New Antipsychotic Medicine Is Called Effective and Safe

In its first Phase Three clinical test, an experimental antipsychotic medicine called lumateperone has shown evidence of being both effective and safe. That is the conclusion of a research team that recently reported results in the journal JAMA Psychiatry.

The need for new medicines to treat people with schizophrenia is universally acknowledged. Medicines to reduce "positive symptoms" of the illness, notably, psychosis, have helped patients for half a century, but are far from perfect.

Neither first- nor second-generation antipsychotics help every patient, and each has characteristic side-effects, such as motor impairments with first-generation drugs and weight gain as well as other metabolic and cardiac impairments with second-generation drugs. Moreover, neither generation of antipsychotics is useful in reducing schizophrenia's "negative symptoms," which include a blunting of affect, a loss of motivation, and retreat from social life.

"An unmet medical need still exists to treat a broad range of symptoms without increasing adverse effects of antipsychotics," noted the research team that conducted the newly reported lumateperone trial. The team was led by Christoph U. Correll, M.D., a 2007 BBRF Young Investigator at the Feinstein Institutes for Medical Research; and Kimberly E. Vanover, Ph.D., of Intra-Cellular Therapies, a company developing lumateperone that funded the study.

One reason lumateperone is of interest to investigators is that it has a mechanism of action that appears to be distinct from that of existing antipsychotic medicines. The drug modifies the activity of three neurotransmitters: serotonin, dopamine, and glutamate. Taken together, the three likely play a role in various symptoms of schizophrenia, including psychosis, as well as in side effects generated by existing antipsychotic medicines.

Perhaps the most important of lumateperone's unique actions is its very potent blockage of the serotonin-2A receptor. Like other antipsychotics, it interacts with the dopamine-2 receptor, although in ways that distinguish it from existing agents. It also acts as a serotonin reuptake inhibitor (the mechanism that characterizes SSRI antidepressants). Finally, lumateperone does not interact with "off-target" receptors that are thought to contribute to the adverse effects of other antipsychotic drugs.

Participants in the randomized, double-blinded trial included 450 patients with schizophrenia, three-fourths were men and with an average age of 42. All were experiencing acute exacerbation of psychosis symptoms as the trial got underway. They were divided into three groups: one received orally delivered lumateperone once daily at a dose of 42mg; a second at a dose of 28 mg; and a third received a placebo. Demographic and clinical characteristics were similar across the three groups. The trial lasted for four weeks, followed by two weeks of follow-up observations.

A total of 359 participants completed the study, including the follow-up. As measured by scores that gauge the intensity of positive and negative schizophrenia symptoms, participants receiving lumateperone at the 42mg dose registered statistically significant improvements compared with those who received placebo. The improvement was noticeable by the eighth day of the trial, the researchers noted and continued through the 28th day. The improvement seen in participants receiving the 28mg dosage was not statistically significant, although, like those receiving the 42mg dose, these participants did see meaningful improvements in a measure of overall symptom severity.

An important part of the results concerned side effects. Although four side effects were seen more with lumateperone than with placebo—sedation (17.3 percent vs 4.0 percent) somnolence (12.7 percent vs 5.4 percent) fatigue (5.3 percent vs 1.3 percent) and constipation (6.7 percent vs 2.7 percent)—none was severe. Equally important, there was no indication that lumateperone was associated with motor abnormalities, weight gain, metabolic, or cardiac side effects.

Taken together, the results justify further Phase Three trials, the researchers said. This would include testing the drug over a much longer period of time since schizophrenia patients typically need to take antipsychotic medicines over periods of years.

In a commentary appearing in JAMA Psychiatry, Joshua T. Kantrowitz, M.D., noted that the trial did not answer the question of whether lumateperone's mechanism of action is in fact novel, or whether it provides clear clinical advantages for patients beyond those offered by currently approved antipsychotics. But even if its efficacy proves to be similar to those of existing medicines, he said, its safety profile, if validated, could provide advantages that might lead fewer patients to stop taking their medications—a major cause of hospitalization and relapse in schizophrenia.

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The research team included Jeffrey A. Lieberman, M.D., BBRF Scientific Council member, 2007 and 1999 BBRF Distinguished Investigator and 2006 Lieber Prize winner; Carol Tamminga, M.D., BBRF Scientific Council member, 2010 and 1988 BBRF Distinguished Investigator and 2011 Lieber Prize winner; and John M. Kane, M.D., 1992 BBRF Lieber Prize winner.