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

Research output: Contribution to journalArticlepeer-review

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.)

Original languageEnglish
Article number103375
JournalAsian Journal of Psychiatry
Volume79
DOIs
Publication statusPublished - 2023 Jan

Bibliographical note

Funding Information:
The study was supported by Tri-Service General Hospital Penghu Branch ( TSGH-PH-E-110011 to T.-C.Y.). The funding source had no role in any process of our study.

Publisher Copyright:
© 2022 Elsevier B.V.

All Science Journal Classification (ASJC) codes

  • Psychology(all)
  • Psychiatry and Mental health

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