September 12, 2014

Schizophrenia ‘switches’ discovered

Drugs developed at Vanderbilt could provide a new way to treat schizophrenia in a personalized way.


A Vanderbilt University study suggests it may be possible to “switch off” genetic mutations associated with schizophrenia to relieve hallmark symptoms of the disorder – delusions, hallucinations and disordered thinking.

Reporting last month in ACS Chemical Biology, Craig Lindsley, Ph.D., and colleagues expressed in cell lines nine mutations in the gene that encodes the metabotropic glutamate receptor subtype 1, which binds the neurotransmitter glutamate.

They showed the mutations caused “loss of function,” or diminished calcium signaling, and that in some cases function could be “rescued” by highly selective compounds called positive allosteric modulators. Vanderbilt has pioneered development of these compounds, which adjust receptor activity like the dimmer switch in an electrical circuit.

Allosteric modulators thus may provide a new way to treat schizophrenia, which affects one in every 100 people. Mutations in other receptors also contribute to the disorder, underscoring “the critical role of patient selection in psychiatric clinical trials to match genotype with therapeutic mechanism,” the researchers concluded.

The research was supported by National Institutes of Health grants MH084659, NS031373, MH062646 and MH097056.

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