Auvelity is a daily oral antidepressant that combines dextromethorphan and bupropion and was FDA-approved in 2022 for major depressive disorder in adults, while esketamine (Spravato) and IM ketamine are rapid-acting treatments given under supervision in a medical setting that act on the brain far more broadly.
If you're comparing Auvelity with ketamine-based treatments, you may be weighing what comes next after antidepressants haven't brought enough relief. That's a hard place to be, and the overlapping names don't make it easier. All three treatments touch glutamate, the brain's main "go" signal, which is why they get compared. But they differ in how you take them, how fast they tend to work, where you receive them, and who they're meant for.
What Is Auvelity, and How Does It Work?
Auvelity is an extended-release tablet that pairs two older medicines: dextromethorphan (the same compound found in many cough medicines) and bupropion (a long-used antidepressant). The FDA approved it in August 2022 for major depressive disorder (MDD) in adults.[7] You take it by mouth at home, usually once a day for the first three days and then twice a day.
The pairing is deliberate.[6] In a live session for families in October 2026, Dr. Ben Yudkoff, Chief Medical Officer and co-founder of Lumin Health, explained that bupropion's role is to slow the body's breakdown of dextromethorphan so that it can reach the brain. Dextromethorphan then blocks the NMDA receptor, one of the main receivers for glutamate. Bupropion also brings its own antidepressant activity.
Dr. Yudkoff was candid that the medicine's early promise hasn't been fully delivered, though some people do respond to it. In the trials that supported its approval, Auvelity reduced depressive symptoms more than placebo, with differences that showed up as early as the first week of treatment.[5]
How Ketamine-Based Treatments Work Differently From an Oral Pill
Ketamine-based treatments also block the NMDA receptor, and that's usually where the comparison stops. It shouldn't. As Dr. Yudkoff put it in the same session, these medicines don't act only on NMDA receptors. Their effects are much more global, and that broader action is something oral options haven't replicated.
Researchers have linked ketamine's rapid antidepressant effects to the fast growth of new connections between brain cells.[1] Its effects also appear to involve the brain's own opioid (endorphin) system.[2] Studies have mapped its actions across several other pathways too.[3] In plain terms, ketamine may help brain cells reach out and reconnect.
- Esketamine (Spravato) is a nasal spray containing the S-enantiomer of ketamine, one of ketamine's two mirror-image forms and the one that binds the NMDA receptor more strongly. It is FDA-approved for adults with treatment-resistant depression and for depressive symptoms in adults with MDD with acute suicidal ideation or behavior.
- IM ketamine is racemic ketamine (a mixture of both S-ketamine and R-ketamine) given as an intramuscular injection. Ketamine for depression is an evidence-based, off-label application of a medicine that's been in use for over 50 years.
For a deeper look at those two, see our guide to the differences between the nasal spray and ketamine.
Auvelity vs. Spravato and IM Ketamine at a Glance
- How you take it: Auvelity is a pill you take at home every day. The nasal spray is self-administered under direct supervision at a certified site. IM ketamine is an injection given by the care team.
- How quickly it may help: Auvelity builds over weeks, like other daily antidepressants. Both ketamine-based options are considered rapid-acting. In a landmark trial, a single dose of ketamine improved depressive symptoms within hours for many participants.[4]
- Where you receive it: Auvelity at home. The rapid-acting options only in a medical setting.
- Monitoring: With Auvelity, your prescriber checks your blood pressure before you start and periodically after. During a session of either rapid-acting treatment, the team watches vital signs like blood pressure and the oxygen saturation of your blood. After the nasal spray, you stay on-site for two hours or more, and you'll need a ride home after either one.
- Who it's for: Auvelity is approved for MDD in adults. The nasal spray is approved for treatment-resistant depression and for MDD with acute suicidal thoughts. IM ketamine is off-label, so eligibility is decided together by you and your psychiatrist.
- Insurance: Auvelity is a pharmacy prescription, and coverage depends on your plan. The nasal spray is often covered for its approved uses. IM ketamine is usually self-pay.
Blood Pressure: Worth Watching With All Three
Auvelity's prescribing information warns that it can raise blood pressure.[7] The ketamine-based treatments raise it too, though only briefly during a session. Dr. Yudkoff described the size of that effect:
"So both ketamine and esketamine can cause transient increases in blood pressure and heart rate, about the equivalent of walking up two or three flights of stairs."
— Dr. Ben Yudkoff, Chief Medical Officer, Lumin Health
Most people tolerate that well. It's one more reason your medication list and heart history matter before any of these treatments begin.
Can Auvelity and Ketamine Be Used Together?
The honest answer is that it depends on you. There's no single rule, but here's what is generally true:
- Many people stay on an oral antidepressant during ketamine-based treatment. The nasal spray is often prescribed alongside one.
- Whether Auvelity in particular is the right oral medicine to keep taking is an individual decision for your prescribing psychiatrist. Both medicines act on NMDA receptors, and both can raise blood pressure. This pairing has not been well studied, so it calls for a careful look at your whole medication list and medical history.
- Auvelity carries its own interaction cautions, including with MAOI antidepressants and with medicines that raise serotonin.[7] Your prescriber will review these with you.
If you take Auvelity now and are curious about the ketamine-based options, please mention it at your evaluation. Sharing every medication you take helps the team plan care that's safe for you. You can read more about how ketamine interacts with common medications.
Other Oral Medicines That Touch the Glutamate System
Dr. Yudkoff noted that some psychiatrists add memantine, a medicine that blocks NMDA receptors, to an antidepressant. Others consider lamotrigine, which has glutamate-modulating properties. These are off-label uses, and none of them reproduce what ketamine does. The research community is actively studying whether new antidepressants can come closer to ketamine's broader effects.
For more background, see our explainers on glutamate and why it matters for ketamine therapy and how ketamine differs from traditional antidepressants.
Which Depression Treatment Fits You?
There isn't a universal "best." A daily pill may make sense if you're earlier in treatment, prefer not to come in for sessions, or want to try a newer mechanism first. A ketamine-based treatment may be worth exploring if your depression hasn't lifted after other medicines, if you need relief to arrive sooner, or if suicidal thoughts are part of what you're living with. What matters most is what feels possible to you, and an honest conversation with a psychiatrist who knows these medicines well.
If you are in crisis or thinking about ending your life, please call or text 988 to reach the Suicide and Crisis Lifeline, or go to your nearest emergency room.
Where Lumin Health Fits
Lumin Health is a psychiatrist-led practice with locations across Massachusetts and Bethesda, Maryland. We offer two rapid-acting options, esketamine (Spravato) and intramuscular (IM) ketamine injections, each given on-site by a team specifically trained in both medicines. Your psychiatrist recommends the single pathway that fits your history, goals, and coverage. With your consent, we also stay in touch with your existing providers about your medicines and how treatment is going.
If you'd like to explore whether one of these options may be a fit, you can review the insurance plans we accept. We would be grateful to talk it through with you.
References
- Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964. PubMed
- Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215. PubMed
- Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621-660. PubMed
- Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. PubMed
- Iosifescu DV, Jones A, O'Gorman C, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. PubMed
- Tabuteau H, Jones A, Anderson A, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry. 2022;179(7):490-499. PubMed
- U.S. Food and Drug Administration. Auvelity (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets: prescribing information. NDA 215430. 2022. FDA
Frequently Asked Questions
Is Auvelity the same as Spravato?
No. Auvelity is a daily oral tablet that combines dextromethorphan and bupropion, FDA-approved in 2022 for major depressive disorder in adults. Esketamine (Spravato) is a nasal spray given under supervision at a certified site, FDA-approved for treatment-resistant depression and for depressive symptoms in MDD with acute suicidal ideation or behavior.
Can you take Auvelity and Spravato together?
Many people stay on an oral antidepressant during esketamine treatment, but whether Auvelity specifically is appropriate is an individual decision for your prescribing psychiatrist. Both act on NMDA receptors and both can raise blood pressure, and the pairing has not been well studied.
Is Auvelity a form of ketamine?
No. Auvelity contains no ketamine. Its dextromethorphan blocks NMDA receptors, as ketamine does, but ketamine acts on many more brain systems, which oral options have not replicated.
Which works faster, Auvelity or ketamine?
Ketamine and esketamine are considered rapid-acting, and some people notice changes within hours to days. Auvelity is a daily antidepressant that builds over weeks, though in trials it separated from placebo as early as the first week.
Does insurance cover Auvelity, Spravato, or IM ketamine?
Auvelity coverage depends on your pharmacy plan. Esketamine (Spravato) is often covered for its FDA-approved uses, while IM ketamine is off-label and usually self-pay. Check with your insurer or use our eligibility form at lumin.health/insurance-we-accept.
