Effects of the cannabinoid-1 receptor antagonist/inverse agonist rimonabant on satiety signaling in overweight people with schizophrenia: a randomized, double-blind, pilot study.

To the Editors: People with schizophrenia have an increased risk of comorbid medical conditions, primarily coronary heart disease, resulting in a 15to 20-year shorter life expectancy than those without the diagnosis. Coronary heart disease is induced largely by high rates of obesity, insulin resistance and type 2 diabetes, hyperlipidemia, and hypertension compounded by smoking, reduced access to care, inadequate health screening rates, poor diet, and metabolic adverse effects of antipsychotic medications. Weight gain is a serious adverse effect of several second-generation antipsychotic (SGA) medications possibly caused by several peripheral and central mechanisms including disturbances in glucose, insulin, leptin, ghrelin, H1 and 5HT2C receptor antagonism, other hormone signaling or function or secretion, or disturbances in satiety signaling. In fact, people with schizophrenia taking SGA medications show lower levels of self-reported satiety after a standardized breakfast than do those not taking SGAs. Rats taking the SGA olanzapine show impeded behaviorally measured satiety and hyperphagia is implicated in the SGA induction of body weight gain. Thus, one key mechanism of weight gain with SGAs may involve disruption or interruption of normal satiety signaling after eating. Cannabinoid-1 (CB1) antagonists and agonists affect food intake through binding to cannabinoid receptors. Hyperphagia (overeating) can be induced by injection of anandamide, an endogenous cannabinoid (endocannabinoid) neurotransmitter, into the ventral medial hypothalamus or by peripheral administration of exogenous cannabinoids. In addition, cannabinoids increase rodents’ preference for sucrose solution or other palatable substances. Pretreatment with rimonabant, a CB1 receptor inverse agonist/antagonist, inhibited this hyperphagia and increased food preference in rats, suggesting that cannabinoids are acting via the CB1 receptor. The natural craving of rats for sweet substances is intensified by enhanced endocannabinoid signaling in the nucleus accumbens, suggesting a relationship between endocannabinoid activity and satiety modulation. Furthermore, endocannabinoids inhibit digestion signals mediated by afferent vagus nerve fibers, such as the release of cholecystokinin, leading to increased food consumption. Because of the potential satiety-inducing effects of cannabinoid receptor antagonism, we hypothesized that rimonabant may enhance satiety signaling in peoplewith schizophrenia taking a SGA. The aim of this studywas to directly test the behavioral effects of rimonabant on satiety signaling as measured by a preload-test meal paradigm. Inpatients and outpatients at the Maryland Psychiatric Research Center with a Diagnostic and Statistical Manual of Mental Disorders, Fourth EditionYdefined diagnosis of schizophrenia or schizoaffective disorder who were treated with an SGA for at least eight weeks on a stable dose for at least one month were enrolled in a 16-week, double-blind, randomized, placebo-controlled study of rimonabant (20 mg/d). Full results on psychiatric symptoms and metabolic data are presented elsewhere. Participants were between the ages of 18 and 55 years, had a body mass index (BMI) of 30 kg/m or greater or a BMI of 27 kg/m or greater plus adult treatment panel III hyperlipidemia or hypertriglyceridemia, no recent depressive symptoms/suicidality, no current substance abuse/dependence (with the exception of nicotine), no more than weekly cannabis use, and were clinically stable (baseline characteristics, Table 1). An exercise and dietary counseling group was offered weekly during the study. The participants were assessed at baseline, midpoint, and end of study using a preload-test meal paradigm designed to assess satiety signaling. After an overnight fast, the participants were given a standardized breakfast preload of 12-oz. vanilla Ensure. The preload was consumed, in its entirety, within 5 minutes. A preweighed test meal (Wheat Thins, Nilla Wafers, and 12-oz. water) was served an hour later. After 30 minutes, the test meal was removed and weighed. The amount consumed was considered a behavioral index of satiety. Rimonabant-placebo differences in test meal consumption were evaluated using mixed models for analysis of covariance to combine data across repeated visits and to adjust for observed between-group differences in baseline consumption. The models took the following form: treatment phase measure = baseline measure + treatment + week + treatment week. In this model, week is a categorical indicator of week 7 versus week 16; the main effect of treatment estimates the average of the rimonabant-placebo differences at weeks 7 and 16; and the treatment week interaction term tests whether the magnitude of treatment effects varies significantly between the follow-up 2 weeks. The models were fitted using SAS PROC MIXED (version 9.1.3, SAS Institute, Cary, NC), and degrees of freedom for hypothesis tests were estimated using the KenwardRoger method. Similar models were fitted to evaluate rimonabant effects on body weight and BMI. The target sample size was 60 participants (30 in each group); however, the study was terminated prematurely when rimonabant was withdrawn from worldwide marketing due to concerns over psychiatric symptoms and suicidality. We excluded participants with depressive symptoms or suicidality at baseline and did not see any increase in suicidality or depressive symptoms throughout the trial. In fact, total Brief Psychiatric Rating Scale (BPRS) scores improved in the rimonabant group compared to the placebo group over the 16 weeks. Fifteen participants were randomized to medication (7 participants, rimonabant; and 8 participants, placebo); 5 participants in each group completed the 16-week trial. Because of early study termination, 2 participants on rimonabant (at weeks 11 and 13) and 2 participants on placebo (both at week 13) did not complete the 16-week trial but completed end-of-study assessments. No participant discontinued because of adverse events. One participant on placebo did not complete the satiety paradigm. At baseline, mean (SD) test meal consumption was lower in the participants randomized to rimonabant for total kilocalories (64.4 [68.0]) andWheat Thins (40.6 [53.1]) compared to placebo (101.0 [55.4] and 58.0 [44.4], respectively). After statistically adjusting for these baseline differences, least square mean (SE) rimonabant-placebo differences in test meal consumption were j42.7 (19.7) for total kcal (F = 4.70; df = 1, 10.8; P = 0.053) and j17.8 (9.3) for Wheat Thins kcal, (F = 3.64; df = 1, 8.93; P = 0.089), giving estimated treatment LETTERS TO THE EDITORS