Lim Tsen Vei, Cardinal Rudolf N, Ziauddeen Hisham, Regenthal Ralf, Sahakian Barbara J, Robbins Trevor W, Ersche Karen D
Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Liaison Psychiatry Service, Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom.
Biol Psychiatry. 2025 Mar 15;97(6):627-636. doi: 10.1016/j.biopsych.2024.10.018. Epub 2024 Oct 29.
Impulsivity is a well-known determinant of maladaptive behavior in cocaine use disorder (CUD), but there are currently no effective strategies for managing excessive impulsivity. Growing evidence from preclinical and clinical studies suggests that atomoxetine, a selective noradrenaline reuptake inhibitor, is effective in improving impulse control in both healthy individuals and individuals with neuropsychiatric conditions.
We investigated the effects of atomoxetine on decisional impulsivity in patients with CUD. In a randomized, double-blind, placebo-controlled, crossover study, 28 patients diagnosed with moderate-to-severe CUD and 28 matched healthy control participants completed the Cambridge Gambling Task in 2 separate sessions, where they received either placebo or a single dose of 40 mg atomoxetine at each session. Computational modeling was used to break down decision making into 3 separable components: value, probability, and decisional impulsivity.
Our analyses revealed that patients with CUD were impaired in all components of decision making. Atomoxetine selectively reduced decisional impulsivity in patients with CUD by reducing their risk-seeking tendencies while enhancing their ability to tolerate delays. By contrast, atomoxetine did not affect impulsivity in control participants, but increased their sensitivity to prospective losses.
Taken together, our findings support the hypothesis of noradrenergic dysfunction in patients with CUD and provide novel translational evidence for the efficacy of atomoxetine in remediating decisional impulsivity in CUD.
冲动性是可卡因使用障碍（CUD）中适应不良行为的一个众所周知的决定因素，但目前尚无有效策略来管理过度冲动。临床前和临床研究的越来越多的证据表明，托莫西汀，一种选择性去甲肾上腺素再摄取抑制剂，在改善健康个体和患有神经精神疾病个体的冲动控制方面是有效的。
我们研究了托莫西汀对CUD患者决策冲动性的影响。在一项随机、双盲、安慰剂对照、交叉研究中，28名被诊断为中度至重度CUD的患者和28名匹配的健康对照参与者在2个单独的疗程中完成了剑桥赌博任务，每个疗程中他们分别接受安慰剂或单剂量40mg托莫西汀。计算建模用于将决策分解为3个可分离的成分：价值、概率和决策冲动性。
我们的分析显示，CUD患者在决策的所有成分上都受损。托莫西汀通过降低CUD患者的冒险倾向，同时增强他们耐受延迟的能力，选择性地降低了决策冲动性。相比之下，托莫西汀对对照参与者的冲动性没有影响，但增加了他们对预期损失的敏感性。
综上所述，我们的研究结果支持CUD患者去甲肾上腺素能功能障碍的假说，并为托莫西汀在纠正CUD患者决策冲动性方面的疗效提供了新的转化证据。
