| Abstract | Schizophrenia is the most severe mental illness affecting humans. When the illness does not respond to treatment, it is even more devastating. When a patient fails to respond to two adequate, consecutive antipsychotic treatments, the illness is termed treatment-refractory schizophrenia (TRS). Clozapine is the only licensed and recognised effective treatment in TRS. Interestingly, rather than its current position as a third-line treatment, there are rather robust and convincing arguments for clozapine to be used as a second line. Sadly, in clinical practice there is widespread underuse of clozapine, with significant delays before it is prescribed in individuals with TRS, being relegated to the fifth or sixth line. Instead, non-evidence-based use of high-dose antipsychotics and the use of antipsychotics in combination is common practice, contributing to even longer delays.
This is a compilation of 33 of my publications and public works (PWs) spanning over two decades, from 1999 to 2021. In these, I explore why clozapine is underused, when it should be used and how it should be used, employing different methodologies. This is a combination of my reviews of the literature and my practical recommendations on how to overcome difficulties in specific situations using case reports and case series. I have collaborated with colleagues from a wide variety of disciplines including psychiatrists, pharmacologists, cardiologists, haematologists and data experts to advance knowledge in the management of TRS through these works. I have investigated various databases and been involved in the design and conduct of randomised controlled trials in schizophrenia.
My work has demonstrated that in the United Kingdom and probably in most other countries, significant variation exists in the rate of clozapine prescribing in patients with TRS. There is thus inequity in patient access to the most effective treatment in refractory schizophrenia. This has an enormous impact on patients and families and may be the difference between long-term institutional care and fulfilling, independent living in the community with freedom and liberty.
The delay and underutilisation of clozapine are centred around four principal factors. These are related to the drug itself, factors that relate to the patient, clinician-related factors and finally, those that pertain to licensing and regulatory control of the drug. Clozapine is a life-prolonging drug, and concerted efforts to overcome these well-recognised barriers would go a long way in improving outcomes in patients with TRS.
I believe that long-term solutions to the underuse of clozapine lie in education. Clinicians treating patients with schizophrenia need to identify patients with TRS as quickly as possible. Health systems to educate, support and encourage clinicians would provide much-needed confidence in evaluating risks and benefit to increase clozapine uptake. The stringent regulatory controls of clozapine should be thoroughly examined. The United States Food and Drugs Administration (FDA) has gone some way by lowering the haematological threshold for clozapine continuation, but more needs to be done.
How can we be confident of overcoming all these seemingly impossible barriers? The answer, I believe, is in developing a national clozapine strategy. The United Kingdom is the centre of research in psychopharmacology. It houses the world-renowned Institute of Psychiatry, Psychology and Neurosciences (IoPPN) with expertise in the management of schizophrenia. A comprehensive national strategy that identifies all the barriers and a systematic approach to addressing the multifaceted problem would address these issues. This approach is not new. It has been successfully applied in countries such as the Netherlands. My PWs have shown that we can not only overcome these barriers, but substantially increase clozapine uptake.
The negative prognostic implications of delay and underuse of clozapine are now becoming glaringly apparent. The outcome for patients where clozapine use is substantially delayed is not as good as in patients where it is initiated as soon as treatment refractoriness is ascertained. When we can fully utilise clozapine in patients with TRS, then we can turn our attention to the 40-50% of patients who have less than satisfactory response to clozapine, or those patients deemed as ultra treatment refractory. |
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