Cognitive deficits in alcohol use disorder : etiology and treatment

Alcohol use disorder (AUD) is a psychiatric disorder characterized by a loss of control over drinking, tolerance, withdrawal and negative psychological, physical and social consequences due to excessive alcohol consumption. Even though not explicitly stated in the diagnostic criteria, it is well known that patients with AUD also exhibit impaired cognitive function, e.g., elevated impulsive behavior and deficits in executive functions such as response inhibition, attention and working memory. The aim of this thesis was twofold: First, to investigate the etiology of cognitive deficits in AUD. Second, to investigate if cognitive deficits in AUD can be a potential target for treatment. Study I was a large-scale population-based epidemiological study of approximately 3 million unique individuals based on Swedish national registries. We investigated the effect of family history across all forms of substance use disorders (SUD), including AUD, on general cognitive ability in offspring. The exposure was defined as having a parent with SUD and the outcomes were cognitive test score at conscription and final school grades in compulsory school. At the population level, parental SUD increased the risk of lower cognitive ability in offspring, after adjusting for several covariates such as age, sex, psychiatric co-morbidity and socioeconomic status. However, when analyzing offspring to sibling-pairs discordant for SUD, the strength of this association was reduced with increasing genetic relatedness in the sibling-pairs (half siblings, full siblings, monozygotic twins). These findings suggest that the observed association between parental SUD and lower cognitive ability in offspring can partly be explained by shared genetic factors between SUD and cognitive ability. Study II was a case-control study which further examined the association between AUD and cognitive function, by investigating whether the cognitive profile of people with family history of AUD is more similar to AUD patients than people with no such family history. The study recruited AUD patients (n = 106) and healthy controls (HC; n = 90), who were then further subdivided into AUD family history positive (FH+) and negative (FH-). All subjects underwent psychiatric evaluation and an extensive neuropsychological test battery assessing different aspects of impulsive behavior, decision making, attention, memory and emotion. FH+ and AUD patients had similar levels of elevated self-rated impulsivity, reduced future planning capability and longer emotional recognition latency compared to FH-, while no differences were found for other cognitive outcomes. These findings strengthen the notion that specific aspects of the cognitive profile associated with AUD, can be partly genetically influenced traits, elevating the risk for AUD. Other cognitive disturbances in AUD on the other hand may to a higher degree depend on non-genetic factors such as alcohol intake. Study III and IV were based on a randomized placebo-controlled trial of a novel pharmacological agent, namely the monoamine stabilizer (-)-OSU6162 (OSU). The aims of the studies were to investigate the treatment effect and possible moderating effect of baseline impulsivity, of OSU on craving (study III) and cognitive function (study IV). Patients with AUD (n = 56) were randomized to receive either 14 days of OSU treatment or placebo. The treatment protocol included weekly visits to the clinic and a final test day where they performed a laboratory craving experiment. The patients also underwent neuropsychological testing at baseline and on the final test day. Study III found that OSU treatment reduced alcohol-induced craving, and the greatest treatment effect was observed for patients with higher baseline levels of impulsivity. Study IV found that OSU had no short-term negative effect on any assessed cognitive domain, while improving future planning capacity, emotional recognition latency and divergent thinking. Collectively, these findings suggest that OSU may have beneficial clinical treatment effects in AUD on both craving and cognition, but larger randomized controlled trials are needed to replicate these preliminary findings. Study V was a randomized controlled trial to investigate the effect of working memory training in AUD on drinking, working memory and transfer effects to other cognitive functions. Patients with AUD (n = 50) were randomized to 5 weeks of active computerized working memory training or control training, and came for weekly follow-up visits to the clinic to report drinking and craving. Neuropsychological testing was performed at baseline and after study completion. Active working memory training improved verbal working memory performance, but no significant effect was found for drinking, craving or any of the other assessed cognitive domains. The results did not provide support for working memory training as a sole treatment for AUD, but future studies could consider combining it with pharmacological or psychological treatments. In summary, the current thesis demonstrated that cognitive deficits observed in AUD are in part due to shared genetic factors between AUD and cognitive function. These cognitive deficits may include impulsive behavior, capacity for future planning and emotional recognition. The treatment studies illustrate that cognitive outcomes can indeed be utilized as predictors of treatment response as well as potential treatment targets. LIST OF SCIENTIFIC PUBLICATIONS IN THE THESIS LIST OF ADDITIONAL PUBLICATIONS I. Khemiri L, Larsson H, Kuja-Halkola R, D'Onofrio BM, Lichtenstein P, JayaramLindström N, Latvala A. Association of Parental Substance Use Disorder with Offspring Cognition: A Population Family-based Study. Addiction (Abingdon, England) 2019, in press. II. Khemiri L, Franck J, Jayaram-Lindström N: Effect of Alcohol Use Disorder Family History on Cognitive Function (Manuscript) III. Khemiri L, Steensland P, Guterstam J, Beck O, Carlsson A, Franck J, JayaramLindström N: The Effects of the Monoamine Stabilizer (-)-OSU6162 on Craving in Alcohol Dependent Individuals: A Human Laboratory Study. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 2015 25;12 2240-51 IV. Khemiri L, Steensland P, Guterstam J, de Manzano Ö, Franck J, Jayaram-Lindström N: Effects of the Monoamine Stabilizer (-)OSU6162 on Cognitive Function in Alcohol Dependence. Psychopharmacology 2019, in press. V. Khemiri L, Brynte C, Stunkel A, Klingberg T, Jayaram-Lindström N. Working Memory Training in Alcohol Use Disorder: A Randomized Controlled Trial. Alcoholism, clinical and experimental research 2019 43;1 135-146 Khemiri L, Jayaram-Lindström N, Hammarberg A. Psychometric evaluation of a Swedish version of the Shortened Desires for Alcohol Questionnaire (Shortened-DAQ). Journal of substance abuse treatment 2017 79; 61-66 Khemiri L, Kuja-Halkola R, Larsson H, Jayaram-Lindström N. Genetic overlap between impulsivity and alcohol dependence: a large-scale national twin study. Psychological medicine 2016 46;5 1091-102 Khemiri L, Jokinen J, Runeson B, Jayaram-Lindström N. Suicide Risk Associated with Experience of Violence and Impulsivity in Alcohol Dependent Patients. Scientific reports 2016 6; 19373Khemiri L, Guterstam J, Franck J, Jayaram-Lindström N. Alcohol dependence associated with increased utilitarian moral judgment: a case control study. PloS one 2012 7;6 e39882 CONTENTS