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June 2014

Bitopertin: The Good News and Bad News

Author Affiliations
  • 1New York Langone Medical Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York
JAMA Psychiatry. 2014;71(6):621-622. doi:10.1001/jamapsychiatry.2014.257

In this issue, Umbricht and colleagues1 reported improvement of negative symptoms of schizophrenia associated with 2 of 3 doses of the glycine transporter type 1 inhibitor bitopertin (RG1678) in a phase 2 placebo-controlled, 8-week add-on trial. Although the therapeutic effect was only modest, this is very welcome news because the path to drug development in schizophrenia has been littered with disappointments. The example of clozapine, which was synthesized in 1958 and received Food and Drug Administration approval in 1989, provided impetus to develop similarly effective new compounds. Since then, a series of preclinical and clinical studies by Paul Janssen, MD, pioneered the addition of 5-hydroxytryptamine type 2A antagonism to D2 antagonism, which launched risperidone, the first of the newer-generation antipsychotics, and refinement of dopamine D2 receptor partial agonism led to aripiprazole. Both developments achieved a reduction in neurologic adverse effects, but the promise of clozapine has yet to be realized. Other approaches that followed from discoveries in neuroscience have failed or have yet to reach clinical validation. Bitopertin represents the culmination of more than 2 decades of basic and clinical research on the glutamatergic model of schizophrenia.2