Dextromethorphan Emerges as a Novel Antidepressant Pathway for Treatment-Resistant Depression

Since their approval in the 1950s, monoamine-based antidepressants have remained a cornerstone treatment in managing major depressive disorder (MDD). Although they have shown massive success over the years, 100 million people globally suffer fromtreatment-resistant depression (TRD), a condition broadly defined as an insufficient response to at least 2 antidepressants for adequate duration use and adherence.¹ This therapeutic need has stimulated research into novel antidepressants aimed at addressing the latency in clinical response some patients experience with conventional treatment. In recent years, research has led to an increased understanding of how abnormalities in glutamate or glutamate production contribute to the pathogenesis of depression.² Glutamate is an excitatory neurotransmitter with multiple receptors. The N-methyl-D-aspartate (NMDA) receptor has the highest affinity for glutamate.² One class of drugs that has garnered much attention is the NMDA antagonists.

In 2019, esketamine (Spravato; Johnson & Johnson) became the first agent in this class to obtain approval by the FDA for TRD.³ Working via non-monoaminergic mechanisms, esketamine provides an alternative option for those with TRD.³It has been suggested that the antidepressant effects are multimodal and may be due both to μ-opioid receptor activation and NMDA antagonism, leading to activation of the mammalian target of rapamycin (mTOR).⁴ This mechanism has been studied in patients with severe suicidal behavior, although the benefits may be temporary.³ Due to esketamine’sdissociative and derealization effects, which can occur in up to 70% of patients, intense monitoring is required during treatment.⁴ These untoward effects and monitoring requirements can be barriers for patients who might otherwise benefit clinically from the drug’s pharmacology.

Interest has grown in other NMDA antagonists with better safety and tolerability profiles. Research suggests that multimodal agents are more effective for clinical depression, including TRD.^5,6 One study showed a greater percentage of patients achieving remission with the use of a combination of antidepressant agents versus monoamine monotherapy.⁷ A surprising candidate for TRD is dextromethorphan (DXM). Originally approved in 1958 as a cough suppressant, DXM exerts antitussive effects by suppressing the excitability of the brainstem cough reflex.⁸ However, in recent years, DXM has been evaluated for potential use in the treatment of central nervous system (CNS) conditions. It inhibits serotonin and norepinephrine transporters while enhancing serotonin availability in synapses, a mechanism which suggests synergy with selective serotonin reuptake inhibitors (SSRIs).^9,10 In addition, DXM exhibits similar pharmacologic effects to ketamine and esketamine, including NMDA antagonism, μ-opioid agonism, and σ-1 receptor agonism.^9,10 DXM has a lower NMDA receptor binding affinity than esketamine. Evidence suggests that NMDA antagonism is more closely associated with dissociative and abuse-related effects than with antidepressant efficacy, which is mediated through downstream glutamatergic pathways; thus, the lower NMDA affinity of DXM may contribute to a reduced risk of dissociative effects compared with esketamine.^3,6,9,10,11

Studies in the early 2000s evaluated a combination of DXM and quinidine for the treatment of pseudobulbar affect (PBA).^12,13 In 2010, a proprietary medication containing this combination (Nuedexta; Otsuka America Pharmaceutical Inc) was the first drug approved for PBA. Despite this approval, the limited data available on the use of DXM with quinidine in MDD or TRD has not shown sufficient benefit.¹²However, research evaluating use of DXM with other medications is more encouraging. In 2019, investigators demonstrated the safety and efficacy of DXM in combination with bupropion (Wellbutrin; Bausch Health), a norepinephrine-dopamine reuptake inhibitor (NDRI).¹⁴ The combination of DXM and bupropion was approved by the FDA in 2022 (Auvelity; Axsome).¹⁵ Both quinidine and bupropion inhibit CYP2D6, the enzyme responsible for metabolizing DXM. Combining DXM with bupropion allows DXM to reach sufficient therapeutic concentrations in the plasma necessary to exert antidepressant effects.^6,8,10,12-15DXM is demethylated to dextrorphan, the metabolite responsible for dissociative effects; however, when combined with a CYP2D6 inhibitor, dextrorphan does not reach concentrations typically associated with dissociation.^6,13,15,16 As a result, expert opinion suggests that the abuse potential of DXM at therapeutic doses may be significantly reduced, especially in comparison to ketamine and esketamine.^6,14 Unfortunately, the combination of DXM and bupropion is not without its limitations. Genetic polymorphisms in CYP2D6 may increase the risk of adverse effects in patients with pharmacogenomic abnormalities.^6,14,15

More recently, DXM has been evaluated as monotherapy for adjunct therapy in treating depression. A 2025 randomized controlled study evaluated 60 patients who received either DXM 30 mg or placebo in addition to a SSRI for 8 weeks. DXM use resulted in significantly greater reduction in Montgomery-Asberg Depression Rating Scale (MADRS) from baseline (mean difference [MD] -3.94; 95% CI -5.81 to -2.06; p<0.001) and a significantly greater reduction in Clinical Global Impression-Severity score (MD -0.4; 95% CI -0.65 to -0.15; p=0.002). Patients receiving DXM also had a higher response rate (80% vs. 43.3%; p=0.008) and greater remission rate (53.3% vs. 16.7%; p=0.007).¹⁷

Although these preliminary data are promising, DXM monotherapy has been neither approved nor endorsed for depression. It is paramount that patients understand that DXM should not be used for depression outside of a prescriber’s care. Although it is available over the counter, DXM self-treatment can lead to dangerous effects if used inappropriately. The most evidence-based dose of DXM that is supported by demonstrated efficacy and safety in adults with MDD is 45 mg twice daily (in combination with 105 mg of bupropion at the same frequency).¹³ Mild neurobehavioral effects can occur with DXM 100 mg and can escalate to complete dissociation with unresponsiveness at doses greater than 600 mg ingested at one time.¹⁶

Additionally, the serotonergic effects of DXM have the potential to cause serotonin syndrome, alone or in combination with other medications with serotonin activity.^16,17 It is also important to note that there are minimal data on the use of DXM for pediatrics with depression. Although DXM has been used as an antitussive in younger patients, differences in pharmacokinetics and pharmacodynamic profiles in children and adolescents warrant caution in extrapolating data from adult studies in depression to this population.^16-19

Although long recognized as a cough suppressant, DXM is emerging as a novel and interesting option in treating therapy-resistant cases of depression. Its distinctive mechanism of action sets it apart from standard antidepressants and opens the door to more targeted relief. Repurposing this older medication builds upon the advancement of pharmaceutical practices to treat modern illnesses. As safety and efficacy continue to be explored through clinical trials, DXM may soon redefine how we approach mood disorders, offering new hope to millions affected by depression. This pivotal revelation of effectively using DXM resides not only as a representation of innovation in treating depression, but also as an encouraging bridge to a new era of fast-acting, patient-centered therapies extending beyond psychiatric care.

References

1. McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394-412. doi:10.1002/wps.21120

2. Niciu MJ, Ionescu DF, Richards EM, Zarate CA. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm. 2014;121(8):907-924. doi:10.1007/s00702-013-1130-x

3. Vasiliu O. Esketamine for treatment‑resistant depression: A review of clinical evidence (Review). Exp Ther Med. 2023;25(3):111. doi:10.3892/etm.2023.11810

4. Wang M, Kaplin A. Explaining naltrexone’s interference with ketamine’s antidepressant effect. AJP. 2019;176(5):410-411. doi:10.1176/appi.ajp.2019.19010044

5. Richelson E. Multi-modality: a new approach for the treatment of major depressive disorder. Int J Neuropsychopharmacol. 2013;16(6):1433-1442. doi:10.1017/S1461145712001605

6. Stahl SM. Dextromethorphan/bupropion: a novel oral NMDA (N-methyl-d-aspartate) receptor antagonist with multimodal activity. CNS Spectr. 2019;24(5):461-466. doi:10.1017/S1092852919001470

7. Zuilhof Z, Norris S, Blondeau C, Tessier P, Blier P. Optimized regimens of combined medications for the treatment of major depressive disorder: a double-blind, randomized-controlled trial. NDT. 2018;Volume 14:3209-3218. doi:10.2147/NDT.S175203

8. Kverno K. Dextromethorphan: from cough suppressant to antidepressant. J Psychosoc Nurs Ment Health Serv. 2022;60(11):9-11. doi:10.3928/02793695-20221005-02

9. Saavedra JS, Garrett PI, Honeycutt SC, Peterson AM, White JW, Hillhouse TM. Assessment of the rapid and sustained antidepressant-like effects of dextromethorphan in mice. Pharmacology Biochemistry and Behavior. 2020;197:173003. doi:10.1016/j.pbb.2020.173003

10. Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Medical Hypotheses. 2011;76(5):717-719. doi:10.1016/j.mehy.2011.02.003

11. Jiang Y, Dong Y, Hu H. The N-methyl-D-aspartate receptor hypothesis of ketamine’s antidepressant action: evidence and controversies. Phil Trans R Soc B. 2024;379(1906):20230225. doi:10.1098/rstb.2023.0225

12. Pattee GL, Wymer JP, Lomen-Hoerth C, Appel SH, Formella AE, Pope LE. An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions. Curr Med Res and Opin. 2014;30(11):2255-2265. doi:10.1185/03007995.2014.940040

13. Yang LPH, Deeks ED. Dextromethorphan/quinidine: a review of its use in adults with pseudobulbar affect. Drugs. 2015;75(1):83-90. doi:10.1007/s40265-014-0328-z

14. Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. AJP. 2022;179(7):490-499. doi:10.1176/appi.ajp.21080800

15. Auvelity [Package Insert]. Axsome Therapeutics Inc; 2022. Accessed June 10, 2025. https://www.auvelityhcp.com

16. Antoniou T, Juurlink DN. Dextromethorphan abuse. CMAJ. 2014;186(16):E631-E631. doi:10.1503/cmaj.131676

17. Maji S, Mishra A, Mohapatra D, et al. Early augmentation therapy with dextromethorphan in mild to moderate major depressive disorder: a group sequential, response adaptive randomized controlled trial. Psychiatry Research. 2024;342:116257. doi:10.1016/j.psychres.2024.116257

18. Paul IM, Reynolds KM, Kauffman RE, et al. Adverse events associated with pediatric exposures to dextromethorphan. Clinical Toxicology. 2017;55(1):25-32. doi:10.1080/15563650.2016.1240803

19. Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics. Chest. 2006;129(1):260S-283S. doi:10.1378/chest.129.1_suppl.260S