Spravato vs. Ketamine Infusions for TRD: What’s the Difference — and Why We Chose Spravato

If you’ve been struggling with depression that hasn’t responded to antidepressants, you’ve probably heard two terms getting a lot of attention: Spravato (esketamine) and ketamine infusions. Both are being called “breakthroughs.” Both work faster than anything psychiatry has offered in decades. And both are showing up in search results alongside the words “treatment-resistant depression.”

But they are not the same treatment — and not every clinic offers both.

At our practice, we offer Spravato (esketamine), and we made that choice deliberately, based on the clinical evidence, the regulatory landscape, the safety infrastructure, and what gives our patients the most dependable, well-monitored path to recovery.

Here’s exactly what you need to know about both options, how they compare, and why Spravato is what we offer.

First: why ketamine-based treatment at all?

For decades, depression treatment lived almost entirely in one biological lane: medications that adjust serotonin, norepinephrine, or dopamine — the monoamine system. SSRIs. SNRIs. MAOIs. If those didn’t work, you cycled through more of the same.

The problem is that for roughly 30% of people with major depression, the monoamine system is not the central issue, or not the only one ^[1]. These patients have a different underlying biology: glutamate system dysfunction, impaired neuroplasticity, HPA axis dysregulation, or neuroinflammation. No amount of sertraline or venlafaxine adequately touches those pathways.

Ketamine-based treatments do.

Both Spravato and IV ketamine work by blocking NMDA receptors, proteins that regulate glutamate, the brain’s most powerful neurotransmitter. When NMDA receptors are blocked, a cascade unfolds within hours: glutamate surges, AMPA receptors activate, and BDNF (brain-derived neurotrophic factor, the brain’s growth hormone) floods into synapses. The brain literally grows new neural connections in circuits that depression has eroded ^[2]. This is why patients sometimes describe the first treatment as “the weight just lifting” — because neurobiologically, something real happened, very quickly.

The question is not whether to use this mechanism. The question is which delivery system is clinically sound, properly regulated, and right for your situation.

The fundamental difference: what they actually are

IV racemic ketamine is a 50/50 mixture of two mirror-image molecular forms (R- and S-enantiomers). It was developed in the 1960s as a surgical anesthetic and has been FDA-approved in that role since 1970. Its use in depression is off-label — meaning evidence supports it, but the FDA has not formally approved it for psychiatric use. There is no standardized dosing protocol, no federal monitoring program, and quality of administration varies widely from clinic to clinic.

Spravato (esketamine) is the isolated S-enantiomer — the same core molecule, refined and reformulated as a nasal spray. It binds NMDA receptors with higher affinity than the R-enantiomer and was developed specifically for psychiatric use. It received FDA approval for treatment-resistant depression in 2019 ^[3]. In January 2025, the FDA expanded that approval to allow Spravato as a monotherapy — the first and only antidepressant ever FDA-approved as a standalone treatment for TRD, without requiring a concurrent oral antidepressant ^[4].

Same fundamental mechanism. Meaningfully different in regulatory status, standardization, safety oversight, and the depth of the clinical trial evidence behind them.

How they’re administered

IV ketamine infusions

• Delivered into a vein as a slow drip, typically 0.5 mg/kg over 40 minutes
• Provides ~100% bioavailability — the full dose reaches the bloodstream immediately
• Most patients notice effects within an hour, sometimes sooner
• Administration protocols vary significantly by clinic; there is no standardized federal monitoring requirement
• Standard induction: 6 infusions over 2–3 weeks, followed by maintenance every 2–4 weeks

Spravato (esketamine) — what we offer

• Administered as a nasal spray; you use the device yourself, under direct supervision in our office
• Mean absolute bioavailability of approximately 48% with peak plasma levels at 20–40 minutes after the last spray, and a gentler onset than IV ^[3]
• Administered only at FDA REMS-certified facilities — we are fully certified ^[3]
• Mandatory 2-hour monitoring period after every session, per FDA safety standards ^[3]
• Standard induction: 8 sessions over 4 weeks (twice weekly), followed by weekly, then biweekly maintenance
• Can now be used without a concurrent antidepressant (monotherapy approval, January 2025) ^[4]

What the clinical evidence shows

Speed and efficacy

The most rigorous head-to-head comparison comes from a 2025 retrospective chart review at McLean Hospital (Harvard Medical School), published in the Journal of Clinical Psychiatry ^[5]:

• IV ketamine (n=111): 49.2% reduction in depression scores by the eighth treatment; significant improvement often visible after the first infusion
• Intranasal esketamine (n=42): 39.6% reduction by the eighth treatment; significant response typically emerged after the second session
• Both treatments significantly outperformed simply switching antidepressants

A 2025 systematic review and meta-analysis published in Therapeutic Advances in Psychopharmacology pooled eight comparable studies (seven covering 915 participants) and found that IV ketamine and intranasal esketamine both produced meaningful clinical outcomes, with neither demonstrating clear superiority on remission rates during the induction phase ^[6]. The numerical edge seen with IV ketamine, driven by its 100% bioavailability, has not yet translated into a definitive superiority finding when remission rates are pooled across studies.

Suicidal ideation

Both treatments reduce suicidal ideation faster than any conventional antidepressant. Spravato holds a specific FDA approval for major depressive disorder with acute suicidal ideation or behavior — the only antidepressant medication with that indication ^[3]. In clinical trials, esketamine produced clinically meaningful reductions in suicidal ideation within just four hours of the first dose ^[1].

Long-term durability

The SUSTAIN-1 and SUSTAIN-2 long-term continuation trials demonstrated that ongoing esketamine significantly delays relapse compared to placebo, confirming it as an effective maintenance strategy, not just an acute intervention ^[1]. Real-world evidence from health-system data supports consistent effectiveness across diverse patient populations.

Why we offer Spravato — not IV ketamine

We get this question often, and it deserves a direct, honest answer.

1. FDA approval means standardized safety for you

Spravato is the only ketamine-based treatment with formal FDA approval for TRD. That approval came after rigorous Phase II and III randomized controlled trials involving thousands of patients — trials that IV ketamine, used off-label, has never been required to complete for its depression indication ^[3,4]. The FDA REMS program ensures that every Spravato administration happens under a standardized safety protocol: mandatory in-clinic monitoring, certified providers, and structured adverse event reporting. That infrastructure protects you in ways that an off-label infusion at a non-standardized clinic cannot.

2. Insurance actually covers it

This matters profoundly, and most clinics don’t say it clearly enough.

Spravato is covered by most major commercial insurance plans and Medicare when you have a TRD diagnosis (two failed adequate antidepressant trials) and receive treatment at a REMS-certified facility. Most of our patients pay only their standard office visit copay, often $30–$50 per session, for a treatment that three years ago would have cost thousands out of pocket.

IV ketamine infusions are almost never covered by insurance. Because IV ketamine is off-label for depression, Medicare, Medicaid, and most commercial insurers classify it as investigational. Out-of-pocket cost typically runs several hundred dollars per infusion, with a standard induction course totaling several thousand dollars before ongoing maintenance is factored in. A small number of regional plans have begun pioneering coverage, but nationally, IV ketamine remains inaccessible to patients who cannot afford that cost.

We believe access to a transformative treatment should not depend on your ability to write a four-thousand-dollar check. Offering Spravato allows us to serve the patients who need it most, not just those who can afford the alternative.

3. Monotherapy — a clinical landmark

As of January 2025, Spravato is FDA-approved as a monotherapy for TRD, meaning patients who cannot tolerate or do not want an oral antidepressant can now use esketamine as their sole pharmacological treatment ^[4]. This is clinically significant. It eliminates the previous requirement to pair esketamine with another antidepressant that may have already failed or caused side effects.

4. The evidence base is prospective and controlled

Esketamine’s approval rests on multiple randomized, double-blind, placebo-controlled trials — the gold standard of clinical evidence ^[1,3]. IV ketamine’s psychiatric evidence base, while substantial and growing, is largely composed of open-label studies, retrospective reviews, and small controlled trials. For the patients in our care, we prioritize treatments where the evidence has been tested under the most rigorous scientific conditions.

A practical side-by-side comparison

Side effects: what to expect with Spravato

Because esketamine’s bioavailability is lower and its absorption slower than IV ketamine, its side effect profile tends to be gentler — though still real and worth knowing ^[3,6]:

• Dissociation — a temporary feeling of detachment or altered perception during and after the session. This is a direct, expected pharmacological effect. It typically resolves within 1–2 hours. Most patients find it manageable; some describe it as restful or floaty.
• Nausea — more common in the first session; typically responsive to anti-nausea medication.
• Dizziness or lightheadedness — common during the monitoring window; resolves before discharge.
• Elevated blood pressure — less pronounced with esketamine than IV ketamine due to its lower peak plasma levels; monitored every session.

You will not be able to drive on the day of treatment. Please arrange transportation. The 2-hour post-dose monitoring period is mandatory, not optional, and is there for your safety.

Spravato is not appropriate if you have uncontrolled hypertension, active psychosis, certain cardiovascular conditions, or a history of dissociative disorders. All of this is evaluated during your pre-treatment psychiatric assessment.

What our Spravato program looks like

Step 1 — Comprehensive psychiatric evaluation. We conduct a full review of your depression history, prior antidepressant trials, and current symptom severity using validated tools (MADRS, PHQ-9, Columbia Suicide Severity Rating Scale). We screen for pseudoresistance, bipolar disorder, and medical contributors to treatment resistance.

Step 2 — Insurance verification and prior authorization. We handle the prior authorization process on your behalf, including clinical documentation of prior failed antidepressant trials, diagnosis confirmation, and REMS enrollment.

Step 3 — Individualized treatment planning. We determine whether Spravato alone, Spravato combined with TMS, or another combination approach is the right clinical fit for your history, biology, and goals.

Step 4 — Monitored treatment, every session. All Spravato sessions are conducted on-site with mandatory 2-hour post-dose monitoring per REMS requirements. Vitals are tracked throughout. You are never alone during or after administration.

Step 5 — Ongoing psychiatric integration. Spravato is most effective, and most durable, when integrated into ongoing psychiatric care. We remain actively involved in your treatment between sessions: adjusting medications, coordinating TMS if indicated, and supporting the other pillars of recovery.

The bottom line

Spravato and IV ketamine are two expressions of the same breakthrough neurobiological insight — that glutamate-system interventions can rapidly rebuild the brain circuits that depression has dismantled ^[2]. The evidence shows both work. The differences lie in regulatory standing, insurance accessibility, safety standardization, and the depth of controlled clinical trial data.

We chose Spravato because it is FDA-approved with a defined safety monitoring program, covered by insurance for most patients who qualify, and backed by the most rigorous controlled trial evidence of any ketamine-based therapy. We chose it because we believe transformative psychiatric treatment should be accessible, safe, and evidence-driven — not dependent on which patients can afford an out-of-pocket infusion.

If you’ve tried two or more antidepressants without meaningful relief, you may already qualify. The first step is a conversation.