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.
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.
|Rubin, Leah H; Li, Siyi; Yao, Li et al. (2018) Peripheral oxytocin and vasopressin modulates regional brain activity differently in men and women with schizophrenia. Schizophr Res 202:173-179|
|Hochberger, W C; Combs, T; Reilly, J L et al. (2018) Deviation from expected cognitive ability across psychotic disorders. Schizophr Res 192:300-307|
|Eum, Seenae; Hill, S Kristian; Rubin, Leah H et al. (2017) Cognitive burden of anticholinergic medications in psychotic disorders. Schizophr Res 190:129-135|
|Lencer, R; Mills, L J; Alliey-Rodriguez, N et al. (2017) Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study. Transl Psychiatry 7:e1249|
|Rubin, Leah H; Yao, Li; Keedy, Sarah K et al. (2017) Sex differences in associations of arginine vasopressin and oxytocin with resting-state functional brain connectivity. J Neurosci Res 95:576-586|
|Stevenson, J M; Reilly, J L; Harris, M S H et al. (2016) Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes. Transl Psychiatry 6:e739|
|Huang, Eric; Zai, Clement C; Lisoway, Amanda et al. (2016) Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. Int J Neuropsychopharmacol 19:|
|Nanda, Pranav; Tandon, Neeraj; Mathew, Ian T et al. (2016) Impulsivity across the psychosis spectrum: Correlates of cortical volume, suicidal history, and social and global function. Schizophr Res 170:80-6|
|Rubin, Leah H; Connelly, Jessica J; Reilly, James L et al. (2016) Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders. Biol Psychiatry Cogn Neurosci Neuroimaging 1:141-151|
|Padmanabhan, Jaya L; Nanda, Pranav; Tandon, Neeraj et al. (2016) Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives. J Psychiatr Res 77:52-8|
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