Obesity and Mental Illness

Second-Generation Antipsychotics

Second-generation antipsychotics are a major source of concern regarding weight gain. Attempts have been made to identify specific receptor-binding profiles of antipsychotics to aid in the prediction of propensity for weight gain, however there is much individual variation, and most of the information available at present comes from clinical observations. In a comprehensive meta-analysis of weight change after 10 weeks of treatment at a standard dose of antipsychotics, mean increases in body weight were calculated for the different medications. Clozapine and olanzapine had the largest weight gains with 4.45 and 4.15 kg, respectively. Risperidone was associated with a more modest 2.10 kg gain. Ziprasidone appeared essentially weight neutral with a mean gain of 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks, but subsequent studies have indicated that quetiapine also has a moderate to high propensity toward gain, particularly over the long term, as demonstrated in a prospective, naturalistic study. Aripiprazole, the newest second-generation antipsychotic medication to become commercially available, is generally considered to be weight neutral.

Examining mean weight change as observed in clinical trials is not always informative as to how often this actually will be encountered in clinical practice. There is large individual variability regarding weight gain, even with agents commonly thought of as being inexorably tied to obesity. In the CATIE study weight change per month of antipsychotic treatment was reported both in terms of mean change and in terms of median and range. Table 2 demonstrates that although mean weight change followed the expected pattern, some patients randomized to olanzapine lost 0.64 kg per month, and some gained 4.3 kg per month. Patients randomized to weight neutral medications still show variability in weight change, with some patients randomized to ziprasidone losing 2.4 kg per month and others gaining 2.7 lb per month. Weight gain greater than 7% from baseline to last observation occurred among 30% of the patients randomized to olanzapine, 16% for quetiapine, 14% for risperidone, 12% for perphenazine, and 7% for ziprasidone. Number needed to treat (NNT) to encounter one additional case of weight gain greater than 7% when using olanzapine versus perphenazine (a first-generation antipsychotic) was 6, versus quetiapine 8, versus risperidone 7, and versus ziprasidone 5. This means for every 5 patients randomized to olanzapine instead of ziprasidone, there was one additional case of a patient on olanzapine gaining greater than 7% of their initial body weight. Keeping in mind patients randomized to olanzapine had a longer mean time on medication than the other antipsychotics, and thus had a greater opportunity to accumulate weight, these single-digit NNTs nevertheless represent clinically significant differences.

Switching antipsychotics can lead to weight loss. Ultimately, there will need to be a favorable balance of benefit to risk. Deciding whether to continue treatment with a particular antipsychotic or switch the patient to another can pose substantial dilemmas for the clinician. The choice to ‘switch or stay’ is a highly individualized decision.

Evidence-based medicine philosophy states that relevant clinical trials can inform the clinician in making thoughtful individualized treatment decisions but there are no guarantees of weight gain or loss or drug efficacy. With these caveats, consideration should be given to switching to a more weight-neutral medication when encountering rapid weight gain with a particular antipsychotic. For example, in the CATIE study, of 61 patients who gained over 7% of their body weight in phase 1, 42% of ziprasidone-treated patients, 20% of risperidone-treated patients, 7% of quetiapine-treated patients, and 0% of olanzapine-treated patients lost over 7% of their body weight during phase 2. The NNT to encounter one additional case of weight loss greater than 7% when using ziprasidone versus olanzapine or quetiapine was 3, and versus risperidone 5. The findings from CATIE are consistent with earlier reports from open-label studies, such as a post-hoc analysis of a 20-week study where switching from olanzapine to risperidone resulted in a reduction of prevalence of metabolic syndrome in overweight or obese patients, including reductions in body weight and BMI.

In another report of 3 studies in which outpatients experiencing were switched to 6 weeks of open-label ziprasidone, patients switched from olanzapine experienced a mean weight loss of 1.76 kg, those switched from risperidone had a lesser reduction in weight (–0.86 kg),  and those switched from first-generation antipsychotics had a non-significant increase (+0.27 kg).  In an 8-week study where patients were switched from other antipsychotics to open-label aripiprazole (92% were receiving olanzapine or risperidone prior to the switch), the mean weight loss from baseline ranged from 1.3 kg to 1.7 kg, the incidence of weight loss of at least 7% of total body
weight ranged from 7% to 15%, and the incidence of weight gain of at least 7% of total body weight ranged from 3% to 5%, depending on the switching technique.

Early weight gain may be predictive of future substantial weight gain. One can use the time course for weight gain with olanzapine for early identification of those at risk before substantial weight gain has occurred. Patients taking olanzapine who gain 5% or more of their body weight within the first 4–12 weeks of treatment and who are going to remain on olanzapine will require more active behavioral and/or pharmacologic interventions than patients who gain weight more slowly or not at all. Although weight gain may plateau after 40 weeks or so, by that time one-half of patients receiving olanzapine will have gained up to 10 kg,  and some substantially more than that. The pattern of weight gain with quetiapine is also consistent with the idea that it can occur early (within 12 weeks). Within the approved range, antipsychotic dose does not appear to be predictive of weight gain for olanzapine but there may be differences at higher-than-approved doses. For risperidone, in a short (6-week) trial, higher doses were associated with more weight gain. Data regarding a dose relationship with weight gain with quetiapine is conflicting.

Low initial BMI (< 25) may be a predictor of some future weight gain in some patients with any of the second-generation antipsychotic medications.

Children and adolescents, and patients in their first episode of psychosis may be at heightened risk for weight gain with antipsychotic medication. In a 52-week randomized double-blind clinical trial in patients early in their course of psychotic illness,  80%  of patients in the olanzapine group,  50%  in the quetiapine group,  and 58% in the risperidone group, gained at least 7% of their baseline weight at week 52. Similarly, in the 1-year European First-Episode Schizophrenia Trial, weight gain greater than 7% from baseline was observed in 86% of the patients randomized to olanzapine, 65% for those on quetiapine, 37% for those on ziprasidone, and 53% for those on haloperidol. Amisulpride, an antipsychotic not commercialized in the USA, was associated with a rate of 63% on this outcome.

Monitoring of patients receiving psychotropic medications for weight and metabolic parameters is crucial. The report from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes Consensus Panel contains valuable advice for appropriate and prudent monitoring.  The most frequently assessed parameter in the recommendations is weight. At a minimum it is obtained at baseline, monthly for the first 3 months, and then quarterly. However, monitoring weight at each and every patient visit will allow the clinician to catch a problem early, before substantial weight gain has set in, and underscore to both the patient and the clinician the importance of physical fitness. Additionally, patients and/or caregivers can be educated about monitoring weight and report back to the clinician.



Leslie Citromea
Betty Vreelandb

New York University School of Medicine, Department of Psychiatry, and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, N.Y.;

University Behavioral HealthCare, the School of Nursing, and the Departments of Psychiatry and Family Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, N.J., USA

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