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

December 21, 2023 updated by: RITUPARNA MAITI, All India Institute of Medical Sciences, Bhubaneswar

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
    • Odisha
      • Bhubaneswar, Odisha, India, 751019
        • All India Institute of Medical Sciences (AIIMS)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Control group
Patients in the control group will get an identical-looking capsule containing placebo (starch) once daily in addition to SSRI.
Drug: Selective Serotonin Reuptake Inhibitors
Patients in both the study arms will receive SSRI for 8 weeks.
Drug: Placebo
Patients in the control group will get placebo tablet once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.
Experimental: Test group
Patients in the test group will get Dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment.
Drug: Selective Serotonin Reuptake Inhibitors
Patients in both the study arms will receive SSRI for 8 weeks.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in severity in depressive symptoms
Time Frame: Baseline and 8 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate treatment response rate
Time Frame: 8 weeks
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
To evaluate the symptom remission rate
Time Frame: 8 weeks
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
Severity of depressive symptoms at baseline
Time Frame: 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
To evaluate the improvement in symptoms of depression
Time Frame: 8 weeks
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
To evaluate the neurotrophic effect of the treatment
Time Frame: Baseline and 8 weeks
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
To evaluate the level of the experimental drug (dextromethorphan)
Time Frame: 8 weeks
Serum dextromethorphan level will be estimated using high-pressure liquid chromatography (HPLC) at 8 weeks after starting the drug.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

All India Institute of Medical Sciences, Bhubaneswar

Investigators

  • Principal Investigator: Rituparna Maiti, M.D., AIIMS, Bhubaneswar

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 10, 2022

Primary Completion (Actual)

September 30, 2023

Study Completion (Actual)

November 30, 2023

Study Registration Dates

First Submitted

December 16, 2021

First Submitted That Met QC Criteria

December 16, 2021

First Posted (Actual)

January 6, 2022

Study Record Updates

Last Update Posted (Actual)

December 22, 2023

Last Update Submitted That Met QC Criteria

December 21, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AIIMSBBSR/PGThesis/21-22/74

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Major Depressive Disorder

Clinical Trials on Selective Serotonin Reuptake Inhibitors

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Kyrgyzstan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe