Repurposing of Dextromethorphan as an Adjunct Therapy in Patients With Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Selective Serotonin Reuptake Inhibitors; Dextromethorphan; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Patients in both the study arms will receive SSRI for 8 weeks.; Patients in the test group will get Dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.; Patients in the control group will get placebo tablet once daily orally as an add-on to ongoing SSRI treatment for 8 weeks.
Intervention MeSH terms: Dextromethorphan; Serotonin; Selective Serotonin Reuptake Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment