Esketamine for Treatment-Resistant Depression: How It Works

Esketamine — sold under the brand name Spravato — is the first FDA-approved ketamine-derived medication for treatment-resistant depression. It is delivered as a nasal spray administered in certified healthcare settings under medical observation. For people who have not responded to multiple conventional antidepressants, esketamine offers a different mechanism of action and a faster onset than traditional pharmacotherapy.

This guide explains how esketamine works, who it is intended for, what the treatment course looks like, and the safety considerations every patient should review with a prescribing clinician.

What Is Esketamine?

Ketamine is a chiral molecule, meaning it exists as two mirror-image forms called enantiomers: S-ketamine (esketamine) and R-ketamine (arketamine). Racemic ketamine is a 50-50 mixture of both. Esketamine binds the NMDA receptor more potently than its counterpart, which is one of the reasons it was selected for development as a separately approved antidepressant.

The FDA approved Spravato in March 2019 for treatment-resistant depression in adults, used together with an oral antidepressant. A second indication was approved in 2020 for adults with major depressive disorder experiencing acute suicidal ideation or behavior. In 2025, Spravato received expanded approval as a monotherapy for treatment-resistant depression in certain patients.

How Esketamine Works in the Brain

Conventional antidepressants such as SSRIs and SNRIs act primarily on serotonin, norepinephrine, and dopamine systems. They take weeks to produce a full clinical effect, and roughly one-third of patients with major depressive disorder do not respond adequately even after multiple trials.

Esketamine works through a different pathway. By blocking NMDA receptors on inhibitory interneurons, it produces a temporary surge of glutamate signaling at AMPA receptors. This activates downstream molecular cascades — including BDNF release and mTOR pathway activation — that promote rapid synaptic growth in prefrontal cortex circuits involved in mood regulation.

In clinical practice, this translates to a faster onset. Studies suggest measurable antidepressant effects within 24 hours of the first dose for a meaningful proportion of patients, with continued benefit over a multi-week induction phase. Response rates in pivotal trials for treatment-resistant depression have generally been in the range of 50-70% when combined with an oral antidepressant, though placebo-controlled effect sizes are smaller and findings vary across studies.

Who Is a Candidate for Esketamine Therapy?

Spravato's primary FDA indication is treatment-resistant depression in adults. Treatment resistance is typically defined as inadequate response to at least two antidepressants of adequate dose and duration during the current depressive episode. The second indication covers depressive symptoms with acute suicidal ideation or behavior in adults with major depressive disorder.

Eligibility also depends on medical and psychiatric history. Esketamine is generally not appropriate for patients with:

• Uncontrolled hypertension or recent cardiovascular events such as myocardial infarction or stroke.
• Active psychosis or untreated bipolar disorder with current manic features.
• Aneurysmal vascular disease or arteriovenous malformation.
• A history of intracerebral hemorrhage.
• Hypersensitivity to esketamine or ketamine.
• Pregnancy, where risk-benefit must be carefully reviewed.

A prescribing clinician completes a full medical and psychiatric evaluation before initiating treatment.

The Treatment Course and REMS Program

Spravato is dispensed only through a restricted distribution program called a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA. Patients self-administer the nasal spray in a certified healthcare setting and remain monitored for at least two hours afterward.

A typical treatment course for treatment-resistant depression includes:

1. Induction phase: twice-weekly sessions for four weeks, starting at 56 mg with most patients increasing to 84 mg by the second dose.
2. First maintenance phase: weekly sessions for weeks five through eight.
3. Second maintenance phase: sessions every one to two weeks, individualized to response and tolerability.
4. Ongoing assessment: standardized depression rating scales and clinician review at each visit to guide continued therapy.
5. Discontinuation planning: gradual reduction in frequency for patients in stable remission, with relapse monitoring.

For the acute suicidal ideation indication, a separate dosing schedule applies — typically twice weekly for four weeks alongside comprehensive standard of care.

Esketamine vs Racemic Ketamine

Patients researching ketamine therapy often encounter both esketamine and racemic ketamine and want to know how they compare. Both share the same core NMDA-receptor mechanism, but they differ in route, regulation, and access.

Feature | Spravato (esketamine) | Racemic ketamine

FDA approval for depression | Yes (TRD, ASI) | No (off-label use)

Primary route | Intranasal spray | IV, IM, sublingual, oral

Setting | REMS-certified clinic only | Variable, including at-home oral/sublingual

Insurance coverage | Often covered for approved indications | Frequently not covered

Observation window | At least 2 hours per session | Varies by route and clinic

Side Effects and Long-Term Considerations

The most common acute side effects include dissociation, dizziness, nausea, sedation, vertigo, anxiety, and transient elevations in blood pressure and heart rate. Studies report that most acute effects resolve during the two-hour observation window. Patients cannot drive on the day of treatment and arrange transportation home.

Less common but more serious risks include severe hypertensive episodes, prolonged dissociation, and rare cases of urinary or bladder symptoms with long-term use. Long-term safety data continue to accumulate as the medication has been in clinical use for several years. Evidence is mixed on optimal duration of maintenance therapy.

Safety Summary

Esketamine is a powerful medication with both clear potential benefit for treatment-resistant depression and well-documented risks. It is not appropriate for everyone, particularly people with uncontrolled cardiovascular disease, active psychosis, untreated bipolar disorder, certain vascular conditions, or pregnancy. The required REMS observation window and the structured treatment course are part of how the medication is delivered safely. Talk to a licensed clinician about whether esketamine fits your medical history and treatment goals.