The effects of atomoxetine on decisional impulsivity in cocaine use disorder: a computational analysis

Abstract:

Background: Impulsivity is a hallmark of cocaine use disorder. Accumulating evidence suggests that patients with cocaine use disorder have a greater tendency to make impulsive decisions [1], but its underlying neurocognitive mechanisms remain unclear. Recently, computational models have emerged as a means to quantify latent, unobservable cognitive processes that underpin behaviour [2]. This methodology is not only useful to clarify the neurocognitive drivers of impulsive decisions, but it can also identify potential treatment targets to address them. Atomoxetine, a selective noradrenaline reuptake inhibitor, has recently been shown to enhance brain networks associated with impulse control in cocaine use disorder [3], but it is unclear how it modulates cognition to reme- diate impulsive decisions. Objectives and hypotheses: The aim of this study is to investigate the effects of atomoxetine on the cognitive subprocesses of decision-making in cocaine use disorder using computational modelling. We hypothesize that the decision- making profile in cocaine use disorder is characterized by an increased pro- pensity for impulsive decisions. We further hypothesize that atomoxetine reduces the propensity to make impulsive decisions in patients with cocaine use disorder. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study, where healthy control volunteers (n 1⁄4 28) and patients diag- nosed with moderate-to-severe cocaine use disorder (n 1⁄4 28) received either a single dose of 40mg atomoxetine or placebo on each session. All participants complete the Cambridge Gamble Task, a well-established decision-making paradigm, approximately 2.5 hours post dosing to allow for peak plasma con- centrations. We estimated the influence of probability, subjective value, and impulsivity on decision-making by deconstructing trial-by-trial task behaviour with a computational model [4]. Results: The computational analyses revealed that patients with cocaine use disorder were impaired in all subcomponents of decision-making: they were less likely to account for probability (posterior median difference [MD] 1⁄4 2.19, posterior probability of a null difference [pZ] < 0.001), less reliant on subjective value (MD 1⁄4 0.609, pZ 1⁄4 0.034), and had a greater tendency to make impulsive choices (MD 1⁄4 0.941, p Z 1⁄4 0.002) during decision-making. Atomoxetine modulated these computational parameters differentially in control participants and cocaine use disorder patients. On the one hand, atomoxetine selectively reduced impulsive choices in cocaine use disorder patients by reducing their preferences for risk (MD 1⁄4 0.251, pZ 1⁄4 0.005), and enhanced their ability to tolerate delays (MD 1⁄4 0.073, pZ < 0.001); other parameters were unaffected by atomoxetine (pZ > 0.05). On the other hand, atomoxetine increased control participants’ sensitivity to prospective losses during decision-making (MD: 0.251, pZ 1⁄4 0.004), but had no effect on other parameters (pZ > 0.05). Conclusion: Our findings not only provide novel translational evidence for the beneficial effects of atomoxetine in reducing decisional impulsivity in cocaine use disorder, but also illustrate the strength of computational models. These models allow for more fine-grained analyses of behaviour that could reveal po- tential treatment targets, thereby offering a promising new avenue for research in human psychopharmacology and psychopathology. References [1] Grant J.E., Chamberlain SR, 2014. Impulsive action and impulsive choice across substance and behavioral addictions: Cause or consequence? Addict Behav 39, 1632–1639. [2] Lim T.V., Ersche K.D., 2023. Theory-driven computational models of drug addiction in humans: fruitful or futile? Addict Neurosci, 5, 100066. [3] Zhukovsky P., Morein-Zamir S., Ziauddeen H., Fernandez-Egea E., Meng C., Regenthal R., Sahakian B.J., Bullmore E.T., Robbins T.W., Dalley J.W., Ersche, K.D., 2022. Prefrontal Cortex Activation and Stopping Performance Un- derlie the Beneficial Effects of Atomoxetine on Response Inhibition in Healthy Volunteers and Those With Cocaine Use Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging 7, 1116–1126. [4] Talwar A., Cormack F., Huys Q.J.M., Roiser J.P., 2022. Individual Variation in Risky Decisions Is Related to Age and Gender but not to Mental Health Symptoms. bioRxiv, doi:10.1101/2022.07.11.499611. Conflict of interest This work was funded by a Medical Research Council grant (MR/J012084/1) and conducted within the Behavioural and Clinical Neuroscience Institute at the University of Cambridge. It was also supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312) and the NIHR Applied Research Collaboration East of England. The views expressed are those of the author(s) and not necessarily those of the Medical Research Council, NIHR or the Department of Health and Social Care. The NIHR and the Medical Research Council had no role in the study design, collection, analysis, and the interpretation of data. RNC consults for Campden Instruments Ltd in the area of research software and receives roy- alties from Cambridge University Press, Cambridge Enterprise, and Routledge. BJS receives funding from the Leverhulme Trust and the Lundbeck Foundation. Her research is conducted within the NIHR Cambridge Biomedical Research Centre Mental Health and Neurodegeneration Themes and the NIHR MedTech and in vitro diagnostic Co-operative. BJS also consults for Cambridge Cognition, and she receives royalties from PopReach. TWR consults for Cambridge Cognition Greenfield BioVentures Arcadia Merck, Sharpe, & Dohme and Lundbeck. He currently receives research grants from Shionogi and GlaxoSmithKline. KDE re- ceives editorial honoraria from Karger Publishers and is a Trustee of the Society for the Study of Addiction. The remaining authors have nothing to disclose.