Collaborative Science: Probing Genetic Connections Leads to Successful New Treatments

Collaboration is key to research at McLean, leading to landmark findings that go beyond the sum of the parts.

Deborah L. Levy, PhD, director of the Psychology Research Laboratory, recently led one such meeting of the minds. Working closely with Laura Godfrey, RPh, J. Alexander Bodkin, MD, Michael Coleman, and other colleagues, Levy ran the first treatment intervention in psychiatry tailored to a specific genetic mutation. The clinical trial had two participants—one suffering from schizophrenia, the other from bipolar disorder. It led to significant clinical improvement in both of them.

“A challenge in this study, given the complexity of the dosing, was ensuring that it was double blind,” said Godfrey, a member of McLean’s Pharmacy Research Core. “We had to find the correct combination of ingredients and dispense them in a way that was accurate yet simple enough to facilitate the participants’ compliance. In the end, safety and rigor matter most.”

“This three-part study could not have been done without Laura’s meticulous work,” stated Levy. The thrice-daily treatment regimen—alternating administration of weight-adjusted doses of the nonessential amino acid glycine in powder form, and placebo (a low-glycemic index sugar), to be reconstituted by the participants—had to be prepared by hand, carefully labeled to permit titration from a low to a therapeutically optimal dose, and shipped out of state.

Levy, who has a distinguished history of probing the genetics of schizophrenia, came to McLean in 1991 from Hillside Hospital-Long Island Jewish Medical Center to work with two of her longtime collaborators, Steven Matthysse, PhD, and the late Philip S. Holzman, PhD.

Her research focuses on identifying genetic mutations linked to schizophrenia and bipolar disorder while understanding their biological effects to advance therapeutic discovery.

The smoking gun in the glycine study, said Levy, was the discovery of a mutation in the glycine decarboxylase (GLDC) gene. GLDC encodes the enzyme that breaks down glycine, a chemical necessary for proper functioning of the brain’s NMDA receptors, which are involved in learning, memory, and other neural processes. People with extra copies of GLDC—a rare mutation—are expected to have low levels of glycine in the brain and hence NMDA receptors with impaired functioning, a deficit that has been implicated in schizophrenia.

“Our plan was to try a targeted treatment of the GLDC mutation,” added Levy, explaining that the study involved selecting people who are likely to respond based on objective evidence, not just relying on a diagnosis that can be hypothetically linked to a possible malfunction in a particular brain system. In this case, DNA analysis had shown that both study participants had extra copies of the gene and therefore were likely to benefit from taking glycine.

During the six-month trial, the participants received glycine or placebo at different times; only Godfrey knew when they received each compound. Then they both received glycine again. At various points, the investigators assessed neurocognitive function and did brain scans to measure glycine metabolism and blood work to check glycine and other amino acid levels.

“It will be important to know if glycine metabolism in the brain was normalized by the treatment,” said Levy.