Atypical antipsychotics are used to reduce relapses, decrease positive symptoms, and improve negative symptoms associated with schizophrenia.1 Unfortunately, due in part to the metabolic adverse-effect profile of atypical antipsychotics, adherence has been an increasing problem.
Decreased adherence poses a threat of relapse. On the other hand, the medications’ adverse effects may cause iatrogenic harm, including diabetes and other health issues related to weight gain. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study showed that 30% of patients with schizophrenia treated with olanzapine (known for its weight gain effect) gained more than 7% of their body weight after starting the drug; other trials have shown an even greater effect.2
The weight gain effects of atypical antipsychotics on a younger population are even more alarming. In a study of patients with a psychiatric disorder aged 4 to 19 years, more than half gained more than 7% of their body weight while taking aripiprazole, risperidone, or quetiapine. A similar effect was found in 84% of patients after treatment with olanzapine for 12 weeks.3
In addition, meta-analysis of the association of atypical antipsychotics with diabetes showed that in young patients treated with clozapine, the risk of type 2 diabetes mellitus (T2DM) was double that in young patients treated with a typical antipsychotic.4 The underlying mechanisms for these effects are not understood. Among other causal factors may be the sedentary lifestyles of patients treated with antipsychotics.
Atypical antipsychotics are also linked with increased appetite and decreased physical activity. The antagonism of histamine H1 causes sedation, and the antagonism of serotonin 2C receptors may down-regulate leptin-mediated satiety, leading to weight gain and insulin resistance.
Atypical antipsychotics reduce levels of heat shock protein 72 (Hsp72); decreased levels of Hsp72 produce metabolic symptoms. The primary function of Hsp72 is to act as a molecular chaperone that stabilizes protein conformation and controls transport of mutant proteins. This function has been shown to protect against insulin resistance, which may lead to ways of minimizing metabolic effects of atypical antipsychotics.
Metformin and lifestyle intervention. Metformin is a biguanide oral antidiabetic medication whose primary mechanism of action is suppression of gluconeogenesis by the liver. Metformin may decrease weight gain by inhibiting the degradation of glucagon-like peptide 1 (GLP-1), which results in appetite suppression.5
A 12-week, randomized, double-blind, placebo-controlled trial tested the efficacy of metformin (750 mg/d) alone and in combination with lifestyle intervention, in preventing weight gain and abnormal insulin sen-sitivity.6 The study included 128 patients who received olanzapine, clozapine, risperidone, or sulpiride, divided into 4 groups: metformin alone, lifestyle changes alone, the combination of the two, or placebo alone. The lifestyle interventions included in this study were diet, exercise, and a psychoeducational program.
Dr Khalafian is a Resident and Dr Tucker is Professor and Arnold and Bess Ungerman Endowed Chair in Psychiatry and Vice Chair of Education in the department of psychiatry and behavioral sciences at the University of Oklahoma Health Sciences Center, Oklahoma City. They report no conflicts of interest concerning the subject matter of this article.
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