Ketamine and esketamine

Is it “ketamine” or “cetamina”?

They are the same substance. “Ketamine” is the English form of the international non-proprietary name; “cetamina” is the Portuguese form, used, for example, in the official Portuguese product information and by the Portuguese Medical Association [3] [4]. The same applies to esketamine (“escetamina” in Portuguese).

What is esketamine?

The ketamine molecule exists in two forms that are mirror images of each other, the S and R enantiomers. The ketamine used in anaesthesia is an equal mixture of both (a racemic mixture); esketamine is the S form on its own [2].

Esketamine was developed as a medicine in its own right, as a nasal spray, for treatment-resistant depression [3]. Because the formulations, routes of administration and authorisations differ, results for one do not automatically apply to the other.

Research in treatment-resistant depression

Depression is called treatment-resistant when symptoms persist despite at least two adequate antidepressant treatments, in dose and duration. Usual antidepressants take weeks to work.

In 2000, a small controlled trial reported an improvement in depressive symptoms within hours of a single ketamine infusion [5], a result confirmed in 2006 in people with treatment-resistant depression [6]. Since then, trials and meta-analyses have confirmed a rapid antidepressant effect [7], and a randomised trial compared ketamine with electroconvulsive therapy in treatment-resistant depression without psychosis [8]. Trials of esketamine nasal spray, combined with an oral antidepressant, supported its authorisation [9] [10], and one trial compared it with quetiapine [11].

The evidence has important limits:

• the effect of each administration is usually short-lived [12], and a Cochrane review considers it not entirely clear how the results translate into clinical practice [13];
• dissociative effects make blinding hard to maintain in trials, because participants often notice whether they received the active substance;
• there are few long-term studies, and doses, intervals and routes of administration vary widely between studies.

What does off-label use of ketamine mean?

Each medicine is authorised for indications, doses, ages and routes of administration defined in its summary of product characteristics (SmPC). Using it outside those terms is off-label use, that is, outside the approved indications [14].

European and Portuguese medicines law regulates marketing authorisation, manufacturing and advertising [15] [16]. It does not regulate how doctors prescribe, and EU law does not prohibit off-label prescribing [17]. In Portugal, such prescribing is an individual clinical decision, under the full responsibility of the physician, who must base it on scientific knowledge, explain it to the patient and obtain their informed consent [14] [18].

Advertising of a medicine must be consistent with the SmPC (article 150 of the Portuguese Medicines Statute), and prescription-only medicines may not be advertised to the public (article 152) [16]. Off-label use therefore cannot be promoted.

Off-label use exists in several areas of medicine; whether it is appropriate always depends on an individual medical assessment.

What is authorised in the European Union and in Portugal?

In the European Union, including Portugal:

• esketamine nasal spray: authorised since December 2019 for adults with treatment-resistant major depressive disorder who have not responded to at least two different antidepressants in the current moderate to severe episode, in combination with an SSRI or SNRI antidepressant. It is also authorised, with an oral antidepressant, as acute short-term treatment for the rapid reduction of depressive symptoms that, according to clinical judgement, constitute a psychiatric emergency [3];
• the decision to prescribe it rests with a psychiatrist; patients administer the spray themselves, under the direct supervision of a healthcare professional, in an appropriate healthcare setting, where they are observed after each administration [3];
• ketamine: approved in Portugal as an anaesthetic, not for depression; its use in psychiatry is therefore off-label [4].

In the United States, esketamine nasal spray was approved in 2019; later changes to the US label do not change the indications approved in the European Union [19] [20].

In Portugal, the College of Psychiatry of the Portuguese Medical Association (Ordem dos Médicos) published a resolution on the clinical use of these substances in 2023 (CEP-2023-R-02 (opens in a new tab)).

What is ketamine-assisted therapy?

In research, ketamine-assisted therapy combines ketamine sessions with structured psychotherapeutic support. The models described in the literature are usually organised in three phases [21] [12]:

• preparation: assessment, setting goals and explaining the expected effects;
• session: administration in a clinical setting, with monitoring and a therapist present;
• integration: later sessions to make sense of what came up during the experience and relate it to everyday life.

“Ketamine therapy” is sometimes used more broadly, for any therapeutic administration with or without psychotherapy. Studies of the combination are still few and small, and it has not been established that the psychotherapeutic component increases or prolongs the effect [12].

Safety, contraindications and monitoring

According to the esketamine SmPC, the most common effects are dizziness, dissociation, nausea, headache, somnolence, altered taste, vertigo, reduced sensation, vomiting and increased blood pressure [3]. Ketamine trials mainly describe dissociation and a transient rise in blood pressure [7].

• Monitoring: for esketamine, blood pressure is measured before administration and about 40 minutes afterwards, and the person stays under the supervision of a healthcare professional until clinically stable. They should not drive or operate machinery until the next day, after a night’s sleep [3].
• Contraindications: conditions in which a rise in blood pressure or intracranial pressure poses a serious risk, such as aneurysmal vascular disease, previous intracerebral haemorrhage or a cardiovascular event in the previous six weeks, including myocardial infarction; and hypersensitivity to esketamine or ketamine [3].
• Careful assessment: a history of psychosis, mania or bipolar disorder, uncontrolled hyperthyroidism and raised intracranial pressure; it is not recommended during pregnancy [3].
• Misuse: there is a risk of misuse and dependence, especially in people with a history of substance use; daily, long-term use of ketamine at high doses is associated with interstitial cystitis and with memory and cognitive impairment [3].

What is still being researched

After decades of use in anaesthesia and more than twenty years of research in depression, ongoing studies are working on several questions [7]:

• how long the benefit lasts and the safest way to maintain it;
• the most suitable dose, frequency and route of administration of ketamine in depression;
• the long-term effects of repeated administration, particularly on cognition, the bladder and the risk of misuse;
• which people are most likely to respond;
• whether accompanying psychotherapy adds benefit, and with which model [12].

Trial results describe group averages and cannot predict how each person will respond, which depends on an individual medical assessment.