Unravelling the paradox of clozapine and mortality in treatment-refractory schizophrenia using linked electronic health records

Schizophrenia is chronic mental disorder characterised by continuous or relapsing episodes of psychosis. During these episodes individuals experience include hallucinations (typically hearing voices), delusions and disorganised thinking. It can be a debilitating condition for patients and their families, with significant wider costs to society.

Individuals with schizophrenia have an estimated 2.5-fold increased risk of premature death compared to the general population and die 15-25-years earlier, mainly due to cardiovascular disease and suicide. This situation is even worse for approximately one quarter of patients with schizophrenia whose illness does not get better with standard antipsychotic medicines: so-called treatment refractory schizophrenia (TRS).

Clozapine is the only antipsychotic that is known to be effective in TRS, and is recommended by the National Institute for Health and Care Excellence (NICE) for all TRS patients.

Given that clozapine is usually prescribed in patients with more severe illness, and clozapine is known to cause a range of potentially fatal side effects, it might be assumed that treatment with clozapine would increase the risk of premature death. Remarkably, the opposite appears to be the case. Several large studies have reported that people who take clozapine are substantially LESS likely to suffer premature death than individuals on other antipsychotics.

Understanding this apparent paradox is crucial, and is the focus of this fellowship. Is clozapine so much more effective at treating schizophrenia that this outweighs the increased risk of side effects? If so, how is clozapine helping?

Is it by reducing suicide, as some studies have suggested, or are other mechanisms at play? Alternatively, were the previous studies which showed this effect biased or otherwise flawed? Will our studies, which will avoid the pitfalls of earlier research, reach the same conclusions?

Using three electronic health records (EHRs), I will investigate the relationship between clozapine and premature mortality risk to see if previous findings showing that clozapine prescription in TRS patients provides a protective effect on mortality, can be replicated. I will design these studies in such a way to avoid the weaknesses of previous studies.

I will also investigate causes of death in patients treated with clozapine, and quantify the protective and detrimental effect of clozapine for these causes of death, to establish if the long-term mortality benefits of clozapine outweigh associated physical health risks. I will then explore the ways in which clozapine might exert its mortality reducing effects.

The EHRs selected span the full care spectrum to offer breadth and richness of information. They will be linked to national clozapine registries, which oversee the prescribing of clozapine in secondary care.

If a clozapine is confirmed to provide a mortality advantage, then wider and earlier use may reduce the mortality gap and health inequalities that exist. Findings could provide reassurance that clozapine's physical health side effects are outweighed by its mortality benefits, and that it should be considered at the earliest opportunity for patients who meet TRS criteria.

Our results may also identify some groups for whom the benefits do not outweigh the risks, and this is important information. Findings may support a case for a review of clozapine treatment guidelines, for restrictions on use to be re-evaluated, and for clozapine to be recommended in some patients but not in others. Elucidating mortality rates from specific causes, would enable prioritisation of specific prevention and intervention strategies.