Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial

Abstract

Aims: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D₂ receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia.

Material and methods: Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis.

Results: Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment.

Conclusions: Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia.

Trial registration: ClinicalTrials.gov NCT01794429.

Keywords: GLP-1 analogue; antidiabetic drug; exenatide; randomized trial schizophrenia.

Figure 1

Study diagram of the patient flow according to CONSORT 2010 statement. Of the 65 patients originally referred to the study, 45 entered the subsequent 3‐month treatment period. Five patients withdrew from trial, resulting in a completion of n = 40 (n = 20 exenatide only weekly, n = 20 placebo).

Figure 2

Time lines of mean body mass index (BMI) over a 3‐month period after glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) treatment in obese patients with schizophrenia. Blue line: exenatide group; red line: placebo group. Repeated measures analysis of variance showed no treatment effect of exenatide treatment, Time × Group interaction (P = .98). The x‐axis shows time points for body weight measurements. Horizontal lines on these time points are BMI standard deviations within the groups.