Auvelity, a new rapid acting medication for depression, is a branded combination of two generic drugs. We look at how it works and the clinical trials, including new data in treatment resistant depression

Publication Date: 02/05/2024

Duration: 14 minutes, 02 seconds

KELLIE NEWSOME: Do two old meds make a new med? We’ll see with today’s case in point, Auvelity.

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: We’re continuing our countdown of the most-read articles from 2023 with one that Dr. Aiken wrote on Auvelity, the fast-acting combo of bupropion and dextromethorphan. You can read all of the top 15 articles free online through the link in the show notes or just Google “Top 15 Carlat Psychiatry Articles of 2023.” Dr. Aiken has nothing to disclose.

CHRIS AIKEN: Well, that’s not exactly true.

KELLIE NEWSOME: Pray, tell.

CHRIS AIKEN: While researching this piece I met a scientist from Axome pharmaceuticals for lunch and he got the bill – I tried to intervene, but my timing was off.

KELLIE NEWSOME: And what did you learn at this lunch.

CHRIS AIKEN: I was trying to get my hands on the unpublished studies – these can be very revealing, although sometimes they aren’t published because of flaws in their methodology rather than flaws in the drug. In this case, I learned that Auvelity was tested in treatment-resistant depression, but it did not separate from placebo in that study. So we start this podcast on a disappointing note, especially as treatment resistant depression is where people will be most likely to try a new drug like this. But I’ll couch that with a reminder that most meds have failed in true treatment resistant depression or TRD – the ones we think of as effective there like atypical antipsychotics were mainly studied in people who failed one antidepressant, not the two failures that are required in true TRD.

KELLIE NEWSOME: Has that study been published yet?

CHRIS AIKEN: Sort of. We weren’t able to get hold of it for the 2023 article, but it has come out in poster form since then, and the details are interesting so I’ll update that in this podcast, along with another new trial that tested Auvelity for a year.

KELLIE NEWSOME: First a fun fact. Where did Auvelity get its name? We don’t know for certain, but we think it’s mean to imply “augment with velocity” au-velity – which is what it does. Auvelity is a combination of two older medications: bupropion (circa 1985) and dextromethorphan (circa 1958), a cough suppressant found in Robitussin dextromethorphan . We know how bupropion works – it’s a norepinephrine and dopamine reuptake inhibitor, so let’s take a look at what dextromethorphan adds to the pharmacodynamics picture.

CHRIS AIKEN: Like ketamine, dextromethorphan increases glutamate transmission through NMDA antagonism. This glutamatergic mechanism is shared by several third-line interventions for treatment-resistant depression (amantadine, d-cycloserine, ketamine, lamotrigine, and minocycline), but Auvelity is the only one of them – except esketamine – to get FDA approva. So it can rightfully claim to be the first oral antidepressant that moves beyond the traditional monoamines of serotonin, norepinephrine, and dopamine. It’s a good guess that glutamate is responsible for dextromethorphan’s benefits, but not necessarily… It also has anticonvulsant and neuroprotective effects, and blocks serotonin and dopamine reuptake, complementing bupropion’s effects on norepinephrine and dopamine.

KELLIE NEWSOME: Pairing it with bupropion accomplishes another goal: it increases dextromethorphan’s half-life, extending it from 4 to 22 hours. Bupropion does this because it inhibits the CYP2D6 enyzme that metabolizes dextromethorphan, and when you inhibit metabolism you raise the serum levels and increase the half-life. You may recognize this effect if you know the medication Nuedexta, which is dextromethorphan’s first neuropsychiatric incarnation. Nuedexta is FDA approved for pseudobulbar affect, a neurologic disorder characterized by sudden, uncontrollable bouts of laughter or tears, made a little infamous by the stigma-tinged movie The Joker, where pseudobulbar affect is used to explain the disturbed laughter of Joaquin Phoenix’s character.Nuedexta also extends dextromethorphan’s half-life by pairing it with quinidine, a strong CYP2D6 inhibitor that otherwise adds nothing to Nuedexta’s therapeutic effects.That’s how Auvelity works – glutamate, norepinephrine, dopamine, and a little bit of serotonin, and there’s a beneficial drug interaction going o that extends dextromethorphan’s half-life. Now let’s look at the clinical trials.

CHRIS AIKEN: We have two published trials and two partly published ones – they came out in poster form. They show that Auvelity is faster and more effective than bupropion alone. Among the fully published trials, one was large (n=327) and one small (n=80). The large trial confirmed that the combo worked better than placebo, which is not a surprise considering it contains a therapeutic dose of bupropion. What did stand out was the speed of onset, with separation from placebo in the first week compared to weeks two to four for other antidepressant trials (Iosifescu DV et al, J Clin Psychiatry 2022;83(4):21m14345). The small trial confirmed the speed-of-onset data and added new information by comparing the combination to bupropion monotherapy. Auvelity was more effective than bupropion alone, with remission rates of 47% vs 16% after six weeks (Tabuteau H et al, Am J Psychiatry 2022;179(7):490–499). However, all these trials involved regular depression, and it’s not clear that Auvelity works in treatment-resistant cases.

KELLIE NEWSOME: Yes you said you had an update on that treatment resistant depression trial.

CHRIS AIKEN: Yes it’s called the STRIDE-1 trial, and it was presented in poster form at the American Society of Clinical Psychopharmacology in 2018. They started with several hundred patients whose depression had failed to respond to 2 or 3 antidepressants. These patients were given a medium dose of buproprion 150mg/day for 6 weeks, and those who did not respond to buproprion were randomized to receive either Auvelity or bupropion with a placebo for another 6 weeks. 312 in all entered this final phase of the study, which means by now they had not responded to 3 or 4 antidepressants. The results are a bit more complicated than “Auvelity did not work.” Basically, it failed on the primary outcome – reduction in depression at the 6 week mark, but it did succeeded in the first week, suggesting a possible rapid action but not a sustained one in this treatment resistant population. There are also a lot of secondary measures that showed possible benefit, like the percentage of those whose depression remitted on Auvelity was about twice as high in the Auvelity group – 18% vs 8% - but none of this is going to make it past the FDA because the differences are so small and the primary outcome failed. The mixed signals in this trial reminds me of the dextromethorphan studies that came out before Axsome Therapeutics took on the drug. There were about 4 small trials – all involving treatment resistant patients. These studies tested dextromethorphan on its own, without bupropion, although some employed quinidine to stretch its half-life. Most of these studies tested it in bipolar disorder, starting in 2014 with a case series of 77 patients with treatment-resistant bipolar depression by Tam Kelly and Dan Lieberman. These were very treatment resistant patients – on average they had failed 21 med trials. However, most improved with the addition of dextromethorphan, although 25% dropped out due to side effects like nausea. The dose they used was dextromethorphan 20 mg once or twice a day and quinidine 10 mg, about half of the dose marketed dose of dextromethorphan which is 90 mg/day when combined with bupropion.

KELLIE NEWSOME: Dedicated readers might remember Tam Kelly – we interviewed him on thyroid and oxcarbazepine in bipolar disorder in the print issues.

CHRIS AIKEN: But that open-label success was followed by a mix of positive and negative results in small controlled trials. I used the drug in my own practice with a similar mix of unclear results. So when the data from the large industry sponsored studies came out I was not expecting it to work – and it didn’t, at least not in treatment resistant cases, but it did work in easier to treat depressions. So that’s what we know about Auvelity so far. Studies are also underway in nicotine cessation and agitation in dementia. We’ll pick up next week with some Auvelity controversies. Now, a preview of the CME quiz for this episode.

KELLIE NEWSOME: Podcast listeners – we need your insights. We're planning an episode on wounded healers - people who work as psychiatrists, therapists, NPs or PAs and live with mental illness themselves. If you'd like to share your wisdom with us, contact caiken@thecarlatreport.com. We will keep your identity as confidential as you like, and even disguise your voice or read your words ourselve. Start earning CME through the link in the show notes, and join us next week for part II on Auvelity. The Carlat Report has operated free of commercial support since 2004, with the exception of a pita sandwich Dr. Aiken enjoyed at Omar's Mediterranean Cuisine in lower Manhattan.

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