Mechanisms of anti-depressant and anti- alcohol effects of ketamine in patients with alcohol use disorder

Abstract Ketamine is known to have anti-depressant effects and is suggested to reduce substance use. However, little is known about the mechanism of these effects. Given evidence from studies in depression of a greater therapeutic effect in those with a family history of AUD, this latter factor was also investigated as a moderating factor. We used data from the KARE trial, a randomised triple-blinded controlled clinical trial, examining the efficacy of three infusions of ketamine each followed by psychological support as a treatment in people with AUD. State anxiety, anhedonia, repetitive negative thoughts (RNT) emerged as factors from a factor analysis of all the trial questionnaires. We replicated original trial analyses to show a significant reduction in percentage days abstinent and extended to demonstrate this survived including data on alcohol use from a time point before participants had become abstinent from alcohol. Ketamine treatment was found to significantly reduce anhedonia and RNT at 3-months follow-up though not at 6-months. Family history of AUD was found to moderate the relationship between drug group and anhedonia and RNT at 3-months, with individuals with a family history of AUD reporting a greater effect of ketamine on anhedonia and RNT. Among people with a family history of AUD, ketamine reduced craving and this reduction then mediated its effects on percentage of abstinent days. This effect was not evident among those without AUD family history. . Neither anhedonia nor RNT scores at 3-months were found to mediate the effects of ketamine on abstinence at 6-months follow-up. Family history of AUD emerged as an important patient characteristic to consider in the clinical use of ketamine in psychiatry.