Drug to Enhance NMDA Receptors Studied to Treat Negative Symptoms

An experimental drug called bitopertin, which enhances NMDA receptor activity—that is, boosts glutamate action in the brain—was found in a phase 2 clinical trial to exert modest effects against the negative symptoms of schizophrenia, according to a study by Luca Santarelli, M.D., senior vice-president of neuroscience at Switzerland-based F. Hoffman-La Roche, and colleagues published online April 2 in JAMA Psychiatry.

Deficient NMDA receptor activity has been thought to play a role in the negative symptoms of schizophrenia. The NMDA receptor transmits the signaling of glutamate, the major excitatory neurotransmitter in the brain. However, to do its job, the receptor also needs the amino acid glucine to bind to it.

Thus Santarelli and his team wondered whether a drug that boosts glycine levels and in turn enhances NMDA receptor activity, such as the experimental drug bitopertin, might counter negative symptoms in individuals with schizophrenia. And they launched a phase 2 randomized, double-blind, placebo-controlled trial in 66 sites in Brazil, France, Germany, Hungary, Japan, Mexico, Poland, Russia, and the United States to find out.

The trial involved 323 subjects with schizophrenia and with predominantly negative symptoms. The subjects were randomized to receive, for eight weeks, not only standard antipsychotic therapy, but one of four treatments—bitopertin in daily dosages of either 10 mg, 30 mg, or 60 mg a day, or a placebo. The main outcome measure was a change from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor score. Functioning was evaluated with the Personal and Social Performance (PSP) scale.

The reduction of the PANSS negative factor score was significantly greater in the subjects who received 10 mg or 30 mg a day of bitopertin than in subjects who received a placebo. In contrast, the reductions of the score in subjects who received 60 mg a day of bitopertin and in subjects who received a placebo were comparable.

Moreover, the greatest effect of bitopertin on functioning as evaluated with the PSP scale was observed in the bitopertin group taking 10 mg a day. Changes from baseline PSP total score for the other two bitopertin dose groups did not differ from those in the placebo group.

“Overall, 10 mg a day of bitopertin was most efficacious in reducing negative symptoms. . .while 30 mg a day produced a similar, but somewhat weaker, effect,” the researchers concluded. They had found comparable results in preclinical studies, they noted. Thus, low or moderate doses of bitopertin appeared to be optimal for best clinical efficacy.

In an accompanying editorial, Donald Goff, M.D., a professor of psychiatry at New York University and an expert on translational schizophrenia research, said, “Although the therapeutic effect [of bitopertin] was only modest, this is very welcome news because the path to drug development in schizophrenia has been littered with disappointments.”

The bad news, however, Goff pointed out, is that on January 21, Roche announced that two phase 3 trials of bitopertin for negative symptoms failed to achieve primary end points. “Once again, we are faced with the dilemma of an initial rigorous trial providing support for a compound that is well-grounded in preclinical and clinical studies, followed by a failure to replicate. . . .”

While expressing his disappointment with the phase 3 results for bitopertin, Serdar Dursun, M.D., a professor of psychiatry and neuroscience at the University of Alberta in Canada, said that he remains optimistic that drugs that enhance the NMDA receptor might ultimately prove useful in treating negative symptoms. “There must be improved clinical trial methods that include identification of biomarkers so as to reduce the patient heterogeneity problem in schizophrenia studies,” he explained. “It is possible that modulating the NMDA receptor complex via the glycine site may require a personalized patient-tailored approach involving perhaps pharmacogenetic and/or other studies on biomarkers.”

Indeed, “It’s possible that a subgroup of patients might benefit from these agents, but Roche wasn’t able to identify a biomarker that would predict response,” Goff commented to Psychiatric News.

The study was funded by F. Hoffman-LaRoche Ltd. ■