Ketamine and Esketamine Therapy

Overview

A Brief History

Ketamine was developed in the 1960s as a derivative of phencyclidine (PCP) and approved by the FDA as an anesthetic in 1970. It rapidly became a workhorse anesthetic in operating rooms, emergency departments, battlefield medicine, veterinary care, and resource-limited settings because of its favorable safety profile in terms of preserved breathing and circulation. In the 1990s and 2000s, researchers — initially at Yale and the National Institute of Mental Health — observed that subanesthetic doses produced rapid antidepressant effects, including in patients with treatment-resistant depression. This finding upended decades of monoaminergic theory and launched a wave of clinical and basic-science research into glutamate as a target for mood disorders.

The Birth of Esketamine

Ketamine is a racemic mixture of two enantiomers: R-ketamine and S-ketamine. Esketamine is the S-enantiomer alone, which binds NMDA receptors more potently and has a somewhat different pharmacological profile. Janssen developed esketamine as an intranasal product (Spravato) specifically for depression, and the FDA approved it in March 2019 for treatment-resistant depression in adults under a Risk Evaluation and Mitigation Strategy (REMS) program. In 2020, the FDA expanded its approval to include depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior.

Why This Matters

For more than half a century, antidepressants worked primarily through monoamines — serotonin, norepinephrine, dopamine — and took weeks to produce benefit. A meaningful minority of patients did not respond to multiple trials. Ketamine and esketamine offered the first widely available mechanism that targeted a different neurotransmitter system, often produced effects within hours, and could provide benefit in patients who had failed multiple monoaminergic agents. The clinical and conceptual significance is substantial.

How Ketamine and Esketamine Work

NMDA Receptor Antagonism

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ion channel central to synaptic plasticity, learning, and memory. Ketamine and esketamine bind inside the open channel and block its function, particularly on inhibitory interneurons. The leading hypothesis is that this preferential blockade reduces inhibition of glutamatergic neurons, producing a brief surge of glutamate signaling. The downstream cascade involves activation of AMPA receptors, release of brain-derived neurotrophic factor (BDNF), and engagement of mTORC1 — leading to rapid synaptic plasticity, including new dendritic spine formation.

Rapid Antidepressant Effects

Within hours of administration, subanesthetic ketamine can produce significant reduction in depressive symptoms. In treatment-resistant depression studies, response rates are substantial. The duration of effect after a single dose is variable — often days to weeks — which is why repeated administration is generally required for sustained benefit. The mechanism behind rapid antidepressant effect remains an active research area; it is likely multifactorial, involving both immediate glutamatergic surge and downstream plasticity-related changes.

Differences from Monoaminergic Antidepressants

Traditional antidepressants act on serotonin, norepinephrine, and dopamine transporters or receptors and typically require 2–6 weeks for full effect. Ketamine and esketamine bypass these systems and target glutamate signaling. They do not replace monoaminergic antidepressants; in fact, they are typically used alongside ongoing antidepressant treatment in clinical practice. The combination has different action timing and target system from any monoaminergic strategy alone.

R- versus S-Ketamine

S-ketamine (esketamine) is roughly four times more potent at NMDA receptors than R-ketamine. R-ketamine, while less potent at the NMDA receptor, may have antidepressant effects through additional or different mechanisms; it remains under investigation as a possible therapy in its own right. The racemic mixture used in IV ketamine therapy combines both enantiomers.

Other Targets

Ketamine has effects beyond NMDA receptors, including interactions with opioid receptors, monoamine reuptake at certain concentrations, and HCN1 channels. The contribution of these non-NMDA actions to the antidepressant effect is debated. Some studies suggest that opioid system engagement may contribute to the antidepressant effect — a finding with implications for understanding both efficacy and potential for tolerance.

Major Formulations and Protocols

Esketamine (Spravato)

Spravato is an intranasal spray containing esketamine hydrochloride. Each device delivers a metered dose. Treatment is administered in a REMS-certified healthcare setting, with the patient observed for at least two hours after each session by trained staff. Typical induction involves twice-weekly dosing for four weeks, followed by once-weekly dosing for several additional weeks, and then maintenance dosing every one or two weeks based on clinical response. Esketamine is always given alongside an oral antidepressant in approved use. The patient cannot drive, operate machinery, or engage in similar activities until the next day after each session.

Intravenous Racemic Ketamine

Intravenous ketamine for depression is administered off-label in specialized clinics. A common protocol involves a subanesthetic infusion (often dosed by body weight) given over approximately 40 minutes, repeated multiple times over two to three weeks during an induction phase, then continued less frequently as maintenance. Vital sign monitoring during and after infusion is standard. Practices vary significantly across clinics; protocols are not standardized across the field.

Intramuscular Ketamine

Some clinics administer ketamine by intramuscular injection, which is simpler than IV but with somewhat less precise dose control. As with IV, this is off-label for depression and is performed in a clinical setting.

Compounded Oral and Sublingual Ketamine

Compounded oral or sublingual ketamine — sometimes prescribed through telehealth platforms and dispensed for home use — has expanded rapidly. These products are not FDA-approved for depression. They are compounded by pharmacies, often with variable quality control, and administered without in-person clinical monitoring. The FDA, professional societies, and many researchers have raised serious concerns about safety, oversight, abuse potential, and consistency of effect with at-home ketamine products. Patients considering them should understand these are not equivalent to esketamine or to clinic-based ketamine.

Ketamine-Assisted Psychotherapy (KAP)

Some clinics combine ketamine administration with psychotherapy, framing the experience around therapeutic processing. This practice draws on broader interest in psychedelic-assisted therapy. Evidence base for the specific combination of ketamine plus structured psychotherapy is still developing.

FDA-Approved and Off-Label Uses

Treatment-Resistant Depression

Esketamine (Spravato) is FDA-approved, in conjunction with an oral antidepressant, for adults with treatment-resistant depression — generally defined as inadequate response to at least two trials of antidepressants of adequate dose and duration in the current depressive episode. Intravenous ketamine is used off-label for the same indication in clinics. Both have substantial evidence for response, with response often emerging quickly.

Major Depressive Disorder with Suicidal Ideation

Esketamine has FDA approval for the treatment of depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior, as adjunct to oral antidepressant therapy. The rapid effect on suicidal symptoms — sometimes within 24 hours — is a key element of this indication. Treatment is part of comprehensive clinical care, not a substitute for hospitalization or safety planning when those are needed.

Anesthesia and Sedation

Ketamine retains a long-standing role in anesthesia, particularly for short procedures and in settings where preservation of respiratory drive is valuable. It is widely used in pediatric procedural sedation, emergency medicine, and operating rooms worldwide.

Acute Pain

Subanesthetic ketamine is used for acute and chronic pain in selected contexts, including postoperative pain, complex regional pain syndrome, and palliative care. This is a distinct clinical literature.

Off-Label Psychiatric Uses

Some clinicians use ketamine off-label for treatment-resistant bipolar depression, PTSD, OCD, anxiety disorders, and other conditions. Evidence varies by indication. Off-label ketamine for non-depression psychiatric conditions remains an area of ongoing research rather than established practice.

Common and Serious Side Effects

Acute Psychoactive Effects

During and shortly after administration, patients commonly experience:

• Dissociation — a sense of detachment from one's body, surroundings, or sense of time
• Perceptual changes, including alterations in vision and sound
• Floating or out-of-body sensations
• Euphoria or, less often, dysphoria
• Anxiety or, conversely, calm and emotional release

These effects typically resolve within 1–2 hours after dosing. The monitored setting allows staff to support patients through unsettling experiences and to identify those needing additional intervention.

Cardiovascular Effects

Transient elevations in blood pressure and heart rate are common during and shortly after ketamine or esketamine administration. Pretreatment cardiovascular assessment is standard, and blood pressure is monitored during sessions. Severe or unstable hypertension is generally a contraindication. Aneurysmal vascular disease, recent myocardial infarction, and certain cardiac conditions may also preclude treatment.

Sedation

Mild to moderate sedation is common during sessions. Patients are not permitted to drive or engage in tasks requiring alertness until the day after each session. Even mild residual effects can impair driving safety.

Nausea and Vomiting

Nausea, sometimes with vomiting, can occur during sessions. Antiemetics are often used preventively when appropriate.

Bladder and Urinary Effects

Chronic high-dose ketamine use — typically seen with recreational abuse rather than therapeutic dosing — can cause ketamine-induced uropathy, including painful bladder symptoms, ulcerative cystitis, and ultimately structural bladder damage. The risk with therapeutic, monitored protocols at appropriate doses appears low but is not zero, particularly with extended treatment courses; urinary symptoms should be reported to the prescriber.

Abuse and Dependence

Ketamine has documented abuse potential. As a Schedule III controlled substance in the United States, it is subject to regulatory controls. Tolerance to ketamine's antidepressant effects has been observed with chronic high-dose recreational use, though tolerance patterns within therapeutic protocols are less clearly established. The dissociative and euphoric properties drive nonmedical use; therapeutic protocols are designed in part to minimize reinforcement.

Cognitive Effects

Short-term cognitive effects during and shortly after sessions are expected. Persistent cognitive effects from therapeutic dosing are less clearly established. Chronic high-dose recreational use has been associated with memory and other cognitive impairments.

Rare and Serious Effects

• Severe dissociative or psychotic reactions
• Severe hypertensive episodes
• Worsening of underlying psychotic disorder
• Mania induction in patients with bipolar disorder
• Allergic reactions (rare)

Drug Interactions and Warnings

REMS Program

Esketamine is available only through the Spravato REMS program. Healthcare settings, prescribers, pharmacies, and patients are all enrolled. Administration occurs only in certified healthcare settings with appropriate monitoring. The program addresses risks of sedation, dissociation, abuse, misuse, and the requirement that patients not drive until the day after a session.

Drug Interactions

• CNS depressants: Benzodiazepines, opioids, and alcohol can intensify sedation and respiratory effects.
• Stimulants and sympathomimetics: May additively raise blood pressure and heart rate.
• MAOIs: Use with caution; theoretical and reported risk of hypertensive effects.
• Other psychoactive medications: Effects may be altered or amplified.
• Lamotrigine: May blunt some of ketamine's psychoactive effects, although the antidepressant effect is not necessarily affected.

Contraindications and Cautions

• Aneurysmal vascular disease (aortic, intracranial, peripheral arterial)
• Arteriovenous malformation
• Intracerebral hemorrhage history
• Hypersensitivity to ketamine or esketamine
• Severe or unstable hypertension
• Significant cardiovascular disease that increases risk with transient blood pressure rise
• Active substance use disorder involving ketamine or related substances (requires careful clinical judgment)
• Psychotic disorders (relative contraindication; requires careful evaluation)

Pregnancy and Lactation

Esketamine is not recommended during pregnancy because of potential developmental effects. Ketamine crosses into breast milk; breastfeeding decisions require clinician input. Reproductive planning is part of treatment conversations.

Starting, Monitoring, and Stopping

Pretreatment Assessment

Before starting ketamine or esketamine, clinicians typically obtain:

• Detailed depression history including prior treatments and responses
• Psychiatric history including bipolar disorder, psychotic symptoms, substance use disorder
• Cardiovascular assessment, including blood pressure and history of cardiac or vascular disease
• Pregnancy status and contraception plans where applicable
• Discussion of expectations, risks, and the experience of dissociation
• Logistical planning: transportation home, post-session recovery

Session Structure

An esketamine session begins with vital sign measurement and self-administration of the intranasal spray under staff supervision. Blood pressure is checked at intervals, and the patient remains in the clinic for at least two hours, with dissociative and sedative effects typically resolving over that time. Intravenous ketamine sessions follow a similar overall structure, with infusion typically lasting around 40 minutes followed by recovery and monitoring.

Course of Treatment

Treatment for depression typically includes an induction phase (weeks of more frequent dosing) followed by tapering frequency during maintenance. Continued response is assessed regularly. Stopping treatment can be followed by gradual return of depressive symptoms, although the time course varies. Tapering frequency rather than abruptly stopping is common.

Combining with Other Treatments

Ketamine and esketamine for depression are typically used alongside ongoing oral antidepressant treatment, not as monotherapy. Therapy — including CBT, behavioral activation, interpersonal therapy, or relapse prevention — remains foundational. Lifestyle factors (sleep, activity, social connection) also matter. The medication is one tool within an integrated plan.

Special Populations

Older Adults

Older adults can benefit from these treatments for treatment-resistant depression. Cardiovascular reserve and risk of cognitive effects warrant additional caution. Doses may be adjusted, and monitoring is particularly important. Esketamine has data in older adult populations supporting selected use.

Adolescents

Esketamine is not FDA-approved for adolescents. Use of ketamine in pediatric depression is investigational. As with other psychiatric interventions in younger populations, expanded use awaits stronger pediatric evidence.

Bipolar Depression

Ketamine has been studied in bipolar depression off-label, with evidence for rapid antidepressant effects in some patients. Mania induction is a risk, particularly without adequate mood stabilization. Specialist evaluation is essential before considering use in bipolar disorder.

Pregnancy

Treatment options during pregnancy require careful evaluation. Esketamine is generally not used during pregnancy. Severe perinatal depression and suicidality, however, demand serious treatment; care plans are individualized with specialist input.

Substance Use Disorders

History of ketamine use disorder or other substance use disorders requires careful assessment. Selected patients with substance use history can still benefit from monitored ketamine or esketamine treatment, but in-clinic monitoring and the avoidance of at-home unsupervised products are central. Active ketamine use disorder is typically a contraindication.

Psychotic Disorders

Ketamine's psychotomimetic effects raise concerns in patients with psychotic disorders. Use in this population is approached with caution and only in carefully selected, monitored contexts.

Controversies and Modern Practice

The Compounded Ketamine Marketplace

The rapid expansion of telehealth-prescribed compounded oral and sublingual ketamine for at-home use has raised significant concerns. Issues include the lack of FDA approval for these compounded products in depression, variable quality across compounding pharmacies, absence of in-person monitoring, potential for unsupervised dose escalation and dependence, and the misleading equation of compounded products with FDA-approved esketamine. Professional societies and the FDA have voiced concern. Patients considering these services should ask detailed questions about safety oversight and consider in-clinic alternatives.

Long-Term Effects

The long-term effects of repeated ketamine or esketamine treatment over years remain incompletely studied. Concerns include possible cognitive effects, urinary tract effects, tolerance, and dependence. Studies are ongoing. Clinical practice attempts to use the lowest effective frequency and to integrate other treatments to reduce reliance on indefinite, frequent dosing.

Cost and Access

Esketamine treatment is expensive, and coverage varies by insurer. Intravenous ketamine for depression is often paid for out of pocket and is similarly costly. The infrastructure required — certified clinics, observation periods, transportation — adds further barriers. Access disparities are pronounced. Compounded products are cheaper and more accessible, which is part of their appeal — and part of the safety concern.

The Psychedelic Question

Ketamine's dissociative experience has led some to position it within the broader psychedelic-assisted therapy movement. Others see it as a distinct pharmacological intervention whose effects can be useful without framing the dissociation as therapeutic in itself. The relationship between dissociation, set and setting, psychotherapy integration, and antidepressant effect is an active area of clinical and theoretical debate.

Equity and the Standard-of-Care Question

As esketamine and clinic-based ketamine become more established, questions arise about when in the depression treatment sequence they should be offered, who has access, and how to integrate them within standard psychiatric care. Many advocates argue that earlier consideration in treatment-resistant cases would shorten suffering. Equity in access remains a substantial concern.

What Patients Should Know

What the Experience Is Like

Most patients describe ketamine and esketamine sessions as unusual but tolerable. Common experiences include floating, time distortion, vivid imagery, emotional release, and a sense of distance from ordinary thinking. These effects fade within about two hours. The clinic setting, supportive staff, and a calm environment make a significant difference in the experience.

Planning Your Day

Plan not to drive after a session. Arrange transportation. Light meals before and after are generally well tolerated; some clinics recommend avoiding food close to dosing. Avoid alcohol, recreational substances, and other CNS depressants around treatment days. Important decisions, work tasks, or strenuous activity should wait until the day after a session.

What Improvement Looks Like

Improvement can be rapid — within hours or days — but is not universal. Some patients respond strongly; others respond modestly or not at all. Sustained benefit usually requires repeated dosing during induction and ongoing maintenance. Tracking symptoms with a clinician-prescribed scale supports treatment planning.

Telehealth and At-Home Ketamine

If considering at-home compounded ketamine, patients should weigh the substantial differences in safety oversight, the lack of FDA approval for these products in depression, and the unknown long-term implications. Asking about quality assurance of the compounding pharmacy, the clinical credentials of those prescribing, the depth of evaluation, and the response plan for serious adverse events is reasonable. Many specialists in mood disorders recommend in-clinic treatment.

Realistic Expectations

Ketamine and esketamine are not cures for depression. They are tools — sometimes powerful ones — that fit within an integrated treatment plan. Therapy, antidepressants, sleep, exercise, social connection, and addressing life circumstances remain part of the picture. Improvement from ketamine often opens a window in which other interventions are more effective; the goal is durable change, not endless dosing.

Stigma and Self-Understanding

The dissociative, "trip-like" nature of ketamine can feel unfamiliar to patients whose depression has not responded to standard approaches. Some find the experience helpful, others tolerable. Either way, the treatment does not signal a deeper or more severe form of illness — it is a different mechanism of action, used when monoaminergic approaches alone have not been enough.