Auvelity, a new rapid acting medication for depression, is a branded combination of two generic drugs. We look at its side effects, addictive potential, and whether you can just use the generic components.

Publication Date: 02/12/2024

Duration: 16 minutes, 44 seconds

Transcript: 

KELLIE NEWSOME: Auvelity. The first fast acting antidepressant. Or is it? Today we look at 4 controversies with this dextromethorphan-bupropion combo.

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: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. We pick up again with Auvelity, the med that augments with velocity. Last week we learned this combination of bupropion and dextromethorphan does indeed work fast, within a week, and is more effective than bupropion alone. But despite those accolades it missed the mark in treatment resistant depression. Today we’re going to talk about its side effects and cover 4 controversies with the drug 1. Is it addictive 2. Does it work long term 3. Can you just use the generic components  And 4. Is it really any different from a popular speed-up strategy from the 1980’s.

CHRIS AIKEN: We’ll start with its side effects, but first a preview of the CME Quiz for this episode

1. What is the main risk of combining dextromethorphan with other antidepressants besides bupropion

A. Neuroleptic malignant syndrome

B. Only bupropion will inhibit dextromethophan’s metabolism

C. Serotonin syndrome

D. Neurotoxicity

KELLIE NEWSOME: In last week’s episode we learned that dextromethorphan makes bupropion work faster and boosts its antidepressant efficacy. But it doesn’t just add benefits to the picture, it also adds side effects, particularly sleepiness – remember, cough medicine tends to make people drowsy. One in 16 patients stopped the medication due to side effects, most often somnolence, nausea, dizziness, headache, and dry mouth. No cases of psychosis, dissociation, serotonin syndrome, or addictive behaviors were seen with Auvelity, although these are possible problems with dextromethorphan – we know that from earlier reports. One side effect we’re not sure about is mania. Most antidepressants can trigger mania, but this one has a very different profile. There are small studies of dextromethorphan alone – without bupropion – in bipolar depression. Those studies found either no manic switching and one found improvement in manic symptoms (Lee SY et al, Int J Bipolar Disord 2020;8(1):11). But mania is still possible on this drug – there is a case report of it from 1996. Next we’re going to cover two other controversies with Auvelity. Can it be abused, and can you use the generic ingredients on their own?

CHRIS AIKEN: Neither Auvelity nor dextromethorphan are classified as a controlled substances. In fact, dextromethorphan is available over the counter – technically behind the counter – you don’t need a prescription but you have to ask the pharmacist and show a driver’s license to buy it in most states. This is because dextromethorphan has a long history of misuse that has earned it the nickname “poor man’s PCP” and “robotripping.” In the clinical trials, there was no evidence of this kind of misuse, and you’re likely to hear from drug reps that this is because dextromethorphan was dosed far below the abusable level (90 mg/day). That is the party line. However, the interaction with bupropion is likely to push dextromethorphan’s serum levels into the abusable range. Based on the pharmacokinetic data we requested from the manufacturer, bupropion raises peak levels of dextromethorphan 40-fold and the total exposure to the drug (area under the curve) 60-fold (www.tinyurl.com/mr37cf8y). Furthermore, patients with a recent history of substance use disorders were excluded from the trials.

KELLIE NEWSOME: The next controversy is generic substitution. Auvelity comes as a tablet containing 45 mg of dextromethorphan and 105 mg of bupropion. The recommended target dose is 45/105 mg twice daily, with a steep out-of-pocket cost of $1,200/month. There are various potential generic workarounds that would make the drug affordable. dextromethorphan is available by prescription or as a low-cost, over-the-counter generic syrup, though it is actually kept “behind the counter” to limit diversion and misuse. The liquid can be given in the same 45 mg BID dose that is contained in Auvelity (for most dextromethorphan products, 7.5 mL = 45 mg at a monthly cost of $20). Bupropion is available generically in doses very close to Auvelity’s 105 mg BID (eg, bupropion IR 100 mg BID or bupropion SR 200 mg). Thus, you can prescribe these separate “ingredients” of Auvelity to your patients and save them thousands of dollars, with presumably the same beneficial effects.

CHRIS AIKEN: So if you can give dextromethorphan on its own, can you give it with other antidepressants? We’re not going to recommend that. In theory, duloxetine, fluoxetine, and paroxetine could give you the CYP2D6 inhibition you need to stretch dextromethorphan’s half-life, but these are all serotonin medications and could cause serotonin syndrome when combined with dextromethorphan, itself a serotonin reuptake inhibitor. There’s already a case report of that with fluoxetine in the literature. 

KELLIE NEWSOME: Auvelity may not work in treatment resistant depression, but its speed of onset makes it ideal for patients who are hospitalized or otherwise in need of rapid relief from depression. Here’s how to dose it: Give one pill per day for 3 days, then 1 pill twice a day. Each pill contains 45mg of dextromethorphan and 105mg of bupropion, for a total daily dose of 90 mg dextromethorphan 210 mg bupropion. 

CHRIS AIKEN: If your patient doesn’t tolerate the manufacturer dosing, I’d recommend switching the the generic drug so you can give less dextromethorphan – that’s the ingredient that causes most of the side effects. Giving it as a separate pill will also allow you to give bupropion all in the morning - I’d give it as 300mg XL – you may as well go to the full dose – and give the dextromethorphan all at night. This method hasn’t been tested in controlled trials, but it should ease tolerability as you raise the dose up. One thing we can say for sure is you don’t need to give bupropion twice a day to keep the drug interaction going and stretch the half-life. Here’s why. For one thing, the enzyme will still be inhibited with daily dosing. Enzyme inhibition takes 2-3 days to come on and lasts 3-5 days after stopping a drug. For another thing, bupropion XL once a day is equivalent to the sustained release twice a day that is used in Auvelity – in other words, if you take XL in the morning, it will still be in your blood stream later that night. 

KELLIE NEWSOME: We leave this podcast with many relevant questions that are left unanswered. Can bupropion be started as monotherapy and dextromethorphan added later if the patient does not respond? Will raising the bupropion or dextromethorphan dose help if the patient doesn’t fully respond? We can take a stab at that last question. Although Auvelity uses dextromethorphan 90 mg/day, the max dose used in the early trials was 120 mg/day, divided as 60 mg BID, and that dose was given in combination with an inhibitor like bupropion or quinidine.

CHRIS AIKEN: Perhaps the most important question is – how long do you need to take this drug? It’s fast acting, but is it long lasting? We have an update on that question from a partly published industry sponsored trial – the COMET study – that followed over a hundred patients for 1 year on the drug. There were no new safety concerns, and 8.4% dropped out due to side effects, but we can’t judge much from this study because there was no control group and we have reason to think that a lot more patients dropped out for reasons other than side effects. We only have a summary of the study which says they started with 865 patients but only 110 made it to the one year finish line. 

KELLIE NEWSOME: That’s a lot of uncertainty. What would you do in practice?

CHRIS AIKEN: As long as Auvelity is tolerable, I’d keep patients on it for 6 months after recovery. I’m borrowing that 6 month number from other studies in depression, where the relapse rates were higher if antidepressants were withdrawn sooner. Another strategy would be to start psychotherapy as they recover – we know from the Sequential Treatment of Depression studies that you could withdrawl the active med sooner – such as tapering dextromethorphan after 2-3 months - if they are in an active psychotherapy. 

KELLIE NEWSOME: OK, so here’s the bottom line. Auvelity gets a thumbs-up for speed and efficacy, but makes little to no difference in treatment-resistant depression. Generic substitution gets a green light. But what about it’s claim to be the first rapid acting oral antidepressant?

CHRIS AIKEN: Well, if we consider FDA approval as the gold standard, that’s true. The only contender is esketaine, which is intranasal, and possibly the atypical antipsychotics, although they are about 1-2 weeks slower than Auvelity. But I wonder whether Auvelity is really breaking new ground here. Look closely at the FDA indication for alprazolam, Xanax.

KELLIE NEWSOME: It says it’s indicated for Generalized Anxiety and Panic Disorder. There’s no mention of depression, no wait, here it says under “patients with depression” that “Benzodiazepines may worsen depression.”

CHRIS AIKEN: This is a major shift from when alprazolam first came out. The FDA almost approved it for depression – which, based on the criteria the FDA uses, would have made sense. Alprazolam treated depression in at least 21 controlled trials, either on its own or as augmentation of antidepressants. And if we look at those augmentation trials it worked quickly, within 1 week, just like Auvelity. When I was training in the 90’s it was a popular strategy to use a short-term benzo to make antidepressants work faster.

KELLIE NEWSOME: OK, so alprazolam and dextromethorphan – both are associated with abuse, both treat depression quickly, but one got FDA approved. Why the difference?

CHRIS AIKEN: The FDA was more conservative back then. They were concerned about long term benzo dependence, so they didn’t pass it for depression. They did allow the company to market it for “Anxiety with depressive symptoms” at first, but any trace of that has been removed from the current prescribing guidelines which instead say the opposite – as you read there – that benzos worsen depression. We covered this in a 2021 podcast – “Do Benzos Treat Depression.”

KELLIE NEWSOME: We should run that again.

CHRIS AIKEN: Yes. Let’s run it on throwback Thursdays this week. Anyway, I’m not suggesting that benzos should be used to treat depression. I am suggesting that we’re entering uncertain territory here with long-term use of Auvelity – the drug isn’t known to work long-term, but long term use tends to be the default option with psych meds. Xanax and dextromethorphan are different drugs with different mechanisms, but both are sedatives with anxiolytic effects, and we have a long history of using drugs like these to speed up antidepressants – barbiturates, benzos, ketamine and now dextromethorphan – and we can learn from that history.

KELLIE NEWSOME: Check out the online article for on Auvelity, and tune in this Thursday for a deep dive on benzos in depression. We’ll be back next week with #3 in the top articles: Stimulant Dosing Limits. Meanwhile, get daily research updates on Dr. Aiken’s social media feeds – search for ChrisAikenMD on twitter, Linkedin, Facebook, and that new one – Threads. Thank you for making us the #1 downloaded psychiatry podcast in 2023.

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.