Table 1.
Characteristics of Included DBRCTs
| Concomitant Drug/ Study (Year) | Duration (wk) | Study Population | Primary Antipsychotic | Intervention Groups (Daily Dose) | n, Randomized/Completeda | Defined Primary Outcome |
|---|---|---|---|---|---|---|
| Amantadine | ||||||
| Deberdt et al (2005) 11 | 8 | - Inpatients and outpatients, 55% with schizophrenia and related disorders, 45% with bipolar I disorder | OLZ | Amantadine 100–300 mg | 60/52 | Effects on body weight |
| - Previous weight gain ≥5% | Placebo | 65/59 | ||||
| Graham et al (2005) 12 | 12 | - Outpatients, 86% with schizophrenia and related disorders, 14% with bipolar disorder | OLZ | Amantadine up to 300 mg | 12/9 | Effects on BMI |
| - Previous weight gain ≥5 lb | Placebo | 9/9 | ||||
| Aripiprazole | ||||||
| Henderson et al (2009) 13 | 10 (4wk of each Tx with 2-wk interval) | - Outpatients with schizophrenia or schizoaffective disorder | OLZ | Aripiprazole 15 mg | 15/14 (crossover) | Effects on body weight, lipids, glucose metabolism, and psychopathology |
| - Previous BMI ≥30 or BMI ≥27 with other metabolic risk factors | Placebo | |||||
| Fleischhacker et al (2010) 14 | 16 | - Outpatients with schizophrenia | CLZ | Aripiprazole 5–15 mg | 108/97 | Effects on body weight |
| - Previous weight gain ≥2.5 kg | Placebo | 99/93 | ||||
| Fan et al (2013) 15 | 8 | - Outpatients with schizophrenia or schizoaffective disorder | CLZ | Aripiprazole 15 mg | 20/16 | Effects on glucose metabolism using the frequently sampled intravenous glucose tolerance test |
| Placebo | 18/14 | |||||
| Atomoxetine | ||||||
| Ball et al (2011) 16 | 24 | - Outpatients with schizophrenia or schizoaffective disorder | OLZ, CLZ, or CLZ + RIS | Atomoxetine 40–120 mg | 20/14 | Effects on body weight |
| - Previous weight gain of ≥7% | Placebo | 17/12 | ||||
| D-Fenfluramine | ||||||
| Goodall et al (1988) 17 | 12 | - Outpatients, 97% with schizophrenia or schizoaffective disorder (diagnostic criteria unspecified) | FPZ, FPX, or CPX | D-Fenfluramine 30 mg | 17/9 | Effects on body weight |
| - Receiving depot antipsychotics | Placebo | 16/7 | ||||
| - Previous BMI ≥27 | ||||||
| Dextroamphetamine | ||||||
| Modell et al (1965) 18 | 16 (8wk of Tx, no Tx 4wk before/after) | - Male inpatients with schizophrenia (diagnostic criteria unspecified) | Thioridazine, chlorpromazine, imipramine, or chlordiazepoxide | Dextroamphetamine 5 mg | 10/10 | Effects on body weight and appetite |
| Placebo | 10/10 | |||||
| Famotidine | ||||||
| Poyurovsky et al (2004) 19 | 6 | - Inpatients with first-episode schizophrenia or schizophreniform disorder | OLZ | Famotidine 40 mg | 7/7 | Effects on body weight |
| Placebo | 7/7 | |||||
| Fluoxetine | ||||||
| Poyurovsky et al (2002) 20 | 8 | - Inpatients with first-episode schizophrenia | OLZ | Fluoxetine 20 mg | 15/11 | Effects on body weight |
| Placebo | 15/13 | |||||
| Bustillo et al (2003) 21 | 16 | - Outpatients with schizophrenia or schizoaffective disorder | OLZ | Fluoxetine 20–60 mg | 15/11 | Effects on body weight |
| - Previous weight gain of ≥3% | Placebo | 15/9 | ||||
| Intranasal insulin | ||||||
| Li et al (2013) 22 | 8 | - Outpatients with schizophrenia or schizoaffective disorder | 54% OLZ, 46% other antipsychotics | Intranasal insulin 160 IU | 21/18 | Effects on body composition and lipid particle sizes using whole body dual-energy X-ray absorptiometry and nuclear magnetic resonance spectroscopy |
| Placebo | 24/21 | |||||
| Metformin | ||||||
| Baptista et al (2006) 23 | 14 | - Inpatients with schizophrenia or schizoaffective disorder | OLZ | Metformin 850–1700 mg | 20/19 | Effects on body weight |
| Placebo | 20/18 | |||||
| Baptista et al (2007) 24 | 12 | - Inpatients and outpatients, 95% with schizophrenia, 5% with bipolar disorder | OLZ | Metformin 850–2550 mg | 40/36 | Effects on body weight |
| Placebo | 40/36 | |||||
| Arman et al (2008) 25 | 12 | - Inpatients with schizophrenia or schizoaffective disorder | RIS | Metformin 1000 mg | 49 recruited, 16 completers in each group | Effects on body weight |
| - Age <20 | Placebo | |||||
| Wu et al (2008) 26 | 12 | - Outpatients with first-episode schizophrenia | CLZ, OLZ, RIS, or SLP | 2×2 design of: | 32/30 | Effects on body weight, BMI, waist circumference, glucose, insulin, and HOMA-IR |
| - Previous weight gain of >10% | - Lifestyle intervention [+]/[−] | 32/29 | ||||
| - Metformin 750mg/placebo | 32/30 | |||||
| 32/29 | ||||||
| Wu et al (2008) 27 | 12 | - Inpatients with first-episode schizophrenia | OLZ | Metformin 750 mg | 20/18 | Effects on body weight, BMI, waist circumference, waist-to-hip ratio, glucose, insulin, >7% gain in body weight, and HOMA-IR |
| Placebo | 20/19 | |||||
| Carrizo et al (2009) 28 | 14 | - Outpatients, 96% with schizophrenia or schizophreniform disorder | CLZ | Metformin 500–1000 mg | 31/24 | Effects on body weight |
| Placebo | 30/30 | |||||
| Wang et al (2012) 29 | 12 | - Outpatients with first-episode schizophrenia | CLZ, OLZ, RIS, or SLP | Metformin 1000 mg | 36/32 | Effects on body weight |
| - Previous weight gain of >7% | Placebo | 36/34 | ||||
| Wu et al (2012) 30 | 24 | - Female outpatients with first-episode schizophrenia | CLZ, OLZ, RIS, or SLP | Metformin 1000 mg | 42/39 | Effects on amenorrhea and body weight |
| - Experiencing amenorrhea with antipsychotic Tx | Placebo | 42/37 | ||||
| Chen et al (2013) 31 | 24 | - Inpatients/outpatients with schizophrenia or schizoaffective disorder | CLZ | Metformin 1500 mg | 28/28 | Effects on body weight and metabolic features |
| - Previous BMI ≥24 or having ≥1 defined metabolic abnormality | Placebo | 27/27 | ||||
| Jarskog et al (2013) 32 | 16 | - Outpatients with schizophrenia or schizoaffective disorder | Various antipsychotics including CLZ and OLZ | Metformin 1000–2000 mg | 75/58 | Effects on body weight |
| - Previous BMI ≥27 | Placebo | 73/58 | ||||
| Metformin-sibutramine combination | ||||||
| Baptista et al (2008) 33 | 12 | - Inpatients with schizophrenia | OLZ | Metformin 850–1700mg and sibutramine 10–20 mg | 15/13 | Effects on body weight, BMI, and waist circumference |
| Placebo | 15/15 | |||||
| Modafinil | ||||||
| Sudhakar et al (2008) 34 | 12 | - Inpatient/outpatient status undescribed, 57% with schizophrenia | CLZ, OLZ, or RIS | Modafinil 200 mg | 36/32 | Effects on body weight and daytime drowsiness |
| - On atypical antipsychotics for <2 wk | Placebo | 36/31 | ||||
| Nizatidine | ||||||
| Atmaca et al (2003) 35 | 8 | - Inpatients and outpatients with schizophrenia | OLZ | Nizatidine 300 mg | 18/17 | Effects on body weight and leptin |
| - Previous weight gain of >2.5 kg | Placebo | 17/17 | ||||
| Cavazzoni et al (2003) 36 | 16 | - Inpatients/outpatients with schizophrenia, schizoaffective disorder or schizophreniform disorder | OLZ | Nizatidine 300mg/600 mg | 57/35 | Effects on body weight |
| Placebo | 58/33 | |||||
| 60/37 | ||||||
| Atmaca et al (2004) 37 | 8 | - Inpatient/outpatient status undescribed | QTP | Nizatidine 300 mg | 14/13 | Effects on body weight and leptin |
| - Schizophrenia patients with “considerable weight gain” | Placebo | 14/12 | ||||
| Assunção et al (2006) 38 | 12 | - Outpatients with schizophrenia, schizoaffective disorder, or schizophreniform disorder | OLZ | Nizatidine 600 mg | 27 randomized to each group, 45 subjects completed | Effects on body weight |
| - Previous weight gain of ≥5% | Placebo | |||||
| Orlistat | ||||||
| Joffe et al (2008) 39 | 16 | - Inpatients/outpatients with “serious mental conditions” (diagnostic criteria unspecified) | CLZ or OLZ | Orlistat 360 mg | 35/28 | Effects on body weight |
| Placebo | 36/29 | |||||
| Phenylpropanolamine | ||||||
| Borovicka et al (2002) 40 | 12 | - Outpatients with treatment intolerant or resistant schizophrenia | CLZ | Phenylpropanolamine 75 mg | 8/6 | Effects on body weight |
| - Previous weight gain of >10% | Placebo | 8/6 | ||||
| Reboxetine | ||||||
| Poyurovsky et al (2003) 41 | 6 | - Inpatients with first-episode schizophrenia | OLZ | Reboxetine 4 mg | 13/10 | Effects on body weight |
| Placebo | 13/10 | |||||
| Poyurovsky et al (2007) 42 | 6 | - Inpatients with first-episode schizophrenia | OLZ | Reboxetine 4 mg | 31/22 | Effects on body weight |
| Placebo | 28/19 | |||||
| Reboxetine-betahistine combination | ||||||
| Poyurovsky et al (2013) 4 | 6 | - Inpatients with schizophrenia or schizophreniform disorder | OLZ | Reboxetine 4mg and Betahistine 48 mg | 29/22 | Effects on body weight |
| - Predominantly first-episode patients | Placebo | 14/10 | ||||
| Rosiglitazone | ||||||
| Baptista et al (2009) 43 | 12 | - Inpatients with schizophrenia | OLZ | Rosiglitazone 4–8 mg | 15/14 | Effects on body weight, waist circumference, HOMA-IR, HbA1c, and serum lipid levels |
| Placebo | 15/15 | |||||
| Henderson et al (2009) 44 | 8 | - Outpatients with schizophrenia or schizoaffective disorder | CLZ | Rosiglitazone 4 mg | 8/8 | Effects on HOMA-IR |
| - Previously showing insulin resistance or impaired glucose metabolism | Placebo | 10/10 | ||||
| Sibutramine | ||||||
| Henderson et al (2005) 45 | 12 | - Outpatients with schizophrenia or schizoaffective disorder | OLZ | Sibutramine 5–15 mg | 19/16 | Effects on body weight |
| - Previous BMI ≥30 or BMI ≥27 with other defined risk factors | Placebo | 18/15 | ||||
| Henderson et al (2007) 46 | 12 | - Outpatients with schizophrenia or schizoaffective disorder | CLZ | Sibutramine 5–15 mg | 11/10 | Effects on body weight |
| - Previous BMI ≥30 or BMI ≥27 with other defined risk factors | Placebo | 10/8 | ||||
| Biedermann (in press) 50 | 24 | - Outpatients with schizophrenia | Various antipsychotics including CLZ | Sibutramine 10 mg | 7/5 | Effects on body weight |
| - Previous weight gain of >7% or BMI >27 | Placebo | 8/5 | ||||
| Topiramate | ||||||
| Ko et al (2005) 47 | 12 | - Inpatients with schizophrenia | RIS, OLZ, QTP, or CLZ | Topiramate 200mg/100 mg | 66 recruited, 17, 16, and 20 completers in each group | Efficacy and tolerability as a weight-controlling agent |
| - Previous BMI ≥25 | Placebo | |||||
| Afshar et al (2009) 48 | 8 | - Outpatients with schizophrenia | CLZ | Topiramate 50–300 mg | 16 randomized to each group, numbers of dropouts are unclear | Efficacy and tolerability as an adjuvant to CLZ |
| - Poor clinical outcome despite Tx with several antipsychotics | Placebo | |||||
| Narula et al (2010) 49 | 12 | - Inpatients and outpatients with first-episode schizophrenia | OLZ | Topiramate 50–100 mg | 36/34 | Effects on body weight and biochemical/metabolic abnormalities |
| Placebo | 36/33 | |||||
| Zonisamide | ||||||
| Ghanizadeh et al (2013) 5 | 10 | - Outpatients, and inpatients close to discharge | Various antipsychotics including CLZ and OLZ | Zonisamide 50–100 mg | 21/19 | Effects on BMI and body weight |
| - Schizophrenia | Placebo | 20/20 | ||||
| Sibutramine | ||||||
| NCT00044187 (Eli Lilly and Company, unpublished data) | Unspecified | - Schizophrenia, schizophreniform disorder, schizoaffective disorder, and bipolar I disorder | OLZ | Sibutramine (dose unreported) | Estimated enrollment: 130 | Effects on body weight (no data) |
| Placebo | Study completed | |||||
| Amantadine | ||||||
| NCT00287352 (University of North Carolina, Chapel Hill, unpublished data) | 16 | - First-episode psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder, and mood disorders with psychotic features | OLZ | Amantadine 300 mg | Enrollment: 40 | Effects on percentages of body fat, fat utilization, and other metabolic profiles (no data) |
| Placebo | Study completed | |||||
| Rimonabant | ||||||
| NCT00547118 (University of Maryland, unpublished data) | 16 | - Clinically stable inpatients and outpatients with schizophrenia or schizoaffective disorder | Second-generation antipsychotics (details undescribed) | Rimonabant 20 mg | 16 in total | Effects on body weight, metabolic parameters, cardiovascular disease risk, and food satiety (no data) |
| - Previous BMI ≥30 or BMI ≥27 with hyperlipidemia/hypertriglyceridemia | Placebo | Study terminated | ||||
| Naltrexone | ||||||
| NCT00567034 (Mclean Hospital, unpublished data) | 12 | - Schizophrenia or schizoaffective disorder | OLZ | Naltrexone 50 mg | Estimated enrollment: 52 | Effects on body weight and BMI (no data) |
| - Previous BMI ≥30 or BMI ≥27 with symptoms of the metabolic syndrome | Placebo | Recruitment status unknown | ||||
| Betahistine | ||||||
| NCT00709202 (Nathan Kline Institute for Psychiatric Research, unpublished data) | 12 | - Adolescents/young adults with schizophrenia and related psychotic disorders, bipolar disorder, autism | CLZ, OLZ, RIS or QTP | Betahistine 8–24 mg | Estimated enrollment: 40 | Effects on body weight and BMI (no data) |
| - Previous weight gain of >2% | Placebo | Recruitment status unknown | ||||
| Zonisamide SR | ||||||
| NCT00734435 (Orexigen Therapeutics, Inc., unpublished data) | 16 | - Outpatients with schizophrenia, schizoaffective disorder, or schizophreniform disorder | OLZ | Zonisamide SR 360 mg | Enrollment: 26 | Effects on body weight (no data) |
| Placebo | Study terminated | |||||
| Telmisartan | ||||||
| NCT00981526 (University of Massachusetts, Worcester, unpublished data) | 12 | - Outpatients with schizophrenia or schizoaffective disorder | CLZ or OLZ | Telmisartan 40–80 mg | Enrollment: 57 | Effects on insulin resistance and fasting triglycerides (no data) |
| Placebo | Study completed | |||||
| GWP42003:GWP42004 (40:1) | ||||||
| NCT01491490 (GW Pharmaceuticals Ltd., unpublished data) | 6 | - Schizophrenia, schizophreniform disorder, or acute psychosis with schizophrenia symptoms | OLZ | GWP42003:GWP42004 (40:1) | Enrollment: 2 | Effects on body weight |
| Placebo | Study terminated | |||||
Notes: BMI, body mass index (kg/m2); CLZ, clozapine; CPX, clopenthixol decanoate; DBRCT, double-blind randomized controlled trial; HOMA-IR, homeostasis assessment for insulin resistance model (fasting insulin [103 µIU/l] × fasting glucose [mmol/l]/22.5); FPX, flupenthixol decanoate; FPZ, fluphenazine decanoate; OLZ, olanzapine; QTP, quetiapine; RIS, risperidone; SLP, sulpiride; SR, sustained release; Tx, treatment.
aNumbers of randomized/completed subjects do not always match the numbers of subjects included in the analysis.