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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 (DXM with bupropion)

"A velvety Dexter"

Visuals of component meds are explained in subsequent sections.

Auvelity components mnemonics by jason cafer md

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.

Auvelity medication mascots cartoon mnemonics by jason cafer md

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.

Visual mnemonic for interaction between bupropion and dextromethorphan relevant to Auvelity by jason cafer md

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)

Dose formulations of dextromethorphan DXM available over the counter (OTC) to use for generic makeshift poor man's Auvelity combination

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 DXM gelcaps softgels available over the counter (OTC) to use for generic makeshift poor man's Auvelity combination

Dextromethorphan hydrobromide 30 mg tablets, to take 1 and 1/2 tabs BID. A 33-day supply of RoboHBr on 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...

dextromethorphan DXM  hydrobromide tablets RoboHBr available over the counter (OTC) to use for generic makeshift poor man's Auvelity combination

​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.

dextromethorphan DXM  hydrobromide tablets and softgels available over the counter (OTC) to used to concoct generic makeshift poor man's Auvelity combination

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

NMDA receptor in context of Auvelity in Cafer's Psychopharmacology mnemonics book

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.


InHibition of cytochrome P450 (CYP450) enzymes

A drug that is biotransformed by a particular enzyme is referred to as a substrate of that enzyme. When the substrate is biotransformed (metabolized) it is then referred to as a metabolite.

biotransformation from substrate to metabolite submarine mneomnic

The substrate du jour is DXM, with dextrorphan the metabolite.

 DXM, with dextrorphan the metabolite as applicable to Auvelity

Each CYP enzyme can metabolize several substrates and most substrates can be metabolized by several CYP enzymes. Substrates are the “victims” of the interactions. Throughout Cafer's Psychopharmacology we use the following visuals for CYP substrates:

Substrates are the “victims” CYP450 interactions visual psychopharm mnemonics
fish representing CYP3A4 substrate in psychopharmacology mnemonics book

“Aggressor” medications affect how long victim substrates linger in the blood, and the relative serum concentration of parent drug (substrate) to metabolite. For a given enzyme, interfering medications (aggressors) are either inDucers or inHibitors. InDucers stimulate (inDuce) production of metabolic enzymes. InHibitors interfere with an enzyme’s ability to metabolize other medications.

InHibition of an enzyme occurs when one drug (the inHibitor) binds more tightly to the enzyme than the victim substrate binds. The inHibitor itself may be metabolized by the enzyme, or act as a non-competitive inhibitor. When an inhibitor is bound to an enzyme, the victim substrate must find another enzyme to metabolize it, or hope that it can eventually be excreted unchanged. Strong inhibitors may cause the victim substrate to linger longer, prolonging the victim’s half-life and elevating its concentration in the blood. For victim substrates that cross the blood brain barrier (as is necessary to be psychoactive), inhibition leads to increased drug concentration in the central nervous system.

Why is H being emphasized? Well, when an inHibitor is added to an individual’s medication regimen, levels of victim drugs can escalate (H for High). InHibition takes effect quickly, within Hours (H for Hurried), although the effect may not be clinically evident for 2 to 4 days, until the victim substrate accumulates.

Submarine for substrate and arrow for inhibitor from psychopharmacology mnemonics book

InHibitors of CYP enzymes will be represented by:

visual mneomnics for drug-drug interactions specifically CYP450 inhibitors from psychopharm mnemonics book by Dr Cafer
Visual mnemonic for CYP3A4 inhibitor from psychopharmacology mnemonics book

InHibition of CYP2D6

InHibition of 2D6 is essential to the mechanism of Auvelity. DXM is a beach ball.

Beach ball mnemonic for CYP2D6 inhibitors from psychopharmacology mnemonics book
Visual psychopharm mnemoncis book for strong CYP2D6 inhibitors - fluoxetine (PROZAC), paroxetine (PAXIL), bupropion (WELLBUTRIN) and quinidine
metabolic pathways for dextromethorphan DXM including dextrorphan

Why was bupropion chosen for the 2D6 inHibitor?

With Auvelity, DXM is considered the main active component. DXM (beach ball) needed to be combined with a strong inHibitor of 2D6 (pump).

The choices were bupropion (Wellbutrin), fluoxetine (Prozac), paroxetine (Paxil), and quinidine.

Quinidine was already in use by another pharmaceutical company (Avanir) in combination with DXM (Nuedexta).

Coadministering an SSRI (fluoxetine or paroxetine) with DXM would pose a risk of serotonin syndrome, because DXM is itself an SRI.

That left bupropion, which is an NDRI antidepressant with no serotonergic effects. In Auvelity the total daily dose of bupropion is 210 mg, which could provide additional antidepressant effects without posing a risk of serotonin syndrome. For context, the usual total daily dose of bupropion SR as a standalone antidepressant is 150 - 400 mg.


Dextromethorphan (DXM)

Dextromethorphan (DXM) is an over-the-counter cough suppressant. DXM is a component of Robitussin, NyQuil, Dimetapp, and Mucinex DM. Dissociative properties of DXM lend to recreational use among young people. DXM is restricted from sale to minors in California and Oregon.

Visual psychopharmacology mnemonic for dextromethorphan (DXM) from Dr Cafer's book

Dextromethorphan is a codeine analog, similar in structure to other opioids. Like codeine, DXM has antitussive effects. Unlike codeine, DXM has minimal interaction with opioid receptors.

The structure of dextromethorphan (DXM) is similar to codeine and other opioids

At high doses, DXM may produce euphoria and dissociative effects similar to ketamine and via the same mechanism—NMDA receptor antagonism.

With prolonged use, psychological dependence is possible. It does not cause physical dependence, but can produce symptoms of antidepressant discontinuation syndrome owing to DXM’s effects as a serotonin reuptake inhibitor (SRI).

In addition to being a NMDA receptor antagonist and SRI, DXM is a sigma-1 receptor agonist. Sigma-1 receptors in the limbic system of the brain may be involved in control of emotions, possibly explaining the benefit of DXM for treatment of pseudobulbar affect (in combination with quinidine, which serves to extend half-life of DXM). An endogenous ligand for the sigma-1 receptor is yet to be identified, but we know some androgenic steroids activate the receptor.

Dextromethorphan drug-drug interaction visual psychopharmacology mneomnics book - beach balls CYP2D6 substrate

See above for comparison of DXM with its active metabolite dextrorphan.

Dosing of DXM for Cough - immediate-release form is 30 mg q6-8h. For extended-release form the dose is 60 mg q 12 hr. Maximum for IR or ER is 120 mg / 24 hr. The typical recreational dose is 250 – 600 mg.


Bupropion (Wellbutrin)

Betty Boop from Psychopharmacology Mnemonics book for bupropion (Wellbutrin)

Wellbutrin helps your mood get well”. Bupropion (Wellbutrin), the #28 most prescribed overall medication, is a stimulating antidepressant that enhances norepinephrine and dopamine activity. Unlike most other modern antidepressants, it has no serotonergic effects. It is used for smoking cessation because it is stimulating like nicotine. These stimulating properties also make it useful for ADHD. Bupropion has demonstrated cognitive benefits. Clinicians tend to avoid prescribing it to individuals with anxiety disorders, but despite its stimulating properties, bupropion does not appear to exacerbate anxiety (Wiseman, 2012).

Pharmacokinetic interactions of bupropion (Wellbutrin) including CYP2D6 and CYP2B6

The serotonergic antidepressants cause sexual dysfunction. Bupropion is not serotonergic and actually improves sexual functioning. It is used as an add-on to SSRIs to ameliorate sexual problems (off-label).

Bupropion is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia because of a higher reported incidence of seizures in such patients taking Wellbutrin.

Bupropion (Wellbutrin) increasing seizure risk by lowering seizure threshold from psychopharm book

Wellbutrin suppresses appetite and may cause modest weight loss. As with other stimulant-type medications, bupropion decreases appetite via adrenergic and dopaminergic receptors in the hypothalamus. The incidence of weight loss greater than 5 pounds is about 28%. CONTRAVE is a fixed-dose combination of bupropion with the opioid antagonist naltrexone, approved for long term treatment of obesity (page 259).