When standard antidepressants don’t work, what’s next? For many people with treatment-resistant depression, the answer isn’t another pill-it’s ketamine or esketamine. These aren’t new drugs, but their use for depression is. Both work fast, often lifting symptoms within hours or days, not weeks. And that’s a game-changer for people who’ve spent years stuck in a dark place with no relief.

How They’re Different

Ketamine and esketamine are closely related, but not the same. Ketamine is the original drug, first approved in 1970 as an anesthetic. It’s a mix of two mirror-image molecules: (R)-ketamine and (S)-ketamine. Esketamine is just the (S)-ketamine part. That small difference changes how they act in the brain-and how they’re given.

Ketamine is usually given through an IV, slowly over 40 minutes. Esketamine is a nasal spray, called Spravato®, and is self-administered under medical supervision. The IV route lets doctors control the dose precisely. The nasal spray is easier to handle but delivers less of the active ingredient into the bloodstream.

Which One Works Better?

A major 2025 study from Harvard-affiliated McLean Hospital looked at 153 patients with treatment-resistant depression. 111 got IV ketamine. 42 got esketamine. The results were clear: IV ketamine worked faster and more strongly.

  • Ketamine users saw a 49.22% drop in depression scores after their full course.
  • Esketamine users saw a 39.55% drop.

And timing mattered. With ketamine, many felt better after just one session. With esketamine, it took two treatments before symptoms started to lift. That’s critical for people in crisis. If you’re suicidal or completely frozen by depression, waiting days for relief isn’t an option.

Side Effects and Safety

Both drugs can cause dissociation-feeling detached from your body or surroundings. It’s not fun, but it’s usually short-lived. In the same 2025 study:

  • 42.3% of ketamine users had dissociation.
  • Only 28.7% of esketamine users did.

That’s because esketamine is a purer molecule and doesn’t trigger as many brain pathways. But ketamine’s stronger effect also means it’s more likely to help someone who’s deeply depressed. The trade-off? More intense side effects for better results.

Esketamine has a better safety profile for outpatient use. It doesn’t require an IV line or deep sedation monitoring. Ketamine, on the other hand, needs providers trained in airway management. That’s why you can’t just walk into a clinic and get it-you need a specific setting.

A patient using esketamine nasal spray under medical supervision, with soft light and neural pathways symbolizing gradual emotional healing.

Cost and Access

Money matters. 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 would anyone pick the pricier option?

Insurance. In 2025, 67.4% of commercial insurers covered Spravato®. Only 38.2% covered IV ketamine. That’s because esketamine is FDA-approved for depression. Ketamine isn’t. Even though doctors have been using it safely for over a decade, insurers see it as "off-label." That means many patients pay out-of-pocket for ketamine-or can’t get it at all.

And access? Only 12.4% of U.S. counties have a certified Spravato® center. Fewer still offer IV ketamine. If you live outside a major city, finding treatment might mean driving hours-or waiting months.

Who Gets Which One?

Experts don’t agree on one-size-fits-all. Dr. John Krystal from Yale says ketamine is best for life-threatening depression. "If someone is actively suicidal, you need the fastest, strongest tool," he said in a 2025 editorial.

Dr. Christine Denny from Columbia sees esketamine differently. "It’s better for maintenance," she wrote. "People can come in, spray it, go home. It fits into life. Ketamine doesn’t."

Real-world feedback backs this up. On PatientsLikeMe, 63.2% of IV ketamine users said they felt relief within 24 hours. But 78.4% of esketamine users rated their overall experience as "good" or "excellent." Why? Less scary side effects. No needles. No long recovery time.

A split-panel scene showing the contrast between intense ketamine relief and gentle esketamine recovery, with a rising EEG wave transforming into a flying bird.

Long-Term Use and Future Options

Neither drug is a cure. Both need maintenance. After the initial phase, patients typically get booster doses every 1 to 3 weeks. One 2024 study found that 56.3% of ketamine responders stayed in remission at six months. Esketamine’s rate was 48.7%.

Science is moving fast. New research from November 2025 found that changes in brainwave patterns-specifically increased gamma power in the frontoparietal region-could predict who will respond. That means one day, a simple EEG might tell your doctor if ketamine will work for you, before you even start.

And new delivery methods are coming. Intramuscular ketamine is now in phase 3 trials. It could offer a middle ground: faster than nasal spray, less invasive than IV. If approved, it might change the game again.

What’s the Bottom Line?

If you’ve tried two or more antidepressants and still feel hopeless, ketamine or esketamine might be worth discussing. Neither is perfect. Ketamine works faster and stronger, but it’s harder to access and more expensive if insurance won’t cover it. Esketamine is more convenient, better covered, and gentler-but it may not be enough for the most severe cases.

Both require medical supervision. You can’t just buy them online. And both carry risks: dissociation, elevated blood pressure, potential for misuse. But for people who’ve run out of options, they offer something rare: hope that works in days, not months.

What’s clear? The future of depression treatment isn’t just another pill. It’s a shift-toward fast-acting, brain-targeted therapies that don’t just mask symptoms, but reset how the brain works. Ketamine and esketamine aren’t the end. They’re the beginning.

Can ketamine or esketamine be used at home?

No. Both require administration under medical supervision with mandatory 2-hour monitoring after each dose. This is due to risks like dissociation, elevated blood pressure, and potential for misuse. Even though esketamine is a nasal spray, it must be given in a certified clinic, not at home.

Is esketamine better than ketamine for long-term use?

Esketamine may be more practical for maintenance because it’s easier to schedule, less disruptive, and has fewer intense side effects. But ketamine shows slightly better long-term remission rates. The choice depends on your symptoms, access to clinics, and how well you tolerate dissociation.

Why isn’t IV ketamine FDA-approved for depression?

Ketamine is FDA-approved only as an anesthetic. Its antidepressant use is off-label because the manufacturer never submitted the full data package required for depression approval. Esketamine, developed as a new drug specifically for depression, went through the full approval process and got the green light in 2019.

Do I need to stop my current antidepressant to start ketamine or esketamine?

No. Esketamine is approved for use alongside oral antidepressants. For IV ketamine, most clinicians also keep patients on their existing meds. Stopping antidepressants suddenly can worsen symptoms. The goal is to combine treatments, not replace them.

How soon can I expect results from ketamine or esketamine?

Some people feel better within hours after the first IV ketamine dose. With esketamine, it usually takes two doses-about a week-before noticeable improvement. Most patients see clear changes by the fourth or fifth session.

Are there long-term side effects of using ketamine or esketamine?

Long-term data is still limited. Chronic, frequent use may affect bladder health or memory, but these risks are mostly tied to recreational misuse, not medical dosing. Under professional care, with controlled frequency, serious long-term effects are rare. Monitoring and dose limits help minimize risks.

Can I drive after receiving ketamine or esketamine?

No. Both drugs cause dizziness, dissociation, and impaired coordination. You must arrange for someone to drive you home after each session. You’re not allowed to drive or operate heavy machinery for at least 24 hours after treatment.

Is ketamine or esketamine covered by Medicare?

Medicare Part B covers Spravato® (esketamine) when administered in a certified clinic, as it’s FDA-approved. IV ketamine is generally not covered by Medicare because it’s off-label. Some Medicare Advantage plans may cover it on a case-by-case basis, but you’ll likely need prior authorization and proof of treatment failure.