Ketamine and esketamine

What ketamine and esketamine are

Ketamine has been used for decades as an anesthetic in surgery, in emergency departments, and in veterinary medicine. In the 2000s, researchers noticed that lower, sub-anesthetic doses given intravenously produced rapid reductions in depression symptoms, often within hours. That observation launched a large body of research and eventually a specific FDA-approved product.

The FDA-approved form is esketamine (Spravato), a nasal spray using the S-enantiomer of ketamine. It has two approvals: as add-on treatment for treatment-resistant depression, and for depression with acute suicidal ideation or behavior. Both approvals require the treatment be administered in a certified clinic under specific monitoring.

Racemic ketamine (the mixture of both enantiomers used as an anesthetic) is not FDA-approved for depression but is widely used off-label, most often as intravenous infusion at doses lower than anesthetic doses. This is what most people mean when they say "ketamine therapy" outside of a Spravato context.

How it works

The mechanism differs from standard antidepressants. Ketamine and esketamine are NMDA receptor antagonists, and downstream they produce a rapid increase in glutamate signaling and, hours to days later, an increase in synaptic connections in some brain regions. This is fundamentally different from the monoamine-based mechanisms of SSRIs, SNRIs, and other conventional antidepressants.

The full mechanism isn't settled. What is clearer clinically: the effects begin within hours, peak within a day or two, and last from days to weeks depending on the person. That's very different from standard antidepressants, which typically take weeks to work.

What treatment looks like

Esketamine (Spravato): given as a nasal spray in a certified clinic, twice weekly for the first four weeks, weekly for weeks five to nine, then every one or two weeks for maintenance. Each session includes at least two hours of monitoring after the dose. It is always combined with a standard oral antidepressant.

IV ketamine: given as an infusion, typically over 40 minutes, at sub-anesthetic doses. A typical induction course is six infusions over two to three weeks, with maintenance infusions thereafter as needed. Protocols vary between clinics.

Sublingual and intramuscular ketamine are also used off-label at some clinics; evidence is less robust than for IV.

During the session, the person is usually awake but experiences some degree of dissociation (the "K-hole" experience at high doses is more intense than what is used clinically for depression). At therapeutic doses, most people describe a mild floating or detached sensation that resolves within an hour or two.

Evidence

For treatment-resistant depression, ketamine and esketamine both have strong evidence for rapid short-term reduction in depression scores in a substantial proportion of people. In esketamine trials, roughly half of participants achieved response and around a third achieved remission by four weeks, added to an oral antidepressant.

For depression with active suicidal ideation, both ketamine and esketamine reduce suicidal ideation more rapidly than standard antidepressants. This is a real clinical advance.

Durability is more variable. Some people maintain the response with maintenance treatment; others lose response over weeks. Optimal maintenance schedules are still being worked out.

Evidence for other indications (PTSD, OCD, bipolar depression, substance use disorders) is smaller and less consistent, though studies are active.

Side effects

The most common short-term side effects during and after a session:

• transient dissociative sensations (feeling detached, unreal, dreamlike)
• transient blood pressure increase
• transient nausea
• transient dizziness or unsteadiness
• headache
• sedation for a few hours after

Most of these resolve within hours. Because of dissociation and sedation, patients are not permitted to drive after a session. Monitoring in the clinic covers the immediate risk period.

Longer-term concerns:

• Bladder problems, including a syndrome of interstitial cystitis with regular high-dose or long-term use. Rates at therapeutic doses in psychiatric clinics appear lower than in illicit high-dose use, but the risk is real.
• Cognitive effects with long-term repeated use, though data on therapeutic dosing is still evolving.
• Potential for misuse. Ketamine is a controlled substance and can produce psychological dependence in some people. Careful patient selection and clinic protocols are important.

Contraindications and cautions include a history of psychosis (relative), uncontrolled hypertension, significant cardiovascular disease, active substance use disorder involving ketamine, and pregnancy.

What ketamine is not

Ketamine is not a cure. Some people have durable responses; others need ongoing treatment. Ketamine is not a first-line antidepressant. Standard antidepressants are tried first, along with therapy. Ketamine is not a substitute for psychotherapy. Ongoing psychosocial care, whether therapy or supportive care, tends to improve durability of response.

Ketamine is also not the same across delivery routes and settings. IV in a monitored medical setting is different from oral ketamine sent through the mail without in-person supervision. The safety profile of the latter is not well established, and the regulatory environment around telehealth ketamine has been evolving.

Cost and access

Esketamine (Spravato) is expensive and, until recently, was covered by many insurance plans in the US after documented failure of prior antidepressant trials. Coverage varies. Out-of-pocket costs for the medication itself run in the thousands per course.

IV ketamine at private clinics is usually paid out of pocket, in the range of $400 to $800 per infusion in the US, and typically not covered by insurance.