Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain:  A Randomized Controlled Trial FREE

Since their introduction, atypical antipsychotic (AAP) medications have been used increasingly for the management of patients with a variety of psychotic disorders and severe behavioral disturbances. In the past decade, there has been a growing concern among clinicians and researchers that use of AAP medications may be related to potentially serious adverse metabolic effects, including weight gain, hyperlipidemia, and glucose intolerance.^1- 5

The induction of obesity by antipsychotic agents has been documented since the introduction of chlorpromazine in the mid-1950s.⁶ According to a recent study, 78.8% of patients receiving antipsychotic agents increased their baseline weight by more than 7%.⁷ Clinical studies indicate that AAP medications may have a greater potential for inducing weight gain than conventional antipsychotic medications and vary in their propensity to induce weight gain. Clozapine and olanzapine produce the most weight gain, quetiapine and risperidone produce intermediate weight gain, and ziprasidone and aripiprazole produce the least weight gain.^8- 12

This antipsychotic-related adverse effect has lately become a major concern in the treatment of psychosis because weight gain not only influences adherence with drug treatment but also is associated with substantial medical morbidity and mortality.¹³ Recent studies^14- 15 suggest that people with severe mental illness die up to 3 decades earlier than the general population. Heart disease is a leading cause of death in these patients. One of the major risk factors for heart disease and early death in these patients is weight gain.

The mechanism underlying weight gain resulting from antipsychotic drugs has not been fully understood, although it might be associated with central histamine H₁ antagonism and increased appetite or with direct impairment of metabolic regulation and alteration of insulin sensitivity.^16- 17 A combination of genetic, environmental, and lifestyle factors could likely play a role in the high rate of weight gain and metabolic dysregulation in patients taking antipsychotics.

Lifestyle intervention has demonstrated efficacy for weight loss in obese persons and has been shown to prevent or delay the development of type 2 diabetes by 40% to 60% in different populations in controlled studies.^18- 19 In patients with schizophrenia, several lifestyle interventions have been used to reduce obesity or to prevent weight gain induced by AAP medications.^20- 23 Preliminary evidence has suggested that behavioral interventions are effective in weight gain control for patients who had weight gain induced by antipsychotics.^7,24

Metformin, which inhibits hepatic glucose production, is well tolerated and prevents continual weight gain while it decreases measures of insulin resistance. Some studies find that metformin can reduce body weight in patients with type 2 diabetes and in obese individuals who do not have diabetes.^25- 26 Metformin can also reduce weight gain induced by antipsychotic agents.^27- 28 However, Baptista et al²⁹ reported that metformin did not improve weight gain induced by antipsychotic agents.

To our knowledge, no double-blind, placebo-controlled studies have directly compared lifestyle intervention and metformin alone or in combination for weight gain induced by antipsychotic medications among patients with schizophrenia. In this article, we report on a 12-week randomized, double-blind, placebo-controlled trial that tested the efficacy of lifestyle intervention and metformin alone and in combination to reduce weight gain and abnormalities of insulin sensitivity induced by antipsychotic medications in patients with schizophrenia.