Human circadian phase-response curves for exercise.

KEY POINTS: Exercise elicits circadian phase-shifting effects, but additional information is needed. The phase-response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity. Fifty-one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night. Temporal changes in the phase of 6-sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase-response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively. Along with known synergism with bright light, the above PRCs with a second phase advance region (afternoon) could support both practical and clinical applications. ABSTRACT: Although bright light is regarded as the primary circadian zeitgeber, its limitations support exploring alternative zeitgebers. Exercise elicits significant circadian phase-shifting effects, but fundamental information regarding these effects is needed. The primary aim of the present study was to establish phase-response curves (PRCs) documenting the size and direction of phase shifts in relation to the circadian time of exercise. Aerobically fit older (n = 51; 59-75 years) and young adults (n = 48; 18-30 years) followed a 90 min laboratory ultrashort sleep-wake cycle (60 min wake/30 min sleep) for up to 5½ days. At the same clock time on three consecutive days, each participant performed 60 min of moderate treadmill exercise (65-75% of heart rate reserve) at one of eight times of day/night. To describe PRCs, phase shifts were measured for the cosine-fitted acrophase of urinary 6-sulphatoxymelatonin (aMT6s), as well as for the evening rise, morning decline and change in duration of aMT6s excretion. Significant PRCs were found for aMT6s acrophase, onset and duration, with peak phase advances corresponding to clock times of 7:00 am and from 1:00 pm to 4:00 pm, delays from 7:00 pm to 10:00 pm, and minimal shifts around 4:00 pm and 2:00 am. There were no significant age or sex differences. The amplitudes of the aMT6s onset and acrophase PRCs are comparable to expectations for bright light of equal duration. The phase advance to afternoon exercise and the exercise-induced PRC for change in aMT6s duration are novel findings. The results support further research exploring additive phase-shifting effects of bright light and exercise and health benefits.

FMR1, circadian genes and depression: suggestive associations or false discovery?

BACKGROUND: There are several indications that malfunctions of the circadian clock contribute to depression. To search for particular circadian gene polymorphisms associated with depression, diverse polymorphisms were genotyped in two samples covering a range of depressed volunteers and participants with normal mood. METHODS: Depression mood self-ratings and DNA were collected independently from a sample of patients presenting to a sleep disorders center (1086 of European origin) and from a separate sample consisting of 399 participants claiming delayed sleep phase symptoms and 406 partly-matched controls. A custom Illumina Golden Gate array of 768 selected single nucleotide polymorphisms (SNPs) was assayed in both samples, supplemented by additional SNPlex and Taqman assays, including assay of 41 ancestry-associated markers (AIMs) to control stratification. RESULTS: In the Sleep Clinic sample, these assays yielded Bonferroni-significant association with depressed mood in three linked SNPs of the gene FMR1: rs25702 (nominal P=1.77E-05), rs25714 (P=1.83E-05), and rs28900 (P=5.24E-05). This FMR1 association was supported by 8 SNPs with nominal significance and a nominally-significant gene-wise set test. There was no association of depressed mood with FMR1 in the delayed sleep phase case-control sample or in downloaded GWAS data from the GenRED 2 sample contrasting an early-onset recurrent depression sample with controls. No replication was located in other GWAS studies of depression. Our data did weakly replicate a previously-reported association of depression with PPARGC1B rs7732671 (P=0.0235). Suggestive associations not meeting strict criteria for multiple testing and replication were found with GSK3B, NPAS2, RORA, PER3, CRY1, MTNR1A and NR1D1. Notably, 16 SNPs nominally associated with depressed mood (14 in GSK3B) were also nominally associated with delayed sleep phase syndrome (P=3E10-6). CONCLUSIONS: Considering the inconsistencies between samples and the likelihood that the significant three FMR1 SNPs might be linked to complex polymorphisms more functionally related to depression, large gene resequencing studies may be needed to clarify the import for depression of these circadian genes.

Short wavelength light administered just prior to waking: a pilot study.

Bright light in the blue-green range, administered in the early morning hours (prior to waking) may be particularly effective in shifting circadian rhythms and may increase gonadotropin production. Accordingly, we tested the feasibility and utility of a mask that emits bright blue/green light (compared to a similar mask that emitted a dim red light) towards the end of sleep in a randomized, placebo-controlled pilot study. The study included a 3-day baseline period, immediately followed by a 12-day intervention period. Subjects were 30 healthy young men with minimal-mild depression. The bright light masks were well-tolerated and demonstrated adequate safety and feasibility. Following the intervention, those who wore the bright light mask demonstrated altered sleep timing suggestive of an earlier sleep period, and excreted a slight increase in follicle-stimulating hormone. Overall, light masks may prove useful in future studies of bright light therapy.

PER2 variation is associated with diurnal preference in a Korean young population.

The PER2 gene has been reported to influence diurnal preference. In this study, we have attempted to characterize the associations between the PER2 gene polymorphisms and diurnal preference in a population of healthy young subjects, controlling for the social and environmental confounding factors. Subjects were 299 students in a college, carefully selected to be mentally and physically healthy. All subjects completed the 13-item composite scale for morningness (CSM). PER2 gene polymorphisms were genotyped by PCR-based methods. Genotype and allele carrier status of a PER2 G3853A polymorphism (rs934945) were associated with CSM scores. Carriers of the 3853G allele showed significantly higher CSM scores (P = 0.004, P = 0.009, and P = 0.001; total, morningness, and activity plan, respectively). There were no significant differences on CSM scores among genotypes and allele status of PER2 rs2304672. This result indicates that rs934945 of PER2 may be associated with diurnal preference in a Korean healthy population.

Polymorphisms in melatonin synthesis pathways: possible influences on depression.

BACKGROUND: It has been reported that rs4446909, a single nucleotide polymorphism (SNP) in the promoter of acetylserotonin methyltransferase (ASMT), influences the expression of the ASMT enzyme. The common G allele is associated with lower ASMT activity, and therefore, diminishes conversion of N-acetylserotonin to melatonin. The G allele was associated with recurrent depressive disorder in a Polish group. ASMT might also affect bipolar relapse, given evidence that N-acetylserotonin might stimulate TRKB receptors, and TRKB may influence mood relapse in bipolar disorder. Additionally, arylalkylamine N-acetyltransferase (AANAT) polymorphisms have been reported associated with depression, perhaps through their influence upon N-acetylserotonin or melatonin synthesis. RESULTS: To replicate and further explore these ideas, rs4446909 was genotyped in four research groups, as part of a panel of 610 SNPs surveyed by an Illumina Golden Gate assay. In 768 cases with delayed sleep phase disorder or matched controls, rs4446909 was indeed associated with the depressive symptoms on a self-report scale (P = 0.01, R2 = 0.007). However, there was no significant association of rs4446909 with self-reported depression in a sleep clinic patient group or with two groups of elderly men and women from multicenter studies, nor was the response to lithium treatment associated with rs4446909 in bipolar patients. No associations of two AANAT SNPs with depression were found. CONCLUSIONS: The evidence did not support a strong influence of rs4446909 upon mood, but the partial replication may be consistent with a modest effect. It is possible that larger or younger subject groups with improved phenotype ascertainment might demonstrate more persuasive replication.

Wrist actigraphic scoring for sleep laboratory patients: algorithm development.

Wrist actigraphy is employed increasingly in sleep research and clinical sleep medicine. Critical evaluation of the performance of new actigraphs and software is needed. Actigraphic sleep-wake estimation was compared with polysomnographic (PSG) scoring as the standard in a clinical sleep laboratory. A convenience sample of 116 patients undergoing clinical sleep recordings volunteered to participate. Actiwatch-L recordings were obtained from 98 participants, along with 18 recordings using the newer Spectrum model (Philips Electronics), but some of the actigraphic recordings could not be adequately aligned with the simultaneous PSGs. Of satisfactory alignments, 40 Actiwatch recordings were used as a training set to empirically develop a new Scripps Clinic algorithm for sleep-wake scoring. The Scripps Clinic algorithm was then prospectively evaluated in 39 Actiwatch recordings and 16 Spectrum recordings, producing epoch-by-epoch sleep-wake agreements of 85-87% and kappa statistics averaging 0.52 (indicating moderate agreement). Wake was underestimated by the scoring algorithm. The correlations of PSG versus actigraphic wake percentage estimates were r = 0.6690 for the Actiwatch and r = 0.2197 for the Spectrum. In general, using a different weighting of activity counts from previous and subsequent epochs, the Scripps Clinic algorithm discriminated sleep-wake more successfully than the manufacturer's Actiware algorithms. Neither algorithm had fully satisfactory agreement with PSG. Further evaluations of algorithms for these actigraphs are needed, along with controlled comparisons of different actigraphic designs and software.

Weak evidence of bright light effects on human LH and FSH.

BACKGROUND: Most mammals are seasonal breeders whose gonads grow to anticipate reproduction in the spring and summer. As day length increases, secretion increases for two gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). This response is largely controlled by light. Light effects on gonadotropins are mediated through effects on the suprachiasmatic nucleus and responses of the circadian system. There is some evidence that seasonal breeding in humans is regulated by similar mechanisms, and that light stimulates LH secretion, but primate responses seem complex. METHODS: To gain further information on effects of bright light on LH and FSH secretion in humans, we analyzed urine samples collected in three experiments conducted for other goals. First, volunteers ages 18-30 years and 60-75 commenced an ultra-short 90-min sleep-wake cycle, during which they were exposed to 3000 lux light for 3 hours at balanced times of day, repeated for 3 days. Urine samples were assayed to explore any LH phase response curve. Second, depressed participants 60-79 years of age were treated with bright light or dim placebo light for 28 days, with measurements of urinary LH and FSH before and after treatment. Third, women of ages 20-45 years with premenstrual dysphoric disorder (PMDD) were treated to one 3-hour exposure of morning light, measuring LH and FSH in urine before and after the treatments. RESULTS: Two of the three studies showed significant increases in LH after light treatment, and FSH also tended to increase, but there were no significant contrasts with parallel placebo treatments and no significant time-of-day treatment effects. CONCLUSIONS: These results gave some support for the hypothesis that bright light may augment LH secretion. Longer-duration studies may be needed to clarify the effects of light on human LH and FSH.

Tolerance of chronic 90-minute time-in-bed restriction in older long sleepers.

STUDY OBJECTIVES: To examine the influence of chronic time-in-bed (TIB) restriction on selected health-related outcome variables in older long sleepers. DESIGN: Randomized, controlled trial. SETTING: Home-based. PARTICIPANTS: Forty-two older adults (aged 50-70 y) who reported sleeping at least 8.5 hours. Following extensive screening, participants were assessed for 10 weeks. INTERVENTION: During a two-week baseline, participants followed their usual sleep-wake habits. Participants were then randomized to one of two eight-week treatments: (1) TIB restriction, in which participants were asked to follow a fixed sleep schedule with a TIB of 90 minutes less than recorded during baseline or (2) a control treatment, which involved following a fixed sleep schedule (consistent with average baseline) but no TIB restriction. MEASUREMENTS AND RESULTS: Continuous wrist actigraphic sleep estimation indicated that TIB restriction elicited significant reductions in TIB and total sleep time compared with the control treatment and significant (albeit modest) improvements in sleep efficiency and sleep latency. However, compared with the control treatment, TIB restriction elicited no significant change in depression, sleepiness, health-related quality of life, or neurobehavioral performance. Moreover, follow-up assessments for one year indicated that, after completing the experiment, the participants assigned to TIB restriction continued to restrict their TIB (at their own initiative) by an average of approximately one hour. CONCLUSIONS: The results suggest good tolerance of chronic moderate TIB restriction, without detrimental effects, among older long sleepers.

Circadian rhythm of CSF monoamines and hypocretin-1 in restless legs syndrome and Parkinson's disease.

The symptoms of restless legs syndrome (RLS) have a circadian pattern and central nervous system dopamine has been implicated in the pathogenesis of the condition. We sought to characterize circadian variation in dopamine and related compounds in human cerebro-spinal fluid (CSF). CSF was continuously withdrawn for 22 h from an implanted lumbar intradural catheter and sampled from three patients with RLS, three patients with Parkinson's disease (PD) and three healthy volunteers. Patients had moderate disease severity and took no medications. We assayed CSF dopamine (DA), homovanillic acid (HVA), dihydroxy-phenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) from samples every 30 min by reversed-phase HPLC coupled with electrochemical detection. We also measured CSF levels of hypocretin-1 every hour by RIA. The procedure was well-tolerated. One patient ended the study early due to lumbar radicular pain and was not included in the analysis. There were no changes in CSF cell counts or protein levels from the first to the last samples. There was no difference in any of the compounds between groups, so we fit 24-h cosines to examine if the entire group had significant phase consistency. There was a peak for dopamine at 10 a.m. (p<0.025) and for HVA at 2 p.m. (p<0.01), but no evidence of a significant 24-h rhythm for DOPAC, 5-HIAA, the HVA/5-HIAA ratio, or hypocretin-1. These results demonstrate a circadian rhythm for CSF dopamine and HVA concentrations in humans, with higher levels in the daytime than at nighttime. This circadian variation could underlie the symptoms of RLS and sleep-related variation in motor function in PD.

Accentuation of suicides but not homicides with rising latitudes of Greenland in the sunny months.

BACKGROUND: Seasonal variation in suicides has been shown in many countries. We assessed the seasonality and the variation with latitude in suicides and homicides, and the impact of alcohol on the seasonality in suicides. METHODS: Official computerized registers on causes of death in all Greenland during 1968-2002 were used. Sales data on beer from one of the major food store chains for July 2005-June 2006 were examined. Seasonal variation was assessed by Rayleigh's test for circular distributions. RESULTS: There were a total of 1351 suicides and 308 homicides. The suicides rate varied from 4.2/100 000 person-years in 1971 to 128.4/100 000 person-years in 1987. The homicide rate varied from 2.1/100000 person-years in 1969-1970 to 34.8/100 000 person-years in 1988. Out of the 1351 suicides, 80.5% were committed by men and 19.5% by women. Median age was 25 years (n = 1351; Range 11-84 years). Violent methods of suicide were used in 95% of all cases (n = 1286). Out of the 308 homicide victims, 61% were men and 39% were women, and 13% were killed in multiple homicide events.There was a significant seasonal variation with peaks in June and troughs in the winter in all suicide cases (n = 1351, r = 0.07; Z = 7.58, p < 0.001), in violent suicides (n = 1286; r = 0.07; Z = 6.97; p < 0,001), in suicides in men (n = 1087; r = 0.07; Z = 5.39; p < 0.002) , and in women (n = 264; r = 0.10; Z = 2.36; p < 0.05), but not in homicides nor in consumption of beer. There was a bi-phasic seasonal variation in suicide victims where an alcohol-related condition was included in the death certificate. Suicides were more concentrated in the summer months north of the Arctic Circle (n = 577, r = 0.09, Z = 4.45, p < 0.01) than south of it (n = 769, r = 0.07, Z = 3.76, p < 0.002) and most concentrated in North Greenland (n = 33; r = 0.35; Z = 4.11; p < 0.01), where 48% of suicides occurred during the period of constant light. When including astronomical twilight in the constant light period 82% occurred during this time. CONCLUSION: There was a concentration of suicides but not homicides in the summer months in all Greenland. The concentration was most pronounced at high latitudes.

Circadian polymorphisms associated with affective disorders.

BACKGROUND: Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies. METHODS: Four groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples. RESULTS: In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample. CONCLUSION: Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders.

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.

Possibility that certain hypnotics might cause cancer in skin.

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause any cancers. The US Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the four drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. There were eight mentions of incident non-melanoma skin cancers among participants receiving hypnotics but no comparable mentions of cancers among those receiving placebo (P = 0.064, one-tailed). There were also four mentions of incident tumors of uncertain malignancy among those receiving hypnotics but none among those receiving placebo, so combining uncertain and definite malignancies yielded a more significant contrast (P = 0.016). FDA files revealed that all four of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, confirmatory research is needed.

No effect of 8-week time in bed restriction on glucose tolerance in older long sleepers.

The aim of this study was to investigate the effects of 8 weeks of moderate restriction of time in bed (TIB) on glucose tolerance and insulin sensitivity in healthy older self-reported long sleepers. Forty-two older adults (ages 50-70 years) who reported average sleep durations of >or=8.5 h per night were assessed. Following a 2-week baseline, participants were randomly assigned to two 8-week treatments: either (i) TIB restriction (n = 22), which involved following a fixed sleep schedule in which time in bed was reduced by 90 min compared with baseline; (ii) a control (n = 18), which involved following a fixed sleep schedule but no imposed change of TIB. Sleep was monitored continuously via wrist actigraphy recordings, supplemented with a daily diary. Glucose tolerance and insulin sensitivity were assessed before and following the treatments. Compared with the control treatment, TIB restriction resulted in a significantly greater reduction of nocturnal TIB (1.39 +/- 0.40 h versus 0.14 +/- 0.26 h), nocturnal total sleep time (TST) (1.03 +/- 0.53 h versus 0.40 +/- 0.42 h), and 24-h TST (1.03 +/- 0.53 h versus 0.33 +/- 0.43 h) from baseline values. However, no significant effect of TIB restriction was found for glucose tolerance or insulin sensitivity. These results suggest that healthy older long sleepers can tolerate 8 weeks of moderate TIB restriction without impairments in glucose tolerance or insulin sensitivity.

Delayed sleep phase cases and controls.

BACKGROUND: Delayed sleep phase disorder (DSPD) is a condition in which patients have difficulty falling asleep before the early morning hours and commonly have trouble awakening before late morning or even early afternoon. Several studies have suggested that variations in habitual bedtime are 40-50% heritable. METHODS: We recruited a case series of 205 participants, along with 221 controls (DSPD-C) with normal sleep, roughly matched for age, gender, and ancestry. A representative sample of San Diego adults recruited some years before was already available to confirm the control group. Both DSPD and DSPD-C provided blood or saliva samples for DNA and completed extensive questionnaires about sleep habits, sleep history, family history, sleep quality, morningness-eveningness traits, depression, mania, and seasonality of symptoms. The DSPD group wore wrist actigraphs for a median of 13.2 days. The representative sample collected previously had undergone actigraphic recordings, from which 48 hours of data were generally available. RESULTS: The DSPD and DSPD-C samples showed almost no overlap on morningness-eveningness scores. DSPD cases went to bed and arose about 3 hours later than the DSPD-C and the representative sample. DSPD cases reported more difficulties with sleep, poorer sleep quality, and more depression, but there was no significant difference in a history of mania. DSPD cases reported more family history of late bedtimes, but female DSPD reported that their fathers' bedtimes were later than the fathers of male DSPD. CONCLUSION: These results indicate a DSPD phenotype is familial and associated with unipolar depression.

Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients.

PURPOSE: To evaluate the effects of laser trabeculoplasty on 24-hour intraocular pressure (IOP) in a group of medically treated open-angle glaucoma patients. DESIGN: Prospective experimental study. PARTICIPANTS: Eighteen open-angle glaucoma patients. METHODS: Laser trabeculoplasty (180 degrees ) was performed on 28 eyes of 18 glaucoma patients. Twenty-four-hour IOP data were collected in a sleep laboratory before and 45 to 80 days after the procedure. Measurements of sitting and supine IOP were taken during the 16-hour diurnal/wake period, and measurements of supine IOP were taken during the 8-hour nocturnal/sleep period in 2-hour intervals. MAIN OUTCOME MEASURES: Changes in the mean, peak, and range of IOP during the office-hour, diurnal, nocturnal, and 24-hour periods. RESULTS: Compared with the baselines, changes in the mean, peak, and range of IOP were not significant during the office-hour period and during the diurnal period in either the sitting or the supine position. The mean, peak, and range of IOP were reduced significantly during the nocturnal period in the supine position. Mean and peak 24-hour IOP were reduced significantly in the habitual body positions (sitting during the diurnal period and supine during the nocturnal period). The reduction of mean 24-hour IOP in the supine position also was significant. CONCLUSIONS: In this group of medically treated open-angle glaucoma patients, laser trabeculoplasty reduced IOP more consistently during the nocturnal period than during the diurnal period.

More prominent reactivity in mood than activity and sleep induced by differential light exposure due to seasonal and local differences.

The aim of this study was to investigate how mood, work time, light exposure, activity, and sleep indices are affected by the differences of latitude and season in healthy volunteers. Twenty-four subjects (38.92+/-11.32 yrs) in Rochester, Minnesota, USA (latitude 44 degrees 1'N) and 30 subjects (47.03+/-16.32 yrs) in San Diego, California, USA (latitude 32 degrees 43'N) completed a 1 yr protocol measuring daily logs including daily work time and sleep diary; the Center for Epidemiologic Studies Depression Scale (CES-D); the eight-item atypical subscore of the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version (SIGH-SAD); and actigraphic measures of light exposure and sleep for one-week in each solstice of summer and winter. Higher scores of CES-D (p=0.038) and the eight-item atypical subscore of SIGH-SAD (p=0.009), and longer indoor (p=0.001) and shorter outdoor (p=0.002) work times were observed during winter than summer only in Rochester, with no differences in San Diego. The mesor of light was decreased in both Rochester (p < or = 0.001) and San Diego (p=0.004) during winter compared to summer, with no differences in the mesors (24 h means) of activity and sleep. The eight-item atypical subscore of SIGH-SAD was significantly negatively correlated with the mesor of light (p=0.034). Sleep indices showed no significant differences between two locales or two seasons. A more prominent depressive mood in Rochester than San Diego during winter can be explained by decreased light exposure of healthy subjects in Rochester. Despite a significant difference of mood and light exposure between the two seasons in Rochester, there were no differences in activity or sleep. Therefore, mood might be more reactive than activity and sleep in the seasonal variation induced by differential light exposure.

Greater incidence of depression with hypnotic use than with placebo.

BACKGROUND: Although it has been claimed that insomnia causes an increased risk for depression, adequate controlled trials testing this hypothesis have not been available. This study contrasted the incidence of depression among subjects receiving hypnotics in randomized controlled trials versus those receiving placebo. METHODS: The incidence of depression among patients randomized to hypnotic drugs or placebo was compiled from prescribing information approved by the United States Food and Drug Administration (FDA) and from FDA New Drug Application documents. Available data for zolpidem, zaleplon, eszopiclone, and ramelteon were accessed. RESULTS: Data for 5535 patients randomized to a hypnotic and for 2318 randomized to placebo were compiled. The incidence of depression was 2.0% among participants randomized to hypnotics as compared to 0.9% among those randomized in parallel to placebo (p < 0.002). CONCLUSION: Modern hypnotics were associated with an increased incidence of depression in data released by the FDA. This suggests that when there is a risk of depression, hypnotics may be contra-indicated. Preventive treatments such as antidepressant drugs, cognitive-behavioral therapy, or bright light might be preferred. Limitations in the FDA data prevented a formal meta-analysis, and there was a lack of information about drop-out rates and definitions of depression. Trials specifically designed to detect incident depression when treating insomnia with hypnotic drugs and better summarization of adverse events in trials submitted to the FDA are both necessary.