Ketamine is a racemic mixture of the R and S enantiomers developed as an anesthetic; esketamine is the S-enantiomer and is also available as an intranasal formulation specifically approved for depressive indications in several regulatory systems. At subanesthetic doses, intravenous ketamine and intranasal esketamine can produce a much more rapid reduction in depressive symptoms than conventional antidepressants, often observable within the first hours or days. However, this rapidity does not equate to a definitive cure: without a continuation strategy, some patients lose the benefit, and treatment requires patient selection, monitoring and integration into a comprehensive plan.
The distinction between molecule, formulation and regulatory indication is fundamental. Intravenous racemic ketamine has been extensively studied in treatment-resistant depression, but in many countries its antidepressant use remains off-label. In the United States, since January 2025, intranasal esketamine has been approved for treatment-resistant depression in adults both as monotherapy and in combination with an oral antidepressant; in the European Union, by contrast, Spravato is authorized for treatment-resistant major depression in combination with an SSRI or SNRI. Approvals apply to specific products, formulations and populations and cannot automatically be extended to compounded preparations or different routes of administration.
The best-defined initial pharmacological target is the NMDA glutamate receptor, which ketamine and esketamine antagonize noncompetitively. However, the antidepressant effect is not explained by a simple “glutamate blockade.” Experimental models propose a transient reorganization of glutamatergic transmission, with a relative increase in signaling through AMPA receptors, modulation of cortical and limbic circuits, and activation of intracellular pathways associated with synaptic plasticity, including BDNF-TrkB and mTOR. These models are biologically plausible and supported by numerous preclinical observations, but not all steps have been demonstrated to be causal mediators of the antidepressant effect in humans.
Pharmacology is further complicated by the presence of active metabolites and differences between R-ketamine and S-ketamine. It is therefore incorrect to reduce the clinical response to a single receptor or to use experimental biomarkers as predictive clinical tests. The acute subjective effect, including dissociation, is not a demonstrated therapeutic requirement and its intensity should not be pursued as a treatment target.
Compared with monoaminergic antidepressants, the clinically distinctive feature is the speed of onset. This rapidity makes these strategies particularly relevant in treatment-resistant depression and high-severity scenarios, but it does not eliminate the need to assess differential diagnosis, suicide risk, bipolar disorder, psychosis, substance use and medical conditions. A rapid improvement on a depression rating scale does not in itself demonstrate a reduction in long-term suicide risk.
Randomized trials of intravenous ketamine have documented a rapid antidepressant effect in patients with treatment-resistant major depression. After a single infusion, the response can be marked but is often transient; studies of repeated administration have shown that an induction phase can consolidate benefit and that maintenance infusions can prolong it in some responders. However, there is no single universal maintenance regimen suitable for everyone, and frequency should be individualized while minimizing cumulative exposure.
For intranasal esketamine, registration trials evaluated its addition to a newly initiated oral antidepressant in treatment-resistant depression and demonstrated acute efficacy in some trials, while other studies helped define safety, maintenance and relapse prevention. In the randomized withdrawal SUSTAIN-1 trial, patients who were stable responders or in remission and continued esketamine plus an oral antidepressant had a lower risk of relapse than those switched to nasal placebo plus an antidepressant. The development program therefore shows that benefit is not limited to a single administration but requires a continuation strategy in patients who respond.
The ESCAPE-TRD trial compared intranasal esketamine plus an SSRI/SNRI with extended-release quetiapine plus an SSRI/SNRI in patients with treatment-resistant depression, providing direct comparative data on remission and maintenance of benefit. These results strengthen the role of esketamine as a treatment option for treatment-resistant depression, but do not mean that it is automatically preferable to every other strategy: choice and sequencing depend on severity, previous treatments, comorbidities, access, preferences, risk and availability of other effective options such as ECT or rTMS.
The rapid effect led to studies of esketamine in patients with a major depressive episode and suicidal ideation with intent requiring hospitalization and urgent standard treatment. In the ASPIRE trials, esketamine produced a more rapid improvement in overall depressive symptoms than placebo, with both added to intensive standard care. However, the between-group difference on the specific measure of suicidality severity was not statistically significant at the primary time point. The correct formulation is therefore that esketamine can rapidly reduce depressive symptoms in this setting, not that an independent suicide-prevention effect has been demonstrated.
A patient at high risk of suicide still requires immediate safety assessment, an appropriate level of observation, crisis treatment, management of access to lethal means, and treatment of the depressive episode. No pharmacological response over the following hours replaces these interventions. Similarly, agitation, psychotic symptoms, catatonia or the need for a highly reliable effect may favor other strategies, including ECT, depending on the clinical picture.
For intranasal esketamine, it is essential to distinguish rapid improvement in depressive symptoms from suicide prevention. The US regulatory indication for patients with major depressive disorder and acute suicidal ideation or behavior concerns reduction of depressive symptoms within a comprehensive care pathway; it does not demonstrate that the drug prevents suicide, removes the need for hospitalization or replaces safety measures. In the ASPIRE trials, treatment was added to intensive standard care that included urgent psychiatric assessment and hospitalization when indicated. Correct clinical interpretation must therefore keep depressive endpoints, suicidal ideation, suicidal behavior and mortality separate.
Before treatment, the diagnosis should be confirmed and treatment resistance should be adequately documented, distinguishing true nonresponse from insufficient doses, inadequate duration, poor adherence or incorrect diagnosis. The history should assess manic or hypomanic episodes, psychotic symptoms, substance use disorders, previous exposure to anesthetics or dissociatives, cardiovascular, neurological, hepatic and urological disease, pregnancy or potential pregnancy, and concomitant medications.
Intravenous ketamine requires a clinical setting capable of monitoring vital signs and managing acute events; intranasal esketamine must be administered under the conditions specified for the product and by the local regulatory system, with clinical observation after the dose. In the United States, distribution and administration of Spravato are subject to a REMS program, with administration under healthcare supervision and monitoring for risks such as sedation, dissociation and respiratory depression. Blood pressure should be assessed because transient increases are common.
The most common acute events include dissociation, dizziness, sedation or somnolence, nausea, perceptual disturbances, anxiety, headache, and transient increases in blood pressure and heart rate. Most are self-limiting, but intensity can vary and justifies administration in a controlled setting. Respiratory depression has also been reported with esketamine and, rarely, events requiring medical intervention. Cardiovascular conditions in which an increase in blood pressure or intracranial pressure poses a risk require particular caution and application of product-specific contraindications.
Ketamine has a recognized potential for abuse and dependence. Risk during supervised medical treatment is not equivalent to that associated with recreational use, but it should be assessed, especially in people with substance use disorders or patterns of dose escalation. Treatment should not become uncontrolled access to at-home administration of unvalidated formulations. Repeated high-dose exposure in nonmedical use is associated with cystitis and urinary tract injury; hepatobiliary abnormalities and possible cognitive effects provide further reasons to limit exposure to what is necessary and monitor compatible symptoms during prolonged treatment.
Maintenance safety data for esketamine are now more extensive than in the first years of use, but remain less mature than those available for antidepressants used for decades. The decision to continue should therefore be based on a periodically reassessed benefit-risk ratio, using the lowest frequency capable of maintaining benefit under applicable protocols.
Ketamine and esketamine should not be considered “definitive cures” or merely pharmacological accelerators. Their best-established role is in treatment resistant depression, after careful evaluation of previous treatments and within a program that includes appropriate pharmacotherapy, psychotherapy when indicated, interventions targeting sleep and comorbidities, risk management and relapse-prevention strategies. When possible, the initial response should be translated into functional recovery and maintenance.
Individual prognosis is heterogeneous. Some patients achieve a rapid, sustainable response with spaced administrations; others respond only transiently or not at all. There is still no validated clinical or biological biomarker that identifies responders with high accuracy. Treatment decisions therefore remain based on group-level evidence, individual appropriateness, prospective monitoring and discontinuation when the benefit-risk balance becomes unfavorable.
After an initial response, a decision is required on whether and how to continue treatment. For esketamine, randomized relapse-prevention studies support a maintenance phase in selected responders or remitters; for intravenous racemic ketamine, maintenance evidence is less standardized and protocols vary between centers. The prognosis of response cannot be inferred from a single infusion: episode duration, number of treatment failures, comorbidities, adherence and continuity of care influence outcome. Even when the effect is rapid, functional recovery and relapse prevention require a longitudinal plan that includes maintenance treatment, psychotherapy when indicated and risk monitoring.
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