Assessment of Withdrawal Symptoms after Discontinuation of AXS-05 (Dextromethorphan-Bupropion) Treatment: Results from the GEMINI Trial

This work was sponsored by Axsome Therapeutics Background: Traditional antidepressants that act via monoamine pathways often lead to withdrawal effects in up to 60% of patients, manifesting as flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal. AXS-05 [dextromethorphan-bupropion (Auvelity® extended-release tablet)] is a novel, oral, NMDA receptor antagonist with multimodal activity approved by the U.S FDA for the treatment of major depressive disorder (MDD) in adults. We evaluated the potential withdrawal symptoms following discontinuation of AXS-05 compared to placebo in patients with MDD using the 20-item Physician Withdrawal Checklist (PWC-20). Methods: GEMINI was a U.S. randomized, double-blind, placebo-controlled study, tested AXS-05 on 327 adults with MDD over 6 weeks. The study compared AXS-05 (comprising dextromethorphan 45 mg- bupropion 105 mg) with a placebo, administered twice daily. After the 6-week trial, medication was stopped abruptly, and a week later, potential withdrawal symptoms were assessed using the Physician Withdrawal Checklist (PWC-20), an instrument designed to measure the presence and severity of 20 specific withdrawal symptoms. Results: No significant differences were observed between the AXS-05 and placebo groups for 18 out of 20 symptoms assessed by the PWC-20. Exceptions were nausea/vomiting (11.7% for AXS-05 vs. 4.7% for placebo, p=0.031) and dizziness/lightheadedness (18.2% for AXS-05 vs. 6.2% for placebo, p=0.002). However, in the majority of these AXS-05 patients (88% for nausea/vomiting and 92% for dizziness), these symptoms were rated as mild or moderate. Conclusion: Following 6 weeks of treatment, discontinuation of AXS-05 without taper was well tolerated with similar rates compared to placebo for almost all PWC-20 symptoms.