TL;DR
- •Auvelity (dextromethorphan-bupropion) and Spravato (esketamine) are both recent FDA approvals (2019-2022) that act on the NMDA/glutamate system rather than serotonin — a newer mechanism associated with faster antidepressant effects.
- •Auvelity is an oral tablet taken at home, approved for major depressive disorder; the bupropion component mainly serves to raise dextromethorphan blood levels by inhibiting its metabolism.
- •Spravato is an intranasal spray restricted to certified clinics under an FDA REMS program — you self-administer under supervision and are monitored for ~2 hours afterward; it is approved for treatment-resistant depression and for depression with acute suicidal ideation.
- •Both can act faster than conventional antidepressants — Auvelity has shown separation from placebo within about a week, and Spravato within hours to days — versus the 4-6 weeks typical of SSRIs/SNRIs.
- •Access and burden differ sharply: Auvelity is a routine oral prescription, while Spravato requires repeated monitored clinic visits, cannot be taken home, and carries a sedation/dissociation and abuse-potential warning.
- •All three NMDA-mechanism options — Auvelity, Spravato, and at-home ketamine — share a glutamatergic rationale; they differ most in route, setting, cost, and accessibility.
- •At-home sublingual ketamine occupies the accessibility middle ground: the same NMDA/glutamate rationale as Spravato, delivered in your own home like Auvelity, without the certified-clinic REMS requirement.
Side by side
Auvelity
Dextromethorphan-bupropion (AXS-05)
Oral NMDA receptor antagonist + sigma-1 agonist (with bupropion)
What it treats
Major depressive disorder
Mechanism
Dextromethorphan is an NMDA-receptor antagonist and sigma-1 agonist acting on the glutamate system; bupropion is included primarily to inhibit CYP2D6 and raise dextromethorphan blood levels (and adds its own NDRI effect). The glutamatergic action is thought to drive the faster onset.
Strengths
- •Oral tablet taken at home — no clinic visit, no supervised administration
- •Rapid onset for an oral antidepressant — separation from placebo seen within about a week
- •Novel NMDA/glutamate plus sigma-1 mechanism, distinct from SSRIs/SNRIs
- •No REMS program or in-office monitoring requirement
Limitations
- •Carries bupropion-related cautions — lowers seizure threshold; contraindicated in seizure history and eating disorders
- •Dizziness, nausea, headache, dry mouth, and possible blood-pressure increase
- •Drug interactions via CYP2D6 and serotonergic combinations
- •Newer agent — less long-term real-world data than established antidepressants
Spravato
Esketamine (intranasal)
Intranasal NMDA receptor antagonist (S-enantiomer of ketamine)
What it treats
Treatment-resistant depression (with an oral antidepressant), Major depression with acute suicidal ideation or behavior
Mechanism
Esketamine is the S-enantiomer of ketamine and blocks the NMDA glutamate receptor, triggering downstream synaptic and neuroplastic changes thought to underlie rapid antidepressant effects. Delivered intranasally and used together with a standard oral antidepressant.
Strengths
- •FDA-approved specifically for treatment-resistant depression and for depression with acute suicidality
- •Rapid effect — improvement within hours to days in responders
- •Direct NMDA/glutamate mechanism with substantial RCT evidence
- •Supervised setting provides monitoring for high-acuity patients
Limitations
- •REMS-restricted — administered only at certified clinics; cannot be taken home
- •Requires ~2 hours of post-dose monitoring; no driving until the next day
- •Dissociation, sedation, transient blood-pressure rise, and abuse potential (controlled substance)
- •High cost and substantial visit burden (twice-weekly induction, then maintenance)
Which one for your situation?
If:
Major depression where you want a novel rapid-onset option taken at home without clinic visits
Verdict:
Auvelity — oral, no REMS, no supervised administration
If:
Treatment-resistant depression that has failed multiple antidepressants
Verdict:
Spravato — specifically FDA-approved for TRD (alongside an oral antidepressant); Auvelity is approved for MDD generally
If:
Depression with acute suicidal ideation needing rapid effect in a monitored setting
Verdict:
Spravato — carries the FDA indication for depression with acute suicidality and is given under supervision
If:
Seizure history or an eating disorder
Verdict:
Spravato over Auvelity — Auvelity contains bupropion, which lowers the seizure threshold and is contraindicated in these conditions
If:
Twice-weekly monitored clinic visits are not feasible (work, travel, caregiving)
Verdict:
Auvelity — at-home oral dosing avoids the Spravato visit and monitoring burden
If:
Want a glutamatergic, rapid-acting option at home but Auvelity is contraindicated or not tolerated
Verdict:
Consider at-home sublingual ketamine — same NMDA/glutamate rationale, home setting, without the REMS clinic requirement
Where ketamine fits
Auvelity, Spravato, and at-home ketamine all share an NMDA/glutamate mechanism — the distinction is route, setting, cost, and accessibility, not the underlying target. Spravato delivers esketamine but only inside certified REMS clinics with monitored visits; Auvelity is oral but carries bupropion's seizure-threshold and interaction cautions. At-home sublingual ketamine sits between them: the same glutamatergic rationale as Spravato, delivered in your own home like Auvelity, without the certified-clinic requirement — positioning it on accessibility, cost, and setting rather than as a mechanistically different drug.
Auvelity: separation from placebo within about a week. Spravato: improvement within hours to days. Sublingual ketamine: mood response within hours of the first session.
5-minute screening · Reviewed by a board-certified physician · FL & NJ
Frequently asked
How are Auvelity and Spravato different?
Both act on the NMDA/glutamate system and act faster than conventional antidepressants, but the delivery and access differ completely. Auvelity is an oral tablet (dextromethorphan plus bupropion) you take at home, approved for major depression. Spravato is an intranasal esketamine spray you can only receive at a certified clinic under FDA REMS rules, with about two hours of monitoring afterward, approved for treatment-resistant depression and depression with acute suicidality.
Is Auvelity the same as ketamine?
Not the same drug, but the same general idea. Auvelity's active component, dextromethorphan, is an NMDA-receptor antagonist acting on the glutamate system — the same broad mechanism as ketamine and esketamine (Spravato). The molecules and routes differ: Auvelity is oral dextromethorphan-bupropion, Spravato is intranasal esketamine, and at-home ketamine is sublingual. All three share the glutamatergic rationale for rapid antidepressant effects.
Why does Spravato require clinic visits when Auvelity doesn't?
Spravato (esketamine) can cause sedation, dissociation, and a transient rise in blood pressure, and it is a controlled substance with abuse potential — so the FDA approved it under a REMS program that requires administration at a certified site with about two hours of monitoring and no driving until the next day. Auvelity is an oral tablet without those acute dissociative effects, so it is a routine at-home prescription (with its own bupropion-related cautions).
Which works faster?
Both are faster than SSRIs/SNRIs, which take 4-6 weeks. Spravato can produce improvement within hours to days in responders. Auvelity has shown separation from placebo within about a week in trials. The trade-off is setting and burden: Spravato's speed comes with monitored clinic visits, while Auvelity's onset is slightly slower but achieved with at-home oral dosing.
Where does at-home ketamine fit between these two?
At-home sublingual ketamine shares the NMDA/glutamate mechanism with both — the same rationale as Spravato's esketamine — but is delivered in your own home like Auvelity, without the certified-clinic REMS requirement. It tends to be positioned on accessibility, cost, and setting rather than as a mechanistically different treatment. A physician reviews your history and medication list during consultation to determine which option fits, including any contraindications.
References
- Iosifescu DV et al. 2022, Journal of Clinical Psychiatry. Phase 3 trial (GEMINI) found dextromethorphan-bupropion (AXS-05, Auvelity) significantly improved depressive symptoms versus placebo in major depressive disorder, with early separation supporting its rapid-acting profile. PMID 35649167
- Tabuteau H et al. 2022, American Journal of Psychiatry. Randomized trial demonstrated the efficacy of AXS-05 (dextromethorphan-bupropion) versus bupropion in major depressive disorder, isolating the contribution of the NMDA-antagonist component. PMID 35582785
- Popova V et al. 2019, American Journal of Psychiatry. Phase 3 RCT showed intranasal esketamine (Spravato) plus a newly initiated oral antidepressant produced significantly greater improvement than the antidepressant alone in treatment-resistant depression. PMID 31109201
- Murrough JW et al. 2013, American Journal of Psychiatry. Ketamine RCT in treatment-resistant depression — 64% response vs 28% placebo — established the rapid NMDA/glutamate antidepressant effect that underlies both esketamine and at-home ketamine. PMID 23982301
- Sanacora G et al. 2017, JAMA Psychiatry. APA consensus statement on the use of ketamine for depression, framing the rapid-acting glutamatergic mechanism shared across this newer class of treatments. PMID 28249076