Esketamine-The First Ketamine-Based Anti-Depressant Approved in US


The US Food and Drug Administration has just approved esketamine as an anti-depressant. Esketamine is the S-enantiomer of ketamine, which is more potent on glutamate receptors than its mirror image, R-ketamine. It is believed that ketamine produces antidepressant effects as it works through the NMDA receptor leading growth of new nerve connection (synapses). The most remarkable feature of this new type of anti-depressant is the speed in which it lifts depression symptoms for Treatment Resistant Depression, which typically fails to respond to other forms of anti-depressant prescribing. In the early studies of ketamine, a significant number of patients experienced dramatic improvement after just 4 hours after administration.

While some patients may need several treatments before effects are noticeable, the possibility of helping patients experience significant improvement after just one treatment. This is major advancement over traditional antidepressants which can take weeks. The patients with Treatment Resistant Depression enrolled in the Esketamine trials had a specific profile. Usually patients with major medical problems or psychiatric comorbidities are excluded in research trials. In the clinical trials of Esketamine that led to FDA approval for Treatment Resistant Depression, key exclusion criteria included active substance use disorder (or within 6 months), history or current psychosis and bipolar depression. These moderately to severely depressed patients had failed two or more antidepressant courses in the current episode but generally no more than 8 (different upper limits were used in different trials; most trials used 5) and have not failed electroconvulsive therapy (ECT).

In selecting appropriate patients for Esketamine treatment, the Interventional Psychiatry Service at Yale strives to align with the key inclusion/exclusion criteria of the trials, with some exceptions. For instance, in clinical practice, there is no legitimate reason to exclude patients if they have failed more than 8 adequate antidepressant trials or if they have failed ECT.

Despite the excitement about Esketamine, it has been a very difficult treatment for psychiatrists to implement. Patients receiving Esketamine must be treated on-site, at a doctor’s office, or other health care facility and be observed for 2 hours following dosing. This includes vital signs that most psychiatrists’ are not equipped the necessary resources this.

There are risks to using the drug. The obvious one of the abuse potential. Patients should not drive on the days they receive treatment and cognition is impaired in the following Esketamine administration, but usually resolves within 60 to 90 minutes.

There is a possible risk of long-term and persistent cognitive impairment as has been observed seen in those who misuse ketamine repeatedly. However, long though a term study generally indicated Esketamine did not have a significant negative effect As with any psychiatric medication, these risks should be weighed carefully against the potential benefit to patients.

Certainly Esketamine offers a promising treatment approach that can promote rapid improvement in patients with depression, who have not been helped by other means. However, questions remains about the long-term approach to treating depression with esketamine.


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