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Meta-Analysis
. 2022 Oct 3;10(10):CD013337.
doi: 10.1002/14651858.CD013337.pub2.

Pharmacological interventions for prevention of weight gain in people with schizophrenia

Sri Mahavir Agarwal #  1 , Nicolette Stogios #  2 , Zohra A Ahsan  1 , Jonathan T Lockwood  1 , Markus J Duncan  3 , Hiroyoshi Takeuchi  1 , Tony Cohn  1 , Valerie H Taylor  4 , Gary Remington  1 , Guy E J Faulkner  3 , Margaret Hahn  1
Affiliations
Meta-Analysis

Pharmacological interventions for prevention of weight gain in people with schizophrenia

Sri Mahavir Agarwal et al. Cochrane Database Syst Rev. .

Abstract

Background: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem.

Objectives: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia.

Search methods: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register.

Selection criteria: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications.

Data collection and analysis: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI.

Main results: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence.

Authors' conclusions: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

Trial registration: ClinicalTrials.gov NCT00176449.

PubMed Disclaimer

Conflict of interest statement

Hioyoshi Takeuchi: has received speaker fees from EA Pharma, Janssen Pharmaceuticals, Kyowa, Lunbeck LLC, Meiji Sieka Pharma, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company, and Yoshitomiyakuhin. He has also received consultant fees from Janssen Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation, and Sumitomo Dainippon Pharma Co., Ltd. However, he declares that he did not receive any direct payment for completion of this review.

Margaret Hahn: has received consultant fees from Alkermes, Inc. However, she declares that she did not receive any direct payment for completion of this review.

Gary Remington: nothing to declare

Valerie Taylor: has been on advisory boards for NovoNordisk and Valeant. She has also received honoraria from Sunovion and Shire. However, she declares that she did not receive any direct payment for completion of this review.

Tony Cohn: has received speaker fees from Pfizer Canada Inc. However, he declares that he did not receive any direct payment for completion of this review.

Guy Faulkner: nothing to declare

Sri Mahavir Agarwal: nothing to declare

Nicolette Stogios: nothing to declare

Zohra A Ahsan: nothing to declare

Jonathan T Lockwood: nothing to declare

Markus J Duncan: nothing to declare

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
1.1
1.1. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 1: Weight: average endpoint/change in body weight
1.2
1.2. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 2: Weight: average endpoint/change in body mass index
1.3
1.3. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 3: Weight: average endpoint/change in waist circumference
1.4
1.4. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 4: Leaving the study early: for any reason
1.5
1.5. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 5: Reports of nausea
1.6
1.6. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 6: Mental state
1.7
1.7. Analysis
Comparison 1: Metformin versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 7: Physiological: laboratory measures
2.1
2.1. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 1: Weight: average endpoint/change in body weight
2.2
2.2. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 2: Weight: average endpoint/change in body mass index
2.3
2.3. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 3: Leaving the study early: for any reason
2.4
2.4. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 4: Reports of nausea
2.5
2.5. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 5: Mental state: BPRS (higher = worse)
2.6
2.6. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 6: Mental state: various scales
2.7
2.7. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 7: Adverse effect: headache
2.8
2.8. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 8: Adverse effect: dry mouth
2.9
2.9. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 9: Adverse effect: anxiety
2.10
2.10. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 10: Adverse effect: depression
2.11
2.11. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 11: Adverse effect: dizziness
2.12
2.12. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 12: Adverse effect: increased appetite
2.13
2.13. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 13: Adverse effect: somnolence
2.14
2.14. Analysis
Comparison 2: H2 antagonists versus placebo, Outcome 14: Adverse effect: SAS
3.1
3.1. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 1: Weight: average endpoint/change in body weight
3.2
3.2. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 2: Weight: average endpoint/change in body mass index (BMI)
3.3
3.3. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 3: Leaving the study early: for any reason
3.4
3.4. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 4: Mental state: SANS (higher = worse)
3.5
3.5. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 5: Mental state: SAPS (higher = worse)
3.6
3.6. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 6: Mental state: CGI (higher = worse)
3.7
3.7. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 7: Mental state: HAM‐D (higher = worse)
3.8
3.8. Analysis
Comparison 3: Monoamine modulators versus placebo, Outcome 8: Adverse effects
4.1
4.1. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 1: Weight: average endpoint/change in body weight
4.2
4.2. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 2: Weight: average endpoint/change in body mass index
4.3
4.3. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 3: Leaving the study early: for any reason
4.4
4.4. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 4: Reports of nausea
4.5
4.5. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 5: Mental state
4.6
4.6. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 6: Adverse effects
4.7
4.7. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 7: Physiological: cardiovascular measures
4.8
4.8. Analysis
Comparison 4: Topiramate versus placebo/no‐pharmacological weight gain prevention treatment, Outcome 8: Physiological: laboratory measures
5.1
5.1. Analysis
Comparison 5: Melatonin versus placebo, Outcome 1: Weight: average endpoint/change in body weight
5.2
5.2. Analysis
Comparison 5: Melatonin versus placebo, Outcome 2: Weight: average endpoint/change in body mass index
5.3
5.3. Analysis
Comparison 5: Melatonin versus placebo, Outcome 3: Weight: average endpoint/change in waist circumference
5.4
5.4. Analysis
Comparison 5: Melatonin versus placebo, Outcome 4: Weight: average endpoint/change in hip circumference
5.5
5.5. Analysis
Comparison 5: Melatonin versus placebo, Outcome 5: Weight: average endpoint/change in waist/hip ratio
5.6
5.6. Analysis
Comparison 5: Melatonin versus placebo, Outcome 6: Leaving the study early: for any reason
5.7
5.7. Analysis
Comparison 5: Melatonin versus placebo, Outcome 7: Mental state
5.8
5.8. Analysis
Comparison 5: Melatonin versus placebo, Outcome 8: Physiological: laboratory measures
6.1
6.1. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 1: Weight: clinically important change in weight > 5%
6.2
6.2. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 2: Weight: clinically important change in weight > 7%
6.3
6.3. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 3: Weight: average endpoint/change in body weight
6.4
6.4. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 4: Weight: average endpoint/change in body mass index
6.5
6.5. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 5: Leaving the study early: for any reason
6.6
6.6. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 6: Mental state
6.7
6.7. Analysis
Comparison 6: Reboxetine + betahistine versus placebo, Outcome 7: Adverse events
7.1
7.1. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 1: Weight: clinically important change in weight > 10%
7.2
7.2. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 2: Weight: clinically important change in weight > 7%
7.3
7.3. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 3: Weight: average endpoint/change in body weight (kg)
7.4
7.4. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 4: Weight: average endpoint/change in waist circumference
7.5
7.5. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 5: Leaving the study early: for any reason
7.6
7.6. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 6: Mental state
7.7
7.7. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 7: Physiological: laboratory measures
7.8
7.8. Analysis
Comparison 7: Olanzapine/samidorphan versus olanzapine only, Outcome 8: Adverse events
8.1
8.1. Analysis
Comparison 8: Sensitivity analyses, Outcome 1: Metformin vs placebo excluding studies with high risk of bias: weight: change in body weight
8.2
8.2. Analysis
Comparison 8: Sensitivity analyses, Outcome 2: Metformin vs placebo, fixed‐effect model: weight, change in body weight
8.3
8.3. Analysis
Comparison 8: Sensitivity analyses, Outcome 3: H2 antagonists vs placebo, fixed‐effect model: weight, change in body weight
8.4
8.4. Analysis
Comparison 8: Sensitivity analyses, Outcome 4: Monoamine modulators vs placebo, fixed‐effect model: weight, change in body weight
8.5
8.5. Analysis
Comparison 8: Sensitivity analyses, Outcome 5: Topiramate vs placebo excluding studies with high risk of bias: weight, change in body weight
8.6
8.6. Analysis
Comparison 8: Sensitivity analyses, Outcome 6: Topiramate vs placebo, fixed‐effect model: weight: change in body weight
See this image and copyright information in PMC

Update of

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Baptista 2008 {published data only}11853
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Baptista 2009 {published data only}13545
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Barak 2010 {published data only}
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Barak 2016 {published data only}
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Borba 2011 {published data only}18533
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Borovicka 2002 {published data only}6341
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Bushe 2010 {published data only}
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Carrizo 2009 {published data only}14023
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Chang 2012 {published data only}
    1. Chang JS, Lee NY, Ahn YM, Kim YS. The sustained effects of aripiprazole-augmented clozapine treatment on the psychotic systems and metabolic profiles of patients with refractory schizophrenia. Journal of Clinical Psychopharmacology 2012;32(2):282-4. - PubMed
Chen 2010 {published data only}
    1. Chen JX, Wu SY, Lin R, Chen HE. Metformin combined behavioral intervention therapy of clozapine in the treatment of schizophrenia in patients with body weight, blood glucose, blood lipids. Sichuan Mental Health 2010;23(04):198-202.
Chen 2013 {published data only}22141
    1. Chen CH, Huang MC, Kao CF, Lin SK, Kuo PH, Chiu CC, et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 2013;74:e424-30. [CSZG: 28657] - PubMed
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Chen 2015 {published data only}
    1. Chen PY, Lu ML, Huang MC, Kao CF, Kuo PH, Chiu CC, et al. The relationships of obesity-related genetic variants with metabolic profiles and response to metformin in clozapine-treated patients with schizophrenia. Journal of Clinical Psychopharmacology 2015;35(5):574-8. - PubMed
Chiu 2016 {published data only}
    1. Chiu CC, Lu ML, Huang MC, Chen PY, Lin YK, Lin SK, et al. Effects of low dose metformin on metabolic traits in clozapine-treated schizophrenia patients: an exploratory twelve-week randomized, double-blind, placebo-controlled study. PloS One 2016;11(12):e0168347. - PMC - PubMed
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Correll 2009 {published data only}
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Correll 2013 {published data only}
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Correll 2020b {published data only}
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CTRI/2013/05/003685 2013 {published data only}
    1. CTRI/2013/05/003685. A clinical trial to study the effects of metformin in prevention of olanzapine induced weight gain, type 2 diabetes mellitus and lipid abnormalities in patients with schizophrenia. https://trialsearch.who.int/?TrialID=CTRI/2013/05/003685 (first received 27 May 2013).
Dai 2014 {published data only}
    1. Dai S, Zhu L, Xiao Y. The effects of metformin on obesity, glucose and lipid metabolism caused by antipsychotic drugs in schizophrenia patients [Er jiǎ shuāng guā duì kàng jīng shén bìng yào suǒ zhì jīng shén fēn liè zhèng huàn zhě féi pàng jí táng zhī dài xiè de yǐng xiǎng]. Cháng Zhì Yī Xué Yuàn Xué Bào 2014;24(6):409-10.
Danilov 2014 {published data only}
    1. Danilov DS. The use of aripiprazole in the treatment of obesity associated with the administration of neuroleptics of the second generation in patients with schizophrenia. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova 2014;114(3):34-40. - PubMed
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De Hert 2006 {published data only}
    1. De Hert M, Kalnicka D, Van Winkel R, Wampers M, Hanssens L, Van Eyck D, et al. Treatment with rosuvastatin for severe dyslipidemia in patients with schizophrenia and schizoaffective disorder. Journal of Clinical Psychiatry 2006;67(12):1889-96. - PubMed
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Eriksson 2019 {published data only}
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Fadai 2014 {published data only}26719
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Faghihi 2012 {published data only}
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Fan 2013 {published data only}22243
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Fleischhacker 2010 {published data only}10531
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Ghanizadeh 2013 {published data only}
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Hadley 2009 {published data only}
    1. Hadley S. Metformin for schizophrenia. Stanley Foundation Research Programs 2009.
Hebrani 2015 {published data only}23352
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Heikkinen 1993 {published data only}
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Henderson 2007 {published data only}11286
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Henderson 2009a {published data only}
    1. Henderson DC, Fan X, Sharma B, Copeland PM, Borba CP, Boxill R, et al. A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia. Acta Psychiatrica Scandinavica 2009;119:457-65. [DOI: 10.1111/j.1600-0447.2008.01325.x] - DOI - PMC - PubMed
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Henderson 2009b {published data only}
    1. Henderson DC, Fan X, Copeland PM, Sharma B, Borba CP, Boxill R, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. Journal of Clinical Psychopharmacology 2009;29(2):165-9. - PMC - PubMed
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Henderson 2011 {published data only (unpublished sought but not used)}11955
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Hoffmann 2012 {published data only}
    1. Hoffmann V, Case M, Jacobson J. Algorithms including amantadine, metformin and zonisamide for mitigation of weight gain during olanzapine treatment in outpatients with schizophrenia. In: 162nd Annual Meeting of the American Psychiatric Association; 2009 May 16-21; San Francisco, CA. 2009.
    1. Hoffmann VP, Case M, Jacobson JG. Assessment of treatment algorithms including amantadine, metformin, and zonisamide for the prevention of weight gain with olanzapine: a randomized controlled open-label study. Journal of Clinical Psychiatry 2012;73(2):216-23. - PubMed
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Holka‐Pokorska 2015 {published data only}9751
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Hu 2013 {published data only}
    1. Hu X，Ouyang Z. Efficacy of metformin on serum homocysteine level in schizophrenia patients with olanzapine － induced weight gain [Er jiǎ shuāng guā duì ào dàn píng zhì tǐ zhì liáng zēng jiā de jīng shén fēn liè zhèng huàn zhě xuè qīng tóng xíng bàn guāng ān suān shuǐ píng de yǐng xiǎng]. China Journal of Health Psychology 2013;21(11):1610-11.
IRCT20191223045870N1 {published data only}
    1. IRCT20191223045870N1. Betahistine and weight- related and metabolic measures in schizophrenic patients treated with olanzapin or risperidone. https://www.irct.ir/trial/44644 (first received 13 March 2020).
Ishoy 2017 {published data only}
    1. Ebdrup BH, Broberg BV, Ishoy PL, Bak N, Andersen UB, Jorgensen NR, et al. Erratum: Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial. Diabetes, Obesity and Metabolism 2018;20(5):1327-8. - PMC - PubMed
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    1. Ishoy PL, Fagerlund B, Broberg BV, Bak N, Knop FK, Glenthoj BY, et al. No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia. Acta Psychiatrica Scandinavica 2017;136(1):52-62. - PubMed
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Jamilian 2018 {published data only}
    1. Jamilian H, Shayganfard M. The effects of topiramate on weight gain in patients with schizophrenia: a double-blind randomized placebo-controlled clinical trial. Journal of Pioneering Medical Sciences 2018;8(2):55-9.
Jarskog 2013 {published data only}13295
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Jarskog 2018 {published data only}
    1. Jarskog L, Stroup TS. Metformin and 5-HT2C agonist lorcaserin for weight loss in schizophrenia. Biological Psychiatry 2018;83(9 Suppl 1):S105-6.
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Jiang 2017 {published data only}
    1. Jiang YW, Jiang WH, Ma LH, Zhang TX, Han JJ, Li L. Efficacy of behavioral intervention adjunctive to rosuvastatin for antipsychotic-induced metabolic syndrome. Chinese Journal of Psychiatry 2017;50:295-301.
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Kang 2018 {published data only}
    1. Kang D, Jing Z, Li R, Hei G, Shao T, Li L, et al. Effect of betahistine and metformin on antipsychotic-induced weight gain: an analysis of two clinical trials. Frontiers in Psychiatry 2018;9:620. - PMC - PubMed
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Kelly 2011 {published data only (unpublished sought but not used)}11944
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Khan 2020 {published data only}
    1. Khan MF, Haq SU, Murad K, Nazar Z. Effect of metformin in reduction of anti-psychotic medication induced weight gain in schizophrenia. Journal of Postgraduate Medical Institute 2020;34(1):41-4.
Kim 2007 {published data only}
    1. Kim SI, Sung YM, Paik KW, Yun KW, Kim YC, Lim W. The efficacy of topiramate for weight loss and psychiatric symptom severity in overweight or obese patients maintained on atypical antipsychotics. In: 160th Annual Meeting of the American Psychiatric Association; 2007 May 19-24; San Diego, CA. 2007.
Kim 2016 {published data only}
    1. Kim NW, Song YM, Kim E, Cho HS, Cheon KA, Kim SJ, et al. Adjunctive alpha-lipoic acid reduces weight gain compared with placebo at 12 weeks in schizophrenic patients treated with atypical antipsychotics: a double-blind randomized placebo-controlled study. International Clinical Psychopharmacology 2016;31(5):265-74. - PubMed
Klein 2006 {published data only}
    1. Cottingham EM, Morrison JA, Klein DJ, Barton BA. A randomized, double-blind placebo-controlled trial of metformin (glucophage®) for weight-gain associated with atypical antipsychotics in children and adolescents. In: 159th Annual Meeting of the American Psychiatric Association; 2006 May 20-25; Toronto, Canada. 2006.
    1. 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. American Journal of Psychiatry 2006;163(12):2072-9. - PubMed
Klein 2008 {published data only}
    1. Klein DJ. Metformin treatment of weight gain associated with antipsychotic drug therapy. International Journal of Neuropsychopharmacology 2008;11 Suppl 1:32.
Ko 2005 {published data only}13507
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Kwon 2006 {published data only}
    1. Kwon JS, Choi J-S, Bahk W-M, Kim CY, Kim CH, Shin YC, et al. Weight management program for treatment-emergent weight gain in olanzapine-treated patients with schizophrenia or schizoaffective disorder: a 12-week randomized controlled clinical trial. Journal of Clinical Psychiatry 2006;67(4):547-53. - PubMed
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    1. NCT00485823. The assessment of a weight management program for treatment-emergent weight gain in patients with schizophrenia, schizophreniform disorder, and schizoaffective disorder during olanzapine therapy. https://clinicaltrials.gov/ct2/show/NCT00485823 (first received 13 June 2007).
Larsen 2017 {published data only}
    1. Larsen JR, Vedtofte L, Holst JJ, Oturai P, Kjaer A, Corell CU, et al. Does a GLP-1 receptor agonist change glucose tolerance in patients treated with antipsychotic medications? Design of a randomised, double-blinded, placebo-controlled clinical trial. BMJ Open 2014;4(3):e004227. - PMC - PubMed
    1. Larsen JR, Vedtofte L, Jakobsen MS, Jespersen HR, Jakobsen MI, Svensson CK, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2017;74(7):719-28. - PMC - PubMed
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Li 2013 {published data only}11957
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Li 2020 {published data only}
    1. ChiCTR1900024422. Effects and mechanism of T-cell subgroup imbalance on antipsychotic drug-induced obesity. http://www.chictr.org.cn/showprojen.aspx?proj=34285 (first received 7 October 2017).
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    1. Liú JB, Wú JH. Chlorpromazine, clozapine, risperidone on glucose metabolism in patients with first-episode schizophrenia, the effects of blood lipids and weight [Dàn píng lì péi tóng duì shǒu fā jīng shén fēn liè zhèng huàn zhě táng dài xiè xuè zhī hé tǐ zhòng de yǐng xiǎng]. Chinese Journal of Nervous and Mental Diseases 2004;30(4):293-5.
Lu 2004 {published data only}
    1. Lu M-L, Lane H-Y, Lin S-K, Chen K-P, Chang W-H. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. Journal of Clinical Psychiatry 2004;65(6):766-71. - PubMed
Lyu 2018 {published data only}
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Maagensen 2021 {published data only}
    1. Larsen JR, Vedtofte L, Jakobsen MS, Jespersen HR, Jakobsen MI, Svensson CK, et al. The GLP-1 analog liraglutide improves glucose tolerance and reduces body weight in schizophrenia spectrum disorder patients treated with clozapine or olanzapine. Acta Neuropsychiatrica 2017;29:12-3.
    1. Maagensen H, Larsen JR, Jorgensen NR, Fink-Jensen A, Vilsboll T. Liraglutide does not change bone turnover in clozapine- and olanzapine-treated schizophrenia overweight patients with prediabetes - randomized controlled trial. Psychiatry Research 2021;296:113670. - PubMed
Martin 2019 {published data only}
    1. Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. American Journal of Psychiatry 2019;176(6):457-67. - PubMed
McElroy 2012 {published data only}
    1. McElroy SL, Winstanley E, Mori N, Martens B, McCoy J, Moeller D, et al. A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain. Journal of Clinical Psychopharmacology 2012;32(2):165-72. [DOI: 10.1097/JCP.0b013e3182488758] - DOI - PubMed
Mehta 2014 {published data only}
    1. CTRI-2014-07-004740. Efficacy of ranitidine in olanzapine induced weight gain: a dose response study. http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=7044&... (first received 15 July 2014).
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    1. Mehta VS, Ram D. Role of ranitidine in negative symptoms of schizophrenia--an open label study. Asian Journal of Psychiatry 2014;12:150-4. - PubMed
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Muscatello 2011a {published data only}
    1. Millar H, Felter C, Landsberg W. The effects of aripiprazole in combination with clozapine: patient functioning results from a double-blind, 16-week study in patients with schizophrenia (CN138-170). Journal of Psychopharmacology (Oxford, England) 2008;22(5):A17.
    1. Muscatello MR, Bruno A, Pandolfo G, Mico U, Scimeca G, Di Nardo F, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophrenia Research 2011;123(1-3):93-9. [DOI: 10.1016/j.schres.2010.12.011] - DOI - PubMed
Muscatello 2011b {published data only}
    1. Muscatello MR, Bruno A, Mico U, Bellinghieri PM, Scimeca G, Cacciola M, et al. Topiramate augumentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Journal of Psychopharmacology 2011;25(5):667-74. [DOI: 10.1177/0269881110372548] - DOI - PubMed
NCT00044187 {unpublished data only}
    1. NCT00044187. The assessment of sibutramine for the treatment of olanzapine-associated weight gain in subjects with schizophrenia, schizophreniform disorder, schizoaffective disorder, and bipolar I disorder. https://clinicaltrials.gov/ct2/show/NCT00044187 (first received 23 August 2002).
NCT00114595 {published data only}
    1. NCT00114595. A double-blind, randomised, parallel-group comparison of ethyl-eicosapentaenoic acid (ethyl-epa) versus placebo as add-on medication in patients with established tardive dyskinesia. https://clinicaltrials.gov/show/NCT00114595 (first received 23 June 2005).
NCT00320723 {published data only}
    1. NCT00320723. Nicotine replacement therapy added to cognitive behavioral therapy for smoking cessation in patients with major mental illness. https://clinicaltrials.gov/show/NCT00320723 (first received 3 May 2006).
NCT00425815 {published data only}
    1. NCT00425815. A placebo-controlled trial of org 24448 (ampakine) added to atypical antipsychotics in patients with schizophrenia. https://clinicaltrials.gov/ct2/show/NCT00425815 (first received 23 January 2007).
NCT00512070 {published data only}
    1. NCT00512070. Melatonin metabolism abnormality in patients with schizophrenia or schizoaffective disorder treated with olanzapine and melatonin dose finding for the correction of the metabolic abnormality. https://clinicaltrials.gov/show/NCT00512070 (first received 7 August 2007).
NCT00672464 {published data only}
    1. NCT00672464. Cardio risk of acute schizophrenia olanzapine Duke (CRASOD). https://clinicaltrials.gov/show/NCT00672464 (first received 5 May 2008).
NCT01491490 {unpublished data only}
    1. NCT01491490. A randomised, double-blind, placebo-controlled parallel group, pilot study of 40:1 ratio of formulated GWP42003:GWP42004 in the treatment of iatrogenic weight gain and dyslipidaemia associated with olanzapine or other antipsychotic(s) treatment in subjects with schizophrenia or other non-affective psychosis. https://clinicaltrials.gov/ct2/show/NCT01491490 (first received 14 December 2011).
NCT03132571 {unpublished data only}
    1. NCT03132571. A pilot study of naltrexone – bupropion combination versus placebo combined with bupropion for weight loss in comorbid schizophrenia. https://clinicaltrials.gov/ct2/show/NCT03132571 (first received 28 April 2017).
Peng 2016 {published data only}
    1. Peng PJ, Ho PS, Tsai CK, Huang SY, Liang CS. A pilot study of randomized, head-to-head of metformin versus topiramate in obese people with schizophrenia. Clinical Neuropharmacology 2016;39(6):306-10. - PubMed
Pierre 2007 {published data only}
    1. Pierre JM, Peloian JH, Wirshing DA, Wirshing WC, Marder SR. A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. Journal of Clinical Psychiatry 2007;68(5):705-10. - PubMed
Qi 2014 {published data only}
    1. Pan Q, Chen F, Ouyang H. Metformin addition therapy attenuates serum levels of leptin in schizophrenia with olanzapine-induced weight gain [èr jiǎ shuāng guā duì ào dàn píng zhì tǐ zhòng zēng jiā de jīng shén fēn liè zhèng huàn zhě xuè qīng shòu sù shuǐ píng de yǐng xiǎng]. China Journal of Health Psychology 2014;22(6):826-8.
Radulovic 2002 {published data only}
    1. Radulovic L, Weiden PJ, Allison DB, Camille C. Sibutramine treatment of obesity in schizophrenia. In: 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia, Pennsylvania, USA. 2002.
Ranjbar 2013 {published data only}
    1. Ranjbar F, Ghanepour A, Sadeghi-Bazargani H, Asadlo M, Alizadeh A. The effect of ranitidine on olanzapine-induced weight gain. Biomedical Research International 2013;2013:639391. - PMC - PubMed
Reeves 2013 {published data only}
    1. Reeves GM, Keeton C, Correll CU, Johnson JL, Hamer RM, Sikich L, et al. Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods. Child and Adolescent Psychiatry and Mental Health 2013;7(1):31. - PMC - PubMed
Simmons 2018 {published data only}
    1. David M, Simmons A, Jiang Y, Graham C, Silverman B. A study comparing weight gain from ALKS 3831 to olanzapine in early-illness young adults with schizophrenia, schizophreniform, or bipolar I disorder. European Neuropsychopharmacology 2017;27 Suppl 4:S954.
    1. EUCTR2017-000497-11-AT. Study to evaluate the efficacy of ALKS 3831 on body weight in young adults who have been recently diagnosed with schizophrenia, schizophreniform or bipolar I disorder. https://www.clinicaltrialsregister.eu/ctr-search/search?query=EUCTR2017-... (first received 2017).
    1. NCT03187769. Study to evaluate the efficacy of ALKS 3831 on body weight in young adults who have been recently diagnosed with schizophrenia, schizophreniform, or bipolar I disorder. https://clinicaltrials.gov/ct2/show/NCT03187769 (first received 15 June 2017).
    1. Simmons A, McDonnell D, Jiang Y, Graham C, Silverman B. A study comparing weight gain from ALKS 3831 to olanzapine in early-illness young adults with schizophreniform, schizophrenia, or bipolar I disorder. Schizophrenia Bulletin 2018;44 Suppl 1:S413-4.
Siskind 2018 {published data only}
    1. ACTRN12615000524594. A pilot study on the effect of once weekly exenatide compared to treatment as usual for weight loss and glycaemic control in schizophrenia patients with obesity and diabetes. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368512 (first received 9 May 2015).
    1. Mayfield K, Siskind D, Winckel K, Hollingworth S, Kisely S, Russell AW. Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: study protocol for a pilot randomised controlled trial. BJ Psych Open 2015;1(1):67-73. - PMC - PubMed
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    1. Siskind D, Russell A, Gamble C, Winckel K, Hollingworth S, Kisely S. Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: a randomised controlled trial. Schizophrenia Bulletin 2018;44 Suppl 1:S178.
    1. Siskind D. Treatment of clozapine-associated obesity and diabetes with exenatide (codex) in adults with schizophrenia. Australian and New Zealand Journal of Psychiatry 2017;51 Suppl 1:68.
Siskind 2020 {published data only}
    1. Siskind D, Russell A, Gamble C, Baker A, Cosgrove P, Burton L, et al. Metabolic measures 12 months after a randomised controlled trial of treatment of clozapine associated obesity and diabetes with exenatide (CODEX). Journal of Psychiatric Research 2020;124:9-12. - PubMed
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Smith 2013 {published data only}
    1. Smith RC, Jin H, Li C, Bark N, Shekhar A, Dwivedi S, et al. Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: a randomized double-blind study. Schizophrenia Research 2013;143(1):18-24. - PubMed
Smith 2018 {published data only}
    1. Smith RC, Maayan L, Wu R, Youssef M, Jing Z, Sershen H, et al. Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study. Psychopharmacology 2018;235(12):3545-58. - PubMed
Strous 2007 {published and unpublished data}
    1. Strous RD, Stryjer R, Maayan R, Gal G, Viglin D, Katz E, et al. Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following dehydroepiandrosterone (DHEA) administration in olanzapine treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Psychoneuroendocrinology 2007;32(2):96-105. [PMID: ] - PubMed
Sulejmanpasic 2019 {published data only}
    1. Sulejmanpasic G, Bise S, Pepic F, Toskic A. Adjunctive treatment of aripiprazole to olanzapine for weight reduction in patients with schizophrenia. European Neuropsychopharmacology 2019;29:S90.
    1. Sulejmanpasic G, Bise S, Toskic A, Pepic F. Olanzapine augmented with aripiprazole in treatment-resistant schizophrenia. European Neuropsychopharmacology 2019;29:S89-S90.
Talaei 2016 {published data only}
    1. Talaei A, Faridhosseini F, Kazemi H, Fayyazi Bordbar MR, Rezaei Ardani A. Effect of topiramate on drug associated weight gain of patients with schizophrenia and bipolar I disorders: a dose ranging randomized trial. Turkish Journal of Psychiatry [Turk psikiyatri dergisi] 2016;27(2):84-91. - PubMed
Tavakoli 2014 {published data only}
    1. Tavakoli E, Rezaei O, Fadai F. A comparison on composition of celery, dill and green tea as three medicinal plants with placebo to treat schizophrenic patients' metabolic syndrome. Afinidad 2014;80(573):1118-23.
Taveira 2014 {published data only}
    1. Taveira TH, Wu WC, Tschibelu E, Borsook D, Simonson DC, Yamamoto R, et al. The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: a randomized double-blind placebo-controlled pilot study. Journal of Psychopharmacology (Oxford, England) 2014;28(4):395-400. - PubMed
Tek 2014 {published data only}
    1. Tek C, Ratliff J, Reutenauer E, Ganguli R, O'Malley SS. A randomized, double-blind, placebo-controlled pilot study of naltrexone to counteract antipsychotic-associated weight gain: proof of concept. Journal of Clinical Psychopharmacology 2014;34(5):608-12. - PMC - PubMed
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    1. Tek C, Ratliff JC, Reutenauer EL, Palmese LB, Tonizzo KM, O'Malley SS. Naltrexone for antipsychotic-induced weight gain in women with schizophrenia. Biological Psychiatry 2011;69(9 Suppl):283.
Terevnikov 2013 {published data only}
    1. Terevnikov V. Clinical effects of mirtazapine added to first generation antipsychotics in schizophrenia [Dissertation]. Helsinki, Finland: Medical Faculty of the University of Helsinki, 2013.
Tiihonen 2005 {published data only}
    1. Tiihonen J, Halonen P, Wahlbeck K, Repo-Tiihonen E, Hyvarinen S, Eronen M, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. Journal of Clinical Psychiatry 2005;66(8):1012-15. - PubMed
Wang 2009 {published data only}
    1. Wang XL. Metformin with life style intervention in treatment of clozapine - induced metabolic disorders. Chinese General Practice 2009;12(5B):840-2.
Wang 2010 {published data only}
    1. Wang SS, Wang CF, Zhang K, Cao CB, Gu DH, Yu ZH. Propofol and etomidate mect combined low-dose aripiprazole in the treatment of schizophrenia control study of 160 cases. Medical Journal of Chinese People's Health 2010;22(3):252-5, 257.
Wang 2012 {published data only}19105
    1. Wang M, Tong J-h, Zhu G, Liang G-M, Yan H-f, Wang X-Z. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophrenia Research 2012;138(1):54-7. [CSZG: 23834] - PubMed
Wang 2020a {published data only}
    1. Wang L, Chen Y, Sui YC, Tan XQ, Zhou Z, Li N, et al. Metformin attenuates liver fat content: finding from schizophrenia patients with olanzapine-induced weight gain. Clinical Psychopharmacology and Neuroscience 2020;18(1):67-74. - PMC - PubMed
Wang 2020b {published data only}
    1. Wang C, Shi W, Xu J, Huang C, Zhu J. Outcomes and safety of concomitant topiramate or metformin for antipsychotics-induced obesity: a randomized-controlled trial. Annals of General Psychiatry 2020;19:68. - PMC - PubMed
Weber 2006 {published data only}
    1. Weber M, Wyne K. A cognitive/behavioral group intervention for weight loss in patients treated with atypical antipsychotics. Schizophrenia Research 2006;83(1):95-101. - PubMed
Weiner 2012 {published data only}
    1. Weiner E, Ball MP, Buchholz BA, Gold JM, Evins AE, McMahon RP, et al. Buproprion sustained release added to group support for smoking cessation in schizophrenia: a new randomized trial and a meta-analysis. Journal of Clinical Psychiatry 2012;73(1):95-101. [NCT00176449] - PubMed
Whicher 2021 {published data only}
    1. EUCTR2017-004064-35-GB. Liraglutide and the management of overweight and obesity in people with schizophrenia. https://www.clinicaltrialsregister.eu/ctr-search/search?query=EUCTR2017-... (first received 2017).
    1. ISRCTN61129760. Liraglutide and the management of overweight and obesity in people with schizophrenia. https://www.isrctn.com/ISRCTN61129760 (first received 29 November 2017).
    1. Whicher CA, Price HC, Phiri P, Rathod S, Barnard-Kelly K, Ngianga K, et al. The use of liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis: results of a pilot randomised double-blind placebo-controlled trial. Diabetes, Obesity and Metabolism 2021;26(6):1262-71. - PubMed
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    1. Whicher CA, Price HC, Rathod S, Phiri P, Barnard K, Thorne K, et al. Trial design for 'liraglutide and the management of overweight and obesity in people with severe mental illness: A pilot study' in southern health NHS foundation trust. Diabetic Medicine 2019;36 Suppl 1:51.
Wu 2012 {published data only}16701
    1. Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. American Journal of Psychiatry 2012;169(8):813-21. [CSZG: 24499] - PubMed
Yagcioglu 2005 {published and unpublished data}
    1. Yagcioglu AE, Akdede BB, Turgut TI, Tumuklu M, Yazici K, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. Journal of Clinical Psychiatry 2005;66(1):63-72. - PubMed
Yoon 2008 {published data only}
    1. Yoon B-H, Bahk W-M, Bae A, Kim M-K, Jon D-I, Min KJ. Effects of 3-months trial of zonisamide and weight management program in obese schizophrenic inpatients. International Journal of Neuropsychopharmacology 2008;11 Suppl 1:150.

References to studies awaiting assessment

Ginsberg 2004 {published data only}
    1. Ginsberg DL. Add-on sibutramine for olanzapine-induced weight gain. Primary Psychiatry 2004;11(7):24.
Mondal 2014 {published data only}
    1. Mondal H, Paul S, Guha P. Role of metformin versus topiramate in preventing olanzapine associated weight gain and metabolic syndrome. Indian Journal of Pharmacology 2014;1:S21.

References to ongoing studies

NCT04524403 {published data only}
    1. NCT04524403. Study evaluating the safety, efficacy, and pharmacokinetics of miricorilant in obese adult patients with schizophrenia while taking antipsychotic medications (GRATITUDE II). https://clinicaltrials.gov/show/NCT04524403 (first received 24 August 2020).
NL8440 {published data only}
    1. De Boer N, Guloksuz S, Van Baal C, Willebrands L, Deenik J, Vinkers CH, et al. Study protocol of a randomized, double-blind, placebo-controlled, multi-center trial to treat antipsychotic-induced weight gain: the Metformin-Lifestyle In Antipsychotic users (MELIA) trial. BMC Psychiatry 2021;21(1):4. - PMC - PubMed

Additional references

ADA/APA 2004
    1. American Diabetes Association, the American Psychological Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27(2):596-601. - PubMed
Aichhorn 2007
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