The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders

Abstract

Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007–2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.

Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records

“…Even though clozapine can very rarely cause fatal agranulocytosis it has been shown that clozapine use reduces total mortality of patients with schizophrenia (24) and reduces the risk of suicide attempts (5). The risk of agranulocytosis is estimated to be around 0.68% (25).…”

The Effect of Clozapine on Hematological Indices

“…51 Interestingly, a prospective 6-month study found similar rates of neutropenia between clozapine and other second generation antipsychotics (ie, olanzapine, risperidone, quetiapine, amisulpride, ziprasidone). 52 Arguably, clozapine's potential benefits outweigh its potential risk of agranulocytosis 46,53 ; as many as 30% of individuals with schizophrenia meet criteria for treatment resistance, with clozapine the only drug currently indicated for TRS. 54 Accordingly, it is important that we minimize barriers to use, and diminishing routine hematologic monitoring for those individuals at low or no risk represents a compelling solution.…”

Data science for mental health: a UK perspective on a global challenge

“…Recent enhancements include the development of natural language processing applications to derive structured information from the text fields present in the electronic mental health record. These include recorded diagnoses, cognitive test scores, pharmacotherapy and symptom profiles [38][39][40][41][42] .…”