The goal of the proposed research is to investigate the relationship of selected glutamate gene variants with cognitive and negative symptom response to the antipsychotic risperidone in first episode patients with schizophrenia who have little or no prior antipsychotic treatment history. Schizophrenia is a highly prevalent (-1% of population) and costly disease associated with marked and persistent cognitive dysfunction. Psychotic symptoms like hallucinations and delusions that occur with this disease often respond well to antipsychotic agents like risperidone. However, cognitive and negative symptom improvement after treatment is modest and highly variable from person to person. Variable responses to treatment are likely in part related to inter-individual genetic differences in drug response and neurotransmitter activity that affect a patient's likelihood of benefiting from a given medication. Characterizing these sources of variability and investigating ways to optimize treatments for individual patients will improve long term outcomes. This will be a pharmacogenetic study of 100 first episode schizophrenia subjects who have been treated with risperidone monotherapy for 4-6 weeks. Selected variants within two glutamate genes will be assessed for their relationships to change in cognitive biomarkers, neuropsychological performance, and clinical symptoms over the course of treatment. Changes in performance will be compared across selected genotype groups while controlling for population stratification assessed with genome wide markers. This research will be conducted in conjunction with a training program in cognitive neuroscience and genetics to prepare the PI for future pharmacogenetic studies using intermediate cognitive phenotypes and clinical symptoms to investigate sources of response variability and novel mechanisms of drug action.

Public Health Relevance

The goal of this application is to generate new scientific knowledge that will improve the treatment of patients with schizophrenia by advancing the field of personalized medicine in psychiatry. Through the investigation of relationships between sensitive measures of brain function with common variations in genes related to drug treatments and disease we will advance our ability to predict response in individual patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Wynne, Debra K
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University of Illinois at Chicago
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Schools of Pharmacy
United States
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Sundermann, Erin E; Bishop, Jeffrey R; Rubin, Leah H et al. (2015) Genetic predictor of working memory and prefrontal function in women with HIV. J Neurovirol 21:81-91
Bishop, Jeffrey R; Reilly, James L; Harris, Margret S H et al. (2015) Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. Psychopharmacology (Berl) 232:145-54
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Drozda, Katarzyna; Müller, Daniel J; Bishop, Jeffrey R (2014) Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy 34:166-84
Ethridge, Lauren E; Soilleux, Melanie; Nakonezny, Paul A et al. (2014) Behavioral response inhibition in psychotic disorders: diagnostic specificity, familiality and relation to generalized cognitive deficit. Schizophr Res 159:491-8
Stein, Mark A; Waldman, Irwin; Newcorn, Jeffrey et al. (2014) Dopamine transporter genotype and stimulant dose-response in youth with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 24:238-44
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Rubin, Leah H; Carter, C Sue; Bishop, Jeffrey R et al. (2014) Reduced levels of vasopressin and reduced behavioral modulation of oxytocin in psychotic disorders. Schizophr Bull 40:1374-84
Sarapas, Casey; Katz, Andrea C; Nelson, Brady D et al. (2014) Are individual differences in appetitive and defensive motivation related? A psychophysiological examination in two samples. Cogn Emot 28:636-55
Roseberry, Jarett E; Kristian Hill, S (2014) Limited practice effects and evaluation of expectation for change: MATRICS Consensus Cognitive Battery. Schizophr Res 159:188-92

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