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The findings support the phase-shift hypothesis for SAD, as well as suggest …

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- The circadian basis of winter depression

Alfred J. Lewy*,, Bryan J. Lefler*, Jonathan S. Emens*, and Vance K. Bauer

*Sleep and Mood Disorders Laboratory, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239; and

Center for Health Research, Kaiser Permanente Northwest, 3800 North Interstate Avenue, Portland, OR 97227

Communicated by Aaron B. Lerner, Yale University School of Medicine, New Haven, CT, March 27, 2006 (received for review June 15, 2005)


The following test of the circadian phase-shift hypothesis forpatients with winter depression (seasonal affective disorder,or SAD) uses low-dose melatonin administration in the morningor afternoon/evening to induce phase delays or phase advances,respectively, without causing sleepiness. Correlations betweendepression ratings and circadian phase revealed a therapeuticwindow for optimal alignment of circadian rhythms that alsoappears to be useful for phase-typing SAD patients for the purposeof administering treatment at the correct time. These analysesalso provide estimates of the circadian component of SAD thatmay apply to the antidepressant mechanism of action of appropriatelytimed bright light exposure, the treatment of choice. SAD maybe the first psychiatric disorder in which a physiological markercorrelates with symptom severity before, and in the course of,treatment in the same patients. The findings support the phase-shifthypothesis for SAD, as well as suggest a way to assess the circadiancomponent of other psychiatric, sleep, and chronobiologic disorders.

chronobiology | circadian rhythms | melatonin | seasonal affective disorder | dim light melatonin onset (DLMO)

PNAS | May 9, 2006 | vol. 103 | no. 19 | 7414-7419. OPEN ACCESS ARTICLE.





The two phase-resetting agents for treating circadian rhythmdisorders are bright light and melatonin (1). The latter isthe only option for totally blind people who cannot synchronizeto the day/night cycle or do so at an abnormal time (2, 3).Both bright light and melatonin are used to treat the circadiandisorders of sighted people [reviewed by Bunney et al. (4)];these include shift-work maladaptation and jet lag, as wellas advanced and delayed sleep phase syndromes. However, thecondition in which bright light is used most often is one inwhich a circadian component has not yet been fully established:winter depression [seasonal affective disorder (SAD)] (5). Infemales of childbearing age, SAD is perhaps the most commonmood disturbance unremittingly experienced year after year duringthe 6 months between the autumnal and vernal equinoxes at temperatelatitudes, such as the northern United States and lower provincesof Canada (6), where there are marked seasonal changes in naturalday length (photoperiod). Accordingly, SAD initially was treatedwith bright light in the early morning and evening to simulatethe longer days of spring (7, 8). However, in 1998 evidencefor the superiority of morning light (vs. evening light) wasestablished in large numbers of subjects (911), a findingthat can be interpreted (to a greater or lesser extent) as supportiveof a number of biological-rhythm hypotheses (1214), includingthe circadian phase-shift hypothesis (PSH) (15).

The PSH is based on the seminal concept that some affectivedisorders might be at least partly due to a mismatch in circadianrhythms (16, 17), specifically, between those rhythms relatedto the sleep/wake cycle and those that are more tightly coupledto the endogenous circadian pacemaker (located in the suprachiasmaticnuclei of the hypothalamus). The PSH postulates that most SADpatients become depressed in the winter because of the laterdawn, causing their circadian rhythms to delay with respectto clock time and with respect to the sleep/wake cycle (18):through providing a corrective phase advance (1), morning lightcould be antidepressant by realigning rhythms with the sleep/wakecycle (15, 18, 19). The PSH further postulates that a smallersubgroup of SAD patients become depressed because of a phaseadvance (perhaps cueing to the early winter dusk) and wouldpreferentially respond to a corrective phase delay from eveninglight (15, 1921).

The proportion of the atypical phase-advanced subgroup has beenassumed to be minimal (15, 18, 22, 23), stemming in part fromsome (14, 15, 22, 24), but not all (14, 25, 26), studies thatfound a small overall delay in the circadian rhythms of patientscompared with normal controls studied in the winter. Furthersupport for the PSH has mainly come from the fact that exposureat any other time of day has never been shown to be more antidepressantthan morning light alone and from some, but not all (22, 26,27), studies that found statistically significant correlations(of varying import) in the predicted direction between moodand circadian phase in response to light: many of these studieshave been recently reviewed (23), except for one cited above(24); in addition, data from two of the first morning vs. eveninglight studies (15, 24) have been independently analyzed (28).The largest was reported by Terman et al. in 2001 (23): percentdecrease in depression ratings after morning light correlated(r = 0.44, df = 26, P = 0.02) with the magnitude of the phaseadvance in the dim light melatonin onset (DLMO) (the most commonlyused marker for assessing endogenous circadian phase positionin humans). {In entrained, sighted people, the DLMO is the interpolatedtime when the evening rise in melatonin levels [sampled underconditions of dim light to avoid suppression of its production(29)] continues above a certain threshold, operationally definedin plasma as 10 pg/ml (unless otherwise specified).} Even thebest of these correlations, however, does not establish causality.For this and other reasons, but most importantly because thereis a continued need to provide the most accurate quantitativeestimate of the circadian component of SAD (and, by inference,of the antidepressant response to light), the present melatonintreatment study was undertaken. Such a study is also crucialin establishing the PSH.

Induction of phase shifts by some agent other than light isa critical test of the PSH. Melatonin is ideal for this purpose,because this "chemical signal of darkness" is thought to beopposite of light (1, 30). Because the duration of melatoninproduction is the neurochemical signal for the annual changein night length in seasonally breeding animals (14, 30), administeringmelatonin in the morning or evening to SAD patients to increasethe duration of "the biological night" would not be expectedto be of any therapeutic benefit, unless it induced circadianphase shifts similar to those caused by light. To accomplishthis goal, melatonin must be taken at the opposite half of thephotoperiod than when bright light is scheduled (1): accordingly,most SAD patients (who are phase delayed) should preferentiallyrespond to afternoon/evening (PM) administration (which causesphase advances) compared with morning (AM) administration (whichcauses phase delays). At doses of 0.1 mg or less, particularlyin patients without insomnia (31), melatonin is minimally soporificand cannot be distinguished from inert filler in otherwise identicalplacebo capsules. In contrast, bright light treatment is accompaniedby a potentially large placebo response that varies betweenstudies and individuals (9).

Fig. 1 shows, in healthy controls studied in the winter, theaverage intervals (in hours rounded to the nearest integer)between sleep times and the DLMO as well as (for reference)the core body temperature minimum, thought to be phase lockedwith the DLMO (27, 32). The following is our first report usingthe phase-angle difference (PAD) between the DLMO and midsleep(normally 6 h), which is calculated by dividing the sleep onset-to-offsetduration by 2 and then subtracting the quotient from the sleepoffset. We have presented or published some preliminary findings(§ , , ||) using the PAD between the DLMO and sleep phasemarkers.

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