A Repeated Time-to-Positive Symptoms Improvement among Malaysian Patients with Schizophrenia Spectrum Disorders Treated with Clozapine

Abstract

Clozapine remains the drug of choice for resistant schizophrenia. However, its dose-response relationship is still controversial. The current investigation aimed to develop a repeated time-to-positive symptoms improvement following the onset of clozapine treatment in Malaysian schizophrenia spectrum disorder patients. Data from patients’ medical records in the Psychiatric Clinic, Penang General Hospital, were retrospectively analyzed. Several parametric survival models were evaluated using nonlinear mixed-effect modeling software (NONMEM 7.3.0). Kaplan–Meier-visual predictive check (KM-VPC) and sampling-importance resampling (SIR) methods were used to validate the final model. A total of 116 patients were included in the study, with a mean follow-up of 306 weeks. Weibull hazard function best fitted the data. The hazard of positive symptoms improvement decreased 4% for every one-year increase in age over the median of 41 years (adjusted hazard ratio (aHR), 0.96; 95% confidence intervals (95% CI), (0.93–0.98)). However, patients receiving a second atypical antipsychotic agent had four-folds higher hazard (aHR, 4.01; 95% CI, (1.97–7.17)). The hazard increased 2% (aHR, 1.02; 95% CI, (1.01–1.03)) for every 1 g increase in the clozapine six months cumulative dose over the median of 34 g. The developed model provides essential information on the hazard of positive symptoms improvement after the first clozapine dose administration, including modifiable predictors of high clinical importance.

Clozapine and norclozapine monitoring in plasma following surfactant assisted dispersive liquid–liquid microextraction

“…Clozapine (CLZ) is a tricyclic dibenzodiazepine antipsychotic and is commonly used in treating schizophrenia, Abbreviations: AM, amperometric; CBZ, carbamazepine; CLZ, clozapine; CMC, critical micelle concentration; CTAB, cetyl trimethyl ammonium bromide; CYP, cytochrome P450; DLLME, dispersive liquid-liquid microextraction; DOX, doxepin; ER, extraction recovery; HALO, haloperidol; LDR, linear dynamic range; NCLZ, norclozapine; SA-DLLME, surfactant-assisted dispersive; liquid-liquid microextraction; TDM, therapeutic drug monitoring especially in nonresponsive patients or those intolerant to the side effects of typical antipsychotics [1]. Norclozapine (NCLZ) or N-desmethylclozapine is the main product of CLZ metabolism by cytochrome P450 (CYP) 1A2 and CYP3A4 enzymes in the liver [2].…”

“…Clozapine (CLZ) is a tricyclic dibenzodiazepine antipsychotic and is commonly used in treating schizophrenia, especially in nonresponsive patients or those intolerant to the side effects of typical antipsychotics [1]. Norclozapine (NCLZ) or N ‐desmethylclozapine is the main product of CLZ metabolism by cytochrome P450 (CYP) 1A2 and CYP3A4 enzymes in the liver [2].…”