A newly published article in the New England Journal of Medicine is reporting the successful results of a clinical trial testing an experimental drug designed to treat psychosis in schizophrenia. The drug works unlike any other existing anti-psychotic medication, and without many of their negative side effects.
The development of anti-psychotic medication in the mid-20th century was a landmark moment in the field of psychiatry. Chlorpromazine (perhaps better known under its trade name, Thorazine) transformed the treatment of schizophrenia in the 1950s. Before it was developed, lobotomy was consistently used as a treatment for major psychosis.
Chlorpromazine, and most subsequent anti-psychotic medications, work by blocking D2 dopamine receptors in the brain. Decreasing dopamine release in certain parts of the brain can result in a reduction of many acute symptoms of psychosis, including delusions and hallucinations. However, these anti-psychotic medications do not generally help the broad volume of other symptoms associated with schizophrenia, and they often result in a number of short and long term side effects.
Over the last few decades researchers have been working hard to develop novel forms of anti-psychotic drugs, that either more specifically target D2 receptors, or home in on entirely new brain pathways. KarXT for example, which targets muscarinic receptors, is currently entering larger Phase 3 trials after reporting successful early results last year.
The latest experimental anti-psychotic to report positive results is called SEP-363856. The new oral compound doesn’t target D2 receptors, but instead activates a pair of different neural receptors, known as TAAR1 and 5-HT1A.
The clinical trial recruited nearly 250 subjects who were suffering from an acute bout of psychosis. The cohort was randomly and blindly split into active and placebo groups, receiving one daily dose of the drug for four weeks.
Efficacy in the trial was calculated using a scale called the Positive and Negative Syndrome Scale (PANSS). The scale ranges from 30 to 210, and the mean score for subjects in the trial experiencing acute psychosis was 101. After the four-week trial the average PANSS score for those in the active treatment group had dropped by 17.2 points, compared to an average drop in the placebo group of 9.7.
Perhaps as importantly, the trial found no significant difference in adverse events between the active and placebo groups. This suggests the experimental drug does not generate the volume of side effects seen with traditional anti-psychotic medications. The longer term effects of the drug are still unclear, but a 26-week extension study did not reveal any significant side effects.
“For the last 60 years, antipsychotics that bind to dopamine receptors have been the standard of care, despite their side effect profile,” says John Krystal, co-author on the new study. “It is my hope that these results for SEP-363856 support a new schizophrenia treatment for people who have been diagnosed with this serious mental health condition. SEP-363856 could have a big impact on people with schizophrenia, their families, and on the public health burden posed by schizophrenia.”
A larger Phase 3 trial is currently underway, spanning a number of sites around the globe. SEP-363856 was granted Breakthrough Therapy status by the FDA in early 2019. So, although a full market approval for the experimental drug may be several years away, the FDA’s designation suggests early data is promising.
The new study was published in The New England Journal of Medicine.
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