Clozapine/norclozapine plasma level ratio and cognitive functioning in patients with schizophrenia spectrum disorders: a systematic review.

Background: Extant research on cognitive functioning in treatment-resistant schizophrenia (TRS) is limited and of poor quality. Cognitive impairments in patients with schizophrenia spectrum disorders (SSD) significantly influence quality of life. In patients with TRS, clozapine (CLO) is not consistently associated with improved cognitive functioning. The active metabolite n-desmethylclozapine (norclozapine (NCLO)) potentially exerts procognitive effects due to cholinergic and glutamatergic activity. Unfortunately, research on CLO/NCLO ratio and cognitive functioning is even more scarce.

Objectives: To review the literature on the effect of the CLO/NCLO ratio on cognitive functioning in patients with SSD.

Design: This is a systematic review.

Data Sources And Methods: A search was carried out in the electronic databases Embase, PsycINFO, PubMed, Cochrane and the Cochrane Controlled Register of Trials with no restrictions in language or publication year.

Results: We identified 15 relevant studies (longitudinal,  = 4; cross-sectional,  = 11). The study population consisted of adult clozapine users ( = 953) with varying degrees of treatment resistance. Specific cognitive domains and overall cognitive functioning were assessed using various neuropsychological tests and a composite score, respectively. Eleven studies were considered of fair quality (longitudinal:  = 2, cross-sectional:  = 9). In one longitudinal study, a negative causal relationship was found between the CLO/NCLO ratio and attention/vigilance and a negative correlation between social cognition and the composite score ( = 11). No significant correlations were found between the CLO/NCLO ratio and the cognitive domains processing speed, reasoning/problem solving, or for working memory ( = 1,  = 11), verbal learning ( = 1,  = 43) or visual learning ( = 2,  = 54). Study designs and populations were heterogeneous, and the analysis of confounding factors was limited and inconsistent.

Conclusion: Clinical evidence is too scarce to support the hypothesis of a procognitive effect of NCLO. Personalised CLO treatment by modulating the CLO/NCLO ratio remains a distant prospect. Recommendations for future CLO research and anticipated limitations are discussed.

Trial Registration: This systematic review was preregistered with PROSPERO (CRD42023385244).