Study reveals cognitive safety of ketamine and esketamine for patients with treatment-resistant depression


Used for the treatment of depression that does not respond to standard antidepressant drugs, the anesthetic drug ketamine – and the related drug esketamine, recently approved for the treatment of depression – does not have significant adverse effects on memory, l attention or other cognitive processes, concludes a systematic review of medical research in the September / October issue of Harvard Journal of Psychiatry. The journal is published in the Lippincott portfolio by Wolters Kluwer.

“Current evidence suggests that ketamine and esketamine do not appear to exert significant deleterious neurocognitive effects in treatment-resistant depression,” according to new research, led by Breno Souza-Marques, BA, and Lucas C. Quarantini, MD, PhD, from Federal University of Bahia, Salvador, Brazil. Indeed, certain cognitive functions improved 7 to 13 days after repeated infusions of ketamine.

Evidence supports cognitive safety of ketamine and esketamine for the treatment of depression

Ketamine is a widely used surgical anesthetic that produces a detached and dreamlike state. Numerous studies have shown that at low doses, ketamine can have rapid antidepressant effects – usually improving mood within 24 hours to 7 days. Similar benefits have been reported with esketamine, a version of the drug recently approved for use in patients with treatment-resistant depression. Although ketamine is not yet approved for the treatment of depression, some doctors prescribe it for this purpose on an “off-label” basis.

However, there are potential safety concerns with ketamine, which is “a much sought-after recreational drug,” according to the authors. Studies have reported impaired memory after long-term recreational use of ketamine, as well as in medical studies in which healthy volunteers received only one infusion. This is particularly concerning because memory problems and other cognitive symptoms – such as difficulty thinking and concentrating – are a key aspect of major depressive disorder. Cognitive symptoms can persist even after an improvement in mood.

To study the cognitive safety of ketamine and esketamine, Dr. Souza-Marques, Dr. Quarantini and their colleagues searched the medical literature for studies in which one of these drugs was administered to patients with treatment-resistant depression. Definitions vary, but most experts consider depression to be “treatment resistant” if it persists after the patient has tried at least two different antidepressants.

The team identified 14 studies collectively involving 1,019 patients: one study of esketamine nasal spray for 44 weeks, seven studies of a single intravenous infusion of ketamine, and six studies in which patients received six out of two ketamine infusions. or three weeks. The assessment of neuropsychological performance was variable for the ketamine studies (1 study at 40 minutes, 1 study at 24 hours, 1 study at 3 days and 1 study at 7 days), while the study with esketamine performed repeated assessments at 28 days, 20 weeks, 32 weeks and 44 weeks.

The esketamine study showed no change in cognitive performance. Five ketamine studies actually reported improvements in memory, processing speed (the time it takes to complete a mental task) or cognitive flexibility (the ability to switch between mental tasks or thoughts).

Only one of 14 studies reported cognitive impairment after treatment with ketamine. Memory was worse 24 hours after six ketamine infusions and the speed of treatment was worse 24 hours after a single infusion, but these deficits were no longer present seven days after treatment. In addition, the group that received multiple infusions showed improved processing speed, cognitive flexibility and memory. Despite this encouraging evidence, more studies are needed to assess the long-term neurocognitive effects of these drugs.

Some studies have shown that people who had certain cognitive attributes before treatment – lower attention, slower processing speed, or better memory – were more likely to respond to ketamine. The researchers conclude: “The results suggest possible neuropsychological profiles predictive of the antidepressant response to ketamine, such as less attention, slower processing speed, or higher working memory, which should be further evaluated in future studies, as these results could provide time-saving evidence for clinicians and mental health practitioners.. “


Journal reference:

Souza-Marques, B., et al. (2021) Neurocognitive effects of ketamine and esketamine for treatment-resistant major depressive disorder: a systematic review. Harvard Journal of Psychiatry.


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