One treatment-resistant depression patient's response to over-the-counter cough medicine led Steven P. Levine, MD, to study the mechanism and effects of dextromethorphan in depression.
One of the most promising recent developments in psychiatry has been intravenous (IV) ketamine infusion for the rapid treatment of severe treatment-resistant depression. But even though multiple studies have demonstrated and replicated the safety and efficacy of the off-label use of the 50-year-old anesthetic, their findings remain limited to acute treatment.
Longer-term maintenance studies on ketamine are not being done, based in part upon the premise that a medication with a similar mechanism to ketamine will emerge as a more widespread antidepressant. Those drugs are currently in development, and if all goes well, they may be available to us within the next few years.
In the meantime, some clinicians have begun to treat severe treatment-resistant depression patients with IV ketamine without evidence-based guidance for maintaining long-term dramatic responses. The rough solution to that problem is to continue what has worked by infusing IV ketamine on a less frequent maintenance basis while weighing the unknown risks of ongoing infrequent exposure to the drug against the risks of recurrence of depressive symptoms. An additional solution is to find another off-label yet orally available medication with a similar mechanism to ketamine that may be sufficient to maintain response.
Several drugs that fit the profile have been studied, either directly following ketamine or on their own. Each of those medications — which include riluzole, scopolamine, amantadine, and memantine — has an unrelated indication approved by the US Food and Drug Administration (FDA) and, like ketamine, promotes activity at the N-methyl-D-aspartate (NMDA) receptor. However, clinical studies on the drugs’ effects in depression have been limited and the results have been somewhat disappointing, which is why I considered another medicine that brings my story full circle.
A few years ago, I met with a patient for a second-opinion consultation. She was on the unfortunately common path of having tried multiple treatments for long-standing depression and anxiety that either failed or had intolerable side effects. However, there was an interesting wrinkle in the case, as the patient had found that over-the-counter cough medicines with cough suppressant dextromethorphan helped her mood and anxiety better than anything else. So, she asked me, “Why can’t I just keeping taking DayQuil?”
At the time, I advised against it because she required relatively high and frequent doses to achieve the effect that, over time, could be toxic. However, it made me curious about the mechanism of dextromethorphan that might account for the patient’s observations. Investigating that mechanism led me to a literature search of similar drugs and their safety and efficacy in depression. It turned out that there were several, including the aforementioned medicines; but when I read the ketamine studies, I knew there was something of value to further explore.
Fast-forward to a year ago, when I had to accept that the available oral options to maintain the effects of IV ketamine were disappointingly limited. A number of factors drew my attention to a new medication comprised of a combination of low-dose dextromethorphan and a tiny dose of the antiarrhythmic, quinidine.
Nuedexta is indicated by the FDA for the relatively uncommon neurologic condition known as pseudobulbar affect (PBA), which is associated with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). But upon closer inspection, I learned that Nuedextra is a cleverly designed medication that takes advantage of the dextromethorphan metabolism-inhibiting properties of quinidine. Slowing the metabolism of dextromethorphan safely allows significant central nervous system (CNS) bioavailability and binding at the serotonin transporter, sigma-1 receptor, norepinephrine transporter, NMDA receptor, and μ-opioid receptor — which just so happen to be the receptor targets of IV ketamine.1
It’s possible that the patient I saw in consultation had an uncommon genetic polymorphism that results in the slow metabolism of dextromethorphan, which would naturally allow her the antidepressant and antianxiety benefits of dextromethorphan without the quinidine component. Despite the details of that case, I began prescribing Nuedexta for my patients following IV ketamine, due to the lack of other options. I have prescribed it to about 40 patients thus far, and almost all of them have tolerated it very well, particularly as it lacks the acute dissociative effects that are linked to ketamine treatment. Many have been able to continue on Nuedexta either alone or in combination with other oral medications without further ketamine infusions, while others have been able to greatly extend the time interval between maintenance ketamine infusions, often up to 2 to 3 months.
An initial study on the effects of Nuedexta without ketamine in treatment-resistant depression has recently begun at the Mount Sinai School of Medicine in New York, NY. Alongside other ketamine-like drugs in development, Nuedexta offers hope that the legacy of ketamine will spawn a new generation of more rapidly effective and well-tolerated treatment options.
Disclosure: Seeking research-based evidence to support my clinical use of Nuedexta, I recently joined an advisory board at Avanir Pharmaceuticals, the manufacturer of Nuedexta. The use of Nuedexta described in this article is a description of my personal experience of prescribing this medication in very specific circumstances with full patient consent and awareness of its use being off-label and non-research based. I do not endorse the use of this product for this indication to other prescribers.
1. Stahl, SM. Mechanism of action of dextromethorphan/quinidine: comparison with ketamine. CNS Spectrums. 2013 Oct;18(5): 225-7. http://journals.cambridge.org/abstract_S109285291300062X
Steven P. Levine, MD, is a board-certified psychiatrist and therapist. He received his psychiatry training at New York Presbyterian Hospital and Memorial Sloan-Kettering Cancer Center and currently practices in Princeton, NJ.