Repurposing of Dextromethorphan as an Adjunct Therapy in Patients With Major Depressive Disorder
Summary
Therapeutic latency, lack of efficacy, and adverse drug reactions are the major concerns in current antidepressant therapies. One-third of the patients with major depressive disorder do not respond to conventional antidepressants that act through the monoaminergic system. To overcome these treatment hurdles, add-on therapy to standard antidepressant drugs may lead to better therapeutic outcomes. The recent discovery of the rapid and sustained antidepressant effect of subanesthetic dose of ketamine led to many extensive clinical and preclinical research in the recent past and has established the possibilities of NMDA receptors as a potential drug target for depression. As repeated doses of ketamine are related to abusive potential and adverse effects, the search for a similar antidepressant agent with a better safety profile is essential. Dextromethorphan has the property of noncompetitively blocking N-methyl-D-aspartate receptors (like ketamine) with additional serotonin transporter and norepinephrine transporter inhibitory action. So, the investigators expect that adding dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) regimen can improve clinical outcomes in major depressive disorder. The literature search found that to date, there is no randomized controlled trial on Dextromethorphan as add-on therapy to first-line antidepressants like SSRIs. So, the present randomized controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to SSRIs in major depressive disorder.
Timeline
- Start
- 2022-02-10
- Primary completion
- 2023-09-30
- Completion
- 2023-11-30
Publications
- Results Wang YT, Wang XL, Feng ST, Chen NH, Wang ZZ, Zhang Y. Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression. Pharmacol Res. 2021 Sep;171:105761. doi: 10.1016/j.phrs.2021.105761. Epub 2021 Jul 7.
- Results Lener MS, Kadriu B, Zarate CA Jr. Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression. Drugs. 2017 Mar;77(4):381-401. doi: 10.1007/s40265-017-0702-8.
- Results 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. Pharmacol Biochem Behav. 2020 Oct;197:173003. doi: 10.1016/j.pbb.2020.173003. Epub 2020 Aug 2.
- Results Henter ID, Park LT, Zarate CA Jr. Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. CNS Drugs. 2021 May;35(5):527-543. doi: 10.1007/s40263-021-00816-x. Epub 2021 Apr 26.
- Results Fogaca MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Mol Psychiatry. 2021 Jul;26(7):3277-3291. doi: 10.1038/s41380-020-00916-y. Epub 2020 Oct 17.
- Results Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018 Apr;23(4):801-811. doi: 10.1038/mp.2017.255. Epub 2018 Mar 13.
- Results Nguyen L, Scandinaro AL, Matsumoto RR. Deuterated (d6)-dextromethorphan elicits antidepressant-like effects in mice. Pharmacol Biochem Behav. 2017 Oct;161:30-37. doi: 10.1016/j.pbb.2017.09.005. Epub 2017 Sep 12.
- Results Kamijima K, Kimura M, Kuwahara K, Kitayama Y, Tadori Y. Randomized, double-blind comparison of aripiprazole/sertraline combination and placebo/sertraline combination in patients with major depressive disorder. Psychiatry Clin Neurosci. 2018 Aug;72(8):591-601. doi: 10.1111/pcn.12663. Epub 2018 May 21.
- Maji S, Mishra A, Mohapatra D, Mishra BR, Jena M, Srinivasan A, Maiti R. Early augmentation therapy with dextromethorphan in mild to moderate major depressive disorder: A group sequential, response adaptive randomized controlled trial. Psychiatry Res. 2024 Dec;342:116257. doi: 10.1016/j.psychres.2024.116257. Epub 2024 Nov 8.
- Maji S, Mohapatra D, Jena M, Srinivasan A, Maiti R. Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol. BMJ Open. 2024 Apr 30;14(4):e080500. doi: 10.1136/bmjopen-2023-080500.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Dextromethorphan | Unknown | 30 mg | Oral |