Why some people become symptomatic when their DLMO becomes delayed or advanced with respect to mid-sleep while others do not Is an Important research question. However, the answer to this may not affect treatment, and would not diminish the clinical importance of the circadian component in SAD: no matter how many necessary-but-not-sufficient causes there may be, correction of just one of these could produce a successful clinical outcome. Implications

for analyses of extant and new data sets It is hoped that the work presented here will Inhibitors,research,lifescience,medical alert researchers to another way of conceptualizing a biological marker, in addition to the current concept of using a biological marker to distinguish between patients and healthy controls, which can often be made by merely taking a good history, that is, identifying patients who are anxious, depressed, obsessivecompulsive, paranoid,

psychotic, substance abusers or poor sleepers, etc. Indeed, a symptom severity biological Inhibitors,research,lifescience,medical marker may be more useful than a chemical test for a DSM diagnosis, particularly if the former informs the type of ROCK activation treatment and provides a way of monitoring treatment in addition to assessing subjective and objective signs and symptoms. Given how relatively inexpensive and noninvasive the salivary DLMO is compared with other markers, neuroimaging for one example, and given how safe and inexpensive low-dose melatonin and Inhibitors,research,lifescience,medical light are compared with most other allopathic treatment modalities, there is ample justification for future investment in circadian research. Our recent study20 establishes the PSH and the circadian component as a necessary but Inhibitors,research,lifescience,medical not sufficient cause of a substantial component of SAD, as well as a biological marker. It is hoped that the

three criteria met by the circadian component for the latter designation will clarify what is important for other biological markers to demonstrate, something like Koch’s postulates. We22 have recently described these; in the same patients: Symptom severity correlates with the biological marker before treatment. Inhibitors,research,lifescience,medical Symptom severity correlates with the biological marker in the course of treatment. Symptom change scores in symptom severity correlate with the change in the biological marker. In our recent study,20 we concluded that (in order of certainty): The prototypical SAD patient is phase and delayed, whereas a less well defined subgroup may be phase advanced; (ii) the circadian component (at least for the prototypical patients) is substantial, and it is consistent with the PSH and a hypothesized therapeutic window for optimal circadian alignment; and (iii) the work presented here will be useful as a template for reanalyzing extant data sets and for implementing new studies of nonseasonal depression, as well as other sleep and psychiatric disorders, in which a circadian component might be present.