Decoding Schizophrenia:
New Classes of Schizophrenia Drugs in Development

By Daniel C. Javitt and Joseph T. Coyle

Unless otherwise noted, the compounds mentioned below are in the early stages of human testing. Their developers or producers are listed in parentheses.

Stimulators of NMDA-type glutamate receptors aim to overcome the signaling deficits that apparently contribute to many schizophrenic symptoms. Examples: Glycine (Medifoods), D-serine (Glytech). As natural substances, both of them are sold, but they remain under evaluation specifically for their value in treating schizophrenia.

Stimulators of AMPA-type glutamate receptors--also called ampakines-- may improve some aspects of memory and cognition in people with schizophrenia. Example: CX516 (Cortex Pharmaceuticals)

Modulators of another class of glutamate receptors--metabotropic receptors--can regulate glutamate release and potentially restore the balance between the activity of NMDA and AMPA receptors. Example: LY354740 (Eli Lilly)

Inhibitors of glycine transport reduce glycine removal from synapses, which should increase signaling by NMDA receptors. Example: GlyT-1 (NPS Pharmaceuticals and Janssen Pharmaceutica)

Stimulators of alpha 7 nicotinic receptors, the same receptors activated by the nicotine in cigarettes, indirectly stimulate the brain's NMDA receptors. Schizophrenics often smoke heavily, probably because the nicotine, acting on alpha 7 receptors, helps them to focus. Example: DMXB-A (University of Colorado Health Sciences Center)

Stimulators of D1 dopamine receptors are being developed mainly for Parkinson's disease and have passed initial safety trials. They might also correct dopamine deficiencies in schizophrenia, but clinical trials for that purpose have not yet been performed. Example: ABT-431 (Abbott Laboratories)

DANIEL C. JAVITT and JOSEPH T. COYLE have studied schizophrenia for many years. Javitt is director of the Program in Cognitive Neuroscience and Schizophrenia at the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., and professor of psychiatry at the New York University School of Medicine. His paper demonstrating that the glutamate-blocking drug PCP reproduces the symptoms of schizophrenia was the second-most cited schizophrenia publication of the 1990s. Coyle is Eben S. Draper Professor of Psychiatry and Neuroscience at Harvard Medical School and also editor in chief of the Archives of General Psychiatry. Both authors have won numerous awards for their research. Javitt and Coyle hold independent patents for use of NMDA modulators in the treatment of schizophrenia, and Javitt has significant financial interests in Medifoods and Glytech, companies attempting to develop glycine and D-serine as treatments for schizophrenia.

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