Clozapine resistant schizophrenia: Newer avenues of management

Table 2 Reviews of antipsychotic augmentation strategies in clozapine-resistant schizophrenia¹

Ref.	Type of review	Details	Effect on positive or psychotic symptoms	Effect on negative or depressive symptoms
Wagner et al[2], 2019	Systematic review	14 meta-analyses of FGA and SGA augmentation of clozapine.	Some evidence of benefits based on low-quality studies (SIGN grade B).
Roerig et al[8], 2019	Systematic review	4 meta-analyses and 1 naturalistic study of FGA and SGA augmentation of clozapine.	No benefits of antipsychotics when high-quality RCTs were considered.
Bartoli et al[22], 2019	Meta-analysis	12 RCTs of SGA augmentation of clozapine-risperidone (n = 5) and aripiprazole (n = 3).	No difference between SGA augmentation and placebo in improving positive symptoms.	A small benefit of SGA augmentation for negative and depressive symptoms.
Siskind et al[23], 2018	Meta-analysis	19 RCTs of FGA and SGA augmentation of clozapine-aripiprazole (n = 7), risperidone (n = 3), and amisulpiride (n = 2).	Evidence for benefit with aripiprazole, but effects were lost when low-quality studies were excluded.
Correll et al[24], 2017	Meta-analysis	Meta-analysis of 29 previous meta-analyses of antipsychotic combinations-5 clozapine combinations examined.	Clozapine combinations no different from clozapine monotherapy for positive symptoms.	Clozapine combinations no different from clozapine monotherapy for negative symptoms.
Galling et al[25], 2017	Meta-analysis	20 RCTs of FGA and SGA augmentation of clozapine-risperidone (n = 6) and aripiprazole (n = 6).	No evidence for additional benefits of augmentation in double-blind, high-quality RCTs.	Improvement in negative symptoms with aripiprazole augmentation. No effect of augmentation on depressive symptoms.
Ortiz-Orendain et al[26], 2017	Meta-analysis	31 RCTs and quasi-RCTs of augmentation with SGAs (n = 26) and FGAs (n = 5) including clozapine augmentation.	Low-quality evidence that augmentation improves global clinical response. No specific effects on positive symptoms.	No effect of augmentation on negative symptoms.
Barber et al[27], 2017	Meta-analysis	5 RCTs of clozapine augmentation with SGAs or haloperidol.	Low-quality evidence that augmentation may improve global clinical response. Effects on positive symptoms not clear.	Effects on negative symptoms not clear.
Jiménez-Cornejo et al[28], 2016	Meta-analysis	17 prior meta-analyses and reviews of FGA and SGA augmentation (62 studies) of clozapine.	Little evidence that augmentation improves clinical response (> 20% reduction in PANSS/BPRS scores).
Taylor et al[29], 2012	Meta-analysis	14 RCTs of FGA and SGA augmentation of clozapine.	A small benefit in overall symptom reduction with augmentation.
Sommer et al[30], 2012	Meta-analysis	10 RCTs of FGA and SGA augmentation of clozapine.	One RCT showed that sulpiride augmentation led to overall symptom reduction. No specific effects on positive symptoms.	No specific effects on negative symptoms.
Porcelli et al[31], 2012	Systematic review and meta-analysis	Systematic review of 25 studies of SGA augmentation of clozapine - risperidone (11 trials) and aripiprazole (6 trials). Meta-analysis of 5 RCTs of risperidone augmentation of clozapine.	Low quality evidence indicated benefits for aripiprazole and amisulpiride augmentation. No benefit of risperidone augmentation.	Some benefit of aripiprazole in reducing negative symptoms from 1 RCT.

¹Several other systematic reviews[9,12,14,32,33] and meta-analyses[17,34-37] have been unable to find significant benefits, while others have reported modest benefits for antipsychotic augmentation of clozapine[38-44].

BPRS: Brief Psychiatric Rating Scale; FGA: First-generation antipsychotic; RCT: Randomized controlled trial; PANSS: Positive and Negative Syndrome Scale; SGA: Second-generation antipsychotic; SIGN: Scottish Intercollegiate Guidelines Network.