An estimated 3.5 million American children and adolescents are prescribed prescription stimulants for the treatment of attention deficit hyperactivity disorder (ADHD). A large body of animal research demonstrates that stimulants induce long-term changes in dopamine systems in the brain that parallel changes observed in individuals with psychosis. Although it is known that stimulants can precipitate acute episodes of psychosis, there is a lack of research on whether stimulants increase long-term risk of developing a psychotic disorder or whether stimulants are associated with an earlier onset of psychosis. To address these gaps, the principal investigator (PI) proposes a career development program that blends rigorous training by Harvard faculty with an innovative research agenda that uses two complementary approaches to study the risk of psychosis with prescription stimulant use: 1) A large-scale longitudinal study using electronic medical records for a New England healthcare system to compare the risk of developing a psychotic disorder in children/adolescents with ADHD based on exposure to prescription stimulants, and 2) a patient-oriented clinical research study in individuals with first-episode psychosis to determine if prescription stimulant use prior to illness onset is associated with an earlier onset of psychosis. The PI is a psychiatrist with clinical expertise in psychotic disorders with a background in neuroimaging research in schizophrenia. Training objectives for this grant are for the PI to: 1) Develop expertise in epidemiology and use of electronic medical records to perform large-scale studies of putative risk factors for psychosis; 1) Develop expertise in research in child and adolescent psychiatry and first-episode psychosis; and 2) Develop advanced skills in complex statistics such as propensity score matching, survival analysis and predictive modeling. These goals will be accomplished by formal coursework and mentorship by an exceptionally-qualified team of scientists who are internationally-recognized leaders in research directly relevant to the current proposal. The proposed research project aligns with the National Institute of Mental Health (NIMH) Strategic Objective 2 on charting mental illness trajectories to allow early intervention. By charting the trajectory from childhood/adolescence to onset of psychosis, this research may potentially identify a modifiable risk factor that could alter the likelihood of progression to psychosis. The successful completion of this career development plan will assist the PI in making the transition to an independent investigator with the long-term goal of identifying risk factors for psychosis to target those individuals most at risk and allow early intervention. In addition, this award will provide the PI with the training and tools necessary for future studies involving the analysis of large-scale multi-element electronic medical record data sets in alignment with objectives of the NIH Big Data to Knowledge (BD2K) program.
/Public Health Relevance An estimated 3.5 million American children and adolescents are prescribed stimulants for the treatment of attention deficit hyperactivity disorder, and 20% of college students are reported to misuse or abuse prescription stimulants. Given the large and rising scope of prescription stimulant use, the finding of an increased risk or earlier onset of psychotic disorders with prescription stimulant use after controlling for potential confounding factors has extraordinary public health significance and could lead to changes in prescribing practices. Identifying modifiable risk factors that increase the risk of psychotic disorders in children and adolescents will enable early intervention through programs such as the Recovery After an Initial Schizophrenia Episode (RAISE) project that could potentially alter the trajectory of progression to psychosis and lead to improved outcomes.
|Moran, Lauren V; Stoeckel, Luke E; Wang, Kristina et al. (2018) Nicotine-induced activation of caudate and anterior cingulate cortex in response to errors in schizophrenia. Psychopharmacology (Berl) 235:789-802|
|Janes, Amy C; Zegel, Maya; Ohashi, Kyoko et al. (2018) Nicotine normalizes cortico-striatal connectivity in non-smoking individuals with major depressive disorder. Neuropsychopharmacology 43:2445-2451|
|Moran, Lauren V; Betts, Jennifer M; Ongur, Dost et al. (2018) Neural Responses to Smoking Cues in Schizophrenia. Schizophr Bull 44:525-534|
|Moran, Lauren V; Stoeckel, Luke E; Wang, Kristina et al. (2018) Nicotine Increases Activation to Anticipatory Valence Cues in Anterior Insula and Striatum. Nicotine Tob Res 20:851-858|
|McCarthy, Julie M; Dumais, Kelly M; Zegel, Maya et al. (2018) Sex differences in tobacco smokers: Executive control network and frontostriatal connectivity. Drug Alcohol Depend 195:59-65|