Brief reportPhase relationships between core body temperature, melatonin, and sleep are associated with depression severity: Further evidence for circadian misalignment in non-seasonal depression
Introduction
Decades of accumulating evidence of sleep and circadian abnormalities in mood disorders have engendered a wide range of explanatory hypotheses. These varied perspectives have focused on factors including sleep processes (e.g., deficiency in slow wave sleep and slow wave activity), neurotransmitter systems (e.g., a cholinergic–aminergic imbalance), or the behavioral–environmental interface (e.g., social rhythm irregularities leading to disruptions in physiological circadian rhythms (reviewed in Benca et al., 1997, Boivin, 2000, Riemann et al., 2001, Germain and Kupfer, 2008, among others). Still another early hypothesis, the internal coincidence hypothesis (Wehr et al., 1979) posited that sleeping at the wrong biological time, with relatively advanced circadian phase, is depressogenic. While none of these competing explanations has emerged as conclusive, recent evidence suggests that hypotheses linking misalignment between the timing of sleep and the endogenous circadian pacemaker to depressive symptomatology may deserve further consideration.
Several recent studies have operationalized circadian misalignment by measuring the interval between the dim light melatonin onset (DLMO), the most robust indicator of the timing of the central pacemaker, and the time of midsleep. In healthy samples on typical sleep/wake schedules, DLMO occurs approximately two to three hours before sleep onset (Benloucif et al., 2008). In a sample of Seasonal Affective Disorder patients, the phase angle difference (PAD), or interval, between the timing of DLMO and that of midsleep was associated with more severe depression. The strongest relationship was observed for phase-delayed individuals (i.e., relatively later DLMOs resulting in shorter PADs) (Lewy et al., 2006). In a group of women with major depressive disorder, the PAD in delayed individuals correlated with depression severity (Emens et al., 2009a). Preliminary findings also suggest a parallel association between the PAD and subclinical depressed mood in healthy individuals (Emens et al., 2009b). In contrast to the original internal coincidence hypothesis, both of these studies suggest that the timing of the circadian clock is delayed rather than advanced relative to the sleep/wake cycle.
These data suggest that circadian misalignment may be relevant to depressive symptomatology across mood disorders, and perhaps also to healthy individuals. However, the published findings have not been independently replicated. Furthermore, less attention has been paid to the respective phase angles between circadian processes other than sleep, phase angles that may reveal other evidence of internal desynchrony. We sought to determine if the respective phase angles between DLMO, core body temperature minimum (CBTmin), and midsleep differed between healthy controls and individuals with major depressive disorder (MDD), and if these phase angles correlated with depression severity. Based on previous findings, we hypothesized that: 1) depressed individuals would be phase-delayed, with shorter DLMO-midsleep and longer midsleep-CBTmin phase angles relative to those of the controls (see Fig. 1); and 2) the extent of phase-delay would correlate with the severity of depression. We included measures of both global and anhedonic depression given recent evidence that the circadian system may be particularly involved in regulation of reward processes (Mcclung, 2007, Murray et al., 2009). Finally, we also explored group differences in the DLMO-CBTmin phase angle as an additional and novel measure of circadian desynchrony.
Section snippets
Methods
Subjects participated in a study investigating circadian, electrophysiological, and cognitive changes around sleep onset in patients with MDD and healthy controls. Inclusion criteria for the patient group included meeting criteria for recurrent unipolar MDD, with a current endogenous depressive episode as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) (First et al., 2002). Patients were required to score > 16 on the 17-item Hamilton Rating Scale for Depression (
Results
The patient group had a mean HAM-D score (± SD) of 21.0 ± 4.07 (range = 16–29) and a mean total BDI score of 25.15 ± 7.15 (range = 12–36); the control group had mean HAM-D and BDI scores below 1. Compared to controls, depressed patients had a lower mean score (greater eveningness) on the MEQ (t(14) = 3.40, P = 0.004), and later mean sleep onset (t(24) = − 4.27, P < 0.001) and sleep midpoint (t(24) = − 2.60, P = 0.02), but did not differ on clock times of sleep offset or CBT minimum. The depressed group's mean DLMO
Discussion
Findings from this exploratory study replicate the observed association between circadian misalignment and depression severity in patients with MDD. Specifically, a larger phase angle difference between midsleep and the core body temperature minimum was associated with greater depression. We also found preliminary evidence of an association between depressive severity and the phase angle between DLMO and CBT minimum. Both of these phase angles correlated with the severity of anhedonic
Acknowledgements
This work was supported by the National Institutes of Health Grant R01-MH24652 and the University of Pittsburgh General Clinical Research Center Grant RR00056 to DJK.
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