Understanding and memorizing AUVELITY and related concepts
Auvelity is the latest medication approved for major depressive disorder. The manufacturer touts Auvelity:
The first and only oral NMDA receptor antagonist for MDD
Symptom improvement at Week 1 and sustained at Week 6
Rapid remission starting at Week 2
Demonstrated safety profile
There are a lot of things to unpack here. This lengthy article, intended for prescribers, will present:
Auvelity medication mascot and general information
InHibition of 2D6 specifically (essential to understanding Auvelity's mechanism of action)
Why was bupropion chosen for the 2D6 inHibitor in Auvelity (as opposed to an SSRI)?
InDuction of CYP2B6 specifically (because Auvelity is contraindicated with strong 2B6 inDucers)
Nuedexta (combo of DXM with quinidine, same concept as Auvelity)
AUVELITY (DXM with bupropion)
"A velvety Dexter"
Visuals of component meds are explained in subsequent sections.
Auvelity (dextromethorphan hydrobromide + bupropion ER) was approved for treatment of major depression in 2022. The approval was with the breakthrough therapy designation, which allows drugs to go to market based on preliminary evidence. Breakthrough drugs have been less thoroughly tested than drugs approved through the regular process.
Dextromethorphan (DXM) is the main active ingredient. The mechanism of DXM is NMDA antagonist and sigma-1 receptor agonist. DXM also has serotonin reuptake blocking properties.
For context, the antidepressant mechanism of ketamine is NMDA antagonism. DXM has been nicknamed “ketamine in a pill”, although it is a much less potent NMDA antagonist. Blocking NMDA receptors modulates glutamatergic signaling which, through complicated downstream molecular events, is believed to elicit the expression of genes involved in neuroplasticity.
The bupropion (Wellbutrin) component of Auvelity serves to block metabolism of DXM by CYP2D6 and may provide antidepressant benefit. This strategic use of a kinetic drug-drug interaction is the same concept described with Nuedexta, with bupropion replacing quinidine as the 2D6 inHibitor.
If not for the 2D6 inHibitor (bupropion), dextromethorphan (DXM) is quickly metabolized to dextrorphan, resulting in low serum levels of the parent compound. This metabolite is spelled similarly to dextromethorphan without the “meth”, which makes sense because this biotransformation is a demethylation. Compared to DXM, the metabolite (dextrorphan) is a more potent NMDA receptor antagonist and less potent serotonin reuptake inhibitor (SRI).
As with its component medications, Auvelity is not a DEA-controlled substance. However, either component is potentially abusable at high dose—DXM as a dissociative and bupropion as a NDRI stimulant.
Antidepressant efficacy of Auvelity was statistically significant starting at 1 week, which is faster than traditional antidepressants. Auvelity was shown to be more effective than bupropion 105 mg alone around 2 weeks. Auvelity has not been tested in treatment-resistant depression.
Most side effects of Auvelity are attributable to DXM rather than bupropion. The most common adverse reactions were dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%).
Note that Auvelity did not cause dissociation in clinical trials. Dissociation with DXM is largely due to dextrorphan, the metabolite. 2D6 inHibition by bupropion slows conversion of DXM to dextrorphan, making dissociation a less likely side effect.
Auvelity contains ER bupropion but IR dextromethorphan hydrobromide (as opposed to ER DXM polistirex) — “Hi, bro!”
Auvelity has the standard black box warning applicable to all antidepressants regarding increased risk of suicidal thoughts and behavior in children and young adults.
Auvelity It is not recommended for bipolar depression due to risk of precipitating a manic episode via serotonergic effects.
Other contraindications and cautions are those applicable to the component drugs. DXM (but not bupropion) can contribute to serotonin syndrome. If not for the risk of serotonin syndrome, fluoxetine (Prozac) or paroxetine (Paxil) could have served as the 2D6 inHibitor instead of bupropion.
Dosing: Start one tablet QD in AM x 3 days, then increase to target dose of 1 tablet BID. Maximum dose equals target dose. With moderate renal impairment the target dose is 1 tab QD. For CYP2D6 poor metabolizers or those taking a strong 2D6 inHibitor, the recommended target dose is 1 tab QD (which is odd given that bupropion itself is a strong 2D6 inHibitor and the other strong 2D6 inhibitors are SSRIs which should not be combined with Auvelity anyhow). Avoid use in severe hepatic or renal insufficiency.
Concocting "Poor Man's Auvelity" with generic medications
Auvelity = Dextromethorphan hydrobromide (DXM HBr) 45 mg + Bupropion SR 105 mg BID
Poor Man's Auvelity:
Bupropion SR 100 mg BID + DXM HBr 45 mg BID (QD for first 3 days)
I see Poor Man's Auvelity as a viable option when prescribed to capable patients who understand that DXM must be taken with bupropion, not alone.
You would prescribe generic bupropion SR 100 mg BID (QD for the first 3 days) and instruct the patient to buy one of the following to take with each bupropion SR dose:
Dextromethorphan hydrobromide 15 mg softgel capsules, to take 3 caps BID (QD for the first 3 days). A 10-day supply on Amazon is currently $14.24, which is $0.72/dose (3 caps), $1.44/day (6 caps), or $42.72/month (180 caps, 3 bottles). It is slightly less expensive if you buy 2 bottles (20 day supply). |  |
Dextromethorphan hydrobromide 30 mg tablets, to take 1 and 1/2 tabs BID. A 33-day supply of RoboHBr on Amazon.com is currently $24. They will need a pill splitter. The tablets are small and may be difficult to split precisely. If this is the case... |  |
The patient could purchase both softgels and tablets, to take one of each BID along with bupropion SR 100 mg. The cost from Amazon is about $33/month. This may be the best option. |  |
Bupropion SR is available in 100 mg tabs. In conclusion, the Auvelity combo is achievable with cheaper drugs, although the individual would be taking 100 mg of bupropion SR rather than 105 mg.
In addition to low cost, a potential advantage of using generic bupropion SR with OTC DXM is the ability to titrate DXM HBr from a lower dose.
It is odd that Axsome Therapeutics sought approval for a dose combination that is easily approximated with less expensive pills. I feel a little bad about prescribing Poor Man's Auvelity, because Axsome made a valuable contribution by earning FDA approval, lending legitimacy to this apparently effective combo.
Important cautions related to serotonergic effects of DXM:
Serotonin syndrome if combined with serotonergic antidepressants, although risk is low.
Potential manic switch if prescribed for bipolar depression.
Please contact the author with any rationale against this approach. And prescribers please revisit this article for updates of any identified pitfalls. After further reflection, I may post a patient handout.
NMDA receptors in context
The N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor and ion channel found on neurons. The receptor also has a glycine binding site. Activity of the NMDA receptor is blocked by many psychoactive drugs that act on an allosteric binding site.
NMDA receptors are involved in synaptic plasticity and memory. Lightly blocking the receptor is neuroprotective. However, if the receptor is blocked completely, neurons cannot function and may be damaged.
The street drug PCP, aka “angel dust”, strongly blocks NMDA receptors, causing psychosis. Ketamine is weaker than PCP, but strong enough to cause anesthesia and dissociation. Namenda blocks the receptor just enough to improve memory.
Dextromethorphan (DXM) is a weak NMDA receptor antagonist. Dextrorphan, a metabolite of DXM, is a stronger NMDA blocker. As a result, dextrorphan is responsible for dissociative effects seen with DXM.
Anti-NMDA receptor encephalitis is a rare disease caused by antibodies targeting NMDA receptors, characterized by psychosis and seizures. This was the condition afflicting a New York Post reporter in the film Brain on Fire.