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”Â 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.Â
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.
FIGURE 5: Estimates of overall weight change by type of intervention
FIGURE 5: Estimates of overall weight change by type of intervention
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: firstname.lastname@example.org
Annals of Clinical Psychiatry ©2012 Quadrant HealthCom Inc.