Insomnia Abstracts 9




The Effects of Lithium Carbonate Supplemented with Nitrazepam on Sleep Disturbance during Cannabis Abstinence.
            (Allsop et al., 2015) Download
STUDY OBJECTIVE:  Sleep disturbance is a hallmark feature of cannabis withdrawal. In this study we explored the effects of lithium treatment supplemented with nitrazepam on objective and subjective measures of sleep quality during inpatient cannabis withdrawal. METHODS:  Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo, twice daily in a double-blind RCT. Restricted nitrazepam (10 mg) was available on demand (in response to poor sleep) on any 3 of the 7 nights. Dependent outcome measures for analysis included repeated daily objective actigraphy and subjective sleep measures throughout the 8 day detox, subjective cannabis withdrawal ratings, and detoxification completion rates. RESULTS:  Based on actigraphy, lithium resulted in less fragmented sleep compared to placebo (p = 0.04), but no other objective measures were improved by lithium. Of the subjective measures, only nightmares were suppressed by lithium (p = 0.04). Lithium did not have a significant impact on the use of nitrazepam. Sleep bout length (p < 0.0001), sleep efficiency (p < 0.0001), and sleep fragmentation (p = 0.05) were improved on nights in which nitrazepam was used. In contrast, only night sweats improved with nitrazepam from the subjective measures (p = 0.04). A Cox regression with daily repeated measures of sleep efficiency averaged across all people in the study a predictor suggests that a one-unit increase in sleep efficiency (the ratio of total sleep time to the total time in bed expressed as a percentage) resulted in a 14.6% increase in retention in treatment (p = 0.008, Exp(B) = 0.854, 95% CI = 0.759-0.960). None of the other sleep measures, nor use of lithium or nitrazepam were significantly associated with retention in treatment. CONCLUSIONS:  Lithium seems to have only limited efficacy on sleep disturbance in cannabis withdrawal. However the nitrazepam improved several actigraphy measures of sleep disturbance, warranting further investigation. Discord between objective and subjective sleep indices suggest caution in evaluating treatment interventions with self-report sleep data only.


Lithium carbonate: effects on sleep patterns of normal and depressed subjects and its use in sleep-wake pathology.
            (Billiard, 1987) Download
The effects of lithium carbonate on sleep patterns have been investigated both acutely in normal and depressed subjects and chronically in depressed subjects. In normal subjects receiving lithium for two weeks total sleep time did not vary, REM sleep decreased and REM sleep latency increased. In depressed subjects, either on short therm therapy or on long term therapy stages 3 and 4 increased, REM sleep decreased, REM latency increased and REM activity/time spent asleep (an index of REM intensity per minute of sleep) decreased. Plasma lithium levels were negatively correlated with REM sleep percentage and positively correlated with REM sleep latency. Besides, it has been shown in one paper that short term therapy with lithium caused small but significant delays in the sleep-wake circadian rhythm. These effects are of interest in view of polygraphic sleep abnormalities found in affective disorders and possible circadian disturbances accounting for these abnormalities. Indeed lithium might act in correcting spezial sleep abnormalities and/or circadian disturbances. In addition to its predominant use for the prophylaxis of recurrent mania and depression, lithium carbonate has been proposed and tried in the prophylactic treatment of abnormally prolonged sleep episodes featuring the Kleine-Levin syndrome.

Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors
            (Friston et al., 1989) Download
The effect of lithium on slow wave sleep (SWS) was studied in ten normal male volunteers using home based cassette sleep recording and automatic sleep stage analysis. Lithium increased SWS, an effect consistent with a reduction in brain 5-HT2 receptor function.

Lithium affects REM sleep occurrence, autonomic activity and brain second messengers in the rat.
            (Jones et al., 2008) Download
The effects of a single intraperitoneal administration of lithium, a drug used to prevent the recurrence of mania in bipolar disorders, were determined in the rat by studying changes in: (i) the wake-sleep cycle; (ii) autonomic parameters (hypothalamic and tail temperature, heart rate); (iii) the capacity to accumulate cAMP and IP(3) in the preoptic-anterior hypothalamic region (PO-AH) and in the cerebral cortex (CC) under an hypoxic stimulation at normal laboratory and at low ambient temperature (T(a)). In the immediate hours following the injection, lithium induced: (i) a significant reduction in REM sleep; (ii) a non-significant reduction in the delta power density of the EEG in NREM sleep; (iii) a significant decrease in the concentration of cAMP in PO-AH at normal laboratory T(a); (iv) a significant increase of IP(3) concentration in CC following exposure to low T(a). The earliest and most sensitive effects of lithium appear to be those concerning sleep. These changes are concomitant with biochemical effects that, in spite of a systemic administration of the substance, may be differentiated according to the second messenger involved, the brain region and the ambient condition.

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.
            (Ota et al., 2013) Download
BACKGROUND:  Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. OBJECTIVE:  To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. DESIGN:  Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. SUBJECTS:  Wistar male rats weighing 300-400 g. RESULTS:  Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. CONCLUSION:  Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus.
            (Welsh and Moore-Ede, 1990) Download
Lithium lengthens the period of free-running circadian rhythms in a variety of species, but this effect has not been demonstrated unequivocally in primates. Because of the possible link between lithium's action on the circadian clock and its therapeutic action in human mood disorders, we tested the ability of lithium to lengthen circadian period in a diurnal primate with circadian properties similar to those of humans. Lithium carbonate was administered in food pellets to 8 adult male squirrel monkeys (Saimiri sciureus) for at least 27 consecutive days. Serum lithium levels on the last day of lithium administration ranged from 0.76 to 2.02 mEq/liter, comparable to the therapeutic range for treatment of bipolar disorder in humans (0.6-1.2 mEq/liter). Circadian periods of perch-hopping activity were longer during lithium treatment than during baseline in 7 of the 8 monkeys (changes of -0.08 to +1.41 hr, mean +0.55 hr, p = 0.01), and returned toward baseline values when lithium was discontinued. In most cases, the period change was evident within a few days after beginning full lithium dose, and was not accompanied by changes in level or pattern of activity, nor in amplitude of the circadian rhythm. Food consumption and body weight were reduced during lithium treatment, and rebounded on return to lithium-free diet. Period change was related to lithium dose (p less than 0.05), but did not correlate with food consumption, body weight, or baseline circadian period. These results, by establishing that lithium lengthens circadian period in primates, suggest that studying the cellular mechanisms of this circadian effect may be relevant to understanding lithium's therapeutic effect on mood in humans.

Lithium lengthens circadian period of cultured brain slices in area specific manner.
            (Yoshikawa and Honma, 2016) Download
Lithium has been used for the treatment of bipolar disorder (BD). However, the mechanisms how lithium exerts its mood stabilizing effects remain to be studied. The disorder in circadian pacemaking has been suggested as an underlying mechanism of the characteristic mood instability of the BD. Lithium is also known to lengthen the circadian periods. We recently proposed that chronic methamphetamine treatment induced circadian oscillation as a complex oscillator including multiple dopaminergic brain areas, and the complex oscillator regulates behavior rhythm independent from the central circadian oscillator in the suprachiasmatic nucleus (SCN). Sleep-wake pattern of rapid cycling BD exhibits similar rhythm disorganization to methamphetamine treated animals. Therefore, we hypothesized that the dysregulated circadian rhythm in BD patients is caused by desynchronization of sleep-wake rhythms from the central clock in the SCN, and that mood stabilizing effect of lithium is achieved through their resynchronization. In the present experiment, we examined how lithium affects the circadian rhythms of brain areas involved in the complex oscillator as well as the SCN. Here we report that lithium lengthens the circadian periods in the SCN, olfactory bulb, median eminence and substantia nigra with dose and area specific manner. The effective lithium dose was much higher than the plasma levels that are required for lengthening the circadian behavior rhythms as well for therapeutic use. Low dose of lithium did not lengthen the period but enhanced the amplitude of circadian rhythms, which may exert therapeutic effects on BD.



Bisphenol-A and Sleep Adequacy among Adults in the National Health and Nutrition Examination Surveys.
            (Beydoun et al., 2016) Download
STUDY OBJECTIVES:  To evaluate bisphenol-A (BPA) level and its relationship to sleep adequacy in a nationally representative sample of U.S. adults. METHODS:  A population-based cross-sectional study was conducted using 2005-2010 National Health and Nutrition Examination Survey whereby data were collected using in-person interviews, physical examination and laboratory testing. BPA level was measured in urine samples and analyzed as loge-transformed variable and in quartiles (< 0.9 ng/mL; 0.9 to < 1.9 ng/mL; 1.9 to < 3.7 ng/mL; 3.7+ ng/mL). Sleep adequacy was operationalized with three questions: "How much sleep do you usually get at night on weekdays or workdays?", "Have you ever told a doctor or other health professionals that you have trouble sleeping?" and "Have you ever been told by a doctor or other health professional that you have a sleep disorder?" Sleep duration was further categorized as (< 6 h, ≥ 6 h); (< 7 h, 7-8 h, > 8 h); (< 5 h, 5-6 h, 7-8 h, ≥ 9 h). Linear, binary, and ordinal logistic regression models were constructed. RESULTS:  Loge-transformed BPA level was inversely related to sleep duration defined, in hours, as a continuous variable, a dichotomous variable (≥ 6, < 6), or an ordinal variable (≥ 9, 7-8, 5-6, < 5), after adjustment for confounders. Help-seeking behavior for sleep problems and diagnosis with sleep disorders were not significantly associated with loge-transformed BPA level in fully adjusted models. CONCLUSIONS:  Loge-transformed BPA level may be associated with fewer hours of sleep among U.S. adults, with implications for prevention. Further research involving diverse populations are needed to confirm these study findings.


Medical comorbidity of sleep disorders.
            (Dikeos and Georgantopoulos, 2011) Download
PURPOSE OF REVIEW:  Recently published literature indicates that sleep disorders present with medical comorbidities quite frequently. The coexistence of a sleep disorder with a medical disorder has a substantial impact for both the patient and the health system. RECENT FINDINGS:  Insomnia and hypersomnia are highly comorbid with medical conditions, such as chronic pain and diabetes, as well as with various cardiovascular, respiratory, gastrointestinal, urinary and neurological disorders. Restless legs syndrome and periodic leg movement syndrome have been associated with iron deficiency, kidney disease, diabetes, and neurological, autoimmune, cardiovascular and respiratory disorders. Rapid eye movement behaviour disorder has been described as an early manifestation of serious central nervous system diseases; thus, close neurological monitoring of patients referring with this complaint is indicated. SUMMARY:  Identification and management of any sleep disorder in medical patients is important for optimizing the course and prognosis. Of equal importance is the search for undetected medical disorder in patients presenting with sleep disorders.

Associations of Self-Reported Sleep Quality with Circulating Interferon Gamma-Inducible Protein 10, Interleukin 6, and High-Sensitivity C-Reactive Protein in Healthy Menopausal Women.
            (Huang et al., 2017) Download
INTRODUCTION:  Sleep disturbance is very common in menopausal women and poor sleep quality has been linked to systemic inflammation. However, the impact of poor sleep quality on health outcomes of menopausal women remains unclear. This study evaluated the relationships between sleep quality and inflammation in menopausal women. PARTICIPANTS AND DESIGN:  This cross-sectional study enrolled 281 healthy women aged 45 to 60 years. The Pittsburgh Sleep Quality Index (PSQI) was used to measure quality of sleep. Multiplex assays were used to measure the levels of 9 cytokines in morning fasting plasma samples. Other variables measured in this study included clinical characteristics and high-sensitivity C-reactive protein (hs-CRP). SETTING:  The study was performed at a medical center. RESULTS:  The 281 participants comprised 79 (28%) perimenopausal women and 202 (72%) postmenopausal women. Global PSQI scores were positively correlated with plasma hs-CRP levels (P = 0.012) and were marginally associated with interferon gamma-inducible protein-10 (IP10), interleukin 6 (IL6), and macrophage inflammatory protein-1beta (MIP-1β) levels. After adjusting for age, body mass index, menopause duration, and follicle stimulating hormone, multiple linear regression analysis revealed that high PSQI scores and sleep efficiency < 65% were associated with elevated plasma levels of hs-CRP, IP10, and IL6. In addition, sleep duration < 5 hours was associated with high hs-CRP levels. CONCLUSION:  Our data show that poor sleep quality and low sleep efficiency are associated with elevated levels of circulating inflammatory factors IP10, IL6 and hs-CRP and that short sleep duration is associated with high levels of hs-CRP in menopausal women. These findings provide novel evidence that poor sleep quality is linked to low-grade systemic inflammation in menopausal women.

Insomnia and high-sensitivity C-reactive protein: the HUNT study, Norway
            (Laugsand et al., 2012) Download
OBJECTIVE: To explore the hypothesis that insomnia may increase the risk of coronary heart disease through inflammatory mechanisms. METHODS: The association of high-sensitivity C-reactive protein (hsCRP) with self-reported symptoms of insomnia was examined. Participants were 8547 men and nonpregnant women who answered one or more insomnia-related questions and who had available hsCRP measurements in the Nord-Trondelag Health Study. In multivariable linear regression analyses of the logarithm of hsCRP, we adjusted for established cardiovascular risk factors, psychosocial distress, chronic pain, and chronic somatic disorders. RESULTS: Among men, difficulties initiating sleep and nonrestorative sleep were associated with increasing hsCRP levels after adjusting for age (B = 0.07, 95% confidence interval [CI] = 0.01-0.14, p for trend = .02 and B = 0.09, 95% CI = 0.02-0.15, p for trend = .006), but after multivariable adjustment, the associations were attenuated (B = 0.03, 95% CI = -0.03 to 0.09, p for trend = .30 and B = 0.06, 95% CI = -0.00 to 0.12, p for trend = .05). HsCRP was not associated with other insomnia-related symptoms. In women, there was no evidence for any association of symptoms of insomnia with hsCRP levels. Results indicated sex differences in the association between sleep characteristics and CRP (difficulties maintaining sleep, p interaction = .018; cumulative number of symptoms of insomnia, p interaction = .014; and symptoms of insomnia influencing work performance, p interaction = .039). CONCLUSIONS: There were no consistent associations between symptoms of insomnia and hsCRP levels. Our results do not support the hypothesis that inflammation, as reflected by elevated levels of hsCRP, is an important factor linking insomnia to coronary heart disease.

Association between sleep quality and C-reactive protein: results from national health and nutrition examination survey, 2005-2008.
            (Liu et al., 2014) Download
OBJECTIVE:  Our objective was to explore the association between poor sleep quality and hs_CRP in an adult U.S. population. METHODS:  This study focused on 9,317 participants in the National Health and Nutrition Examination Survey (NHANES) from 2005-2008 who were aged 20-85 years, completed a sleep disorder questionnaire, and had available information on serum hs_CRP. Sleep quality was classified into three categories (good, moderate, poor) based on the responses of participants to the NHANES sleep disorder questionnaire. High CRP was defined as hs-CRP >1 md/dL. Linear regression model was applied to investigate the association between poor sleep quality and log-transformed hs_CRP. And logistic regression model was fitted to evaluate the association between sleep quality and the risk of high CRP. RESULTS:  Females were more likely to report poor sleep quality than males (26% vs. 19%, p<0.0001). Each sleep disorder was significantly associated with increased hs_CRP and correlative to other sleep disorders. In fully-adjusted linear regression model, poor sleep quality was significantly associated with elevated hs_CRP (log transformed) among the overall sample and in females only (β = 0.10, se = 0.03, p<0.01 and β = 0.13, se = 0.04, p<0.01, respectively). In fully-adjusted logistics regression model, poor sleep quality was linked with risk of high CRP(OR: 1.42, 95%CI: 1.15-1.76 in overall sample and OR: 1.59, 95%CI: 1.18-2.14 in females, respectively). CONCLUSION:  We found that poor sleep quality was independently associated with elevated hs_CRP in females but not in males in a U.S. adult population.

Actigraphy- and Polysomnography-Measured Sleep Disturbances, Inflammation, and Mortality Among Older Men.
            (Smagula et al., 2016) Download
OBJECTIVES:  To evaluate whether objectively measured sleep characteristics are associated with mortality risk independent of inflammatory burden and comorbidity. METHODS:  The Osteoporotic Fractures in Men Sleep Study (conducted in 2003-2005) included community-dwelling older men (n = 2531; average [standard deviation, SD age = 76.3 (5.5) years). Sleep measures from in-home polysomnography and wrist actigraphy and assessments of serum inflammatory markers levels (C-reactive protein, interleukin-6, tumor necrosis factor α, tumor necrosis factor α soluble receptor II, and interferon-γ) were obtained. Vital status was ascertained over an average (SD) follow-up of 7.4 (1.9 SD) years. RESULTS:  Three of the seven main sleep measures examined were independently associated with greater inflammatory burden. Mortality risk associated with prolonged (≥10% total sleep time) blood oxygen desaturation and short (<5 hours) sleep duration was attenuated to nonsignificance after adjusting for inflammatory burden or medical burden/lifestyle factors. Severe blood oxygen desaturation (adjusted hazard ratio [aHR] = 1.57, 95% confidence interval [CI] = 1.11-2.22), sleep fragmentation (aHR = 1.32, 95% CI = 1.12-1.57), and a lower percentage of sleep in rapid eye movement (aHR per SD = 0.90, 95% CI = 0.93-0.97) were independently associated with mortality. CONCLUSIONS:  Short sleep duration and prolonged blood oxygen desaturation were independently associated with inflammatory burden, which attenuated associations between these sleep characteristics and mortality. Medical and life-style factors also substantially attenuated most sleep-mortality associations, suggesting complex relations between sleep, inflammation, and disease. Sleep fragmentation, severe blood oxygen desaturation, and the percentage of sleep time in rapid eye movement were independently related to mortality risk. Future studies with repeated measures of mediators/confounds will be necessary to achieve a mechanistic understanding of sleep-related mortality risk.



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Beydoun, HA, et al. (2016), ‘Bisphenol-A and Sleep Adequacy among Adults in the National Health and Nutrition Examination Surveys.’, Sleep, 39 (2), 467-76. PubMed: 26446109
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