3/5 Selective Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (CLOZAPINE)

B-SNIP Biotype-1 (CLOZAPINE) 中氯氮平的选择性抗精神病反应为 3/5

• 批准号: 10396432
• 负责人: GODFREY D PEARLSON
• 金额: $ 35.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396432
• 关键词: Antidepressive Agents; Antipsychotic Agents; Bacterial Artificial Chromosomes; Biological Markers; Blinded; Blood; Characteristics; Chemistry; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Clinical Trials Design; Clinical assessments; Clozapine; Cognition; Communities; Complex; Consent; Custom; Diagnosis; Diagnostic; Dose; Double-Blind Method; Dropout; Drug Monitoring; Electrocardiogram; Electroencephalography; Future; Goals; Grant; Individual; Libraries; Measures; Monitor; Myocarditis; National Institute of Mental Health; Neurobiology; Neutropenia; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physicians; Physiological; Plasma; Preparation; Prognosis; Psychoses; Randomized; Regimen; Resistance; Risperidone; Saccades; Safety; Sampling; Schedule; Schizophrenia; Seizures; Site; Specific qualifier value; Strategic Planning; Subgroup; Symptoms; Testing; Therapeutic; Time; Titrations; Work; base; clinical efficacy; deviant; forging; improved; phenomenological models; phenotypic biomarker; predictive marker; proband; recruit; relating to nervous system; research clinical testing; response; side effect; specific biomarkers; stimulus processing; symptomatic improvement; treatment duration; volunteer

Project Summary Treatment advances in psychosis are limited by the use of phenomenology-defined diagnoses based on symptomatic outcomes, rather than by neurobiological constructs monitored by quantitative characteristics. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) uses biomarkers to define psychosis subgroups with the goal of testing the advantages of B-SNIP biomarkers for diagnostic and therapeutic decisions, consistent with principles in the NIMH Strategic Plan (NSP). With >3000 phenotyped psychosis probands, relatives and healthy controls (HC), B-SNIP has a multilevel biomarker library for psychosis and used that library to re-conceptualize psychosis subgroups as biomarker-defined Biotypes (B1, B2, B3), where B1 and B2 are the low cognition/high symptom groups and B3 shows lower symptoms and relatively normal cognition. We replicated Biotypes in a new sample, “forging a future where measures of an individual’s … neural and physiological state will form the basis of an increasingly specific and informative diagnosis” (NSP). In this grant we propose that B1, with its low cognition and low cortical activity, will respond uniquely to clozapine, a drug which will generate active cortical attractor networks in B1 to support symptomatic improvement. Clozapine is the most effective antipsychotic drug (APD) with unique clinical efficacy. It is the least used APD because its side effects are serious (neutropenia, myocarditis, seizures) and its administration complex. A predictive biomarker would allow targeting of cases most likely to respond and improve prognosis in psychosis. B-SNIP has shown that clozapine is associated with increases in EEG measures of alpha/theta power, and we identify this increase in time periods without stimulus processing requirements as intrinsic EEG activity (IEA), across all Biotypes. Because B1 cases express low IEA, clozapine’s action to increase EEG power will be normalizing for this psychosis subgroup, with increased cortical attractor states. Because B2 express accentuated IEA, clozapine is associated with more deviant IEA in B2. We propose to test B1 psychosis cases with clozapine vs. risperidone (n=40/group clinical trial completers), over a 6 week cross-titration (to therapeutic plasma levels) and a 9 week stable dose extension, predicting that the B1/clozapine group will respond significantly better, as measured with total PANSS, than the B1/risperidone group and also better than either B2 group. It is our hypothesis that the cortical attractor networks will be normalized and their function increased by the increase in intrinsic EEG activity.

项目总结