Combination Therapy for Treatment-Resistant Schizophrenia?

Psychiatric TimesVol 37, Issue 11
Volume 37
Issue 11

Recent research sheds light on the role of adjunctive long-acting injectable antipsychotics in treatment-resistant schizophrenia.



Clozapine is the “gold-standard” antipsychotic for treatment-resistant schizophrenia, with a 30% to 60% response rate.1 There is evidence to suggest a 6-month trial of clozapine monotherapy to maximize the likelihood of clinical response.2 Presently, there is inconsistent evidence regarding the efficacy of clozapine augmentation with a second antipsychotic.3 No previous studies have explored the potential benefits of the combination of clozapine and a long-acting injectable (LAI) antipsychotic.

Grimminck et al4 aimed to evaluate the effectiveness of this combination using a range of outcome measures including symptomatology, health care utilization, and quality of life. The present study sampled outpatients attending assertive community treatment team clinics in Calgary, Alberta, Canada. They included patients aged 18 years or older with DSM-5 schizophrenia or schizoaffective disorder (with or without comorbid substance use) currently on the combination of clozapine an a LAI antipsychotic. Current treatment with mood stabilizers, benzodiazepines, anticholinergics, and antidepressants were not exclusionary. Exclusion criteria were age > 65; dementia; or a primary substance use disorder diagnosis.

The authors conducted a retrospective observational study with a 2-year mirror image design to compare measures pre- and post the addition of either clozapine or an LAI. In this design, the patient serves as their own control with the only new variable being the initiation of combination treatment.

Outcome measures collected for subjects annually included symptomatology (eg, Brief Psychiatric Rating Scale [BPRS] and the Clinical Global Impressions Scale [CGI]); health care utilization (eg, the number of hospitalizations and emergency department [ED] visits); and quality of life (eg, the World Health Organization Quality of Life scale). Data pre- versus post-combination treatment with clozapine and an LAI antipsychotic were analyzed using paired t-tests.

Twenty patients were included in the study. The mean age was 43 years; 70% were male; and all patients had a diagnosis of schizophrenia. The most common LAI antipsychotics were risperidone (n = 8), paliperidone (n = 6), and zuclopenthixol (n = 3). The authors found a significant reduction in mean ED visits (1.8) and hospital admissions (0.9) in the 2 years post-combination. There was a trend for reduction in alcohol and drug use, though only 3 participants of the study had a diagnosis of comorbid substance use disorder, and a non-significant reduction in the mean number of inpatient mental health days pre- versus post-combination (77 versus 33). Unfortunately, there was significant missing data for psychopathology and quality-of-life scales that precluded formal analysis of these measures.

The authors concluded that the combination of clozapine and an LAI antipsychotic appeared to decrease health care utilization. The primary limitation of the study was missing data on psychopathology and quality of life, as well as the retrospective study design and small sample size.

The bottom line

Further investigation of combination treatment with clozapine a LAI antipsychotic in patients with treatment-resistant schizophrenia is warranted.

Dr Miller is Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

This article was originally posted on September 21, 2020, and has since been updated. Scroll down for the PDF of the full print issue in which it appeared. -Ed


1. Iqbal MM, Rahman A, Husain Z, et al. Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003;15:33-48.

2. Kerwin RW, Bolonna A. Management of clozapine-resistant schizophrenia. Adv Psychiatr Treat. 2005;11:101-106.

3. Barber S, Olotu U, Corsi M, et al. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2010;(1):CD008215.

4. Grimminck R, Oluboka O, Sihota M, et al. Combination of clozapine with long-acting injectable antipsychotics in treatment-resistant schizophrenia: evidence from health care utilization indices. Prim Care Companion CNS Disord. 202;22:19m02560.

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