Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment

Ta-Chuan Yeh; Christoph U Correll; Fu-Chi Yang; Mu-Hong Chen; Ping-Tao Tseng; Chih-Wei Hsu; Andre F Carvalho; Brendon Stubbs; Trevor Thompson; Che-Sheng Chu; Chia-Ling Yu; Jae Il Shin; Szu-Nian Yang; Yu-Kang Tu; Chih-Sung Liang

doi:10.1016/j.ajp.2022.103375

Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment

Asian J Psychiatr. 2023 Jan:79:103375. doi: 10.1016/j.ajp.2022.103375. Epub 2022 Nov 26.

Authors

Ta-Chuan Yeh¹, Christoph U Correll², Fu-Chi Yang³, Mu-Hong Chen⁴, Ping-Tao Tseng⁵, Chih-Wei Hsu⁶, Andre F Carvalho⁷, Brendon Stubbs⁸, Trevor Thompson⁹, Che-Sheng Chu¹⁰, Chia-Ling Yu¹¹, Jae Il Shin¹², Szu-Nian Yang¹³, Yu-Kang Tu¹⁴, Chih-Sung Liang¹⁵

Affiliations

¹ Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Psychiatry, Penghu Branch, Tri-Service General Hospital, Penghu, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
² Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany.
³ Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁴ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City, Taiwan; Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁶ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College, Taiwan.
⁷ IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
⁸ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK.
⁹ Centre for Chronic Illness and Ageing, University of Greenwich, London, UK.
¹⁰ Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan; Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung City, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹¹ Department of Pharmacy, Chang-Gung Memorial Hospital, Linkou, Taiwan.
¹² Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
¹³ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Psychiatry, Armed Forces Taoyuan General Hospital, Taoyuan, Taiwan; Graduate Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁴ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. Electronic address: yukangtu@ntu.edu.tw.
¹⁵ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: lcsyfw@gmail.com.

PMID: 36470132
DOI: 10.1016/j.ajp.2022.103375

Abstract

Objective: To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS).

Methods: Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking.

Results: We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93).

Conclusion: Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).

Keywords: Antipsychotic agent; Electroconvulsive therapy; Psychotropic drug; Schizophrenia; Transcranial magnetic stimulation.

Publication types

Meta-Analysis
Systematic Review

MeSH terms

Antipsychotic Agents* / therapeutic use
Clozapine* / therapeutic use
Entropy
Humans
Memantine
Mirtazapine / pharmacology
Mirtazapine / therapeutic use
Network Meta-Analysis
Schizophrenia* / drug therapy

Substances

Clozapine
Memantine
Mirtazapine
Antipsychotic Agents