Clozapine resistant schizophrenia: Newer avenues of management

Table 4 Electroconvulsive therapy and recurrent transcranial magnetic stimulation augmentation in clozapine-resistant schizophrenia

ECT
Ref.	Study/review	Details	Results
Masoudzadeh et al[56], 2007	Controlled trial, (non-randomized, non-blinded)	18 patients with TRS; 3 groups of clozapine-ECT treatment, only clozapine and only ECT treatment (n = 6 each)	Significant differences between the clozapine- ECT combination and monotherapy groups in reduction of PANSS scores.
Petrides et al[54], 2015	Single-blind cross-over RCT	39 patients with TRS randomized to clozapine-ECT (n = 20) and clozapine only treatment (n = 19)	Significantly greater response on BPRS psychosis & CGI scores in the clozapine-ECT combination group.
Melzer-Ribeiro et al[55], 2017	Single-blind sham-controlled RCT	23 patients with CRS randomized to treatment with clozapine-ECT (n = 13) and clozapine-sham ECT (n = 10)	No significant differences between the groups on PANSS total and positive symptom scores and CGI scores.
Kupchik et al[57], 2000	Systematic review	Case reports of 36 patients with TRS and clozapine non-responders	67% of the patients on the clozapine-ECT combination showed good response.
Braga et al[58], 2005	Systematic review	12 case reports or chart reviews of patients with TRS and clozapine non-responders	The clozapine-ECT combination was efficacious.
Havaki-Kontaxaki et al[59], 2006	Systematic review	One open trial and 6 case studies of patients with CRS	73% patients on the clozapine-ECT combination showed marked improvement.
Pompili et al[60], 2013	Systematic review	31 studies examining indications for ECT in schizophrenia	The clozapine-ECT combination was efficacious in patients resistant to medications.
Grover et al[61], 2015	Systematic review	40 studies, mainly case reports of patients with CRS	Short-term response rates of the clozapine-ECT combination varied from 37%-100%.
Lally et al[62], 2016	Systematic review and meta-analysis	Pooled analysis of patients with TRS treated with clozapine and ECT based on 4 open trials, 2 controlled trials (1 RCT)1, 2 chart reviews, 6 case series, and 15 case reports	Pooled response rate with the clozapine-ECT combination was 54% on meta-analysis. Systematic review showed 76% overall response rate with clozapine-ECT treatment and a relapse rate of 32%.
Manubens et al[63], 2016	Systematic review and meta-analysis	6 systematic reviews of ECT in TRS including 6 controlled trials of the clozapine-ECT combination in clozapine non-responders (1 RCT)1	Modest effect of ECT in augmenting clozapine response with low certainty of evidence.
Ahmed et al[64], 2017	Systematic review and meta-analysis	9 studies of the clozapine-ECT combination in TRS including 2 controlled trials (1 RCT)1, 3 open trials, and 4 case series/chart-reviews vs 9 studies of ECT-non-clozapine antipsychotic combination	The ECT-clozapine combination was significantly better than the ECT-non-clozapine antipsychotic combinations in reducing positive symptoms on the PANSS and the BPRS.
Wang et al[52], 2018	Meta-analysis	18 RCTs of clozapine augmentation in CRS (17 from China and 1 from the United States1)	Adjunctive ECT was superior to clozapine monotherapy in reducing positive symptoms after 1–2 wk but with moderate effect size.
rTMS
Wagner et al[66], 2020	Meta-analysis	Pooled data from 10 RCTs for 131 patients with persistent positive and negative symptoms being treated with clozapine	No differences between active and sham rTMS in improving clinical response and reducing PANSS scores. No benefit of rTMS augmentation for patients with persistent symptoms on clozapine.

¹The RCT from United States is by Petrides et al[54].

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression scale; CRS: Clozapine-resistant schizophrenia; ECT: Electroconvulsive therapy; PANSS: Positive and Negative Syndrome Scale; RCT: Randomized controlled trial; rTMS: Recurrent transcranial magnetic stimulation; TRS: Treatment resistant schizophrenia.