Study Objectives: To provide guidelines for collecting and analyzing urinary, salivary, and plasma melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs and facilitating the comparison of data between laboratories. Methods: A modified RAND process was utilized to derive recommendations for methods of measuring melatonin in humans. results: Consensus-based guidelines are presented for collecting and analyzing melatonin for studies that are conducted in the natural living environment, the clinical setting, and in-patient research facilities under controlled conditions. conclusions: The benefits and disadvantages of current methods of collecting and analyzing melatonin are summarized. Although a single method of analysis would be the most effective way to compare studies, limitations of current methods preclude this possibility. Given that the best analysis method for use under multiple conditions is not established, it is recommended to include, in any published report, one of the established low threshold measures of dim light melatonin onset to facilitate comparison between studies.

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The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep-wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a 'state marker' and a 'trait marker' of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

Does the evidence now available support the concept of premenstrual dysphoric disorder (PMDD) as a distinct clinical disorder such that the relative safety and efficacy of potential treatment can be evaluated? In a roundtable discussion of this question, a wealth of information was reviewed by a panel of experts. The key characteristics of PMDD, with clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability, and internal tension, were contrasted with those of known mood and anxiety disorders. PMDD displays a distinct clinical picture that, in the absence of treatment, is remarkably stable from cycle to cycle and over time. Effective treatment of PMDD can be accomplished with serotinergic agents. At least 60% of patients respond to selective serotonin reuptake inhibitors (SSRIs). In comparison with other disorders, PMDD symptoms respond to low doses of SSRIs and to intermittent dosing. Normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis, biologic characteristics generally related to the serotonin system, and a genetic component unrelated to major depression are further features of PMDD that separate it from other affective (mood) disorders. Based on this evidence, the consensus of the group was that PMDD is a distinct clinical entity. Potential treatments for this disorder can now be evaluated on this basis to meet the clear need for effective therapy.

Objective-To test the hypothesis that disturbances in plasma melatonin distinguish pregnant and postpartum patients with major depression (DP) from matched healthy comparison (HC) women.Method-In 25 pregnant (15 HC, 10 DP) and 24 postpartum (11 HC, 13 DP) women, we measured plasma melatonin every 30 minutes from 18:00 -11:00 hours (h) in dim (< 30 lux) light. The values were log-transformed and calculations made for baseline and synthesis onset and offset times, duration, peak concentration and area under the curve (AUC). Groups were compared by analyses of covariance using age, weeks pregnant or postpartum, breastfeeding status and body mass index (BMI) as covariates.Results-Morning melatonin levels were significantly lower in pregnant DP from 02:00 -11:00 h, but were significantly higher in postpartum DP across time intervals, relative to matched HC women. Pregnant (but not postpartum) women with a personal or family history of depression, regardless of current diagnosis, had significantly earlier melatonin synthesis and baseline offsets than those without such a history. In pregnant HC, but not in DP, melatonin levels increased during the course of pregnancy. No such relationship existed for postpartum HC or DP.Conclusions-Plasma nocturnal melatonin concentrations, especially in the morning hours, were lower in depressed pregnant, but elevated in depressed postpartum women, compared with HC women. Melatonin timing measures were advanced in pregnant women with a personal or family history of depression. These findings implicate disturbances in the regulation of the melatonin generating system in pregnancy and postpartum depression.

The aim of this study was to replicate and extend previous work in which the authors observed lower, shorter, and advanced nocturnal melatonin secretion patterns in premenstrually depressed patients compared to those in healthy control women. The authors also sought to test the hypothesis that the therapeutic effect of bright light in patients was associated with corrective effects on the phase, duration, and amplitude of melatonin rhythms. In 21 subjects with premenstrual dysphoric disorder (PMDD) and 11 normal control (NC) subjects, the authors measured the circadian profile of melatonin during follicular and luteal menstrual cycle phases and after 1 week of light therapy administered daily, in a randomized crossover design. During three separate luteal phases, the treatments were either (1) bright (> 2,500 lux) white morning (AM; 06:30 to 08:30 h), (2) bright white evening (PM; 19:00 to 21:00 h), or (3) dim (< 10 lux) red evening light (RED). In PMDD subjects, during the luteal phase compared to the follicular menstrual cycle phase, melatonin onset time was delayed, duration was compressed, and area under the curve, amplitude, and mean levels were decreased. In NC subjects, melatonin rhythms did not change significantly during the menstrual cycle. After AM light in PMDD subjects, onset and offset times were advanced and both duration and midpoint concentration were decreased as compared to RED light. After PM light in PMDD subjects, onset and offset times were delayed, midpoint concentration was increased, and duration was decreased as compared to RED light. By contrast, after light therapy in NC subjects, duration did not change; onset, offset, and midpoint concentration changed as they did in PMDD subjects. When the magnitude of advance and delay phase shifts in onset versus offset time with AM, PM, or RED light were compared, the authors found that in PMDD subjects light shifted offset time more than onset time and that AM light had a greater effect on shifting melatonin offset time (measured the following night in RED light), whereas PM light had a greater effect in shifting melatonin onset time. These findings replicate the authors' previous observation that nocturnal melatonin concentrations are decreased in women with PMDD and suggest specific effects of light therapy on melatonin circadian rhythms that are associated with mood changes in patient versus control groups. The differential changes in onset and offset times during the menstrual cycle, and in response to AM and PM bright light compared with RED light, support a two-oscillator (complex) model of melatonin regulation in humans.

Women have twice the incidence of major depression compared with men. They are prone to develop episodes of depression during times of reproductive hormonal change at puberty, with use of oral contraceptives, during the premenstrual phase of the menstrual cycle, postpartum and during the perimenopause (see review: Parry 1995a). WirzJustice (1995) In women, hormonal changes associated with the reproductive cycle may provoke affective changes in predisposed individuals. Examples include depression associated with oral contraceptives (Parry and Rush 1979), the luteal phase of the menstrual cycle (Hamilton et al. 1984;Endo et al. 1978;Halbreich and Endicott 1985), the postpartum period (Parry and Hamilton 1990), and menopause (Winokur 1973). Sex differences in the rates of depression begin to appear after puberty (Weissman et al. 1984;Angold et al. 1998), a time of major change in the neuroendocrine reproductive axis. From this time onward, women have a greater lifetime risk for major depression than men. Women predominate with respect to unipolar depression (Weissman et al. 1984), the depressive subtype of bipolar illness (Angst 1978), and cyclical forms of affective illness such as rapid cycling manic-depressive illness (Wehr 1984) and seasonal affective disorder (Rosenthal et al. 1984). Furthermore, the risk for major depression in both men and women appears to be increasing in recent generations (Weissman et al. 1984;Klerman and Weissman 1989).The fluctuation of ovarian steroids during specific phases of the reproductive cycle may bear some relationship to the particular vulnerability of women for mood disorders. The ovarian hormones could exert their effects on mood directly or indirectly by their effect on neurotransmitter, neuroendocrine, or circadian systems (McEwen and Parsons 1982;Albers 1981;Albers et al. 1981;Thomas and Armstrong 1989; Parry 1995a,b). Although each of these systems has been implicated in the pathogenesis of depressive illness, the circadian basis of these disorders has received the least attention. We have designed our studies with their particular chronobiological focus because the predisposition of women for major depression has not been investigated systematically with respect to the interaction of Chronobiology, Women and Depression S103 the unique cyclic reproductive neuroendocrine axis in women and circadian physiology. Although chronobiological disturbances have been described in depression (Kripke et al. 1978;Wehr and Goodwin 1980), the characterization of chronobiological disturbances in reproductive-related mood disorders in women remains to be elucidated. Below we review the circadian rhythm abnormalities that we have observed in premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. As reproductive hormones modulate the synchrony or coherence between different components of the circadian system (Thomas and Armstrong 1989), we hypothesize that these changing hormones during the premenstrual, postpartum and menopausal periods may destabilize circ...

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