November 2008

Atomoxetine versus Methylphenidate for Pediatric ADHD
Methylphenidate (Ritalin and others) appears to be more efficacious than atomoxetine (Strattera) for treating attention-deficit/hyperactivity disorder in children but has more adverse effects.

Rivastigmine (Exelon) Patch
A transdermal system for delivering rivastigmine (Exelon) is now available in the United States for treating dementia associated with Alzheimer's or Parkinson's disease.

Metformin for Antipsychotic-Associated Weight Gain
Most studies with metformin (Avandamet and others) suggest that it attentuates weight gain or actually promotes weight loss in patients who are taking antipsychotics.

In Brief
Valproate Teratogenicity Increased by High Dose, Concomitant Drugs;Celecoxib, Naproxen Do Not Protect Against Alzheimer's Disease

Metformin for Antipsychotic-Associated Weight Gain

November 2008

Many people taking antipsychotic agents gain weight,1 which adds to the morbidity and mortality already associated with chronic mental illness. Metformin (Avandamet and others) is one of an increasing number of drugs prescribed to combat weight gain with antipsychotic medication. Indicated for the treatment of hyperglycemia in type II diabetes, metformin has been associated with weight loss.

Baptista and coworkers randomly assigned 40 patients with schizophrenia who were taking olanzapine (Zyprexa), 10 mg daily, to receive either metformin, 850 to 1700 mg daily, or placebo in double-blind fashion for 14 weeks.2 In this study, metformin did not prevent olanzapine-induced weight gain. Other trials, however, have been more positive.

Morrison and others enrolled 19 children and adolescents, aged 10 to 18 years, who had gained weight with olanzapine, risperidone (Risperdal), quetiapine (Seroquel), or valproate (Depakote and others).3 Doctors prescribed metformin, 500 mg tid, for 12 weeks. Fifteen of the 19 lost weight, 1 showed no change in weight, and only 3 gained—up to 1.6 kg (3.6 lb). Over the 12 weeks, the group lost a mean of 2.93 ± 3.13 kg (6.51 ± 6.96 lb) (P = .008).

Klein et al studied 39 young people, aged 10 to 17 years, whose weight had increased more than 10% during up to 1 year's treatment with olanzapine, risperidone, or quetiapine.4 In a 16-week, double-blind trial, the subjects were assigned to treatment with metformin, 850 mg bid, or placebo, while antipsychotic medication was continued at stable doses. All patients and their families received dietary counseling. Patients assigned to placebo continued to gain weight at an average of 0.31 kg (0.69 lb) per week. Those taking metformin, by contrast, maintained stable weight during the trial. Body mass index (BMI) decreased in the metformin group, while it increased in the placebo group. Insulin resistance increased among placebo subjects but decreased in those taking metformin.

Baptista and coauthors studied 80 patients with bipolar disorder or schizophrenia who had been taking olanzapine, 5 to 20 mg/day, for at least 4 months.5 Subjects were randomly assigned to receive metformin, 850 to 2550 mg/day, or placebo for 12 weeks. Those taking metformin lost an average of 1.4 kg (3.1 lb), while placebo-treated subjects lost an average of 0.2 kg (0.4 lb). Insulin resistance increased in the placebo group but did not change with metformin.

Chen and coworkers recruited 24 patients with schizophrenia who had been taking olanzapine for at least 3 months.6 While the antipsychotic dosage was held constant, patients were treated in open-label fashion with metformin, 1500 mg/day. By 8 weeks, the group had lost an average of 2.2 ± 1.8 kg (4.9 ± 4.0 lb), and BMI had decreased by 3.5%. Almost 30% of subjects lost at least 5% of initial body weight.

Forty patients with a first episode of schizophrenia who had not previously been treated with antipsychotics took olanzapine, 15 mg/day, in a 12-week study by Wu and colleagues.7 Patients were also randomly assigned to take either placebo or metformin, 750 mg/day, in double-blind fashion. Weight and BMI increased a mean of 6.87 ± 4.23 kg (15.27 ± 9.40 lb) in the placebo group but only 1.90 ± 2.72 kg (4.22 ± 6.04 lb) in the subjects who received concomitant metformin (P < .02). Increase in BMI was statistically less in the metformin group, and fewer metformin-treated patients gained more than 7% in body weight. Insulin resistance increased significantly in those who received placebo but remained unchanged in the metformin group.

In another study, Wu and coworkers compared the effects of metformin alone, lifestyle intervention alone, and the combination on antipsychotic-induced weight gain.8 The authors enrolled 128 inpatients with a first psychotic episode of schizophrenia who were between 18 and 45 years old and had gained more than 10% of pre-drug body weight during their first year of treatment with one of four antipsychotics: clozapine (Clozaril and others), olanzapine, risperidone, or sulpiride.* Participants were randomly assigned to one of four treatment groups: metformin, 750 mg/day; placebo; lifestyle intervention—which included psychoeducational, dietary, and exercise programs—plus placebo; or lifestyle intervention plus metformin.

All patients maintained psychiatric stability throughout this 12-week trial. Placebo-treated patients gained an average of 3.1 kg (6.9 lb). The other three groups lost weight: 1.4 kg (3.1 lb) with lifestyle intervention alone, 3.2 kg (7.1 lb) with metformin alone, and 4.7 kg (10.4 lb) with the combination. Change in body mass index (BMI) followed the same pattern, as did waist circumference and indications of insulin resistance. The combination treatment was statistically significantly superior to metformin alone and to lifestyle intervention plus placebo for weight, BMI, and waist circumference reduction. Metformin alone was superior to lifestyle intervention alone in weight loss and improving insulin sensitivity.

In children, adolescents, and adults, most studies with metformin, 750 to 1500 mg/day, suggest that it attenuates weight gain or actually promotes weight loss in patients who are taking antipsychotics. In all of these trials, it was well tolerated. Of course, no effective drug is totally benign. In addition to decreasing absorption of vitamins B12 and folic acid, metformin has caused rare but potentially fatal cases of lactic acidosis in patients with diabetes.

Someday we will have agents that can treat psychosis without creating medical burden—including weight gain, diabetes, and associated problems. In the meantime, the results from Dr Wu's group suggest the possible advantages of combined behavioral and pharmacologic intervention in patients who benefit from antipsychotic drugs but gain weight.

We thank Dr Chittaranjan Andrade, whose article on this topic in his newsletter, Synergy Times, inspired this piece.

*Not available in the United States.

1Alvarez-Jiménez M, González-Blanch C, Vázquez-Barquero JL, Pérez-Iglesias R, Martínez-García O, Pérez-Pardal T, Ramírez-Bonilla ML, Crespo-Facorro B: Attenuation of antipsychotic-induced weight gain with early behavioral intervention in drug-naïve first-episode psychosis patients: A randomized controlled trial. J Clin Psychiatry 2006;67:1253-1260.

2Baptista T, Martinez J, Lacruz A, Rangel N, Beaulieu S, Serrano A, Arapé Y, Martinez M, de Mendoza S, Teneud L, Hernández L: Metformin for prevention of weight gain and insulin resistance with olanzapine: A double-blind placebo-controlled trial. Can J Psychiatry 2006;51:192-196.