Which subjectively perceived side-effects occur the most in high-dose clozapine use

Abstract

Background: Awareness of severe clozapine side-effects is an important factor for good therapeutic alliance and for prevention of treatment discontinuation. Professionals worry the most about agranulocytosis and routine blood screening, while patients are mainly concerned about physical symptoms, such as hypersalivation and sleepiness [1,2]. While the life-threatening side effects are dose independent and typically occur during the initial phase, the more common, non-lethal side effects,can occur at all times during clozapine treatment. The Glasgow antipsychotic side-effects scale for clozapine (GASS-C), developed for measurement of subjective side-effects has been validated in clozapine-treated in- and outpatients [3]. The aim of our study was to investigate whether subjectively perceived clozapine side-effects are dose-dependent. Methods: A demographic questionnaire and GASS-C were given to 95 participants who fulfilled the diagnostic inclusion criteria (age>18, diagnosis of schizophrenia, schizoaffective disorder or unspecified nonorganic psychosis according to ICD-10, and an ongoing treatment with clozapine for at least 7 days). The GASS-C version used in this study contained 16 questions and for each side effect of clozapine, patients noted how often hey had experienced it in the past week (0-never, 1-once, 2-a few times, 3-everyday). Total scores were separated as: 0-16 absent or mild side effects, 17-32 moderate, and 33-48 severe side effects. The participants were instructed to tick a box if they felt a symptom was particularly distressing, no matter how often it occurred. Dosage of clozapine was assessed through patient medical charts. Partial correlation was used to determine how much clozapine doses correlated with the intensity of side effects, controlling for gender and age. Results: Sample consisted of 53.7% male subjects, mean age 46.11±11.61, diagnosed as: F20 (76.8%), F29 (14.7%), F25 (8.4%). Clozapine doses ranged from 25-425mg/day (M=158.16±98.47). Fourty-five patients (47.4%) received another antipsychotic together with clozapine. There was a weak correlation between mean clozapine dose and sexual issues (r=.23, p<0.05), hypersalivation (r=.25, p<0.05), as well as total GASS-C scores (r=.22, p<0.05), and moderate correlation between mean clozapine dose and obstipation (r=.30, p<0.05). Conclusion: We found a significant correlation between several distressful side effects and mean clozapine dose. Other studies have shown conflicting reports on this correlation – Yusufi et al. [4] found a reduction of side effectsS106 Abstracts when reducing doses of clozapine, but the study of Hynes et al. [3] did not find any correlation between these two variables. Although they are not life-threatening, the importance of these side effects should not be underestimated as they can lead to treatment cessation. A limitation of our study is that no therapeutic drug monitoring took place, so therapy (in-)compliance could be a potential explanation for the weak to moderate correlation coefficients we found. Also, antipsychotic polypharmacy was not corrected for, which should be rectified in future studies. Furthermore, additional research is needed to explore the link between patients’ reported adverse effects, mean clozapine doses and clozapine serum concentrations.