Efficacy of Metformin and Topiramate in Prevention

Psychiatry

Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-Generation Antipsychotic–Induced Weight Gain Lara K Ellinger, Heather J Ipema, and Joan M Stachnik

ntipsychotics are used in the treatment of schizophrenia and other psychiatric disorders, including schizoaffective disorder, bipolar disorder, and depression.1 These disorders create a large social burden for families, health-care resources, and society.2 Although antipsychotics are the mainstay of pharmacologic treatment for schizophrenia and are commonly used in other disorders, their adverse effect profiles can create challenges for use of these agents. Antipsychotics are generally classified as first-generation antipsychotics (FGAs, typical agents) or second-generation antipsychotics (SGAs, atypical).1 FGAs exert pharmacologic activity by blocking central dopamine receptors.2,3 Use of FGAs is limited mainly by adverse effects, including tardive dyskinesia (TD), extrapyramidal symptoms (EPS), and moderate risk of weight gain.3 SGAs include aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and 2 agents that have recently been approved, iloperidone and asenapine. Clozapine is also an SGA; however, it has increased serious adverse effects, such as agranulocytosis, compared to the other agents and is usually reserved for treatment-resistant patients.3

A

OBJECTIVE:

To review the literature describing the efficacy of metformin and topiramate for the treatment of second-generation antipsychotic–induced weight gain.

DATA SOURCES: Articles were identified by searching the MEDLINE database (from 1949 through January 2010) using the key words metformin, topiramate, antipsychotic, weight, weight gain, and obesity. STUDY SELECTION AND DATA EXTRACTION: All randomized, placebo-controlled trials of metformin and topiramate were selected for review. DATA SYNTHESIS:

Weight gain due to second-generation antipsychotic use is a concern due to the risk of long-term metabolic and cardiovascular effects with these agents. These effects include obesity, hyperglycemia, and insulin resistance, all of which may contribute to diabetes and cardiovascular disease. Secondgeneration antipsychotics vary in the degree to which they cause weight gain, and dietary and lifestyle changes may not be feasible or sufficient in counteracting this weight gain. Although other pharmacologic agents may be beneficial to prevent and treat antipsychotic-induced weight gain, metformin and topiramate have been the most extensively studied in this setting. Metformin acts peripherally to cause weight loss, while topiramate acts centrally. Review of 11 randomized, controlled trials demonstrates beneficial effects of metformin and topiramate in prevention and treatment of weight gain. Metformin is generally well tolerated and has been studied in pediatric patients, while topiramate is associated with more drug interactions and may possibly interfere with control of schizophrenia.

CONCLUSIONS: Data for the use of metformin and topiramate in the treatment and prevention of second-generation antipsychotic–induced weight gain are limited. Both may be effective in helping patients lose weight via mechanisms that have yet to be clearly defined. The use of metformin results in greater weight loss than topiramate, and topiramate is associated with more risks and may compromise the treatment of schizophrenia. Treatment of antipsychotic-induced weight gain with metformin may be an option after lifestyle and dietary changes have failed. KEY WORDS: atypical antipsychotic, metformin, obesity, schizophrenia, topiramate,

weight gain.

Ann Pharmacother 2010;44:668-79. Published Online, 16 Mar 2010, theannals.com, DOI 10.1345/aph.1M550

Author information provided at end of text.

668

n

The Annals of Pharmacotherapy

n

2010 April, Volume 44

Downloaded from aop.sagepub.com by guest on October 11, 2013

theannals.com

SGAs act by blocking a serotonin receptor subtype (5HT2A) along with dopamine receptors.2,3 While SGAs are less likely to cause TD and EPS than are FGAs, they are not without adverse effects; SGAs may cause hyperlipidemia, hyperglycemia, cardiac arrhythmias, sedation, hypotension, and anticholinergic adverse effects.3 Weight gain is commonly reported and warrants significant concern. Among the SGAs, the propensity of each drug to cause these adverse effects is variable. Because minimal difference in efficacy has been reported between these agents, the choice of SGA is guided by the patient’s comorbid disease states, medication history, and drug tolerability.3 Antipsychotics and Weight Gain

and colleagues estimated a mean change in weight of 5.56 kg after 10 weeks of therapy with clozapine and 4.17 kg after 10 weeks of therapy with olanzapine.4 Findings of longer-term studies suggest that weight gain continues with the chronic use of SGAs but may plateau after a certain number of months depending on the agent. It is difficult to determine the extent to which other factors, such as sedentary lifestyle and increased caloric intake, affect SGA-induced weight gain.8 It is recommended that patients who gain 5% or greater of their baseline weight while taking an antipsychotic switch to an agent with less potential for weight gain.8 It is not uncommon for some of the SGAs to induce weight gain of 5% or more. Table 1 summarizes the magnitude of weight gain and receptor affinities for the SGAs; however, these data were compiled from multiple trials, so differences in patient population and study designs may limit the validity of comparison between agents regarding the potential degree of weight gain.6,9-14

The proposed mechanisms by which SGAs cause weight gain are histaminergic, serotonergic, dopaminergic, and possibly cholinergic, although these mechanisms are not completely understood.4 Kroeze and colleagues studied antipsychotic binding affinities for 12 receptors and correImplications of Weight Gain lated the affinities to antipsychotic weight gain data, In patients of all ages, antipsychotic-induced weight demonstrating the histamine1 (H1) receptor to be mainly regain is a concern for several reasons. First, patients with sponsible for short-term weight gain.5 H1 receptors have schizophrenia may already have difficulty with medication been shown to interfere with leptin-mediated appetite supadherence, so undesirable effects such as weight gain may pression, which may lead to weight gain and insulin resisincrease the likelihood of nonadherence, possibly due to tance.5,6 Antagonism of the H1 receptor causes sedation, low self-esteem or poor self-image.2 Medication nonadherwhich may make patients less physically active, and also interferes with satiety signaling from the gut, causing inence is a major factor in schizophrenic symptom relapse, 2 creased appetite. Stimulation of H2 receptors causes gaswith reports that up to 60–70% of patients will relapse in 1 tric acid secretion, which may also result in increased apyear and 90% will relapse in 2 years without antipsychotic petite.7 There is some thought that the serotonin 2C (5-hymaintenance therapy.3 Obese patients in the general popudroxytryptamine, 5-HT2C) receptor may also be involved lation may be 2.5 times more likely to discontinue their in weight gain, although SGA binding affinity to this receptor was not found to be a predictor of weight gain in the Kroeze study.2,5 Despite Table 1. Second-Generation Antipsychotic Profiles: the strong correlation between H1 receptors Weight Gain and Receptor Affinity and weight gain, other mechanisms are likely Patients Who responsible because some antipsychotic agents Experienced Weight-Related that have little or no affinity for H1 receptors Weight Gain Receptor Affinity6,10,12,b Weight >7% from still cause substantial weight gain (such as Gaina SGA Baseline, %9-14 H1 5-HT2C D2 M3 sulpiride, a dopamine antagonist not approved Aripiprazole ++ 19 ++ + ++++ +/– for use in the US).5 Although not directly corAsenapine ++ 14.7 ++ +++ ++ NA related with weight gain, antagonism of the +++ ++ + ++ 54 +++ Clozapine muscarinic M3 receptor has been implicated in Iloperidone ++ 12–18 + NA +++ +/– diabetes and dyslipidemia.6 Antagonism of the Olanzapine +++ 30 +++ +++ ++ ++ dopamine D2 receptor has also been implicated 6–9 ++ ++ ++ NA + Paliperidone in weight gain.6 Quetiapine ++ 16 +++ +/– + +/– The weight gain associated with SGAs Risperidone ++ 14 ++ ++ +++ +/– 7 + ++ +++ +/– + Ziprasidone varies with each agent.4 Olanzapine and clozapine have the greatest affinity for the H1 recepNA = not available; SGA = second-generation antipsychotic. a tor and cause the most weight gain. ZiprasiExtrapolated from weight gain observed in clinical trials to date. Key for weight gain: +++ = high, ++ = moderate, + = low. done and aripiprazole cause the least weight b Key for receptor affinity: ++++ = very high, +++ = high, ++ = moderate, + = minimal, 3,5 gain. In a meta-analysis of effects of antipsy+/– = negligible. chotic medications on body weight, Allison theannals.com


n


n

669

LK Ellinger et al.

medications than nonobese patients, and this may also be true for patients receiving antipsychotic therapy.2 Discontinuation of antipsychotics in patients with schizophrenia is also associated with a higher rate of hospitalization and emergency department visits.2 Obesity is a risk factor for diabetes, and both obesity and diabetes are risk factors for cardiovascular disease, which is a leading cause of death among patients with schizophrenia.1-3,8 Concerns regarding other metabolic effects of antipsychotics have led to the Food and Drug Administration (FDA) requirement that manufacturers include warnings of the risk of hyperglycemia and diabetes in the product labeling along with a recommendation that clinicians regularly monitor patients’ blood glucose levels.3 Guidelines from the American Psychiatric Association state that diet and exercise interventions should be initiated in patients experiencing antipsychotic-induced weight gain and, if this is not effective, patients can switch to an SGA associated with less weight gain.3,7,15 Weight gain associated with antipsychotic use is particularly concerning in children. The use of SGAs is increasing in this population, exposing greater numbers of pediatric patients to the adverse metabolic effects associated with this drug class.16 Starting antipsychotic therapy at an earlier age increases the duration of medication exposure, which may result in earlier onset of these complications. In the largest pediatric study of first-time SGA use and their effects on patient weight and metabolic parameters, a shift to an overweight or obese status was observed with all medications (olanzapine, quetiapine, risperidone, aripiprazole) over a 12-week period.17 The use of olanzapine resulted in the most weight gain, with a mean increase of 8.5 kg (95% CI 7.4 to 9.7). Other clinical trials of SGAs in pediatric patients have resulted in an average weight gain of as much as 7.2 ± 0.1 kg over an 8-week period.18 This rapid increase in weight places children at risk for insulin resistance and subsequent diabetes and cardiovascular disease similar to adults. An insurance database review of 4140 pediatric patients with an average age of 10.4 ± 3.6 years demonstrated that exposure to SGA therapy more than doubled the odds of receiving a diagnosis of obesity, type 2 diabetes, and cardiovascular disorders.19 The increased risk of death attributed to cardiovascular disease in adults with psychiatric disorders may also be present in children.8 Drugs Used for Antipsychotic-Induced Weight Gain In addition to lifestyle and dietary modifications, exercise programs, and switching to alternative SGAs, various pharmacologic agents have been used to counteract antipsychotic-induced weight gain.7,15 Recent advances in understanding the receptors involved in this weight gain process have led to the use of multiple agents with various 670

n


n

mechanisms of action.7 Table 2 summarizes the data supporting the use of these drugs.20-79 Metformin and topiramate are the agents with the most promising preliminary data to suggest their efficacy for attenuation of weight gain in patients taking SGAs. Metformin is indicated for treatment of type 2 diabetes.80 Offlabel uses of metformin include prophylaxis of gestational diabetes, polycystic ovarian syndrome, non-alcoholic steatohepatitis, and antiretroviral-associated lipodystrophy.81 Common adverse effects of metformin include abdominal bloating, diarrhea, and flatulence. Lactic acidosis is a serious but rare adverse effect occurring in approximately 3 per 100,000 metformin-treated patients per year.82 Metformin decreases insulin resistance by reducing hepatic glucose production and intestinal glucose absorption, as well as improving cellular uptake and utilization of glucose. Unlike other antidiabetic agents, metformin has not been shown to cause weight gain, and some data associate metformin with weight loss. The mechanism for this weight loss may involve an increased plasma level of glucagon-like peptide 1 (GLP-1).83 Metformin may inhibit the degradation of this endogenous compound, resulting in appetite suppression. The drug has no effect on plasma leptin levels but does have a beneficial effect on lipid levels.7,83 These metabolic effects of metformin provide a rationale for testing its use for antipsychotic-induced weight gain. Topiramate is indicated for the management of epilepsy and migraine headaches.84 It is also used off-label for psychiatric disorders such as bipolar disorder. Common adverse effects of topiramate include paresthesias, fatigue, dizziness, appetite loss, and difficulty concentrating. A more serious adverse effect of topiramate is metabolic acidosis due to increased renal bicarbonate excretion, but this has been rarely reported. Topiramate acts at voltage-dependent sodium channels, γ-aminobutyric acid (GABA) receptors, high-voltage calcium channels, carbonic anhydrase enzymes, and kainite and α-amino-3-hydroxy-5methylisoxazole- 4-propionic acid (AMPA) glutamate receptor subtypes.85 Case reports and anecdotal clinical experience have noted that some patients experience weight loss with topiramate; it has been hypothesized that this may be due to appetite suppression resulting from both antagonism of AMPA receptors and metabolic acidosis.75,85 The remainder of this article reviews the clinical data supporting the use of metformin and topiramate for prevention and treatment of SGA-induced weight gain. Metformin and Topiramate for SGA-Induced Weight Gain DATA SOURCES AND SELECTION

Articles were identified by searching the MEDLINE database (1949–January 2010) using the key words metformin, topiramate, antipsychotic, weight, weight gain, and


theannals.com

theannals.com


Histamine (H1) agonist and histamine (H3) antagonist

Dopaminergic effects, noradrenergic effects

Histamine (H2) antagonist

SSRI, serotonergic effects

SSRI, serotonergic effects

NMDA antagonist

Decreases insulin resistance, inhibits GLP-1 breakdown, which may cause appetite suppression

CNS stimulant; may promote weight loss

Histamine (H2) antagonist; may correlate with leptin levels

Inhibits dietary fat absorption

Appetite suppression

Histamine (H2) antagonist

SNRI, alpha-2 receptor antagonist

Decreases insulin resistance

Betahistine

Bupropion

Famotidine

Fluoxetine

Fluvoxamine

Memantine

Metformin

Modafinil

Nizatidine

Orlistat

Phenylpropanolamine

Ranitidine

Reboxetine

Rosiglitazone

n


Possible appetite suppression

Significantly less weight gain compared to placebo Lack of weight gain after 2 wk of betahistine Conflicting results No significant effect compared to placebo No significant effect compared to placebo Significantly less weight gain with fluvoxamine Patient experienced weight loss

1 noncontrolled trial (N = 3)26 1 noncontrolled trial (N = 8)27 1 randomized, double-blind, placebo-controlled trial (N = 14)28 1 randomized, double-blind, placebo-controlled trial (N = 31)29 1 placebo-controlled trial (N = 30)30 1 noncontrolled trial (N = 68)31 1 case report (N = 1)32

No significant effect compared to placebo

No significant effect compared to placebo Ranitidine 600 mg daily resulted in weight loss; statistical significance not reported Significantly less weight gain vs placebo No significant effect vs placebo

1 randomized, double-blind, placebo-controlled trial with no dietary restrictions (N = 71)54 1 open-label trial/case series (N = 14)55 2 case reports (N = 2, N = 1)56,57 1 randomized, double-blind, placebo-controlled trial (N = 16)58 1 noncontrolled trial (N = N/A)59 2 randomized, double-blind, placebo-controlled trials (N = 59, N = 26)60,61 1 randomized, double-blind, placebo-controlled trial (N = 30)62

1 randomized, double-blind, placebo-controlled trial powered to assess improvement in psychiatric symptoms (N = 32)66 1 randomized, double-blind, placebo-controlled trial in women (N = 43)67 1 randomized, placebo-controlled trial (N = 53)68 1 noncontrolled follow-up trial (N = 27)69 4 noncontrolled trials (N = 10, N = 60, N = 10, N = 26)70-73 2 retrospective reviews (N = 100, N = 10)74,75 1 case series (N = 3)76 3 case reports (N = 1, N = 1, N = 1)77-79

Significantly more weight loss vs placebo, sustained for up to 18 mo

Significantly more weight loss compared to placebo; no difference vs topiramate

May be effective for up to 8 wk; conflicting results

4 randomized, double-blind, placebo-controlled trials (N = 54, N = 28, N = 35, N = 175)48-51 1 noncontrolled trial (N = 10)52 1 case report (N = 1)53

2 randomized, double-blind, placebo-controlled trials (N = 21, N = 37)63,64 1 randomized, active-controlled, open-label trial (N = 46)65

Significantly more weight loss compared to placebo

1 randomized, double-blind, placebo-controlled trial (N = 50)46 1 case report (N = 1)47

7 randomized, double-blind, placebo-controlled trials in adults (N = 54, N = 32, N = 30, N = 128, N = 80, N = 40, N = 40)33-39 1 randomized, double-blind, placebo-controlled trial in children (N = 38)40 2 open-label, noncontrolled trials in adults (N = 24, N = 5)41,42 2 open-label, noncontrolled trials in children (N = 11, N = 19)43,44 1 case report (N = 1)45

Effects similar to topiramate

1 case report (N = 1)20

Summary

2 randomized, double-blind, placebo-controlled trials (N = 21, N = 125)21,22 3 noncontrolled trials (N = 30, N = 12, N = 9)23-25

Evidence

CNS = central nervous system; GLP-1 = glucagon-like peptide 1; NA = not available; NMDA = N-methyl-D-aspartate receptor; SNRI = selective norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

Topiramate

Serotonergic effects, appetite suppression

NMDA antagonist, dopaminergic effects

Sibutramine

Decreased lipogenesis

Amantadine

Rationale for Use

Acetazolamide

Drug

Table 2. Pharmacologic Agents Used for Management of Antipsychotic-Associated Weight Gain

Metformin and Topiramate for Second-Generation Antipsychotic–Induced Weight Gain

n

671

LK Ellinger et al.

obesity. Randomized, placebo-controlled trials assessing the efficacy of metformin and topiramate in the prevention and treatment of SGA-induced weight gain were selected for inclusion. Most studies included only patients diagnosed with schizophrenia, although some also included patients diagnosed with schizoaffective or bipolar disorders. Table 3 summarizes the 11 trials included in this review (8 with metformin and 3 with topiramate).33-40,66-68 Additional information from open-label studies and case reports is briefly described within the text. METFORMIN

Treatment

Of the 6 randomized, placebo-controlled trials evaluating metformin for treatment of antipsychotic-induced weight gain in adults, 2 found metformin to be significantly more effective than placebo.33,36 Over 12–14 weeks, patients lost approximately 1.9–3.2 kg while taking metformin in doses ranging from 750 to 2550 mg/day in addition to SGA therapy. Patients in the placebo groups of both trials gained between 0.2 and 3.1 kg during the study periods. The trials also found a significant decrease in body mass index (BMI) in patients receiving metformin compared to placebo. Wu and colleagues incorporated lifestyle intervention into their trial design.36 The study demonstrated that an education program focusing on healthy diet, exercise, and weight management may augment weight loss due to metformin. Patients who received metformin and lifestyle intervention lost an average of 4.7 kg, which was significantly more than the average weight loss of 3.2 kg seen with metformin alone (p = 0.02). The average weight gain with placebo was 3.1 kg (p < 0.001 vs metformin and lifestyle intervention). Metformin was well tolerated in both trials, and there was no significant difference in adverse effects between groups in either study.33,36 The study by Wu and colleagues noted EPS and nausea as the most common adverse effects, suggesting that both the SGA agent and metformin were responsible.36 However, limitations exist with both studies that make extrapolation of the data to the US population difficult.33,36 Carrizo and colleagues included patients who had been taking clozapine for approximately 6–9 years.33 Clozapine is used by fewer patients with schizophrenia than other SGAs because it is not recommended for first-line therapy.3 It cannot be assumed that results would be similar in patients receiving first-line SGAs. Also, 7 patients dropped out of the metformin group before the first followup, but none dropped out of the placebo group. The analysis did not include the dropouts, so the results may not accurately reflect what would be seen in clinical practice. Patients in the study by Wu and colleagues received lower SGA doses than those commonly used in the US.36 Al672

n


n

though weight gain is not known to be a dose-related effect, it is possible that patients receiving higher doses may experience more weight gain, limiting the external validity of these study results. A study by Klein and colleagues found that metformin significantly attenuated weight gain in pediatric patients who had gained at least 10% of their baseline body weight during 12 months of treatment with olanzapine, risperidone, or quetiapine.40 This study adjusted for normal weight gain in a pediatric population and demonstrated a significant decrease in body weight, BMI, and waist circumference compared to placebo after 16 weeks of treatment with metformin (p = 0.002, p < 0.001, p = 0.003, respectively). Adverse events did not differ significantly between groups. The 3 studies that did not find metformin to significantly decrease or attenuate weight gain were either underpowered, of short duration, or did not comment on power.34,35,37 These were each 12 weeks in length and the dose of metformin ranged from 1000 to 2550 mg/day. Arman and colleagues included pediatric patients taking risperidone and did not account for normal weight gain associated with growth.34 Patients in both the metformin and placebo groups gained weight. However, it was found that 6 patients in the placebo group gained 7% or greater of their baseline body weight compared to only 1 in the metformin group (p < 0.033). The other 2 trials by Baptista and colleagues were in the inpatient setting.35,37 In both studies, patients receiving metformin lost weight (mean 1.4–2.8 kg), which did not differ significantly from weight loss experienced by the placebo group. Nutrition advice, physical activity programs, and the control of interventions available in an inpatient setting may explain the weight loss observed in the 2 trials. Had these trials been adequately powered or extended beyond 12 weeks, a difference attributed to metformin therapy may have been found. Prevention

Two randomized, placebo-controlled trials have been performed evaluating metformin for prevention of antipsychotic-induced weight gain.38,39 Both studies included inpatient adults taking olanzapine and did not control for diet or exercise. Patients in the metformin and placebo groups of both trials gained weight during the 12- to 14-week studies. Wu and colleagues included patients initiating antipsychotic therapy for a first psychotic episode.38 In this population, metformin was associated with less weight gain than in the placebo group (1.9 vs 6.9 kg, p < 0.02). This study also found BMI increase to be significantly less in the metformin group than in the placebo group (p < 0.01). The authors concluded that metformin can attenuate weight gain in patients initiating olanzapine therapy. Baptista and colleagues, however, did not find that metformin


theannals.com


prevented weight gain or an increase in BMI.39 Patients in this trial had been taking FGAs for 30 or more years prior to switching to olanzapine, and depot formulations of other antipsychotics were allowed, which may have contributed to overall weight gain. Metformin was not associated with worsening of psychiatric symptoms and was well tolerated in both trials, with reports of adverse effects limited to mild gastrointestinal discomfort.38,39 Other Literature

Open-label trials of metformin support its use for treatment of antipsychotic-induced weight gain in adults and children.41,43,44 Patients in these trials were taking olanzapine, risperidone, quetiapine, aripiprazole, and clozapine. Metformin doses varied from 500 to 2550 mg/day. Weight loss from baseline was statistically significant with metformin in 2 of the 3 trials.41,44 However, Baptista and colleagues found that patients receiving therapy with predominantly FGAs lost more weight with placebo than with metformin.42 A case reported by Ozenoglu and colleagues further supports use of metformin; a woman taking clozapine for 15 years experienced a 27-kg weight loss over 18 months after initiation of metformin.45 TOPIRAMATE

Treatment

Three randomized, placebo-controlled trials found topiramate to be effective for weight loss or decreasing BMI in patients taking antipsychotics.66-68 Afshar and colleagues used topiramate as adjunctive therapy in patients receiving clozapine for schizophrenia.66 Doses of both agents varied, and weight changes were not reported. BMI decreased in the topiramate group compared to an increase in the placebo group (p < 0.05), but this decrease was not significant from baseline. The addition of topiramate to clozapine therapy was accompanied by significantly more adverse events, including psychomotor retardation, drooling, and paresthesias (p < 0.05). Nickel and colleagues conducted a 10-week trial in women taking olanzapine and found that topiramate reduced weight by 4.4 kg, while patients taking placebo gained 1.2 kg (p < 0.001).67 Of note, patients were allowed to take concomitant medications that may have affected weight (eg, mirtazapine). The authors found significant correlations between the amount of weight gain before the trial and amount of weight loss with topiramate (R2 = 0.79, p < 0.01). Dizziness, headache, and paresthesias were reported, but it is unclear whether these events were more common in one group or the other. Interestingly, 6 subjects from the placebo group withdrew from the study, while no patients receiving topiramate withdrew, which may suggest that patient satisfaction was higher with topiramate. theannals.com

The third study was conducted by Ko and colleagues and randomized patients taking different SGAs to 3 treatment arms (topiramate 100 mg/day or 200 mg/day, or placebo).68 Weight loss after 12 weeks was greater in the topiramate 200-mg/day group (5.35 kg), compared to weight loss in the topiramate 100-mg/day and placebo groups (1.68 and 0.3 kg, respectively, p = 0.002). Decreases in BMI and waist circumference were also greatest in the topiramate 200-mg/day group. More patients experienced weight loss of at least 5% in the topiramate 200mg/day group than in the other groups. The incidence of paresthesias was significantly higher with topiramate 200 mg/day (nearly 60%), compared to 25% and 10% with topiramate 100 mg/day and placebo, respectively (p < 0.01). Patients taking topiramate experienced notable worsening of schizophrenia when compared to patients taking placebo. These findings warrant consideration when weighing risks and benefits of topiramate use, although this trend was not observed in the other 2 topiramate trials. Other adverse events included psychomotor slowing, fatigue, dizziness, headache, and gastrointestinal disturbances. Other Literature

Additional studies of topiramate support the findings of these randomized, placebo-controlled trials. Patients in the study by Nickel and colleagues were allowed to enroll in an open-label study to assess the safety and efficacy of topiramate over 18 months.67,69 Repeated measures analysis demonstrated a significant interaction between change in weight and all scales of the SF-36 Health Survey (p < 0.01), and topiramate was well tolerated. Two retrospective reviews of topiramate for treatment of drug-induced (mainly antipsychotic-induced) weight gain in Switzerland and Canada also found topiramate to be effective over longer treatment periods (average of 10 mo).74,75 Several open-label, noncontrolled studies suggest that topiramate may attenuate antipsychotic-induced weight gain in a variety of disease states.70-73 Discussion The goal of this review was to critically assess the 2 pharmacologic agents that have been most extensively studied for use in antipsychotic-induced weight gain. The limited data available demonstrate some efficacy for metformin and topiramate in the treatment of antipsychotic-induced weight gain, but this evidence is not overwhelming. Only 1 study found significance in the use of metformin for prevention of antipsychotic-induced weight gain, and currently no prevention studies have been conducted with topiramate. The main limitations of the data for both agents include a small number of controlled trials, short treatment durations, and inclusion of a small number of pa-


n


n

673

674

n

Designa

SGA Use and Duration

Intervention

12 wk R, DB, PC N = 32 Children Mean 9–11 y Outpatient Iran

12 wk R, DB, PC N = 30 Mean 47.5 y Inpatient Venezuela

12 wk R, DB, DD, PC N = 128 Mean 26 y Outpatient Asia >10% weight gain at baseline

12 wk R, DB, PC, MC N = 80 Mean 43 y Inpatient and outpatient Venezuela

16 wk R, DB, DD, PC N = 38 Mean 13 y >10% weight gain at baseline Outpatient US

Arman (2008)34

Baptista (2008)35


Wu (2008)36

Baptista (2007)37

Klein (2006)40

Week 1: metformin 500 mg/day After week 1: metformin 500 mg twice daily

n


Olanzapine Risperidone Quetiapine 6–8 Mo

Olanzapine 6.7 ± 10.8 mo (range 4–84 mo)

Clozapine Olanzapine Risperidone Sulpiride 8 Mo

Week 1: metformin 500 mg/day Weeks 2–16: metformin 850 mg/day Nutrition counseling

Metformin 850 mg/day up to 2550 mg/day by week 4 Recommendations for healthy diet and exercise

Group 1: metformin 750 mg/day Group 2: placebo Group 3: lifestyle intervention (education, AHA diet, exercise training) plus metformin 750 mg/day Group 4: lifestyle intervention plus placebo

Olanzapine 4 mo (>10 y prior FGA use) Weeks 1–4: metformin 850 mg/day and sibutramine 10 mg/day Weeks 5–12: metformin 1700 mg/day and sibutramine 20 mg/day Educational healthy lifestyle program

Risperidone

Placebo-controlled trials of metformin for treatment of weight gain Carrizo 14 wk Clozapine >3 mo (mean 80–98 mo) Weeks 1–2: metformin XR 500 mg/day (2009)33 R, DB, DD, PC After week 2: metformin XR 1000 mg/day N = 61 Clinic lifestyle education for all pts. Mean 39 y Outpatient Venezuela

Trial

–0.13 ± 2.88 (M) 4.01 ± 6.23 (P) (p = 0.002)b

–1.40 ± 3.2 (M) –0.18 ± 2.8 (P) (p = 0.09)

Group 1: –3.2 (95% CI –3.9 to –2.5) Group 2: 3.1 (95% CI 2.4 to 3.8) Group 3: –4.7 (95% CI –5.7 to –3.4) Group 4: –1.4 (95% CI –2.0 to –0.7) (all between-group comparisons p < 0.05)

–2.8 ± 3.2 (M) –1.4 ± 2.6 (P) (p = 0.19)

0.81 ± 0.33 (M) 2.2 ± 2.54 (P) (p < 0.147)

–1.87 ± 2.9 (M) 0.16 ± 2.9 (P) (p = 0.01)

Mean Change in Weight (kg)

BMI: –1.12 ± 1.43 (M minus P) (p < 0.001)b WC: –4.65 ± 8.17 (p = 0.003)

BMI: –0.47 ± 1.2 (M) –0.07 ± 1.1 (P) (p = 0.1) WC: –0.1 ± 5.9 (M) 0.5 ± 5.6 (P) (p = 0.6)

Primary outcomes for the study: BMI –1.2, 1.2, –1.8, –0.5 (groups 1–4, respectively) WC –1.3, 2.2, –2.0, 0.1 (groups 1–4, respectively) (all between-group comparisons p < 0.05)

BMI: –1.1 ± 1.2 (M) –0.59 ± 1.2 (P) (p = 0.25) WC: –6.6 ± 8.1(M) –3.2 ± 4.2 (P) (p = 0.17)

BMI increase from baseline: 0.48 (M) 1.1 (P) (p < 0.099) Weight gain >7%: 6 vs 1 (P vs M) (p < 0.033)

BMI: –0.68 ± 1.0 (M) 0.05 ± 0.9 (P) (p = 0.04) WC: –1.4 ± 3.5 (M) 0.2 ± 3.6 (P) (p = 0.2)

Mean Change in Secondary Outcomes

Table 3. Summary of Trials of Metformin and Topiramate for Treatment and/or Prevention of Second-Generation Antipsychotic-Induced Weight Gain

LK Ellinger et al.

theannals.com

theannals.com

14 wk R, DB, PC N = 40 Mean 47 y Inpatient Venezuela

Olanzapine 10 mg (30.7 ± 10.1 y prior FGA use)


Risperidone Olanzapine Quetiapine Clozapine mean 9.8 mo

12 wk R, DB, PC N = 53 Mean 36 y Inpatient Korea

Ko (2005)68

Topiramate 25 mg bid for week 1, then 50 mg bid for week 2, then increased weekly by 25 mg/day until target dose of 200 or 100 mg/day Exposure to food and physical activity were controlled

Topiramate 50 mg/day titrated weekly to 250 mg/day by the 5th wk

Topiramate 25 mg twice daily, increased every 3–4 days by 25 mg/day up to maximum of 300 mg/day

Metformin 850–1750 mg/day Diet provided (2500–3000 kcal/day)

–5.35 (T 200 mg/day) –1.68 (T 100 mg/day) –0.3 (P) (p = 0.002)

–4.4 (T) 1.2 (P) (p < 0.001)

Not recorded

5.5 ± 3.3 (M) 6.3 ± 2.3 (P) (p > 0.05)

1.90 ± 2.72 (M) 6.87 ± 4.23 (P) (p < 0.02)

BMI: –2.04 (T 200 mg/day) –0.62 (T 100 mg/day) –0.13 (P) (p = 0.002)

Topiramate therapy resulted in greater improvements in the SF-36, EWL-60-S, and Bf-S well-being scales vs placebo (p < 0.001 for all comparisons)

BMI: –0.91 (T) 0.21 (P) p < 0.05

(p > 0.05)

BMI: 2.2 (M) 2.5 (P) (p > 0.05) WC: 5.2 (M) 3.7 (P)

BMI: 0.54 ± 0.92 (M) 2.26 ± 1.12 (P) (p < 0.01) WC: 0.46 ± 0.14 (M) 1.37 ± 0.62 (P) (p = 0.954)

AHA = American Heart Association; BMI = body mass index (kg/m2); DB = double-blind; DD = double-dummy; FGA = first-generation antipsychotic; M = metformin group; MC = multicenter; P = placebo group; PC = placebo-controlled; R = randomized; SGA = second-generation antipsychotic; T = topiramate group; WC = waist circumference (cm); XR = extended release formulation. a Study design also includes duration, number of patients, mean age, setting (inpatient vs outpatient), and location. b z Score for weight F = 5.13, df = 4, 116, p = 0.0008; z score for BMI F = 5.30, df = 4, 115, p = 0.0006.

Olanzapine Mean 4–5 mo

10 wk R, DB, PC N = 43 All female Mean 35 y Outpatient Germany

Nickel (2005)67

Clozapine 2 mo

8 wk R, DB, PC N = 32 Mean 38 y Outpatient Iran

Afshar (2009)66

Placebo-controlled trials of topiramate for treatment of weight gain

Baptista (2006)39

Placebo-controlled trials of metformin for prevention of weight gain Wu 12 wk Olanzapine 15 mg (no antipsychotic Metformin 750 mg/day (250 mg before each meal) (2008)38 R, DB, DD, PC use for 3 mo prior) Exercise 30 minutes daily N = 40 Diet provided Mean 25.4 y Inpatient First psychotic episode Asia


n


n

675

LK Ellinger et al.

tients. It is difficult to extrapolate some of these data to the US population; a majority of the included trials were performed outside of the US (eg, in China, Germany, Iran, Korea, Venezuela) and it can be assumed that cultural, lifestyle, and metabolic differences exist between these populations and individuals in the US. Antipsychotic doses used in these trials may differ from standard practice in the US, and not every trial controlled for interventions that can affect weight (including additional medications and lifestyle and diet interventions). These factors have the potential to confound results. Studies involving inpatients may not be applicable to an outpatient population, where variables such as diet and exercise are uncontrolled and more difficult to monitor. Also, some trials included only patients who were willing and motivated to lose weight. Compared to topiramate, metformin has a better safety profile, a larger body of clinical evidence for weight loss, and data for use in pediatrics. There is also evidence that metformin improves other metabolic and anthropometric parameters affected by SGAs, such as glucose control, insulin secretion, and waist circumference.80,86 The evidence for topiramate found that weight loss was often accompanied by notable adverse effects. Also, despite a significant difference found between topiramate and placebo in the study by Afshar and colleagues, the decrease in BMI seen with topiramate was nonsignificant from baseline.66 Unlike topiramate, metformin does not act centrally, so there is much less concern for drug-disease interactions in a psychiatric population. There is a concerning drug-drug interaction between topiramate and risperidone; topiramate has been associated with a 25% decrease in risperidone serum concentrations. Monitoring or adjustments of risperidone doses may be necessary if these agents are used concomitantly.87 The FDA released a warning in 2008 regarding increased risk of suicidal behavior or ideation in patients taking antiepileptic drugs, including topiramate.87 This possible effect is concerning in any psychiatric population. Two recent reviews of metformin concluded that there was insufficient evidence to recommend its use for weight loss, and a recent Cochrane review concluded that evidence was inadequate to recommend use of pharmacologic agents for weight loss in patients with schizophrenia.86,88,89 However, the risks associated with weight gain and obesity in patients with schizophrenia are concerning enough to justify treatment of antipsychotic-induced weight gain in some situations. When dietary and exercise interventions have failed, metformin may be a viable option in light of evidence suggesting its efficacy and low potential for adverse effects. Summary Weight gain in patients with schizophrenia secondary to antipsychotic use is concerning because it can affect medi676

n


n

cation adherence and increase risk factors for cardiovascular disease. Clinical trials provide limited evidence to support widespread use of metformin or topiramate for SGAinduced weight gain due to limited external validity of the available data. However, the safety profile of metformin and its many years of clinical use for other conditions justify larger, adequately powered, controlled studies to support the currently available data. Lifestyle and dietary interventions may be difficult to implement in patients with schizophrenia for reasons of adherence and cost, and the efficacy of these interventions in promoting weight loss may be limited in a population predisposed to weight gain. After careful consideration of the patient’s medical, social, and behavioral history, it is reasonable to consider the addition of a pharmacologic agent for SGA-induced weight gain when nonpharmacologic options alone have failed. Multiple clinical trials support metformin’s efficacy and it is associated with fewer and less serious adverse effects than is topiramate. Ongoing clinical trials with pharmacologic agents and a greater understanding of the mechanisms of SGA-induced weight gain will provide further evidence for the place in therapy, if any, for metformin and topiramate. Lara K Ellinger, PharmD Student, University of Illinois at Chicago College of Pharmacy

Heather J Ipema PharmD, PGY2 Drug Information Resident, University of Illinois at Chicago College of Pharmacy Joan M Stachnik PharmD BCPS, Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago Reprints: Dr. Stachnik, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (M/C 886), Chicago, IL 60612, fax 312/996-0448, [email protected]

Financial disclosure: None reported

References 1. Crimson ML, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: a pathophysiologic approach, 7th ed. New York, NY: McGraw-Hill, 2008:1099-139. 2. Endow-Eyer RA, Mitchell MM, Lacro JP. Schizophrenia. In: Koda-Kimble M, Young LY, Alldredge BK, et al., eds. Applied therapeutics: the clinical use of drugs, 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:78-1, 78-34. 3. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161:1-56. 4. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156: 1686-96. 5. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003;28:519-26. DOI 10.1038/sj.npp.1300027 6. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008;13:27-35. DOI 10.1038/sj.mp.4002066 7. Werneke U, Taylor D, Sanders TA. Options for pharmacological management of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol 2002;17:145-60.


theannals.com

Metformin and Topiramate for Second-Generation Antipsychotic–Induced Weight Gain 8. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601. 9. Product information. Abilify (aripiprazole). Tokyo, Japan: Otsuka Pharmaceutical Co., Ltd., July 2009. 10. Product information. Saphris (asenapine). Kenilworth, NJ: ScheringPlough Corporation, August 2009. 11. Umbricht DS, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994;55(suppl B):157-60. 12. Product information. Fanapt (iloperidone). Rockville, MD: Vanda Pharmaceuticals Inc., July 2009. 13. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23. DOI 10.1056/NEJMoa051688 14. Product information. Invega (paliperidone). Mountain View, CA: Alza Corporation, July 2009. 15. Hester EK, Thrower MR. Current options in the management of olanzapine-associated weight gain. Ann Pharmacother 2005;39:302-10. DOI 10.1345/aph.1D423 16. Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of adults and adolescents with antipsychotic drugs. Arch Gen Psychiatry 2006;63:679-85. 17. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009; 302:1765-73. DOI 10.1001/jama.2009.1549 18. Shin L, Bregman H, Frazier J, Noyes N. An overview of obesity in children with psychiatric disorders taking atypical antipsychotics. Harv Rev Psychiatry 2008;16:69-79. DOI 10.1080/10673220802073915 19. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med 2008;162:929-35. DOI 10.1001/archpedi.162.10.929 20. Schneiderhan ME, Marvin R. Is acetazolamide similar to topiramate for reversal of antipsychotic-induced weight gain? Am J Ther 2007;14:581-4. DOI 10.1097/MJT.0b013e31813e65b7 21. Graham KA, Gu H, Lieberman JA, Harp JB, Perkins DO. Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. Am J Psychiatry 2005;162: 1744-6. DOI 10.1176/appi.ajp.162.9.1744 22. Deberdt W, Winokur A, Cavazzoni PA, et al. Amantadine for weight gain associated with olanzapine treatment. Eur Neuropsychopharmacol 2005;15:13-21. DOI 10.1016/j.euroneuro.2004.03.005 23. Bahk WM, Lee KU, Chae JH, Pae CU, Jun T, Kim KS. Open label study of the effect of amantadine on weight gain induced by olanzapine. Psychiatry Clin Neurosci 2004;58:163-7. 24. Floris M, Lejeune J, Deberdt W. Effect of amantadine on weight gain during olanzapine treatment. Eur Neuropsychopharmacol 2001;11:181-2. 25. Gracious BL, Krysiak TE, Youngstrom EA. Amantadine treatment of psychotropic-induced weight gain in children and adolescents: case series. J Child Adolesc Psychopharmacol 2002;12:249-57. DOI 10.1089/104454602760386941 26. Poyurovsky M, Pashinian A, Levi A, Weizman R, Weizman A. The effect of betahistine, a histamine H1 receptor agonist/H3 antagonist, on olanzapine-induced weight gain in first-episode schizophrenia patients. Int Clin Psychopharmacol 2005;20:101-3. 27. Gadde KM, Zhang W, Foust MS. Bupropion treatment of olanzapine-associated weight gain: an open-label, prospective trial. J Clin Psychopharmacol 2006;26:409-13. DOI 10.1097/01.jcp.0000227354.54074.5d 28. Poyurovsky M, Tal V, Maayan R, Gil-Ad I, Fuchs C, Weizman A. The effect of famotidine addition on olanzapine-induced weight gain in firstepisode schizophrenia patients: a double-blind placebo-controlled pilot study. Eur Neuropsychopharmacol 2004;14:332-6. DOI 10.1016/j.euroneuro.2003.10.004 29. Bustillo JR, Lauriello J, Parker K, et al. Treatment of weight gain with fluoxetine in olanzapine-treated schizophrenic outpatients. Neuropsychopharmacology 2003;28:527-9. DOI 10.1038/sj.npp.1300089

theannals.com

30. Poyurovsky M, Pashinian A, Gil-Ad I, et al. Olanzapine-induced weight gain in patients with first-episode schizophrenia: a double-blind, placebocontrolled study of fluoxetine addition. Am J Psychiatry 2002;159:1058-60. 31. Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry 2004;65:766-71. 32. Schaefer M, Leopold K, Hinzpeter A, Heinz A, Krebs M. Memantine-associated reversal of clozapine-induced weight gain. Pharmacopsychiatry 2007;40:149-51. DOI 10.1055/s-2007-984391 33. Carrizo E, Fernandez V, Connell L, et al. Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study. Schizophr Res 2009;113:19-26. DOI 10.1016/j.schres.2009.05.007 34. Arman S, Sadramely MR, Nadi M, Koleini N. A randomized, doubleblind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents. Saudi Med J 2008;29:1130- 4. 35. Baptista T, Uzcategui E, Rangel N, et al. Metformin plus sibutramine for olanzapine-associated weight gain and metabolic dysfunction in schizophrenia: a 12-week double-blind, placebo-controlled pilot study. Psychiatry Res 2008;159:250-3. DOI 10.1016/j.psychres.2008.01.011 36. Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008;299:185-93. DOI 10.1001/jama.2007.56-b 37. Baptista T, Rangel N, Fernandez V, et al. Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial. Schizophr Res 2007;93:99-108. DOI 10.1016/j.schres.2007.03.029 38. Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 2008;165:352-8. DOI 10.1176/appi.ajp.2007.07010079 39. Baptista T, Martinez J, Lacruz A, et al. Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial. Can J Psychiatry 2006;51:192-6. 40. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry 2006;163:2072-9. DOI 10.1176/appi.ajp.163.12.2072 41. Chen CH, Chiu CC, Huang MC, Wu TH, Liu HC, Lu ML. Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:925-31. DOI 10.1016/j.pnpbp.2007.11.013 42. Baptista T, Hernandez L, Prieto LA, Boyero EC, de Mendoza S. Metformin in obesity associated with antipsychotic drug administration: a pilot study. J Clin Psychiatry 2001;62:653-5. 43. Shin L, Bregman H, Breeze JL, Noyes N, Frazier JA. Metformin for weight control in pediatric patients on atypical antipsychotic medication. J Child Adolesc Psychopharmacol 2009;19:275-9. DOI 10.1089/cap.2008.094 44. Morrison JA, Cottingham EM, Barton BA. Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry 2002;159: 655-7. 45. Ozenoglu A, Ugurlu S, Balci H, Eker E. Nutritional approach to metabolic changes arising out of schizophrenia therapy: case report. Intern Med 2007;46:1213-8. 46. Roerig JL, Steffen KJ, Mitchell JE, Crosby RD, Gosnell BA. An exploration of the effect of modafinil on olanzapine associated weight gain in normal human subjects. Biol Psychiatry 2009;65:607-13. DOI 10.1016/j.biopsych.2008.10.037 47. Henderson DC, Louie PM, Koul P, Namey L, Daley TB, Nguyen DD. Modafinil-associated weight loss in a clozapine-treated schizoaffective disorder patient. Ann Clin Psychiatry 2005;17:95-7. 48. Assuncao SS, Ruschel SI, Rosa Lde C, et al. Weight gain management in patients with schizophrenia during treatment with olanzapine in association with nizatidine. Rev Bras Psiquiatr 2006;28:270-6.


n


n

677

LK Ellinger et al. 49. Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Nizatidine treatment and its relationship with leptin levels in patients with olanzapine-induced weight gain. Hum Psychopharmacol 2003;18:457-61. DOI 10.1002/hup.514 50. Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Kilic N. Nizatidine for the treatment of patients with quetiapine-induced weight gain. Hum Psychopharmacol 2004;19:37- 40. DOI 10.1002/hup.477 51. Cavazzoni P, Tanaka Y, Roychowdhury SM, Breier A, Allison DB. Nizatidine for prevention of weight gain with olanzapine: a double-blind placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:81-5. 52. Pae CU, Kim JJ, Lee KU, et al. Effect of nizatidine on olanzapine-associated weight gain in schizophrenic patients in Korea: a pilot study. Hum Psychopharmacol 2003;18:453-6. DOI 10.1002/hup.507 53. Sacchetti E, Guarneri L, Bravi D. H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients. Biol Psychiatry 2000;48:167-8. 54. Joffe G, Takala P, Tchoukhine E, et al. Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008;69:706-11. 55. Carpenter LL, Schecter JM, Sinischalc J, Leon Z, Price LH. A case series describing orlistat use in patients on psychotropic medications. Med Health R I 2004;87:375-7. 56. Anghelescu I, Klawe C, Benkert O. Orlistat in the treatment of psychopharmacologically induced weight gain. J Clin Psychopharmacol 2000;20:716-7. 57. Pavlovic ZM. Orlistat in the treatment of clozapine-induced hyperglycemia and weight gain. Eur Psychiatry 2005;20:520. DOI 10.1016/j.eurpsy.2005.07.005 58. Borovicka MC, Fuller MA, Konicki PE, White JC, Steele VM, Jaskiw GE. Phenylpropanolamine appears not to promote weight loss in patients with schizophrenia who have gained weight during clozapine treatment. J Clin Psychiatry 2002;63:345-8. 59. Lopez-Mato A, Rovner J, Illa G, Vieitez A, Boullosa O. Randomized, open label study on the use of ranitidine at different doses for the management of weight gain associated with olanzapine administration. Vertex 2003;14:85-96. DOI 10.1267/science.040579197 60. Poyurovsky M, Fuchs C, Pashinian A, et al. Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: a double-blind placebo-controlled study. Psychopharmacology (Berl) 2007;192:441-8. DOI 10.1007/s00213-007-0731-1 61. Poyurovsky M, Isaacs I, Fuchs C, et al. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind, placebo-controlled study. Am J Psychiatry 2003;160:297-302. 62. Baptista T, Rangel N, El Fakih Y, et al. Rosiglitazone in the assistance of metabolic control during olanzapine administration in schizophrenia: a pilot double-blind, placebo-controlled, 12-week trial. Pharmacopsychiatry 2009;42:14-9. DOI 10.1055/s-0028-1085438 63. Henderson DC, Fan X, Copeland PM, et al. A double-blind, placebocontrolled trial of sibutramine for clozapine-associated weight gain. Acta Psychiatr Scand 2007;115:101-5. DOI 10.1111/j.1600-0447.2006.00855.x 64. Henderson DC, Copeland PM, Daley TB, et al. A double-blind, placebocontrolled trial of sibutramine for olanzapine-associated weight gain. Am J Psychiatry 2005;162:954-62. DOI 10.1176/appi.ajp.162.5.954 65. McElroy SL, Frye MA, Altshuler LL, et al. A 24-week, randomized, controlled trial of adjunctive sibutramine versus topiramate in the treatment of weight gain in overweight or obese patients with bipolar disorders. Bipolar Disord 2007;9:426-34. DOI 10.1111/j.1399-5618.2007.00488.x 66. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 2009;23:157-62. DOI 10.1177/0269881108089816 67. Nickel MK, Nickel C, Muehlbacher M, et al. Influence of topiramate on olanzapine-related adiposity in women: a random, double-blind, placebocontrolled study. J Clin Psychopharmacol 2005;25:211-7. 68. Ko YH, Joe SH, Jung IK, Kim SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol 2005;28:169-75.

678

n


n

69. Egger C, Muehlbacher M, Schatz M, Nickel M. Influence of topiramate on olanzapine-related weight gain in women: an 18-month follow-up observation. J Clin Psychopharmacol 2007;27:475-8. DOI 10.1097/jcp.0b013e31814b98e5 70. Tramontina S, Zeni CP, Pheula G, Rohde LA. Topiramate in adolescents with juvenile bipolar disorder presenting weight gain due to atypical antipsychotics or mood stabilizers: an open clinical trial. J Child Adolesc Psychopharmacol 2007;17:129-34. DOI 10.1089/cap.2006.0024 71. Kim JH, Yim SJ, Nam JH. A 12-week, randomized, open-label, parallelgroup trial of topiramate in limiting weight gain during olanzapine treatment in patients with schizophrenia. Schizophr Res 2006;82:115-7. DOI 10.1016/j.schres.2005.10.001 72. Canitano R. Clinical experience with topiramate to counteract neuroleptic induced weight gain in 10 individuals with autistic spectrum disorders. Brain Dev 2005;27:228-32. DOI 10.1016/j.braindev.2004.06.006 73. Vieta E, Sanchez-Moreno J, Goikolea JM, et al. Effects on weight and outcome of long-term olanzapine-topiramate combination treatment in bipolar disorder. J Clin Psychopharmacol 2004;24:374-8. 74. Khazaal Y, Chatton A, Rusca M, Preisig M, Zullino D. Long-term topiramate treatment of psychotropic drug-induced weight gain: a retrospective chart review. Gen Hosp Psychiatry 2007;29:446-9. DOI 10.1016/j.genhosppsych.2007.05.001 75. Levy E, Agbokou C, Ferreri F, Chouinard G, Margolese HC. Topiramate-induced weight loss in schizophrenia: a retrospective case series study. Can J Clin Pharmacol 2007;14:e234-9. 76. Lin YH, Liu CY, Hsiao MC. Management of atypical antipsychotic-induced weight gain in schizophrenic patients with topiramate. Psychiatry Clin Neurosci 2005;59:613-5. DOI 10.1111/j.1440-1819.2005.01424.x 77. Levy E, Margolese HC, Chouinard G. Topiramate produced weight loss following olanzapine-induced weight gain in schizophrenia. J Clin Psychiatry 2002;63:1045. 78. Lessig MC, Shapira NA, Murphy TK. Topiramate for reversing atypical antipsychotic weight gain. J Am Acad Child Adolesc Psychiatry 2001; 40:1364. 79. Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry 2000;45:198. 80. Triplitt CL, Reasner CA, Isley WL. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: a pathophysiologic approach, 7th ed. New York, NY: McGraw-Hill, 2008:1205-41. 81. Metformin. DRUGDEX System. Greenwood Village, CO: Thomson Micromedex, last modified 2009 Oct 30 (accessed 2009 Nov 22). 82. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009;37:2191-6. DOI 10.1097/CCM.0b013e3181a02490 83. Mannucci E, Ognibene A, Cremasco F, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 2001;24:489-94. 84. Topiramate. DRUGDEX System. Greenwood Village, CO: Thomson Micromedex, last modified 2009 Oct 20 (accessed 2009 Nov 22). 85. Rogers SJ, Cavazs JE. Epilepsy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: a pathophysiologic approach, 7th ed. New York, NY: McGraw-Hill, 2008:927-51. 86. Desilets AR, Dhakal-Karki S, Dunican KC. Role of metformin for weight management in patients without type 2 diabetes. Ann Pharmacother 2008;42:817-26. DOI 10.1345/aph.1K656 87. Product information. Topamax (topiramate). Titusville, NJ: Ortho-McNeil Neurologics, April 2008. 88. Bushe CJ, Bradley AJ, Doshi S, Karagianis J. Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do the data inform as to potential guideline development? A systematic review of clinical studies. Int J Clin Pract 2009;63:1743-61. DOI 10.1111/j.1742-1241.2009.02224.x 89. Faulkner G, Cohn T, Remington G. Interventions to reduce weight gain in schizophrenia. Cochrane Database Syst Rev 2007;(1):CD005148. DOI 10.1002/14651858.CD005148.pub2


theannals.com


Eficacia de la Metformina y el Topiramato en la Prevención y el Tratamiento del Aumento de peso Inducido por Antisicóticos de Segunda Generación

Efficacité de la Metformine et du Topiramate pour la Prévention et le Traitement du Gain de Poids Induit par les Antipsychotiques Atypiques

LK Ellinger, HJ Ipema, y JM Stachnik

LK Ellinger, HJ Ipema, et JM Stachnik

Ann Pharmacother 2010;44:668-79.

Ann Pharmacother 2010;44:668-79.

EXTRACTO

RÉSUMÉ

Revisar la literatura que describe la eficacia de la metformina y el topiramato en el tratamiento del aumento de peso inducido por los antisicóticos. FUENTES DE INFORMACIÓN: Se identificaron artículos en la base de datos de MEDLINE (1949–enero 2010) usando las palabras clave: metformina, topiramato, antisicótico, peso, aumento de peso y obesidad. SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE LA INFORMACIÓN: Se seleccionaron y se revisaron todos los estudios aleatorios, controlados con placebo de la metformina y el topiramato. SÍNTESIS DE LOS DATOS: El aumento de peso debido al uso de antisicóticos de segunda generación es una preocupación por el riesgo a largo plazo de los efectos metabólicos y cardiovasculares de estos agentes. Estos efectos incluyen obesidad, hiperglucemia y resistencia a la insulina, que todos pueden contribuir a la diabetes y la enfermedad cardiovascular. Los antisicóticos de segunda generación varían en el grado en el cual causan aumento de peso, y los cambios en la dieta y el estilo de vida puede que no sean posibles ni suficientes para contrarrestar este aumento de peso. Aunque otros agentes farmacológicos pueden ser beneficiosos para prevenir y tratar el aumento de peso inducido por los antisicóticos, la metformina y el topiramato han sido los más extensamente estudiados para este propósito. La metformina actúa a nivel periférico causando pérdida de peso, mientras que el topiramato actúa a nivel central. Una revisión de 11 estudios aleatorios y controlados demostró los efectos beneficiosos de la metformina y el topiramato en la prevención y el tratamiento del aumento de peso. La metformina, por lo general, se tolera bien y ha sido estudiada en pacientes pediátricos, mientras que el topiramato está asociado con más interacciones entre fármacos y, posiblemente, puede interferir con el control de la esquizofrenia. CONCLUSIONES: Los datos en cuanto al uso de la metformina y el topiramato en el tratamiento y la prevención del aumento de peso inducido por los antisicóticos son limitados. Ambos pueden ser efectivos en ayudar a los pacientes a perder peso mediante mecanismos que aún no se han definido con claridad. El uso de la metformina resulta en una mayor pérdida de peso que el topiramato, y el topiramato está asociado con más riesgos y puede comprometer el tratamiento de la esquizofrenia. El tratamiento del aumento de peso inducido por los antisicóticos utilizando la metformina puede ser una opción cuando los cambios en estilo de vida y la dieta han fracasado.

OBJECTIF: Revoir la littérature médicale concernant l’efficacité de la metformine et du topiramate pour le traitement du gain de poids induit par les antipsychotiques. REVUE DE LITTÉRATURE: Les articles ont été identifiés lors d’une recherche dans la banque informatisée MEDLINE (1949–janvier 2010) en utilisant les mots-clé metformine, topiramate, antipsychotiques, poids, gain de poids et obésité. SÉLECTION DES DONNÉES ET DE L’INFORMATION: Toutes les études randomisées, contrôlées contre placebo portant sur la metformine et le topiramate ont été sélectionnées pour cette revue. SYNTHESE DES DONNÉES: Le gain de poids secondaire à l’utilisation des antipsychotiques atypiques représente une préoccupation en raison des effets métaboliques et cardiovasculaires de ces agents à long terme. Ces effets sont : obésité, hyperglycémie et résistance à l’insuline, effets qui peuvent tous contribuer à l’apparition d’un diabète ou de maladies cardiovasculaires. Les antipsychotiques atypiques causent une augmentation de poids, augmentation variable selon l’agent utilisé, et la diète et les modifications du style de vie peuvent ne pas être suffisants pour contrer le gain de poids ou être non applicables. Même si d’autres agents pharmacologiques peuvent être efficaces pour prévenir et traiter le gain de poids induit par les antipsychotiques, la metformine et le topiramate sont les 2 agents les plus étudiés. La metformine agit en périphérie pour causer une perte de poids alors que le topiramate agit au niveau du système nerveux central. La revue de onze études randomisées et contrôlées montre les effets bénéfiques de la metformine et du topiramate pour la prévention et le traitement du gain de poids. La metformine est généralement bien tolérée et le topiramate est associé à plus d’interactions médicamenteuses et pourrait interférer avec le contrôle de la schizophrénie. CONCLUSIONS: Les données pour l’utilisation de la metformine et du topiramate pour la prévention et le traitement du gain de poids induit par les antipsychotiques sont limitées. Ces 2 agents peuvent être efficaces en aidant les patients à perdre du poids via des mécanismes non encore tous élucidés. L’emploi de la metformine procure une plus grande perte de poids que le topiramate et le topiramate est associé à plus de risques et peut compromettre le contrôle de la schizophrénie. Le traitement du gain de poids induit par les antipsychotiques atypiques avec la metformine peut être une option de traitement efficace lorsque la diète et les modifications du style de vie ont échoués pour contrôler le poids.

Traducido por Rafaela Mena

Traduit par Denyse Demers

OBJETIVO:

theannals.com


n


n

679