Absolute and Dose-Adjusted Serum Concentrations of Clozapine in Patients Switching vs. Maintaining Treatment: An Observational Study of 1979 Patients

Abstract

Background Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment. Objective We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service. Methods Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005-2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included. Results In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032). Conclusions The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

Associations of the Gut Microbiome With Treatment Resistance in Schizophrenia

“…Primary traits included schizophrenia diagnosis (72 individuals with schizophrenia and 25 control individuals), treatment resistance (48 individuals with treatment-resistant schizophrenia and 24 with treatment-responsive schizophrenia), and clozapine response (26 responsive vs 22 nonresponsive). Secondary traits included antipsychotic dosage factor using criteria from the British National Formulary (eTable 2 in Supplement 1); clozapine concentration-to-dose ratio (clozapine serum concentration in nanomoles per liter relative to clozapine dose in milligrams per day); metabolic syndrome incorporating waist circumference, blood pressure, triglycerides, cholesterol, fasting plasma glucose, and medications (eTable 3 in Supplement 1); constipation (none/mild or moderate/severe extracted from the Structured Assessment of Gastrointestinal Symptoms Scale question 10, SAGIS); nonpsychiatric medications, including metformin, laxatives, and proton-pump inhibitors; and illness duration since first symptoms and first treatment (in years). Age, sex, BMI, stool type, diet (eFigure 2 in Supplement 1), and physical activity were used as covariates in the variance components and diversity analyses and were also investigated as focal traits in variance components analyses (eMethods in Supplement 1).…”

“…Primary traits included schizophrenia diagnosis (72 individuals with schizophrenia and 25 control individuals), treatment resistance (48 individuals with treatment-resistant schizophrenia and 24 with treatment-responsive schizophrenia), and clozapine response (26 responsive vs 22 nonresponsive). Secondary traits included antipsychotic dosage factor using criteria from the British National Formulary 18 (eTable 2 in Supplement 1); clozapine concentration-to-dose ratio (clozapine serum concentration in nanomoles per liter relative to clozapine dose in milligrams per day) 19 ; metabolic syndrome incorporating waist circumference, blood pressure, triglycerides, cholesterol, fasting plasma glucose, and medications 20…”

Effects of smoking cessation on plasma clozapine concentrations in male patients with schizophrenia during the COVID-19 pandemic

“…It is primarily metabolized by CYP1A2 to its major metabolite N-desmethylclozapine (8). Other cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A4, CYP2C9, and CYP2C19, flavin monooxygenase 3, UDP glucuronosyltransferase 1A4, and the P-glycoprotein transporter ABCB1 are also involved in CLO metabolism (2,(8)(9)(10).…”

Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment

“…28 Recently, we reported that the absolute and dose-adjusted serum concentrations of clozapine were reduced in patients where clozapine was replaced by other antipsychotic drugs. 29 The aim of the present study is therefore to compare metabolite profiles in clozapine patients switching versus maintaining treatment by performing a comprehensive metabolite profiling of clozapine, accounting for smoking habits, which is the major factor determining the rate of clozapine metabolism.…”