A nose for innovation: Scientists and clinicians unite to rethink schizophrenia treatment
A neuroscientist, a chemist and a psychiatrist, united by a passion to solve one of the most pressing mental health challenges, have hit on a formulation that may revolutionise the treatment of schizophrenia.
At The University of Queensland, this trio of experts are combining their unique perspectives and knowledge to improve the delivery of clozapine – the most effective anti-psychotic drug.
The Clozapine conundrum: effective but potentially lethal
For the neuroscientist, QBI Professor Darryl Eyles, the project marks the culmination of a distinguished career studying dopamine systems and the underlying risk factors for schizophrenia. A career spanning three decades that has made him acutely aware of the problematic and potentially lethal side effects of clozapine, the ‘gold standard’ in treatment-resistant schizophrenia.
“Many of clozapine’s side effects are peripherally derived, meaning they occur in the body’s organs and systems outside the brain, even though the drug is intended to act in the brain."
“Clozapine’s side-effects can alter the function of the pancreas, the heart, the gut, and the bone marrow, severely impacting the length and quality of a person’s life. Yet, there is no drug-alternative for people who are treatment-resistant.”
Professor Dan Siskind, a long-term research collaborator, agreed. He is an international expert in the treatment of schizophrenia and works clinically as a psychiatrist in Brisbane. He understands only too well the need for a safer, more effective and targeted treatment.
“Clozapine is often the last resort for people with schizophrenia who haven't responded to other medications. For many, it is life-changing – reducing symptoms, hospitalisations, and even suicide risk. But it’s not without risks. Constipation and pneumonia, for example, are the two leading causes of clozapine-related deaths. The drug also carries a tremendous monitoring burden for patients and doctors, with blood tests required before and constantly during its use.”
“How do you avoid the drug hitting the periphery - the gut, the bone marrow, the heart? You deliver it in a more targeted way to the brain through the nose, rather than as a tablet taken orally.”
Professor Dan Siskind, Dr Harendra Parekh, and Dr Preeti Pandey
Professor Dan Siskind, Dr Harendra Parekh, and Dr Preeti Pandey
Rethinking clozapine’s delivery: a more direct route to the brain
The team started to explore the idea of not changing the drug but changing its delivery method.
This is where chemist Dr Harendra Parekh’s expertise comes in. At UQ’s School of Pharmacy and Pharmaceutical Sciences, Dr Parekh was experimenting with packaging drugs to deliver them in alternative ways. Dr Parekh developed a novel intranasal formulation of clozapine, but before it can proceed to human trials, it needed testing in the lab
From the chemist back to the lab
With extensive knowledge of the actions of anti-psychotics in experimental animals, Professor Eyles and his team are leading the preclinical studies.
“When administered intranasally to rats, the new formulation achieved high concentrations of clozapine in the brain while significantly limiting its presence in the bloodstream. In addition, we found that the nasal dose required for antipsychotic-like actions was far less than oral clozapine."
“The intranasal thermoresponsive sol-gel formulation produced an industry-standard antipsychotic effect at just 3.5% of the oral dose required for the same effect.”
Thermoresponsive means the drug carrier is designed to change from a liquid to a watery gel (like weak jelly) when it warms to body temperature, helping the medication to stay in place, releasing into the brain slowly and more effectively.
The dramatic reduction in dosage maintained therapeutic efficacy but also minimised the risk of metabolic side effects, such as elevated blood glucose.
Building on promising preclinical results
The team’s initial findings are limited to animal models in an acute setting; however, they pave the way for further research and future human clinical trials.
Dr Xiaoying Cui and Dr Mia Langguth from the Eyles lab are already testing the longer-term antipsychotic potential of intranasal delivery in rats, as some people take clozapine for life.
Dr Cui explained that alongside these studies, they are conducting more detailed ones examining the drug’s side effects, based on the premise that a lower, more targeted intranasal dose may positively impact peripheral side effects.
“We have started by studying the metabolic outcomes in rats because they are also susceptible to the development of type 2 diabetes, just like people who take clozapine.”
"We will compare the results for animals who are given clozapine intranasally with those taking oral the oral dose for the longer-term side effects and metabolic disease."
Next step: human trials
“We will also test the nasal delivery vehicle in people, checking that it is tolerated and safe. Then, the next challenge is determining the correct dosing for people living with schizophrenia".
“This project is a perfect example of reverse translation, where we have taken clinical observations and built an animal model to better understand the neurobiology. Our hope is that these findings can be forward translated back to the clinic to develop better treatments.”
A new chapter for clozapine
While patients have previously used this drug, they have not encountered it in this form, and clinical trials are required before it can be adopted in practice.
Given its potential to dramatically improve patients' lives, pharmaceutical companies and investors are paying close attention to the intranasal formulation.
The team's findings also underscore the broader potential of advanced drug delivery techniques to enhance outcomes in psychiatric care.
The initial research results are published in Translational Psychiatry.
Professor Eyles' work is funded by The Queensland Centre for Mental Health Research.
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