A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies, but the range in the studies varied widely from 1.19 to 3.37. No study provided data on variability of the CLO/NCLO ratios within individual patients. The CLO/NCLO ratio is not a measure of CYP1A2 activity and is not associated with clinical response. The association of the CLO/NCLO ratio with cognitive measures is unclear (4 cross-sectional studies were positive and post-hoc analysis of a randomized clinical trial was negative). Future studies must replicate the finding of a case report that gemfibrozil may invert the CLO/NCLO ratio (making it <1), indicating that gemfibrozil inhibits the renal transporter that excretes NCLO.