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 REVIEW ARTICLE

Second-generation antipsychotic use in schizophrenia and associated weight gain: A critical review and meta-analysis of behavioral and pharmacologic treatments

Chandan Das, BS

Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Guillermo Mendez, PhD

Department of Mathematics and Statistics, Arizona State University, Tempe, AZ, USA

Sonal Jagasia, MD

Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR, USA, Department of Psychiatry, Georgetown University, Washington, DC, USA

Lawrence A. Labbate, MD

Department of Psychiatry, University of Arkansas for Medical Sciences, Mental Health Service, Central Arkansas Veterans Healthcare, System, Little Rock, AR, USA

BACKGROUND: Weight gain in schizophrenia, particularly secondary to second-generation antipsychotic (SGA) use, is a common adverse effect and often is associated with significant physical and psychological morbidity.

METHODS: We performed a critical literature review of all controlled clinical trials for pharmacologic and/or behavioral management of SGA-induced weight gain in schizophrenia patients by searching PubMed and Google Scholar. A meta-analysis was performed to estimate and compare weight changes for various medications and behavioral interventions.

RESULTS: Sample sizes generally were small. Clinical trials were 6 weeks to 1 year, and weight loss was modest with any treatment. Although several adjunctive pharmacologic treatments showed no weight loss, sibutramine, metformin, and topiramate showed some benefit. Amantadine and orlistat were somewhat less effective and had lower rates of tolerability. Among the behavioral therapies, nutritional counseling combined with exercise showed the most benefit. Behavioral therapies, although modest, showed the most consistent benefits compared with controls.

CONCLUSIONS: Scheduled pharmacologic treatment to prevent weight gain or promote weight loss in schizophrenia patients on SGA therapy is limited based on current studies. Switching antipsychotic agents has not been established as a long-term solution. Additional long-term studies are required to influence clinical practice.

KEYWORDS: second-generation antipsychotics, weight gain, schizophrenia

ANNALS OF CLINICAL PSYCHIATRY 2012;24(3):225-239

  INTRODUCTION

Second-generation antipsychotics (SGAs) are widely used for a myriad of mental illnesses because of their purported tolerability and mild side-effect profile. Even though SGAs have been broadly adopted and have largely supplanted first-generation antipsychotics (FGAs) for treating schizophrenia, SGAs have significant side effects associated with their use. One of the most debilitating and important adverse effects of SGAs is weight gain. A number of studies and treatment guidelines have examined weight loss strategies, but a recent comprehensive synthesis is lacking. This review will focus on weight gain in schizophrenia, proposed mechanisms of weight gain associated with SGAs, and treatments for weight gain associated with these antipsychotics.

  METHODS

We conducted a comprehensive literature search with PubMed and Google Scholar using combinations of the search terms schizophrenia, weight gain, weight loss, antipsychotics, behavioral therapies, non-pharmacologic, second-generation antipsychotic, and switching with limits of clinical trials. Studies were combined using meta-analytic techniques to assess the impact on weight change,

, of various pharmacologic and behavioral treatments. Included for the figures were identified randomized controlled studies for weight loss methods. Studies were classified in the same group if they addressed a similar question (ie, weight loss caused by a specific pharmacologic intervention). Given the different implementations and sample sizes of the SGA studies, pharmacologic treatment studies, and behavioral treatment studies, the following methods were applied to each treatment type, ie, a model for all SGAs studies, a model for all behavioral interventions studies, and a model for all pharmacologic intervention studies.

For each of the 3 treatment types, we identified k specific treatments (i = 1,…,k). We then selected ni studies for each treatment, and recorded the reported estimated weight changes

ij (j = 1,…,ni; ni > 1) along with the corresponding reported standard errors sij of the estimates. We assume that each
ij has a normal distribution, ie,
ij ~ Ni,s2ij) and each θi follows the form θi = τi + βlxl where τi is the effect of treatment i, xl is a covariate representing the reported length of the study (in weeks), and βl is the marginal effect of length of study. We included this covariate to control for the various time frames across the studies, which can range from 8 weeks to 5 years. Incorporating all of the reported data from the various treatments, the model becomes
i = τi + βlxl + εij where it is assumed that εij ~ N(0,s2ij + σi2i). The s2ij are assumed fixed while the parameters τi, βl, and σ2 are estimated from the data using maximum likelihood estimation. By fixing the s2ij in the estimation of the parameters, we essentially weigh the reported
ij inversely to their corresponding variances. This puts more weight on the studies that had low standard errors and vice versa.1 Using standard errors in this way also accounts for sample size differences among the studies, because the calculation of standard errors inherently incorporates the size of the study. We used the procedure PROC MIXED within the SAS statistical software package, version 9.1 (Statistical Analysis System, Cary, NC) for all the statistical analyses.

One concern in any meta-analysis is that of heterogeneity, ie, unexplained variability across the selected studies. To investigate whether heterogeneity was present, we first fitted random-effects models with the reported data from the studies within each treatment type separately (SGAs, behavioral interventions, and pharmacologic interventions). Based on the results from those analyses, we found no evidence that significant heterogeneity was present among the selected studies within any of the 3 types. Therefore, fixed-effects models were used throughout this meta-analysis. One reason heterogeneity was not prevalent in these meta-analyses may be that by including length of study as a covariate in the model we controlled for 1 contributing factor that typically creates differences between the studies.

In this article, we report the least squares means of each specific treatment controlling for the effect of study length. The figures also show 95% confidence intervals (CIs) for each least squares mean assuming normality. One way to interpret the CIs is by concluding that the treatment does not lead to significant weight gain if the interval includes zero.

To obtain average study duration endpoints, a weighted average of the lengths of individual studies using sample size as the weighting factor was calculated. Standard deviations were not available for quetiapine and ziprasidone studies.

Weight gain

Weight gain is a complex phenomenon in patients with schizophrenia, with multiple contributing factors. High-calorie diet, lack of physical activity, and appetite stimulation associated with antipsychotic use are contributors. Interestingly, the illness itself may predispose patients to adiposity. Newly diagnosed patients with schizophrenia were found to have more intra-abdominal fat on CT imaging than appropriately matched controls.2 In a recent study of first-episode schizophrenia, patients experienced hypothalamic-pituitary-adrenal (HPA) axis dysfunction resulting in higher baseline cortisol and adrenocorticotropic hormone, implicating a drug-independent mechanism that may be caused by active psychosis.3 High cortisol levels are known to alter metabolism and have been linked to obesity,4 which likely is a contributing factor to weight gain in schizophrenia. In addition, medication-independent factors such as increased appetite,5 increased lipid storage,6 and lowered energy expenditure7 all have been implicated.

Multiple controlled studies have shown that all SGAs are associated with weight gain compared with placebo treatment, although some (eg, olanzapine, clozapine, and quetiapine) are more problematic than others (eg, ziprasidone and aripiprazole). FIGURE 18-33 shows weight changes associated with controlled clinical trials in schizophrenia, although a weighted average for study duration shows that most trials are brief. Results from the meta-analysis show that in these short-term trials olanzapine, quetiapine, and clozapine were associated with the greatest weight gain, with less mean weight gain with risperidone and essentially no weight gain with ziprasidone and aripiprazole.

Weight gain is strongly associated with an increased incidence of diabetes,34 cardiovascular complications, and increased morbidity and mortality. Even in antipsychotic-naïve patients with psychosis, cardiovascular disease is the largest cause of death.35

FIGURE 1: Weight change associated with second-generation antipsychotics in schizophrenia
Data are represented as a difference from controls. Error bars represent 95% CI from the mean.
CI: confidence interval.
Source: References 8-33.

Body mass index and weight gain

Recent studies have examined the likelihood of SGA-induced weight gain based on demographics. Low baseline body mass index (BBMI) consistently has been proven to be a demographic risk factor with nearly every SGA.17,20,36,37 Low BBMI patients consistently gain weight at an increased rate compared with their heavier counterparts, although often they do not gain as much weight.38 However, some clinical evidence from a small randomized clinical trial demonstrates that therapeutic response is linked with weight gain.39 Because low BBMI patients may have a higher resting metabolic rate, weight gain may be explained by a proportional decrease in metabolic rate in response to therapy. Other statistically significant predictors of increased risk of weight gain were younger age at treatment initiation, female sex, first exposure to antipsychotics, family history of high BMI, and non-smoking status.38

Time course

Weight gain with SGA treatment generally occurs during the first 3 months of treatment,40 although medications differ with regards to when they cause the most weight gain. FIGURE 2,41-44 adapted from a recent comprehensive review by Newcomer,45 shows time-distribution trends of metabolic events with several SGAs. Data points were extracted from histograms of pooled data representing 4 different medications and plotted against time. Metabolic events are defined as onset of diabetes mellitus for clozapine and onset of hyperglycemia for olanzapine, risperidone, and quetiapine. Although weight gain time course data were not available for our use, it is interesting to note differences in peak time to metabolic events, which in most cases occurred in the first few months and declined thereafter. However, clozapine showed a bimodal distribution of metabolic events. This is important in determining when a caregiver should expect to see weight gain, in order to determine if treatment for metabolic effects is required.

FIGURE 2: Time distribution of metabolic events with various second-generation antipsychotics
Metabolic events are defined as onset of DM for clozapine and onset of hyperglycemia for olanzapine, risperidone, and quetiapine.
DM: diabetes mellitus.
Source: References 41-44.

Treatments for weight gain

There are many approaches to treating antipsychotic-induced weight gain, including behavioral therapy, pharmacologic additions or switches, and bariatric surgery. Most studies are relatively brief and few long-term studies have been conducted.

Behavioral treatments. Behavioral modification is the cornerstone of weight loss treatment, but has not been well studied for SGA-induced weight gain. A few inpatient studies outlined specific strategies that are effective, such as increased exercise and proper diet, although it is assumed that inpatient programs show benefit because of tight dietary control.46 However, these behavioral strategies may not translate to sustained weight loss after hospital discharge. A number of outpatient studies have found modest to no benefit when using combined nutritional and behavioral counseling.47-50FIGURE 348,49,51-58 shows the mean weight change associated with behavioral treatments. On average, behavioral treatments led to modest weight loss compared with controls, ranging from 0.5 to 4.0 kg. Cognitive-behavioral interventions combined with nutrition and exercise counseling appeared to be most effective.

FIGURE 3: Weight change with behavioral interventions
Error bars represent 95% CI from the mean.
CBI: cognitive-behavioral intervention; CI: confidence interval.
Source: References 48,49,51-58.

Nutrition and exercise counseling. A 12-week study looked at managing olanzapine-associated weight gain in 48 patients with schizophrenia.48 Intervention included diet, nutrition education, exercise education, exercise diaries, discussion of progress, and weight and circumference measurements weekly for the first 4 weeks and then monthly. Control patients were asked to diet and exercise and visited the clinic monthly. Thirty-six patients completed the study. Although there was some weight loss in the intervention group compared with controls (4.1 kg vs 1.4 kg, respectively), there were no changes in quality-of-life measures and no follow-up to assess long-term benefits.48

Although exercise is considered a mainstay of weight loss therapy in psychiatrically well patients, 1 small trial of 17 outpatients who were receiving SGAs concluded that because of generally poor adherence to exercise regimens among patients with schizophrenia or schizoaffective disorder, a weight loss plan should emphasize dietary education and caloric restriction.59 This study suggests that consistent and ongoing intervention with proper nutrition counseling, diet plans, regular exercise sessions, and behavioral counseling are needed to achieve significant weight loss in patients taking SGAs.

Some arguments challenge the purported efficacy of behavioral and diet modification, the first of which is study design. It is likely that in outpatient studies, there is a selection bias of patients who regularly attend their appointments and adhere to physician instructions. Non-adherent patients, who require the most treatment, often can be neglected. Second, with inpatient interventions, the amotivational component of schizophrenia often intercedes after discharge and much of the learned behavior is extinguished. There are isolated reports of modest weight loss in an inpatient setting. In a 6-month study (N = 53) comparing patients on a regular diet vs a low-calorie diet combined with exercise, patients in the intervention group lost 4.1 kg whereas the treatment-as-usual group gained 0.9 kg.58 With outpatient studies, weight loss is observed at the study measurement points of 8, 12, and 16 weeks, but many patients regain the weight at follow-up. Only a few studies have documented long-term weight maintenance with behavioral approaches.49,59 One study reported maintenance of weight loss 3 months after the active study,49 while another recent trial documented 48 weeks of weight maintenance after the study ended.59 However, these results appear to be atypical and the follow-up suffers from the inherent bias of selecting patients well enough to keep appointments 3 months after treatment. It also appears that repeated reinforcement in follow-up appointments may have a positive outcome on weight loss.

Nutritional counseling. A small study of olanzapine-related weight gain in patients with schizophrenia or schizoaffective disorder evaluated the effectiveness of a 10-week Weight Watchers program. Patients in the Weight Watchers group were selected based on having taken olanzapine for at least 6 months at dosage of 15 to 40 mg/d, and having gained at least 7% of their pretreatment weight (n = 11). A comparison group (n = 11) was selected based on matched criteria. Patients in the Weight Watchers group participated in weekly Weight Watchers meetings and supervised exercise sessions 3 times a week for 10 weeks. The Weight Watchers meetings taught patients to use a points system to assess food choices. Patients in the comparison group did not participate in the Weight Watchers program but continued olanzapine treatment. Patient’s weight, BMI, and psychiatric symptoms were assessed. Individuals in the Weight Watchers group showed an average weight loss of 2.3 kg (baseline weight 107.7 ± 26.3 kg; endpoint body weight 105.8 ± 25.9 kg). Patients in the control group showed no weight change (baseline weight 87.6 ± 24.3 kg; endpoint body weight 87.5 ± 24.0 kg).47 This study was not statistically significant, although it was not powered to find such a small difference.

Group nutrition and exercise counseling. One study looked at weight changes with behavioral interventions in diabetic patients age ≥40 who were clinically stable on SGAs (N = 57).55 The control group received usual care plus information and the treatment group was enrolled in a weekly 90-minute program designed to teach patients with diabetes proper nutrition and exercise. At the end of 24 weeks, the patients’ weight and metabolic parameters were measured. The treatment group lost a mean of 2.3 kg and the control group gained a mean of 2.7 kg.

In a 6-month study (N = 70), patients with schizophrenia or schizoaffective disorder were switched from FGAs to olanzapine. They were randomized to either usual care or a 16-week educational intervention in the form of weekly group didactic sessions emphasizing the importance of proper nutrition and exercise.54 Patients in the control group gained 4.5 kg, and patients in the intervention group maintained baseline weight. This suggests that behavioral treatments at the onset of olanzapine treatment may prevent weight gain.

Cognitive-behavioral intervention. An outpatient study of psychotic patients (75% schizophrenia) employed 3 months of behavioral treatment and follow-up measurements after 6 months.49 This study was designed to address cognition about eating, which was aimed at altering intake. A total of 61 patients taking SGAs were randomized to weekly behavioral therapy or a 1-time, 2-hour informational session. Most patients were taking olanzapine or clozapine. Mean age was 41, and nearly one-half of the patients were men. Behavioral therapy was designed for “severe psychiatric patients” and was geared to allow patients to control their eating behavior. Patients were taught to observe their eating behaviors, instructed about restructuring maladaptive beliefs regarding weight and eating, and shown how to reduce food intake through attention to the taste of food and satiety attainment. Physical activity was encouraged, but there was no exercise program. Moderate food intake was the principle aim of the therapy. Patients in the intervention group met for 2 hours per week, whereas controls met only once. In this study, the mean weight/BMI of the intervention group was higher than in the control group (90.9 kg/32 vs 84.1 kg/29). Over the 3 months of the study and 3 months after the intervention concluded, intervention patients lost approximately 4.1 kg, and control patients gained 2.1 kg. This study suggests that regular attention to eating behaviors may lead to modest weight loss.

Cognitive-behavioral intervention + nutritional counseling. In a 14-week multicenter trial (N = 72) evaluating behavioral treatment for olanzapine-associated weight gain, the authors found no significant change in weight (–1.9 kg vs –1.1 kg) between patients who underwent behavioral therapy and patients who received usual clinical care.52 The authors used a manual-driven standardized behavioral treatment program that included techniques such as simulated exercise training sessions, food diaries, and cognitive techniques to reinforce abstinence from snacks.

In the longest behavioral study of patients with schizophrenia treated with SGAs included in this review, day treatment behavioral therapy (n = 31) was compared with usual care (n = 20).50 Over the course of a year, study patients attended intensive twice-weekly weight control group meetings, and a 15-minute weekly individual session for 12 weeks, followed by maintenance weekly groups and a monthly 15-minute session for 9 months. Over the course of the year, study patients’ BMI dropped from 34 to 32, and control patients’ BMI rose from 32 to 34. In overall weight, patients in the study group lost a mean of 3.2 kg and the usual care group gained 3.2 kg. Although this finding is encouraging for behavioral therapy, the weight loss was modest, and the expense was prohibitive.

More expensive than other behavioral treatments and therefore unlikely to be widely used, cognitive-behavioral therapy (CBT) has been shown to be an effective adjunct to traditional weight loss methods for quantitatively improving weight loss compared with nutritional and behavioral counseling alone.49,60 CBT methods adapted for patients with SGA-induced weight gain consist of weekly 2-hour group sessions led by trained clinical psychologists, with the goal of restructuring maladapted cognitions related to weight and eating behavior.49 One uncontrolled study of 6 outpatients with schizophrenia participating in biweekly therapy sessions over 10 weeks showed a 4.5 kg weight loss from baseline with CBT.

Switching antipsychotic agents. One consistently suggested approach to treating antipsychotic-induced weight gain is switching the antipsychotic. Ziprasidone and aripiprazole often are cited as options for patients who have gained weight on other SGAs. Unfortunately, there are few studies evaluating if the switch works, and there is almost no information about the long-term weight loss benefits of switching. Most studies suggest that switching from olanzapine to another SGA may lead to weight loss.

One study consisted of three, 6-week, open-label studies evaluating switches from olanzapine (n = 104), risperidone (n = 58), or conventional antipsychotics (n = 108) to ziprasidone in outpatients with schizophrenia or schizoaffective disorder.61 The studies were designed to detect health benefits for patients switched to ziprasidone. The study also evaluated gradual switching compared with 2 different cross-over titration methods of switching drugs. The target ziprasidone dose was 60 to 160 mg/d, with a mean dose of 90 mg/d. No behavioral or nutritional counseling was provided. Patients were young (mean age 37) and baseline weight was approximately 91 kg before the crossover. Among the 3 groups, 72% of patients switched from olanzapine, 79% of patients switched from risperidone, and 79% of patients switched from conventional antipsychotics and completed the crossover, with <5% dropping out because of loss of clinical benefit. Patients tolerated the switch well. After the 6-week study, patients showed modest weight loss, with those previously treated with olanzapine losing approximately 1.8 kg and those treated with risperidone losing 0.9 kg. Patients in the conventional antipsychotic group gained approximately 0.25 kg. There also was a significant drop in triglyceride concentration in those switched from olanzapine to ziprasidone (–50 mg/dL). This brief study, although promising, resulted in relatively minor weight loss, and yielded no information regarding whether this weight loss would continue, plateau, or reverse with long-term ziprasidone treatment.

The largest study evaluating switching to aripiprazole looked at 311 outpatients with schizophrenia who were switched from antipsychotic monotherapy (96% were on olanzapine or risperidone) to aripiprazole in an 8-week, open-label study.62 The study aimed to determine if different titration crossover schedules affected clinical stability. Behavior therapy related to weight loss or exercise was not included in the study. Mean age was 40, and mean weight was approximately 90 kg. Seventy percent of the patients were men. Over the course of the study, patients showed mean improvement in their clinical status as measured by the Positive and Negative Syndrome scale (PANSS), and lost 1.6 kg, with approximately 10% losing >7% of body weight. There was no follow-up to evaluate if the weight loss persisted or changed over time. This study suggests that patients switched to aripiprazole may experience some short-term weight loss, but it remains unknown if longer treatment would lead to greater health benefit.

The Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study was the largest naturalistic study of weight change with various antipsychotics.63 This study compared treatment of several SGAs with perphenazine over a maximum of 18 months. This study of 1,432 patients with chronic schizophrenia found that those who were switched from their pre-study antipsychotic gained weight with olanzapine (+0.9 kg/month), quetiapine (+0.23 kg/month), and risperidone (+0.23 kg/month), but they lost weight when switched to ziprasidone (–0.14 kg/month), or perphenazine (–0.1 kg/month),63 therefore supporting the belief that switching to ziprasidone may be helpful for weight loss, even if the magnitude of change was small. Aripiprazole was not included in the study, therefore no conclusions can be made about whether similar modest benefits would be gained by switching to aripiprazole. Weight loss would have to be balanced by continued control of psychotic symptoms.

A 20-week, post-hoc study of weight change in patients with schizophrenia who were switched from olanzapine to risperidone found modest benefit.64 The study was completed in 2 phases—an initial 6-week switch phase and a 14-week continuation phase. Patients entering both phases of the study (n = 71) had a mean BMI of 35 at baseline. Patients had a mean age of 40, and slightly more than half were female. After the switch, patients were randomized to usual care or weekly behavior therapy for weight loss. At the end of the study, patients switched from olanzapine to risperidone had lost approximately 1.4 kg, but the addition of behavior therapy had a nonsignificant benefit compared with switching alone. Similarly, the rate of patients meeting criteria for metabolic syndrome dropped from 53% to 38% over the course of the study. The drug switch was not associated with worsening psychosis. Lastly, a small study (N = 16, of which 8 had schizophrenia) found minor weight loss over 4 weeks when patients were switched from olanzapine to quetiapine. During the 10-week study, patients switched to quetiapine lost an average of approximately 2.3 kg, from their pre-switch weight of 102 kg.65

There is little information regarding switching patients from SGAs to FGAs. It appears that switches from olanzapine to other SGAs, particularly aripiprazole or ziprasidone, may be of benefit. However, in short-term studies the gains are modest, and these benefits must be weighed against clinical stability. There is some meta-analysis evidence that aripiprazole may be less effective than olanzapine in treating schizophrenia.66 However, if adequate treatment response can be obtained with the switched drug, then the improved side-effect profile justifies its use.

Pharmacologic treatments

A number of drugs have been studied to promote weight loss in patients with schizophrenia treated with SGAs. The psychopharmacology of weight loss with some of these medications is poorly understood. Moreover, there is little evidence that pharmacologic treatment is superior to behavioral treatment. It is unclear how effective pharmacologic treatments will be without behavior changes. There has been little research on combining behavioral and pharmacologic treatment. FIGURE 45,67-82 shows mean weight change with pharmacologic adjuncts. Of the medications studied, only sibutramine and topiramate showed appreciable weight loss compared with placebo. Weight loss was modest with these 2 medications, approximately 2 to 3 kg in short-term studies.

FIGURE 4: Weight change with pharmacologic intervention
Based on well-controlled schizophrenia patients maintained with olanzapine, clozapine, quetiapine, or risperidone. Error bars represent 95% CI from the mean.
CI: confidence interval.
Source: References 5,67-82.

Metformin and other insulin sensitizers. Metformin is an insulin sensitizer with well-documented anorectic side effects. The drug works by increasing peripheral insulin sensitivity. It has been studied for its efficacy in preventing and reversing weight gain in patients taking SGAs.5,77,82,83 Metformin has a good safety profile, and starting metformin before hyperglycemia onset does not place patients at risk for hypoglycemia unless the drug is administered with another insulin sensitizer.84 Metformin can prevent the onset of diabetes in patients with metabolic syndrome.85 A recent randomized controlled trial of first-episode psychosis in Chinese patients with schizophrenia evaluated metformin combined with lifestyle modification in patients taking SGAs.83 Patients were randomly divided into 4 groups, each consisting of 32 patients, in a 2 × 2 factorial design: metformin alone (750 mg/d), placebo alone, lifestyle intervention plus metformin (750 mg/d), or lifestyle intervention plus placebo. Metformin was titrated to 250 mg, 3 times a day over 8 days. Lifestyle interventions consisted of psychoeducational, dietary, and exercise programs. The study measured outcomes over 12 weeks. Patients were maintained on their prescribed antipsychotics and the only allowed additional medications were trihexyphenidyl for extrapyramidal symptoms or lorazepam for insomnia or agitation. Lifestyle intervention and metformin alone and in combination were effective for weight loss and increasing insulin sensitivity, with average weight loss of 1.4 kg, 2.7 kg, and 5 kg, respectively (starting weight was similar in all patient groups, at 64.5 kg). Lifestyle intervention plus metformin had the greatest effect on weight loss, and metformin alone was more effective than lifestyle intervention alone in increasing insulin sensitivity and reversing weight gain in patients with schizophrenia. Despite metformin’s long history and demonstrated tolerability,86 many clinicians are reluctant to prescribe this drug to patients who do not yet have diabetes.

Other combination therapies with metformin have been evaluated, but none have demonstrated efficacy better than metformin alone. For example, sibutramine, a centrally acting serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines, was coadministered with metformin in a randomized controlled trial, but showed no added benefit.70

Rosiglitazone, a member of the thiazolidinedione class of insulin sensitizers, also has been studied for efficacy in preventing weight gain.71 In a 12-week, double- blind, placebo-controlled study of 30 patients with schizophrenia receiving olanzapine monotherapy (mean dose 10.5 mg/d), patients were divided into 2 groups: rosiglitazone treatment (n = 15) and placebo (n = 15). Rosiglitazone was started at 4 mg/d and titrated to 8 mg/d by week 4. After 8 months of olanzapine monotherapy, patients gained an average of 4.1 kg. This study aimed to assess rosiglitazone-induced prevention or reversion of weight gain secondary to olanzapine therapy. Outcome measures were body weight, BMI, and waist circumference. At the end of the study, rosiglitazone did not prevent or reverse weight gain. In fact, on average, patients in the rosiglitazone group gained more weight (3.2 kg) than those in the placebo group (2.3 kg).71 In this study, rosiglitazone was well tolerated at its maximum dose; however, other studies found rosiglitazone was associated with edema, making it an unlikely candidate to induce therapeutic weight loss.87

Appetite suppressants. Sibutramine has been evaluated in 3 small studies of weight gain associated with olanzapine or clozapine. Results have been mixed. As mentioned previously,70 sibutramine coadministered with metformin (N = 28) did not result in weight loss in olanzapine-treated patients diagnosed with schizophrenia. Similarly, sibutramine did not lead to weight loss in clozapine-treated patients (N = 21).76 In contrast, sibutramine was effective for olanzapine-associated weight gain in 1 study (N = 37).75 In this study, patients diagnosed with schizophrenia or schizoaffective disorder taking olanzapine for at least 4 months were randomized to placebo or sibutramine, up to 15 mg/d, for 12 weeks. Patients participated in weekly group sessions that emphasized nutrition and behavioral interventions. The drug was well tolerated, with 84% completion rate and no worsening of psychotic symptoms. Baseline weight was approximately 109 kg in the placebo group and 103 kg in the treatment group. Sibutramine patients lost 3.6 kg while placebo-treated patients lost 0.9 kg. Plasma lipid and glucose concentrations were not affected significantly, although systolic blood pressure rose in the sibutramine group (magnitude not provided by authors).

Although 1 study was promising, other studies did not show significant benefits with adding sibutramine.88 Further studies with sibutramine and other SGAs are needed to determine if it is clinically useful in preventing or reversing weight gain associated with SGA use.

Antidepressants. Several antidepressants have been known to suppress appetite, including fluoxetine, fluvoxamine, and bupropion. Fluoxetine and fluvoxamine induce appetite suppression by altering serotonin neurotransmission. Although it has been suggested that fluoxetine is not an effective mitigator of SGA-induced weight gain,89 fluvoxamine may promote weight loss and improve serum glucose and triglyceride levels in the absence of SGAs. Based on animal studies, it has been suggested that fluvoxamine could decrease corticotropin-releasing hormone or corticotropin releasing hormone-like peptides, which are known to play a critical role in regulation of food intake and body weight homeostasis.90 Based on the results of this animal study, 1 open-label study evaluated the effectiveness of fluvoxamine in preventing clozapine-associated weight gain91 at the start of treatment. The 12-week, open-label study included 68 Chinese inpatients diagnosed with schizophrenia who were evaluated for the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities. Patients were randomly assigned to 2 treatment groups: the monotherapy group (n = 34) received clozapine ≤600 mg/d and the coadministration group (n = 34) received fluvoxamine 50 mg/d plus clozapine ≤250 mg/d (fluvoxamine inhibits clozapine metabolism and dosage of clozapine coadministered with fluvoxamine was adjusted). Study measures included BMI and serum glucose and cholesterol levels. Patients in the coadministration group had baseline weight of 67.7 kg and weighed 68.6 kg at the end of the 12-week study, and patients in the clozapine monotherapy group had baseline weight of 65.5 kg and weighed 68.6 kg at the end of the study. Patients in the monotherapy group had statistically significant increases in weight, BMI, and serum glucose and triglyceride levels compared with the fluvoxamine plus clozapine group. Although the study was brief, the findings suggest that adding fluvoxamine to clozapine at the start of treatment may prevent clozapine-associated weight gain. Further study is warranted.

Bupropion may reduce appetite and contribute to weight loss in obese individuals, although it has not been well studied for SGA-associated weight gain.92 No double- blind studies have been conducted using bupropion to treat SGA-associated weight gain, although a small open-label study suggests bupropion may reduce olanzapine-associated weight gain.93 In this trial, 8 patients (2 diagnosed with schizophrenia) who had gained a mean of 13.2 kg after olanzapine treatment were treated for 24 weeks with add-on bupropion, up to 300 mg/d. Brief nutritional counseling that emphasized portion control was provided 4 times during the study period. Over 6 months, patients lost an average of 3.4 kg, having started at a mean weight of 100 kg. Two of the patients did not lose any weight.

Orlistat. Orlistat inhibits pancreatic lipase and decreases gastrointestinal (GI) fat uptake. It is highly effective for treating obesity, but side effects of steatorrhea and fecal incontinence make it intolerable for many patients. Anecdotal evidence exists for its use to curtail obesity related to psychopharmaceuticals.94,95 A 16-week, randomized, double-blind, placebo-controlled control trial with 71 patients evaluated the effect of adjunctive orlistat therapy in patients with olanzapine- or clozapine-induced weight gain.96 Patients were randomly divided into 2 groups: orlistat group (n = 35) and placebo group (n = 36). Patients in the orlistat group received orlistat, 120 mg coadministered with their usual dose of olanzapine or clozapine. Efficacy measures included body weight change, serum cholesterol, and glucose levels. Patients in the orlistat group lost an average of 1.4 kg (average baseline weight 102.3 kg) compared with 0.5 kg average weight gain observed in the placebo group (average baseline weight 98.6 kg). Interestingly, sex-specific differences were observed from the collected data and suggest that adjunctive orlistat with olanzapine or clozapine resulted in weight loss in men (average weight loss 2.3 kg; baseline weight 105.5 kg), but was no better than placebo in women (weight gain was 1.8 kg in the orlistat group and 0.23 kg in the placebo group; baseline weight was 92.3 kg).96

Although there is some evidence of weight loss with orlistat coadministration in severely mentally ill patients on SGAs, the high incidence of GI side effects such as fecal incontinence could contribute to the high attrition rate. Studies in healthy patients have shown a high attrition rate with the use of orlistat ranging from 33% to 77%.97,98

Amantadine. Amantadine is a dopamine agonist theorized to decrease appetite by decreasing prolactin release. A 12-week study (N = 21) evaluated adding amantadine, up to 300 mg/d, or placebo to patients (86% with schizophrenia or schizoaffective disorder) with olanzapine-associated weight gain.74

In addition to amantadine treatment, patients attended at least 3 “lifestyle education sessions” and were given gym membership. At the start of adjunctive treatment, patients had a mean BMI of 32 kg/m2. Patients tolerated the medication and there was no worsening on PANSS scores, although 1 patient dropped out because of worsening psychosis. After the 12 weeks, patients on amantadine did not lose appreciable weight, but the placebo-treated patients gained nearly 4.1 kg. This was a small study, but it suggests the possibility that amantadine may ameliorate weight gain if started with SGA treatment.

Histamine-2 receptor antagonists. Histamine (H)-2 receptor antagonists have been known to cause weight loss in healthy patients and several theories have been proposed to explain this phenomenon. One theory involves the role of H1 receptors. Animal studies have shown that histamine treatment results in decreased adiposity, presumably through appetite suppression.99 One theory for SGA-induced weight gain is that competitive inhibition of H1 receptors may lead to a decreased ability to suppress appetite, or may directly increase appetite, resulting in weight gain.100 Although all SGAs antagonize H1 receptors, olanzapine and clozapine show the greatest affinity for H1 receptors.101 H2 blockers suppress appetite by cross-reacting in a stimulatory fashion with H1 receptors, which has prompted researchers to study drugs in this class for potential weight loss effects.102 Nizatidine, famotidine, and cimetidine all have been studied.72,103 Clinical trials demonstrating that H2 blockers effectively suppress appetite and reduce weight are lacking.

A 16-week, double-blind, placebo-controlled study evaluated for the efficacy of 2 fixed doses of nizatidine, 300 mg/d (n = 35) and 600 mg/d (n = 33), compared with placebo (n = 37) for controlling olanzapine-induced weight gain in 105 patients with schizophrenia or related illness. Patients selected for this study had not been treated with antipsychotics for at least 3 months and were started on olanzapine at the beginning of the study (mean dose 11.2 mg in the placebo group, 11.8 mg in the 300 mg/d treatment group, and 12.6 mg in the 600 mg/d treatment group). Patients gained an average of 4.1 kg in the placebo group, 3.6 kg in the 300 mg/d treatment group, and 3.2 kg in the 600 mg/d treatment group at the end of the study. Patients receiving 600 mg of nizatidine showed limited weight gain for a short period of time during the study; however, this transient effect disappeared, and both groups receiving nizatidine did not differ from the placebo group for weight gain at the end of 16 weeks.72 Similar negative results for famotidine and cimetidine have been shown and these H2 antagonists do not seem to be effective in preventing weight gain secondary to antipsychotic therapy.103,104

Another theory proposes that H2 receptor stimulation by olanzapine results in increased gastric acid secretion. Patients may develop an increased appetite or increase food consumption in an effort to counter gastritis secondary to the increased gastric acid secretion. Therefore, the use of H2 antagonists, aside from those already studied, may be effective in reducing gastric acid secretion and, indirectly, may suppress appetite and decrease food consumption.101 Although this theory is reasonable, studies to support the theory are lacking.

Anticonvulsants. In clinical trials, topiramate and lamotrigine have been shown to have appetite-reducing effects and lead to decreases in BMI in mentally well obese patients.105,106 The mechanism involved in anticonvulsant-induced weight loss is not understood, although it is theorized that inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) glutamate receptors and potentiation of gamma-aminobutyric acid (GABA) receptors may explain weight loss associated with topiramate use.79 To date, evidence for lamotrigine-associated weight loss is anecdotal, but there has been 1 randomized, placebo-controlled study evaluating weight loss in patients with schizophrenia treated with antipsychotics and topiramate.78 Overweight inpatients treated for schizophrenia with SGAs (N = 66) began a 12-week, randomized, placebo-controlled prospective study. Fifty-three patients completed the study, and approximately one-half were men. Patients were randomized to 3 groups: placebo (n = 20), topiramate, 100 mg/d (n = 16), and topiramate, 200 mg/d (n = 17). Baseline antipsychotic drug doses were reported as risperidone equivalent doses. The mean risperidone doses was approximately 5.5 mg/d and similar among groups. Topiramate was started at 50 mg/d in the treatment groups and slowly titrated to reach target doses. Efficacy assessment measures were based on body weight, BMI, waist measurement, hip measurement, and waist-to-hip ratio. At the end of the study, the 200 mg/d topiramate treatment group showed significantly greater weight loss compared with the other groups. Mean weight loss was: topiramate 200 mg/d, –6.8% (–5.5 kgs); topiramate 100 mg/d, –2.2% (–1.8 kg); and placebo, –0.4% (–0.23 kg), with an average starting weight of 75 kg among the 3 groups.78 Although topiramate can be administered safely at higher doses in most individuals, safety data in patients with schizophrenia are lacking. Further, it is unclear if long-term weight loss was attained beyond the 12-week study and if topiramate had any long-term negative effects on patients’ health.

One study evaluated starting adjunctive topiramate at the beginning of olanzapine treatment.107 In this 12-week study, 60 men with schizophrenia were randomized to adjunctive topiramate or placebo at the start of olanzapine treatment. Olanzapine dose was <20 mg/d. There was no behavioral therapy, diet education, or changes in diet. Topiramate dose started at 25 mg twice daily and increased to 50 mg twice daily after 1 week. The combination was well tolerated; only 12% of patients dropped out. Baseline weight was not listed in the study, but both patient groups gained weight. The adjunctive topiramate-treated patients gained less weight on average than the placebo-treated patients (2.3 kg vs 4.1 kg). This suggests that topiramate may ameliorate, but not prevent, weight gain.

A study from Iran randomized 32 clozapine-treated patients diagnosed with chronic schizophrenia to adjunctive topiramate or placebo for 56 days.108 The study was designed to determine if adding topiramate would improve signs and symptoms of schizophrenia. No nutritional education or weight loss intervention was included in the study design. Average age was 38 and patients had a BMI of approximately 25 kg/m2 at baseline. Although patients taking topiramate improved clinically compared with those taking placebo, there was no weight loss associated with topiramate treatment. Patients were gradually titrated from 50 mg/d up to a maximum of 300 mg/d. PANSS was used to assess change in clinical status over the course of the study. 

Based on the results of these studies, there is preliminary evidence that ≥200 mg of topiramate may contribute to weight loss in patients with schizophrenia who have been treated with SGAs other than clozapine. It is not, however, an effective adjuvant therapy for patients starting an SGA. Further studies including long-term follow-up are needed to determine whether topiramate is an effective weight loss agent in schizophrenia.

Surgical approaches

Gastric bypass has been used to treat morbidly obese patients for many years, with positive results in many patients. There are no systematic studies of gastric bypass or gastric banding in patients with schizophrenia. One group reported the outcome of gastric bypass surgery in 5 stable outpatients with schizophrenia taking SGAs, whose median BMI was 54.109 All patients did not respond to other weight loss measures before surgery. It is unclear if these patients had antipsychotic-induced weight gain, because 1 had a history of morbid obesity that began in childhood and the other 4 patients had a history of obesity that began in early adulthood. Patient outcome measures included perioperative exacerbation of psychoses, perioperative complications, duration of hospital stay, postoperative weight loss in terms of percent excess weight loss (EWL), and postoperative psychiatric status. Percent EWL is a measure used to assess efficacy of bariatric surgery. The total amount of excess weight is based on each individual’s ideal body weight and the EWL is the percent of excess weight lost as a result of bariatric surgery. Over a 6-month period, EWL in this study was 39.5% (range 29.4% to 62.9%) in the patients with schizophrenia compared with 46.9% (range 30% to 95.5%) in 165 nonpsychotic patients who served as controls. None of the patients required psychiatric hospitalization during the follow-up period. Although the study does not discuss which characteristics would predict favorable outcome in patients with schizophrenia, it does suggest that bariatric surgery may be an option for morbidly obese psychiatric patients who are taking an antipsychotic, based on preliminary evidence. Further study is required to evaluate these results, but surgical approaches may be a reasonable therapeutic approach in selected patients with weight gain refractory to pharmacologic or behavioral intervention.

  CONCLUSIONS

Although widely used to treat schizophrenia, SGAs are encumbered by their metabolic side effects. Weight gain and metabolic dysfunction perhaps are not as immediate a risk as sequelae from psychosis, but they still lower quality and length of life and contribute to discontinuation of therapy. For these reasons, treatment for metabolic conditions is important for patients with schizophrenia who take SGAs. There are few weight loss treatment studies, which generally have a small sample size.

Behavioral therapies to treat weight gain associated with SGAs have had the most consistent beneficial results. Although behavioral treatments may be effective in a controlled environment, they tend to be more modest when treatment migrates to outpatient follow-up. It remains to be seen how or if booster sessions can extend the benefits for longer periods in patients with schizophrenia. Because of relative safety and ease of practice, behavioral modifications may be first-line therapies for SGA-induced metabolic dysfunction.

We have included a summary of weight loss interventions reviewed in this paper (FIGURE 5).

FIGURE 5: Estimates of overall weight change by type of intervention
SGA: second-generation antipsychotic; Tx: treatment.

Although pharmacologic intervention may benefit SGA-induced weight gain and metabolic dysfunction, controlled clinical trials show modest benefit, with only 2 add-on strategies showing preliminary benefits in short-term studies. Metformin and topiramate were associated with weight loss, whereas other options showed little benefit. Topiramate dosing needs to be at least 200 mg, and may not be helpful for clozapine-associated weight gain; in addition, the psychoactive side effects of topiramate make it a difficult drug for many patients to tolerate. Metformin coadministered with SGAs may be an appropriate treatment for weight loss or prevention of weight gain, although hepatic and renal toxicity need be considered. Additional studies for long-term weight loss, tolerability of the drugs, as well as therapeutic outcomes in the treatment of schizophrenia are needed.

Although switching SGAs is commonly practiced to treat SGA-induced weight gain, short-term randomized clinical trials showed modest weight loss with this method, and there is a lack of long-term evidence to substantiate this method.

Despite moderate weight loss observed with behavioral and pharmacologic interventions, bariatric surgery seems a reasonable, if not well-studied option, for morbidly obese psychiatric patients taking SGAs. Given the risks of surgery and post-operative complications, bariatric surgery may be a reasonable final therapeutic approach to patients refractory to pharmacologic and/or behavioral interventions for weight loss. Further study is required to assess long-term outcomes in psychiatric patients who undergo bariatric surgery before it can be used definitively as a treatment for SGA-induced weight gain.

DISCLOSURE: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: Lawrence A. Labbate, MD, Central Arkansas Veterans Healthcare, System, Mental Health Service, 2200 Fort Roots Drive, North Little Rock, AR 72114 USA E-MAIL: llabbate@uams.edu