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Dr. Philip Corlett: Testing a Potential Schizophrenia Drug Based on Neurocognitive Theory

IMHRO / Janssen Rising Star Translational Research Awardee, 2013

People with schizophrenia tend to express unrealistic beliefs, and to lack interest in ordinarily pleasant activities; delusions and anhedonia are two of schizophrenia’s signature symptoms. Medications generally used to treat delusions block dopamine receptors—but about a third of patients with psychotic delusions are not helped, and some patients find their anhedonia worsened by antipsychotic therapy. What if, for some patients, a single neurobiological process underlies both delusions and anhedonia? If this process could be pinpointed and addressed with an original therapy, a large proportion of people with schizophrenia could benefit.

Philip Corlett, Ph.D., Assistant Professor of Psychiatry at Yale University, has an idea what that process might be—and a good idea for how to treat it. His interest in a field of cognitive neuroscience called Bayesian brain theory leads him to propose that delusions and anhedonia arise as follows:

  1. A person makes a prediction about his world based on expectation from past experience. [e.g. If I walk down the street innocently, people will mind their own business.]
  2. A new experience shows that prediction to be incorrect. [That man just looked at me funny.]
  3. The person unhealthily updates his expectations based on the new experience. [I must be to blame for something important. Maybe people will persecute me now.]
  4. The process repeats, the person becomes ever more sensitive to non-salient cues, and the delusion snowballs.
  5. Meanwhile, the person becomes less interested in reliably rewarding events, and may even start to lose interest in healthy activities.

 

Dr. Corlett proposes that this psychology is the product of a parallel underlying neurophysiology:  Individual neurons in a psychotic brain appear to make aberrant predictions about incoming stimuli based on previous stimuli, and repeatedly adjust their sensitivity to new stimuli unhealthily. It appears that as this process continues, the neuron’s voltage gated potassium channels, which enact healthy sensitivity, close down.

If his hypothesis is correct, then wouldn’t a drug which could open potassium channels be worth a try for treating delusions and anhedonia? Is it possible that the drug Retigabine, a potassium-channel opener already in use to treat epilepsy, could also treat these symptoms?

Dr. Corlett will use his Rising Star Award funds to enact a pilot study of Retigabine treatment with a cohort of human patient volunteers who have not been helped by traditional antipsychotic therapy. He will observe their brain activity using functional MRI to understand why this treatment might help some of these patients better than others, in the hope to enable more personalized approaches to schizophrenia therapy.

Dr. Corlett hopes that this study “will aid a more consilient explanation of psychosis in terms of cells, brain function and symptoms. More crucially, it will test a novel therapeutic approach to a pathophysiological mechanism implicated not by serendipity but by empirical data. Ultimately, the work addresses a severe unmet clinical need in a manner informed by translational neuroscience.”

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