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

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.