. 2009;70(7):1041-1050.

3. de Leon J, Diaz FJ, Josiassen RC, et al. Weight gain during a double-blind multidosage clozapine study. J Clin Psychopharmacol. 2007;27(1):22-27.

4. Jalenques I, Tauveron I, Albuisson E, et al. Weight gain as a predictor of long term clozapine efficacy. Clin Drug Investig. 1996;12:16-25.

5. Lau SL, Muir C, Assur Y, et al. Predicting weight gain in patients treated with clozapine: the role of sex, body mass index, and smoking. J Clin Psychopharmacol. 2016;36(2):120-124.

6. Wysokiński A. Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy. Diabetes Metab Syndr. 2014;8(4):236-241.

7. Henderson DC, Nguyen DD, Copeland PM, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66(9):1116-1121.

8. Kamil Gharab KM, Onmaz DE, Abusoglu S, et al. The relationship between serum clozapine concentrations and hematological parameters by a validated mass spectrometric method. J Pharm Biomed Anal. 2020;180:113056.

9. Piras M, Chahma J, Ranjbar S, et al. Is clozapine-induced weight gain dose-dependent? Results from a prospective cohort study. Schizophr Bull. Published online February 26, 2023;sbad009.