Can J Psychiatry. 2025 Dec 19:7067437251408172. doi: 10.1177/07067437251408172. Online ahead of print.
ABSTRACT
BackgroundGuidelines for treatment-resistant schizophrenia (TRS) advocate for a trial of clozapine monotherapy before the consideration of antipsychotic augmentation. Commonly cited justifications for augmentation include inadequate response to clozapine monotherapy and the potential to lower the necessary clozapine dose or serum concentration, thereby reducing dose-dependent adverse effects. Nonetheless, the degree to which these outcomes are realized in routine clinical practice, particularly among individuals with concurrent disorders, remains uncertain. This study aimed to explore the extent to which clozapine monotherapy is utilized before the initiation of antipsychotic augmentation strategies, and to assess the effects of antipsychotic augmentation on clozapine serum concentrations and the incidence of related adverse effects.MethodsWe retrospectively analyzed clinical and drug monitoring data from 80 adults with TRS and substance use disorder (SUD) comorbidity at a provincial inpatient centre for concurrent disorders. Antipsychotic augmentation was quantified using Defined Daily Dose (DDD). Generalized and linear mixed models compared the impact of monotherapy vs. augmentation on clozapine serum levels and adverse effects, adjusting for covariates.ResultsMost patients receiving antipsychotic augmentation (78%) did not have an adequate trial of clozapine monotherapy. Analysis revealed that clozapine with antipsychotic augmentation was modestly and negatively associated (B = -0.039; 95% CI = -0.078 – -0.001) with clozapine serum concentrations, particularly at higher DDD (≥2). Clozapine with antipsychotic augmentation was not associated with reduced incidence of dose-dependent adverse events (tachycardia, constipation, or overall anticholinergic medication use).ConclusionFindings from this study indicate that commonly cited rationales for combining clozapine with antipsychotic augmentation – namely, enhancing tolerability through clozapine dose reduction or mitigating inadequate response to monotherapy – are not consistently supported by real-world outcomes. These results underscore the necessity for clinical guidelines to incorporate context-sensitive recommendations that address the complexities inherent in managing individuals with TRS and comorbid SUDs, while integrating real-world considerations and the perspectives of those with lived experience.
PMID:41417801 | DOI:10.1177/07067437251408172
Share Evidence Blueprint
Save to Google Notes
Search Google Scholar
Save as PDF
⭐ My Revision List
