Comparing Spravato vs ketamine infusion treatment means comparing two versions of the same idea: using ketamine's fast action on the brain's glutamate system to treat depression that standard antidepressants haven't relieved. The best comparison so far, a 2025 meta-analysis by Mayo Clinic researchers, found no statistically significant difference in how often the two lead to response or remission. What separates them is everything around the drug: FDA status, how it's given, how quickly it tends to work, what it costs, and who pays.
So far, neither has been shown to be the better drug.
What Is Spravato (Esketamine)?
Esketamine vs ketamine comes down to chemistry. Standard ketamine is an equal mix of two mirror-image forms of the same molecule. Esketamine is one of those forms on its own, and Spravato is esketamine delivered as a nasal spray.
The FDA first approved Spravato in 2019 for treatment-resistant depression, taken together with an oral antidepressant, as the Mayo Clinic review notes. A second approval, again paired with an oral antidepressant, covers depressive symptoms in adults with major depressive disorder who have acute suicidal thoughts or behavior. And the most recent change came in January 2025, when the FDA added standalone use for treatment-resistant depression, as the current prescribing information shows.
Every dose happens in a certified healthcare setting under the Spravato REMS, an FDA-required safety program. Each device delivers 28 mg, and a session uses two or three devices (56 or 84 mg), with a five-minute wait after each one. You're then monitored for at least two hours, and you can't drive again until the next day, once you've had a restful night's sleep. The label sets the early schedule: twice a week for weeks one through four, once a week for weeks five through eight, then weekly or every two weeks, adjusted to the least frequent dosing that maintains the response.
What Is Ketamine Infusion Therapy?
A ketamine infusion uses standard ketamine, both mirror-image forms together, delivered through an IV line. Ketamine has been FDA-approved as an anesthetic since 1970, but for depression, IV ketamine "remains an off-label treatment," in the Mayo Clinic review's words. Off-label prescribing is legal and common in medicine. It also means there is no FDA-approved depression regimen, so dosing schedules and safety protocols are set by each clinic.
The most studied dose is 0.5 mg per kilogram of body weight, infused over about 40 minutes with continuous heart and blood pressure monitoring. A first course typically runs two to three infusions a week for about three to six treatments, followed by maintenance sessions on a schedule that varies from clinic to clinic.
Spravato vs Ketamine Infusion: Side-by-Side Comparison
Efficacy: What the Research Shows
The most complete head-to-head evidence is the 2025 Mayo Clinic meta-analysis in Therapeutic Advances in Psychopharmacology. The authors identified eight studies with 978 patients in total. Only one was a randomized trial, and it compared IV ketamine with an IV form of esketamine rather than the nasal spray, so the pooled comparison rests on observational studies of IV ketamine versus nasal esketamine.
In those studies, the odds of response were 1.26 times higher with IV ketamine and the odds of remission 1.31 times higher, but neither difference was statistically significant. The authors concluded that the evidence suggests no significant difference in short-term efficacy, with a slight numerical trend favoring IV ketamine.
Speed may be where the two differ. In one Mayo Clinic observational study included in the review, people reached remission after a median of two IV ketamine treatments, compared with seven nasal esketamine treatments. That's a real gap in lived experience. But it comes from observational data, where the people who choose or can access each treatment may differ in ways a study can't fully account for.
So is Spravato better than ketamine infusions? On current evidence, neither has been shown to be. A randomized trial built to settle the question, called EQUIVALENCE, plans to assign 400 people to one treatment or the other for eight sessions over four weeks. Its protocol was published in 2026, and results are not yet available.
FDA Approval and Insurance Coverage
FDA approval changes who pays. Because Spravato has approved indications, insurers can write coverage criteria around it, and they typically require prior authorization and documentation of earlier antidepressant trials. Ketamine infusions for depression are off-label, so coverage is inconsistent, and many people pay out of pocket.
The Spravato vs ketamine cost comparison has a twist. Economic modeling cited in the Mayo Clinic review found nasal esketamine unlikely to be cost-effective compared with IV ketamine from a health-system perspective. Yet an individual patient's out-of-pocket cost for Spravato may be lower, thanks to insurance coverage or manufacturer assistance. Published price estimates vary too widely by dose, frequency, and coverage to quote a single figure, so ask each provider and your insurer for the numbers that apply to you.
Side Effects and Safety Considerations
Because both drugs act on the same receptor, their side effects overlap. In Spravato's clinical trials, 48% to 61% of people developed sedation, and 61% to 84% experienced dissociative or perceptual changes, such as distortions of time or space, according to the prescribing information. Dizziness, nausea, vertigo, anxiety, and a temporary rise in blood pressure are also common, which is why blood pressure is rechecked about 40 minutes after dosing. IV ketamine produces the same family of effects, concentrated during and shortly after the infusion.
Direct safety comparisons are limited. In one retrospective analysis included in the Mayo Clinic review, a rise in blood pressure during treatment occurred in 45% of IV ketamine patients versus 9.2% of nasal esketamine patients, and dissociative effects were also more frequent with IV ketamine, though they were described as transient. That is one retrospective study. It doesn't establish either drug as safer overall.
Both drugs carry a potential for misuse, which shapes who is a candidate, and each has its own exclusions. Spravato, for example, isn't used in people with aneurysmal blood vessel disease, an arteriovenous malformation, or a history of bleeding in the brain.
What Influences the Choice Between Them
There isn't a universal right answer. A psychiatrist weighing the two usually considers:
- Coverage and cost. Whether insurance will cover Spravato in your situation, and whether infusions are affordable out of pocket.
- How quickly relief is needed. Early data suggest infusions may reach remission in fewer sessions, which matters more when symptoms are severe.
- Medical history. Blood pressure, vascular conditions, and any history of substance misuse.
- Route. Some people would rather avoid an IV line. Others prefer an infusion that can be slowed or stopped.
- Logistics. Spravato means at least two hours in the clinic and no driving until the next day, twice a week at first. Infusions take about 40 minutes, plus recovery time that varies by clinic.
- Continuity. Whether you're already established with a psychiatrist or clinic that offers one of them.
The choice belongs in a conversation with a psychiatrist who knows your treatment history, not in a ranking of favorites.
Making the Decision With a Psychiatrist
Spravato and ketamine infusions are tools for treatment-resistant depression, not a complete plan. They work alongside medication, therapy, and ongoing psychiatric care, and they sit among other options, including TMS therapy for depression that hasn't responded to medication. When depression brings thoughts of suicide, care for suicidal thoughts comes first.
We don't offer Spravato at Amae. Our psychiatrists treat depression that hasn't responded to medication through our integrated care model, with therapy, medication management, and TMS, which we provide in Los Altos, San Mateo, and Los Angeles. Whether the question is Spravato vs ketamine infusion or something else entirely, talk through your options with an Amae psychiatrist, including ones we don't provide ourselves. For anyone in crisis right now, 988 is a call or text away.
Frequently Asked Questions
Is Spravato more effective than ketamine infusions?
Not on current evidence. A 2025 meta-analysis found no statistically significant difference in response or remission between IV ketamine and nasal esketamine, only a slight numerical trend favoring IV ketamine. Most of that evidence is observational, and a large randomized head-to-head trial is still underway.
Which works faster, Spravato or ketamine infusions?
IV ketamine may reach remission in fewer sessions. In one observational study, the median was two IV infusions versus seven nasal esketamine treatments. Because that finding comes from observational data rather than a randomized trial, treat it as preliminary.
Is Spravato safer than ketamine infusions?
Neither has been established as safer overall. The two share a similar side-effect profile because they act on the same receptor. One retrospective comparison found more blood pressure spikes and dissociation with IV ketamine, but a single study can't settle the question, and individual risk depends on your medical history.
Why is Spravato covered by insurance but ketamine infusions often aren't?
Spravato has FDA approval for treatment-resistant depression, which gives insurers defined criteria for covering it, usually with prior authorization. IV ketamine for depression is off-label, so coverage is inconsistent and infusions are often self-pay.
Can I switch between Spravato and ketamine infusions?
That's a clinical decision to make with a psychiatrist, based on how you've responded, the side effects you've had, your goals, and your coverage. It isn't something to change on your own.
How many sessions does each treatment typically require?
Spravato starts at twice a week for four weeks, then weekly, then weekly or every two weeks based on response. Ketamine infusions often begin with three to six sessions given two to three times a week, followed by maintenance on a schedule that varies by clinic.
Citations
- Elmosalamy A, Tarikogullari I, Patarroyo-Rodriguez L, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Therapeutic Advances in Psychopharmacology. 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12615959/ (Tier 1)
- U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray prescribing information, revised January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf (Tier 2)
- Wilkinson ST, Prashad S, Dalthorp R, et al. Non-inferiority, comparative effectiveness study of intravenous ketamine v. intranasal esketamine for treatment-resistant depression: the EQUIVALENCE trial protocol. Contemporary Clinical Trials. 2026;164:108273. https://pubmed.ncbi.nlm.nih.gov/41780747/ (Tier 1, trial protocol)
- 988 Suicide and Crisis Lifeline. https://988lifeline.org (Tier 2)
