Global Research Offers New Hope for Treatment-Resistant Schizophrenia

Imagine hearing voices or seeing things no one else can see or hear. For people with schizophrenia, this is an everyday reality. And for the one in three who have a more severe and intractable form of schizophrenia called treatment-resistant schizophrenia (TRS), the usual medications don’t help.

TRS is one of the most complex and misunderstood disorders in mental health. The go-to treatment, clozapine, is the most effective antipsychotic for reducing symptoms, hospital admissions and mortality for people with TRS. However, clozapine comes with serious side effects and burdensome access requirements for people who rely on the drug to help them function. The very medication that offers hope can also complicate lives.

Since 2016, Professor Dan Siskind and his team at the Queensland Centre for Mental Health Research have been working to change that. Their mission was to make clozapine safer, easier to access and tackle the dangerous physical health side effects that often occur.

“Many people who take clozapine often experience extreme weight gain and other severe side effects that make life tough,” says Professor Siskind. “So, we started running clinical trials that improve the physical and mental health aspects of treatment.”

One of their early breakthroughs came through pairing clozapine with metformin, a common diabetes medication that manages high blood sugar levels. The team discovered that metformin could significantly reduce the extreme weight gain many patients experience, a side effect that often leads people to stop treatment altogether.

But they didn’t stop there. The team conducted nine clinical trials delving into every corner of care: gut health, exercise programs, peer support systems, and even reimagining the staffing models in mental health clinics. In some cases, they brought endocrinologists - specialists in hormonal and metabolic health - directly into psychiatric care. It was a move that changed how patients experienced treatment.

In some cases, clozapine can also cause a condition called neutropenia, where the body struggles to produce enough white blood cells to fight infections. As a result, people taking clozapine are required to undergo monthly blood testing, placing a huge burden on individuals and the health-care system.

“To understand the true risk of clozapine induced neutropenia, my team analysed data from more than 26,000 patients over 32 years and millions of blood tests,” Professor Siskind said.

“Our findings revealed that the risk of neutropenia drops significantly  after the first two years, meaning that strict monthly blood monitoring may not be necessary after this time.”

“We are currently running a global campaign to change the rules around blood monitoring in clozapine. Our work has already influenced changes to the US clozapine monitoring program, by reducing barriers to its access.”

During COVID-19, people on clozapine faced new dangers: the drug they depended on became much harder to access. Dan and his team provided critical guidance on how to safely continue clozapine treatment during the pandemic. Their work helped inform policies in Australia, the UK, France, Japan, and the U.S, and ensured people with TRS were prioritised for vaccinations.

In Australia, Professor Siskind’s research has been a major catalyst for change, spurring one major hospital to increase funding for clozapine services five-fold. It has also inspired new clinic models that bring endocrinologists directly into mental health care, integrating physical and mental health care more seamlessly than ever before. Overseas, the data has guided the creation of new models of care and updates to international guidelines.

The impact of this work is hard to overstate. With more than 180 publications, policy influence in 21 countries, and citations in global media from Al Jazeera to the New York Times, the team’s work has led to real-world changes in how care is delivered worldwide.

Most importantly, their research sends a powerful message: even the most complex mental health conditions are not beyond hope. For the millions around the world living with schizophrenia, especially those with TRS, a brighter future is beginning to take shape. It’s a future made possible by the tireless work of Professor Dan Siskind and his team, whose research proves that with dedication and innovation, better care isn’t just possible, it’s already happening.

Established in 1987, QCMHR is funded by Queensland Health to work state-wide and contribute to the local, national, and global research efforts to improve mental health.

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Laura Corcoran, Research Communications Officer

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