Intranasal delivery of clozapine in treatment resistant schizophrenia to reduce side-effects: The preclinical evidence - Professor Darryl Eyles (QBI)

Abstract

Clozapine is the most effective antipsychotic drug in the treatment of schizophrenia. It is the only recommended therapy for treatment resistant schizophrenia but comes with an extensive range of debilitating side-effects. Rare, but serious side-effects involve “off target” actions on bone marrow to produce neutropenia thus compromising the patient’s immune system or gut hypomotility inducing sometimes severe life-threatening constipation. In addition, the onset of metabolic syndrome (a constellation of metabolic problems involving appetite regulation, weight gain, insulin resistance leading to diabetes, and cardiovascular disease) is very common i.e 72% of patients become obese, 48% meet criteria for T2DM, 70% have elevated triglycerides, 56% elevated blood pressure and 45% meet criteria for metabolic syndrome. This is the major reason for patient’s non-compliance. Clinicians are understandably often reluctant to prescribe clozapine thereby increasing psychiatric disease burden. In the absence of any new antipsychotic to rival clozapine, clinicians concentrate on managing these adverse outcomes.

But what if we could change the way the drug was administered to minimize or even avoid such side-effects?

Many of clozapine’s adverse actions come from the drug accessing peripheral sites like bone marrow and the gut. We contend that if the drug could be administered via a route that minimised access to these sites whilst still exerting its antipsychotic actions in the brain then we may be able to greatly reduce side-effect burden. In preclinical studies we have shown acute administration of clozapine intra-nasally gains ready access to the brain and produces an industry-standard antipsychotic action at doses far lower (28 fold), than the corresponding oral dose used to produce the same antipsychotic effect. Here I outline the collaboration between clinical psychiatry, innovative pharmaceutical chemistry and behavioural neuroscience that has achieved this remarkable outcome and what our next steps are prior to clinical trials. 

Bio

Darryl is the Neurobiology laboratory director of the Queensland Centre for Mental Health Research based within the Queensland Brain Institute. He has published 180 manuscripts focused primarily on the basic neurobiology behind the risk factor epidemiology of severe mental illnesses such as schizophrenia and more recently autism. His group models how multiple epidemiologically-validated developmental risk factors for schizophrenia affect brain development. A key discovery is the convergent evidence that foetal dopamine systems are particularly vulnerable to maternal diet/infection/hypoxia creating hyperactive dopamine systems in adults.

This work has led to a reconceptualization of the dopamine hypothesis of schizophrenia as the “dopamine ontogeny hypothesis of schizophrenia.” He has recently established a collaboration between pharmaceutical chemists and consultant clinicians aimed at reducing or even eliminating debilitating side-effects associated with antipsychotic therapy.