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.

A systematic review of cortisol, thyroid-stimulating hormone, and prolactin in peripartum women with major depression.

Pregnancy and postpartum are periods of high susceptibility to major depression (MD) and other mood disorders. The peripartum period is also a time of considerable changes in the levels of hormones, including cortisol, thyroid-stimulating hormone (TSH), prolactin, gonadotropins, and gonadal steroids. To investigate the relationship between mood and hormonal changes during and after pregnancy, we reviewed published reports of hormonal measures during this time frame, searched via PubMed and Web of Science. Studies were included if women in the antepartum or postpartum periods were clinically diagnosed with MD, and if there were repeated measures of cortisol, TSH, or prolactin. For these three hormones, the numbers of human studies that met these criteria were 15, 7, and 3, respectively. Convergent findings suggest that morning cortisol is reduced in pregnant and postpartum women with MD. Evidence did not support changes in TSH as a marker of MD during the peripartum period, and evidence for changes in prolactin in peripartum MD was equivocal. Aside from reduced morning cortisol in peripartum women with MD, definitive evidence for an association between specific hormonal fluctuations and mood disorders in the peripartum period remains elusive.

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.

Polysomnographic evaluation of sleep quality and quantitative variables in women as a function of mood, reproductive status, and age.

This archival cross-sectional investigation examined the impact of mood, reproductive status (RS), and age on polysomnographic (PSG) measures in women. PSG was performed on 73 normal controls (NC) and 64 depressed patients (DP), in the course of studies in menstruating, pregnant, postpartum, and peri- and postmenopausal women. A two-factor, between-subjects multivariate analysis of variance (MANOVA) was used to test the main effects of reproductive status (RS: menstrual vs pregnant vs postpartum vs menopausal) and diagnosis (NC vs DP), and their interaction, on PSG measures. To further refine the analyses, a two-factor, between subjects MANOVA was used to test the main effects of age (19 to 27 vs 28 to 36 vs 37 to 45 vs 46+ years) and diagnosis on the PSG data. Analyses revealed that in DP women, rapid eye movement (REM) sleep percentage was significantly elevated relative to NC across both RS and age. Significant differences in sleep efficiency, Stage 1%, and REM density were associated with RS; differences in total sleep time, Stage 2 percentage, and Stage 4 percentage were associated with differences in age. Both RS and age were related to differences in sleep latency, Stage 3 percentage, and Delta percentage. Finally, wake after sleep onset time, REM percentage, and REM latency did not vary with respect to RS or age. Overall, this investigation examined three major variables (mood, RS, and age) that are known to impact sleep in women. Of the variables, age appeared to have the greatest impact on PSG sleep measures, reflecting changes occurring across the lifespan.

Esta investigación evaluó el impacto del ánimo, del estado reproductive (ER) y de la edad en las mediciones polisomnográficas (PSG) de registros de corte transversal en mujeres. Las mediciones PSG se realizaron en 73 controles normales (CN) y 66 pacientes con depresión (PD), en estudios durante la etapa menstrual, el embarazo, el postparto y, la peri y postmenopausia. Para evaluar los principales efectos del estado reproductivo (ER: menstrual v/s embarazo v/s postparto v/s menopausia) y del diagnóstico (CN v/s PD) en la interacción con las mediciones PSG se utilizó un análisis de la varianza multivariado (MANOVA) entre sujetos, para dos factores. Para perfeccionar aun más los análisis en la evaluación de los principales efectos de la edad (19 a 27 v/s 28 a 36 v/s 37 a 45 v/s 46 y más años) y del diagnóstico respecto a los datos PSG se empleó MANOVA entre sujetos, para dos factores. Los análisis revelaron que en las mujeres con depresión el porcentaje de sueño de movimientos oculares rápidos (REM) fue significativamente mayor en relación a los CN tanto para ER como para edad. Hubo diferencias significativas para la eficiencia del sueño, el porcentaje de la etapa 1 y la densidad del sueño REM que se asociaron con el ER. Diferencias para el tiempo total de sueño y el porcentaje de las etapas 2 y 4 se asociaron con diferencias en la edad. Tanto el ER como la edad se relacionaron con diferencias en la latencia de sueño, el porcentaje de la etapa 3 y el porcentaje de delta. Por último, el tiempo para despertar después de iniciar el sueño, el porcentaje de sueno REM y la latencia REM no variaron con relación al ER ni a la edad. Esta investigación examinó globalmente tres importantes variables (ánimo, ER y edad) que se sabe que influyen en el sueño en la mujer. De estas variables la edad tuvo el mayor impacto en las mediciones PSG del sueño, reflejando los cambios que ocurren a lo largo de la vida.

Cette étude croisée d'archives a analysé l'impact de l'humeur, de l'état reproducteur (ER) et de l'âge sur les mesures polysomnographiques (PSG) des femmes. Des mesures PSG ont été réalisées sur 73 patientes témoins normales (TN) et 64 patientes déprimées (PD), au cours d'études chez des femmes ayant leurs règles, enceintes, pendant le postpartum, en périménopause ou déjà ménopausées. Une analyse de variance multivariée (MANOVA) à deux facteurs intersujets a testé les principaux effets de l'état reproducteur (ER: femmes ayant leurs règles vs enceintes vs pendant le postpartum vs ménopausées), du diagnostic (TN vs PD), et leur interaction sur les mesures PSG. Pour affiner ultérieurement les résultats, une analyse MANOVA à deux facteurs intersujets a été utilisée pour tester les principaux effets de l'âge (19 à 27 vs 28 à 36 vs 37 à 45 vs + de 46 ans) et du diagnostic sur les données PSG. Les analyses ont montré que chez les PD, le pourcentage de sommeil à mouvements oculaires rapides (REM) ou sommeil paradoxal était significativement élevé par rapport aux TN, à ER et âge équivalents. L'ER était associé à des différences significatives de fonctionnement du sommeil, de pourcentage de sommeil de stade 1 et de densité de sommeil REM ; avec l'âge, la durée totale du sommeil et le pourcentage de sommeil des stades 2 et 4 étaient changé. L'ER et l'âge ont influé sur la latence du sommeil, le pourcentage de sommeil de stade 3 et le delta. Finalement, l'ER ou l'âge n'ont rien changé au réveil après l'installation du sommeil, au pourcentage et à la latence de sommeil REM. Cette étude a analysé globalement trois variables principales (humour, ER et âge) connues pour influer sur le sommeil chez les femmes. Parmi les variables, l'âge semble avoir le plus grand impact sur les mesures PSG du sommeil, reflétant les changements intervenant au cours de la vie.

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.