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Managing Side Effects of Antipsychotic Medications

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As described in the 2004 guideline, weight gain and metabolic side effects are common or frequent adverse effects of the second-generation antipsychotics clozapine, olanzapine, risperidone, and quetiapine. The guideline recommends regular monitoring of weight, body mass index, serum lipids, and fasting glucose levels of all patients. When patients gain weight, it is recommended that clinicians discuss treatment options, which may include switching medications, to prevent further weight gain and encourage weight loss.

Several clinical trials have investigated pharmacological and cognitive-behavioral treatments that may attenuate or reverse antipsychotic-related weight gain and lipid, glucose, and insulin changes (10). The nonpharmacological weight management interventions are described in greater detail in the subsection "Psychosocial Interventions for Weight Management," later in this watch. There have been several pharmacological clinical trials investigating metformin (a peripheral insulin-sensitizing agent), topiramate (an anticonvulsant), reboxetine (a selective norepinephrine reuptake inhibitor), and amantadine (a dopamine agonist). Metformin has been investigated in five randomized controlled studies, with four showing some indication of benefits (11–14), and one negative trial (15). The most promising results were reported in a randomized, double-blind trial in which 128 olanzapine-treated first-episode patients received adjunctive metformin 750 mg/day, metformin 750 mg/day plus lifestyle changes, lifestyle changes plus placebo, or placebo (11). The patients who received adjunctive metformin plus lifestyle changes had the most robust weight loss, body mass index (BMI) reduction, waist circumference reduction, and fasting insulin and insulin-resistance level reduction; these outcomes were significantly better than lifestyle changes plus placebo or placebo alone. For example, BMI significantly decreased by 1.8 units on average in the metformin plus lifestyle changes group, by 1.2 units in the metformin alone group, and by 0.5 units in the lifestyle changes plus placebo group. In the placebo group, in contrast, BMI increased by an average of 0.7 units. No increase in adverse events, including nausea, occurred in the patients treated with metformin.

Two randomized, placebo-controlled trials of adjunctive topiramate have reported weight loss in overweight patients who were already receiving treatment with olanzapine (16) or with risperidone, olanzapine, quetiapine, or clozapine (17). In patients who had gained weight during olanzapine treatment, two randomized, placebo-controlled trials reported that further weight gain was less pronounced with adjunctive amantadine treatment (18,19). Two randomized, placebo-controlled trials also reported significant attenuation of weight gain when adjunctive reboxetine was initiated concomitantly with olanzapine in patients with a first episode of schizophrenia (20,21). However, the clinical utility of these adjunctive treatments is unclear, given their relatively small impact on weight as well as their cost, potential side effects, and potential interactions with other medications.

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