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Gregory P. Daily

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Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant Properties

Abstract

Background

The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock–associated molecules, and clinical studies of Ketamine online plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis.

Methods

Wrist-activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. Circadian amplitude and timing of activity at baseline, postinfusion day 1 (D1), and day 3 (D3) were measured in 51 patients with major depressive disorder or bipolar disorder.

Results

Compared with either placebo or baseline, a mood-independent decrease of the central circadian value (mesor) was present on D1 after ketamine treatment. Mood-associated circadian effects between rapid (D1) responders and nonresponders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from nonresponders. On D1, ketamine nonresponders had a lower mesor and a blunted 24-hour amplitude relative to baseline. On D3, patients with a persisting clinical response exhibited a higher amplitude and mesor compared with nonresponders.

Conclusions

The findings are the first to demonstrate an association between ketamine’s clinical antidepressant effects and circadian timekeeping. The results suggest that traitlike circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system.

 Ketamine is a versatile medicine and possibly the most widely used anaesthetic in the world.1

It is listed as an essential medicine, meaning that it should be available at all times in

adequate amounts for health care needs. It was added to the WHO Model List of Essential

Medicines in 1985 and is also on the Model List of Essential Medicines for Children.

Ketamine is also effective for relieving pain. In addition, it is the most widely used

anaesthetic in veterinary surgery. In recent years, there has been extensive research into the

potential use of ketamine as a treatment for depressive disorders and in epilepsy.

Why is ketamine used instead of other types of anaesthetic?

In many parts of the world, there is no choice: ketamine is often the only anaesthetic at hand.

Ketamine is extremely safe because, unlike other anaesthetic agents, it does not depress

breathing or blood pressure. This means it is relatively easy to administer, and is an excellent

anaesthetic for patients who have lost a lot of blood or who have dangerously low blood flow

due to septic shock.

Ketamine’s high level of safety also makes it unique amongst other anaesthetics, as it does

not require reliable electricity supply, oxygen, highly trained staff or monitoring systems to

administer. That makes it critical in surgery in low- and middle-income countries and in

conflict and disaster zones where such resources are often unavailable.

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