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Metformin and Lifestyle Intervention as Treatment for Antipsychotic-Induced Weight Gain

Since their introduction, atypical antipsychotic medications have been used increasingly for the management of patients with psychotic disorder and severe behavioral disturbances. Weight gain, hyperlipidemia, and glucose intolerance are common adverse effects that have been associated with taking these antipsychotic medications.

Studies have shown that clozapine and olanzapine produce the most weight gain, quetiapine and risperidone produce intermediate weight gain, and ziprasidone and aripiprazole produce the least weight gain.  The mechanism underlying weight gain resulting from antipsychotic drugs has not been fully understood, but might be associated with central histamine H1 antagonism and increased impairment of metabolic regulation and alteration of insulin sensitivity, as well as genetic, environmental, and lifestyle factors.

Lifestyle intervention has been shown to prevent or delay the development of type 2 diabetes by 40% to 60% in different populations. Metformin, which inhibits hepatic glucose production, is well tolerated and prevents continual weight gain while it decreases measures of insulin resistance.  Some studies have found that metformin can reduce body weight in patients with or without type 2 diabetes.

A study published in JAMA in January 2008, followed128 Chinese adult first-episode schizophrenia patients to gather information about weight loss in patients who had gained more than 10% of their predrug weight. The study was organized into four groups, one placebo alone, one metformin (750 mg/d) alone group, one lifestyle intervention group plus placebo, and one with both metformin (750mg/d) and lifestyle intervention.

The lifestyle intervention group included: 1) psychoeducation, which focused on the roles of eating and activity in weight management, 2) dietary, with the American Heart Association’s step 2 diet prescribed—deriving 30% of total calories from fat with less than 7% from saturated fat and less than 200mg of cholesterol, 55% of total calories from carbohydrate, and 15% from protein each day, along with increased fiber intake, 3) exercise programs supervised by an exercise physiologist, including 30 minute exercise sessions seven times weekly.

To obtain results, researchers measured the change in body mass index, waist circumference, insulin levels, and insulin resistance index over twelve weeks.  What they found is that subjects in the lifestyle-plus-metformin group had the highest reduction of BMI (1.8 points), waist circumference (2.0 cm), and insulin resistance index (3.6). The metformin-alone group had mean decreases of BMI (1.2 points), waist circumference (1.3 cm), and insulin resistance index of (3.5).  The lifestyle-plus-placebo group had mean decreases in BMI (0.5 points) and insulin resistance index (1.0). And finally, the placebo-alone group had mean increases in BMI (1.2 points), waist circumference (2.2 cm) and insulin resistance index (0.4).

This study concluded that the combination of lifestyle intervention and metformin or metformin alone demonstrated efficacy for reducing antipsychotic-induced weight gain.  Lifestyle intervention plus metformin showed the best effect on weight loss.  Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone.

While reading, my attention was drawn to the fact that the participants of all four groups had elevated insulin levels, with the lowest group’s being 25.3 µIU/mL. Additional weight loss and lower insulin levels may have been obtained by decreasing the amount of carbohydrate recommended, and increasing lean protein to replace the caloric loss—as I have found effective in my clinical practice with insulin resistant patients.

JAMA, January 2008—Vol 299, No. 2. pp185-193.

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