Clozapine resistant schizophrenia: Newer avenues of management

Table 6 Augmentation of clozapine with long-acting antipsychotic injections in clozapine-resistant schizophrenia

Ref.	Study details	Results
Kim et al[92], 2010	4 patients treated with clozapine and risperidone LAI for 1 yr	Reduction in number and length of hospitalizations and improvement in social skills after LAI addition. Fewer side effects with the combination.
Malla et al[93], 2013	One patient with poor response to clozapine treated with clozapine and an LAI	Improvement in symptoms and social functioning without any increase in side effects with combination treatment.
Baruch et al[94], 2014	8 patients, 6 with TRS. Treated with olanzapine LAI and clozapine or other antipsychotics up to 2 yr	Reduction in aggression in all 8 patients and in symptom severity in 6 patients.
Maia-de-Oliveira et al[95], 2015	2 patients with CRS treated with clozapine and paliperidone LAI for 9-10 mo	Remission of positive symptoms after LAI augmentation.
Kasinathan et al[96], 2016	9 patients with TRS and comorbid personality disorders/substance use and violence; 1 on clozapine but non-adherent treated with olanzapine LAI combination	1 yr of retrospective pre- and post-LAI comparisons showed significant improvements in psychotic symptoms, violence, and reduction in number and length of hospitalizations and emergency visits.
Sepede et al[97], 2016	One patient with poor response to clozapine treated with clozapine and aripiprazole LAI for 1 yr	Symptoms reduced by 50% with the combination without any increase in side effects.
Oriolo et al[98], 2016	Retrospective observational of 23 patients with TRS in whom paliperidone LAI was added toclozapine	Significant reductions in severity of global, positive, negative, depressive, and cognitive symptoms with the combination. Significantly lower doses of clozapine and paliperidone LAI required with combination treatment vs monotherapy.
Souaiby et al[99], 2017	Retrospective observational study with a mirror-image design of 20 patients with TRS treated with clozapine and LAIs for 32 mo	Significant reductions in number and length of hospitalizations during 32 mo of combination treatment vs 1 yr of monotherapy. No increase in side effects with the combination.
Grimminck et al[100], 2020	Retrospective observational study with a mirror- image design of 20 patients with poor response to clozapine or LAIs treated with clozapine and LAI combinations for 2 yr	Significant reductions in hospital admissions and emergency visits during 2 yr of combination treatment vs 2 yr of monotherapy. Overall improvement in behaviour and social functioning but no change in symptoms.
Bioque et al[101], 2020	Retrospective observational study with a mirror- image design of 50 patients with TRS treated with clozapine and paliperidone LAI for 6 mo	Significant reductions in BPRS scores, emergency visits, number and length of hospitalizations, and number and severity of adverse effects as well as significant improvements in social functioning during 6 mo of combination treatment vs 6 mo of monotherapy.
Caliskan et al[102], 2021	Retrospective observational study with a mirror- image design in 29 patients with TRS treated with clozapine and LAI combinations for 1 yr	Significant reductions in number of relapses and number and length of hospitalizations during 1 yr of combination treatment vs 1 yr of monotherapy. No differences in side effects with the combinations.

BPRS: Brief Psychiatric Rating Scale; CRS: Clozapine resistant schizophrenia; LAI: Long-acting antipsychotic injection; TRS: Treatment resistant schizophrenia.