Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder

Abstract

Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received 3 months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. We performed plasma proteomics using the Olink target 96 inflammation panel and identified that baseline plasma TNF superfamily member 10 (TNFSF10) concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the 3 months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response.

Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice

“…In the ventral striatum, the majority of DEGs (n=71) were significantly downregulated in the Acss2 KO animals compared to WT littermates (Figure 2B). Intriguingly, several of the ventral striatal DEGs were previously identified in human AUD patients, including downregulated Akap12 ( A-kinase anchoring protein 12 ), as well as upregulated Camkk2 ( Ca/calmodulin-dependent protein kinase kinase 2 ) and Mef2C ( myocyte enhancer factor 2C ) 50 . Further, we found a significant enrichment of delayed primary response genes and secondary response genes 51 among the ventral striatal DEGs (hypergeometric p=0.000148).…”

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

“…As a result, the differences in baseline PBMC expression profiles between the two groups are unlikely to be related to recent exposure to alcohol. We should point out that all subjects were required to maintain abstinence before medication started [ 21 , 22 ]. We did not measure blood alcohol concentration at the time of enrollment [ 22 ].…”

“…We should point out that all subjects were required to maintain abstinence before medication started [ 21 , 22 ]. We did not measure blood alcohol concentration at the time of enrollment [ 22 ]. However, we used self-report Timeline Follow Back (TLFB) to track alcohol use from 90 days before enrollment to 90 days after initiating acamprosate treatment [ 20 , 24 ].…”

“…We collected comprehensive clinical information for this study cohort before and after three months of acamprosate treatment. The primary outcome of the clinical trial was acamprosate treatment response [ 21 , 22 ]. We previously identified alcohol craving as the most significant clinical phenotype associated with treatment outcomes [ 23 , 24 ].…”

“…We previously identified alcohol craving as the most significant clinical phenotype associated with treatment outcomes [ 23 , 24 ]. Specifically, higher baseline craving intensity was associated with relapse to alcohol use during the three months of acamprosate treatment [ 22 , 23 , 25 ]. A recent study suggested that astrocytes displayed a higher number of differentially expressed genes (DEGs) in the prefrontal cortex of alcohol-dependent subjects compared to control donors [ 26 ].…”