Ketamine and esketamine for depression

How it works

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. The current best understanding is that blocking NMDA receptors triggers a cascade that briefly increases glutamate signaling, activates AMPA receptors, increases brain-derived neurotrophic factor (BDNF), and promotes the formation of new synaptic connections, particularly in the prefrontal cortex. The acute receptor effect lasts hours; the changes in synaptic structure and connectivity take days to weeks and appear to underlie the sustained antidepressant effect.

This is a different mechanism from SSRIs, which act on serotonin reuptake. The different mechanism is part of why ketamine works for some patients who have not responded to multiple traditional antidepressants.

Evidence

The evidence base is substantial and growing.

• Speed. A single dose can produce a meaningful improvement in depression scores within hours to days, with peak effect around 24 hours.
• Response rates. In treatment-resistant depression, a single ketamine infusion produces a response in roughly 50 to 70 percent of patients within 24 hours. Repeated dosing (typically 6 sessions over 2 to 3 weeks) increases response rates and extends durability.
• Suicidal ideation. Ketamine and esketamine reduce acute suicidal thoughts within hours, an effect distinct from the broader antidepressant effect. This is the basis for the FDA approval of esketamine for major depressive disorder with acute suicidal ideation.
• Esketamine specifically. The TRANSFORM trials (2019) and the SUSTAIN trials showed efficacy in treatment-resistant depression and in maintenance.
• ECT comparison. A 2023 trial in NEJM (Anand et al.) found that intravenous ketamine was non-inferior to ECT in treatment-resistant depression without psychosis, with fewer cognitive side effects.

How treatment is delivered

Esketamine (Spravato): a nasal spray administered in a certified clinic under a Risk Evaluation and Mitigation Strategy (REMS) program. The patient self-administers under direct observation, then is monitored for at least two hours for sedation and blood pressure changes. The induction phase is twice weekly for 4 weeks, then weekly, then every one to two weeks for maintenance. Esketamine must be given alongside an oral antidepressant per the FDA label.

Intravenous ketamine: an off-label use, typically dosed at 0.5 mg per kg over 40 minutes. The induction phase is six infusions over two to three weeks, followed by a maintenance schedule that varies widely between clinics. The patient is monitored throughout the infusion and for one to two hours afterward.

Intramuscular and oral ketamine are also used in some clinics. The evidence base is smaller. Sublingual or oral ketamine through telehealth-only programs has come under increased FDA and state regulatory scrutiny because of safety concerns, particularly for patients receiving the medication without in-person evaluation.

Who is a candidate

The FDA indication for esketamine is treatment-resistant depression (failure of at least two adequate antidepressant trials in the current episode) or major depressive disorder with acute suicidal ideation. Generic intravenous ketamine is most often used in similar populations. Some clinics also use ketamine in patients who cannot wait the typical six to eight weeks for an SSRI to work, particularly when severity or suicidality makes that wait risky.

Who should not have ketamine

• People with poorly controlled hypertension, recent stroke, or severe cardiovascular disease (ketamine raises blood pressure transiently).
• People with active psychosis or a primary psychotic disorder.
• People with a history of severe ketamine misuse or active substance use disorder involving dissociatives.
• People with active mania.
• Pregnancy and breastfeeding are generally contraindications outside of specific clinical situations.

Side effects

The most common acute effects during and after a ketamine session are dissociation (a sense of being detached from body or surroundings), perceptual changes, transient elevation of blood pressure and heart rate, dizziness, nausea, and sedation. These usually resolve within one to two hours. The patient cannot drive for the rest of the day.

Less common but worth knowing about:

• Bladder symptoms (ketamine cystitis). Reported with high-dose, frequent, or recreational use. Rare in standard medical protocols but a reason to use the lowest effective frequency.
• Cognitive effects. Mild and short-term in standard medical protocols. Long-term cognitive risk from chronic recreational use is established; the long-term risk from monitored medical use is less clear and appears low at standard doses.
• Misuse and dependence. Real risks for any psychoactive substance. Treatment in a clinical setting with monitoring rather than at home reduces the risk.

Durability and maintenance

The antidepressant effect of a single dose typically wanes over one to two weeks. The induction series of six infusions or six esketamine doses extends durability into weeks to months for many patients. Without ongoing treatment, relapse rates are high. Most patients who benefit transition to a maintenance schedule (every one to four weeks) for at least several months, often combined with a standard oral antidepressant and psychotherapy.

Cost and access

Esketamine (Spravato) is FDA approved and covered by Medicare and most commercial insurers for the approved indications, though prior authorization is usually required. Out-of-pocket costs without coverage range from roughly $600 to $900 per treatment session. Generic intravenous ketamine, used off-label, is rarely covered by insurance. Out-of-pocket costs run from roughly $400 to $800 per infusion.

Telehealth-only ketamine programs that ship oral or sublingual ketamine to patients have been a source of growing concern. The FDA issued warnings in 2023 about safety risks of compounded ketamine without in-person evaluation. Programs that include in-person evaluation, monitored dosing, and integration with overall mental health care are the safer model.

Where ketamine fits in the treatment ladder

For most patients, the order is still SSRIs and other oral antidepressants first, with psychotherapy alongside. Ketamine and esketamine are usually considered after two or more antidepressant trials, or earlier when severity, urgency, or suicidality makes a faster-acting treatment preferable. They are not first-line for uncomplicated depression.

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