Esketamine for Treatment-Resistant Depression: How It Works

Esketamine for treatment-resistant depression is delivered as Spravato, a nasal spray and the first FDA-approved ketamine-derived medication for this condition. The Food and Drug Administration approved Spravato in March 2019 for adults who have not responded adequately to at least two other antidepressants. It works through a different biological pathway than standard antidepressants such as SSRIs and SNRIs, and clinical trials report measurable effects within 24 hours of the first dose for many patients. Esketamine is administered only in certified healthcare settings under direct medical observation as part of a federal safety program. This guide explains how esketamine works in the brain, who qualifies for treatment, what the dosing schedule and monitoring program involve, and the safety considerations a prescribing clinician reviews before starting therapy.

Ketamine is a chiral molecule, meaning it exists as two mirror-image forms called enantiomers: S-ketamine (esketamine) and R-ketamine (arketamine). Racemic ketamine, the form used in IV infusions and compounded ketamine treatments, is a 50-50 mixture of both. Esketamine binds more potently to the NMDA receptor, a glutamate receptor involved in synaptic plasticity, than its mirror-image counterpart.

That pharmacological difference is part of why esketamine was developed and pursued as a separately approved medication rather than seeking FDA approval for the racemic mixture itself. Racemic ketamine remains FDA-approved only as an anesthetic, so its use for depression is off-label, meaning clinicians prescribe it based on clinical judgment and published research rather than an FDA-reviewed depression indication. For a closer side-by-side breakdown, see our guide on esketamine vs. racemic ketamine.

Spravato was approved in March 2019 for treatment-resistant depression in adults, for use in conjunction with an oral antidepressant. A second indication followed in 2020, covering adults with major depressive disorder who are experiencing acute suicidal ideation or behavior. In 2025, the FDA expanded Spravato's approval to include monotherapy use for treatment-resistant depression in certain patients, meaning it no longer needs to be paired with a second antidepressant in all cases.

Conventional antidepressants such as SSRIs and SNRIs act primarily on serotonin, norepinephrine, and dopamine systems, and they typically take several weeks to produce a full clinical effect. According to the National Institute of Mental Health, roughly one-third of people with major depressive disorder do not achieve remission even after trying multiple antidepressant medications.

Esketamine works through a different pathway. It blocks NMDA receptors located on inhibitory interneurons, which produces a temporary surge of glutamate signaling at AMPA receptors elsewhere in the brain. This cascade includes BDNF (brain-derived neurotrophic factor) release and activation of the mTOR pathway, both of which support rapid synaptic growth in prefrontal cortex circuits tied to mood regulation. For a broader look at this mechanism across ketamine treatments, see our guide on how ketamine works.

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

Spravato's primary FDA indication is treatment-resistant depression in adults, generally defined as an 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. A prescribing clinician completes a full medical and psychiatric evaluation before initiating treatment, reviewing cardiovascular health, current medications, and psychiatric diagnoses. For more on what that evaluation process typically covers, see our guide on getting started with ketamine treatment.

Spravato is dispensed only through a restricted distribution program called a Risk Evaluation and Mitigation Strategy (REMS), a type of safety program the FDA requires for certain medications with serious risks. Patients self-administer the nasal spray in a certified healthcare setting and remain monitored for at least two hours afterward, since dissociation and blood pressure changes are most likely during this window. For more on what that dissociative experience feels like, see our guide on understanding dissociation.

For the acute suicidal ideation indication, a separate dosing schedule applies, typically twice weekly for four weeks alongside comprehensive standard psychiatric care. General safety and side effect information across ketamine treatments is covered in our guide on safety and side effects.