Patients researching ketamine-based treatment usually encounter the comparison framed as a product choice: FDA-approved versus off-label, insurance-covered versus cash-pay, nasal spray versus IV. Those distinctions are real. They are also not where a psychiatrist starts.
We offer both treatments at WIP. That matters for a specific reason: a clinic that offers only one of them can only recommend one of them. When both are available, the recommendation can reflect the evaluation rather than the inventory. This post describes the actual differences between esketamine (Spravato) and IV ketamine, and the factors our psychiatrists weigh when recommending one over the other..
The same drug, in two forms.
Ketamine is a racemic compound — a mixture of two mirror-image molecules, S-ketamine and R-ketamine. IV ketamine contains both. Spravato contains only the S-enantiomer, esketamine, delivered as a nasal spray.Both act on the brain’s glutamate system rather than the serotonin pathways targeted by conventional antidepressants, and both can produce antidepressant effects within hours to days rather than weeks. The evidence base differs in kind more than in conclusion: Spravato’s efficacy was established in the randomized controlled trials that supported FDA approval, while IV ketamine’s is supported by more than two decades of clinical research beginning with the Yale and NIMH studies of the early 2000s. Observational comparisons of the two have generally found similar antidepressant efficacy, with some data suggesting IV ketamine achieves remission in fewer sessions, and in our clinical experience its effects appear more durable between treatments. Neither has been shown to be categorically superior in controlled head-to-head trials. If a clinic tells you otherwise, ask what they offer.
Where they genuinely differ.
While both therapies can be effective, they differ in administration, side effects, and long-term maintenance. Having a general understanding of Spravato (esketamine) vs. ketamine infusions can help patients choose the most suitable option based on their needs. Below, we break down the key differences between Spravato and ketamine infusions to provide a clearer picture of what to expect.
1. Regulatory status
- SPRAVATO™ (Esketamine): nasal inhalation, FDA-approved for treatment-resistant depression and for major depressive disorder with acute suicidal ideation or behavior, and more recently as a standalone therapy for treatment-resistant depression
- Ketamine Infusion: Administered via IV infusion over 40-60 minutes. IV ketamine is FDA-approved as an anesthetic; its psychiatric use is off-label. Off-label prescribing is a standard, legal part of medical practice — roughly a fifth of all prescriptions in the United States are off-label — but it has one large practical consequence: insurance.
2. Cost structure
Because Spravato is FDA-approved, most commercial insurers cover the medication itself for its approved indications after prior authorization. But the medication is only part of each visit. Every Spravato session includes a mandatory two-hour observation period under the REMS safety program, and how insurers reimburse that monitoring time varies dramatically from plan to plan — some patients pay a simple copay, others face substantial per-session costs for the observed visit. “Covered by insurance” is where the cost question begins, not where it ends, and we verify the specifics of a patient’s plan before treatment rather than promising copay-only economics. IV ketamine is rarely covered and is paid out of pocket, but it requires substantially fewer visits over a full course. Patients weighing the two should compare total cost against total time, not sticker price against sticker price.
3. Dose control
IV ketamine is dosed by body weight, in milligrams per kilogram, and because it is delivered as an infusion over roughly forty minutes, it can be adjusted throughout the treatment — slowed, paused, or titrated in response to how the patient is actually doing. Because intravenous delivery is complete by definition, the dose administered is the dose received. Spravato is different on every count. It comes in fixed doses of 56 mg or 84 mg regardless of body weight, so a 50-kilogram patient and a 110-kilogram patient receive the same amount; the full dose is self-administered at the front end of the session, so once taken there is nothing to adjust; and intranasal absorption is lower and more variable than IV delivery, so the effective dose varies in ways the clinician cannot fully control. The constraint extends beyond the dose itself: both the dosing options and the treatment frequency for Spravato are set by the FDA label and REMS program, not by clinical judgment. With IV ketamine, the psychiatrist and patient retain control over both — dose, titration during the infusion, and the spacing of maintenance treatments can all be individualized. For many patients these constraints never matter. For some — those with unusual sensitivity, partial responses, or bodies far from the dosing average — they are the deciding factor.
4. Time to a completed induction
IV ketamine is dosed by body weight, in milligrams per kilogram, and because it is delivered as an infusion over roughly forty minutes, it can be adjusted throughout the treatment — slowed, paused, or titrated in response to how the patient is actually doing. Because intravenous delivery is complete by definition, the dose administered is the dose received. Spravato is different on every count. It comes in fixed doses of 56 mg or 84 mg regardless of body weight, so a 50-kilogram patient and a 110-kilogram patient receive the same amount; the full dose is self-administered at the front end of the session, so once taken there is nothing to adjust; and intranasal absorption is lower and more variable than IV delivery, so the effective dose varies in ways the clinician cannot fully control. The constraint extends beyond the dose itself: both the dosing options and the treatment frequency for Spravato are set by the FDA label and REMS program, not by clinical judgment. With IV ketamine, the psychiatrist and patient retain control over both — dose, titration during the infusion, and the spacing of maintenance treatments can all be individualized. For many patients these constraints never matter. For some — those with unusual sensitivity, partial responses, or bodies far from the dosing average — they are the deciding factor.
5. Side effects
The two treatments share a side-effect profile, which follows from being the same molecule family: dissociation during treatment, dizziness, nausea, sedation, and a transient rise in blood pressure. All of it is monitored, and all of it resolves before discharge — which is why neither treatment permits driving afterward. The dissociative experience itself is expected rather than avoided; it may be part of how ketamine produces its antidepressant effect. The practical difference between the two forms is not which side effects occur but what can be done about them in the moment: an infusion can be slowed or paused if a patient is tolerating it poorly, while a Spravato dose, once taken, runs its course.
6. Logistics
Spravato is self-administered under supervision; no IV access is required, which matters for patients in whom venous access is difficult. Both treatments require monitored recovery, and neither permits driving afterward.
How we decide.
The evaluation comes first. Not every patient who asks about ketamine-based treatment should receive it, and among those who should, the choice between forms follows from the clinical picture rather than from preference alone. The factors that most often decide it:
- Medical Considerations: If you have a history of high blood pressure or cardiovascular conditions, your provider may recommend one treatment over another based on your need for monitoring potential side effects. Research suggests that ketamine therapy could potentially increase blood pressure, so it’s essential to share your complete medical history with your provider.
- Effectiveness and Side Effects: While both treatments have shown effectiveness for conditions like depression, PTSD, and anxiety, some patients may respond better to one method. If you experience significant side effects with one, your healthcare provider may recommend switching to the alternative to see if your side effects are reduced or the effectiveness of the treatment is enhanced.
- Cost and Insurance Coverage: Spravato is FDA-approved, which means it is more likely to be covered by insurance. In contrast, ketamine infusion therapy is considered off-label, so it may require an out-of-pocket expense. Before starting ketamine treatment for depression or another mental health condition, check with your insurance provider and discuss pricing with your healthcare provider to ensure financial feasibility.
- Psychological Support: Ketamine therapy often works best when paired with ongoing psychological support, such as therapy. For patients pursuing ketamine-assisted psychotherapy, the infusion format integrates directly with the therapeutic session in a way Spravato’s protocol does not.
- Visit Burden: Spravato’s protocol — twice-weekly visits for a month, weekly for another, each with a two-hour hold — is workable for some patients and prohibitive for others. A patient who cannot reliably attend that schedule is set up to fail on a treatment whose benefit depends on completing the full course. An IV induction concentrates the commitment into two to three weeks and then spaces out.
- Acute suicidality: Spravato carries a specific FDA indication for depressive symptoms in MDD with acute suicidal ideation. In these situations the decision also involves level-of-care questions that go beyond the choice of drug, and we address those first.
None of these factors operates alone. The recommendation is a judgment made by a board-certified psychiatrist who has taken a full history — and who, because both treatments are available here, has no structural reason to prefer one answer.
When the first choice isn’t the last.
Treatment response is observed, not assumed. Patients at WIP are tracked with clinical and measurement-based care, and a partial response to one formulation sometimes leads us to another tool — a switch that happens within the same practice, the same chart, and the same treating psychiatrist. The same oversight governs maintenance: intervals are stretched as response allows, and treatment stops when it is no longer needed. When neither form of ketamine produces adequate response, the conversation turns to TMS, medication changes, or other options. That conversation happens here too. This is the practical meaning of interventional psychiatry within a psychiatric practice: the treatment is a tool in a plan, not the end of therelationship — and ketamine, in any form, is a drug that warrants a psychiatrist’s ongoing judgment, not just a technician’s schedule.
At WIP, we provide ketamine therapies with specialists that have extensive experience in ketamine-based treatments for depression, anxiety, and PTSD.
Initial consultations with our psychiatrists are complimentary. If you have been evaluated elsewhere and told the answer is whichever treatment that clinic happens to offer, a second opinion is reasonable.
Contact WIP today to schedule a free consultation.
