Mood Effects of Ketamine Linked to Circadian Timekeeping

The drug and mood-dependent effects of ketamine may be linked to circadian activity patterns, according to recent research.

A study, led by Wallace C. Duncan (pictured), Jr., PhD, of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health in Bethesda, Maryland, designed to investigate the effects of one ketamine injection on circadian rhythm expression in patients with bipolar disorder (BD) or major depressive disorder (MDD) found that there is a link between them.

“This is the first clinical evidence linking circadian timekeeping to the rapid mood elevating effects of ketamine,” Duncan told MD Magazine. “This linkage suggests trait-like differences as well as circadian and sleep related mechanisms that mediate the clinical response.”

The researchers recruited 51 subjects, 30 diagnosed with MDD and 21 with BD. All of the participants had not responded to previous treatments. Each participant wore an Actiwatch wrist activity monitor for 3 to 4 days before a scheduled ketamine or placebo infusion. The participants wore the activity monitor for an additional 5 days following the infusion.

The 24-hour wrist monitor patterns were analyzed to identify differences in phase, amplitude, and mesor at baseline (2 days pre-infusion), the authors noted. The patients were then classified according to scores on the Montgomery-Asberg Depression Rating Scale (MADRS) at Day 0 (230 minutes post-infusion), Day 1 (1 day post-infusion), and Day 3 (3 days post-infusion). Patients with a 50% reduction in MADRS scores were considered ketamine responders, and those with a less than 50% improvement were considered non-responders.

The researchers found that both Day 1 and Day 3 responders had lower MADRS scores than non-responders. “AM activity and MADRS scores were positively correlated on [Day 1], but not on [Day 3],” the researchers reported. For PM activity, there were significant negative correlations on Day 3, but not on Day 1.

The study discovered — no surprise to the researchers – that ketamine had “distinct mood-dependent effects on wrist-activity markers of circadian timekeeping.”

“Changes in circadian amplitude and phase have frequently been reported in the literature as a result of various treatment interventions,” Duncan said, noting that rapid mood effects are often associated with interventions such as sleep restriction and light therapy. “However, this is the first report of a pharmacological intervention producing both rapid mood elevating and circadian timekeeping effects, thus typing the different treatment approaches together.”

Certainly, the results of this study are promising, however, Duncan emphasized the preliminary nature and need for replication. He noted that it was conducted in a clinical research setting with treatment resistant patients. “Whether the results extend to an outpatient setting with other patient groups requires further evaluation,” Duncan said.

In addition to replication, particularly using additional markers of circadian timing, Duncan said that there may be an opportunity to predict which and when patients need additional ketamine treatments.

“Another step will be to identify the utility of using specific circadian activity and sleep markers to predict both the rapid and extended treatment responses (and relapses) so that clinicians might anticipate the need for repeated ketamine treatments,” he said.

The full study was published online in the journal Biological Psychiatry.

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