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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

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).

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