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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

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.

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