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.

项目概要/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 精神疾病 (AUD) 与同时发生 AUD 和 BD (AUD+BD) 的个体相比，其临床结果要差得多。然而，对于患有 BD 或 AUD 的患者的最佳治疗知之甚少。 AUD+BD。一种为 AUD+BD 治疗试验选择和理想开发药物的新方法。我们的实验室针对 AUD 和 BD 患者特有的神经化学功能障碍进行了研究。前额叶γ-氨基丁酸（GABA）和谷氨酸的独特干扰被证明使用质子磁共振波谱 (1H-MRS) 计算该群体的浓度，并使用 AUD+BD GABA 和谷氨酸水平显着较低的个体，这与渴望增加有关和冲动，相对于仅患有 BD、仅 AUD 或健康对照的个体。随机、交叉研究正在评估：a) 已证明药物是否可以使病情正常化其他疾病中的皮质 GABA（即加巴喷丁）和谷氨酸（即 N-乙酰半胱氨酸 [NAC]）水平可能会降低类似地，AUD+BD 中的前额 GABA 和谷氨酸水平正常化，b) 是否正常化这些水平将与大脑功能活动对抑制和酒精反应的改善有关线索反应任务以及饮酒和情绪症状可能支持调查。加巴喷丁和/或 NAC 在大规模临床试验中作为 AUD+BD 的辅助治疗，并提供成功演示了多模式神经影像平台，用于评估 GABAergic 和不幸的是，经过 3 年的成功，大约有 80% 的患者使用谷氨酸药物治疗 AUD 和/或 BD。达到了年终入学目标并超出了参与者保留预期，我们的研究达到了 COVID-19大流行的爆发严重阻碍了这项研究的进展。过去两年，威胁到我们结果的有效性以及新/早期研究者的生存能力 Prisciandaro 博士在 BD+AUD 患者治疗开发方面的研究生涯。 Prisciandaro (PI) 与他的项目官员协商后，请求提供为期 1 年的行政补助（即“资金延期”），以减轻疫情大流行可能造成的重大损失如果有资助，允许他将参与者的注册期限再延长一年，以对我们的研究和他的职业生涯产生影响。本补充文件将恢复我们研究的统计能力和有效性，促进成功 Prisciandaro 博士的第一笔 R01 资助的竞争性延续（更新）。

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.