A translational neuroscience & computational evaluation of a D1R partial agonist for schizophrenia (TRANSCENDS): Rationale and study design of a brain-based clinical trial.
Протокол клинического исследованияСтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Fonteneau Clara, Tamayo Zailyn, Price Ally, Pan Lining, Afriyie-Agyemang Yvette, Agrawal Shriya, Butler Audrey, Cail Courtney, Calkins Monica, Chakilam Ananthsrinivas Rao, Forselius-Bielen Kimberlee, Fram Geena, Frazier Allea, Gil Roberto, Govil Preetika, Gray David L, Grinband Jack, Gur Ruben C, Haubold Natalka K, Heffernan Zachary, Heneks Mara, Kegeles Larry, Kohler Christian, Lin Chenyang, Lu Jing, Mayer Megan, Pham Phuong, Perlman Greg, Rahmati Masih, Ranganathan Mohini, Santamauro Nicole P, Schutte Christopher W, Selloni Alexandria, Van Snellenberg Jared, Surti Toral, Wolf Daniel H, Zharyy Catrin, TRANSCENDS Group, Abi-Dargham Anissa, Gur Raquel E, Lieberman Jeffrey A, Kantrowitz Joshua T, Anticevic Alan, Cho Youngsun T, Krystal John H
Аннотация
Despite decades of research, cognitive impairment remains a critical untreated symptom for many patients with schizophrenia. One way to accelerate the development of pro-cognitive therapies for schizophrenia is to evaluate compounds using biomarker approaches tailored to relevant neural mechanisms. While D1/D5 receptor (D1R/D5R) agonism has been extensively studied in neuroscience, its therapeutic potential for cognitive impairment in schizophrenia remains untapped. The Translational Neuroscience & Computational Evaluation of a D1R Partial Agonist for Schizophrenia (TRANSCENDS) clinical trial tests this mechanism using a 'target engagement' approach. Multiple, double-blind doses of a D1/D5R partial agonist were administered in advance of a functional neuroimaging (fMRI) session that deployed a cognitive paradigm explicitly designed to capture a translational micro-circuit mechanism underlying spatial working memory in patients with schizophrenia. Specifically, this study will assess whether the D1R/D5R partial agonist CVL-562 induces a dose-dependent engagement of spatial working memory circuits in schizophrenia using fMRI. This design, and the use of spatial working memory neural circuits as a dependent measure, was selected on the basis of a translational and computational understanding of prefrontal micro-circuitry and a mechanistic understanding of the role of D1R/D5Rs in schizophrenia. To enhance data integration and scalability, TRANSCENDS employs an automated informatics framework for seamless neuroimaging data sharing and electronic clinical data capture. This ensures high-standards for regulatory compliance, data quality, and data sharing across sites, improving aspects of current clinical trial data management. We share the study design and approach with the goal of advancing future pro-cognitive drug development and strategies for developing mechanistically-driven biomarkers in psychiatry.