Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant Properties
Open accessAbstract
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 on 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.
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Clock gene expression could be more a long-term mechanism of ketamine, with the increase in sleep, SWS/SWA and more acute circadian rhythm changes being more linked to the rapid effects.
“As such, clock gene expression could be more a long-term mechanism of ketamine, with the increase in sleep, SWS/SWA (which has been described as a proxy for sleep homeostasis) and more acute circadian rhythm changes being more linked to the rapid effects.141”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [141]
Small studies have shown that ketamine responders exhibit more phase advance and a stronger amplitude increase in 24 h motor activity, indicating a more robust circadian rhythm.
“Small studies have shown ketamine responders exhibit more phase advance and a stronger amplitude increase in 24 h motor activity, indicating a more robust circadian rhythm.141,142”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [141]
The rapid and lasting antidepressant effects of low-dose ketamine can be predicted based on measures of locomotor activity rhythms before treatment and on how well the treatment strengthens low-amplitude activity rhythms.
“the rapid and lasting antidepressant effects of low-dose ketamine can be predicted based on measures of locomotor activity rhythms before treatment and on how well the treatment strengthens low-amplitude activity rhythms”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [218]
The therapeutic effects of ketamine are directly related to the strengthening of the circadian system.
“suggesting that the therapeutic effects are directly related to the strengthening of the circadian system218”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [218]
In 51 patients with major depressive disorder or bipolar disorder, circadian activity patterns prior to and following the administration of ketamine are linked to therapeutic response of mood symptoms.
“In a study of 51 patients with major depressive disorder or bipolar disorder, circadian activity patterns prior to and following the administration of ketamine are linked to therapeutic response of mood symptoms.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [218]
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- Authors
- Duncan, W. C., Slonena, E., Hejazi, N. S., Brutsche, N., Yu, K. C., Park, L., Ballard, E. D., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Duncan, Wallace C.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 82
- Issue
- 5
- Pages
- 361-369
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5546993
- OpenAlex
- W2599480332
- Cited by
- 93
- References
- 68
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 20 · 2020: 8 · 2019: 12 · 2018: 7 · 2017: 2
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002927)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, rapid antidepressant effects, circadian timekeeping, circadian rhythm, major depressive disorder, bipolar disorder, circadian amplitude, circadian phase, mesor, sleep-wake behavior, synaptic plasticity
- MeSH terms
- Adult, Affect, Aged, Antidepressive Agents, Bipolar Disorder, Circadian Rhythm, Major Depressive Disorder, Depressive Disorder, Major, Drug Resistance, Female, Humans, Ketamine, Male, Middle Aged, Motor Activity, Sleep, Time Factors, Treatment Outcome, Young Adult, Actigraphy, Depressive Disorder, Treatment-Resistant
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