Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit [version 3; referees: 2 approved]

This is a review of hypnotic drug risks and benefits. Almost every month, new information appears about the risks of hypnotics (sleeping pills). The most important risks of hypnotics include excess mortality (especially overdose deaths, quiet deaths at night, and suicides), infections, cancer, depression, automobile crashes, falls, other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with even greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse (not better) and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>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</p> <p>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.</p> <p>Conclusion</p> <p>There was a concentration of suicides but not homicides in the summer months in all Greenland. The concentration was most pronounced at high latitudes.</p

Hypnotics' association with mortality or cancer: a matched cohort study

Objectives: An estimated 6%e10 % of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality. Setting: A large integrated health system in the USA. Design: Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis. Subjects: Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 year

Circadian phase-shifting effects of a laboratory environment: a clinical trial with bright and dim light

BACKGROUND: Our aims were to examine the influence of different bright light schedules on mood, sleep, and circadian organization in older adults (n = 60, ages 60–79 years) with insomnia and/or depression, contrasting with responses of young, healthy controls (n = 30, ages 20–40 years). METHODS: Volunteers were assessed for one week in their home environments. Urine was collected over two 24-hour periods to establish baseline acrophase of 6-sulphatoxymelatonin (aMT6s) excretion. Immediately following home recording, volunteers spent five nights and four days in the laboratory. Sleep periods were fixed at eight hours in darkness, consistent with the volunteers' usual sleep periods. Volunteers were randomly assigned to one of three light treatments (four hours per day) within the wake period: (A) two hours of 3,000 lux at 1–3 hours and 13–15 hours after arising; (B) four hours of 3,000 lux at 6–10 hours after arising; (C) four hours of dim placebo light at 6–10 hours after arising. Lighting was 50 lux during the remainder of wakefulness. The resulting aMT6s acrophase was determined during the final 30 hours in the laboratory. RESULTS: Neither mood nor total melatonin excretion differed significantly by treatment. For the three light treatments, significant and similar phase-response plots were found, indicating that the shift in aMT6s acrophase was dependent upon the circadian time of treatment. The changes in circadian timing were not significantly correlated to changes in sleep or mood. CONCLUSION: The trial failed to demonstrate photoperiodic effects. The results suggest that even low levels of illumination and/or fixed timing of behavior had significant phase-shifting effects

Circadian phase response curves to light in older and young women and men

<p>Abstract</p> <p>Background</p> <p>The phase of a circadian rhythm reflects where the peak and the trough occur, for example, the peak and trough of performance within the 24 h. Light exposure can shift this phase. More extensive knowledge of the human circadian phase response to light is needed to guide light treatment for shiftworkers, air travelers, and people with circadian rhythm phase disorders. This study tested the hypotheses that older adults have absent or weaker phase-shift responses to light (3000 lux), and that women's responses might differ from those of men.</p> <p>Methods</p> <p>After preliminary health screening and home actigraphic recording baselines, 50 young adults (ages 18–31 years) and 56 older adults (ages 59–75 years) remained in light-controlled laboratory surroundings for 4.7 to 5.6 days, while experiencing a 90-min ultra-short sleep-wake cycle. Following at least 30 h in-lab baseline, over the next 51 h, participants were given 3 treatments with 3000 lux white light, each treatment for 3 h, centered at one of 8 clock times. The circadian rhythms of urinary aMT6s (a melatonin metabolite), free cortisol, oral temperature, and wrist activity were assessed at baseline and after treatment.</p> <p>Results</p> <p>Light (3000 lux for 3 h on 3 days) induced maximal phase shifts of about 3 h. Phase shifts did not differ significantly in amplitude among older and young groups or among women and men. At home and at baseline, compared to the young, the older adults were significantly phase-advanced in sleep, cortisol, and aMT6s onset, but not advanced in aMT6s acrophase or the temperature rhythm. The inflection from delays to advances was approximately 1.8 h earlier among older compared to young participants in reference to their aMT6s rhythm peaks, and it was earlier in clock time.</p> <p>Conclusion</p> <p>In these experimental conditions, 3000 lux light could shift the phase of circadian rhythms to about the same extent among older and young adults, but the optimal light timing for phase shifting differed. For an interval near 4 PM, bright light produced only negligible phase shifts for either age group.</p

Circadian polymorphisms associated with affective disorders

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>In <it>NR1D1</it>, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in <it>PER3 </it>and <it>CSNK1E </it>were associated with the BALM score. A <it>PPARGC1B </it>coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In <it>TEF</it>, 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.</p> <p>Conclusion</p> <p>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.</p

Daily illumination exposure and melatonin: influence of ophthalmic dysfunction and sleep duration

BACKGROUND: Ocular pathology lessens light's efficacy to maintain optimal circadian entrainment. We examined whether ophthalmic dysfunction explains unique variance in melatonin excretion of older adults over and above the variance explained by daily illumination, medical, and sociodemographic factors. We also examined whether ophthalmic dysfunction influences relationships between ambient illumination and melatonin. METHODS: Thirty older adults (mean age = 69 years; Blacks = 42% and Whites = 58%) of both genders participated in the study. Demographic and health data were collected at baseline. Participants underwent eye exams at SUNY Downstate Medical Center, wore an actigraph to monitor illumination and sleep, and collected urine specimens to estimate aMT6s concentrations. RESULTS: Hierarchical regression analysis showed that illumination factors explained 29% of the variance in aMT6s mesor. The proportion of variance explained by ophthalmic factors, sleep duration, and race was 10%, 2%, and 2%, respectively. Illumination factors explained 19% of the variance in aMT6s acrophase. The proportion of variance explained by ophthalmic factors, sleep duration, and race was 11%; 17%; and 2%, respectively. Controlling for sleep duration and race reduced the correlations between illumination and melatonin, whereas controlling for ophthalmic factors did not. CONCLUSION: Ophthalmic exams showed that elevated intraocular pressure and large cup-to-disk ratios were independently associated with earlier melatonin timing. Lower illumination exposure also had independent associations with earlier melatonin timing. Conceivably, ophthalmic and illumination factors might have an additive effect on the timing of melatonin excretion, which in turn might predispose individuals to experience early morning awakenings