The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

BACKGROUND: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. METHODS: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. RESULTS: Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. CONCLUSIONS: The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.

Causes of death in clozapine-treated patients in a catchment area: a 10-year retrospective case-control study.

Uncertainty regarding the excess of mortality in patients treated with clozapine persists. A decrease in all-cause mortality, and perhaps also in suicide, after clozapine initiation has been reported, but there are no studies in which preventable causes were ascertained in those taking medication in the long term. Here, we aimed to assess a decade of causes of deaths in a catchment area in patients with schizophrenia chronically treated with clozapine and compared them to a clozapine-treated control cohort. Causes of deaths were classified as suicide, expected (e.g. cancer), and unexpected deaths (encompassing causes of death potentially due to clozapine side effects, and unexplained sudden death). We used descriptive statistics for comparing socio-demographic and clinical factors between the three groups. Logistic regression models were used to examine risk factors associated with unexpected death compared to the control group. We found that the overall mortality was similar to that in previous studies (at 0.8% yearly on average) with unexpected deaths accounting for 52% of total deaths. The unexpected deaths group was on average treated with higher clozapine doses (mean 460 mg/day). A small but significant peak of unexpected deaths was found during the 2018 summer heat wave, which might have exacerbated dose-dependent side effects of clozapine. We suggest increased monitoring for those on higher doses of clozapine as one potential intervention to decrease mortality in this population.