Is Clozapine-Induced Weight Gain Dose-Dependent?


Research investigated this association in a prospective cohort study.




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

Mrs Green returned for another outpatient visit 6 weeks later and had gained 40 pounds during that timeframe. Through improved nutrition and exercise, she managed to have a sustained weight loss of 25 pounds from her highest recorded weight.

However, at age 52 years, she was diagnosed with type 2 diabetes mellitus. Although she has been psychiatrically stable on clozapine 300 mg for a decade, she inquires about her risk of weight gain if she were to require 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, but it is associated with substantial risk of cardiometabolic adverse effects.1 However, whether there is a dose-dependent association regarding cardiometabolic effects of clozapine is unclear.2 There are mixed findings for effects of clozapine on weight3-5 and glucose and lipids.6-8

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 present study included 115 participants.

The authors compared clinical variables between patients taking ≥ 200 mg and < 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, smoking, diagnosis, and treatment setting (inpatient vs outpatient). Logistic regression was used to detect whether clozapine dose was associated with substantial weight gain (≥ 5% at 1 month and ≥ 7% during follow-up).

Patients taking ≥ 200 mg clozapine 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 vs >3 months (+0.84% and +0.47% per month, respectively).

Dose increments of 100 mg were also associated with weight increases of +0.71% among adults, +1.91% among the elderly, and +1.32% among men, with no associations among 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 that the influence of multiple covariates that 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 of clozapine dose on weight increase, but not other metabolic parameters, over 1 year, 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 and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysisLancet Psychiatry. 2020;7(1):64-77.

2. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? a literature reviewJ 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 studyJ 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 smokingJ 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 monotherapyDiabetes 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 studyJ 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 methodJ 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 [published online ahead of print, 2023 Feb 26]. Schizophr Bull. 2023;sbad009.

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