Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine’s impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (r_s = −0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, R²β = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine’s capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.

工作记忆 （WM） 是认知功能的关键组成部分，在精神分裂症等精神疾病中经常受损。通过基因组引导的药物再利用方法，我们确定了氨吡啶，一种用于改善多发性硬化症行走的钾通道阻滞剂，是调节 WM 的候选药物。在随后对 43 名健康年轻人 （ClinicalTrials.gov、 NCT04652557） 进行的双盲、随机、安慰剂对照、交叉试验中，我们评估了氨吡啶对重复给药 3.5 天后 WM （3-back d-prime，主要结果） 的影响 （10 mg 每日两次）。独立于基线认知表现，未观察到显着的主效应 （Wilcoxon P = 0.87，r = 0.026）。然而，与安慰剂相比，重复摄入氨吡啶后，较低的基线表现与较高的工作记忆表现相关 （r_s = -0.37，P = 0.014，n = 43）。此外，重复摄入氨吡啶降低了静息运动阈值 （F（1,37） = 5.31，P = 0.027，R²β = 0.01），这是非行为次要结果，表明与认知功能相关的皮质兴奋性增加。 Fampridine 增强低表现个体的 WM 和增加大脑兴奋性的能力表明其治疗 WM 缺陷的潜在价值。