Spravato (Esketamine) for Depression: Who It Is For, What a Visit Is Like, and What the Evidence Shows

A nasal spray sounds like the simplest thing in medicine. This one reshapes an afternoon: no food beforehand, a blood-pressure cuff, a staff member watching you dose, two hours in a chair, and someone else driving you home. That gap between how it sounds and what it is deserves a straight explanation.

Disclosure, before you read further

• Inland Psychiatric Medical Group offers Spravato at its clinics, and I practice through IPMG. This article is about a treatment my organization provides and is paid to provide. That is a conflict of interest, and it belongs at the top of the page rather than the bottom.

• Nothing here is a recommendation to start Spravato, and nothing here is an offer of treatment. I have kept in the trials that failed, the endpoints that were missed, and the limits written into the FDA label itself. Every factual claim is cited to a primary source and listed at the end, so you can check the article against the evidence instead of taking my word for it.

What to know

• Spravato is esketamine, delivered as a nasal spray. It is not IV ketamine, and it is not a compounded nasal ketamine from a wellness clinic. The evidence for one is not evidence for the others.[1,12]
• It has two separate FDA-approved uses in adults, and they follow different rules. For treatment-resistant depression it may now be used alone or with an oral antidepressant. For depressive symptoms in adults with major depression and acute suicidal thoughts or behavior, an oral antidepressant is still required.[1,2,3]
• You cannot take it home. Every dose is self-administered in a certified healthcare setting under direct observation, with at least two hours of monitoring afterward. That is a federal safety requirement, not a clinic preference.[1,4]
• The average benefit is real and modest. In the pivotal add-on trial, the advantage over placebo at four weeks was 4.0 points on a 60-point depression scale. One acute fixed-dose trial and the dedicated trial in adults 65 and older missed their primary endpoints entirely.[5,6,7]
• It has not been shown to prevent suicide. The label says so directly. The approval for acute suicidal thoughts covers depressive symptoms — it is not a substitute for emergency care.[1]
• Temporary dissociation, sedation, dizziness, nausea, and a rise in blood pressure are common. Serious breathing problems are rare but have been reported after approval, which is why the pulse oximeter and the two hours exist.[1]

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The short answer

Spravato is the brand name for esketamine, given as a nasal spray. In the United States it is approved for two things, both in adults:

1. Treatment-resistant depression — used either on its own or added to an oral antidepressant.
2. Depressive symptoms in adults with major depressive disorder who have acute suicidal thoughts or behavior — used together with an oral antidepressant.[1]

You spray it yourself, but you do it in a REMS-certified healthcare setting while a staff member watches. Blood pressure, alertness, and breathing are checked before and after. You stay for at least two hours. Someone else drives you home, and you do not drive again until the next day, after a restful sleep.[1,4]

The trials show that symptoms improve, on average, for some people. Not everyone responds. Benefit can fade. And the label is explicit that Spravato has not been shown to prevent suicide.[1,5,8]

Spravato is not the same thing as ketamine

This is the single most common confusion, and it matters for safety, cost, and what any of the evidence means.

Esketamine is the S-enantiomer of ketamine — one of the two mirror-image forms of the same molecule. Racemic ketamine, the kind given by IV, contains both the R and the S forms. The two are chemically related the way your left hand is related to your right. That relationship does not make them interchangeable.[1,12]

A Spravato device delivers 28 mg in two sprays — one in each nostril. A full 56 mg treatment uses two devices; 84 mg uses three. There are five minutes between devices.[1]

Those milligram numbers should never be converted into an IV ketamine dose. The route, the absorption, the drug itself, the metabolites, and the speed of delivery are all different. For the infusion side of this — its own evidence, its own risks, and its own regulatory footing — see the full IV ketamine guide.

Spravato is a Schedule III controlled substance, meaning it has an accepted medical use alongside a recognized risk of misuse and dependence. It is not an ordinary nasal spray, and it is not a take-home medicine.[1,13,31]

What the FDA has actually approved

The two indications are not variations on a theme. They carry different rules:

If you are in danger right now

• If you may act on suicidal thoughts, or you cannot keep yourself safe, call 911 or go to the nearest emergency department.

• In the United States, call or text 988 for the Suicide & Crisis Lifeline.

• Neither Spravato nor IV ketamine replaces urgent evaluation or a hospital stay when one is needed.[18]

What Spravato is not approved for

The label itself states only two exclusions outright: Spravato is not approved for use in children, and it is not approved as an anesthetic agent — its safety and effectiveness for anesthesia have not been established.[1]

Everything else follows from the fact that the approved indications stop at those two adult depression uses. So Spravato is also not FDA approved for bipolar depression, psychotic disorders, PTSD, OCD, chronic pain, or substance-use disorders — not because the label rules them out by name, but because no application was ever approved for them.

Some off-label prescribing is lawful and sometimes reasonable — the FDA itself explains that a licensed prescriber may use an approved drug outside its labeling.[33] But an off-label use sits outside what the FDA reviewed, and the honest framing is that nobody has shown it works for those conditions.

One more boundary that gets crossed constantly in marketing: evidence for IV ketamine is not evidence for Spravato. Neither is evidence for compounded intranasal ketamine, oral ketamine, or ketamine-assisted psychotherapy. Different product, different route, different dosing pattern, different safety system.

“Treatment-resistant” is a label, not a diagnosis

People are often told the FDA has a definition. It does not. The label names the condition and moves on. The wording everyone quotes comes from the Clinical Studies section, describing who was allowed into the trials: patients who had “not responded adequately to at least two different antidepressants of adequate dose and duration” in the current episode.[1]

Note different — two distinct medicines, not two attempts at the same one.

Even as a trial-entry rule, that sounds clean. In practice it rarely is. Trials and guidelines differ on how carefully they check dose, duration, adherence, the accuracy of the diagnosis, and whether psychotherapy or an augmentation strategy was ever tried.

Before anyone accepts the term, a few questions are worth asking:

• Were those two antidepressants actually taken at a therapeutic dose, for long enough? Why antidepressants take time explains what an adequate trial looks like.
• Is the diagnosis right? Bipolar depression treated as unipolar depression is one of the most common reasons treatment appears to fail — and the pattern is easy to miss. That is the subject of why bipolar disorder gets called depression first.
• Is something else keeping the symptoms alive — a thyroid problem, sleep apnea, anemia, alcohol, a medication side effect, chronic pain, or a life situation that would flatten anyone?

None of this is a reason to delay care. It is a reason to make sure the door being opened is the right one.[1,14,15]

How it may work — and where the map runs out

Glutamate is the brain’s main excitatory messenger, and NMDA receptors are one of the receptor types it acts on. The label describes esketamine as a non-selective, non-competitive antagonist of the NMDA receptor — which it calls an ionotropic glutamate receptor. That much is established.[1]

What happens after that is where confident explanations outrun the evidence. Researchers have proposed a chain: shifts in glutamate signaling, increased activity through AMPA receptors, downstream changes involving BDNF and mTOR, new synaptic connections, and altered activity across brain networks. Much of that chain was mapped in animal and cell studies. Human imaging, electrical, and drug-interaction studies add real supporting evidence for individual steps — but no one has demonstrated the whole pathway in people.[12,16]

One caveat that belongs here, by the same standard this article applies everywhere else: most of that mechanism research studied racemic ketamine and its metabolites, not esketamine specifically.[12,16]

The FDA label does not hedge about this. It states that the mechanism by which esketamine exerts its antidepressant effect is unknown.[1]

Think of an old sea chart. The coastline is surveyed in ink because ships sailed it and measured it. The interior is sketched in dotted lines, drawn from second-hand accounts. Both appear on the same beautiful map, and only one of them is knowledge.

Zoom

One correction worth making early, because patients are often told the opposite: dissociation is not proof that the medicine is working. Feeling far away from the room is a side effect. It is not a signal of benefit, and its absence is not a sign of failure.[12,16]

What the body does with it

About 48% of an intranasal dose reaches the bloodstream compared with the same dose given intravenously. Blood levels peak 20 to 40 minutes after the last spray of a treatment session, though exposure varies widely between people.[1]

The drug distributes widely — the mean steady-state volume of distribution after intravenous administration is 709 liters, and 43% to 45% binds to blood proteins. The liver enzymes CYP2B6 and CYP3A4 do most of the initial work of breaking it down, with smaller contributions from CYP2C9 and CYP2C19. Esketamine becomes noresketamine, then other metabolites, most of which leave in urine. Less than 1% of a nasal dose is excreted unchanged.[1]

After intranasal dosing, blood levels fall in two phases: a rapid drop over the first two to four hours, then a mean terminal half-life ranging from 7 to 12 hours. Clearance after intravenous administration is about 89 liters per hour.[1]

A few practical consequences:

• Moderate liver impairment raises exposure and may call for a longer monitoring period. Severe liver impairment has not been studied, and use is not recommended.[1]
• For kidney impairment, the label gives no dose-adjustment instruction, and there is no clinical experience in patients on dialysis.[1]

And one conceptual point that gets lost constantly: a blood-level peak is not the moment mood improves, and a half-life is not a treatment schedule. In the trials, the group difference in depression scores persisted across dosing intervals far longer than the drug remains measurable in blood.[1,5] A brief exposure may start changes that outlast it — which is plausible, and still not fully explained.

Before the first dose

A good evaluation starts further back than the prescription.

The diagnosis. Confirm major depression, gauge severity and function, and review what has actually been tried — which medicines, at what doses, for how long, taken how consistently, alongside what therapy. Screening should also cover bipolar symptoms, psychosis, substance use, trauma, sleep, and medical contributors.[14,15]

The medical review. Blood pressure and cardiovascular history matter most, along with any history of bleeding in the brain, aneurysms or abnormal blood-vessel connections, breathing risk, liver disease, urinary symptoms, pregnancy plans, and breastfeeding. The medication list should be read with attention to stimulants, monoamine oxidase inhibitors, opioids, benzodiazepines, alcohol, and anything else sedating. Nothing on that list should be stopped or changed on your own.[1]

Blood pressure before a dose. A reading above roughly 140/90 mm Hg is a label guide for weighing benefit against risk and possibly delaying that day’s dose. It is a prompt for judgment, not an automatic disqualification — the actual contraindications are listed further down.[1]

The plan. Before starting, it is worth settling what improvement would count, how it will be measured, when it will be reassessed, and what happens if the answer is that this is not helping.

What a treatment day is actually like

The visit works like a canal lock. A boat does not simply pass through; it enters, the gate closes, the water is allowed to settle, and only then does the far gate open. The waiting is the mechanism, not a delay in it.

Before you arrive. No food for at least two hours. No liquids for at least 30 minutes. If you need a nasal corticosteroid or decongestant that day, take it at least one hour before.[1]

On arrival. Staff check your blood pressure before anything else.[1]

Dosing. You hold the device and spray it yourself, one spray per nostril, while a staff member watches. Five minutes pass, then the next device. Two devices for 56 mg, three for 84 mg. The medicine never leaves the building with you.[1]

Monitoring. Blood pressure is rechecked at about 40 minutes — near the usual peak — and monitored for at least two hours after the dose, then as clinically warranted until it comes back down. Alertness, breathing, and dissociation are watched across that same two hours, including blood oxygen on a pulse oximeter.[1,4]

How it can feel. Detached, dreamy, dizzy, sleepy, nauseated, anxious, unsteady. The room may look changed. Time may stretch or compress. These effects usually peak during the monitored window and ease before discharge.[1]

Going home. After the monitoring period, a healthcare provider assesses you and decides when you are clinically stable and ready to leave — which includes seeing your blood pressure coming down. You need a ride. No driving, no machinery, and nothing requiring full alertness until the next day after a restful sleep — even if you feel completely normal an hour after leaving.[1]

Behind all of this sits the REMS, a federal Risk Evaluation and Mitigation Strategy. It requires certified healthcare settings and certified pharmacies, with a limited exception for certain inpatient pharmacies in the same location. Outpatients enroll before treatment. A prescriber must be onsite throughout administration and monitoring. A Patient Monitoring Form is documented and submitted after every outpatient dose, currently within seven calendar days.[4]

That is why “can I just get a prescription and use it at home?” has a one-word answer.

The labeled schedule

This describes the U.S. label. It is education, not dosing advice for any individual.[1]

For treatment-resistant depression, the label directs clinicians toward the least frequent schedule that maintains response or remission. Continuing care should follow measured benefit, tolerability, and burden — not momentum.[1]

How fast might it help?

In the pivotal treatment-resistant depression trials, the first planned group comparison was often at 24 hours. In the positive add-on trial, most of the average four-week difference was already visible at 24 hours, though the groups did not differ at every later timepoint.[5] In the monotherapy trial, the groups separated by Day 2 and again at Day 28.[8]

Those are averages across hundreds of people, not forecasts for one. Some people feel nothing after a first dose, or after a full four-week induction. Others improve and later relapse.

And the 20-to-40-minute absorption peak is not when depression lifts. Judging a course of treatment usually means completing the induction and measuring symptoms and function, unless safety requires stopping sooner.[1,5,8]

What the pivotal trials found

The positive add-on trial: TRANSFORM-2

227 adults who had already failed prior antidepressants were randomly assigned to flexible-dose Spravato or a placebo nasal spray for four weeks. Everyone in both groups also started a new oral antidepressant on the day of randomization — so this trial compared antidepressant plus Spravato against antidepressant plus placebo spray.

Depression was measured with the MADRS, which runs from 0 to 60. Lower is better.

Two things about that table. The first pair of response and remission figures are completer rates — they count only the people who finished four weeks. Counting everyone who was randomized, dropouts included, shaves several points off each of them. And all of these figures are descriptive: an earlier step in the trial’s statistical testing sequence meant these later outcomes could not be claimed formally.[5]

Look at the placebo column. Those people also improved by nearly 16 points — on a newly started antidepressant, with frequent clinical contact and a nasal spray of their own. That is most of the movement seen in the Spravato group.

The trial that missed: TRANSFORM-1

TRANSFORM-1 is the study that rarely makes it into a brochure, and it belongs in any honest account.

The planned 84 mg comparison did not meet its primary endpoint. The adjusted difference was 3.2 points, with a confidence interval running from a 0.45-point disadvantage to a 6.88-point advantage (p=0.088). The 56 mg comparison was nominally positive, but because of the order in which the statistical tests were run, it could not be treated as confirmatory.[6]

Monotherapy without an antidepressant

The trial supporting the 2025 monotherapy expansion randomly assigned 378 adults after an antidepressant-free period — 197 to placebo, 86 to 56 mg, and 95 to 84 mg. These are the numbers the FDA label reports.

One design detail worth knowing, because it is unusual: the trial ran two prespecified randomization lists in parallel, splitting participants before assignment according to whether they met a site-blinded symptom-severity threshold. The 378 above are the group that met it and formed the efficacy analysis. Nobody was dropped after randomization.

Note that this trial used a stricter remission cutoff than the adjunctive studies, so those remission percentages are not comparable across trials.[8] The manufacturer sponsored the study, and several authors were employees or reported related patents or financial ties — which does not invalidate the result, but is part of reading it.

Relapse prevention: SUSTAIN-1

SUSTAIN-1 used an enriched withdrawal design. Everyone first received Spravato with an oral antidepressant. Only those who reached stable response or remission moved into the randomized phase, where they either continued Spravato or switched to a placebo spray while staying on the oral antidepressant.

This is genuinely good evidence for one specific thing: continuing Spravato, alongside an oral antidepressant, helps selected people who already responded stay well. It does not prove long-term monotherapy maintenance, it says nothing about people who never responded, and it cannot speak for the people trials excluded.[9]

Long-term follow-up: SUSTAIN-3

SUSTAIN-3 followed 1,148 participants openly for up to 79 months — 3,777 participant-years of exposure, with a mean of 42.9 months. Everyone remained on an oral antidepressant. Symptoms stayed improved on average among those who continued, and no new safety signal emerged.[10]

The caveat is structural rather than nitpicking: there was no blinded control group, and the study population is by definition people who tolerated the treatment and chose to stay. That design can produce reassuring long-term safety data. It cannot demonstrate long-term efficacy.

Older adults: TRANSFORM-3

TRANSFORM-3 enrolled adults 65 and older, and its primary result did not reach statistical significance — an estimated MADRS difference of 3.6 points, confidence interval from a 0.07-point disadvantage to a 7.20-point advantage (p=0.059).[7]

The trial did include a comparison by age band that was planned before the results were known. Among people 65 to 74, the MADRS difference was 4.9 points in Spravato’s favor (95% CI 0.89 to 8.96, nominal p=0.017). Among people 75 and older it was 0.4 points, with an interval running from a 9.50-point disadvantage to a 10.38-point advantage (nominal p=0.930).

Read that second interval carefully: it is so wide that it is compatible with almost anything. Both p values are nominal, sitting outside the trial’s confirmatory testing plan, and a further comparison by age at depression onset was added only after the results were seen. This suggests a pattern rather than proving one. Evidence in frail older adults, and in people carrying several medical conditions, remains thin.[7]

Acute suicidal thoughts: ASPIRE I and II

These two trials studied adults in the hospital. Everyone received full standard care plus a newly started or optimized oral antidepressant, then Spravato or placebo on top.

At 24 hours, the Spravato groups showed a MADRS advantage of 3.8 points in ASPIRE I and 3.9 points in ASPIRE II.[11,17]

But the planned clinician-rated measure of suicidality severity was not significantly different in either trial. Depression scores improving and suicidal thinking changing are two different outcomes, and only one of them moved.

One further gap worth naming. Measures of function, disability, and quality of life — the Sheehan Disability Scale, the EQ-5D — did move alongside symptom scores. But they sat low in the testing hierarchy: in TRANSFORM-2 the statistical sequence stopped before them, so they could not be formally tested at all.[2,5] And no pivotal trial was designed to show a return to work, a benefit to caregivers, fewer hospitalizations, fewer suicide attempts, or lower mortality.

So how strong is the evidence, really?

Short-term symptom improvement: moderate certainty, for the specific groups studied. Several randomized trials show a small-to-moderate average benefit. One acute fixed-dose trial and the dedicated older-adult trial missed their primary endpoints. And placebo spray plus a newly started antidepressant plus frequent clinical contact produced large improvements of its own — roughly 15 to 16 MADRS points across four weeks in the two adjunctive trials.[5,6,19]

That pattern did not hold everywhere, which is worth knowing before treating it as a rule. In the older-adult trial the placebo group improved by 6.3 points.[7] In the monotherapy trial, where the comparison group got a placebo spray and no oral antidepressant at all, it also improved by 6.3 points.[8] The size of a placebo response depends heavily on what is sitting underneath it.

Blinding is a real problem here. Dissociation, sedation, and altered perception can tell participants which group they are in. Expectations shape ratings. Most pivotal studies were industry-sponsored, and they excluded many people with unstable medical illness, psychosis, significant active substance-use disorder, or immediate suicide risk outside the ASPIRE program.[5,6,7,8,19] In the individual-patient-data review, about 75% of the esketamine group and 50% of the control group correctly guessed their assignment by Day 28 — which is what functional unblinding looks like when someone measures it.[19] None of that erases the findings. It lowers confidence that trial averages transfer cleanly to the person sitting in a clinic.

Relapse prevention: randomized, but enriched. Long-term data: mostly open-label. Controlled long-term monotherapy maintenance: still not established.

A 2025 registered-report review re-analyzed individual patient data from the randomized trials. Across five trials of Spravato added to an antidepressant, it found a 2.94-point MADRS advantage at four weeks (95% CI 0.48 to 5.39), graded moderate certainty — statistically significant, but less than half the 6.5-point difference the pivotal trials themselves had treated as clinically meaningful. The reviewers called its clinical relevance unclear.

The review also noted a larger effect of about 6.3 points, but that came from a single monotherapy trial whose individual data they could not obtain, and they warned that excluding people who improved during the drug-free lead-in, plus probable unblinding, may have inflated it.[19]

Common side effects, and what they feel like

In short-term add-on trials, reported adverse events included:[1]

In the short-term monotherapy trial, with the 56 mg and 84 mg groups combined, reports included dissociation in 28% versus 4%, nausea in 25% versus 8%, dizziness in 22% versus 7%, and headache in 19% versus 9%.[1]

In plain terms: far from the room, heavy, spinning, sleepy, numb, or sick to the stomach.

One number worth understanding before you encounter it elsewhere. When trials used formal rating scales rather than adverse-event reporting, they found sedation in 48% to 61% and dissociation or perceptual change in 61% to 84%.[1] Those are much higher figures, and they are measuring something different — a scale asks everyone, while an adverse-event table records what got reported. The two sets of numbers should never be mixed.

Most acute effects settle during the observation period — nausea and vomiting typically occur on the dosing day and resolve the same day, and dissociation is likewise transient. Not all of them are mild, though. Vomiting, marked anxiety, severe dizziness, or prolonged sedation can push back the discharge check.[1]

Serious risks, and who should not take it

The boxed warning covers sedation, dissociation, respiratory depression (breathing that becomes too slow or too shallow), abuse and misuse, and suicidal thoughts and behaviors. That last item comes from pooled antidepressant-class data in children and young adults — it is not a finding from Spravato’s own trials.[1]

Blood pressure

The label does not hedge on this one: Spravato raises blood pressure at every recommended dose. The rise peaks about 40 minutes after dosing and lasts roughly four hours.

Across trials, 3% to 19% of Spravato-treated patients — versus 1% to 4% on placebo — had a marked increase within the first 90 minutes after a dose, on at least one occasion during the first four weeks. “Marked” means a rise of at least 40 mm Hg systolic, at least 25 mm Hg diastolic, or both.[1]

The actual contraindications

Spravato is contraindicated in:[1]

• Aneurysmal vascular disease — including the thoracic or abdominal aorta, the vessels inside the skull, and the peripheral arteries, meaning any artery outside the heart and brain, not only those in the arms and legs
• Arteriovenous malformation
• A history of intracerebral hemorrhage
• Hypersensitivity to esketamine, ketamine, or any excipient

Other cardiovascular and cerebrovascular conditions, psychosis, and a history of substance use all call for careful assessment before treatment, with the label asking whether the benefit outweighs the risk in each case.[1] Bipolar disorder is not addressed in the label at all — but it deserves a careful diagnostic review before anyone starts, for the reasons above. None of these is an automatic contraindication, and none should be presented as one.

Sedation, breathing, and thinking

Deep sedation can occur. Loss of consciousness was reported in roughly 0.3% to 0.4% of treated patients in trials, and post-approval reports include respiratory depression and rare respiratory arrest. This is precisely why pulse oximetry and two hours of observation are required rather than suggested.[1]

Testing shows short-term effects on attention, judgment, thinking, and reaction speed after a dose. Open-label cognitive testing at one and three years was generally stable — reassuring, though an uncontrolled extension cannot prove that long-term cognitive harm never occurs.[1,10]

Bladder, liver, pregnancy, and misuse

Urinary symptoms were more common with Spravato than placebo, and no esketamine-related interstitial cystitis was observed in studies lasting up to a year. That is not the same as zero bladder risk. New pain on urinating, urgency, frequent night-time urination, or difficulty passing urine should be evaluated.[1]

Liver. Moderate impairment increases exposure; severe impairment was not studied and is not recommended. Warnings about bile-duct injury from repeated ketamine injection belong to the ketamine injection label, and copying them onto Spravato is not accurate.[1,20]

Pregnancy and breastfeeding. Spravato is not recommended during pregnancy because fetal harm is possible, and the label advises against breastfeeding during treatment. Anyone pregnant, planning pregnancy, or breastfeeding should discuss the evidence and the alternatives directly.[1]

Misuse and dependence are possible with any Schedule III medicine. REMS supervision removes the possibility of diversion from a home supply; it does not reduce the risk to zero. A personal or family history of substance use calls for a careful, non-judgmental review and ongoing check-ins — not exclusion by default.[1]

Interactions. CNS depressants — opioids, benzodiazepines, alcohol — can deepen sedation. Stimulants and monoamine oxidase inhibitors can raise blood pressure. Any change belongs with the treating clinicians, together.[1]

Spravato and suicidal thoughts

This deserves its own section, because it is the part most often overstated.

The second indication is narrow: depressive symptoms in adults with major depression who have acute suicidal thoughts or behavior, treated together with an oral antidepressant. In ASPIRE I and II, depression scores improved more at 24 hours, while the planned clinician-rated suicidality measure did not differ significantly.[1,11,17]

The label states directly that effectiveness in preventing suicide, or in reducing suicidal thoughts or behavior, has not been demonstrated.[1]

What that means practically: Spravato does not replace repeated suicide-risk assessment, a safety plan, the involvement of family or other support, or treatment of the underlying illness. It does not replace emergency care or a hospital stay. If you are considering it during a crisis, urgent mental health care covers what to do while you wait.

Spravato compared with IV ketamine

How to read that table. The regulatory and operational rows are simply official facts. The IV column is compressed here; the IV ketamine guide covers the infusion trials, the clinic-safety questions, and the liver and bladder warnings in full.

The comparative-effectiveness question is different. It rests almost entirely on observational comparisons. The one randomized trial in the 2025 review compared two intravenous formulations rather than the nasal spray, and was not pooled with the rest. That review’s pooled estimates found no significant difference — response odds ratio 1.26 (95% CI 0.92 to 1.71), remission 1.31 (0.93 to 1.86) — and its authors describe these as associations that are hypothesis-generating, while calling for large head-to-head randomized trials.[25,26]

Comparing each treatment against its own placebo across separate trials is context, not a head-to-head result. Anyone telling you one is definitively better than the other is filling in the dotted-line part of the map.

Practical tradeoffs

In Spravato’s favor: a standardized FDA-approved product, a defined dosing framework for adult treatment-resistant depression, randomized evidence for the actual product, and a REMS that sets a common safety floor no matter which clinic you walk into.

Against it: repeated clinic visits, at least two hours of observation each time, a ride home, next-day driving limits, prior authorization, genuinely unpleasant acute effects, and unresolved questions about long-term monotherapy maintenance.

Preferring a nasal spray to an IV is a legitimate preference. It is not evidence of better safety or greater benefit.

Where any of this lands depends on access to a certified site, medical risk, past treatment response, whether the relevant indication requires an oral antidepressant, work and caregiving obligations, and how a person feels about the visit itself. There is no universal winner here.

Cost, insurance, and access

Access information verified August 23, 2026.

Total cost is not just the medicine. It includes the evaluation, the drug, administration, the observation period, rating scales, lab work, copays or coinsurance, transportation, parking, and time away from work or caregiving.

Coverage varies by plan and by indication. Prior authorization commonly requires records, symptom scores, a REMS-certified site, and documentation of past adequate treatments. Some payer policies still lag behind the FDA’s 2025 monotherapy expansion. One current public policy — Aetna’s — recognizes treatment-resistant depression monotherapy, which is useful context but does not promise payment for any specific member.[27]

On the billing side, the CMS descriptors for G2082 and G2083 cover an established-patient outpatient visit with clinician supervision, the medication, and up to two hours of observation. G2082 covers up to 56 mg; G2083 covers more than 56 mg. J0013 identifies esketamine by the milligram. It replaced S0013 on January 1, 2026 and is flagged “not payable by Medicare” — which is a statement about the code, not about the drug. For Medicare, the medicine is paid inside the G2082 or G2083 bundle instead. Other payers may use J0013 or a different path, and a code existing never guarantees coverage.[29,30]

One item worth flagging because it still circulates: CMS article A59249 retired on December 18, 2025. It was regional billing guidance rather than national coverage policy, and it is not current 2026 policy.[32]

The manufacturer’s savings program is limited to REMS-enrolled adults with commercial or private insurance who owe money for the medication. It states that eligible patients may pay as little as $10 per treatment, with the annual benefit capped at the medication’s list price. Limits run to three devices per day and 23 devices in 24 days, with a one-time lifetime allowance of 24 devices in 24 days. Observation is not covered.

Anyone using a state or federal government-funded healthcare program is excluded — the program names Medicare, Medicaid, TRICARE, Department of Defense, and Veterans Administration as examples, not as the full boundary. Patients whose plan partners with SaveOnSP, and patients whose plan already eliminates their out-of-pocket cost, are also excluded, and monthly maximums may apply. Terms expire each calendar year and can change without notice.[30]

The single most useful thing to ask for: a written estimate listing the drug, the visit, the monitoring, and anything not covered.

Questions to ask a Spravato clinic

1. Is this setting currently certified in the Spravato REMS?
2. Who confirms the diagnosis and reviews my past treatments for adequacy?
3. Which indication applies to me — and does it require an oral antidepressant?
4. Who is the onsite prescriber medically responsible during treatment?
5. How do you monitor blood pressure, alertness, breathing, and oxygen?
6. What emergency equipment and transfer plan do you have?
7. How do you decide that recovery is adequate for discharge?
8. Which symptom and function measures will you track — and at what point would you stop for lack of benefit?
9. How will you coordinate with my regular prescriber and therapist?
10. What is the maintenance or tapering plan if I improve, or if I relapse?
11. What are the total estimated fees, and who handles prior authorization and appeals?
12. What transportation and next-day activity plan do I need to arrange?

Related reading

• IV ketamine for depression: what the infusions do, what the trials show, and how it compares with Spravato
• Why antidepressants take time, and how to make the first six weeks count
• TMS for depression: benefits, protocols, safety, and what the evidence really shows
• Why bipolar disorder gets diagnosed as depression first
• Urgent mental health care: finding the support you need right away
• Psilocybin: a once-sacred mushroom making its way into modern medicine

Frequently asked questions

Is Spravato the same as ketamine?

No. Spravato is a standardized nasal esketamine product — the S form only. Racemic ketamine contains both R and S forms and is usually given by IV in depression clinics and research. Doses and evidence do not transfer between them.[1,12]

What is Spravato FDA approved to treat?

Adult treatment-resistant depression, alone or with an oral antidepressant; and, with an oral antidepressant, depressive symptoms in adults with major depression and acute suicidal thoughts or behavior.[1]

Can Spravato be used without an oral antidepressant?

Yes — for the treatment-resistant depression indication, since January 2025. The acute-suicidal-symptoms indication still requires one.[1,3]

How fast might it help?

Some trials found an average group difference by 24 hours or Day 2. That is not a promise of relief after one dose. For many people the four-week induction result is more informative.[5,8]

How long does a visit take?

Monitoring alone is at least two hours. Add check-in, preparation, dosing with five-minute gaps between devices, recovery, and the discharge check, and the full visit runs meaningfully longer.[1,4]

What does dissociation actually feel like?

Often a sense of distance from your body or the room, altered time, dreaminess, numbness, or a feeling that things are not quite real. It is usually brief — and it does not predict whether the medicine will work.[1]

Can I drive myself home?

No. You need safe transportation, and driving or any hazardous task must wait until the next day after a restful sleep.[1]

Does Spravato prevent suicide?

It has not been shown to prevent suicide or to reduce suicidal thoughts or behavior. Urgent evaluation or hospitalization may still be necessary.[1]

Is Spravato addictive?

Misuse and dependence are possible. It is Schedule III and carries a boxed warning for abuse and misuse. Supervised clinic administration removes home-supply diversion but does not make the risk zero.[1,13,31]

How long does treatment continue?

For treatment-resistant depression the label provides an ongoing framework built around the least frequent dosing schedule that maintains remission or response — the dose stays 56 mg or 84 mg; it is the interval that stretches out. The right total duration is not knowable in advance, and benefit versus burden should be revisited over time.[1]

Does insurance cover it?

Some plans do, under specific criteria and usually with prior authorization. Coverage, copays, and the billing of drug versus monitoring all vary. Get it in writing before starting.[27,29]

Who is not a candidate?

The explicit contraindications are certain aneurysmal vascular diseases, arteriovenous malformation, a history of intracerebral hemorrhage, and hypersensitivity. Other conditions may call for caution and an individual review rather than a blanket rule.[1]

Bottom line

Spravato is a real, FDA-approved option for specific forms of adult depression, supported by several randomized trials and wrapped in a required safety system that exists for good reasons.

Some people get a meaningful benefit from it. Many do not. The negative trials are part of the record, the placebo and standard-care improvements were substantial, the side effects are not trivial, relapse happens, the access burden is significant, and the long-term picture has real gaps.

A sound decision starts where every sound psychiatric decision starts: a confirmed diagnosis, an accurate treatment history, a medical and safety review, goals you can actually measure, and an agreed plan for what happens next — whether it works, whether it does not, and how it would eventually end.

Educational disclaimer

Disclosure: Inland Psychiatric Medical Group offers Spravato at its clinics, and I practice through IPMG. This article covers a treatment my organization provides and is paid to provide. It is written as education, not as marketing, and it is not an offer of treatment.

This article is for education. It does not diagnose any condition, choose a treatment for anyone, or replace the judgment of the clinician who knows your history. Do not start, stop, or change any medication without your prescriber. If there is imminent danger, or you cannot keep yourself or someone else safe, call 911 or go to the nearest emergency department. In the United States, call or text 988, or chat at 988lifeline.org, for any mental-health crisis.[18] Every regulatory, numeric, and citation claim in this article was verified against primary FDA, REMS, and journal sources on August 23, 2026. Labels, approvals, payer policies, and program terms change; confirm current status before acting on anything here.

References

1. Janssen Pharmaceuticals, Inc. SPRAVATO (esketamine) nasal spray — full prescribing information, Medication Guide, and Instructions for Use. Prescribing information revised March 2026; Medication Guide revised January 2025. Hosted on DailyMed, U.S. National Library of Medicine, SPL version 19, updated July 29, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d81a6a79-a74a-44b7-822c-0dfa3036eaed. Accessed 2026-08-23.
2. U.S. Food and Drug Administration. Drugs@FDA: Spravato, NDA 211243 — approval history, letters, and reviews. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211243. Accessed 2026-08-23.
3. U.S. Food and Drug Administration. Supplement approval letter, NDA 211243/S-016 — monotherapy for adults with treatment-resistant depression. January 17, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/211243Orig1s016ltr.pdf. Accessed 2026-08-23.
4. U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategy (REMS) Document: SPRAVATO (esketamine) REMS. NDA 211243; most recent REMS update June 2026. https://www.accessdata.fda.gov/drugsatfda_docs/rems/Spravato_2026_06_24_REMS_Document.pdf. Accessed 2026-08-23. The FDA-approved REMS is the operative instrument and states “within 7 calendar days”; the manufacturer’s plain-language overview compresses this to “7 days.” Companion patient-facing materials: Janssen Pharmaceuticals, Inc. SPRAVATO REMS Program Overview, version June 2025. https://www.spravatorems.com/pdfs/REMSProgramOverview
5. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. PMID 31109201. doi:10.1176/appi.ajp.2019.19020172. ClinicalTrials.gov NCT02418585.
6. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630. PMID 31290965. doi:10.1093/ijnp/pyz039. ClinicalTrials.gov NCT02417064.
7. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression — TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141. PMID 31734084. doi:10.1016/j.jagp.2019.10.008. ClinicalTrials.gov NCT02422186.
8. Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2025;82(9):877-887. PMID 40601310. doi:10.1001/jamapsychiatry.2025.1317. ClinicalTrials.gov NCT04599855.
9. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial (SUSTAIN-1). JAMA Psychiatry. 2019;76(9):893-903. PMID 31166571. doi:10.1001/jamapsychiatry.2019.1189. ClinicalTrials.gov NCT02493868.
10. Zaki N, Chen LN, Lane R, et al. Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study. Int J Neuropsychopharmacol. 2025;28(6):pyaf027. PMID 40319349. doi:10.1093/ijnp/pyaf027. ClinicalTrials.gov NCT02782104 — the SUSTAIN-3 open-label extension.
11. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191. PMID 32412700. doi:10.4088/JCP.19m13191. ClinicalTrials.gov NCT03039192.
12. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621-660. doi:10.1124/pr.117.015198. https://pmc.ncbi.nlm.nih.gov/articles/PMC6020109/
13. U.S. Drug Enforcement Administration. Ketamine drug fact sheet. https://www.dea.gov/factsheets/ketamine. Accessed 2026-08-23.
14. Swainson J, McGirr A, Blier P, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the use of racemic ketamine in adults with major depressive disorder. Can J Psychiatry. 2021;66(2):113-125. PMID 33174760. doi:10.1177/0706743720970860. https://pmc.ncbi.nlm.nih.gov/articles/PMC7918868/
15. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. 2022. https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFinal508.pdf. Accessed 2026-08-23.
16. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801-811. PMID 29532791. doi:10.1038/mp.2017.255.
17. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31. PMID 32861217. doi:10.1093/ijnp/pyaa068. ClinicalTrials.gov NCT03097133.
18. 988 Suicide & Crisis Lifeline. Get Help. https://988lifeline.org/get-help/. Accessed 2026-08-23.
19. Naudet F, Pellen C, Fodor LA, et al. Efficacy and safety of esketamine for “treatment resistant depression”: registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials. BMC Med. 2025;23(1):677. PMID 41310599. doi:10.1186/s12916-025-04435-x. PROSPERO CRD42021290721.
20. Par Health USA, LLC. KETALAR (ketamine hydrochloride) injection — prescribing information. Revised March 2026. Hosted on DailyMed, U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e8f864-8b8a-4e7e-8439-e510d3107063. Accessed 2026-08-23.
21. Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456-466. PMID 29870457. doi:10.1097/AAP.0000000000000806. Cited here only for general infusion-safety principles; it is a pain-medicine guideline, not a psychiatric one.
22. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. doi:10.1176/appi.ajp.2013.13030392. https://pmc.ncbi.nlm.nih.gov/articles/PMC3992936/
23. Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25(7):1592-1603. PMID 30283029. doi:10.1038/s41380-018-0256-5.
24. Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-409. PMID 30922101. doi:10.1176/appi.ajp.2018.18070834.
25. Elmosalamy A, Tarikogullari I, Patarroyo-Rodriguez L, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Ther Adv Psychopharmacol. 2025;15:20451253251394127. PMID 41244961. doi:10.1177/20451253251394127. Pooled response OR 1.26 (95% CI 0.92-1.71) and remission OR 1.31 (95% CI 0.93-1.86), neither statistically significant; the evidence base is almost entirely observational.
26. 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. Contemp Clin Trials. 2026;164:108273. PMID 41780747. doi:10.1016/j.cct.2026.108273. ClinicalTrials.gov NCT06713616 — Yale University with the Patient-Centered Outcomes Research Institute; recruiting, no results posted as of August 2026.
27. Aetna. Esketamine (Spravato) — Clinical Policy Bulletin 0950. https://www.aetna.com/cpb/medical/data/900_999/0950.html. Accessed 2026-08-23. One payer’s policy, cited as an example. It does not establish coverage for any individual member.
28. Massachusetts General Hospital. Ketamine Clinic for Depression — treatment options and cost. Archived February 18, 2026; the page was subsequently removed and now redirects to a Mass General Brigham service page carrying no pricing. https://web.archive.org/web/20260218003156/https://www.massgeneral.org/psychiatry/treatments-and-services/ketamine-clinic-for-depression. Accessed 2026-08-23. Archived text: “Ketamine: $550 per infusion (ketamine is currently not covered by most insurances and should be considered an out-of-pocket expense).” One academic center’s published pricing at one point in time, not a national average. Current program information: https://www.massgeneralbrigham.org/en/services/ketamine.
29. Centers for Medicare & Medicaid Services. HCPCS Quarterly Update — Alpha-Numeric HCPCS File. https://www.cms.gov/medicare/coding-billing/healthcare-common-procedure-system/quarterly-update. Accessed 2026-08-23.
30. Johnson & Johnson. SPRAVATO withMe savings program — requirements and terms. April 2026 (cp-337003v8). https://www.spravatohcp.com/savingsrequirements. Accessed 2026-08-23.
31. Electronic Code of Federal Regulations. 21 CFR 1308.13(c)(7) — Schedule III, ketamine. https://www.ecfr.gov/current/title-21/chapter-II/part-1308/section-1308.13. Accessed 2026-08-23.
32. Centers for Medicare & Medicaid Services. Billing and Coding: Esketamine (A59249). Retired December 18, 2025. https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleid=59249. Accessed 2026-08-23.
33. U.S. Food and Drug Administration. Understanding unapproved use of approved drugs “off label.” https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label. Accessed 2026-08-23.

If you or someone you know is in crisis

• Call 911 or go to your nearest emergency room for any life-threatening emergency.
• 988 Suicide & Crisis Lifeline — call or text 988, available 24/7. En español: marque 988 y oprima 2. Veterans: 988 and press 1, or text 838255.
• Crisis Text Line — text HOME to 741741.
• The Trevor Project (crisis support for LGBTQ+ young people) — call 1-866-488-7386, or text START to 678-678.
• National Sexual Assault Hotline (RAINN) — call 1-800-656-HOPE (4673) or text HOPE to 64673; free, confidential, 24/7. Online chat at RAINN.org/hotline.
• National Domestic Violence Hotline — call 1-800-799-SAFE (7233) or text START to 88788; 24/7, help in 200+ languages. Online chat at TheHotline.org. If your phone or computer may be monitored, calling from a safer device is an option.
• Riverside County — Inland SoCal Crisis Helpline 951-686-HELP (4357), 24/7 (Inland SoCal United Way / 211+, in partnership with RUHS-BH); Community Access, Referral, Evaluation and Support (CARES) Line 800-499-3008, 24/7.
• San Bernardino County — Access Unit (Behavioral Health Helpline) 888-743-1478, 24/7; Mobile Crisis/CCRT 800-398-0018 (24/7, all ages) or text 909-420-0560. Arrowhead Regional Medical Center (ARMC) has a dedicated walk-in adolescent psychiatric ER (ages 13–17).
• Children under 13 — call 911 for immediate danger, contact your county's mobile crisis team (they respond to all ages), or go to the nearest pediatric emergency room.
• California Peer-Run Warm Line (non-crisis — someone to talk to) — call or text 1-855-600-WARM (9276); daytime and evening hours, not a 24/7 line.
• NP Fady (non-emergency) — for routine scheduling or questions, call (909) 707-6261. This line is not monitored for emergencies.