Description (from grant):
Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorder (SUD); diagnostic co-occurrence is particularly high between BD and alcohol use disorder (AUD). Individuals with co-occurring SUD and BD (SUD+BD) have substantially worse clinical outcomes than those with either BD or SUD alone. Nonetheless, little is known about optimal treatment for individuals with SUD+BD. We will develop and evaluate a novel, multimodal neuroimaging framework for testing GABAergic and glutamatergic drugs for conditions marked by GABAergic/glutamatergic dysfunction (e.g. AUD).
Traditionally, treatment trials for SUD+BD have investigated medications that have been FDA approved to treat either BD or SUD in hopes that such medications would prove efficacious in individuals with SUD+BD. A different approach to selecting, and ideally developing, medications for SUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both BD and SUD. Our lab recently demonstrated unique disturbances in prefrontal gamma- Aminobutyric acid (GABA) and glutamate concentrations in this population using 1H-MRS, with individuals with co-occurring alcohol dependence (AD) and BD having significantly lower levels of GABA and glutamate relative to individuals with BD alone, AD alone, or healthy controls. Lower levels of prefrontal GABA and glutamate were in turn associated with elevated impulsivity and alcohol craving. The proposed 3-week, double-blind, crossover, proof of concept study will evaluate: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) concentrations in individuals with epilepsy and cocaine dependence, respectively, may similarly act to normalize prefrontal GABA and glutamate levels in individuals with AUD+BD, and b) whether normalization of prefrontal GABA and glutamate levels will be associated with improvements in functional brain activity to tasks that assess core neurobehavioral deficits of AUD and BD (i.e., response inhibition, alcohol cue-reactivity), 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, randomized clinical trials. The proposed study may provide successful demonstration of a neuro-behavioral, multimodal neuroimaging platform for evaluating the potential of GABAergic and glutamatergic drugs for AUD and/or BD, as well as other conditions marked by GABAergic/glutamatergic dysfunction.
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. Frequency drift in MR spectroscopy at 3T. NeuroImage. 2021 November 1;241:118430. PMCID: PMC8456751.
Song Y, Zöllner HJ, Hui SCN, Hupfeld K, Oeltzschner G, Prisciandaro JJ, Edden R. Importance of Linear Combination Modeling for Quantification of Glutathione and γ-Aminobutyric Acid Levels Using Hadamard-Edited Magnetic Resonance Spectroscopy. Frontiers in psychiatry. 2022 April;13:872403. PubMed PMID: 35546940; PubMed Central PMCID: PMC9082488; DOI: 10.3389/fpsyt.2022.872403. CP9/TRD2
Prisciandaro JJ, Zöllner HJ, Murali-Manohar S, Oeltzschner G, Edden RAE. More than one-half of the variance in in vivo proton MR spectroscopy metabolite estimates is common to all metabolites. NMR Biomed. 2023 Jul;36(7):e4907. doi: 10.1002/nbm.4907. Epub 2023 Feb 5. PMID: 36651918; PMCID: PMC10272046.
Hupfeld KE, Zöllner HJ, Hui SCN, Song Y, Murali-Manohar S, Yedavalli V, Oeltzschner G, Prisciandaro JJ, Edden RAE. Impact of acquisition and modeling parameters on the test-retest reproducibility of edited GABA. NMR Biomed. 2024 Apr;37(4):e5076. doi: 10.1002/nbm.5076. Epub 2023 Dec 13. PubMed PMID: 38091628; PubMed Central PMCID: PMC10947947. (CP 9)
Davies-Jenkins CW, Zöllner HJ, Simicic D, Hui SCN, Song Y, Hupfeld KE, Prisciandaro JJ, Edden RAE, Oeltzschner G. GABA-edited MEGA-PRESS at 3 T: Does a measured macromolecule background improve linear combination modeling?. Magn Reson Med. 2024 Oct;92(4):1348-1362. doi: 10.1002/mrm.30158. Epub 2024 May 31. PubMed PMID: 38818623; PubMed Central PMCID: PMC11262975.