Ketamine and Esketamine for Depression: Evidence and Safety

Author: Angela Bogdanova · Published: October 8, 2026 · Editorial Policy

Research cluster: Depression & Depressive Disorders · Written by Artificial Sapiens

Ketamine and esketamine are rapid-acting treatments considered in selected adults with major depressive disorder, particularly when depression has not responded adequately to established care. They act on glutamatergic signaling and can reduce depressive symptoms much sooner than a conventional antidepressant is usually expected to show its full benefit. Their clinical use nevertheless depends on diagnosis, route of administration, evidence quality, trained monitoring, adverse effects, and a plan for care after the acute treatment. The most important regulatory distinction in the United States is that intranasal esketamine (Spravato) is FDA-approved for specified adult indications, whereas racemic ketamine prescribed for depression is an off-label use of a drug approved for anesthesia. FDA prescribing information; FDA compounded-ketamine risk communication.

This article examines the evidence for depressive-symptom improvement, explains which formulations and patients have actually been studied, describes the on-site experience and required monitoring, and compares treatment with psychotherapy, antidepressants, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). It addresses the limits of current knowledge on relapse prevention, cognition, bladder health, substance-use risk, and suicide-related outcomes. Readers beginning with the diagnosis or conventional treatments can also consult Depression: Symptoms, Causes, Diagnosis, and Treatment and the Hub's depression treatment overview.

I. What are ketamine and esketamine?

Ketamine is an established anesthetic that contains two mirror-image forms, or enantiomers, of the same molecule. The usual racemic preparation includes both R-ketamine and S-ketamine. Esketamine is S-ketamine alone. Both affect N-methyl-D-aspartate (NMDA) receptors and other downstream processes involved in glutamate signaling. The shared chemistry explains why research on these agents is related; it does not make different formulations, doses, routes, regulatory approvals, or trial outcomes interchangeable. FDA Spravato label; CANMAT adult depression guideline.

1. Racemic intravenous ketamine

For depression research and specialty clinical practice, racemic ketamine has commonly been given by intravenous infusion at doses below those used for general anesthesia. This is a medical procedure involving vital-sign observation and recovery, even when performed outside a hospital. The drug's FDA approval for anesthesia does not confer an FDA-approved psychiatric indication or an official depression-specific dosing schedule. When a qualified prescriber uses an approved anesthetic drug for depression, that is off-label treatment. Off-label care can be medically legitimate, but the evidence, informed consent, setting, and safety oversight must be assessed independently. FDA compounding alert; VA/DoD major depressive disorder guideline.

2. Intranasal esketamine (Spravato)

Spravato is a specific prescription nasal-spray product containing esketamine. It is administered under the supervision of a healthcare professional at an appropriately certified care setting, followed by at least two hours of observation and an assessment of readiness to leave. It is not an at-home spray that a patient picks up for unsupervised use. In January 2025, the FDA expanded the treatment-resistant depression indication to permit esketamine on its own, without an oral antidepressant, as well as with one. The FDA's second indication, for depressive symptoms associated with major depressive disorder and acute suicidal ideation or behavior, still specifies combination with an oral antidepressant. Current FDA prescribing information; FDA approval letter for monotherapy.

3. Compounded, oral, sublingual, and take-home products

Oral lozenges, sublingual preparations, compounded nasal sprays, and mailed ketamine kits should not be assumed equivalent to either the approved Spravato product or monitored intravenous treatment. Compounded ketamine products are not FDA-approved; the agency has not evaluated each compounded product's safety, effectiveness, or quality before marketing. Absorption, blood concentrations, side effects, and monitoring differ across routes. The FDA has specifically warned about serious risks when compounded ketamine is used at home without an onsite professional assessing sedation, dissociation, respiratory status, and vital signs. FDA compounded-ketamine safety alerts.

II. Which types of depression are relevant?

1. Major depressive disorder and a current episode

Major depressive disorder (MDD) is diagnosed through a clinical assessment of symptoms, duration, distress or impairment, medical and psychiatric history, and alternative explanations. Depressed mood is a symptom; a major depressive episode is a defined syndrome; MDD is the disorder diagnosed when the episode and its history satisfy the relevant criteria. A screening questionnaire may help describe severity or monitor change, but a score by itself cannot establish MDD or qualify someone for ketamine treatment. Our clinical evaluation guide explains the diagnostic route. NIMH depression overview; NICE adult depression guideline.

2. Treatment-resistant depression

Treatment-resistant depression (TRD) is often operationally defined as inadequate improvement during the current depressive episode despite at least two adequate antidepressant trials. Definitions vary between studies, insurance policies, specialty programs, and clinical guidelines. Adequacy includes a reasonable dose and duration, actual medication exposure, tolerability, and what changed during treatment. A drug stopped almost immediately because of side effects provides different information from one taken consistently at a therapeutic dose without meaningful response. The exact two-trial history is therefore evaluated by a clinician rather than inferred from a list of prescriptions. See Treatment-Resistant Depression: Definition, Assessment, and Options. CANMAT; VA/DoD.

Some patients meet a research definition of TRD and later respond to a conventional change in medication, psychotherapy, augmentation, TMS, or ECT. Others need urgent coordinated care before completing a standard sequence of medication trials. The reason for discussing ketamine is a carefully evaluated treatment need, not an irreversible label or a promise that every earlier treatment was ineffective. Clinical planning should also identify residual symptoms, medical conditions, substance use, psychosocial adversity, and obstacles to receiving appropriate care. CANMAT; NICE.

3. Bipolar disorder, psychosis, and mixed features

A history of mania, hypomania, decreased need for sleep with unusually elevated or irritable energy, or mixed symptoms warrants a bipolar-spectrum assessment. Trials and regulatory indications for unipolar TRD cannot simply be applied to bipolar depression. Standard antidepressant choices and the risk of mood switching can differ substantially when bipolar disorder is present. Psychotic depression also requires a specialized assessment because delusions, hallucinations, severe impairment, and urgent clinical risk can alter the preferred treatment pathway. These situations demand diagnosis-specific psychiatric decision-making rather than selecting a rapid-acting drug from a symptom checklist. VA/DoD guideline; NICE guideline.

4. Children, adolescents, and perinatal contexts

Spravato is not FDA-approved for patients younger than 18. Evidence from adult trials does not establish pediatric efficacy or safety. Depression in children and adolescents needs age-appropriate assessment and specialized care; the Hub's Depression in Teens covers that separate question. Pregnancy, attempts to conceive, and breastfeeding require additional assessment because the approved labeling warns of potential fetal harm and advises against breastfeeding during treatment. Perinatal and reproductive mental health are their own clinical fields, and no adult TRD result automatically resolves their treatment choices. FDA label, pregnancy, lactation and pediatric sections.

III. How might these treatments work?

Ketamine and esketamine are NMDA-receptor antagonists. Their antidepressant effects are thought to involve complex changes in excitatory neurotransmission, downstream signaling, synaptic plasticity, and network functioning. Experimental models implicate glutamatergic circuits and signaling mechanisms that differ from the primary monoamine-transporter actions of most commonly used antidepressants. Researchers continue to investigate which changes are causal, which are associated with improvement, and why some patients respond while others do not. Describing these mechanisms as hypotheses supported by converging evidence is more accurate than asserting that ketamine permanently repairs a defective brain pathway. CANMAT guideline; NIMH depression research overview.

Dissociation, altered perception, or a subjective sense of emotional distance may occur during treatment. These acute experiences are possible adverse effects and do not provide a validated measure of whether depression treatment will succeed. Mechanistic proposals about psychedelic-like experiences or psychotherapy-assisted dosing do not demonstrate that the intensity of an altered state predicts benefit for an individual. Clinical response is assessed through symptoms, functioning, adverse effects, and longitudinal follow-up. FDA label; 2025 systematic review of ketamine-assisted psychotherapy.

IV. What does the evidence show for intravenous ketamine?

1. Speed of change

In randomized studies of adults with depressive disorders, intravenous racemic ketamine can produce noticeable average symptom improvement within hours to approximately one day, faster than the usual evaluation window for many conventional antidepressants. Clinical trials measure symptom scores at defined time points; the meaning of an early change depends on its size, duration, side effects, and comparator. A group-level rapid response does not imply that every patient improves after one infusion or that severe symptoms disappear immediately. The depression-specific evidence base is strongest for short-term outcomes in selected, medically monitored adults. VA/DoD MDD guideline; CANMAT 2024.

2. Response, remission, and durability

Response generally means a substantial reduction in depressive symptoms, often a 50% decrease on a research scale; remission means symptoms have reached a very low level. These endpoints differ from enduring recovery, return of function, and prevention of future episodes. After one infusion, benefits in responders may fade over days or weeks. Repeated infusions can extend benefit in some clinical series, but prolonged treatment protocols, optimal intervals, and the long-term balance between benefit and harm are less securely established than short-term antidepressant effects. CANMAT guideline; VA/DoD guideline.

3. How intravenous ketamine compared with ECT in a randomized trial

In the 2023 multicenter randomized noninferiority trial by Anand and colleagues, adults with nonpsychotic treatment-resistant major depression were assigned to intravenous ketamine or ECT. Among participants who started their assigned treatment, a prespecified self-reported response after three weeks occurred in 55.4% of the ketamine group and 41.2% of the ECT group. The study supported noninferiority of ketamine for its primary endpoint in this defined population and protocol. It did not show that ketamine is superior to ECT for all depressive disorders, for psychotic depression, for emergencies, or over the long term. Anand et al., New England Journal of Medicine.

The ECT comparison was open-label, participants and clinicians knew the assigned treatment, and some randomized patients did not begin the allocated intervention. These details matter when interpreting comparative results and what an individual patient might expect. ECT retains an important role for certain very severe or urgent presentations, including some forms of psychotic depression and states where a reliable rapid intervention is clinically critical. Treatment selection considers medical anesthesia risks, cognitive outcomes, patient preferences, availability, and urgency. Anand et al.; NICE recommendations.

V. What does the evidence show for intranasal esketamine?

1. Short-term trials with oral antidepressants

Esketamine was originally studied for TRD mainly as an addition to a newly initiated oral antidepressant. Some randomized trials showed greater average improvement than control treatment, whereas others did not meet their primary statistical endpoint. A 2025 systematic review and meta-analysis in the American Journal of Psychiatry concluded that the pooled additional effect was statistically detectable but modest, with reported standardized effect sizes approximately 0.15–0.23 at weeks two through four. This is one evidence synthesis, not a personal probability of success. Trial design, patient selection, placebo response, dissociation-related unblinding, and differences between studies influence interpretation. Fountoulakis, Saitis, and Schatzberg, 2025.

Another systematic review and meta-analysis found advantages in depressive symptom outcomes during treatment and some measures of relapse prevention, but estimates vary by included trials, comparison, timing, and outcome definitions. These analyses should be read with their uncertainty intervals and risk-of-bias assessments. They also distinguish improvement in depressive symptoms from improvement in suicidal behavior. Regulatory approval rests on a wider evidence package evaluated for specified indications; it does not eliminate scientific disagreement over effect size, long-term harms, or real-world generalizability. Wang et al. evidence synthesis; Fountoulakis et al.; FDA label.

2. The 2025 esketamine monotherapy trial

A multicenter randomized clinical trial published in JAMA Psychiatry in 2025 evaluated nasal esketamine without a concurrent oral antidepressant in adults with TRD. In the efficacy analysis population of 378 patients receiving at least one treatment, twice-weekly esketamine at 56 mg or 84 mg improved depression scores more than intranasal placebo by day 28, with a statistically significant separation also measured about 24 hours after the first dose. Reported day-28 adjusted mean differences versus placebo were −5.1 and −6.8 points, respectively, on the Montgomery–Åsberg Depression Rating Scale. Those values are trial-specific differences, not an amount that can be guaranteed to an individual. Janik et al., randomized trial.

This study matters because it directly informs the U.S. monotherapy indication and questions about patients who cannot continue an oral antidepressant. The trial had defined eligibility criteria, an antidepressant-free lead-in, a limited double-blind period, and industry sponsorship; these features should accompany the headline efficacy result. Potential functional unblinding from recognizable acute drug effects is a challenge across this research area. Replication, independent comparisons, and longer follow-up remain relevant when determining how well study outcomes transfer to routine care. Janik et al., study and methods; Fountoulakis et al., meta-analysis.

3. Maintenance treatment and relapse

For patients who improve with esketamine, continuation treatment may reduce the probability of subsequent depressive relapse while treatment continues. The randomized withdrawal SUSTAIN-1 study enrolled patients who achieved stable remission or response after earlier treatment, then compared continued esketamine plus an oral antidepressant with switching to placebo nasal spray plus the oral antidepressant. The results supported relapse prevention in that selected responder population. They do not show what happens to every person beginning treatment or establish that indefinite dosing is necessary. Study designs that enrich for early responders can make maintenance effects difficult to generalize to nonresponders. Daly et al., JAMA Psychiatry; FDA labeling.

4. Is IV ketamine better than esketamine?

Direct high-quality randomized head-to-head trials comparing monitored intravenous racemic ketamine with FDA-approved intranasal esketamine remain limited. Indirect comparisons across distinct studies cannot establish which drug is better for an individual: severity, number of prior treatments, blinding, concurrent medication, dosing, and outcomes differ. IV ketamine may offer a different route and clinical schedule; intranasal esketamine offers a specifically regulated, FDA-approved TRD pathway with defined monitoring and maintenance labeling. A specialist should compare evidence, feasibility, risk, and coverage rather than choose a winner from cross-trial percentages. CANMAT; comparative safety systematic review.

VI. FDA indications, restrictions, and what approval does and does not mean

1. U.S. approval for adult TRD

The 2025 U.S. Spravato label states two ways to treat adult TRD: esketamine monotherapy, or esketamine in conjunction with an oral antidepressant. These are drug-label options and are distinct from which arrangement a clinician recommends after reviewing prior treatment, adverse effects, and insurance conditions. The product carries a boxed warning, is controlled under Schedule III, and is distributed through a Risk Evaluation and Mitigation Strategy (REMS). The agency's approval is specific to this product, indication, and conditions of use. It is not an approval of all ketamine-containing nasal sprays, tablets, or ketamine clinics. FDA label.

2. Depressive symptoms and acute suicidal ideation or behavior

The same label separately permits Spravato together with an oral antidepressant for depressive symptoms in adults with MDD and acute suicidal ideation or behavior. This wording requires care: the FDA specifically states that effectiveness in preventing suicide, or in reducing suicidal ideation or behavior, has not been demonstrated. Improvement in a depression rating scale and prevention of a suicide attempt are different outcomes. Clinically necessary hospitalization, observation, emergency evaluation, and other safety measures must proceed according to the person's actual risk even when mood symptoms improve after treatment. FDA approved indications and limitations; 2025 suicidality review.

A person who is currently at risk of acting on suicidal thoughts needs immediate in-person safety assessment and a crisis-care pathway, not a delay while arranging a future infusion appointment. In the United States, 988 is the Suicide & Crisis Lifeline; elsewhere local emergency and crisis services apply. The appropriate care plan may include emergency medical assessment and hospitalization. Ketamine or esketamine may be discussed within specialist treatment, but the research does not establish them as substitutes for suicide prevention or emergency care. FDA label; NIMH depression information.

3. Regional policies

Approval and reimbursement vary between countries. European regulatory labeling and reimbursement policies differ from the U.S. label, and the UK National Institute for Health and Care Excellence has not recommended esketamine for routine NHS use for treatment-resistant depression under its technology appraisal TA854, in part on clinical and cost-effectiveness grounds. This difference reflects different legal and health-system decisions, not a proof that one jurisdiction's treatment is universally effective or ineffective. The appropriate local prescribing information and service requirements should always take precedence. European Medicines Agency; NICE TA854.

VII. What actually happens during treatment?

1. Before treatment: assessment and informed consent

A safe evaluation begins with the depression diagnosis, current severity, prior medication trials, psychotherapy history, bipolar and psychosis screening, present suicidal risk, substance-use history, other medications, physical health, blood pressure, pregnancy-related considerations where relevant, and the capacity to attend monitored sessions. An assessment also asks about cardiovascular or cerebrovascular risks and possible contraindications. Patients should know the anticipated course, possible acute perceptual changes, monitoring requirements, out-of-pocket cost, alternative treatments, and what happens if benefit is absent or short-lived. FDA label; CANMAT treatment pathway.

2. A monitored intranasal esketamine session

For Spravato, the patient self-administers the nasal spray under direct professional supervision in the certified setting; staff monitor blood pressure, oxygenation and breathing as appropriate, awareness, and symptoms after dosing. The label requires observation for at least two hours after each administration and discharge only after clinical reassessment. A session may involve dizziness, nausea, temporary detachment, fatigue, anxiety, or increases in blood pressure. Patients should arrange a way home and should not drive or operate machinery until the following day after a restful sleep. FDA label and REMS requirements.

3. Typical label schedule and reassessment

For adult TRD, the FDA-labeled intranasal schedule has an induction period of twice-weekly sessions in weeks 1–4, followed by weekly sessions in weeks 5–8, and thereafter typically every one or two weeks depending on clinical response and the need for the least frequent effective dosing. Dosing details vary with indication, tolerability, and clinical judgment, and the labeled range is not a personal dosing instruction. The clinician evaluates benefit after induction and at later intervals, including whether the treatment continues to justify its burden and risks. The separate acute-suicidality indication has different scheduling and evidence limits. FDA prescribing information, dosage sections.

4. Intravenous ketamine workflow

For IV ketamine used off-label for depression, published protocols commonly involve supervised infusions, assessment before each session, monitored recovery, and reassessment after a short series. There is no universally FDA-approved psychiatric infusion regimen or long-term maintenance interval. Clinics may differ in staff qualifications, medical equipment, contraindication screening, emergency preparedness, integration with ongoing depression treatment, and follow-up. Patients should ask which clinical guideline or trial supports a proposed regimen and what objective criteria determine continuation. VA/DoD guidance; CANMAT guideline.

5. How improvement is monitored

Clinicians track changes in symptoms and meaningful daily function alongside adverse events. Sleep, concentration, appetite, ability to work, social engagement, and self-care provide context to a rating-scale score. A single low score is not an independent psychiatric diagnosis or proof of sustained recovery. If benefit occurs, treatment planning asks whether it persists between sessions and how psychotherapy, medication, social care, and relapse-prevention strategies will continue. If benefit is absent, an appropriate response is structured reassessment rather than escalating exposure indefinitely. NICE; CANMAT.

VIII. Short-term side effects and serious safety issues

1. Dissociation, sedation, and impaired judgment

Commonly described acute effects include dissociation, changes in perception, dizziness, vertigo, nausea or vomiting, headache, fatigue, anxiety, and transient cognitive or psychomotor impairment. Some people feel detached from their bodies or surroundings; others experience unpleasant anxiety or disorientation. Sedation can vary in intensity. Monitoring is necessary because patients may be unable to judge their own readiness to leave, and acute symptoms can complicate assessment of distress or emerging risk. Recognizable effects may also compromise masking in randomized trials and contribute to uncertain comparative effect estimates. FDA label; comparative safety meta-analysis.

2. Blood pressure and cardiovascular risks

Ketamine-related sympathomimetic effects can raise blood pressure and heart rate. Spravato labeling requires assessment of blood pressure before administration and reassessment after dosing, with particular care for people in whom an increase could pose serious danger. Certain aneurysmal vascular diseases, arteriovenous malformations, prior intracerebral hemorrhage, and hypersensitivity are listed contraindications to Spravato. Other cardiovascular or cerebrovascular conditions require individualized evaluation, and a clinic must be prepared to respond to concerning reactions. FDA contraindications and warnings.

3. Breathing, other medications, and driving

Respiratory depression has been reported after marketed esketamine use, leading to explicit monitoring requirements including pulse oximetry. Combining treatment with other central nervous system depressants may increase sedation. Psychostimulants and monoamine oxidase inhibitors may increase blood-pressure concerns. A full medication review should include prescribed drugs, alcohol, and other substances, without requiring the patient to make unsupervised medication changes. Driving and safety-sensitive work are restricted after treatment, with the label specifying no driving until the next day following restful sleep. FDA prescribing information, warnings and interactions.

4. Psychological vulnerability and clinical supervision

Some people find dissociative effects frightening, particularly if they have past traumatic experiences, severe anxiety, or difficulty tolerating altered perception. A supportive setting, explanation of expected sensations, respectful communication, and responsive observation can improve the clinical experience. A history of psychosis, manic or mixed symptoms, substance-use problems, or serious behavioral instability requires specialist judgment about risk and the appropriate intervention. Treating an unusual acute mental state as evidence that a specific psychological breakthrough has occurred would exceed the available clinical evidence. FDA warnings; CANMAT depression guideline.

IX. What is known about long-term safety?

1. Bladder and urinary concerns

Heavy nonmedical ketamine exposure is associated with serious urinary-tract injury, including bladder pain and inflammation. Controlled therapeutic exposure is different in dose and setting, and its long-term urinary risk cannot be quantified by simply importing rates from recreational populations. The Spravato label includes a warning concerning ulcerative or interstitial cystitis and recommends monitoring for urinary and bladder symptoms. Persistent urinary frequency, pain, blood in urine, or other concerning changes deserve medical evaluation. Long-term exposure should be reviewed rather than assumed harmless because treatment is prescribed. FDA label, cystitis warning.

2. Cognition, memory, and neurotoxicity questions

Attention, judgment, reaction time, and immediate learning can be impaired during or after dosing. Research has not fully determined the consequences of repeated long-term ketamine exposure for cognition in every clinical population, and reports from nonmedical heavy use are not a direct estimate of risk under specialist treatment. The right question for ongoing care is whether the patient is gaining durable functional benefit while maintaining safety, including cognition, work capacity, and daily independence. FDA cognitive impairment warning; CANMAT.

3. Misuse, craving, tolerance, and dependence

Ketamine and esketamine have abuse and misuse potential. Spravato is a Schedule III controlled substance and carries an FDA boxed warning about misuse. A history of substance-use disorder is relevant to risk assessment, monitoring, and treatment-setting choice; it does not justify an automatic diagnosis based solely on a patient's interest in care. With repeated exposure, clinicians should watch for drug-seeking patterns, problematic changes in treatment frequency, cravings, and adverse functional effects. Restricted distribution and onsite administration are important parts of the approved product's safety architecture. FDA label; FDA compounding risk alerts.

4. Pregnancy, breastfeeding, and younger patients

Animal evidence and regulatory labeling identify potential embryo-fetal harm. Patients who are pregnant, planning pregnancy, or breastfeeding need a pregnancy-specific treatment discussion; the U.S. label advises against breastfeeding during treatment. Spravato's efficacy and safety are not established for pediatric depression. Serious depression in these populations still deserves timely evidence-based care, with interventions chosen for the population and urgency rather than extrapolated automatically from adult ketamine trials. FDA prescribing information; NICE adult depression guideline for scope distinction.

X. Ketamine, esketamine, and suicidality: interpreting a sensitive evidence base

Researchers have examined whether rapid decreases in suicidal thoughts occur after ketamine or esketamine. Some controlled trials of IV ketamine report short-term reductions in suicidal-ideation scores. However, the clinical meaning and duration of those changes depend on the population, comparator, concurrent intensive care, and how suicidality is measured. A systematic review of trials since 2020 evaluated these outcomes and emphasized the need for careful distinction between suicidal thinking and suicidal behavior. A reduction in a questionnaire score is not proof of fewer attempts or deaths. Sajid, Mann, and Grunebaum, 2025.

In the 2025 esketamine meta-analysis, evidence for a significant direct effect on suicidality was absent across the examined time points. This finding aligns with the explicit FDA label limitation that Spravato has not been demonstrated to prevent suicide or reduce suicidal ideation or behavior, even though it may reduce depressive symptoms. Some studies report different short-term measures of suicidal thinking for ketamine. Accordingly, both positive and negative findings require outcome-specific language, and imminent self-harm risk always calls for direct clinical management. Fountoulakis et al.; FDA limitations of use.

For family members and patients, a practical principle is to tell the treating team immediately about worsening suicidal thoughts, severe agitation, impulsivity, unusual energy accompanied by little sleep, hallucinations, or an inability to remain safe. If danger is imminent, seek emergency help now; in the United States contact 988 or emergency services. Prescribed treatment should be coordinated with a safety plan and ongoing follow-up, not treated as a one-session replacement for crisis assessment. FDA label; NIMH depression information.

XI. How do these treatments compare with other depression care?

1. Conventional antidepressants and psychotherapy

For many adults, first-line care includes evidence-based psychotherapy, antidepressant medication, or both, chosen according to severity, prior history, preferences, contraindications, and accessibility. Ketamine-based treatments are mainly specialist options when the course of depression warrants them. Rapid improvement should be evaluated alongside longer-term self-management, psychotherapy access, social support, and relapse-prevention planning. It would be inaccurate to infer from a quick response that a patient no longer needs comprehensive care or that their condition arose from a simple imbalance of one brain chemical. NICE; CANMAT; depression treatment overview.

2. Transcranial magnetic stimulation

TMS uses externally delivered magnetic pulses to stimulate selected brain regions and has its own evidence base, indications, treatment schedule, contraindications, and access considerations. It usually involves a course of repeated sessions rather than a pharmacologically induced dissociative state. Choice between TMS, ketamine, and esketamine depends on the treatment history, likely benefit, medical risks, preferences, financial burden, and logistics; broad across-study rankings can mislead. Where a direct comparative trial is unavailable, clinicians should describe that uncertainty rather than invent precise superiority. VA/DoD; CANMAT. For details about eligibility, evidence and procedures, see TMS for Depression: Evidence, Eligibility, and Treatment Process.

3. Electroconvulsive therapy

ECT is an established procedure with particular importance in severe, psychotic, or urgently deteriorating depressive illness and in some cases where other treatments have failed. It involves anesthesia and procedure-related considerations, including possible cognitive adverse effects. The trial comparing ECT with IV ketamine in nonpsychotic TRD provides valuable evidence for that specific population; it does not settle the preferred intervention for psychotic depression, catatonia, medically compromised patients, or patients whose clinical risk demands a different response. Anand et al.; NICE.

4. Maintaining recovery after any rapid treatment

A rapid pharmacological effect can create a window for broader recovery work. Treatment planning may include identifying early warning signs of relapse, protecting sleep, managing co-occurring conditions, reviewing medication, supporting daily function, and ensuring psychotherapy or social care when appropriate. These supports are not proven substitutes for indicated medical treatment, and supportive advice alone does not constitute a validated ketamine maintenance protocol. The Hub's evidence-informed depression self-help guide addresses complementary practical strategies. CANMAT; NICE.

XII. How to evaluate a clinic or treatment offer

A credible medical service makes its model of care explicit. It identifies the patient's diagnosis and indication, whether treatment is FDA-approved esketamine or off-label racemic ketamine, who is licensed and trained to administer it, how vital signs and breathing are monitored, what happens if symptoms become serious, and how effectiveness is documented. It gives the patient a clear plan for transport, informed consent, follow-up, adverse events, and treatment discontinuation. For Spravato, certification and REMS requirements are central. For IV or compounded ketamine, claims of FDA approval for depression should be scrutinized closely. FDA label; FDA compounding safety information.

1. Questions to ask before committing

Useful questions include: What exact diagnosis and previous treatment history support this recommendation? Is the product Spravato or racemic ketamine, and by which route is it administered? What clinical evidence supports this schedule? How are blood pressure, oxygenation, consciousness, psychiatric status, and recovery assessed? Who handles emergencies? What is the expected out-of-pocket cost, including monitoring and follow-up? How will benefit, nonresponse, or relapse be recognized? What happens when a course ends? These questions help patients obtain informed, individualized care rather than a generic guarantee of relief. FDA label; CANMAT.

2. Marketing claims that need scrutiny

Be cautious of promises that ketamine permanently resets the brain, guarantees remission after one session, cures trauma by inducing dissociation, prevents suicide, or works equally well in every diagnosis. A clinic that markets unmonitored at-home compounded ketamine as identical to an FDA-approved product is making an important regulatory error. Likewise, a price quote without an explanation of associated assessments and follow-up omits a meaningful part of care. The scientific evidence supports clinically valuable short-term benefit in some settings while preserving substantial uncertainty about durability and individual response. FDA risk alerts; Fountoulakis et al..

XIII. Evidence quality, research limitations, and unanswered questions

1. Placebo response and functional unblinding

Ketamine can produce recognizable sensations that differ from inert placebo. Patients and clinicians may therefore guess treatment assignment, potentially influencing reported outcomes or care interactions. Active controls can reduce some masking problems but have their own effects and limitations. This challenge does not invalidate all trial findings; it affects confidence in effect size and in differences between treatments. Evidence appraisal should examine trial blinding, missing data, sample selection, preregistered outcomes, sponsor involvement, and whether benefits persist beyond the acute phase. Fountoulakis et al.; Janik et al..

2. Clinical heterogeneity

TRD trial participants vary in illness duration, prior treatment adequacy, co-occurring anxiety, trauma exposure, medical disease, age, sleep problems, and baseline severity. A statistically significant mean improvement can coexist with excellent benefit in some people and little benefit in others. Current research does not offer a universally reliable biomarker that can tell an individual in advance whether ketamine or esketamine will produce sustained remission. Personalized decisions therefore rely on a full history, clinical monitoring, and ongoing revision of the treatment plan. CANMAT; NIMH.

3. Long-term outcomes and real-world access

Important remaining questions include the ideal duration of maintenance, stopping rules, long-term urinary and cognitive outcomes, dependence risk under repeated exposure, the comparative effectiveness of IV ketamine and intranasal esketamine, how to integrate treatment with psychotherapy, and how outcomes vary outside trial populations. Cost, geographic access, insurance coverage, and the ability to take time off for monitored sessions also shape real-world benefit. Differences between FDA approval and NICE reimbursement decisions illustrate why efficacy, safety, affordability, and health-system value need distinct assessments. CANMAT; NICE TA854; FDA label.

XIV. Frequently asked questions

1. Is ketamine the same as esketamine?

No. Racemic ketamine contains two enantiomers and is generally administered by injection or infusion when used in depression trials; esketamine is the S-enantiomer alone. The FDA-approved Spravato nasal spray is a particular formulation with specified adult indications and distribution controls. Their related pharmacology does not make different products clinically interchangeable. FDA label.

2. Is ketamine FDA-approved for depression?

Racemic ketamine is FDA-approved for anesthesia, not for depression. Clinician-supervised depression use is off-label. Intranasal esketamine Spravato has FDA approval for specified adult depressive indications. Compounded ketamine preparations are not FDA-approved products. FDA compounding alert; Spravato label.

3. Can esketamine be used without an antidepressant?

Yes, for adult treatment-resistant depression in the United States, the FDA permits Spravato as monotherapy or in conjunction with an oral antidepressant under its approved labeling. For its separate indication concerning depressive symptoms in adults with MDD and acute suicidal ideation or behavior, the label specifies use alongside an oral antidepressant. The clinical decision still depends on specialist evaluation. FDA label; Janik et al..

4. How quickly can ketamine or esketamine work?

Some trial participants show reduced depressive symptoms within hours or by the next day. Others have a slower or insufficient response, and early improvement may not persist. One treatment session cannot establish long-term remission or predict an individual course. Janik et al.; Anand et al..

5. How long do the effects last?

The duration varies. Some effects following a single IV infusion diminish after days or weeks, while esketamine maintenance trials support relapse reduction in selected people who responded to initial treatment. The duration of an individual's benefit should be measured between sessions and after treatment changes. Daly et al.; CANMAT.

6. How many Spravato sessions are usually required?

The U.S. label for TRD describes twice-weekly treatment during weeks 1–4, weekly treatment during weeks 5–8, and then weekly or every-other-week maintenance when clinically warranted. Individual dosing, continuation and stopping decisions belong to the treating clinician. Other indications and other routes have different evidence and schedules. FDA dosage instructions.

7. Can I drive home after treatment?

No. Spravato recipients must arrange transportation and must not drive or operate machinery until the next day after a restful night's sleep. Similar practical caution applies after medically administered ketamine, according to the clinician's instructions. FDA label.

8. Is esketamine addictive?

Esketamine and ketamine have abuse and misuse potential, and Spravato is a controlled substance. Clinical monitoring, restricted access, substance-use assessment, and attention to problematic patterns matter. Having TRD or seeking treatment is not itself evidence of a substance-use disorder. FDA boxed warning.

9. Can ketamine prevent suicide?

The evidence does not establish that ketamine-based treatment prevents suicide. The FDA specifically states that Spravato has not been demonstrated to prevent suicide or reduce suicidal ideation or behavior. A person in immediate danger needs urgent safety care regardless of whether rapid-acting depression treatment is considered. FDA label; Fountoulakis et al..

10. Can someone with bipolar depression receive it?

Bipolar depression has a distinct diagnostic and treatment pathway. Findings from unipolar TRD trials and U.S. Spravato indications should not be transferred automatically to bipolar disorder. A specialist should first assess lifetime mania, hypomania, mixed symptoms, and individual safety factors. FDA indication; CANMAT depression guideline, scope.

11. Is treatment suitable for teenagers?

Spravato is not FDA-approved for pediatric patients. Adolescent depression is treated through age-appropriate diagnostic and clinical pathways, and evidence for adults cannot simply be presumed to apply. See Depression in Teens. FDA label.

12. Does more dissociation mean better results?

No reliable clinical rule establishes that stronger dissociation produces superior or longer-lasting antidepressant benefit. Dissociation is an acute drug effect that may be distressing or impair functioning, and improvement is assessed through depression symptoms and recovery over time. FDA label; CANMAT.

13. What about ketamine-assisted psychotherapy?

Ketamine-assisted psychotherapy combines drug administration with psychotherapy or psychological support in varying ways. It is an emerging intervention area with heterogeneous protocols; evidence for the drug alone cannot establish the added benefit of a particular psychotherapy arrangement, or vice versa. Any psychological treatment should be delivered by qualified practitioners and evaluated on its own evidence. Systematic review of ketamine-assisted psychotherapy.

14. How much does treatment cost?

Costs depend on jurisdiction, insurance, clinic type, whether the drug is an approved product, number of monitored visits, transport, and follow-up. A quoted drug or infusion price alone may exclude required safety assessment and observation. Patients should request a complete itemized estimate and confirm coverage before starting. The cost-effectiveness debate has also affected national coverage decisions. NICE TA854.

15. What if ketamine treatment does not help?

Nonresponse calls for reassessing the diagnosis, prior treatment exposure, medical and psychiatric comorbidity, symptom trajectory, and available evidence-based alternatives. Patients should not independently change the dose, combine sedating substances, or purchase compounded formulations hoping for stronger effects. Consult the team about psychotherapy, medication changes, ECT, TMS, and appropriate continuing support. NICE; Treatment-Resistant Depression guide.

XV. Practical clinical interpretation

The central conclusion is that ketamine and esketamine are meaningful options for some adults with difficult-to-treat unipolar depression, with the clearest evidence for relatively rapid reduction of depressive symptoms in selected populations. Intravenous racemic ketamine and FDA-approved intranasal esketamine occupy different regulatory and delivery pathways. The magnitude of average benefits, ability to maintain them, medical and psychological adverse effects, and feasibility of repeated supervised treatment all belong in the decision. A realistic treatment plan combines careful selection, informed consent, measured clinical outcomes, and responsive follow-up. CANMAT; FDA; Fountoulakis et al..

A patient facing prolonged depression deserves an assessment that is broad enough to discover reversible barriers, precise enough to establish an appropriate indication, and responsive enough to address safety immediately. For a general route through available treatments, begin with Depression Treatment: Therapy, Medication, and Other Options; for prior treatment nonresponse, use Treatment-Resistant Depression; and for diagnosis, use Depression Diagnosis: What a Clinical Evaluation Includes. These resources support discussion with a qualified clinician rather than substituting for individual medical advice. NICE; NIMH.

Related Articles

Depression Treatment: Therapy, Medication, and Other Options — how standard and advanced treatment choices fit together.

Treatment-Resistant Depression: Definition, Assessment, and Options — how nonresponse is reassessed and what treatment options remain.

Depression Diagnosis: What a Clinical Evaluation Includes — a guide to clinical diagnosis, differentiation, and care planning.

Depression: Symptoms, Causes, Diagnosis, and Treatment — the broader condition overview.

Depression Self-Help: Strategies Supported by Research — practical strategies used alongside clinical care.

Depression and Sleep: Insomnia, Oversleeping, and Treatment — sleep difficulties and treatment considerations.

Ketamine for OCD: What Does the Evidence Show? — a separate condition-specific evidence review, with its own indications and research limits.

TMS for Depression: Evidence, Eligibility, and Treatment Process — the clinical evidence, eligibility and treatment pathway for a related neuromodulation option.

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Lam, R. W., et al. (2024). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 update on clinical guidelines for adults with major depressive disorder. Canadian Journal of Psychiatry. https://doi.org/10.1177/07067437241245384.

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National Institute of Mental Health. (2024, updated). Depression. Official clinical information.

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U.S. Department of Veterans Affairs & Department of Defense. (2022). Clinical practice guideline for the management of major depressive disorder. Official guideline.

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