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Gene Variation Accounts for Why Antipsychotics Reduce Cognitive Symptoms in Some Patients

eNews from the Brain and Behavior Research Foundation

Antipsychotic medications are a cornerstone of treatment for schizophrenia and related disorders. They prevent hallucinations and delusions for most people, and for some, they also help reduce the cognitive impairments associated with these illnesses, such as problems with memory and attention. Now, researchers have identified a genetic factor that determines which patients are likely to experience cognitive benefits from antipsychotic medications.

The cognitive symptoms of schizophrenia are often the symptoms most debilitating and difficult to treat, and clinicians have lacked tools to help determine the best approach for managing these symptoms in individual patients. The new finding could enable a more personalized treatment approach.

The study, published June 11 in Nature Communications, was led by 2015 Independent Investigator Francesco Papaleo, Ph.D. at Istituto Italiano di Tecnologia in Italy. The research team also included Marco Armando, M.D., Ph.D., a 2013 Young Investigator at the University of Geneva; Joel E. Kleinman, M.D., Ph.D., a 2013 Distinguished Investigator and 2011 Lieber Prizewinner at the Lieber Institute for Brain Development; Thomas M. Hyde, M.D., Ph.D., a 1989 Young Investigator at the Lieber Institute for Brain Development; and Daniel R. Weinberger, M.D., a Scientific Council Member, 2000 and 1990 Distinguished Investigator, and 1993 Lieber Prizewinner at Johns Hopkins University.

Antipsychotic medications work by modulating signaling from the brain’s dopamine D2 receptors. Dr. Papaleo and his colleagues discovered that these drugs are most likely to improve cognitive function in people who, due to specific genetic variations, produce low levels of a protein called dysbindin-1. Dysbindin-1 influences how many D2 receptors are available on neurons’ outer surfaces to receive dopamine signals from neighboring cells.

In animal experiments, the team determined that dysbindin-1’s effect on drug response was due to its activity in the prefrontal cortex, a part of the brain involved in higher cognitive functions such as planning, decision making, and problem-solving.

Dr. Papaleo and colleagues said this about the significance of the new findings: “We provide evidence for a biologically supported approach to antipsychotic treatment response. This might open new avenues in the application of genetics to psychiatric disorders in order to optimize the efficacy of current available drugs and develop new ones by dissecting subpopulations of responders and non-responders based on concrete mechanistic insights.”

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