Ketamine for Depression: What Patients Need to Know

Every antidepressant approved before 2019 worked on the same system. Serotonin. Norepinephrine. Dopamine. The mechanisms varied, but the target was always the monoamine neurotransmitter system. For patients who responded to that approach, it worked. For the 30% who did not, it meant cycling through medications that were all, at the mechanistic level, variations on the same theme.

Ketamine changed the framework entirely.

Ketamine and its FDA-approved form esketamine (Spravato) target the glutamate system, specifically NMDA receptors, through a mechanism that has nothing in common with conventional antidepressants. The clinical implications of that difference are significant: rapid onset measured in hours rather than weeks, response in patients who have been treatment-resistant for years, and a growing body of evidence that extends beyond symptom relief to potential neuroprotective effects.

What This Page Covers

• What ketamine and esketamine are and how they differ from each other
• The mechanism: why glutamate targeting is clinically distinct
• The 2025 FDA monotherapy approval and what it changed
• IV ketamine versus esketamine: the clinical and practical differences
• What patients experience during sessions
• Who qualifies and who does not
• Side effects, risks, and what monitoring involves
• How ketamine fits into a broader treatment approach

Two Related But Different Treatments

The name “ketamine for depression” covers two distinct treatment options that are related but not the same.

Racemic IV ketamine: The original research compound. Given as an intravenous infusion at sub-anesthetic doses, typically 0.5 mg/kg over 40 minutes. Not FDA-approved for depression, making it off-label. Available from specialized ketamine clinics. Has extensive clinical experience from over two decades of research. Initial studies found that a single sub-anesthetic IV ketamine infusion rapidly improved depressive symptoms in individuals with major depression and bipolar depression, with antidepressant effects lasting three to seven days.

Esketamine (Spravato): The S-enantiomer of ketamine, delivered as an intranasal spray. FDA-approved for two indications with a third added in 2025. Administered only in certified healthcare settings under the Risk Evaluation and Mitigation Strategy (REMS) program. Backed by Phase 3 clinical trials and post-market safety data from over 140,000 patients worldwide.

Racemic IV ketamine is not FDA-approved for psychiatric conditions. Esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression in 2019 and for MDD with acute suicidal ideation in 2020.

The Mechanism: Why This Is Different

All SSRIs, SNRIs, TCAs, and MAOIs work by affecting the monoamine neurotransmitter system. They adjust levels of serotonin, norepinephrine, or dopamine by blocking their reuptake, inhibiting their metabolism, or otherwise altering their availability.

Ketamine and esketamine do not touch the monoamine system. They work by blocking NMDA (N-Methyl-D-Aspartate) glutamate receptors, which are a different type of receptor involved in synaptic plasticity, learning, and memory. Ketamine is an open channel blocker of ionotropic glutamatergic NMDA receptors. This mechanism is why it can produce antidepressant effects in patients who have not responded to multiple monoamine-targeting medications, since those patients likely have a pathology that is not primarily monoaminergic.

The downstream effect is rapid. Conventional antidepressants are slow-acting. Esketamine works by targeting glutamate, increasing levels of this abundant brain messenger, producing a greater impact on more brain cells at one time. This produces measurable changes in mood and cognition within hours, not weeks.

There is also evidence that ketamine has neuroprotective properties. Animal studies show that connections between brain cells diminish under chronic stress, but esketamine reverses these stress-related changes, not only preventing neurotoxic effects of depression on the brain but also appearing to have a growth-promoting effect.

The 2025 FDA Monotherapy Approval

In January 2025, the FDA approved a supplemental new drug application making esketamine the first and only monotherapy for treatment-resistant depression in adults. The approval was based on data demonstrating that Spravato alone met its primary endpoint at 4 weeks and led to rapid and superior improvement in depressive symptoms compared to placebo as early as 24 hours.

This was clinically significant. The earlier 2019 approval required esketamine to be used alongside an oral antidepressant. The 2025 monotherapy approval means that patients who cannot tolerate or do not respond to any oral antidepressant can now receive esketamine as a standalone treatment.

Esketamine’s three current FDA-approved indications:

1. Treatment-resistant depression, adjunctive to oral antidepressant (2019)
2. Major depressive disorder with acute suicidal ideation or behavior (2020)
3. Treatment-resistant depression, monotherapy (January 2025)

What the Clinical Evidence Shows

The TRANSFORM-2 trial, which provided core data for the 2019 FDA approval, was a Phase 3 randomized controlled trial (N=223). Intranasal esketamine in conjunction with a newly-initiated oral antidepressant significantly improved depressive symptoms after four weeks compared to placebo plus oral antidepressant, with a mean difference of four points on the MADRS.

The SUSTAIN trials examined relapse prevention. Patients who achieved remission or response during an induction phase were randomized to continue esketamine or switch to placebo. Those who continued esketamine had significantly lower relapse rates compared to those switched to placebo.

Intranasal esketamine, when used as an adjunct to oral antidepressants, shows greater efficacy in treating treatment-resistant depression compared to oral antidepressants and placebo alone.

The meaningful caveat: not everyone responds. Not every session produces transformative effects. For those who do respond, the speed and depth of response for patients with years of treatment-resistant depression is often described as unlike anything in prior treatment experience.

What to Expect: The Session

Esketamine is administered in a certified healthcare setting. Here is the sequence:

Before the session: No food for at least two hours. No drink except water for 30 minutes before. Blood pressure is measured. A dose of 56 mg or 84 mg is prepared.

During the session: The patient self-administers the nasal spray under supervision. Within 30 to 60 minutes, dissociative and perceptual effects begin. These include a sense of floating, altered time perception, and visual changes. Most patients describe them as unusual but not distressing. The prescriber and monitoring staff are present throughout.

After the session: Monitoring continues for at least two hours. Blood pressure is rechecked. Side effects typically resolve within this window. Dissociative effects tend to peak at around 40 minutes and wear off within two hours. Side effects are usually most intense during the first two sessions and tend to lessen after that.

Patients cannot drive on treatment days. A plan for getting home is required before each session.

The induction schedule: Twice weekly for four weeks. After assessment, the maintenance phase typically transitions to once weekly or once every two weeks.

Side Effects and Risks

The most clinically significant side effects of esketamine are dissociation and blood pressure elevation.

Dissociation: The perception of unreality, disconnection from body or surroundings, and altered sensory experience during and after administration. These are expected and known effects, not signs that something has gone wrong. They resolve within two hours.

Blood pressure: Esketamine temporarily raises blood pressure. Patients with pre-existing uncontrolled hypertension require assessment before starting.

Nausea and dizziness: Common during sessions. Taking medication with food beforehand, as recommended by the prescriber, reduces this.

Potential for misuse: Ketamine has known potential for abuse and misuse. The REMS requirement for supervised in-clinic administration is specifically designed to manage this risk. Esketamine is a Schedule III controlled substance.

Contraindications include uncontrolled hypertension, history of intracerebral hemorrhage, aneurysmal vascular disease, and active psychosis.

Who Qualifies

Esketamine is indicated for adults who:

• Have not had adequate response to at least two prior antidepressant treatments (TRD)
• OR have major depressive disorder with acute suicidal ideation or behavior
• Do not have contraindications (uncontrolled hypertension, certain cardiovascular conditions, psychosis)

A thorough clinical evaluation assesses prior treatment history, confirms the TRD diagnosis, and rules out contraindications. The evaluation also confirms that prior treatment failures were genuine adequate trials, not pseudo-resistance from insufficient duration or dose.

IV racemic ketamine from a ketamine clinic is available to a broader patient population since it is off-label and each clinic sets its own criteria. Some patients access IV ketamine before esketamine, others access it as an alternative when insurance does not cover Spravato.

What Ketamine Does Not Replace

Ketamine and esketamine are not permanent cures for depression. They produce response and remission in a meaningful proportion of treatment-resistant patients, but maintenance treatment is required to sustain that benefit.

For many patients, esketamine becomes part of an ongoing treatment regimen alongside other psychiatric care. The induction phase addresses the acute depressive state; ongoing medication management addresses the chronic condition.

SiggyMD’s scope does not include esketamine administration, which requires in-person certified settings. What SiggyMD provides is the ongoing medication oversight and daily monitoring for the anxiety and depression that may persist alongside or between ketamine treatments.

“Ketamine has genuinely changed what is possible for treatment-resistant patients,” says Daniel Montville, MD, Psychiatrist at SiggyMD. “I have seen patients who had not responded to six medications experience meaningful remission after an esketamine induction course. The mechanism is different enough that it can unlock response where everything else has failed. The practical question after that is maintenance: what keeps the response alive between sessions, and how do we track it?”

The anonymous intake at SiggyMD requires no name, email, or account to begin. A licensed prescriber reviews every treatment plan.

For more on treatment-resistant depression and what happens after multiple failed antidepressants, read our comprehensive guide on treatment-resistant depression. For the non-pharmacological alternative with strong evidence for TRD, read our guide on TMS for treatment-resistant depression.

Start your anonymous intake with SiggyMD to discuss depression treatment, medication management, and what options may be appropriate for your specific situation.

What Members Are Saying

RA

R.A., 48

Treatment-Resistant Depression

“I had tried seven antidepressants across eleven years. Some helped briefly. None lasted. My psychiatrist referred me for esketamine. The first session was disorienting but after the induction course I had two months without the flat gray nothing that had been my baseline. That had not happened in a decade. I stay on the maintenance schedule now because stopping is not something I want to risk.”

JS

J.S., 35

Major Depression with Suicidal Ideation

“The IV ketamine I received during a hospitalization was the only thing that cut through quickly enough to matter at the time. I understand now why the emergency use case is different from the maintenance case. After that crisis was stabilized, I was connected with a prescriber for ongoing care. The ketamine got me to a place where ongoing treatment could actually work.”

Member stories reflect real experiences. Names and identifying details have been changed to protect privacy. Results vary. You can begin anonymous intake without an account, name, email, or payment.

If you are in crisis or experiencing thoughts of self-harm, call or text 988. If there is immediate danger, call 911.

Sources

1. Kraus C, et al. Ketamine treatment for depression: a review. Translational Psychiatry. 2022;12:156.

2. Kumari P, et al. Exploring Esketamine’s Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review. Cureus. 2024;16(2):e53987.

3. Gerhard DM, Bhatt S. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49:41-50.

4. Johnson & Johnson. SPRAVATO approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. Press Release. January 2025.

5. Johns Hopkins Medicine. Esketamine for Treatment-Resistant Depression. Accessed June 2026.

6. National Institute of Mental Health. Major Depression. NIMH. Accessed June 2026.