Reboxetine Reduces Overall Narcolepsy Symptom Severity and Improves EDS, Mood-Related Symptoms

Reboxetine (AXS-12; Axsome Therapeutics) demonstrated reductions in the clinical impression of overall narcolepsy symptom severity, according to findings presented at the American Academy of Neurology 2026 Annual Meeting. The data were from the phase 3 SYMPHONY clinical trial (NCT05059223).^1,2

Reboxetine is a selective noradrenergic reuptake inhibitor that acts by binding to the norepinephrine transporter to block the reuptake of extracellular norepinephrine back into terminals. This compound has low affinity for other transporters and receptors. The treatment has undergone investigation in depressive disorders and is considered a potential treatment for sleep-related disorders, such as narcolepsy. Narcolepsy type 1 (NT1) is a chronic neurologic condition that is associated with severe symptom burden, impaired functioning, and a reduced quality of life because of symptoms. Comorbid mood disorders—such as anxiety and depression—are also common and can further impact daily life.^1-3

SYMPHONY, the randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial, assessed the efficacy and safety of reboxetine when treating cataplexy and excessive daytime sleepiness (EDS) in patients with NT1. Patients were eligible if they had a diagnosis of narcolepsy per the International Classification of Sleep Disorders and exhibited cataplexy- and EDS-related symptoms. Enrolled patients aged 15 to 75 years were randomly assigned to receive either reboxetine or placebo for a 5-week duration. The trial’s primary end point was the frequency of cataplexy attacks, which was assessed by the average number of attacks per week. Secondary end points included the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) anxiety/depression domain.^1,2

A total of 90 participants were enrolled. Mean baseline CGI-S and FOSQ-10 scores were about 5.2 and 11.1 for the reboxetine group and 4.9 and 11.6 for the placebo group. At the week 5 period, reboxetine was observed to significantly improve CGI-S (LS mean difference = 0.72 [95% CI, 0.29–1.16]; P = .001) and FOSQ-10 (LS mean difference = 1.66 [0.51, 2.82]; P = .005) compared with placebo.¹

Further, approximately 47.8% of participants in the reboxetine arm and 45.5% in the placebo arm reported having anxiety or depression (EQ-5D-5L) at baseline. Numerically, the authors wrote that more participants improved 1 or more levels when treated with reboxetine (55.0%) than when treated with a placebo (31.6%) at the 5-week point (P = .146).¹

These findings further emphasize the potential of reboxetine when used to treat NT1. In a previous analysis, reboxetine was shown to reduce the number of cataplexy attacks by approximately 83% compared with placebo (66%) at week 5 (rate ratio = 0.49; P = .018; baseline mean weekly cataplexy attacks: 27.7 and 35.4, respectively). At week 1, reductions were 56% (reboxetine) compared with 31% (rate ratio = 0.65; nominal P = .007), and cataplexy remission occurred more frequently at week 5 in patients receiving reboxetine (33%) than in those receiving placebo (9.5%; nominal P = .008).⁴

Further, mean percentages of cataplexy-free days at week 5 were approximately 84.5% and 22.6% for the reboxetine and placebo groups, respectively (nominal P = .014). Changes in CGI-S for EDS at week 5 were −1.8 (AXS-12) compared with −0.9 (placebo; nominal P = .027), and patients who were treated with reboxetine reported fewer inadvertent naps (54%) than those treated with placebo (28%; nominal P = .016). Additionally, reboxetine led to greater improvements in concentration and memory (1.6 vs 0.7, respectively; nominal P = .004).⁴

As the treatment landscape for NT1 continues to change, pharmacists must ensure that optimization of treatment is done safely and effectively. Because of reboxetine’s mechanism as a selective noradrenergic reuptake inhibitor, pharmacists are well-positioned to evaluate potential drug–drug interactions—particularly with other central nervous system agents or antidepressants—and to ensure appropriate patient selection, especially in those who have comorbid anxiety or depression. Additionally, pharmacists serve as educators, and they must counsel patients on expected benefits while setting realistic expectations about onset of effect and possible adverse events. Adherence can be supported by helping patients navigate dosing schedules and monitoring for tolerability during the early weeks of therapy.

REFERENCES

1. Thorpy M, Krahn L, Bogan R, et al. Impact of AXS-12 on Symptom Severity and Functional Impairment in Narcolepsy: Results From the Phase Three SYMPHONY Trial. Presented at: American Academy of Neurology 2026 Annual Meeting. Chicago, Illinois; April 18-22.

2. A Study to Assess the Efficacy and Safety of AXS-12 (Reboxetine) in Patients With Narcolepsy (SYMPHONY). ClinicalTrials.gov identifier: NCT05059223. Updated March 19, 2025. Accessed April 17, 2026. https://clinicaltrials.gov/study/NCT05059223

3. Page ME. The promises and pitfalls of reboxetine. CNS Drug Rev. 2003;9(4):327-342. doi:10.1111/j.1527-3458.2003.tb00258.x

4. Thorpy M, Krahn L, Bogan R, et al. AXS-12 for the Treatment of Narcolepsy: Topline Results from the Phase 3 SYMPHONY Trial (PL5.007). Neurology. 2025;104(7_Supplement_1):1510. doi:10.1212/WNL.0000000000208585