Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial

Abstract

Clozapine is associated with significant weight gain and metabolic disturbances. This multicentre, randomized study comprised a double-blind, placebo-controlled treatment phase of 16 wk, and an open-label extension phase of 12 wk. Outpatients who met DSM-IV-TR criteria for schizophrenia, who were not optimally controlled while on stable dosage of clozapine for > or =3 months and had experienced weight gain of > or =2.5 kg while taking clozapine, were randomized (n=207) to aripiprazole at 5-15 mg/d or placebo, in addition to a stable dose of clozapine. The primary endpoint was mean change from baseline in body weight at week 16 (last observation carried forward). Secondary endpoints included clinical efficacy, body mass index (BMI) and waist circumference. A statistically significant difference in weight loss was reported for aripiprazole vs. placebo (-2.53 kg vs. -0.38 kg, respectively, difference=-2.15 kg, p<0.001). Aripiprazole-treated patients also showed BMI (median reduction 0.8 kg/m(2)) and waist circumference reduction (median reduction 2.0 cm) vs. placebo (no change in either parameter, p<0.001 and p=0.001, respectively). Aripiprazole-treated patients had significantly greater reductions in total and low-density lipoprotein (LDL) cholesterol. There were no significant differences in Positive and Negative Syndrome Scale total score changes between groups but Clinical Global Impression Improvement and Investigator's Assessment Questionnaire scores favoured aripiprazole over placebo. Safety and tolerability were generally comparable between groups. Combining aripiprazole and clozapine resulted in significant weight, BMI and fasting cholesterol benefits to patients suboptimally treated with clozapine. Improvements may reduce metabolic risk factors associated with clozapine treatment.

Atypical antipsychotics and effects on feeding: from mice to men

“…Studies in AP-naïve individuals show that patients treated with low metabolic liability APs experience significant weight gain (Correll et al 2009;Perez-Iglesias et al 2008;Zipursky et al 2005) and, in general, experience a three-to fourfold larger magnitude of antipsychotic-related weight gain compared to chronically ill patients (Alvarez-Jimenez et al 2008). In contrast, but in keeping with the presented rodent data, chronically treated patients have been reported to lose weight with ARI when added to CLO Fleischhacker et al 2010;Henderson et al 2006). It is unclear why this discrepancy exists between weight effects in individuals with little prior AP exposure and chronically ill patients; it is possible that different mechanisms underlie the more acute metabolic changes versus chronic weight gain (where additional factors related to illness and lifestyle may also come into play).…”

Treatment of clozapine-associated weight gain: a systematic review

“…The authors described significant reductions in both weight (−2.70 kg) and Body Mass Index (BMI) without worsening of psychotic symptoms. Significant decreases in weight (−2.15 kg) were also seen in a 2010 16-week trial of 5-15 mg adjunctive aripiprazole in clozapine-treated patients [31]. Aripiprazole Non-pharmacological interventions may therefore be beneficial in decreasing weight gain in clozapine-treated patients with schizophrenia, but, as with other SGAs, the side effect profile should be considered in balance with the potential benefits.…”

Metabolic syndrome in psychiatry: advances in understanding and management

“…Correll et al (2007) reported that the prescription of multiple antipsychotics was associated with a significant increase in the incidence of metabolic syndrome (50%) compared with antipsychotic monotherapy (34%). Conversely, the combination of clozapine and aripiprazole has been found to reduce triglyceride levels, LDL cholesterol, BMI and waist circumference, as well as negative symptoms, in patients with schizophrenia and metabolic syndrome (Fleischhacker 2010). This is probably because aripiprazole is a partial dopamine agonist that stimulates extracerebral presynaptic D 2 receptors, which decreases sympathetic tone and anabolic effects, thereby reducing the risk of metabolic syndrome.…”