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.

Brain metabolism during hallucination-like auditory stimulation in schizophrenia.

Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia.