Patients with schizophrenia are predisposed to becoming overweight through lifestyle factors, including sedentary lives, unhealthy diet, and socioeconomic status [
This study was conducted to review systematically adjunctive treatments for weight reduction in patients with schizophrenia and compare efficacies of clinical trials through meta-analysis, so as to provide effective clinical guideline regarding weight control for patients taking atypical antipsychotics.
Candidate clinical trials were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO. Relevant trials were searched using the following keywords: “weight gain,” “weight loss,” “weight reduction,” “antipsychotics,” “atypical,” “schizophrenia,” “adjunctive,” “additional,” “combine,” “coadministration,” “treatment,” “therapy,” “effect,” “efficacy,” and “clinical trial.” Reference lists of retrieved articles were searched for additional studies. Inclusion criteria for this research were treatment effectiveness from clinical trials of adjunctive treatments added on atypical antipsychotics for adult schizophrenia population and containing outcome data regarding weight and clinical evaluation. Primary outcomes included the reduction in weight determined by body weight (BWT) or body mass index (BMI). Secondary outcomes included psychiatric symptom evaluations measured by the brief psychiatric rating scale (BPRS), the positive and negative syndrome scale (PANSS), or the scale for assessment of positive symptom (SAPS). The exclusion criteria included research from nonpharmacological treatments, secondary data sources, unclear research procedures or outcomes, subjects with comorbid disorders, and population of children or adolescents. Initially, one hundred and thirty-one trials were retrieved by searching for keywords from the databases. Ninety-three trials were excluded after evaluation of abstracts. Full papers of thirty-eight potential trials for inclusion were reviewed using the Joanna Briggs Institute data extraction form [
The trial selection process for inclusion.
Primary outcomes included the Jadad score, atypical antipsychotics as concurrent therapy, type and daily maximum dose of adjunction, treatment duration, sample size and number of drop, weight reduction and significance between groups as primary outcome, and psychiatric symptom evaluation and significance between groups as secondary outcome. Efficacies of adjunctive treatments were compared by primary as well as secondary outcomes including mean change from baseline. Meta-analyses were conducted using the Comprehensive Meta-Analysis version 2 regarding adjunctive treatments with topiramate, sibutramine, metformin, and reboxetine.
Fourteen randomized clinical trials published from 2002 to 2010 were included for this systematic review and meta-analysis (Table
Characteristics of studies for systematic review and meta-analysis.
Number | First author | Jadad score | Concurrent therapy | Augmentation |
Duration (weeks) |
|
Primary outcome |
|
Secondary outcome |
|
---|---|---|---|---|---|---|---|---|---|---|
1 | Fleischhacker (2010) [ |
4 | Clozapine | Aripiprazole (15) |
16 | 108 (0) |
BWT | <0.001 | PANSS | 0.37 |
|
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2 | Narula (2010) [ |
3 | Olanzapine | Topiramate (100) |
12 | 33 (3) |
BMI | 0.004 | PANSS | 0.00 |
|
||||||||||
3 | Afshar (2009) [ |
4 | Clozapine | Topiramate (300) |
8 | 16 (0) |
BMI | ≤0.05 | PANSS | <0.001 |
|
||||||||||
4 | Baptista (2008) [ |
4 | Olanzapine | Metformin (1700) + sibutramine (20) |
12 | 13 (0) |
BWT | 0.19 | BPRS | 0.15 |
|
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5 | Wu (2008) [ |
5 | Olanzapine | Metformin (750) |
12 | 20 (2) |
BWT | <0.02 | SAPS | 0.52 |
|
||||||||||
6 | Baptista (2007) [ |
4 | Olanzapine | Metformin (2250) |
12 | 40 (4) |
BWT | 0.09 | BPRS | ns |
|
||||||||||
7 | Henderson (2007) [ |
5 | Clozapine | Sibutramine (15) |
12 | 10 (0) |
BWT | 0.31 | PANSS | 0.96 |
|
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8 | Poyurovsky (2007) [ |
5 | Olanzapine | Reboxetine (4) |
6 | 31 (9) |
BWT | 0.013 | SAPS | 0.96 |
|
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9 | Baptista (2006) [ |
4 | Olanzapine | Metformin (1700) |
14 | 20 (1) |
BWT | 0.4 | BPRS | ns |
|
||||||||||
10 | Henderson (2005) [ |
4 | Olanzapine | Sibutramine (15) |
12 | 19 (3) |
BWT | 0.009 | PANSS | ns |
|
||||||||||
11 | Poyurovsky (2004) [ |
3 | Olanzapine | Famotidine (40) |
6 | 7 (0) |
BWT | 0.91 | SAPS | 0.54 |
|
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12 | Cavazzoni (2003) [ |
2 | Olanzapine | Nizatidine (300) |
16 | 57 (0) |
BWT | 0.36 | BPRS | 0.63 |
|
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13 | Poyurovsky (2003) [ |
3 | Olanzapine | Reboxetine (4) |
6 | 13 (3) |
BWT | 0.03 | SAPS | 0.83 |
|
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14 | Poyurovsky (2002) [ |
3 | Olanzapine | Fluoxetine (20) |
8 | 15 (4) |
BWT | 0.44 | SAPS | 0.83 |
Meta-analysis of topiramate (
Number | First author | Concurrent therapy | Adjunctive agent |
Duration (weeks) |
|
Primary outcome | Secondary outcome | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Weight reduction | Mean outcome | Mean difference |
|
Psychiatric evaluation | Mean baseline | Mean change |
| ||||||
2 | Narula (2010) [ |
Olanzapine | Topiramate (100) |
12 | 33 (3) |
BMI (kg/m2) | 20.1 |
|
0.004 | PANSS | 102.9 |
−71.7 |
0.001 |
|
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3 | Afshar (2009) [ |
Clozapine | Topiramate (300) |
8 | 16 (0) |
BMI (kg/m2) | 23.2 |
|
≤0.05 | PANSS | 96.9 |
−20 |
<0.001 |
Number | First author | Statistics for each study | Difference in means and 95% CI | Relative weight | ||||
---|---|---|---|---|---|---|---|---|
Difference in means | Standard error | Variance |
|
|
||||
2 |
Narula (2010) [ |
−2.500 |
0.990 |
0.980 |
−2.525 |
0.012 |
|
69.41 |
Heterogeneity:
Meta-analysis of sibutramine (
Number | First author | Concurrent therapy | Adjunctive agent (mg/day, daily max. dose) | Duration (weeks) |
|
Primary outcome | Secondary outcome | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Weight reduction | Mean baseline | Mean change |
|
Psychiatric evaluation | Mean baseline | Mean change |
| ||||||
7 | Henderson (2007) [ |
Clozapine | Sibutramine (15) |
12 | 10 (0) |
BWT (kg) | 104.8 |
−1.9 |
0.310 | PANSS | 63 |
5.3 |
0.96 |
|
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10 | Henderson (2005) [ |
Olanzapine | Sibutramine (15) |
12 | 19 (3) |
BWT (kg) | 102.7 |
−6.8 |
0.009 | PANSS | 54.9 |
−1.9 |
ns |
Number | First author | Statistics for each study | Difference in means and 95% CI | Relative weight | ||||
---|---|---|---|---|---|---|---|---|
Difference in means | Standard error | Variance |
|
|
||||
7 |
Henderson (2007) [ |
−1.400 |
1.335 |
1.783 |
−1.048 |
0.294 |
|
37.18 |
Heterogeneity:
Meta-analysis of metformin (
Number | First author | Concurrent therapy | Adjunctive agent (mg/day, daily max. dose) | Duration (weeks) |
|
Primary outcome | Secondary outcome | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Weight reduction | Mean baseline | Mean change |
|
Psychiatric evaluation | Mean baseline | Mean change |
| ||||||
5 | Wu (2008) [ |
Olanzapine | Metformin (750) |
12 | 20 (0) |
BWT (kg) | 55.7 |
1.9 |
<0.02 | SAPS | 8.5 |
−6.3 |
0.52 |
|
|||||||||||||
6 | Baptista (2007) [ |
Olanzapine | Metformin (2250) |
12 | 40 (4) |
BWT (kg) | 66.2 |
−1.4 |
0.090 | BPRS | 15.2 |
|
|
|
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9 | Baptista (2006) [ |
Olanzapine | Metformin (1700) |
14 | 20 (1) |
BWT (kg) | 58.3 |
5.5 |
|
BPRS | 18.3 |
−6.6 |
|
Number | First author | Statistics for each study | Difference in means and 95% CI | Relative weight | ||||
---|---|---|---|---|---|---|---|---|
Difference in means | Standard error | Variance |
|
|
||||
5 |
Wu (2008) [ |
−5.000 |
2.051 |
4.207 |
−2.438 |
0.015 |
|
6.94 |
Heterogeneity:
Meta-analysis of reboxetine (
Number | First author | Concurrent therapy | Adjunctive agent (mg/day, daily max. dose) | Duration (weeks) |
|
Primary outcome | Secondary outcome | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Weight reduction | Mean baseline | Mean change |
|
Psychiatric evaluation | Mean baseline | Mean change |
| ||||||
8 | Poyurovsky (2007) [ |
Olanzapine | Reboxetine (4) |
6 | 31 (9) |
BWT (kg) | 67.1 |
3.3 |
0.013 | SAPS | 6.4 |
−3.2 |
0.96 |
|
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13 | Poyurovsky (2003) [ |
Olanzapine | Reboxetine (4) |
6 | 13 (3) |
BWT (kg) | 65.8 |
2.4 |
0.03 | SAPS | 23.2 |
−18.4 |
0.83 |
Number | First author | Statistics for each study | Difference in means and 95% CI | Relative weight | ||||
---|---|---|---|---|---|---|---|---|
Difference in means | Standard error | Variance |
|
|
||||
8 |
Poyurovsky (2007) [ |
−1.600 |
0.624 |
0.389 |
−2.564 |
0.010 |
|
81.29 |
Heterogeneity:
Psychiatric evaluations, evaluated by PANSS, BPRS, and SAPS, did not show statistically significant changes between treatment groups and placebo groups except topiramate adjunction (
Since the occurrence of dilemma of weight gain in patients receiving atypical antipsychotics, various efforts have been tried to solve the problem. Present study shows the trends of trials by time transition. In the early 2000s, fluoxetine, nizatidine, and famotidine were examined as choices of adjunctive treatments for weight control regarding atypical antipsychotics [
Reboxetine is a selective norepinephrine reuptake inhibitor (NRI) and is a new psychotropic drug broadly used as an antidepressant and antianxiety agent, which has been reported to have effects on weight loss [
Sibutramine is a weight loss agent affecting both serotonin and norepinephrine reuptake, which partly mediates activation of the serotonin 5-HT2c receptor that associated with weight loss [
Since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, and myocardial infarction) were reported in sibutramine-treated patients [
Metformin is a hepatic-selective insulin sensitizer, which reduces weight, blood glucose, insulin, and hemoglobin A1c (HbA1c) levels in obese nondiabetic adults [
Aripiprazole is a partial agonist at D2 dopamine and 5-H
Topiramate has been associated with weight loss as a side effect by reduced appetite related to the mechanism of potentiating GABAergic transmission and antagonism of AMPA glutamate receptors; its precise mechanism remains under investigation [
Limitations of this study include that small number of trials have been selected as relevant trials among 131 trials, which may prohibit direct application or generalization of the results. In addition, there is still controversy regarding weight gain and metabolic side effects across available antipsychotic drugs showing distinction between typical and atypical drugs. Thus, in this study, we have focused on the issue related with olanzapine and clozapine, which have evidences of side effects concerning weight gain and metabolic syndrome, which needs conscious deliberation on discourse concerning results of this study.
Adjunctive treatments of metformin, sibutramine, topiramate, and aripiprazole are significantly effective to reduce weight for patients receiving atypical antipsychotics. While it presented larger weight reduction, sibutramine is not a choice of option, which was withdrawn from the US market for critical cardiovascular adverse events. Although metformin outperformed other agents that have been studied against placebo, the current evidence is too limited to support its regular clinical use as an adjunctive medication and it needs additional proofs of safety regarding Alzheimer’s disease. Though having several reports related to exacerbation of psychiatric symptoms, topiramate and aripiprazole are more efficacious than other medications in regard to weight reduction and less burden of critical adverse effects as well as being beneficial for clinical improvement. Results of this study provide opportunity to consider adjunctive treatments added to atypical antipsychotics for weight control and/or metabolic syndrome in patients with schizophrenia.
The author declares no conflict of interests in the paper.