Ketamine and Esketamine: Fast-Acting Depression Treatments Compared

When standard antidepressants fail, people with treatment-resistant depression don’t have time to wait weeks for relief. For many, the answer lies in two powerful but very different options: ketamine and esketamine. Both work fast-sometimes within hours-but they’re not the same. Understanding the differences can mean the difference between getting better and staying stuck.

How Ketamine and Esketamine Work

Ketamine was first approved in 1970 as an anesthetic. Decades later, doctors noticed patients who received it for surgery often reported feeling better emotionally-even before the anesthesia wore off. That led to research into its antidepressant effects. Esketamine is a purified version: just the (S)-enantiomer of ketamine. It’s not a new drug, just a more targeted piece of it.

Both work by targeting glutamate, a brain chemical involved in mood, memory, and learning. Unlike SSRIs that take weeks to boost serotonin, ketamine and esketamine quickly rebuild connections between brain cells. In some patients, the shift happens after the first dose. Brain scans show increased activity in areas tied to emotional regulation within hours. This isn’t just placebo-it’s measurable neuroplasticity.

Administration: IV vs Nasal Spray

How you get the drug matters as much as what you get. IV ketamine is delivered through a vein over 40 minutes in a clinic. You’re monitored the whole time. Esketamine comes as a nasal spray-Spravato®-and you self-administer it under supervision.

IV ketamine gives you full control over the dose. The standard is 0.5 mg per kilogram of body weight. Esketamine comes in fixed doses: 56 mg or 84 mg, sprayed into each nostril. That means less flexibility but also less variability. One big advantage of the nasal spray? No needles. For people terrified of needles or with difficult veins, that’s huge.

But there’s a catch. The body absorbs IV ketamine faster and more completely. With the nasal spray, only about 50% of the dose actually enters your bloodstream. That’s why esketamine often needs more frequent doses to catch up.

Efficacy: Which Works Better?

A 2025 study from Mass General Brigham tracked 153 adults with treatment-resistant depression. 111 got IV ketamine. 42 got esketamine. After a full course, ketamine users saw a 49.22% drop in depression scores. Esketamine users saw 39.55%. That’s not a small gap-it’s clinically meaningful.

Ketamine also acted faster. Many patients felt better after the first IV session. With esketamine, most needed at least two treatments before noticing real change. This matches earlier studies: ketamine consistently shows stronger and quicker effects across multiple time points-from 24 hours to eight weeks out.

But efficacy isn’t just about numbers. One patient told me: “I felt like myself again after ketamine, but I spent the whole hour in a fog.” Another said: “Spravato didn’t knock me out. I could drive home. I felt like I had my life back without losing my mind.”

Safety and Side Effects

Both drugs cause dissociation-feeling detached from your body or surroundings. But IV ketamine triggers it more often: 42.3% of patients reported it versus 28.7% with esketamine. Hallucinations, dizziness, and nausea are more common with IV too.

Esketamine’s side effects are milder on average, but it still carries risks. The FDA requires all patients to stay in the clinic for two hours after each dose. Why? Because blood pressure can spike, and dissociation can be scary-even dangerous-if you’re alone.

Abuse potential is real. Ketamine is a Schedule III controlled substance. So is esketamine. That means you can’t just pick it up at your local pharmacy. Both require strict oversight. But because esketamine is FDA-approved for depression, it’s easier to track and regulate in clinical settings.

Cost and Insurance

Money talks. A full course of eight IV ketamine infusions costs between $4,200 and $5,600. A comparable course of Spravato® runs $5,800 to $6,900. So why is esketamine more expensive? Because it’s branded. Ketamine is generic. No patent. No marketing. Just a drug in a bag.

Insurance coverage is the real kicker. About 67% of commercial plans cover Spravato®. Only 38% cover IV ketamine. That’s because Spravato® has FDA approval for depression. Ketamine doesn’t. Even though doctors use it legally off-label, insurers treat it like an experimental treatment.

Here’s the twist: IV ketamine is actually more cost-effective. A 2025 JAMA Psychiatry analysis found it delivers better value per quality-adjusted life year (QALY)-$14,327 versus $18,764 for esketamine. That means for every dollar spent, IV ketamine gives you more long-term health benefit.

Who Gets Which Treatment?

There’s no one-size-fits-all. Here’s how experts break it down:

• If you’re in crisis-suicidal, unable to function, losing hope-IV ketamine is often preferred. It works faster and stronger. Dr. John Krystal at Yale says it’s the best option for life-threatening depression.
• If you’re stable enough to manage outpatient care and want less intense side effects, esketamine makes sense. Dr. Christine Denny at Columbia says it’s better for long-term maintenance.
• If you hate needles, have poor veins, or anxiety around medical settings, the nasal spray is easier to tolerate.
• If you’re paying out-of-pocket, IV ketamine saves money. But if insurance covers Spravato®, the difference shrinks.

Real-world data backs this up. On PatientsLikeMe, 63% of IV ketamine users felt major relief within 24 hours. But 78% of esketamine users rated their overall experience as “good” or “excellent”-mostly because they didn’t feel like they’d been hit by a truck.

Access and Availability

Here’s the harsh truth: even if you qualify, you might not be able to get either treatment. Only 12.4% of U.S. counties have certified Spravato® centers. IV ketamine clinics are more common-1,087 as of 2025-but still concentrated in big cities.

Most rural areas have zero options. And even in cities, waitlists can be months long. Insurance approvals take time. Some clinics require you to try five or six other meds before they’ll even consider you.

There’s hope on the horizon. Janssen is testing a higher-dose Spravato® (112 mg). Phase 3 trials are underway for intramuscular ketamine-potentially a middle ground between IV and nasal. That could mean faster delivery without a needle.

Long-Term Outlook

Neither drug is a cure. Both require maintenance. After the initial six to eight sessions, most patients need booster treatments every few weeks. The 2024 follow-up study found 56% of IV ketamine responders stayed in remission at six months with maintenance. For esketamine, it was 49%.

Scientists are now looking for biomarkers to predict who will respond. Early EEG studies show that patients whose brain gamma waves increase in the frontoparietal region after treatment are more likely to improve. That could one day mean a simple brain scan tells your doctor whether ketamine is right for you.

For now, the choice comes down to this: speed and strength versus safety and convenience. Ketamine hits harder and faster. Esketamine is gentler and easier to fit into life. Neither is perfect. But for people who’ve lost years to depression, even one option that works is a lifeline.