In the continuing effort to develop new medicines to treat schizophrenia, a team led by BBRF Scientific Council member Jeffrey Lieberman, M.D., and including nine other Council Members, BBRF grantees and prize winners, has reported encouraging results from a test of two drugs that target a novel mechanism in the brain. The study was a collaboration between researchers at Columbia, NYU, UC Davis, UCLA, Yale, and University of Alabama at Birmingham.

All currently approved antipsychotic medicines target the brain’s dopamine neurotransmitter system, and specifically, act to inhibit the D2 dopamine receptor. Such medicines include antipsychotics of both the 1st generation (such as chlorpromazine and haloperidol) and 2nd generation (such as clozapine, risperidone and aripiprazole). The compounds tested in the new trial target the glutamate neurotransmitter system, and specifically, act to stimulate two receptors called mGluR2 and mGluR3.

While effective and safe, existing antipsychotic medicines have limitations and leave unmet clinical needs in the treatment of schizophrenia. The so-called “positive symptoms” such as hallucinations and delusions of as many as 30% of people with schizophrenia do not respond to medications, and another 20%-30% of patients only partially respond. Moreover, medicines targeting the D2 receptor, which can have significant neurologic and metabolic side effects, do not have a therapeutic impact on schizophrenia’s “negative symptoms,” which include flat affect, social withdrawal, and the inability to experience pleasure.

There is substantial preclinical and clinical rationale for targeting the glutamate system in developing drugs to treat schizophrenia. The National Institute of Mental Health, hoping to spur development of new medicines to treat psychiatric disorders, has initiated a “Fast-Fail” clinical trial program, in which candidate drugs that have already proven safe in humans can be moved into phase 1B and 2A studies to determine if they engage the biological target(s) in the brain that their hypothesized effectiveness depends upon.

Dr. Lieberman and colleagues conducted an NIMH-supported study of one of the two glutamate-targeting drugs, called POMA (pomaglumetad) and simultaneously, in parallel, conducted a virtually identically designed trial of the other, called TS-134, which was sponsored by its developer, Taisho Pharmaceutical of Japan. In addition to serving on the BBRF Scientific Council, Dr. Lieberman, of Columbia University, is a 2006 Lieber Prize winner for Outstanding Schizophrenia Research and a two-time BBRF Distinguished Investigator.

His team posed the question: do POMA and TS-134 engage with their receptor-targets in brain cells, and if so, at what dosages? POMA had already been tested in a phase 3 study by its developer, Eli Lilly, and failed to generate therapeutic effects at a dosage of 80mg/day per patient. Lilly subsequently discontinued its program to develop the drug. Dr. Lieberman and colleagues postulated that POMA failed to generate therapeutic effects because the doses tested were too low, and perhaps too low to engage the drug’s receptor-target. A parallel study of TS-134 using doses of presumably equal potency was performed in tandem. Such comparisons of novel drugs in early development are highly informative but rarely done.

To determine if the drugs worked and which was better, they were tested in healthy volunteers who were administered the drug ketamine to produce a “pharmacologic model” of schizophrenia. These subjects were individuals aged 18-55 who volunteered to receive a single dose of ketamine known to generate transient psychotic symptoms. In the POMA trial, data from 76 individuals were analyzed: 27 received the high dose (320 mg/day), 21 the low dose (80 mg/day), and 28 received a placebo treatment. The low dose was that used in Lilly’s failed phase 3 trial.

The TS-134 study analysis included 59 healthy volunteers, 25 of whom received the high dose, 24 the low dose and 10 placebo treatment. The only differences in the two studies were: 1) in the POMA study subjects received 10 days of treatments, while those in the TS-134 study were treated for 6 days; and 2) TS-134 study subjects were hospitalized for the duration of the study whereas POMA subjects remained outpatients.

All of the participants were given functional MRI scans to determine whether the drugs were engaging with their receptor-targets, particularly in a region of the brain called the dorsal anterior cingulate cortex (dACC), important in glutamate activity. They were also carefully assessed clinically to determine if ketamine did in fact induce psychosis-like symptoms and whether or how much these were lessened by the administration of POMA or TS-134.

The results supported the studies’ hypotheses and were interpreted by the investigators as warranting continued investigation. “Both drugs ameliorated ketamine-induced symptoms specific to schizophrenia,” they reported in Neuropsychopharmacology, “although only the low dose of TS-134 demonstrated engagement with the target.” They went on to propose that “prior negative results from Lilly’s phase 3 studies may have been due to inadequate doses.” Giving POMA at four times the dose “did show significant suppression of ketamine-induced symptoms,” supporting the notion that the drug was in fact engaging its target.

TS-134 appeared to be more potent, achieving target engagement and symptom reduction at the low dose but not at the high dose tested in the trial. Both drugs were generally safe, but generated some nausea and/or vomiting. TS-134 appeared to be the more potent in generating such effects, a side-effect issue the team dealt with by ramping up dosage gradually as treatments began.

The team concluded: “Our results demonstrate sufficient proof of principle and mechanism to support continued development of mGluR2/3 agonists as treatments for schizophrenia at empirically optimized doses.”

In addition to Dr. Lieberman, the investigators included: Daniel Javitt, M.D., Ph.D., BBRF Scientific Council member, 1995 Independent Investigator and 1990 Young Investigator; John Krystal, M.D., BBRF Scientific Council member, 2019 Colvin Prize winner, 2006 and 2000 Distinguished Investigator and 1997 Independent Investigator; Guillermo Horga, M.D., Ph.D., 2018 BBRF Maltz Prize winner; Junghee Lee, Ph.D., 2012 BBRF Young Investigator; Ragy Girgis, M.D., 2015 and 2010 BBRF Young Investigator; Lawrence Kegeles, M.D., Ph.D., 2010 BBRF Independent Investigator and 1997 and 1995 Young Investigator; Stephen Marder, M.D., 2016 BBRF Lieber Prize winner and 2011 Distinguished Investigator; Adrienne Lahti, M.D., 2000 BBRF Independent Investigator; and Donald Goff, M.D., 2009 and 2003 BBRF Independent Investigator.