Ketamine and esketamine in treatment-resistant depression

Ketamine is an injectable general anaesthetic, used to induce and maintain anaesthesia, for procedural sedation and for pain relief; it has been on the World Health Organization Model List of Essential Medicines since 1984.³

It acts mainly by blocking the NMDA receptor, one of the receptors for glutamate, the brain’s main excitatory messenger.¹ The molecule exists in two mirror-image forms; the ketamine used in anaesthesia is a racemic mixture of both, esketamine and arketamine.¹

Esketamine is the S form of the ketamine molecule, used on its own. Like ketamine, it is a non-competitive NMDA receptor antagonist.¹

As a nasal spray, it has held an authorisation valid throughout the European Union since 18 December 2019, for adults with treatment-resistant depression and no response to two or more different antidepressants during the current moderate or severe episode, always together with an SSRI or SNRI antidepressant.^1,2 Since February 2021, the authorisation also covers short-term treatment, with an oral antidepressant, to rapidly reduce depressive symptoms that, in clinical judgement, constitute a psychiatric emergency.⁴

The conditions of use are part of the authorisation. The decision to prescribe rests with a psychiatrist; the spray is self-administered in an appropriate clinical setting under the direct supervision of a healthcare professional; blood pressure is measured before and about 40 minutes after; and the person stays under observation until clinically stable.¹

It shows a rapid antidepressant effect. The first controlled trial, published in 2000, recorded improvement within 72 hours of a ketamine infusion compared with placebo.⁵ In 2006, a trial in treatment-resistant depression confirmed an effect starting within hours and lasting about a week.⁶

Esketamine nasal spray was assessed in phase 3 trials. Added to a newly started oral antidepressant, it was superior to the antidepressant with a placebo spray;⁷ continued in people who had responded, it delayed relapse.⁸ In a 2023 trial, it led to more remissions at eight weeks than augmentation with an atypical antipsychotic.⁹

Also in 2023, in a randomised trial in treatment-resistant depression without psychosis, intravenous ketamine was non-inferior to electroconvulsive therapy.¹⁰ An international expert consensus regards ketamine and esketamine as the first non-monoaminergic agents with proven rapid-onset efficacy in depression, with questions still open about their place in treatment algorithms and the conditions for giving them.¹¹ An earlier consensus from the American Psychiatric Association stressed the limits of the data and the need for caution.¹⁸

It is a research model that combines ketamine with structured psychotherapy in three stages: preparation, before the session; the session itself, with support; and integration, afterwards, to work through what came up.¹²

A systematic review suggests that psychotherapy before, during and after the sessions may prolong the benefits, with wide variation between studies; the authors call for larger randomised trials.¹² The remaining data come from case series without a control group¹³ and from a phase 2 trial in alcohol use disorder, in which ketamine with psychological therapy was followed by more days of abstinence at six months.¹⁴ In depression, this model is still under investigation.

It needs a prior assessment and monitoring at every administration. The most typical effects occur on the day itself and are transient: dissociation, a sense of distance from one’s body or surroundings that usually passes in about an hour and a half, and a temporary rise in blood pressure, peaking about 40 minutes later.¹

Before starting, the following are assessed:

• cardiovascular and cerebrovascular disease: esketamine is contraindicated in people with aneurysmal vascular disease, a history of intracerebral haemorrhage, or a cardiovascular event in the last six weeks, including myocardial infarction;¹
• blood pressure, measured before and after each administration;¹
• the risk of abuse or misuse, assessed beforehand and monitored during treatment; dependence and tolerance have been reported with prolonged ketamine use;¹
• urinary symptoms: chronic recreational ketamine use is associated with bladder toxicity, and monitoring is recommended during longer treatment;^1,15,16
• other medication, to identify relevant interactions.

On the day of treatment, driving or operating machinery should wait until the next day, after a restful night’s sleep.¹ Esketamine has not been shown to prevent suicide or reduce suicidal thoughts, and it does not replace hospital admission when admission is indicated.¹

In Portugal, Infarmed approved public funding of esketamine nasal spray in May 2025 for hospital use in the national health service, for a narrower group than the European authorisation covers: adults with no response to at least three antidepressants, including combination or augmentation strategies, with prior psychotherapy, and for whom electroconvulsive therapy has not worked, is contraindicated, is not accessible or has been declined.¹⁷

Ketamine is authorised as an anaesthetic, and its use in depression is outside the approved indications (“off-label”).^3,18 Off-label use means prescribing an authorised medicine for a situation not included in its summary of product characteristics. It is an individual clinical decision, made with informed consent, and it may not be advertised.¹⁹

In Portugal, the Psychiatry Specialty College of the Portuguese Medical Association published a resolution on the clinical use of these substances in 2023 (CEP-2023-R-02).

• Were previous treatments given at an adequate dose and for long enough?
• What other options are there in my case, such as transcranial magnetic stimulation or electroconvulsive therapy?
• Do I have any condition that rules out esketamine?
• Where and how would treatment take place, and how do I get home that day?
• What effects should I expect on the day itself?
• How is the response measured, and when is the decision made to continue or stop?

• The exact place of ketamine and esketamine in treatment algorithms and how they compare directly with other options.¹¹
• The ideal conditions for giving them: setting, infrastructure and staff.¹¹
• The long-term effects of repeated treatment, including on the bladder.¹⁵
• The contribution of accompanying psychotherapy, which needs larger randomised trials.¹²