Trial to combat medication-led obesity

13 December 2016

While most Australians enjoy one of the highest life expectancies of any country in the world, people with mental illness are dying 16 to 20 years younger than the rest of the population. Many of the excess deaths amongst people with illnesses such as schizophrenia are due to obesity and cardiovascular disease, caused in part by the very medications which we use to treat psychosis. “There’s a big health gap for people living with schizophrenia, in that they die 16 to 20 years younger than the rest of the population,” said Associate Professor Dan Siskind, a psychiatrist and researcher with Metro South Addiction and Mental Health Services, at the Princess Alexandra Hospital in Brisbane. “If you look at profile of the essential ‘closing the gap’ policy for indigenous health, we need something similar for people with mental illness. We’re not closing the gap for people with mental illness. The gap is getting wider.” Dr Siskind is leading a trial, underway in Brisbane, to improve the health of people living with schizophrenia who are on an anti-psychotic drug that can also cause obesity. Clozapine is an effective drug used to treat what’s called treatment refractory schizophrenia; schizophrenia that doesn’t respond to other antipsychotic medications. “One of the concerns that people on clozapine tell me, is that they gain weight with the medication, and find it very hard to lose it,” said Dr Siskind. “In part, it’s because the drug they’re taking stops the production of a chemical in the stomach that tells people when they’re full. “About half the people will get metabolic syndrome and become obese. Almost a half will get diabetes over time. Unfortunately, clozapine is far and away our most effective medication for psychosis, and no better medications are in the pipeline.” To help solve the problem of clozapine’s obesity causing side effects, Dr Siskind is involved in a trial of an existing diabetes medication, exenatide. In the lab, exenatide has been shown to stop and even reverse the weight-gaining effects of clozapine. “The research idea came from the consumers I see, who were saying, ‘I’ve become obese and I can't lose weight’.” One of the reasons the anti-psychotic drug clozapine seems to cause weight gain, is that is stops the stomach releasing a chemical that tells people that they’re not hungry anymore. Normally, a chemical called a “glucagon-like peptide” tells the brain during a meal that the stomach is full, and tells the body to process sugar into energy, not fat. It’s believed clozapine suppresses that chemical. A diabetes medication called exenatide, however, has been found to mimic that chemical. The trial is examining if exenatide can prevent excessive weight gain in people on clozapine. The results so far are encouraging. “When I talk to consumers about joining the trial I can say with a fair bit of honesty, ‘I think this is going to help you’,” said Dr Siskind. “I can't guarantee it, but I'm hopeful.” The first randomised control trial of exenatide to treat people living with schizophrenia on clozapine began in April 2016 with funding from Brisbane’s Princess Alexandra Hospital Research Support Scheme, will be run at Metro South Addiction and Mental Health Service, and is one of the projects of the Brisbane Diamantina Health Partners collaboration. If successful, the repurposing of this diabetes drug to treat people on clozapine could save and improve thousands of lives. Clozapine, despite its side effects, remained the best treatment for refractory schizophrenia, but Dr Siskind, who recently co-authored a paper on the subject in the British Journal of Psychiatry, said the side effects of clozapine meant many doctors were reluctant to prescribe it. “Only about eight percent of all people with schizophrenia in Australia get clozapine. One of the barriers is that clinicians are reluctant to give it to them because of the side effects,” he said. “So, if we can ameliorate the side-effects, we can get clozapine to more people who need it, and do less harm.” Although psychosis remains a big health issue in Australia (one in 100 people are diagnosed with schizophrenia), there were few new anti-psychotic drugs coming onto the market. “With that in mind I thought, if we can reduce some of the side-effects of our existing, most effective, medications, we can help more people, and cause less harm.” Treating some of the worst side effects of anti-psychotic drugs will continue to improve the outcome for people with mental illness.

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