Ketamine Therapy Is Now FDA-Approved. What Patients Should Know

Ketamine went from anesthetic to antidepressant in a single decade — and in 2019 became the first genuinely new class of depression treatment approved by the FDA in thirty years. Understanding what that approval actually means, who it covers, and where the evidence runs thin is important for anyone navigating treatment-resistant depression or tracking the broader psychedelic medicine pipeline.

The Drug That Became a Therapy

Ketamine was synthesized in 1962 and FDA-approved as an anesthetic in 1970. For decades it was used primarily in surgical settings and emergency medicine — valued for its ability to induce anesthesia without suppressing breathing. It also acquired a parallel life as a recreational drug ("Special K"), which complicated its scientific reputation.

The pivot toward psychiatry came from a 2000 study published in Biological Psychiatry by Berman et al., which found that a single low dose of IV ketamine produced rapid and significant antidepressant effects in patients with major depression — within hours, not weeks. This was remarkable. SSRIs take four to eight weeks to work. Ketamine worked the same day. The finding was small, but it launched a research program that has now produced hundreds of studies across two decades.

The compound that eventually reached FDA approval was not ketamine itself, but esketamine — the S-enantiomer of ketamine, developed by Janssen Pharmaceuticals as a nasal spray under the brand name Spravato. The nasal formulation allowed for a controlled-delivery product that could be administered in clinical settings, which was essential for navigating the regulatory process given ketamine's Schedule III status and abuse potential.

How It Works in the Brain

Standard antidepressants — SSRIs and SNRIs — work primarily on the serotonin and norepinephrine systems. They are effective for many patients, but the mechanism requires weeks of receptor adaptation to produce therapeutic change. They also fail entirely for a substantial minority of patients.

Ketamine works through a different pathway. It is an NMDA receptor antagonist — it blocks N-methyl-D-aspartate receptors in the glutamate system, the brain's primary excitatory neurotransmitter network. The exact mechanism by which NMDA antagonism produces antidepressant effects is still debated, but the leading hypothesis involves downstream stimulation of AMPA receptors and subsequent release of BDNF (brain-derived neurotrophic factor), a protein associated with synaptic plasticity and neuronal growth.

The practical implication is speed. By acting on glutamate rather than serotonin, ketamine produces antidepressant effects within hours to days. For patients with treatment-resistant depression who have failed multiple medication trials, and especially for patients with acute suicidal ideation, that speed can be clinically significant in ways that standard medications simply cannot match.

What FDA Approval Actually Means

Spravato (esketamine nasal spray) received FDA approval for treatment-resistant depression in March 2019. In August 2020, the indication was expanded to include major depressive disorder with acute suicidal ideation or behavior — the first time any medication had been specifically approved for that indication.

The approval came with strict conditions. Spravato is dispensed only through certified healthcare settings under a Risk Evaluation and Mitigation Strategy (REMS) program. Patients cannot take it home. Each dose must be self-administered in a clinical setting under direct medical supervision, and patients must be monitored for at least two hours afterward for dissociation, sedation, and blood pressure changes. The REMS requirement exists because of ketamine's dissociative effects and its potential for misuse.

The insurance landscape for Spravato is uneven. Some major insurers cover it for patients who meet the TRD criteria; others require extensive prior authorization documentation. The out-of-pocket cost without coverage can reach several hundred dollars per session. The clinical protocol involves twice-weekly sessions for four weeks, then weekly or biweekly maintenance — making cost a real access barrier.

Who Qualifies?

The FDA approval for treatment-resistant depression is defined by a specific clinical threshold: patients who have not responded adequately to at least two different antidepressant treatments in the current depressive episode. This is the standard TRD definition used across most regulatory contexts — not just "tried a medication" but "failed two adequate trials."

An adequate trial typically means taking the medication at a therapeutic dose for a sufficient duration (usually six to eight weeks). Patients who stopped a medication due to side effects in the first two weeks, or who were never titrated to a therapeutic dose, may not meet the criteria even if they feel they have "tried everything."

The 2020 expansion to cover MDD with acute suicidal ideation applies to a different population — patients in acute psychiatric crisis, not just those with chronic treatment failure. This indication is typically used in inpatient or emergency settings where rapid onset is the primary need.

The Evidence — and the Gaps

The pivotal trials supporting Spravato's approval were the TRANSFORM studies run by Janssen. TRANSFORM-2 and TRANSFORM-3 were randomized, double-blind, placebo-controlled trials that enrolled several hundred patients each. The primary outcome was change in depressive symptom score at 28 days. Both studies demonstrated statistically significant improvement over placebo, with the effect appearing as early as day 2.

The durability question is more complicated. The rapid onset is real; the long-term maintenance is less clear. A separate set of studies (the SUSTAIN trials) looked at relapse prevention in patients who had already responded to Spravato. SUSTAIN-1 showed that continuing Spravato after remission reduced relapse rates compared to switching to placebo — but the absolute relapse rates were still substantial in both groups. Many patients require ongoing maintenance dosing, which raises questions about long-term cost and the nature of the treatment effect.

Compared to the psilocybin pipeline, ketamine's regulatory position is more mature but its effect durability is considered a weakness. Psilocybin trials have produced remission data showing effects maintained at twelve weeks after a small number of sessions, without maintenance dosing. Whether that durability advantage will hold in larger Phase 3 trials remains to be seen — but it is one reason researchers and patients are watching the psilocybin data closely. For a fuller picture of where psilocybin stands, see our article on psychedelics and depression.

What About IV Ketamine Clinics?

Alongside the Spravato approval, a separate ecosystem of off-label IV ketamine clinics has grown rapidly in the US over the past decade. These clinics administer racemic ketamine (both enantiomers, not just the S-form in Spravato) intravenously, at doses and protocols that vary considerably between providers. IV ketamine is not FDA-approved for depression. Ketamine is FDA-approved as an anesthetic, and physicians may prescribe it off-label, but there is no standardized protocol, no REMS requirement, and no specific regulatory oversight for this use.

The lack of standardization matters. Doses, infusion rates, session frequencies, and integration support vary widely between clinics. Some clinics provide robust psychiatric oversight and preparation; others are closer to infusion mills with minimal clinical context. The evidence base for IV ketamine in depression is real — dozens of trials show efficacy — but it is mostly short-term and drawn from academic research settings with more oversight than typical commercial clinics provide.

Cost at IV ketamine clinics typically runs $400–$800 per infusion, with standard initial protocols of six infusions over two to three weeks. Insurance coverage is rare for the off-label indication. For patients who do not qualify for or cannot access Spravato, IV ketamine may be a practical option — but it requires careful vetting of the clinic's clinical standards and medical oversight.

For context on how ketamine fits into the broader landscape of psychedelic-adjacent treatments for depression, see our overview of psychedelics and depression, our explainer on what psilocybin is, and our guide to MDMA therapy.