Mood disorders and the reproductive cycle.

Women have a significantly higher risk for developing mood disorders than men. Although reasons for this gender difference are not fully understood, it is clear that changing levels of reproductive hormones throughout women's life cycles can have direct or indirect effects on mood. Fluctuations in reproductive hormones may interactively affect neuroendocrine, neurotransmitter, and circadian systems. Reproductive hormones also may affect response to some antidepressant drugs and alter the course of rapid-cycling mood disorders. Nonpharmacologic interventions, such as light therapy and sleep deprivation, may be beneficial for mood disorders linked to the reproductive cycle. These interventions may have fewer side effects and a greater potential for patient compliance than some antidepressant drugs.

Blunted phase-shift responses to morning bright light in premenstrual dysphoric disorder.

Patients with premenstrual dysphoric disorder (PMDD) respond therapeutically to sleep deprivation and light therapy. They have blunted circadian rhythms of melatonin. The authors sought to test the hypothesis that these disturbances are a reflection of a disturbance in the underlying circadian pacemaker or, alternatively, that they reflect a disturbance in the input pathways to the clock. To test these hypotheses, after a 2-month diagnostic evaluation, 8 patients who met DSM-IV criteria for PMDD and 5 normal control (NC) subjects underwent two studies to determine whether PMDD subjects showed (1) altered melatonin sensitivity to light suppression (Study 1) and (2) altered phase-shift responses to morning light as a measure of the functional capacity of the underlying pacemaker (Study 2). In both studies, measurements were made during asymptomatic follicular and symptomatic luteal menstrual cycle phases in PMDD patients. The results of Study 1 showed no significant effect of group or menstrual cycle phase on the amount or percentage of suppression of melatonin by light. The results of Study 2 showed that with respect to the variable of offset time, PMDD subjects, when symptomatic, showed a reduced and directionally altered melatonin phase-shift response to a morning bright light stimulus; in 4 of 5 NC subjects, melatonin offset was advanced by bright morning light, whereas in PMDD subjects, it was delayed (3 subjects) or not shifted (5 subjects) (group effect, p = .045). Study 2 also revealed that area under the curve also changed differentially in PMDD versus NC subjects. In summary, the primary findings from this pilot study suggest that in PMDD there is a maladaptive (directionally altered and blunted) response to light in the symptomatic luteal phase. Because the suppressive effects of light were similar in PMDD and NC subjects, the previously observed low melatonin levels in this disorder do not likely represent a disturbance in pineal reactivity to suprachiasmatic nucleus efferents. Instead, the findings support a possible disturbance in PMDD in the clock itself or its coupling mechanisms.

Plasma melatonin circadian rhythms during the menstrual cycle and after light therapy in premenstrual dysphoric disorder and normal control subjects.

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.

Neuroendocrine effects of light therapy in late luteal phase dysphoric disorder.

In 20 late luteal phase dysphoric disorder (LLPDD) and in 11 normal control (NC) subjects, circadian profiles of cortisol, prolactin, thyrotropin-stimulating hormone (TSH), and core body temperature were measured during midfollicular (MF) and late luteal (LL) menstrual cycle phases and after 1 week of light therapy either with (1) bright (tau 2500 lux) white morning (6:30 AM to 8:30 AM), (2) bright white evening (7 PM to 9 PM) or (3) dim (< 10 lux) red evening light, randomly administered in three separate luteal phases. In NC but not PMDD subjects, the cortisol peak significantly delayed in the LL compared with the MF phase. In PMDD, prolactin peak and amplitude were higher, prolactin acrophase earlier, and temperature amplitude higher during both the MF and LL phases. After light treatment, prolactin amplitude remained higher in LLPDD than in controls. In both groups, bright light shifted the cortisol acrophase, and AM light increased the prolactin nadir. Bright PM light increased the TSH nadir in LLPDD, but decreased it in controls. Thus, menstrual cycle phase, diagnosis, and light therapy may differentially affect neuroendocrine systems.

Light therapy of late luteal phase dysphoric disorder: an extended study.

Nineteen patients with late luteal phase dysphoric disorder (LLPDD) and 11 healthy comparison subjects underwent a 3-month crossover trial of bright (more than 2500 lux) white morning, bright white evening, and placebo dim (less than 10 lux) red evening light, administered daily for 1 week during the premenstrual phase of the menstrual cycle. All light treatments significantly reduced depressive ratings from baseline levels.

Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

Night light alters menstrual cycles.

Dewan asserted 20 years ago that a bedside light could shorten and regularize the menstrual cycle among women with long and irregular menstrual patterns. To replicate this, seven volunteers slept with a 100-watt bulb by the bedside from days 13-17 of their menstrual cycles, while nine controls similarly used a dim red placebo (photographic safe light). Indeed, the 100-watt bulbs shortened menstrual cycles from a mean of 45.7 days to 33.1 days and reduced variability, but the placebo had no effect. These results suggest that light may have promise for treatment of infertility, for contraception, and for other endocrine interventions.

Morning versus evening bright light treatment of late luteal phase dysphoric disorder.

Six women with late luteal phase dysphoric disorder had a significant reduction in depression ratings after treatment with evening, but not morning, bright light. Bright light may offer an alternative to the pharmacologic treatment of premenstrual mood disorders.

Atenolol in seasonal affective disorder: a test of the melatonin hypothesis.

To test the hypothesis that the antidepressant effects of bright light in seasonal affective disorder are mediated by the suppression of melatonin, 19 patients with this disorder were given atenolol, which suppresses melatonin secretion, and placebo in a double-blind crossover study. No difference in antidepressant efficacy was found between drug and placebo in the sample as a whole, which argues against the melatonin hypothesis of phototherapy. However, in three of the patients atenolol provided repeated, marked, and sustained relief of symptoms, suggesting that it may be useful in treating the winter depressive symptoms of some patients with seasonal affective disorder.

Treatment of a patient with seasonal premenstrual syndrome.

The authors identified a patient who had premenstrual syndrome (late luteal phase dysphoric disorder) only in the fall and winter and was virtually asymptomatic during the spring and summer. On the basis of previous experience with seasonal affective disorder, they treated the patient with bright artificial light, which reversed her symptoms. On subsequent occasions they reversed this treatment effect with oral melatonin administration and found that propranolol and atenolol, beta-antagonists that inhibit the production of melatonin, had a therapeutic effect similar to that of light. They discuss the implications of these findings in relation to the importance of melatonin as a mediator of seasonal rhythms in biology.

Seasonal affective disorder in children and adolescents.

The authors studied seven children with symptoms of seasonal affective disorder. During the winter months the children regularly experienced irritability, fatigue, school difficulties, sadness, and sleep changes as well as other symptoms of seasonal affective disorder found in adults. An open trial of bright environmental light reversed many of these symptoms and improved mood and psychosocial functioning in the winter months. School counselors and therapists should consider seasonal affective disorder in the differential diagnosis of children with school difficulties that are most prominent in the fall-winter semester.

Melatonin in seasonal affective disorder and phototherapy.

In several studies we have found that treatment with bright environmental light, capable of suppressing human melatonin, reverses the winter depressive symptoms of patients with seasonal affective disorder (SAD), whereas light too dim to suppress human melatonin is therapeutically ineffective. This finding, as well as the central importance of melatonin as a hormonal mediator of photoperiodic changes on seasonal rhythms in animals, led us to test the hypothesis that melatonin mediates the effects of shortening days on the winter symptoms of SAD and that the modification of melatonin secretion by bright light mediates its antidepressant effects. We partially reversed the antidepressant effects of phototherapy in 8 SAD patients by oral melatonin administration, but in another study of 19 SAD patients we failed to find any therapeutic difference between the beta-adrenergic blocker, atenolol, which inhibits melatonin secretion, and placebo. In a third study of 7 SAD patients we showed that the anti-depressant effects of phototherapy were not photoperiodic and appeared to be independent of melatonin suppression. There is some preliminary evidence that melatonin secretion may be abnormal in SAD. We conclude that while melatonin may play some role in the symptoms of SAD and the effects of phototherapy, it cannot by itself account for these phenomena.

Treatment of seasonal affective disorder with light in the evening.

A cross-over comparison study of exposure, in the evenings only, to bright versus dim light was carried out on nine female patients with seasonal affective disorder. A significant antidepressant effect of the bright lights was shown. No consistent observable effects were produced by the dim lights. These results support earlier studies demonstrating the efficacy of bright light given morning and evening. The antidepressant effect of light is not mediated by sleep deprivation, and the early morning hours are not crucial for a response.

Antidepressant effects of light in seasonal affective disorder.

The authors treated winter depression in 13 patients with typical seasonal affective disorder by extending the length of winter days with bright and dim light in the morning and evening in a balanced-order crossover study. Bright light had a marked antidepressant effect, whereas the dim light did not. This response could not be attributed to sleep deprivation. Subsequent pilot studies indicated that bright evening light alone is probably also effective. Several patients were able to maintain the antidepressant response throughout the winter months by continuing daily light treatments.