Repurposing of Dextromethorphan as an Adjunct Therapy in Patients With Major Depressive Disorder

Major Depressive Disorder Clinical Trial

Official title:

Repurposing of Dextromethorphan as an Adjunct Therapy in Patients With Major Depressive Disorder: A Randomized, Group Sequential, Adaptive Design, Controlled Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05181527
• Other study ID #: AIIMSBBSR/PGThesis/21-22/74
• Status: Completed
• Phase: Phase 4
• Start date: February 10, 2022
• Est. completion date: November 30, 2023

Study information

• Verified date: December 2023
• Source: All India Institute of Medical Sciences, Bhubaneswar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Major depressive disorder (MDD) is a common psychiatric disorder with a substantial socioeconomic burden with a global prevalence rate of 16%. The underlying pathophysiology of depression is still not understood completely. Among the different proposed hypotheses, the most accepted is the monoamine hypothesis which is the basis of most of the available drugs like tricyclic antidepressants, Monoamine oxidase Inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs). Although many medications are available, a significant proportion of patients become either non-responders or treatment-resistant depression patients. Another major concern is the therapeutic lag period with all of these monoaminergic antidepressants. Additionally, most of the available antidepressant drugs have many adverse effects, which increase with increments in dose. The discovery of the rapid and sustained antidepressant effect of subanesthetic dose of ketamine, especially in the treatment of non-responders and treatment-resistant cases leads to many extensive clinical and preclinical research in the recent past. As repeated doses of ketamine are related to abusive potential and many other adverse effects, the search for a similar antidepressant agent is going on, which acts via a similar mechanism with a better safety profile. Dextromethorphan, an FDA-approved over-the-counter antitussive drug, has a similar property of non-competitively blocking N-methyl-D-aspartate receptors of glutamate, like ketamine. Additionally, Dextromethorphan has serotonin transporter inhibitory and NET inhibitory properties, so it can also increase the availability of serotonin in synapses, hence may achieve a synergistic effect with SSRIs. In 2010, US-FDA approved Dextromethorphan plus quinidine (Nuedexta) for use in pseudobulbar affect (PBA), and currently, it is under investigation as a potential antidepressant agent in MDD (NCT01882829, NCT02153502). In the phase, IIa clinical trial by Murrough et al. have reported acceptable tolerability and efficacy of dextromethorphan/quinidine combination in treatment-resistant depression (TRD). Another combination of Dextromethorphan and bupropion is currently in phase III clinical trial for TRD. In the present background, the investigators hypothesize that the major concerns of antidepressant therapy like therapeutic latency, lack of efficacy, and adverse drug reactions may be overcome by adding Dextromethorphan to SSRI in MDD. As SSRIs inhibit CYP2D6, the addition of quinidine with Dextromethorphan may not be reasonable and hence, not considered in the present study. The literature search found that to date, there is no randomized controlled trial on Dextromethorphan as an 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: November 30, 2023
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patients diagnosed with major depressive disorder of either gender within the age group of 18-65 years
• Patients with MADRS score = 7 and = 34 (patients having mild to moderate MDD).
• Patients who are on a stable dose of Sertraline 50 mg or any other Selective Serotonin Reuptake Inhibitor (SSRI) therapy in equivalent dose for less than equal to 4 weeks.
• Patients who have given written informed consent.

Exclusion Criteria:

• Patients who have been treated with Electro Convulsive Therapy (ECT) recently.
• History of epilepsy, or other major neurological or medical disorders, head trauma.
• Patients with a history of Bipolar Depression (BPD).
• Patients with schizophrenia or other psychotic disorder.
• Patients with suicidal thoughts or risk.
• Patients with cognitive impairment.
• Initiating or stopping formal psychotherapy within six weeks before enrolment.
• Patients with comorbidities like any malignancies, hepatic, renal, cardiovascular,
• neurological or endocrinal, respiratory dysfunction.
• Substance abuse history of psychoactive agents.
• Pregnant and lactating mothers.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Selective Serotonin Reuptake Inhibitors
Patients in both the study arms will receive SSRI for 8 weeks.
• Dextromethorphan
Patients in the test group will get Dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.
• Placebo
Patients in the control group will get placebo tablet once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences (AIIMS)	Bhubaneswar	Odisha

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, Bhubaneswar

Country where clinical trial is conducted

India, 

References & Publications (8)

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. — View Citation

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. — View Citation

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- — View Citation

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. — View Citation

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. — View Citation

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 2 — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in severity in depressive symptoms	Will be assessed by Montgomery-Asberg Depression Rating Scale score. The overall score ranges from 0 to 60. A higher score denotes greater severity of depression.	Baseline and 8 weeks
Secondary	To evaluate treatment response rate	Treatment response rate will be assessed as a percentage of patients showing 50% change in Montgomery-Asberg Depression Rating Scale scores from baseline, after 8-week follow-up.	8 weeks
Secondary	To evaluate the symptom remission rate	Symptom remission rate will be assessed as a percentage of patients achieving Montgomery-Asberg Depression Rating Scale scores <7 at 8-week follow-up.	8 weeks
Secondary	Severity of depressive symptoms at baseline	Severity of depressive symptoms at baseline will be assessed by Clinical Global Impression- severity (CGI-S) score. The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale and the higher value suggests greater severity of the disease.	At baseline
Secondary	To evaluate the improvement in symptoms of depression	The improvement in symptoms of depression will be assessed by Clinical Global Impression- Improvement (CGI-I) score. The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale and a lower value suggests greater improvement in symptoms.	8 weeks
Secondary	To evaluate the neurotrophic effect of the treatment	The neurotrophic effect of the treatment will be assessed by estimating Serum Brain-Derived Neurotrophic Factor (BDNF) level at baseline and at 8-week.	Baseline and 8 weeks
Secondary	To evaluate the level of the experimental drug (dextromethorphan)	Serum dextromethorphan level will be estimated using high-pressure liquid chromatography (HPLC) at 8 weeks after starting the drug.	8 weeks