Updated: Jul 29
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 bupropion and dextromethorphan hydrobromide (as opposed to ER DXM polistirex) in an extended-release tablet— “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 DYI Auvelity with generic medications
Auvelity = Dextromethorphan hydrobromide (DXM HBr) 45 mg + Bupropion SR 105 mg BID
Bupropion SR 100 mg BID + DXM HBr 45 mg BID (QD for first 3 days)
I see DIY Auvelity as a viable option when prescribed to capable patients who understand that DXM must be taken with bupropion, not alone. (See update below).
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.
Update (7/29/2023): Two respondents expressed concerns about liability with recommending DIY Auvelity to patients. Also, a doctor reported submitting a Medicaid prior authorization for Auvelity, which was denied, but the state's Drug Prior Authorization Committee and Drug Utilization Review Board granted approval for reimbursement of the individual ingredients in place of Auvelity. This approach minimizes liability when prescribing the combo to those with public insurance, who are ineligible to use discount vouchers from Axsome. For those with commercial insurance, the vouchers make Auvelity cheaper than the generic components.
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.
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.
The substrate du jour is DXM, with dextrorphan the metabolite.
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:
“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.
InHibitors of CYP enzymes will be represented by:
InHibition of CYP2D6
InHibition of 2D6 is essential to the mechanism of Auvelity. DXM is a beach ball.
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) 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.
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.
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.
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.
“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).
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.
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).
If taken by individuals with bipolar disorder, bupropion appears less likely to induce mania compared to serotonergic antidepressants.
Bupropion’s chemical structure is similar to synthetic “bath salt” drugs. Wellbutrin is not a controlled substance and is not generally considered a drug of abuse. It increases dopamine levels in the prefrontal cortex (underactive in ADHD) but not in the nucleus accumbens (reward center), at least not at standard doses. However, bupropion is avoided by many prescribers in correctional facilities because inmates have collected tabs to crush and snort as “poor man’s cocaine”.
Bupropion, an NDRI, is a much weaker inhibitor of DA and NE reuptake than the Schedule II controlled stimulants approved for ADHD like methylphenidate (Ritalin) and amphetamine (Adderall). Ritalin and Adderall are referred to as DNRIs because their dopaminergic effect is stronger than their noradrenergic effect. Solriamfetol (Sunosi), approved for excessive daytime sleepiness (due to narcolepsy or sleep apnea) is a Schedule IV NDRI.
Bupropion has anti-inflammatory properties as a tumor necrosis factor (TNF) inhibitor. For treatment-resistant depression, adding bupropion to an SSRI is effective for patients who are overweight or have high C-reactive protein (CRP), a marker of inflammation (Jha MK, 2017). Otherwise, adding bupropion to an SSRI appears to be of minimal to no benefit for treatment-resistant depression.
Risk of overdose mortality with bupropion is higher than with most other modern antidepressants. Of 51,118 single-drug exposures to bupropion reported to Poison Control, there were 3,239 major serious outcomes and 47 deaths (Nelson & Spyker, 2017).
InDuction of CYP450 enzymes
The opposite of inHibition is inDuction. InDuction occurs when an inDucer stimulates the liver to produce extra enzymes, leading to enhanced metabolism and quicker clearance of victim drugs.
The D is for Down, i.e., Decreased serum concentrations of victim substrates. Unlike inHibition (H for Hurried), inDuction is Delayed, not taking full effect for 2 to 4 weeks while we…wait for the liver to ramp up enzyme production.
InDucers are depicted in Cafer's Psychopharmacology as:
InDuction of CYP2B6 specifically
The label for Auvelity advises to avoid co-administration of Auvelity with strong CYP2B6 inDucers because it decreases plasma concentrations of DXM and bupropion and may decrease efficacy of Auvelity. I did not identify DXM as a major substrate of 2B6. According to drugbank.com, the strong inDucers of 2B6 are carbamazepine, fosphenytoin, nevirapine, phenobarbital, and phenytoin.
Nuedexta (DXM with quinidine)
Nuedexta is the only FDA-approved medication for pseudobulbar affect (PBA), a condition characterized by sudden and uncontrollable laughing or crying, disproportionate to the emotion being experienced. PBA is a neurologic condition, not a psychiatric disorder. It occurs with a wide range of diseases including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS, aka motor neuron disease, Lou Gehrig's disease, or Stephen Hawking’s disease). Prevalence of PBA with ALS is about 50%. The emotional outbursts are believed to originate in the brain stem due to loss of regulatory control by the frontal lobe. PBA rarely occurs without an underlying neurologic condition.
Nuedexta provides a great example of strategic use of a kinetic drug-drug interaction, similar to that employed with Auvelity (DXM + bupropion).
Quinidine, derived from the bark of the cinchona tree, is a class IA antiarrhythmic no longer produced as a standalone drug. Quinidine is included in Nuedexta at a tiny dose. Contraindications for quinidine include prolonged QT interval, complete AV block (without pacemaker), or heart failure. Use caution when combining quinidine with other QT prolonging medications, but keep in mind the dose of quinidine in Nuedexta is too small to realistically cause cardiac conduction problems.
Nuedexta has shown modest efficacy for Alzheimer’s-related agitation, off-label (Cummings et al, 2015). The drug company incurred a $100 million fine for promoting Nuedexta to geriatric psychiatrists for this off-label use. Some physicians were accused of fraudulently diagnosing nursing home residents with PBA to obtain Medicare coverage for this expensive drug.
Agitation with dementia is challenging, considering black-box warnings for antipsychotics and risk of falls with other sedatives. So, Nuedexta is a reasonable option for this indication. The main risk is falls (~8% vs ~4% with placebo). Side effects are minimal, with dizziness of ~5%, which is about double that of placebo (~2.5%). It goes without saying that non-pharmacologic interventions for agitation (music therapy, activities, etc) should be used before resorting to medication.
Adverse effects of Nuedexta are infrequent, but may include dizziness, falls, and diarrhea. Quinidine can cause several kinds of toxicity but is not a factor at this dose.
Generic DXM is available but generic quinidine is no longer produced. Is there another suitable 2D6 inhibitor we could combine with DXM to make a poor man’s Nuedexta? Tonic water contains quinine, which is the stereoisomer of quinidine. Tonic water plus generic DXM would not be a suitable replacement because quinine in dietary doses do not sufficiently inhibit 2D6. Quinine sulfate capsules (FDA-approved for malaria) are 324 mg, which is much higher than needed and may cause hematologic toxicity.
A feasible alternative is to use a compounding pharmacy. It is not allowable to compound a pill with 20 mg DXM and 10 mg quinidine because of patent law. You can order the combo as two separate drugs: quinidine compounded suspension (10 mg daily) plus dextromethorphan ER 20 mg/5 mL (5 mL daily). Alternately, you can compound a single capsule containing a different dose combo, such as 10 mg quinidine plus 30 mg DXM (instead of 20 mg DXM), which should cost between $45–$80 monthly (Chris Aiken, MD; The Carlat Psychiatry Report, February 2020).
Dosing: Nuedexta is a fixed-dose combination of 20 mg DXM and 10 mg quinidine sulfate. Give one capsule daily x 7 days, then one capsule BID. For perspective, a typical DXM dose for cough is 30 mg, and quinidine tablets for arrhythmia (when available) were 200–300 mg.
Pharmacogenetics relevant to DXM
The label for Auvelity recommends for Known CYP2D6 Poor Metabolizers (PMs) that dose shown be decreased to one tablet once daily in the morning.
For 2D6 PMs (10% of the population) the bupropion component may be unnecessary to inHibit metabolism of DXM. These patients may be able to take 45 mg of DXM without dissociating.
The label does not mention 2D6 ultrarapid metabolizers (5% of the population). Presumably a strong inHibitor of 2D6 (bupropion) would override the genetic phenotype. If not, 2D6 UMs would be more likely to experience dissociative symptoms with Auvelity.
Pharmacogenetics relevant to bupropion
Bupropion is metabolized by CYP2B6.
3% of individuals are 2B6 ultrarapid metabolizers (UMs).
7% are 2B6 poor metabolizers (PMs).
The label for Auvelity does not mention 2B6 metabolizer phenotypes.
2B6 UMs (3% of population) may have more side effects from bupropion. I could not identify whether hydroxy-bupropion inHibits 2D6. If not, 2D6 UMs will be more likely to experience dissociative effects of DXM.
The label advises not to co-administer Auvelity with a strong 2B6 inDucer. It would stand to reason that 2B6 UMs should not take Auvelity because it is "as if" they were taking a 2B6 inDucer on the basis of their genes.
For 2B6 PMs (7% of the population) serum bupropion concentration and bupropion/OH-bupropion ratio will be higher. I estimate 2B6 PMs would tolerate Auvelity fairly well, since 210 mg bupropion/day is a relatively low dose. Risk of seizure from bupropion may be higher, however.
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