At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed.
The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10 mg by mouth administered every 12 h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion.
There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: −13.0±11.5, t 19 =5.0, p <0.001), as was QIDS-SR score (mean change: −5.9±6.6, t 19 =4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively.
Open-label, proof-of-concept design.
Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10 mg administered every 12 h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.
- • Targets for novel antidepressants include the glutamate NMDA and sigma-1 receptors.
- • Dextromethorphan displays activity at these receptors and other targets.
- • Dextromethorphan plus quinidine (DM/Q) was tested in treatment-resistant depression.
- • DM/Q showed acceptable tolerability and preliminary efficacy in this population.
Major depressive disorder (MDD) represents one of the major sources of disease related disability worldwide, accounting for more than 40% of the 184 million disability-adjusted life years (DALYs) attributed to all mental and substance use disorders in 2010 ( Whiteford et al., 2013 ). It is estimated that only one out of three patients with MDD treated with a first-line antidepressant medication will achieve full symptom remission ( Rush et al., 2006 ), and up to one-third of patients will remain symptomatic despite multiple optimized treatment steps ( Trivedi et al.2006a ). Patients who have failed to respond to two or more antidepressant medication trials of adequate dose and duration may be classified as experiencing treatment-resistant depression (TRD), and as a group these patients suffer a more chronic and severe disease course and account for up to half of the total economic cost of the illness ( Mathew, 2008;Shelton et al., 2010 ). All antidepressant medications currently marketed in the United States (U.S.) act mechanistically by enhancing monoamine signaling in the brain, for example via serotonin or norepinephrine transporter blockade. This mechanistic homogeneity likely contributes substantially to the prevalence of TRD by limiting the pharmacotherapeutic options available to treatment providers.
A critical need in neuropharmacology research is to identify safe and more effective treatments for depression by targeting neural receptors and signaling pathways outside of the monoamine system ( Berton and Nestler, 2006;Mathew et al., 2008;Papakostas and Ionescu, 2015 ). In this context, the discovery of a rapid antidepressant effect of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine now more than a decade ago, has provided a major impetus for drug discovery research focused on the NMDA receptor and other targets linked to glutamate signaling ( Sanacora et al.2008 ). One potentially fruitful research strategy involves the conduct of proof-of-concept (POC) clinical trials of agents with known effects at the NMDAR receptor or other novel molecular targets in patients with TRD, taking advantage of the availability of marketed drugs as tool compounds. This strategy essentially ‘re-purposes’ existing compounds as pharmacological probes in order to gain information concerning the viability of a given target for a new indication (e.g., TRD).
Dextromethorphan (DM) is an antitussive medication with a complex pharmacology that includes inhibition of NMDA receptors, as well as interactions with serotonin and norepinephrine transporters, nicotinic acetylcholine receptors, and sigma-1 (σ 1 ) receptors (reviewed in Taylor et al. (2016) ). A fixed-dose combination product of DM and the cytochrome P450 (CYP) 2D6 enzyme inhibitor quinidine (Q) gained approval for the treatment of pseudobulbar affect (PBA) in the U.S. in 2010 [DM 20 mg/Q 10 mg every 12 h (Nuedexta®, Avanir Pharmaceuticals, Inc.)]. Although early clinical trial experience with DM in neurological disorders showed minimal efficacy, low plasma levels of DM owing in part to substantial first-pass metabolism may have largely limited brain exposure ( Pope et al., 2004;Werling et al., 2007 ). The concurrent administration of Q with DM, in contrast, substantially increases DM plasma levels by reducing the first-pass metabolism of DM by CYP2D6 (Yang and Deeks, 2015 ). Given the unique pharmacology of DM that includes NMDA receptor antagonism, we took advantage of the availability of DM/Q to conduct a phase IIa open-label POC study of DM/Q dosed up to 45 mg/10 mg every 12 h in patients with TRD. Our goal was to examine initial feasibility, tolerability, and open-label antidepressant efficacy of this approach.
Herein we report on the feasibility, tolerability, and initial antidepressant efficacy of DM/Q dosed up to 45/10 mg every 12 h in patients with TRD in a current MDE. Study patients had failed a median of 2 adequate antidepressant trials in the current episode. We observed acceptable tolerability in this TRD group, with AE frequencies similar to what has been observed previously in studies of PBA ( Doody et al., 2015;Pioro et al., 2010 ). Patients showed a large mean reduction in MADRS score of −13.0 at study end and 50% of patients were classified as ‘improved’ or ‘very much improved.’ Response and remission rates were 45% and 35%, respectively in the ITT sample. The magnitude of improvement was similar between individuals who were taking a concomitant antidepressant medication and those who were not, and between patients with a moderate level of treatment-resistance and those with a higher level. Although direct comparisons between studies are difficult to make, the observed remission rate of 35% in the current study compares to remission rates of 25–39% in level 2% and 8–25% in level 3 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Warden et al., 2007 ). Remission rates following acute treatment with repetitive transcranial magnetic stimulation (rTMS) in patients with moderate levels of treatment resistance are reported to be 15–33% ( Perera et al., 2016 ) .Taken together, the current POC study supports the hypothesis that DM/Q represents a promising pharmacotherapeutic strategy in patients with TRD. Future randomized, controlled trials will be required to further examine the antidepressant potential of this approach.
As noted in the introduction, DM possesses a complex pharmacology that features NMDA receptor antagonism, σ1 receptor agonism, and effects on serotonin and norepinephrine signaling, among others ( Taylor et al., 2016 ). NMDA receptor antagonism in particular may be an important aspect of DM’s putative antidepressant mechanism of action given the growing evidence that ketamine, a non-competitive high-affinity NMDA receptor antagonist, possess rapid and robust antidepressant effects in patients with TRD ( Caddy et al., 2015;Murrough et al., 2013;Newport et al., 2015;Singh et al., 2016;Zarate et al., 2006 ). More broadly, glutamate signaling via NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and metabotropic glutamate receptors (mGluRs) has been implicated in the pathophysiology and treatment of MDD and other mood disorders (Abdallah et al., 2015;Manji et al., 2003;Sanacora et al., 2008 ). Electrophysiological studies show that DM exerts voltage-dependent blockade of the NMDA receptor, likely binding to a site within the channel pore, similar to ketamine and other channel blockers such as MK-801 ( Ferrer-Montiel et al., 1998 ). DM shows a somewhat lower affinity for the NMDA receptor channel compared to ketamine (K i =780 and 200, respectively), but similar to memantine (K i =700) ( Taylor et al., 2016 ). Interestingly, a recent study showed that DM exerted an antidepressant-like behavioral effects in the tail suspension test (TST) that were blocked by administration of AMPA receptor antagonist NBQX, similar to ketamine and other glutamate-based antidepressant candidates (Nguyen and Matsumoto, 2015 ).
Sigma-1 receptors are transmembrane proteins located in the endoplasmic reticulum (ER), and constitute a class of receptors distinct from ligand-gated ion channels and G-protein coupled receptors ( Hayashi, 2015 ). These receptors were first characterized in the 1990’s and their potential role in neuropsychiatric disease mechanisms and as potential novel treatments is only beginning to be explored. Several lines of evidence suggest that DM acts as an agonist at σ 1 receptors. For example, the antitussive, anticonvulsant, and neuroprotective effects of DM can be blocked in model systems by administration of a selective σ 1 receptor antagonist ( Shin et al.2005 ). More recently, pretreatment with the σ 1 receptor antagonist BD1063 was shown to attenuate the antidepressant behavioral effects of DM in the forced swim test (FST) ( Nguyen et al., 2014 ). Sigma-1 receptors appear to function as chaperone proteins, and may have a role in regulating the cellular effects of oxidative stress and free radical generation, among other functions (see ( Hayashi, 2015 ) for a recent review).
In addition to PBA, prior clinical trials have examined DM or DM/Q for the treatment of pain, seizure, and traumatic brain injury (TBI), among other neuropsychiatric conditions ( Nguyen et al., 2016 ). In the area of mood disorders, two studies are reported in the literature, both of which involved patients with bipolar disorder (Chen et al., 2014;Kelly and Lieberman, 2014 ). One prior study conducted in patients with bipolar II disorder or bipolar disorder not otherwise specified consisted of a retrospective chart review of the efficacy of augmentation treatment with DM/Q 20/10 mg either once or twice daily ( Kelly and Lieberman, 2014 ). Patients in this study had a predominance of depressive symptoms, and had high levels of treatment-resistance and chronicity. Of the 77 patients met the study eligibility criteria, 19 patients discontinued due to adverse effects attributed to treatment with DM/Q; this discontinuation rate of ~25% compares to a discontinuation rate observed in the current study of 30%. Among the remaining 58 patients, state of illness showed on average between ‘slightly improved’ and ‘much improved’ on a clinical global impression scale. The effect of treatment on depression or other symptoms specifically, however, was not reported. In the second study, patients with bipolar disorder on a stable dose of valproic acid were randomized to adjunctive treatment with DM at a dose of 30 or 60 mg per day (no concurrent Q) or placebo for 12 weeks ( Chen et al., 2014 ). Both depression and mania symptoms improved in both groups to a similar degree.
The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS
Dextromethorphan is an over-the-counter antitussive agent that may be a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA receptor antagonist.
We conducted a retrospective chart review of depressed patients with treatment resistant bipolar II or bipolar NOS disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ taken once or twice a day was added to participants׳ drug regimen. No changes were made to the pre-existing drug regimen during the course of treatment with DMQ. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment.
Seventy-seven participants met the inclusion criteria. All had been experiencing depressive symptoms for at least two years, and the mean number of failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1–2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse effects, chiefly nausea.
Because this was a retrospective chart review with no control group, conclusions about causation cannot be made. Nevertheless, the duration of depressive symptoms prior to starting DMQ makes spontaneous recovery less likely.
DMQ, an NMDA antagonist, may be effective in the treatment of bipolar depression. Because its putative mechanism does not depend on the monoaminergic system, it may be appropriate for patients who have not responded to other medications. Unlike ketamine, DMQ does not require IV administration.
AVP-786 (dextromethorphan/quinidine). AVP-786 is an experimental compound developed by Avanir (Aliso Viejo, CA, USA). A combination of deuterium-modified dextromethorphan hydrobromide and ultra-low dose quinidine sulfate, AVP-786 is similar to Nudexta, a medication approved to treat pseudobulbar affect. (Of note, a trial of Nuedexta for treatment-resistant depression (NCT01882829) was recently completed; results are pending). Mechanistically, dextromethorphan is an uncompetitive NMDAreceptor antagonist, as well as a sigma-1 receptor agonist; these properties theoretically have antidepressant effects. Low-dose quinidine (a CYP2D6 enzyme inhibitor) works to increase the bioavailability of dextromethorphan by inhibiting its breakdown. In addition, the deuterium incorporation into dextromethorphan contributes to its bioavailability by strengthening chemical bonds within the molecule, making it less susceptible to metabolic breakdown. Together, this combination may serve to bypass metabolic breakdown of the molecule, allowing for increased NMDA-receptor antagonism by dextromethorphan in the brain. A clinical trial of AVP-786 as adjunctive therapy in MDD was recently completed with results pending (ClinicalTrials.gov ID: NCT02153502). AXS-05 (dextromethorphan/bupropion). In addition to the NMDAreceptor blocking properties of dextromethorphan, AXS-05 contains bupropion (a norepinephrine and dopamine reuptake inhibitor that is currently approved for the treatment of depression), which may also work to increase the bioavailability of dextromethorphan in the brain. Axsome (New York, NY, USA) is currently conducting Phase III trials (ClinicalTrials.gov ID: NCT02741791). Specifically, patients will have a 6-week lead-in period with open-label bupropion, followed by a 6-week, doubleblind treatment period to compare the efficacy of AXS-05 augmentation to bupropion versus bupropion monotherapy in patients with treatment-resistant depression (defined as failure of one to two antidepressant treatments in the current episode and a treatment failure to the lead-in trial of bupropion). Because quinidine can cause cardiac toxicity when used excessively, AXS-05 may offer a theoretical advantage over AVP-786 in patients at a risk of overdose or with cardiac conduction concerns.
Dextromethorphan (DM) may have ketamine—like rapid—acting, treatment—resistant, and conventional antidepressant effects.1,2 This reports our initial experience with DM in unipolar Major Depressive Disorder (MDD). A patient with treatment—resistant MDD (failing adequate trials of citalopram and vortioxetine) with loss of antidepressant response (to fluoxetine and bupropion) twice experienced a rapid— acting antidepressant effect within 48 hours of DM administration and lasting 7 days, sustained up to 20 days with daily administration, then gradually developing labile loss of antidepressant response over the ensuing 7 days. Upon full relapse in DSM-5 MDD while taking 600 mg/day of the strong CYP2D6 inhibitor bupropion XL, a 300 mg oral loading dose of DM was given, followed by 60 mg po bid after an additional dose— finding period, without side effects. DM exhibited a ketamine—like rapid—acting antidepressant effect, thought to be mediated by mTOR activation (related to NMDA PCP site antagonism, sigma-1 and beta adrenergic receptor stimulation) and 5HTT inhibition, resulting in AMPA receptor trafficking, and dendritogenesis, spinogenesis, synaptogenesis, and increased neuronal survival (related to NMDA antagonism and sigma-1 and mTOR signaling). This report appears to be the first report of a rapid—acting effect in unipolar MDD and adds to antidepressant effects observed in the retrospective chart review of 77 patients with Bipolar II Disorder (Kelly and Lieberman 2014). If replicated, there is some reason to think that the administration of other agents with DM, such as lithium or D-cycloserine, might prolong the duration of the rapid-antidepressant effect. Psychopharmacology Bulletin. 2016;46(2):53–58.