Circadian rhythms and mood disorders: a guide for the perplexed.

J Clin Psychiatry 2015;76(5):e662–e664 (doi:10.4088/JCP.14com09716). © Copyright 2015 Physicians Postgraduate Press, Inc. O and coworkers’ present contribution1 to this journal invites the opportunity to outline some of the fundamentals concerning circadian rhythms and affective illness. Consensus or near-consensus has been reached on the tools for assessing and adjusting circadian rhythms, if not on the hypotheses for their role in seasonal affective disorder (SAD, typically winter depression), non-seasonal unipolar major depressive disorder (MDD), and bipolar disorder. First proposed in the 1980s,2,3 the dim light melatonin onset (DLMO) is now acknowledged as the most accurate biomarker for circadian phase position.4,5 It can be obtained at home in saliva,5 conveniently occurring in most cases before habitual bedtime. The dim light requirement was one of many important developments6(p15) that have resulted from the discovery that intensity-dependent light suppresses nighttime melatonin production in humans.7 This discovery continues to advance the field that now includes perhaps the first comprehensively useful laboratory test in psychiatry. Two types of phase-resetting agents are used to shift circadian rhythms. Bright light (as in the present study1) and low-dose melatonin can be given as adjunctive therapy, because they have few contraindications. However, a phase shift in the wrong direction may result if they are not scheduled at the correct time. Patients should first be phase typed, as either advanced (“morning larks”) or delayed (“night owls”). An early versus late DLMO is the best way to accomplish objective phase typing, even for circadian disorders in which adjusting the timing of sleep is the clinical goal.5 Phase-delayed disorders require bright light in the morning and/or low-dose melatonin in the afternoon/ evening to provide a corrective phase advance; phaseadvanced disorders require bright light in the evening and/or low-dose melatonin in the morning to provide a therapeutic phase delay.8,9 Among individuals, optimal treatment times can differ greatly; these are phase-locked to the internal body clock, marked by the DLMO. The resulting shift in the DLMO monitors treatment efficacy and provides for further refinement of optimal treatment times. Thus, the DLMO is comprehensively useful in the diagnosis, and in all stages of treatment, of circadian rhythm disorders. Over a wide range of intensities, the brighter the light, the greater is its phase-shifting effect. However, higher doses of melatonin are not necessarily more effective than lower ones.10 Although there is a dose-response relationship in the physiologic range,11 higher doses do not confer any additional benefit and increase the risk of sleepiness immediately after taking melatonin (which occurs in approximately one-third of the population). High doses may also be less efficacious in causing phase shifts.10 Burke and coworkers12 recently reported that the effects of light and melatonin are equal and additive; however, while their choice of 3,000 lux may approximate the optimal light intensity, their 5-mg melatonin dose was probably an order of magnitude too high and they might have achieved greater phase-shifting effects with lower doses. The phase shift hypothesis (PSH) is the leading6 explanation of why SAD patients typically become depressed in the winter and how bright light is antidepressant.13,14 Accordingly, as day length shortens, circadian rhythms drift out of phase with the sleep/wake cycle, creating a mismatch (internal misalignment) between the set of circadian rhythms tightly coupled to the body clock (cued to the light/dark cycle) and the less tightly coupled set encompassing the sleep/wake cycle and its evoked rhythms. The DLMO and the sleep midpoint, respectively, are the best phase markers for these two sets. The time interval between them, or phase angle difference (PAD), is the best marker for circadian misalignment.15 Although an optimal alignment “sweet spot” of PAD 6 (an interval of 6 hours between the DLMO and midsleep) has been documented in SAD,15 the jury is out as to the optimal PAD in MDD and bipolar disorder. PAD is also used for phase typing SAD patients: PAD ≤ 6 indicates phase-delayed circadian misalignment (a DLMO that is delayed with respect to midsleep) and requires treatment with bright light in the morning and/or low-dose melatonin in the afternoon/ evening; PAD > 6 (up to one-third of SAD patients15) indicates phase-advanced circadian misalignment (a DLMO that is advanced with respect to midsleep) and requires treatment with bright light in the evening and/or low-dose melatonin in the morning. Monitoring PAD can be used to assess correction of circadian misalignment. Phasedelayed circadian misalignment appears to predominate in MDD,16–19 although each patient may have his or her own ipsative14 sweet spot, longer or even shorter than PAD 6. It is not known which specific rhythm(s) in the two sets marked by the DLMO and midsleep are pathogenic when misaligned (in an otherwise vulnerable individual); the endogenous melatonin rhythm is not likely to be one of them. It is also important to keep in mind that while the DLMO marks the phase of the circadian rhythm of sleep Th is w or k m ay n ot b e co pi ed , d is tr ib ut ed , d is pl ay ed , p ub lis he d, re pr od uc ed , t ra ns m itt ed , m od ifi ed , p os te d, s ol d, li ce ns ed , o r u se d fo r c om m er ci al p ur po se s.