If you’ve been researching options for treatment-resistant depression, you’ve almost certainly come across both Spravato and IV ketamine. They sound similar, they work on the same brain pathway, and both can produce dramatic improvement when traditional antidepressants haven’t. But they’re not interchangeable. The differences matter for cost, insurance coverage, treatment experience, and which one might actually be right for you.

Here’s a straight-talking comparison.

The short version

Spravato is a nasal spray (esketamine) that’s FDA-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation. It’s a refined molecule — the “S” enantiomer of ketamine — and it’s manufactured by Janssen.

IV ketamine is the original racemic ketamine molecule, infused intravenously. It has been used in medicine since the 1960s as an anesthetic. Its use for depression is supported by a substantial body of clinical research but remains officially off-label, meaning the FDA hasn’t formally approved it for that indication.

Both work by modulating glutamate signaling through the NMDA receptor — a fundamentally different mechanism from SSRIs and other traditional antidepressants. Both can produce rapid relief of depressive symptoms when oral medications haven’t worked. The differences are in the delivery, the regulatory status, the cost, and what the experience actually feels like.

FDA approval and insurance coverage

This is the single biggest practical difference for most patients.

Spravato is covered by most insurance. Because it’s FDA-approved with a specific indication, commercial insurers, Medicare, and many Medicaid plans cover it when prescribed by a psychiatrist for treatment-resistant depression. You’ll typically pay your specialty drug copay — often $20 to $100 per session, sometimes less with manufacturer copay assistance.

IV ketamine is rarely covered by insurance for depression. Because the FDA hasn’t formally approved it for psychiatric use, most insurers consider it off-label or experimental for this purpose. That means most patients pay out of pocket — typically $400 to $800 per infusion, with a typical induction series of six infusions running $2,500 to $5,000 total.

For many patients, this single fact decides the question. If you have insurance and Spravato is appropriate for your situation, the cost difference is enormous.

How they’re administered

Spravato is a nasal spray you administer to yourself under direct healthcare supervision. The dose is delivered in two to three sprays per nostril over a few minutes. Because of FDA-mandated REMS requirements, you must remain at the clinic for at least two hours after each dose for monitoring. You will not be able to drive home and must arrange transportation.

IV ketamine is administered slowly through an IV line over approximately 40 minutes. You’re monitored continuously throughout, and most clinics keep you for an additional 30 to 60 minutes of post-infusion observation. Like Spravato, you can’t drive afterward.

Total time at the clinic is roughly comparable — about two and a half hours for Spravato, about 90 minutes for IV ketamine.

The treatment experience

Both produce dissociative effects during the dose itself — a temporary sense of being detached from your body or surroundings. Many patients describe it as dreamlike. For some this feels neutral or even pleasant; for others it’s uncomfortable. The effect typically resolves within an hour or two.

Spravato tends to produce a slightly more variable absorption pattern because it’s nasal — bioavailability depends on whether you have congestion, how the spray is administered, and individual mucosal anatomy. IV ketamine produces more consistent blood levels because the dose goes directly into circulation.

In clinical practice, neither is clearly “stronger” than the other. Response varies more by individual than by molecule.

Treatment schedule

Spravato follows a defined schedule: twice weekly for the first four weeks (induction), then weekly for four weeks, then every one to two weeks for maintenance. This is the protocol the FDA approved and that insurance covers.

IV ketamine protocols vary by clinic. The most common approach is six infusions over two to three weeks for induction, followed by maintenance infusions every two to six weeks based on clinical response. There’s less standardization, which can be a feature or a bug depending on your perspective.

Side effects and safety

Both share a similar side effect profile because they work on the same receptor:

Long-term concerns with repeated ketamine use include potential effects on bladder function (cystitis) and cognitive effects, though these are far more associated with high-dose recreational use than with monitored therapeutic protocols. Both Spravato and IV ketamine have similar long-term safety profiles when administered correctly.

How quickly do they work?

This is one of the genuinely remarkable things about NMDA-receptor therapies — and it applies equally to both. Many patients notice meaningful improvement in mood, motivation, and suicidal thinking within hours to days of their first session. This stands in stark contrast to traditional antidepressants, which typically take four to eight weeks to show effect.

That said, not every patient responds. Roughly 50 to 70 percent of patients show meaningful improvement after a full induction course of either treatment. The remaining 30 to 50 percent see partial or no benefit, which is similar to what we see with most depression treatments.

Which one should you ask about?

For most patients with treatment-resistant depression who have insurance, Spravato is the more practical first choice simply because of cost. Insurance coverage means you can complete a full induction protocol — which is necessary to fairly evaluate response — without facing thousands of dollars in out-of-pocket charges.

IV ketamine may be a better fit if:

This is genuinely a conversation to have with a prescribing psychiatrist, not a decision to make based on internet research. Both treatments have a place, and the right choice depends on your specific clinical history, your insurance, and your goals.

At Arbor

We administer both Spravato and IV ketamine at our North Atlanta center under the supervision of a prescribing physician. Learn more about Spravato, read about IV ketamine, or contact our team to discuss whether either is right for you.

If you’re currently in crisis or having thoughts of suicide, please call or text 988 (Suicide and Crisis Lifeline) immediately, or go to your nearest emergency department. These therapies are administered as part of an ongoing treatment plan with a psychiatrist — not as emergency care.