The circadian basis of winter depression

Abstract

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)

Abstract 

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.

 

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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.


Results

Phase-Shifting Effects of Melatonin Were Sufficient to Test the PSH. PM melatonin caused a 0.89-h phase advance in the clock timeof the DLMO (t = 7.61, df = 21, P < 0.001) and a 0.69-h increasein PAD (advance in the DLMO with respect to midsleep: t = 4.66,df = 21, P < 0.001). (After PM-melatonin treatment, meanDLMO clock time was 20:18 ± 0:14.) AM melatonin did notsignificantly delay the DLMO (0.18 h) or decrease PAD (0.01h). Placebo treatment was associated with nonsignificant trends,an advance in the DLMO and an increase in PAD of both 0.17 h(t = 1.71, df = 23, P = 0.10; and t = 1.76, df = 23, P = 0.09,respectively), consistent with the photoperiod that lengthenedthroughout the study. Nevertheless, because AM melatonin andplacebo treatments did not produce statistically significantchanges in circadian phase, these treatment groups were appropriatelycollapsed in one of the analyses below (see Fig. 6). Shiftsin sleep times were mostly small and statistically insignificantand were in a direction consistent with the treatment and theconstraints on bedtimes: the largest statistically significantshift was an 18-min delay in sleep onset after AM melatonin(t = 2.57, df = 21, P = 0.02). Baseline Structured InterviewGuide for the Hamilton Depression Rating Scale: Seasonal AffectiveDisorder Version (SIGH-SAD) (33) ratings (27, 28, and 28, respectively)were the same for the placebo, AM- and PM-melatonin treatmentgroups; there were no significant pretreatment vs. posttreatmentpercent change differences [ANOVA: F (2, 66) = 1.65, P = 0.20;and Kruskal-Wallis H test: {chi}2 = 4.09, df = 2, P = 0.13] amongthe three treatment groups.

Pretreatment Phase Typing of SAD Patients and Its Implications. In Fig. 2, the statistically significant parabola [R2 = 0.17,df = (2, 65), P = 0.003] has a minimum at 5.88, which validatesthe choice of PAD 6 (see Fig. 1) for phase typing these subjectsbefore doing change-score and treatment-response analyses. Furthermore,in the present data set, neither parabolic nor absolute deviationlinear plots from the parabolic minimum were statistically significantwhen any other circadian marker comprising the DLMO and/or sleeptimes was substituted for PAD. Even the two constituents ofthe PAD (DLMO and midsleep clock times) had nonsignificant paraboliccorrelations [R2 = 0.006, F (2, 65) = 0.21, P = 0.81; and R2= 0.05, F (2, 65) = 1.64, P = 0.20, respectively] with depressionratings.

The implicit phase typing done above was explicitly done beforeconducting all of the remaining analyses. Those who at baselinehad PADs ≤ 6 (n = 48; 71%) were designated as phase-delayed types,and those who had PADs > 6 (n = 20; 29%) were consideredphase-advanced. (Unless otherwise specified, the use of theterms advanced and delayed applies to these pretreatment assignmentsand not to posttreatment phase.) With one exception (see Fig. 5),when the advanced and delayed groups are separated in all ofthe correlational analyses, statistical significance is foundonly in the delayed group, and analyses confined to this groupare almost always more robust than in those with the advancedand delayed groups combined.

Response to Treatment Correlates with Correcting Circadian Misalignment. The day after treatment was discontinued, posttreatment (Fig. 3),the statistically significant parabolic relationship remainedbetween depression score and PAD [R2 = 0.11, df = (2, 65), P= 0.02]; a second parabola fitted to the data of the subsetof (delayed) subjects with pretreatment PADs ≤ 6 was also significant[R2 = 0.19; df = (2, 45); P = 0.009; minimum = 5.85]. This groupis analyzed in more detail in Fig. 4.

Linear regressions restricted to the delayed group appear inFig. 4, as well as the parabola for delayed subjects treatedwith PM melatonin. The regression that did not exclude subjectswith posttreatment PADs > 6 (overshifters) did not quitereach statistical significance (r = –0.27, r2 = 0.07,df = 46, P = 0.07; however, Spearman's {rho} = –0.33, n = 48,and P = 0.02 and Kendall's {tau} = –0.20, n = 48, and P = 0.04were statistically significant). [These statistics are reportedfor comparison with those of the parabolic curves presentedin Figs. 3 and 4 (in all of the above analyses, statisticalsignificance was lost when the data fitted to a significantparabolic curve were fitted to a linear regression).] If theovershifters and undershifters (those who remained ≤ PAD 6) areanalyzed separately, the linear regressions were statisticallysignificant, despite the reduction in sample size (respectively:r = 0.72, r2 = 0.52, df = 9, P = 0.01; and r = –0.44,r2 = 0.19, df = 35, P = 0.007). Thus, the data in Fig. 4 confirmthe therapeutic window of about PAD 6, at least for the phase-delayedgroup: indeed, the parabolic fit of the data for the delayedsubjects who received PM melatonin, the treatment that causedthe greatest phase shifts, is remarkably impressive, particularlyfor such a small sample [R2 = 0.65, df = (2, 8), P = 0.01, minimum= 5.56].

As mentioned above, analyses of the delayed group, rather thanthe advanced group, appear to be the driving force behind mostof the statistically significant findings. This finding alsoapplies to the linear regression (raw data not shown) of pretreatmentto posttreatment percent changes in depression scores vs. shiftstoward or away from PAD 6 (for delayed subjects, r = 0.35, r2= 0.12, df = 46, P = 0.01; and for all subjects, r = 0.32, r2= 0.10, df = 66, P = 0.007); the three delayed subjects whoworsened the most received the "incorrect" treatment (AM melatonin),which caused a phase delay away from PAD 6 [it is not surprisingthat only a few subjects actually became more depressed duringthe study, given the small, but significant, antidepressantresponse to placebo (see Fig. 6)]. The plot for this type ofanalysis appears in Fig. 5 for all phase-advanced and phase-delayedsubjects who received PM melatonin, the treatment that causedthe greatest phase shifts: the linear regression between percentchange in depression ratings and shifts toward or away fromPAD 6 was quite robust, despite the relatively small samplesize (r = 0.59, r2 = 0.35, df = 20, P = 0.004). {Furthermore,the data in this figure make clear that most of the advancedtypes (who, in response to PM melatonin, usually advanced furtheraway from PAD 6) had a worse clinical response than the delayedtypes (for whom PM melatonin would be expected to be the treatmentof choice); notably, the subject who shifted away from PAD 6more than anyone else and whose depression scores worsened morethan those of all but two other subjects [phase-delayed typeswho also received the incorrect treatment (AM-melatonin); datanot shown] was from the advanced subgroup for whom PM melatoninwould have been predicted to be the incorrect treatment.} Ther2 of 0.35 is the largest found in the combined group of phase-advancedand phase-delayed subjects (second only to the R2 of 0.65 inthe PM-treated delayed group alone in Fig. 4).

Subjects were retrospectively (and blindly) assigned to correctvs. incorrect treatments: PM melatonin is the correct treatmentfor delayed types (n = 11) and AM melatonin for advanced types(n = 6); AM melatonin is the incorrect treatment for delayedtypes (n = 16) and PM melatonin for advanced types (n = 11).Accordingly, 17 subjects received the correct treatment and27 the incorrect one (24 received placebo). The correct treatmentdecreased depression ratings by 34%, compared with {approx}13–15%for the other treatment groups, separately or combined (Fig. 6).Two ways of calculating effect sizes were considered (Fig. 6);the more conservative ones were based on percent differencesin change scores compared with the correct treatment: 0.61 (incorrecttreatment), 0.83 (placebo), and 0.69 (the latter two groupscombined).


Discussion


Toward Estimating the Circadian Component of SAD and the Antidepressant Response to Light. SAD may be the first psychiatric disorder in which statisticallysignificant correlations are found between overall symptom severityand a physiological marker before, and in the course of, treatmentin the same patients. Including those reviewed by Brody et al.(
34), there are a few studies in which significant correlationswere found either before treatment (3537) or in responseto treatment. In any event, our correlations compare favorablywith these, as well as those reported in light-treatment studies(23, 32). Consistent with Fig. 3 (above), Burgess, Eastman,and coworkers (32) recently found a parabolic correlation [R2= 0.33, df = (2, 22), P = 0.01] between a corresponding posttreatmenttherapeutic window (3-h PAD between the temperature minimumand waketime; see Fig. 1) and the change in SIGH-SAD scoresin SAD subjects who received morning light, evening light, orplacebo. In a somewhat similar analysis to theirs (that is,plotting the change in SIGH-SAD score against posttreatmentDLMO/midsleep PAD), we found a statistically significant parabola[R2 = 0.27, F (2, 19) = 3.60, P = 0.05; minimum = 5.55] in delayedsubjects treated with PM melatonin (data not shown); however,we think that the more informative analysis in these subjectsis posttreatment SIGH-SAD score vs. PAD [plotted above (seeFig. 4): R2 = 0.65, F (2, 8) = 7.57, P = 0.01; minimum = 5.56].

Explaining 65% of the variance in the parabolic correlationof phase-delayed subjects and 35% of the variance in the changescores of the combined group in response to PM melatonin (thetreatment that caused the greatest phase shifts) are our bestestimates of the circadian component of SAD and the antidepressanteffect of melatonin and, by inference, light. As mentioned above,most of the statistical significance in the above findings isdriven by the delayed types: to what extent this differencecan be explained by greater heterogeneity, smaller size, orgreater influence of noncircadian factors in the advanced groupis not yet known; also, the phase-shifting effects of AM melatonin(which was intended to be a control rather than an active treatment)were not optimized as much as those of PM melatonin (which correspondsto morning light, the treatment of choice for most patients).Post hoc analyses might identify sources of heterogeneity inthe advanced group (and possibly in the delayed group). Iterativeanalyses may lead to methodological refinements, for example,reduction of the inherent noise in the behavioral/cognitive/moodassessments. These analyses also may reduce the proportion ofthe advanced group, as well as result in: (i) a therapeuticwindow with more resolution than our integer of six; (ii) separatetherapeutic windows for advanced and delayed groups; and/or(iii) different ways of phase typing. In any event, phase typingalone will probably not be useful in diagnosing SAD patients,because the means and ranges of their circadian phase markersdo not appear to markedly differ from those of healthy controls;in other words, as-yet-to-be-identified variables are requiredfor circadian misalignment to result in a winter depression.Perhaps SAD patients are uniquely vulnerable to clinical manifestationsof changes in circadian phase. Studies throughout the year maybe helpful in determining meaningful normative and ipsativedifferences (18). Furthermore, although PAD 6 appears to bea useful way to subtype SAD for guiding treatment choices, wewould not be surprised if each person had a therapeutic windowthat differed from the group mean. We also would not be surprisedif the therapeutic window had some relevance for healthy individuals.

Integrating and Reconciling Past and Present Findings. The findings of this study, which phase types large numbersof SAD patients based on a reliable physiological marker withrespect to actigraphically documented sleep times, are consistentwith those previously reported and provide explanations formost of the discrepancies in the literature. For example, absenceof PAD 6 phase typing could be why some studies did not findantidepressant differences between morning and evening light(26, 38) and why these differences were usually more apparentin complete remission rates (9, 11) (perhaps the complete remitterswere the ones who received the correct treatment). Failure toconsistently find a statistically significant pretreatment phasedelay (14, 25, 26) is explained by a phase-advanced subgrouplarger than previously assumed.

In the Terman et al. (23) morning vs. evening light cross-overstudy, the correlation with morning light did not reveal a therapeuticwindow for optimal circadian alignment (instead, they founda statistically significant linear relationship: the greaterthe phase advance to morning light, the greater the antidepressantresponse). We undertook several types of analyses (in additionto those reported above) on our corresponding data, but we werenot able to replicate their finding. However, their subjectsmay not have shifted across the therapeutic window to the sameextent as our PM-melatonin-treated subjects, because the averageposttreatment DLMO clock time of our PM-melatonin subjects was37 min earlier than their morning light subjects. Perhaps amore important difference between our conclusions and thoseof the Terman group is that theirs include a recommendationof earlier morning light exposure for SAD patients who are relativelyless phase delayed, whereas we might have considered some ofthese patients as belonging to the phase-advanced subgroup,for whom, even before the present study was undertaken (19),we would have recommended evening light treatment.

Is Melatonin a Treatment for SAD? Our study was not designed to assess the optimal potential formelatonin treatment. Nevertheless, the clinical benefit appearsto be substantial, although not as robust as light treatment;it should be noted, however, that there is a much less placebocomponent in the present study. In any event, these effect sizes(see Fig. 6), as well as the 19–21% separations betweenthe correct treatment and the other treatments, are greaterthan what is usually reported in fixed-dose clinical trialsof antidepressants (3941). Although the delayed grouphad larger effect sizes when analyzed alone than when combinedwith the advanced group, separate analyses of these two groupswere not statistically meaningful because of reduced samplesize. Over the four weeks of SIGH-SAD ratings, only the meanscores for the correct-treatment group steadily improved (28.9-> 23.8 -> 20.2 -> 18.9). Because AM melatonin did not cause the samemagnitude of phase shifts as PM melatonin, the treatment effectsfound above are probably underestimates, particularly for theadvanced group. Although more studies are needed, these datasuggest that most SAD patients might benefit from an appropriatelow-dose formulation of melatonin taken in the afternoon.


Conclusions

In order of certainty, we conclude that (i) the prototypicalSAD patient is phase delayed, whereas a less well defined subgroupmay be phase advanced; (ii) the circadian component (at leastfor the prototypical patients) is substantial, and it is consistentwith the PSH and a hypothesized therapeutic window for optimalcircadian alignment; and (iii) the work presented here willbe useful as a template for reanalyzing extant data sets andfor implementing new studies of nonseasonal depression, as wellas other sleep and psychiatric disorders, in which a circadiancomponent might be present.


Materials and Methods

  
For more details on experimental techniques used in this study,see Supporting Materials and Methods and Fig. 7, which are publishedas
supporting information on the PNAS web site. Plasma DLMOassessments (see also Fig. 1) and reliably documented sleeptimes were done on what turned out to be a total of 68 SAD patients(see below) before and after 3 weeks of taking melatonin orplacebo capsules. Depression ratings were done weekly by usingthe SIGH-SAD (33). Subjects were randomly assigned to morningor afternoon/evening melatonin treatment or to placebo. Sevento eight capsules per day were taken every 2 h, to produce physiologicallevels of exogenous melatonin to extend the endogenous melatoninprofile either earlier or later, to cause either a phase advanceor a phase delay, respectively, in the endogenous circadianpacemaker (as marked by a shift to an earlier or later time,respectively, in the DLMO) with respect to sleep times thatwere held constant.

At least 27 subjects met established SAD screening criteriaeach year and engaged in 4 weeks of sleeping at home at negotiatedsleep onset and offset times (with the first cohort of 9 subjectsstarting the first or second week of January, and cohorts 2and 3 starting 2 and 4 weeks later, respectively). Sleep timeswere based on self-selected weekday schedules that were heldconstant throughout the protocol and monitored by daily diaries(and, for years 2–4, more reliably by wrist actigraphy).Depression severity (SIGH-SAD score) was assessed weekly, andDLMOs were obtained at the end of the baseline week and after3 weeks of taking 7–8 capsules per day (one every 2 hbeginning at waketime and ending 4 or 2 h before sleep, respectively).Capsules contained placebo or melatonin [0.075 or 0.1 mg (totaling0.225 or 0.3 mg per day), depending on the year of the study]either in the morning (AM) or in the afternoon/evening (PM),or placebo at all times.

Statistical significance is reported above only if linear regressionshad a P value of at least 0.05, by using Pearson's r, confirmedby rank-order Kendall's {tau} and Spearman's {rho} tests, but only Pearson'sis reported, unless otherwise specified. A parabolic curve wasconsidered statistically significant only if it was also significantwhen plotted linearly as a function of the absolute deviationfrom the parabolic minimum. Means are followed by ±SEMs.For comparisons of means between different groups, we used themore conservative Welch two-sample t test, which does not assumeequal variances. Data from the first year of the study wereexcluded in the following analyses, because of the absence ofactigraphic recordings of sleep times. Of the remaining 81 subjects,complete data sets were available for 69, of whom 66 were femalesand the average age was 39 ± 1.1 (range: 23–59),consistent with the known demographics of SAD (5, 6); the outlier(see Fig. 2) was removed, leaving a sample size of 68. Therewere no significant differences between treatment groups (placebo:n = 25; AM = PM = 22) in either (age and gender) demographicor baseline (SIGH-SAD and waketime) variables.


Acknowledgements

Acknowledgements 

We thank the research subjects, the nursing staff of the OregonHealth & Science University (OHSU) General Clinical ResearchCenter, Neil Cutler, Rick Boney, Krista Yuhas, Angie Koenig,Nancy Stahl, Brant Hasler, Rebecca Bernert, Cathy Evces, AnushaChhagan, Anju Bhargava, Dr. Les Christianson, Dr. Darian Minkunas,and Dr. Laurie Vessely. We also thank Dr. Keith Parrott, Pharm.D.,for preparation of the capsules and Enviro-Med for help in providingbright-light fixtures to the subjects following the study. Thiswork was supported by Public Health Service Grants R01 MH55703,R01 MH56874, R01 AG21826, and R01 HD42125 (to A.J.L.) and 5M01 RR000334 (to the General Clinical Research Center of OHSU).A.J.L. was supported by the National Alliance for Research onSchizophrenia and Depression 2000 Distinguished InvestigatorAward. J.S.E. was supported by Public Health Service Grant K23RR017636-01.

Footnotes 

Abbreviations: SAD, seasonal affective disorder; PSH, phase-shift hypothesis; DLMO, dim light melatonin onset; PAD, phase angle difference; SIGH-SAD, Structured Interview Guide for the Hamilton Depression Rating Scale–SAD version

{dagger}To whom correspondence should be addressed. E-mail: [email protected]

Freely available online through the PNAS open access option.

Author contributions: A.J.L. designed research; A.J.L. and V.K.B.performed research; A.J.L., B.J.L., J.S.E., and V.K.B. analyzeddata; and A.J.L., B.J.L., J.S.E., and V.K.B. wrote the paper.

§ Lewy, A. J., Lefler, B. J., Hasler, B. P., Bauer, V. K., Bernert,R. A. & Emens, J. S. (2003) Chronobiol. Int. 20, 1215–1217(abstr.).,Back

Lewy, A. J., Lefler, B. J., Yuhas, K., Hasler, B. P., Bernert,R. A. & Emens, J. S. (2004) Neuropsychopharmacology 29,S103–S104 (abstr.).Back

|| Lewy, A. J., Emens, J. S., Lefler, B. J. & Bauer, V. K.(2005) Neuropsychopharmacology 30, S62–S63 (abstr.).Back

Conflict of interest statement: A.J.L. is coinventor on severalmelatonin use-patents owned by Oregon Health & Science Universitycurrently not licensed to any company.

© 2006 by The National Academy of Sciences of the USA


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Figures

Fig. 1. Schematic diagram of normal phase relationships (rounded to the nearest integer) between sleep phase markers, the 10 pg/ml plasma DLMO (10), and the core body temperature minimum (Tmin) (27, 32) derived from historical controls. The present study used the DLMO/midsleep interval PAD of 6 h as the hypothesized therapeutic window for optimal circadian alignment. Sleep times were determined actigraphically. Plasma melatonin levels were obtained under dim light every 30 min in the evening. The operational definition of the DLMO is the interpolated time of continuous rise above the threshold of 10 pg/ml; for example, if the melatonin level at 8 p.m. was 5 pg/ml and at 8:30 p.m. was 15 pg/ml, the DLMO would be 8:15 p.m.

figure 1

Fig. 2. Pretreatment SIGH-SAD depression score as a function of PAD (the interval between the DLMO and midsleep). [The circled data point (from a 36-year-old female subject who was assigned to placebo treatment) was the only one that met outlier criteria (z = 3.02) and was therefore removed from all subsequent analyses and did not substantially affect any of the above findings (no outliers were detected in any other analyses).] The parabolic curve (minimum = 5.88) indicates that PAD accounts for 17% of the variance in SIGH-SAD scores [F (2, 65) = 6.43]. [A significant linear correlation was found for the absolute deviation from the parabolic minimum (r = 0.39, r2 = 0.15, df = 65, P = 0.001), confirming the validity of the parabolic curve fit.]

figure 2

Fig. 3. Posttreatment SIGH-SAD score as a function of PAD. The parabolic curve (minimum = 6.18) indicates that PAD accounts for 11% of the variance in SIGH-SAD scores [F (2, 65) = 3.96] for all subjects and 19% for phase-delayed subjects [F (2, 45) = 5.19]. Absolute deviations from the parabolic minima (6.18 and 5.85, respectively) were statistically significant (advanced and delayed subjects: r = 0.29, r2 = 0.09, df = 65, P = 0.02; delayed subjects: r = 0.48, r2 = 0.23, df = 65, P = 0.001).

figure 3

Fig. 4. Posttreatment SIGH-SAD score as a function of PAD in delayed subjects. (The parabolic curve and related statistics for the delayed subjects are provided in Fig. 3.) The linear correlation between PAD and SIGH-SAD score (diagonal hatched line) did not reach statistical significance, confirming that the parabolic curve in Fig. 3 for delayed subjects (R2 = 0.19, P = 0.009) is the better fit for these data. Directional linear correlations for under- and overshifters (to the right and left of PAD 6, respectively) were both statistically significant. The parabolic curve for subjects receiving PM melatonin indicates that PAD accounts for 65% of the variance in SIGH-SAD scores [F (2, 8) = 7.57; minimum = 5.56]; the correlation between the absolute deviation from the parabolic minimum was also statistically significant (r = 0.75, r2 = 0.56, df = 8, P = 0.01).

figure 4

Fig. 5. Percent change in SIGH-SAD score as a function of net change in absolute deviation toward and away from PAD 6 in PM-melatonin treated advanced and delayed subjects. Pretreatment vs. posttreatment shifts with respect to PAD 6 account for 35% of the variance.

figure 5

Fig. 6. Percent change in (SIGH-SAD) depression score after correct treatment, incorrect treatment, and placebo, as well as incorrect treatment and placebo combined (see text for details of the composition of these treatment groups). Baseline SIGH-SAD scores for the three treatment groups (correct treatment, incorrect treatment, and placebo) were 28.9 ± 1.0, 28.8 ± 1.3, and 26.6 ± 1.4, respectively. The Kruskal–Wallis H test ({chi}2 = 5.83, df = 2, P = 0.05) was statistically significant, but not the one-way ANOVA [F = 2.96 on (2, 65), P = 0.06]. By using the Welch two-sample t test to compare differences in the change scores of the correct-treatment group with those of the other groups, correct treatment significantly decreased depression ratings more than the other groups: incorrect (19.1%: t = 2.09, df = 40.8, P = 0.04); placebo (20.9%: t = 2.60, df = 34.2, P = 0.01); the latter two groups combined (19.9%: t = 2.65, df = 32.1, P = 0.01). Pretreatment to posttreatment percent changes were significant for all groups: correct (t = 5.43, df = 16, P < 0.001), incorrect (t = 2.20, df = 26, P = 0.04), placebo (t = 2.50, df = 23, P = 0.02), and the latter two groups combined (t = 3.25, df = 50, P = 0.002). Effect sizes (ES) are shown for pretreatment to posttreatment percent change scores for each group; also shown are the more conservative ES for differences in change scores between the correct-treatment group and the other groups. [Before phase typing, percent change in the PM-treated group was –28.5 ± 5.6, and percent change in the AM-treated group was –15.5 ± 8.0, although there were no statistically significant differences between the three treatment groups in percent changes in SIGH-SAD scores (see above).]

figure 6


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