Weight loss associated with exenatide in an obese man with diabetes commenced on clozapine

To the Editor

Clozapine is the gold-standard for treatment-refractory schizophrenia, but has significant metabolic sequalae, including an average 13.5 kg weight gain over 10 years (Henderson et al., 2005). Clozapine is believed to interfere with glucagon-like-peptide (GLP-1), an intestinal epithelial produced peptide involved in glycaemic regulation and satiety, which contributes to risk of weight gain and type 2 diabetes-mellitus (T2DM) (Mayfield et al., 2016). There is increasing interest in exogenous GLP-1 agents such as exenatide for obese people on clozapine (Mayfield et al., 2015). We present a consented case of a man with newly diagnosed T2DM coincidentally commenced on both exenatide (Byetta) and clozapine.

Mr R is a 43-year-old man with a 20-year history of schizophrenia, refractory to multiple adequate antipsychotic trials, most recently of olanzapine 25 mg nocte. His general physician (GP) commenced Mr R on metformin 1 gm nocte in response to a raised blood sugar level (BSL) = 6.6, 1 year before Mr R and his family agreed to a trial of clozapine. Prior to the commencement of clozapine, Mr R had a Brief Psychiatric Rating Scale (BPRS) score of 60. His weight was 186.9 kg, height = 201 cm, body mass index (BMI) = 46.3 kg/m² and waist = 160 cm. One week before starting clozapine, his GP added exenatide (Byetta) 5 mcg s/c bid.

Mr R was titrated up to clozapine 250 mg during a 3-week psychiatric admission. In the following months, his dose was increased to 500 mg po nocte (clozapine levels = 420 ng/mL). Six months following commencement of clozapine and exenatide, Mr R had a BPRS of 46, weight = 145.4 kg, BMI = 36.0 kg/m², waist = 132 cm and HbA1c = 5.1%. He was euthyroid (thyroid stimulating hormone [TSH]-1.9 mIU/L) and not addisonian (adrenocorticotropic hormone [ACTH]-37 ng/L and cortisol 278 nmol/L).

Mr R reported a reduced appetite with exenatide, and achieved satiety after smaller meals. He reported nausea when his exenatide was increased to 10 mcg s/c bid, but this resolved when reduced back to 5 mcg s/c bid. He engaged in minimal physical activity either before or after starting clozapine.

The concomitant commencement of exenatide and clozapine was not intentional, however after 6 months, Mr R had lost 41.5 kg, reduced his BMI by over 10 kg/m² and reduced his waist circumference by 28 cm. The contribution of metformin versus exenatide to this weight loss could be debated. Our group’s metanalysis of metformin used in patients on clozapine have shown an average weight loss of 3 kg (in submission) hence metformin is felt to be unlikely to be responsible for this degree of weight loss. Further study into the role of exenatide for weight loss for obese people on clozapine with and without T2DM is required.