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Background: Abnormalities of heart rate (HR) and its variability are characteristic of major depressive disorder (MDD). However, circadian rhythm is rarely taken into account when statistically exploring state or trait markers for depression. Methods: A 4-day electrocardiogram was recorded for 16 treatment-resistant patients with MDD and 16 age- and sex-matched controls before, and for the patient group only, after a single treatment with the rapid-acting antidepressant ketamine or placebo (clinical trial registration available on https://www.clinicaltrialsregister.eu/ with EUDRACT number 2016-001715-21). Circadian rhythm differences of HR and the root mean square of successive differences (RMSSD) were compared between groups and were explored for classification purposes. Baseline HR/RMSSD were tested as predictors for treatment response, and physiological measures were assessed as state markers. Results: Patients showed higher HR and lower RMSSD alongside marked reductions in HR amplitude and RMSSD variation throughout the day. Excellent classification accuracy was achieved using HR during the night, particularly between 2 and 3 a.m. (90.6%). A positive association between baseline HR and treatment response (r = 0.55, p = 0.046) pointed toward better treatment outcome in patients with higher HR. Heart rate also decreased significantly following treatment but was not associated with improved mood after a single infusion of ketamine. Limitations: Our study had a limited sample size, and patients were treated with concomitant antidepressant medication. Conclusion: Patients with depression show a markedly reduced amplitude for HR and dysregulated RMSSD fluctuation. Higher HR and lower RMSSD in depression remain intact throughout a 24-h day, with the highest classification accuracy during the night. Baseline HR levels show potential for treatment response prediction but did not show potential as state markers in this study.
Circadian oscillations in circulating leukocyte subsets including immature hematopoietic cells have been appreciated; the origin and nature of these alterations remain elusive. Our analysis of wild-type C57BL/6 mice under constant darkness confirmed circadian fluctuations of circulating leukocytes and clonogenic cells in blood and spleen but not bone marrow. Clock gene deficient Bmal1-/- mice lacked this regulation. Cell cycle analyses in the different hematopoietic compartments excluded circadian changes in total cell numbers, rather favoring shifting hematopoietic cell redistribution as the underlying mechanism. Transplant chimeras demonstrate that circadian rhythms within the stroma mediate the oscillations independently of hematopoietic-intrinsic cues. We provide evidence of circadian CXCL12 regulation via clock genes in vitro and were able to confirm CXCL12 oscillation in bone marrow and blood in vivo. Our studies further implicate cortisol as the conveyor of circadian input to bone marrow stroma and mediator of the circadian leukocyte oscillation. In summary, we establish hematopoietic-extrinsic cues as causal for circadian redistribution of circulating mature/immature blood cells.