Imaging Framework for Testing GABAergic Drugs in Bipolar Alcoholics

用于测试双相酗酒者中 GABA 能药物的成像框架

基本信息

批准号：
10544656
负责人：
James Joseph Prisciandaro
金额：
$ 14.9万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544656
关键词：
Acetylcysteine Administrative Supplement Alcohol dependence Bipolar Disorder Brain COVID-19 pandemic Characteristics Clinical Clinical Trials Cocaine Dependence Consultations Cross-Over Studies Diagnostic Disease Double-Blind Method Enrollment Epilepsy FDA approved Functional Magnetic Resonance Imaging Functional disorder Funding Glutamates Grant Image Impulsivity Individual Investigation Lithium Magnetic Resonance Spectroscopy Moods National Institute on Alcohol Abuse and Alcoholism Outcome Pharmaceutical Preparations Placebos Population Protons Randomized Randomized Clinical Trials Research Research Personnel Substance Use Disorder Testing alcohol abuse therapy alcohol craving alcohol cue alcohol use disorder career craving cue reactivity drinking expectation gabapentin gamma-Aminobutyric Acid improved mood symptom multimodal neuroimaging neurobehavioral neurochemistry novel novel strategies optimal treatments pandemic disease participant enrollment participant retention problem drinker programs randomized placebo controlled trial response success therapy development treatment trial valproate

项目摘要

Project Summary / Abstract Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with alcohol use disorder (AUD). Individuals with co-occurring AUD and BD (AUD+BD) have substantially worse clinical outcomes than those with either BD or AUD alone. Nonetheless, little is known about optimal treatment for individuals with AUD+BD. A novel approach to selecting, and ideally developing, medications for AUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both AUD and BD. Our lab has demonstrated unique disturbances in prefrontal gamma-Aminobutyric acid (GABA) and glutamate concentrations in this population using proton magnetic resonance spectroscopy (1H-MRS), with AUD+BD individuals having significantly lower levels of GABA and glutamate, which were associated with elevated craving and impulsivity, relative to individuals with BD alone, AUD alone, or healthy controls. Our ongoing double-blind, randomized, crossover study is evaluating: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) levels in other diseases, may similarly act to normalize prefrontal GABA and glutamate levels in AUD+BD, and b) whether normalization of these levels will be associated with improvements in functional brain activity to response inhibition and alcohol cue-reactivity tasks, as well as drinking and mood symptoms. Positive results may support investigation of gabapentin and/or NAC as adjunctive treatments for AUD+BD in large-scale clinical trials, as well as provide successful demonstration of a multimodal neuroimaging platform for evaluating the promise of GABAergic and glutamatergic drugs for AUD and/or BD. Unfortunately, following a 3-year period of success, with roughly 80% of year-end enrollment targets met and participant-retention expectations exceeded, our study was brought to a screeching halt by the COVID-19 pandemic. The pandemic has severely impeded the progress of the study over the past 2 years, threatening both the validity of our results as well as the viability of New/Early-Stage Investigator Dr. Prisciandaro's research career in treatment development for individuals with BD+AUD. As a result, Dr. Prisciandaro (PI), in consultation with his Program Officer, is requesting a 1-year Administrative Supplement (i.e., “Extension with Funds”) in order to mitigate the substantial damage that the pandemic will otherwise inflict on our study and his career by allowing him to extend participant enrollment for one additional year. If funded, this Supplement will restore the statistical power and validity of our study, thereby facilitating successful competitive continuation (renewal) of Dr. Prisciandaro's first R01 grant.

项目摘要 /摘要双相情感障碍（BD）是与酒精使用障碍最密切相关的轴I精神病（aud）。同时发生的AUD和BD（AUD+BD）的临床结果要比那些拥有BD或单独使用的人。尽管如此，对于患有最佳治疗的人，知之甚少 aud+bd。一种新型的选择和理想开发的AUD+BD治疗试验的药物靶向具有AUD和BD的个体的神经化学功能障碍。我们的实验室有在额叶γ-氨基丁酸（GABA）和谷氨酸盐中表现出独特的灾难使用质子磁共振光谱（1H-MR），该人群的浓度，AUD+BD 具有显着降低GABA和谷氨酸水平的个体，这与渴望升高有关相对于单独具有BD，单独使用BD或健康对照的个体，冲动性和冲动性。我们正在进行的双盲，随机，跨界研究正在评估：a）是否已证明已证明的药物是否正常化皮质GABA（即加巴喷丁）和谷氨酸（即其他疾病中的N-乙酰半胱氨酸[NAC]）水平，可能类似地作用于AUD+BD中的前额叶GABA和谷氨酸水平正常化，b）是否正常化这些水平将与功能性脑活动的改善对反应抑制和酒精有关提示反应性任务以及饮酒和情绪症状。积极的结果可能支持调查 Gabapentin和/或NAC作为大规模临床试验中AUD+BD的辅助处理，并提供成功演示了一个多模式神经影像平台，以评估GABA能和 AUD和/或BD的谷氨酸能药物。不幸的是，在3年的成功期之后，约有80％年终注册目标达到并超出了参与者的预期，我们的研究被带入了 COVID-19大流行的停止尖叫。大流行严重阻碍了研究的进步过去两年，威胁我们结果的有效性以及新的/早期调查员的生存能力 Prisciandaro博士针对BD+AUD的人的治疗开发研究生涯。结果，博士 Prisciandaro（PI）在与他的计划官员协商时，要求为期1年的行政补充（即“资金扩展”），以减轻大流行将造成的重大损害在我们的学习和他的职业生涯中，他可以将参与者的入学人数增加一年。如果资助，这种补充将恢复我们研究的统计能力和有效性，从而支持成功 Prisciandaro博士的第一个R01赠款的竞争延续（续签）。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Importance of Linear Combination Modeling for Quantification of Glutathione and γ-Aminobutyric Acid Levels Using Hadamard-Edited Magnetic Resonance Spectroscopy.

DOI：
10.3389/fpsyt.2022.872403
发表时间：
2022
期刊：
FRONTIERS IN PSYCHIATRY
影响因子：
4.7
作者：
Song, Yulu;Zollner, Helge J.;Hui, Steve C. N.;Hupfeld, Kathleen;Oeltzschner, Georg;Prisciandaro, James J.;Edden, Richard
通讯作者：
Edden, Richard

Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

DOI：
10.1111/adb.13085
发表时间：
2022-01
期刊：
ADDICTION BIOLOGY
影响因子：
3.4
作者：
Prisciandaro, James J.;Mellick, William;Squeglia, Lindsay M.;Hix, Sara;Arnold, Lauren;Tolliver, Bryan K.
通讯作者：
Tolliver, Bryan K.

Effects of Gabapentin on Dorsal Anterior Cingulate Cortex GABA and Glutamate Levels and Their Associations With Abstinence in Alcohol Use Disorder: A Randomized Clinical Trial.

DOI：
10.1176/appi.ajp.2021.20121757
发表时间：
2021-09-01
期刊：
AMERICAN JOURNAL OF PSYCHIATRY
影响因子：
17.7
作者：
Prisciandaro, James J.;Hoffman, Michaela;Brown, Truman R.;Voronin, Konstantin;Book, Sarah;Bristol, Emily;Anton, Raymond F.
通讯作者：
Anton, Raymond F.

Frequency drift in MR spectroscopy at 3T.

DOI：
10.1016/j.neuroimage.2021.118430
发表时间：
2021-11-01
期刊：
NeuroImage
影响因子：
5.7
作者：
Hui SCN;Mikkelsen M;Zöllner HJ;Ahluwalia V;Alcauter S;Baltusis L;Barany DA;Barlow LR;Becker R;Berman JI;Berrington A;Bhattacharyya PK;Blicher JU;Bogner W;Brown MS;Calhoun VD;Castillo R;Cecil KM;Choi YB;Chu WCW;Clarke WT;Craven AR;Cuypers K;Dacko M;de la Fuente-Sandoval C;Desmond P;Domagalik A;Dumont J;Duncan NW;Dydak U;Dyke K;Edmondson DA;Ende G;Ersland L;Evans CJ;Fermin ASR;Ferretti A;Fillmer A;Gong T;Greenhouse I;Grist JT;Gu M;Harris AD;Hat K;Heba S;Heckova E;Hegarty JP 2nd;Heise KF;Honda S;Jacobson A;Jansen JFA;Jenkins CW;Johnston SJ;Juchem C;Kangarlu A;Kerr AB;Landheer K;Lange T;Lee P;Levendovszky SR;Limperopoulos C;Liu F;Lloyd W;Lythgoe DJ;Machizawa MG;MacMillan EL;Maddock RJ;Manzhurtsev AV;Martinez-Gudino ML;Miller JJ;Mirzakhanian H;Moreno-Ortega M;Mullins PG;Nakajima S;Near J;Noeske R;Nordhøy W;Oeltzschner G;Osorio-Duran R;Otaduy MCG;Pasaye EH;Peeters R;Peltier SJ;Pilatus U;Polomac N;Porges EC;Pradhan S;Prisciandaro JJ;Puts NA;Rae CD;Reyes-Madrigal F;Roberts TPL;Robertson CE;Rosenberg JT;Rotaru DG;O'Gorman Tuura RL;Saleh MG;Sandberg K;Sangill R;Schembri K;Schrantee A;Semenova NA;Singel D;Sitnikov R;Smith J;Song Y;Stark C;Stoffers D;Swinnen SP;Tain R;Tanase C;Tapper S;Tegenthoff M;Thiel T;Thioux M;Truong P;van Dijk P;Vella N;Vidyasagar R;Vovk A;Wang G;Westlye LT;Wilbur TK;Willoughby WR;Wilson M;Wittsack HJ;Woods AJ;Wu YC;Xu J;Lopez MY;Yeung DKW;Zhao Q;Zhou X;Zupan G;Edden RAE
通讯作者：
Edden RAE

Identification and initial validation of empirically derived bipolar symptom states from a large longitudinal dataset: an application of hidden Markov modeling to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.