Effects of Clozapine on Cognition in Treatment-Resistant Schizophrenia


Researchers performed a systematic review and meta-analysis of the effects of clozapine on cognitive function in patients with treatment-resistant schizophrenia.




“Ms Cross” is 25-year-old Caucasian female with a 4-year history of schizophrenia, including 4 psychiatric hospitalizations in the past year. She has treatment-resistant positive symptoms, including auditory hallucinations, thought blocking, and grandiose and persecutory delusions. She has associated cognitive impairments, including attention, concentration, and memory.

She has failed previous trials of oral olanzapine, risperidone, and aripiprazole, as well as long-acting injectable paliperidone. She has no medical comorbidities and does not use illicit substances.

Ms Cross’ father, who is her legal guardian, is interested in a trial of clozapine. In addition to the potential for improvement in positive symptoms, he asks about the potential benefits of clozapine on cognition, as Ms Cross dropped out of college following the onset of her illness. As Ms Cross’ outpatient psychiatrist, how would you respond?

Approximately one-third of patients have treatment-resistant schizophrenia (TRS),1 which is associated with poorer functional outcomes.2 Cognitive impairment in schizophrenia is also associated with poorer functional outcomes.3 There is meta-analytic evidence for pronounced deficits in all cognitive domain in patients with TRS compared with antipsychotic-response patients.4

Clozapine is the “gold-standard” medication for patients with TRS.5 Previous reviews of the cognitive effects of clozapine have not explored its effects in the TRS population. Clozapine’s complex pharmacodynamics profile also predicts variable effects on cognition.

The Current Study

Cheuk and colleagues6 performed a systematic review and meta-analysis of the effect of clozapine on 6 domains of cognitive function outcomes in patients with TRS, considering effects of study duration and clozapine dose.

The investigators searched PubMed, PsycINFO, Embase, Web of Science, and Scopus from inception until January 2023. Inclusion criteria were peer-reviewed studies in English of adults who had been diagnosed of DSM or ICD schizophrenia and met operationalized definitions of TRS, clozapine treatment, and cognitive function assessed at baseline and follow-up.

The investigators excluded unpublished studies, abstracts, theses, case reports, series, animal studies, studies without quantitative assessments of cognition, and studies without a clear definition of TRS. The study followed PRISMA guidelines and was registered in PROSPERO.

Cognitive measures were categorized according to 6 key neurocognitive domains: executive function, complex attention, language, learning and memory, perceptual-motor function, and social cognition. Data on study design, sample size, ethnicity, follow-up period, study dropouts, definition of TRS, diagnostic criteria, age, sex, mean clozapine dose, responder/non-responder status, and concurrent medications were extracted.

For each cognitive measure for each study, the investigators computed standardized mean differences (SMD) using Hedges’ g for differences in cognitive performances before and after clozapine treatment.

Data were analyzed used random-effects meta-analysis. Sensitivity analyses were performed based on study duration (<6 vs ≥6 months) and clozapine dose (<450 vs ≥450 mg). Mixed-effects multiple regression models were used to analyze potential moderating variables. Potential publication bias was investigated using Funnel plot analysis and Egger’s test. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist.

The investigators retrieved 27 articles were assessed for eligibility, of which 19 full-text articles (comprising 20 studies) were included in the systematic review. Approximately 13 of these reports (14 studies) were included in the meta-analysis. The 20 studies comprised 490 patients.

The mean age ranged from 32 to 43 years, and approximately 70% of participants were male. The mean illness duration ranged from 1.3 to 21 years, mean follow-up ranged from 6 weeks to 16 months, and mean clozapine dose ranged from 200 to 850 mg/day. Among the included studies, 50 cognitive function measures were reported, of which 12 were included in the meta-analysis.

The overall meta-analysis of cognitive function measures was significant with a small effect size (SMD=0.11, 95% CI 0.02-0.20). In terms of executive function, there were no significant effects of clozapine on the Stroop Test, the Trail Making Test B, or the Wisconsin Card Sorting Test. Regarding complex attention, there was a significant influence of clozapine on Digit Symbol Coding with a small to medium effect size (SMD=0.46, 95% CI 0.17-0.75), but not Trail Making Test A.

In terms of language, there was a significant increase in performance on the Controlled Oral Word Association Test (COWAT) with a small to medium effect size (SMD=0.33, 95% CI 0.06-0.60), but not Trail Making Test A.

Regarding learning and memory, there were no significant effects of clozapine on the Logical Memory and Visual Reproduction immediate and delayed recall under the Wechsler Memory Scale. In terms of perceptual-motor function, there were no significant effects of clozapine on the Perceptual Reasoning Index Scale or the Block Design under the Wechsler Adult Intelligence Scale.

Regarding social cognition, in 2 studies, there were no significant differences in facial recognition or facial emotion recognition with clozapine.

Significant moderators included age, years of education, and change in positive symptoms, but not gender or illness duration. Between-study heterogeneity was significant, but the findings remained significant after removal of 1 outlier (for Digit Symbol Coding). In subgroup analyses, a significant overall effect of clozapine was found only in studies with follow-up periods of ≥6 months (SMD=0.22, 95% CI 0.09-0.37).

In contrast, there was no significant effect on overall cognition based on mean clozapine dose. There were no identified studies with a high risk of bias. However, Egger’s test for potential publication bias was significant.

Study Conclusions

The investigators concluded that clozapine was associated with modest improvements in overall cognitive function in patients with TRS, particularly in studies with a duration of ≥6 months. Patients with younger age, higher education, and more clinical improvement with clozapine have greater improvement in cognitive function.

In terms of specific cognitive domains, clozapine was associated with improvements in complex attention (Digit Symbol Coding) and language (COWAT). Clozapine dose was not associated with changes in cognition.

Study strengths included the larger cumulative sample size of patients with TRS, and the exploration of potential moderating factors through subgroup meta-analysis and meta-regression. Study limitations included the large variation in study designs and reporting quality, that most study populations were Caucasian, and the inability to control for smoking status and concomitant medications that may have impacted on cognition.

The Bottom Line

Clozapine may improve some domains of cognitive function in patients with TRS, particularly over a longer duration. Regular monitoring of cognitive function in this patient population with a brief, easily administered tool such as the Digit Symbol Coding test may have clinical utility.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Conley RR, Kelly DL. Management of treatment resistance in schizophreniaBiol Psychiatry. 2001;50(11):898-911.

2. Iasevoli F, Giordano S, Balletta R, et al. Treatment-resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestonesProg Neuropsychopharmacol Biol Psychiatry. 2016;65:34-48.

3. Green MF. Impact of cognitive and social cognitive impairment on functional outcomes in patients with schizophreniaJ Clin Psychiatry. 2016;77 Suppl 2:8-11.

4. Millgate E, Hide O, Lawrie SM, et al. Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysisPsychol Med. 2022;52(1):1-13.

5. Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophreniaJAMA Psychiatry. 2017;74(7):686-693.

6. Cheuk NKW, Tse W, Tsui HKH, et al. A systematic review and meta-analysis of the effect of clozapine on cognitive functions in patients with treatment-resistant schizophreniaSchizophr Res.

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