Sleep-light interventions that shift melatonin rhythms earlier improve perimenopausal and postmenopausal depression: preliminary findings.

OBJECTIVE: Testing the hypothesis that a sleep-light intervention, which phase-advances melatonin rhythms, will improve perimenopausal-postmenopausal (P-M; by follicle-stimulating hormone) depression. METHODS: In at-home environments, we compared two contrasting interventions: (1) an active phase-advance intervention: one night of advanced/restricted sleep from 9 pm to 1 am , followed by 8 weeks of morning bright white light for 60 min/d within 30 minutes of awakening, and (2) a control phase-delay intervention: one night of delayed/restricted sleep (sleep from 3 to 7 am ) followed by 8 weeks of evening bright white light for 60 min/d within 90 minutes of bedtime. We tested 17 P-M participants, 9 normal controls and 8 depressed participants (DPs) (by Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria). Clinicians assessed mood by structured interviews and subjective mood ratings. Participants wore actigraphs to measure sleep and activity and collected overnight urine samples for the melatonin metabolite, 6-sulfatoxymelatonin (6-SMT), before, during, and after interventions. RESULTS: Baseline depressed mood correlated with delayed 6-SMT offset time (cessation of melatonin metabolite [6-SMT] secretion) ( r = +0.733, P = 0.038). After phase-advance intervention versus phase-delay intervention, 6-SMT offset (start of melatonin and 6-SMT decrease) was significantly advanced in DPs (mean ± SD, 2 h 15 min ± 12 min; P = 0.042); advance in 6-SMT acrophase (time of maximum melatonin and 6-SMT secretion) correlated positively with mood improvement ( r = +0.978, P = 0.001). Mood improved (+70%, P = 0.007) by both 2 and 8 weeks. CONCLUSIONS: These preliminary findings reveal significantly phase-delayed melatonin rhythms in DP versus normal control P-M women. Phase-advancing melatonin rhythms improves mood in association with melatonin advance. Thus, sleep-light interventions may potentially offer safe, rapid, nonpharmaceutical, well-tolerated, affordable home treatments for P-M depression.

Critically-timed sleep+light interventions differentially improve mood in pregnancy vs. postpartum depression by shifting melatonin rhythms.

BACKGROUND: Testing the hypothesis that combined wake + light therapy improves mood in pregnant vs. postpartum depressed participants (DP) by differentially altering melatonin and sleep timing. METHODS: Initially 89 women, 37 pregnant (21 normal controls-NC; 16 DP) and 52 postpartum (27 NCs; 25 DP), were randomized to a parallel trial of a phase-delay intervention (PDI): 1-night of early-night wake therapy (sleep 3-7 am) + 6-weeks of evening bright white light (Litebook Advantage) for 60 min starting 90 min before bedtime, vs. a Phase-advance intervention (PAI): 1-night of late-night wake therapy (sleep 9 pm-1 am) + 6-weeks of morning bright white light for 60 min within 30 min of wake time. Blinded clinicians assessed mood weekly by structured interview, and participants completed subjective ratings, a Morningness-Eveningness questionnaire, actigraphy, and collected 2 overnight urine samples for 6-sulphatoxy melatonin (6-SMT). RESULTS: In pregnant DP, mood improved more after the PDI vs. PAI (p = .016), whereas in postpartum DP, mood improved more after the PAI vs. PDI (p = .019). After wake therapy, 2 weeks of light treatment was as efficacious as 6 weeks (p > .05). In postpartum DP, PAI phase-advanced 6-SMT offset and acrophase (p < .05), which correlated positively with mood improvement magnitude (p = .003). LIMITATIONS: Small N. CONCLUSIONS: Mood improved more after 2 weeks of the PDI in pregnant DP, but more after 2 weeks of PAI in postpartum DP in which improvement magnitude correlated with 6-SMT phase-advance. Thus, critically-timed Sleep + Light Interventions provide safe, efficacious, rapid-acting, well-tolerated, at-home, non-pharmaceutical treatments for peripartum DP.

A 1-week sleep and light intervention improves mood in premenstrual dysphoric disorder in association with shifting melatonin offset time earlier.

To test the hypothesis that 1 week of combined sleep and light interventions (SALI), which phase-advance (shift earlier) melatonin circadian rhythms, improves mood significantly more than phase-delay (shift later) SALI. After a 2-month diagnostic evaluation for premenstrual dysphoric disorder (PMDD per DSM-5 criteria) in a university clinical research setting, 44 participants enrolled in baseline studies were randomized in the luteal phase at home to (A) a phase-advance intervention (PAI): 1 night of late-night wake therapy (LWT: sleep 9 pm-1 am) followed by 7 days of the morning (AM) bright white light (BWL), or (B) a phase-delay intervention (PDI): 1 night of early-night wake therapy (EWT: sleep 3-7 am) plus 7 days of the evening (PM) BWL. After a month of no intervention, participants underwent the alternate intervention. Outcome measures were mood, the melatonin metabolite, 6-sulfatoxymelatonin (6-SMT), and actigraphy (to assess protocol compliance). At baseline, atypical depression correlated positively with phase delay in 6-SMT offset time (r = .456, p = .038). PAI advanced 6-SMT offset from baseline more than PDI (p < .05), and improved raw mood scores more than PDI (p < .05). As hypothesized, percent improvement in mood correlated positively with a phase advance from baseline in 6-SMT offset time (p < .001). Treatment with 1 night of advanced/restricted sleep followed by 7 days of AM BWL (PAI) was more efficacious in reducing PMDD depression symptoms than a PDI; mood improvement occurred in association with phase advance in 6-SMT offset time. Combined SALIs offer safe, efficacious, rapid-acting, well-tolerated, non-pharmacological, non-hormonal, affordable, repeatable home interventions for PMDD. Clinical Trials.gov NCT # NCT01799733.

Early versus late wake therapy improves mood more in antepartum versus postpartum depression by differentially altering melatonin-sleep timing disturbances.

BACKGROUND: Peripartum major depression (MD) disables mothers and impairs emotional and neurocognitive development of offspring. We tested the hypothesis that critically-timed wake therapy (WT) relieves peripartum MD by altering melatonin and sleep timing, differentially, in antepartum vs. postpartum depressed patients (DP). METHODS: In a university clinical research center, we initially randomized 50 women - 26 antepartum (17 healthy comparison-HC, 9 DP) and 24 postpartum (8 HC, 16 DP) - to a cross-over trial of one night of early-night wake therapy (EWT: sleep 3:00-7:00 am) vs. late-night wake therapy (LWT: sleep 9:00 pm-01:00 am). Ultimately, we obtained mood, overnight plasma melatonin and polysomnography for: 15 antepartum women receiving EWT, 18 receiving LWT; 15 postpartum women receiving EWT, 14 receiving LWT. RESULTS: EWT improved mood more in antepartum vs. postpartum DP in conjunction with reduced (normalized) melatonin-sleep phase-angle differences (PADs) due to delayed melatonin onsets and advanced sleep onsets, and increased (from baseline) total sleep times (TST). LWT improved mood more in postpartum vs. antepartum DP in conjunction with increased TST. LIMITATIONS: Small samples potentially rendered the study underpowered to detect group differences, making confirmation with larger samples essential. Sufficient follow-up data were not available in most women to document the duration of the mood response to wake therapy. CONCLUSIONS: EWT benefitted antepartum DP more by realigning melatonin and sleep timing, whereas LWT benefitted postpartum DP more by increasing TST. Thus, consistent with precision medicine aims, maximum mood benefits accrue from timing sleep/wake interventions to specific peripartum circadian pathophysiologies.

Antepartum depression severity is increased during seasonally longer nights: relationship to melatonin and cortisol timing and quantity.

Current research suggests that mood varies from season to season in some individuals, in conjunction with light-modulated alterations in chronobiologic indices such as melatonin and cortisol. The primary aim of this study was to evaluate the effects of seasonal variations in darkness on mood in depressed antepartum women, and to determine the relationship of seasonal mood variations to contemporaneous blood melatonin and cortisol measures; a secondary aim was to evaluate the influence of seasonal factors on measures of melancholic versus atypical depressive symptoms. We obtained measures of mood and overnight concentrations of plasma melatonin and serum cortisol in 19 depressed patients (DP) and 12 healthy control (HC) antepartum women, during on-going seasonal variations in daylight/darkness, in a cross-sectional design. Analyses of variance showed that in DP, but not HC, Hamilton Depression Rating Scale (HRSD) scores were significantly higher in women tested during seasonally longer versus shorter nights. This exacerbation of depressive symptoms occurred when the dim light melatonin onset, the melatonin synthesis offset, and the time of maximum cortisol secretion (acrophase) were phase-advanced (temporally shifted earlier), and melatonin quantity was reduced, in DP but not HC. Serum cortisol increased across gestational weeks in both the HC and DP groups, which did not differ significantly in cortisol concentration. Nevertheless, serum cortisol concentration correlated positively with HRSD score in DP but not HC; notably, HC showed neither significant mood changes nor altered melatonin and cortisol timing or quantity in association with seasonal variations. These findings suggest that depression severity during pregnancy may become elevated in association with seasonally related phase advances in melatonin and cortisol timing and reduced melatonin quantity that occur in DP, but not HC. Thus, women who experience antepartum depression may be more susceptible than their nondepressed counterparts to phase alterations in melatonin and cortisol timing during seasonally longer nights. Interventions that phase delay melatonin and/or cortisol timing-for example, increased exposure to bright evening light-might serve as an effective intervention for antepartum depressions whose severity is increased during seasonally longer nights.

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.

Reduced phase-advance of plasma melatonin after bright morning light in the luteal, but not follicular, menstrual cycle phase in premenstrual dysphoric disorder: an extended study.

The authors previously observed blunted phase-shift responses to morning bright light in women with premenstrual dysphoric disorder (PMDD). The aim of this study was to determine if these findings could be replicated using a higher-intensity, shorter-duration light pulse and to compare these results with the effects of an evening bright-light pulse. In 17 PMDD patients and 14 normal control (NC) subjects, the authors measured plasma melatonin at 30-min intervals from 18:00 to 10:00 h in dim (<30 lux) or dark conditions the night before (Night 1) and after (Night 3) a bright-light pulse (administered on Night 2) in both follicular and luteal menstrual cycle phases. The bright light (either 3000 lux for 6 h or 6000 lux for 3 h) was given either in the morning (AM light), 7 h after the dim light melatonin onset (DLMO) measured the previous month, or in the evening (PM light), 3 h after the DLMO. In the luteal, but not in the follicular, phase, AM light advanced melatonin offset between Night 1 and Night 3 significantly less in PMDD than in NC subjects. The effects of PM light were not significant, nor were there significant effects of the light pulse on melatonin measures of onset, duration, peak, or area under the curve. These findings replicated the authors' previous finding of a blunted phase-shift response to morning bright light in the luteal, but not the follicular, menstrual cycle phase in PMDD compared with NC women, using a brighter (6000 vs. 3000 lux) light pulse for a shorter duration (3 vs. 6 h). As the effect of PM bright light on melatonin phase-shift responses did not differ between groups or significantly alter other melatonin measures, these results suggest that in PMDD there is a luteal-phase subsensitivity or an increased resistance to morning bright-light cues that are critical in synchronizing human biological rhythms. The resulting circadian rhythm malsynchonization may contribute to the occurrence of luteal phase depressive symptoms in women with PMDD.

Increased sensitivity to light-induced melatonin suppression in premenstrual dysphoric disorder.

Increased sensitivity to light-induced melatonin suppression characterizes some, but not all, patients with bipolar illness or seasonal affective disorder. The aim of this study was to test the hypothesis that patients with premenstrual dysphoric disorder (PMDD), categorized as a depressive disorder in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), have altered sensitivity to 200 lux light during mid-follicular (MF) and late-luteal (LL) menstrual cycle phases compared with normal control (NC) women. As an extension of a pilot study in which the authors administered 500 lux to 8 PMDD and 5 NC subjects, in the present study the authors administered 200 lux to 10 PMDD and 13 NC subjects during MF and LL menstrual cycle phases. Subjects were admitted to the General Clinical Research Center (GCRC) in dim light (<50 lux) to dark (during sleep) conditions at 16:00 h where nurses inserted an intravenous catheter at 17:00 h and collected plasma samples for melatonin at 30-min intervals from 18:00 to 10:00 h, including between 00:00 and 01:00 h for baseline values, between 01:30 and 03:00 h during the 200 lux light exposure administered from 01:00 to 03:00 h, and at 03:30 and 04:00 h after the light exposure. Median % melatonin suppression was significantly greater in PMDD (30.8%) versus NC (-0.2%) women (p = .040), and was significantly greater in PMDD in the MF (30.8%) than in the LL (-0.15%) phase (p = .047). Additionally, in the LL (but not the MF) phase, % suppression after 200 lux light was significantly positively correlated with serum estradiol level (p = .007) in PMDD patients, but not in NC subjects (p > .05).

Plasma melatonin circadian rhythm disturbances during pregnancy and postpartum in depressed women and women with personal or family histories of depression.

OBJECTIVE: The purpose of this study was to test the hypothesis that disturbances in levels of plasma melatonin differentiate pregnant and postpartum women with major depression from matched pregnant and postpartum healthy comparison women. METHOD: Participants were 25 pregnant women (10 with major depression, 15 healthy) and 24 postpartum women (13 with major depression, 11 healthy). Healthy comparison women were matched on the number of weeks pregnant or postpartum. Plasma melatonin levels for each subject were measured every 30 minutes, in dim light (<30 lux), from 6:00 p.m. to 11:00 a.m. The values of plasma melatonin levels were log-transformed, and calculations were determined for the following measures: baseline and synthesis onset and offset times, duration, peak concentration, and area under the curve. Groups were compared by analyses of covariance, with age, number of weeks pregnant or postpartum, breast-feeding status, and body mass index as covariates. RESULTS: Morning melatonin levels from 2:00 a.m. to 11:00 a.m. were significantly lower in pregnant women with major depression relative to healthy pregnant women. However, these levels were significantly higher in postpartum women with major depression across time intervals relative to postpartum healthy women. Pregnant but not postpartum women with a personal or family history of depression, regardless of their current diagnosis, had significantly earlier melatonin synthesis and baseline offset times relative to women without a family history of depression. In pregnant healthy women but not pregnant women with major depression, melatonin levels increased during the course of pregnancy. This association was not found among postpartum women with major depression or postpartum healthy women. CONCLUSIONS: Plasma nocturnal melatonin concentrations, particularly during morning hours, were lower in depressed pregnant women but elevated in depressed postpartum women relative to matched healthy comparison women. In addition, 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.

Late, but not early, wake therapy reduces morning plasma melatonin: relationship to mood in Premenstrual Dysphoric Disorder.

Wake therapy improves mood in Premenstrual Dysphoric Disorder (PMDD), a depressive disorder in DSM-IV. We tested the hypothesis that the therapeutic effect of wake therapy in PMDD is mediated by altering sleep phase with melatonin secretion. We measured plasma melatonin every 30 min (18:00-09:00 h) in 19 PMDD and 18 normal control (NC) women during mid-follicular (MF) and late luteal (LL) menstrual cycle phases, and during LL interventions with early wake therapy (EWT) (sleep 03:00-07:00 h)(control condition) vs. late wake therapy (LWT) (sleep 21:00-01:00 h)(active condition). Melatonin offset was delayed and duration was longer in the symptomatic LL vs. asymptomatic MF phase in both NC and PMDD subjects. LWT, but not EWT, advanced offset and shortened duration vs. the LL baseline, although they improved mood equally. Later baseline LL morning melatonin offset was associated with more depressed mood in PMDD patients, and longer melatonin duration in the MF phase predicted greater mood improvement following LWT. That LWT, but not EWT, advanced melatonin offset and shortened duration while they were equally effective in improving mood suggests that decreasing morning melatonin secretion is not necessary for the therapeutic effects of wake therapy in PMDD.

Increased melatonin and delayed offset in menopausal depression: role of years past menopause, follicle-stimulating hormone, sleep end time, and body mass index.

CONTEXT: The constellation of endocrine patterns accompanying menopausal depression remains incompletely characterized. OBJECTIVE: Our objective was to test the hypothesis that the amplitude or phase (timing) of melatonin circadian rhythms differs in menopausal depressed patients (DP) vs. normal controls women (NC). DESIGN: We measured plasma melatonin every 30 min from 1800-1000 h in dim light (<30 lux) or dark, serum gonadotropins and steroids (1800 and 0600 h), and mood (Hamilton and Beck depression ratings). SETTING: The study was conducted at a university hospital. PARTICIPANTS AND SETTING: Twenty-nine (18 NC, 11 DP) peri- or postmenopausal women participated. MAIN OUTCOME MEASURES: We measured plasma melatonin (onset, offset, synthesis offset, duration, peak concentration, and area under the curve) and mood. RESULTS: Multi- and univariate analyses of covariance showed that melatonin offset time was delayed (P = 0.045) and plasma melatonin was elevated in DP compared with NC (P = 0.044) across time intervals. Multiple regression analyses showed that years past menopause predicted melatonin duration and that melatonin duration, body mass index, years past menopause, FSH level, and sleep end time were significant predictors of baseline Hamilton (P = 0.0003) and Beck (P = 0.00004) depression scores. CONCLUSIONS: Increased melatonin secretion that is phase delayed into the morning characterized menopausal DP vs. NC. Years past menopause, FSH, sleep end time, and body mass index may modulate effects of altered melatonin secretion in menopausal depression.

Hormonal basis of mood and postpartum disorders.

Mood disorders during the postpartum period occur in 10% to 15% of women. The hormonal basis of these disorders, however, has not been investigated systematically and extensively. We review recent studies, primarily from the past 5 years, in which investigators examined the major categories of proposed hormonal etiologies, including gonadal steroids, thyroid hormones, cortisol, prolactin, and melatonin, and then present descriptive statistics of our preliminary findings in these hormonal dimensions from a group of 20 depressed and normal control pregnant and postpartum women.