Sketamine is a medication that comes in a nasal spray to be dispensed as a spray and is indicated in the treatment of resistant depression and as a general anesthetic. It is a relatively new and promising drug in the field of major depressive disorders that do not respond to conventional antidepressant treatment.
In this article we explain what sketamine is, what are its medical uses and its mechanism of action, the main side effects and contraindications to be taken into account.
What is sketamine?
Sketamine is a drug used as a general anaesthetic and as a drug therapy to address treatment resistant depression . It was developed in 1997 by the Johnson & Johnson laboratory, initially as a fast-acting antidepressant medication.
In 2017, this drug was approved for the treatment of adults with depressive conditions refractory to conventional pharmacotherapy and with a high risk of suicide, a profile of subjects who cannot wait the time it takes for classic antidepressant drugs to take effect.
Sketamine is a chemical variation (the enantiomer S) of a popular medical and recreational substance: ketamine . This drug is used as a general anaesthetic in hospital settings and its possible antidepressant effect has been investigated, although it is also used for recreational purposes in sub-anaesthetic doses, causing hallucinatory effects and near-death experiences, in which the individual experiences extracorporeal sensations and mystical states.
However, sketamine is presented in the form of a nasal spray for administration as an aerosol, a form that also serves to prevent possible abuse of the substance, although it is not yet available in Spanish pharmacies.
Sketamine is used as a general anesthetic, as is its chemical variant, ketamine, with which it shares therapeutic indications. Induction of anaesthesia is performed in high-risk patients , such as those in anaphylactic shock, septic shock, severe bronchospasm, severe liver failure, cardiac tamponade and constrictive pericarditis.
Its anesthetic potential is also used for other types of conditions, such as in the treatment of burns and in situations where it is needed as a supplement to local anesthesia with incomplete nerve blocks.
Another common use of sketamine is as a fast-acting antidepressant , specifically for treatment-resistant depression. This clinical picture describes people who have a major depressive disorder that does not respond adequately, and over time, to conventional antidepressant medication.
The nasal spray presentation has the advantage of being a non-invasive technique (as opposed to intravenous injection) and more suitable for the profile of the subjects treated with the drug. However, studies have shown that patients, after having been administered the drug through the nose, had to remain seated for 2 hours, in order to avoid side effects associated with the use of sketamine.
Clinical studies with intranasal sketamine have shown rapid and substantial efficacy. In the 2018 study by Canuso et al, sketamine given intranasally twice weekly in combination with oral antidepressants reduced suicidal ideation and depression at 4 and 24 hours, although at the end of treatment, after 4 weeks, its effect was not superior to intranasal placebo given with antidepressant treatment.
Mechanism of action
Sketamine is approximately twice as potent as the racemic mixture of ketamine and has a three to four times greater affinity for NMDA receptors . These receptors play an important role in cognitive processes such as learning, neuronal plasticity and memory.
Basically, the mechanism of action of sketamine is to act as an uncompetitive antagonist of the NMDA receptor, facilitating the modulation of glutamate receptors and AMPA receptors . The activation of these receptors increases the signalling of neurotrophic factors (proteins that favour the survival of groups of neurons) that favour short- and long-term antidepressant effects.
The modulation of glutamate receptors (and the restoration of synaptic connections between neuronal groups) is one of the distinctive features of this drug, since most classical antidepressants do not act on this system but on other systems such as dopaminergic or serotonergic.
Sketamine also acts, to some extent, as a dopamine reuptake inhibitor , but unlike ketamine, it does not interact with sigma receptors. On the other hand, this drug tends to increase glucose metabolism in the frontal cortex; this may be due to the dissociative or hallucinogenic effect that sketamine may have in a certain range of doses.
The vast majority of studies conducted with sketamine have confirmed the safety and efficacy of the drug. However, like any medication, is not free from possible side effects after administration . Among the most common ones, the following should be highlighted:
- Alterations in the sense of taste
- Metallic flavor
- Paresthesia (tingling sensation)
- Blurred vision
- Nervousness or anxiety
Before using the nasal spray of sketamine, one should consider the contraindications to the use of this drug and consult with the health professional in charge of your medical follow-up. The following are some of the precautions to be taken into account:
- Allergy to sketamine, ketamine, or any medication or ingredients included in the nasal spray
- Use of amphetamines, anxiolytics, armodafinil, MAO inhibitors such as phenelzine, procarbazine, tranylcypromine, selegiline, methylphenidate, modafinil, opioid drugs, anti-seizure drugs, sedatives.
- Disease in the blood vessels of the brain, chest, stomach, arms, or legs; arteriovenous malformations or a history of brain hemorrhage
- A history of stroke, heart attack, brain injury, or conditions that cause increased brain pressure Heart valve disease, heart failure, high blood pressure, slow or irregular heartbeat, shortness of breath, chest pain, heart or liver disease.
- Being pregnant or breastfeeding.
- If you’re having surgery, including dental surgery.
- Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., … & Drevets, W. C. (2018). Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. American journal of psychiatry, 175(7), 620-630.
- Freedman, R., Brown, A. S., Cannon, T. D., Druss, B. G., Earls, F. J., Escobar, J., … & Mayberg, H. S. (2018) Can a framework for the safe use of ketamine be established? Am J Psychiatry, 175(7).