Auvelity works in several different ways because it contains two different ingredients, dextromethorphan and bupropion, although the exact way it works for depression is unknown.

The dextromethorphan component targets the NMDA receptor (N-methyl-D-aspartate), the serotonin transporter (SERT), the norepinephrine transporter (NET), and the sigma-1 receptor, to regulate levels of glutamate and other neurotransmitters such as serotonin and norepinephrine. It has a similar effect to ketamine, but the main problem with dextromethorphan is that it is quickly metabolized. To slow the metabolism of dextromethorphan, Auvelity also contains bupropion which inhibits cytochrome P450 2D6 enzymes. By inhibiting these enzymes, less dextromethorphan is metabolized, prolonging its effect. Bupropion also has antidepressant effects and primarily acts through the NET and the dopamine transporter (DAT).

Auvelity is an orally administered combination antidepressant that contains dextromethorphan and bupropion, both of which have antidepressant effects. It starts working within one to two weeks.

What is different about how Auvelity works for depression?

Auvelity is an oral antidepressant with a rapid onset of action that requires little patient monitoring. It works quickly to reduce symptoms of depression.

Most other currently available antidepressants increase levels of neurotransmitters soon after starting administration, but therapeutic effects are often delayed by several weeks and not everybody responds.

Esketamine (Spravato) approved in 2019 for treatment-resistant depression reinforced the need for antidepressants with a rapid onset of action with a unique mechanism of action which paved the way for the development of Auvelity. Esketamine is a nasal spray that also targets the NMDA receptor but it must be administered by a clinician.

Is Auvelity use supported by research?

Two large trials have confirmed the effectiveness of Auvelity.

GEMINI was a placebo-controlled trial (n=327) that compared twice-daily Auvelity (45mg dextromethorphan and 105mg bupropion) with a placebo tablet (an inactive medicine). The primary outcome was a change after 6 weeks in the total score of the Montgomery-Asberg Depression Rating Scale (MADRS) – a scale that doctors use to assess how depressed a person was. MADRS scores dropped an average of 16 points in those receiving Auvelity compared to 12 points in those receiving placebo. Differences were evident within a week of starting treatment and 40% of those taking Auvelity achieved remission (MADRS score of less than or equal to 10), compared to 17% assigned placebo.

The ASCEND trial involved 97 adults who received either Auvelity or bupropion (105mg) twice daily. Reductions in MADRS scores after 6 weeks were a mean of 14 points with Auvelity compared to 9 points with bupropion. 47% of Auvelity patients achieved remission compared with 16% of bupropion patients. This trial proved that the combination of dextromethorphan and bupropion contained in Auvelity offers benefits beyond just bupropion alone.

What are the side effects of Auvelity?

Auvelity is well tolerated and the most common side effects affecting more than 4% of people include:

• Dizziness
• Nausea
• Headache
• sleepiness
• Dry mouth
• Sexual dysfunction
• Increased sweating
• Anxiety
• Constipation
• Decreased appetite
• Sleeplessness.

Are there any interactions with Auvelity?

Dextromethorphan is metabolized through CYP 2D6 and is affected by those medicines that inhibit these enzymes. It also interacts with other medications that release serotonin. Common interactions include:

• Digoxin
• Dopaminergic drugs such as levodopa or amantadine
• Drugs that lower the seizure threshold such as antipsychotics, diphenhydramine, or tricyclic antidepressants,
• MAOIs, such as isocarboxazid, phenelzine, selegiline, linezolid, IV methylene blue, and tranylcypromine. Increased risk of hypertensive crisis and serotonin syndrome. Do not administer together within 14 days.
• Serotonergic drugs, such as lithium, ondansetron, SSRIs (eg, fluoxetine, sertraline), St. John’s Wort, tramadol
• Strong inhibitors of CYP2D6 such as fluoxetine, paroxetine, quinidine, or terbinafine
• Strong inducers of CYP2B6 such as clotrimazole, phenytoin, and carbamazepine
• CYP2D6 substrates such as antidepressants (amitriptyline, citalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, maprotiline, nortriptyline, fluoxetine, paroxetine), antipsychotics (chlorpromazine, clozapine, haloperidol, perphenazine, risperidone, thioridazine, zuclopenthixol), antiarrhythmics (flecainide, mexiletine, propafenone), beta-blockers (carvedilol, metoprolol, yohimbine, timolol), opioid analgesics (codeine, dihydrocodeine, morphine, tramadol), anticancer agents (debrisoquine, gefitinib, tamoxifen), and assorted other drugs (atomoxetine, dextromethorphan, perhexiline, tolterodine).

Bupropion contained in Auvelity can also increase the risk of neuropsychiatric adverse events or reduce alcohol tolerance.

Is Auvelity a controlled substance?

Auvelity is not a controlled substance because it contains dextromethorphan and bupropion which are not controlled substances.

What is the potential for of Auvelity?

Auvelity was not studied in clinical trials for its abuse or dependence potential. Auvelity contains dextromethorphan and bupropion and cases of dextromethorphan abuse have been reported.

Clinical studies of Auvelity did not report any drug-seeking behavior or misuse; however, these studies were not designed to do so. Patients with a history of drug abuse or misuse should be observed closely.

Auvelity is for oral administration only. Seizures and fatalities have been reported when bupropion has been given intranasally or by injection.