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August 2010

Anticonvulsants and Suicide Risk
Findings from a recent study support the US Food and Drug Administration's 2008 conclusion that anticonvulsants increase the risk of suicidal ideation and behavior.

The Generic Medication Question
Variability in the bioavailability of generic medications can affect efficacy and tolerability in some patients.

Antidepressant-Induced Mania?
Evidence from a meta-analysis of controlled and open trials suggests that antidepressants increase the risk of a switch from depression into hypomania or mania in patients with bipolar disorder and in those with major depression.

Medications to Reduce Antipsychotic-Induced Weight Gain
The overall effect of medications as antidotes to antipsychotic-induced weight gain is modest; diet and exercise should be the first-line strategy.

In Brief
Veterans with PTSD Have Greater Risk of Dementia; Bupropion Safe and Effective Aid for Smoking Cessation in Schizophrenia

Smoking and Clozapine Levels
Elevations in plasma clozapine (Clozaril and others) concentrations following smoking cessation can be dramatic and potentially lead to serious toxicity.

Medications to Reduce Antipsychotic-Induced Weight Gain

August 2010

BTP has frequently reviewed the worrisome issue of weight gain and metabolic abnormalities associated with antipsychotic drug therapy (BTP 2010;33:17-18, 2009;32:5-6,34-35). Many medications have been studied as potential antidotes to prevent or attenuate these problems. Maayan and collaborators conducted a systematic review and meta-analysis of such strategies.1

The authors examined 32 placebo-controlled trials that enrolled 1482 subjects and tested 15 different interventions. The overall effect of medications as antidotes to antipsychotic-induced weight gain was modest: a mean weight loss of 1.99 kg (4.42 lb) versus placebo over a mean of 13 weeks. Results were highly heterogeneous, with differences across studies and even among studies of the same medication. Metformin (Glucophage and others) had the largest database and showed the greatest

superiority over placebo, with a mean weight loss of 2.94 kg (6.53 lb). Even so, treatment response varied substantially across studies. Additional agents superior to placebo were fenfluramine* (-2.60 kg [-5.78 lb]), sibutramine (Meridia and others; -2.56 kg [-5.69 lb]), topiramate (Topamax and others; -2.52 kg [5.60 lb]), and reboxetine* (-1.90 kg [4.22 lb]). Metformin and rosiglitazone (Avandia) demonstrated significant benefits for secondary outcomes chosen by the investigators—including waist circumference, blood glucose, and insulin levels. Of interest, metformin demonstrated significant weight loss over placebo when it was given as an intervention after weight gain had occurred. However, when started concomitantly with an antipsychotic, it did not attenuate weight gain any better than placebo.

The authors lament the lack of head-to-head studies comparing medications to control antipsychotic-mediated weight gain. Only one study compared pharmacologic, nonpharmacologic, and combined pharmacologic plus nonpharmacologic intervention against placebo.2 Dr Maayan's group further notes the particular need for more studies in antipsychotic-treated children and adolescents. Finally, they call for studies of patients who take antipsychotics for indications other than schizophrenia—eg, for bipolar disorder.

At this time adjunctive medication should be viewed as a limited approach to preventing or reversing weight gain and metabolic abnormalities from antipsychotics. The first-line strategy should be weight control via diet and exercise. Switching to a different antipsychotic is another option.

*Not available in the United States.

1Maayan L, Yakhrusheva J, Correll CU: Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: A systematic review and meta-analysis. Neuropsychopharmacology 2010;35:1520-1530.

2Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, He YQ, Liu YJ, Chen JD, Li LH: Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: A randomized controlled trial. JAMA 2008;299:185-193.