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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Selective Serotonin Reuptake Inhibitors
* Drug: Dextromethorphan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control group<br>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<br>* Patients in both the study arms will receive SSRI for 8 weeks.<br>Drug: Placebo<br>* Patients in the control group will get placebo tablet once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.<br>|
| Experimental: Test group<br>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<br>* Patients in both the study arms will receive SSRI for 8 weeks.<br>Drug: Dextromethorphan<br>* Patients in the test group will get Dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |