Dataset Information

Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

ABSTRACT: Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, tramadol, olanzapine, mirtazapine, bupropion, and atomoxetine were associated with increased odds of OUD remission (adjusted odds ratio: 1.51 [1.38-1.66], 1.90 [1.66-2.18], 1.38 [1.31-1.46], 1.37 [1.29-1.46], 1.48 [1.25-1.76], p value < 0.001, respectively). Genetic and functional analyses showed these five candidate drugs directly target multiple OUD-associated genes including BDNF, CYP2D6, OPRD1, OPRK1, OPRM1, HTR1B, POMC, SLC6A4 and OUD-associated pathways, including opioid signaling, G-protein activation, serotonin receptors, and GPCR signaling. In summary, we developed an integrated drug repurposing approach and identified five repurposed candidate drugs that might be of value for treating OUD patients, including those suffering from comorbid conditions.

SUBMITTER: Zhou M

PROVIDER: S-EPMC7797705 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

Zhou Mengshi M Wang QuanQiu Q Zheng Chunlei C John Rush A A Volkow Nora D ND Xu Rong R

Molecular psychiatry 20210111 9

Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, t ...[more]

PMID: 33432189

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Project description:Background and aimsCocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment.DesignOur drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD.SettingThe study utilized TriNetX to access EHRs from more than 90 million patients world-wide. Genetic- and functional-level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases.ParticipantsA total of 7742 CUD patients who received anesthesia (3871 ketamine-exposed and 3871 anesthetic-controlled) and 7910 CUD patients with depression (3955 ketamine-exposed and 3955 antidepressant-controlled) were identified after propensity score-matching.MeasurementsEHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription.FindingsPatients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42-2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling and cocaine abuse/dependence.ConclusionsKetamine appears to be a potential repurposed drug for treatment of cocaine use disorder.

Project description:Previous research suggests that predictive mechanisms are essential in perceiving social interactions. However, these studies did not isolate action prediction (a priori expectations about how partners in an interaction react to one another) from action integration (a posteriori processing of both partner's actions). This study investigated action prediction during social interactions while controlling for integration confounds. Twenty participants viewed 3D animations depicting an action-reaction interaction between two actors. At the start of each action-reaction interaction, one actor performs a social action. Immediately after, instead of presenting the other actor's reaction, a black screen covers the animation for a short time (occlusion duration) until a still frame depicting a precise moment of the reaction is shown (reaction frame). The moment shown in the reaction frame is either temporally aligned with the occlusion duration or deviates by 150 ms or 300 ms. Fifty percent of the action-reaction trials were semantically congruent, and the remaining were incongruent, e.g., one actor offers to shake hands, and the other reciprocally shakes their hand (congruent action-reaction) versus one actor offers to shake hands, and the other leans down (incongruent action-reaction). Participants made fast congruency judgments. We hypothesized that judging the congruency of action-reaction sequences is aided by temporal predictions. The findings supported this hypothesis; linear speed-accuracy scores showed that congruency judgments were facilitated by a temporally aligned occlusion duration, and reaction frames compared to 300 ms deviations, thus suggesting that observers internally simulate the temporal unfolding of an observed social interction. Furthermore, we explored the link between participants with higher autistic traits and their sensitivity to temporal deviations. Overall, the study offers new evidence of prediction mechanisms underpinning the perception of social interactions in isolation from action integration confounds.

Dataset Information

Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

Publications

Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

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