Biomarkers of Conversion Risk and Treatment Response in Early-Stage Schizophrenia

早期精神分裂症转化风险和治疗反应的生物标志物

• 批准号: 10163261
• 负责人: Ragy Ramsis Girgis
• 金额: $ 68.69万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163261
• 关键词: Age; Amino Acid Neurotransmitters; Aminobutyric Acids; Antipsychotic Agents; Automobile Driving; Behavioral; Biological Markers; Brain; Chronic Schizophrenia; Clinical; Data; Data Reporting; Diagnosis; Disease; Disease Progression; Dorsal; Future; Generations; Glutamates; Grant; Incidence; Individual; Interdisciplinary Study; Lead; Magnetic Resonance Spectroscopy; Measures; Medial; Meta-Analysis; Monitor; Outcome; Patients; Pharmaceutical Preparations; Population; Prefrontal Cortex; Protons; Psychoses; Reporting; Research Personnel; Research Project Grants; Risk; Risperidone; Schizophrenia; Site; Stratification; Symptoms; Syndrome; System; Testing; base; cohort; disability; first episode psychosis; first episode schizophrenia; high risk; in vivo; insight; multidisciplinary; neurochemistry; neuroimaging marker; neuropsychiatric disorder; novel; response; sex; standard of care; treatment effect; treatment response; young adult

ABSTRACT Schizophrenia (SZ) is a highly debilitating neuropsychiatric disorder of young adulthood onset and a leading cause of disability worldwide. While treatments delivered at early stages of the disorder may be effective at reducing psychosis or altering the course of the disease, there are currently no biomarkers capable of identifying subjects at ultra-high risk (UHR) for psychosis who are likely to convert to the full clinical syndrome; or those in early stages of SZ who are likely to respond to treatment and would be good candidates for available proactive, symptomatic or future disease-modifying treatments; or those who would not respond and can be spared unnecessary medication exposure. The lack of these vitally important biomarkers provides a compelling rationale for the present multidisciplinary, transnational research project, which aims to develop and validate highly promising noninvasive and objective proton magnetic resonance spectroscopy (1H MRS)-based biomarkers for assessing conversion risk in UHR subjects and monitoring treatment response in first-episode psychosis (FEP) patients. In support of the viability of this overall objective is a large body of data, reported by the applicants and others, that show (a) that levels of glutamate (Glu) and -aminobutyric acid (GABA) – respectively, the major excitatory and inhibitory amino acid neurotransmitter systems - are abnormally elevated in medication-naïve and unmedicated UHR, FEP and chronic SZ cohorts; (b) that the effect of treatment with antipsychotic medications may be to lower or normalize brain levels of both Glu and GABA; and (c) that Glu elevations at baseline in UHR subjects may be a reliable predictor of conversion to full psychosis. To investigate the potential of these in vivo brain Glu and GABA abnormalities to serve as biomarkers of conversion risk in UHR subjects and of treatment response in early-stage SZ, the applicants propose to use 1H MRS to measure Glu and GABA levels in the largest cohorts of medication-naïve UHR and FEP subjects to date, at baseline and at conversion or at 2 years in UHR subjects; and at baseline and following 4 weeks of antipsychotic treatment in FEP subjects. The hypotheses to be tested are that (1) baseline elevations of Glu and GABA in UHR subjects will predict the risk of conversion to full psychosis; that (2) both GABA and Glu will be elevated at baseline in FEP subjects and decrease or normalize with second-generation antipsychotic treatment; and that (3) levels of both GABA and Glu will correlate positively with clinical measures in both groups at baseline and or negatively or not with treatment response in FEP subjects. If successful, the proposed studies have the potential to establish 1H MRS measures of brain GABA and Glu as predictors of conversion risk and biomarkers of treatment response or non-response, support the exploration of novel glutamate- or GABA-based treatments that may be more effective and present lower risks, and contribute new insights into the brain mechanisms of the emergence and progression of neurochemical abnormalities in SZ.

摘要

项目成果

Gamma-Aminobutyric Acid, Glutamate, and Cognition in Early Stages of Psychosis: Are We Closing the Gap?

γ-氨基丁酸、谷氨酸和精神病早期阶段的认知：我们正在缩小差距吗？

• DOI: 10.1016/j.bpsc.2020.04.006
• 发表时间: 2020
• 期刊: Biological psychiatry. Cognitive neuroscience and neuroimaging
• 作者: Kegeles,LawrenceS;delaFuente-Sandoval,Camilo
• 通讯作者: delaFuente-Sandoval,Camilo

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

• DOI: 10.1038/s41380-023-01991-7
• 发表时间: 2023-05
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Merritt, Kate;McCutcheon, Robert;Aleman, Andre;Ashley, Sarah;Beck, Katherine;Block, Wolfgang;Bloemen, Oswald J. N.;Borgan, Faith;Boules, Christiana;Bustillo, Juan R.;Capizzano, Aristides;Coughlin, Jennifer Q.;David, Anthony;de la Fuente-Sandoval, Camilo;Demjaha, Arsime;Dempster, Kara;Do, Kim;Du, Fei E.;Falkai, Peter;Galinska-Skok, Beata;Gallinat, Juergen;Gasparovic, Charles;Ginestet, Cedric E.;Goto, Naoki;Graff-Guerrero, Ariel;Ho, Beng-Choon;Howes, Oliver;Jauhar, Sameer;Jeon, Peter;Kato, Tadafumi;Kaufmann, Charles A.;Kegeles, Lawrence S.;Keshavan, Matcheri S.;Kim, Sang-Young;King, Bridget;Kunugi, Hiroshi;Lauriello, J.;Leon-Ortiz, Pablo;Liemburg, Edith;Mcilwain, Meghan;Modinos, Gemma;Mouchlianitis, Elias;Nakamura, Jun;Nenadic, Igor;Ongur, Dost;Ota, Miho;Palaniyappan, Lena E.;Pantelis, Christos;Patel, Tulsi F.;Plitman, Eric;Posporelis, Sotirios R.;Purdon, Scot;Reichenbach, Juergen R.;Renshaw, Perry C.;Reyes-Madrigal, Francisco;Russell, Bruce A.;Sawa, Akira;Schaefer, Martin;Shungu, Dikoma C.;Smesny, Stefan;Stanley, Jeffrey;Stone, James G.;Szulc, Agata;Taylor, Reggie;Thakkar, Katharine N.;Theberge, Jean J.;Tibbo, Philip;van Amelsvoort, Therese;Walecki, Jerzy;Williamson, Peter;Wood, Stephen;Xin, Lijing;Yamasue, Hidenori;McGuire, Philip K.;Egerton, Alice
• 通讯作者: Egerton, Alice

Dysconnectivity in Schizophrenia Revisited: Abnormal Temporal Organization of Dynamic Functional Connectivity in Patients With a First Episode of Psychosis.

• DOI: 10.1093/schbul/sbac187
• 发表时间: 2022-12
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Juan P. Ramirez-Mahaluf;Ángeles Tepper;L. M. Alliende;Carlos Mena;C. Castañeda;Barbara Iruretagoyena;Rubén Nachar;Francisco Reyes-Madrigal;P. León-Ortíz;Ricardo Mora-Durán;T. Ossandón;Alfonso González-Valderrama;J. Undurraga;C. de la Fuente-Sandoval;N. Crossley

Social cognition and its association with the duration and severity of psychosis in antipsychotic-naïve individuals at different stages of the schizophrenia spectrum disorders.

社会认知及其与精神分裂症谱系障碍不同阶段未接受过抗精神病药物治疗的个体精神病持续时间和严重程度的关系。

• DOI: 10.1016/j.schres.2022.08.019
• 发表时间: 2022
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: León-Ortiz,Pablo;Reyes-Madrigal,Francisco;Mondragón-Maya,Alejandra;Mora-Durán,Ricardo;González-Manríquez,Luz;Menéndez-Manjarrez,Fernanda;Solís-Vivanco,Rodolfo;delaFuente-Sandoval,Camilo
• 通讯作者: delaFuente-Sandoval,Camilo

Gender, age and geographical representation over the past 50 years of schizophrenia research.

• DOI: 10.1016/j.psychres.2021.114279
• 发表时间: 2022-01
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Alliende LM;Czepielewski LS;Aceituno D;Castañeda CP;Diaz C;Iruretagoyena B;Mena C;Mena C;Ramirez-Mahaluf JP;Tepper Á;Vasquez J;Fonseca L;Machado V;Hernández CE;Vargas-Upegui C;Gomez-Cruz G;Kobayashi-Romero LF;Moncada-Habib T;Evans-Lacko S;Bressan R;Gama CS;Lopez-Jaramillo C;de la Fuente-Sandoval C;Gonzalez-Valderrama A;Undurraga J;Gadelha A;Crossley NA;ANDES Network
• 通讯作者: ANDES Network