The relationship of nocturnal melatonin to estradiol and progesterone in depressed and healthy pregnant women.

PURPOSE: To assess the relationship between nocturnal plasma melatonin and serum estradiol (E(2)) and progesterone (P(4)) levels in depressed pregnant women (DW) and matched healthy women (HW). METHODS: We used analysis of variance (ANOVA) and linear regression analyses on data obtained from pregnant HW and DW. RESULTS: Log E(2) and log P(4) were positively correlated with measures of melatonin quantity in HW (p<0.05) but not DW, controlling for age. Log E(2) and log P(4) were positively correlated with melatonin offset and duration in DW (p<0.01) but not HW. CONCLUSIONS: Pregnant DW may be less sensitive than HW to modulation of melatonin secretion by E(2) and P(4). That melatonin timing measures are more sensitive to E(2) and P(4) variation in DW may reflect a circadian system more attuned to the need for realignment in DW than in HW. These altered sensitivities to reproductive hormones may reflect a biologic vulnerability that predisposes some pregnant women to depression.

Screening women for postpartum depression at well baby visits: resistance encountered and recommendations.

OBJECTIVE: Postpartum major depression afflicts 10-15% of childbearing women and can have serious consequences. Unrecognized and therefore untreated episodes of postpartum major depression can predispose women to future depressive episodes, especially those related to other reproductive events. In the United States, women typically have one visit at six weeks postpartum with their obstetrician which is focused on physical recovery from delivery. Pediatricians typically see new mothers 4-6 times per year at well baby visits. Therefore, our objective is to test the utility of screening women for postpartum depression at each well baby visit over the course of the first postpartum year as compared with controls derived from clinical practice and chart review. METHOD: Subjects for this prospective study were recruited at their first well baby visit at the UCSD Primary Care Pediatric Clinic and interviewed by telephone. Subjects then were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory (BDI) at intervals consistent with the timing of well baby visits. If scores on the EPDS or the BDI exceeded the thresholds (EPDS >or= 12 and BDI >or= 10) then subjects were assessed further with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (SCID-DSM IV). If diagnosed with postpartum major depression, subjects were referred for appropriate treatment. RESULTS: Out of 160 study packets distributed, only 7 women volunteered for the study, despite endorsement and presentation of the study by their pediatricians. Of those participants, five scored above threshold values at some point in the interval studied. DISCUSSION: The difficulty in recruitment in this study highlights some of the problems encountered in clinical practice in terms of identifying and referring women with postpartum mental illnesses. We recommend further study be focused on how to attract potentially affected women while simultaneously addressing their fears of stigma. Since resistance also was encountered in other physicians, we recommend that educational efforts be aimed at increasing knowledge and awareness of postpartum mental illnesses in both the lay and professional spheres.

Chronobiological basis of female-specific mood disorders.

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: ). describes the variety of disturbances in biological rhythms observed in mood disorders. In this report, we describe the chronobiological disturbances observed in female-specific mood disorders, namely, premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. We hypothesize that changing reproductive hormones, by affecting the synchrony or coherence between components of the circadian system, may alter amplitude or phase (timing) relationships and thereby contribute to the development of mood disorders in predisposed individuals.

The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: therapeutic implications.

Premenstrual dysphoric disorder (PMDD), as defined in DSM-IV, is a mood disorder. One of the leading theories for the pathogenesis of mood disorders is dysfunction of the serotonergic system. An increasing database suggests that serotonergic dysfunction also characterises PMDD. Evidence that treatments which enhance serotonergic function are beneficial in reducing the symptoms of PMDD support this hypothesis. Indeed, most of the evidence from baseline studies suggests predominantly a serotonergic rather than a noradrenergic or dopaminergic dysfunction. Challenge studies further support this hypothesis. These findings of neurotransmitter dysfunction are more consistent than those of other neuroendocrine abnormalities for example. Based on treatment studies, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, has been approved for use in PMDD by the US Food and Drug Administration.

Can critically timed sleep deprivation be useful in pregnancy and postpartum depressions?

BACKGROUND: The aim of this study was to test the efficacy of critically timed sleep deprivation in major mood disorders (MMD) occurring during pregnancy and postpartum. METHODS: Nine women who met DSM-IV criteria for a MMD with onset during pregnancy or within 1 year postpartum underwent a trial of either early-night sleep deprivation (ESD), in which they were sleep deprived in the early part of one night and slept from 03:00-07:00 h, or late-night sleep deprivation (LSD), in which they were deprived of sleep in the latter part of one night and slept from 21:00-01:00 h. Mood was assessed before the night of sleep deprivation, after the night of sleep deprivation, and after a night of recovery sleep (sleep 22:30-06:30 h) by trained clinicians, blind to treatment condition, using standardized scales. RESULTS: More patients responded to LSD (nine of 11 trials: 82%) compared with ESD (two of six trials: 33%) and they responded more after a night of recovery sleep (nine of 11 nights: 82%) than after a night of sleep deprivation (six of 11 nights: 55%). Pregnant women were the only responders to ESD and the only nonresponders to LSD. LIMITATIONS: The small and heterogeneous sample size prevents us from making more definitive conclusions based on statistical analyses. CONCLUSIONS: Although the findings are preliminary, the results suggest that with further study, critically timed sleep deprivation interventions may benefit women with pregnancy or postpartum major mood disorders and potentially provide a viable alternative treatment modality for those women who are not candidates for pharmacologic or psychotherapeutic interventions. Such interventions are needed to help prevent the devastating effects of depression during pregnancy and the postpartum period on the mother, infant, her family and society.

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.

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.

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30-06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

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.

Temperature circadian rhythms during the menstrual cycle and sleep deprivation in premenstrual dysphoric disorder and normal comparison subjects.

The aim of this study was to test the hypothesis that the circadian rhythm of core body temperature is altered in premenstrual dysphoric disorder (PMDD) subjects compared to that in normal comparison (NC) subjects and that it is normalized in PMDD subjects after treatment with early night partial sleep deprivation (ESD) or late night partial sleep deprivation (LSD). A total of 23 subjects meeting DSM-IV criteria for PMDD and 18 NC subjects had 24-h core body temperature recordings taken during the following conditions: (1) baseline midfollicular (preovulatory) and (2) late luteal (postovulatory) menstrual cycle phases and after a randomized crossover trial in subsequent luteal phases of (3) ESD, in which subjects slept from 03:00 to 07:00 h, followed by (4) a night of recovery sleep (ESD-R: sleep 22:30 to 06:30 h), and (5) LSD, in which subjects slept from 21:00 to 01:00 h, also followed by (6) a night of recovery sleep (LSD-R: sleep 22:30 to 06:30 h). Temperature amplitudes were significantly decreased in the luteal phase compared to those in the follicular menstrual cycle phase and increased after nights of recovery sleep. Compared to the baseline late luteal phase, during LSD, temperature amplitude increased in PMDD subjects but decreased in NC subjects. During ESD, the temperature acrophase was delayed in PMDD subjects but was advanced in NC subjects; during LSD, the temperature acrophase was advanced in PMDD subjects but was delayed in NC subjects compared to the late luteal baseline. Nocturnal temperature and temperature maxima and mesors tended to be higher in PMDD subjects than in NC subjects; when not reduced during sleep deprivation interventions, these were not associated with therapeutic effects. Alterations in both phase and amplitude of temperature circadian rhythms characterize PMDD subjects as contrasted with NC subjects in response to sleep deprivation. The changes in phase reflected more shifts in temperature acrophase in response to shifts in sleep in PMDD subjects. This realignment of the timing of sleep and temperature in addition to the enhancement of blunted amplitude rhythms during recovery nights of sleep may provide corrective mechanisms that contribute to the therapeutic effects of sleep deprivation.

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.

Psychobiology of premenstrual dysphoric disorder.

Premenstrual Dysphoric Disorder (PMDD) is the new terminology used in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). It more rigorously defines criteria for what historically has been referred to as premenstrual syndrome (PMS). Based on studies of its phenomenology and course, PMDD was categorized in DSM-IV as a depressive mood disorder. Findings support low serotonin and melatonin metabolism in PMDD compared with healthy control subjects, and an increasing number of rigorous studies report a reduction of symptoms with selective serotonin reuptake inhibitors (SSRIs).

Circadian rhythms of prolactin and thyroid-stimulating hormone during the menstrual cycle and early versus late sleep deprivation in premenstrual dysphoric disorder.

The present study extended previous work by examining whether disturbances in the circadian rhythms of prolactin (PRL) and thyroid-stimulating hormone (TSH) distinguish patients with premenstrual dysphoric disorder (PMDD) from normal volunteers. In addition, the effects of therapeutic interventions with early and late partial sleep deprivation were explored. Both PRL and TSH levels were measured every 30 min from 18:00 h to 09:00 h during midfollicular and late luteal menstrual cycle phases in 23 PMDD patients and 18 normal volunteers. Hormone levels were measured again after a randomized crossover trial of early (sleep 03:00-07:00 h) versus late (sleep 21:00-01:00 h) partial sleep deprivation administered in two separate luteal phases. Compared with normal volunteers, PMDD patients had higher PRL concentrations, consistent with previous findings. TSH rhythms occurred earlier in PMDD than in normal subjects. PRL levels decreased and TSH levels increased with sleep deprivation compared with baseline conditions. The timing of PRL secretion shifted earlier with late sleep deprivation and later with early sleep deprivation. Although circadian disturbances of PRL and TSH were found in PMDD patients compared with normal volunteers, the therapeutic effects of early and late sleep deprivation do not appear to be mediated by correcting these disturbances.

Menstrual cycle effects on catecholamine and cardiovascular responses to acute stress in black but not white normotensive women.

This study examined cardiovascular and catecholamine responses to two standardized laboratory stressors in 33 healthy age- and weight-matched black and white normotensive women (mean age, 32 years) during two phases of the menstrual cycle. Subjects were studied in a randomized order at the same time of day on two separate occasions approximately six weeks apart, once during the follicular phase (days 7 to 10 after menses) and once during the luteal phase (days 7 to 10 after the leutenizing hormone surge) of the menstrual cycle. Black women has higher systolic (P=.01) and diastolic (P=.01) pressures compared with white women. Black women showed greater diastolic pressure (P <.01) and plasma epinephrine (P <.05) responses to stress during the follicular compared with the luteal phase of the menstrual cycle; white women showed no significant changes in these variables. The findings extend the literature on race differences in responsivity to stress and indicate that in contrast to white women, reproductive hormones do influence cardiovascular and catecholamine responsivity to stress in black women.

Electrophysiological findings during the menstrual cycle in women with and without late luteal phase dysphoric disorder: relationship to risk for alcoholism?

This study evaluated electrophysiological (EEG, ERGs), and cognitive (neuropsychological testing) responses in patients with late luteal phase dysphoric disorder (LLPDD, DSM-III-R) and controls over the menstrual cycle. In both groups, the frequency and stability of electroencephalogram (EEG) alpha activity significantly differed over the menstrual cycle. The latency of the P3 components of the auditory event-related potentials (ERPs) did not vary as a function of the menstrual cycle, but the P3 latency was found to be later in LLPDD subjects as a group. When the LLPDD subjects were assessed based on family history of alcoholism, it was found that those with alcoholic relatives had more high-frequency alpha (9-12 Hz) in their EEG, lower P3 component amplitudes, and longer P3 component latencies when compared to LLPDD subjects without alcoholic relatives or controls. These data suggest that LLPDD may have persistent neurophysiological correlates, some of which are also in common with risk for alcoholism.

Personality traits in LLPDD and normal controls during follicular and luteal menstrual-cycle phases.

In 15 women with Late Luteal Phase Dysphoric Disorder (LLPDD) and in 15 normal control subjects, personality traits were assessed using the Millon Clinical Multiaxial Inventory (MCMI) during follicular and luteal menstrual-cycle phases. Compared with controls, LLPDD subjects had less compulsive but more passive/aggressive and borderline/cycloid traits, and more depression and hypomania. Menstrual-cycle phase did not significantly affect personality variables in either group. In particular, depression and hypomania in LLPDD subjects suggests a relationship with affective disorders.

Enumerative immune changes following acute stress: effect of the menstrual cycle.

This study examined enumerative immune and catecholamine measures and their response to a speaking stressor in 20 healthy women during two phases of the menstrual cycle. Subjects were studied at the same time of day on two separate occasions approximately 6 weeks apart, once during the follicular phase (Days 7-10 following menses) and once during the luteal phase (Days 7-10 following the LH surge) of the cycle. The stressor was associated with significantly increased CD8 cells (p < .001). NK cells (CD16, CD56, and CD57, p < .001), and plasma norepinephrine (p < .01) and decreased CD4/CD8 ratio (p < .001). There were no significant main effects for menstrual phase nor significant interactions for menstrual phase by task for any dependent variable. Baseline and stress test-retest correlation coefficients were similar to those reported in the literature for men and indicate a moderate test-retest reliability. Change score test-retest correlation coefficients were consistently smaller and only CD56 (r = .49) and the CD4/CD8 ratio (r = .55) correlated significantly. The findings suggest that the changes in reproductive hormones associated with the menstrual cycle have no appreciable effect on lymphocyte numbers or their response to acute stress. Given estrogen's long-term duration of action, it may be that their menstrual cycle does not afford an adequate window of time to scrutinize reproductive hormone effects on the immune functioning.

Early versus late partial sleep deprivation in patients with premenstrual dysphoric disorder and normal comparison subjects.

OBJECTIVE: The aim of this study was to compare the clinical effects of early-night and late-night partial sleep deprivation in patients with premenstrual dysphoric disorder and normal comparison subjects. METHOD: In the premenstrual phase of two menstrual cycles, 23 subjects with DSM-IV premenstrual dysphoric disorder and 18 normal comparison subjects underwent a randomized crossover trial of 1) early-night sleep deprivation, in which subjects slept from 3:00 a.m. to 7:00 a.m., followed by a night of recovery sleep (11:00 p.m. to 7:00 a.m.), and 2) late-night sleep deprivation, in which subjects slept from 9:00 p.m. to 1:00 a.m., followed by a night of recovery sleep. RESULTS: For the subjects with premenstrual dysphoric disorder, in both partial sleep deprivation conditions the Hamilton and Beck depression ratings were significantly lower after recovery sleep than at baseline. Ratings on the day after early or late partial sleep deprivation tended to be lower than at baseline but were not statistically different. The normal comparison subjects showed no clinically important mood changes. A factor analytic approach used with the Hamilton depression scores showed that depressive retardation symptoms were the most responsive to sleep deprivation in the premenstrual dysphoric disorder subjects. CONCLUSIONS: These results are consistent with the reported efficacy of sleep deprivation for major depressive disorder. However, the premenstrual dysphoric disorder subjects improved after the recovery sleep rather than directly after partial sleep deprivation. That late-night sleep deprivation did not have greater benefit than did the hypothesized sham treatment, early-night sleep deprivation, also suggests that placebo effects cannot be ruled out.