Research report
Depression and endogenous melatonin in postmenopausal women

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Abstract

Background: Previous reports on melatonin secretion in depression are numerous but conflicting. There are very few studies relating the duration of the nocturnal melatonin peak to depression, and the results of those studies have been equivocal. Methods: We studied mood disorders and urinary melatonin excretion in 382 postmenopausal women. Psychiatric diagnoses and global assessment of functioning (GAF) scores were determined based on a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Urinary 6-sulfatoxymelatonin (6-SMT) samples were collected for two 24-h periods at home. Results: A positive family history of depression was significantly related to a longer duration of 6-SMT excretion. There were marginally significant associations between current major depression and delayed offset of 6-SMT excretion and between later acrophase and lifetime major depression, even with control for age, ethnicity, season, and several medications. Limitations: The subjects were studied in their home environments, where light effects were not controlled. Data were restricted to postmenopausal women, including a limited number of subjects with current major depression. Conclusions: These results suggest that there might be a familial vulnerability in the endogenous melatonin signal in subjects prone to depression, and an abnormality in the duration of the melatonin signal in those with current major depression.

Introduction

Disruption in circadian organization has been hypothesized to be a causal factor in mood disorders. Patients may be phase advanced so that their circadian rhythms peak earlier than normal (Wehr and Goodwin, 1981, Goodwin et al., 1982, Kripke, 1983), or phase delayed, where their rhythms may peak later than normal (Lewy et al., 1987, Sack and Lewy, 1988). In addition, increased circadian phase heterogeneity may be associated with symptoms among affective patients without consistent phase trends (Kripke et al., 1979).

Melatonin, the nocturnal hormone produced by the pineal gland, is an accurate indicator of circadian timing because it is relatively unaffected by external masking effects, except light. Thus, melatonin secretion is an excellent marker for studies of circadian factors which may contribute to mood disorders. Blood has been most commonly used to examine melatonin secretion. The main metabolite of melatonin, urinary 6-sulfatoxymelatonin (6-SMT), corresponds well with blood levels, and it is a reliable indicator of melatonin secretion (Cook et al., 2000). Moreover, 6-SMT might be a better measure of secretion than serum melatonin, because blood concentrations reflect not only production but also binding and metabolic rate (Sack and Lewy, 1988).

Several parameters of the circadian rhythm of melatonin secretion can be studied. The main circadian measures are the acrophase (the calculated peak time of a fitted cosine), the mesor (the mathematical mean of the cosine), and the amplitude (the difference between mesor and peak). The overall pattern or shape of the 6-SMT excretion curve can also be assessed by measuring the duration of the nocturnal peak. In animal studies, duration of the elevated melatonin signal is considered to be the most important factor reflecting photoperiodic and related responses in seasonal species (Bartness et al., 1993). In humans, duration of nocturnal melatonin secretion responds to day length as well (Wehr, 1997), although the clinical importance of the duration of the nocturnal melatonin peak in humans remains uncertain.

Previous reports on melatonin secretion in depression are numerous but conflicting. Numerous studies have analyzed serum melatonin concentrations in various patient groups, but the evaluation of onset and offset has been sparse. The most consistent finding has been a lower blood concentration in depression compared to controls (Wetterberg et al., 1979, Claustrat et al., 1984, Nair et al., 1984, Beck-Friis et al., 1985), including bipolar disorder (Kennedy et al., 1996, Nurnberger et al., 2000), and premenstrual dysphoric disorder (Parry et al., 1990, Parry et al., 1997). A low-melatonin syndrome has been described (Beck-Friis et al., 1985). Nevertheless, melatonin concentrations have been reported to be above average in premenopausal women with depression (Rubin et al., 1992, Sekula et al., 1997). Also, there are reports of no differences in melatonin secretion between patients and controls (Jimerson et al., 1977, Thompson et al., 1988, Voderholzer et al., 1997).

A few studies on phase deviation abnormalities in depression have shown a phase advance or a trend toward phase advance (Claustrat et al., 1984, Nair et al., 1984, Beck-Friis et al., 1985). Only one study (Rubin et al., 1992) has observed a trend toward a later nocturnal melatonin peak in unipolar depression, and a recent report described a later peak in euthymic bipolar I patients (Nurnberger et al., 2000). In seasonal affective disorder (SAD), phase delays have been observed (Rosenthal et al., 1985, Sack and Lewy, 1988). A few observations have related the duration of nocturnal melatonin secretion to depression. An increased duration (Rubin et al., 1992), a delayed onset (Nair et al., 1984), a trend toward an earlier onset (Rubin et al., 1992), or a delayed offset (Sekula et al., 1997) have been reported. In patients with SAD, the onset of melatonin secretion has been delayed (Sack and Lewy, 1988). In premenstrual dysphoric disorder, the offset was advanced in one study (Parry et al., 1990), but duration tended to be increased in another (Parry et al., 1997). Treatment of SAD patients with natural light has resulted in advance of both the onset and the offset (Wirz-Justice et al., 1996). Inconsistent findings may be partly due to small samples, study designs with heterogeneous patient groups, and different analyses for circadian variables. Moreover, several factors such as age, gender, and medication use may influence results (Goodwin et al., 1982, Arendt, 1995).

The aim of this cross-sectional study was to evaluate depressive disorders and melatonin excretion in postmenopausal women enrolled in the Observational Study at the San Diego site for the Women’s Health Initiative (WHI).

Section snippets

Participants

Participants for the San Diego WHI Clinical Center were recruited through mass mailing, media, advertising, and community institutions. The WHI includes clinical trials, an observational study (OS) and community studies. This ancillary study was designed to evaluate sleep and mood in this postmenopausal sample. The volunteers for the present study were recruited by writing and calling women who had already entered the WHI OS. The exclusion criteria for the OS study have been reported elsewhere (

SCID diagnoses

Twelve out of 382 subjects (3.1%) had current major depression disorder. Current depressive diagnoses of any kind (for the past month) were found in 26 (6.8%) participants. Lifetime history of mood-related diagnosis of any kind (current or past) was found for 153 (40.1%) of participants. Major depression was the most common lifetime diagnosis, found in 89 women (23.3%). Most of the remainder had experienced episodes of minor depressive disorder. None of the volunteers with current major

Discussion

Our study in postmenopausal women showed that a family history of depression was positively related to a longer duration of 6-SMT excretion. Moreover, a later offset of 6-SMT excretion was marginally related to current major depression, and a later acrophase to a lifetime major depression, even when several other contributing factors were controlled. The offset was likewise later when related to midsleep among those with major depression.

The marginally significant associations between a delayed

Acknowledgements

Supported by The National Institutes of Health (Women’s Health Initiative, HL 55983, HL62180, and AG 15763). Dr. Tuunainen has received grants from the Academy of Finland, the Finnish Cultural Foundation, the Finnish Medical Foundation, the Jalmari and Rauha Ahokas Foundation, and the Paulo Foundation. We thank Ms. M.A. Mowen, Dr. T.S. Oprendek, Mrs. G. Wallace-Guy, Dr. R.L. Hauger, Mr. T. Hayes, Mr. A. Turken, Ms. S. Kim, Ms. J. Li, Mr. G. Huegel and Mr. R.L. Fell for assistance in this

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