Sequential psychological and pharmacological therapies for comorbid and primary insomnia: Study protocol for a randomized controlled trial

Background: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. Methods/design: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. Discussion: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions

Greater incidence of depression with hypnotic use than with placebo

Abstract 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 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.</p

Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: A randomized placebo-controlled pilot study

<p>Abstract</p> <p>Background</p> <p>Despite being the most commonly used herbal for sleep disorders, chamomile's (<it>Matricaria recutita</it>) efficacy and safety for treating chronic primary insomnia is unknown. We examined the preliminary efficacy and safety of chamomile for improving subjective sleep and daytime symptoms in patients with chronic insomnia.</p> <p>Methods</p> <p>We performed a randomized, double-blind, placebo-controlled pilot trial in 34 patients aged 18-65 years with DSM-IV primary insomnia for ≥ 6-months. Patients were randomized to 270 mg of chamomile twice daily or placebo for 28-days. The primary outcomes were sleep diary measures. Secondary outcomes included daytime symptoms, safety assessments, and effect size of these measures.</p> <p>Results</p> <p>There were no significant differences between groups in changes in sleep diary measures, including total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO), sleep quality, and number of awakenings. Chamomile did show modest advantage on daytime functioning, although these did not reach statistical significance. Effect sizes were generally small to moderate (Cohen's <it>d </it>≤ 0.20 to < 0.60) with sleep latency, night time awakenings, and Fatigue Severity Scale (FSS), having moderate effect sizes in favor of chamomile. However, TST demonstrated a moderate effect size in favor of placebo. There were no differences in adverse events reported by the chamomile group compared to placebo.</p> <p>Conclusion</p> <p>Chamomile could provide modest benefits of daytime functioning and mixed benefits on sleep diary measures relative to placebo in adults with chronic primary insomnia. However, further studies in select insomnia patients would be needed to investigate these conclusions.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01286324">NCT01286324</a></p

The incidence of unpleasant dreams after sub-anaesthetic ketamine

Ketamine is an N-methyl-D-aspartate (NMDA)receptor antagonist with psychotogenic effects and for whichthere are diverse reports of whether pleasant or unpleasantdreams result during anaesthesia, post-operatively or aftersub-anaesthetic use. The aim was to assess in healthy volunteers the incidence ofunpleasant dreams over the three nights after receiving asub-anaesthetic dose of ketamine, in comparison to placebo,and with retrospective home nightmare frequency as acovariate.Thirty healthy volunteers completed questionnairesabout retrospective home dream recall and were then giveneither ketamine or placebo. Ketamine resulted in significantly more meandream unpleasantness relative to placebo and caused athreefold increase in the odds ratio for the incidence of anunpleasant dream. The number of dreams reported over thethree nights did not differ between the groups. Theincidence of unpleasant dreams after ketamine use waspredicted by retrospectively assessed nightmare frequencyat home.Ketamine causes unpleasant dreams over thethree post-administration nights. This may be evidence of aresidual psychotogenic effect that is not found on standardself-report symptomatology measures or a result of disturbedsleep electrophysiology. The results have theoretical implications for the relationship between nightmares and schizotypy

Postmenopausal hormones and sleep quality in the elderly: a population based study

<p>Abstract</p> <p>Background</p> <p>Sleep disturbance and insomnia are commonly reported by postmenopausal women. However, the relationship between hormone therapy (HT) and sleep disturbances in postmenopausal community-dwelling adults is understudied. Using data from the multicenter Study of Osteoporotic Fractures (SOF), we tested the relationship between HT and sleep-wake estimated from actigraphy.</p> <p>Methods</p> <p>Sleep-wake was ascertained by wrist actigraphy in 3,123 women aged 84 ± 4 years (range 77-99) from the Study of Osteoporotic Fractures (SOF). This sample represents 30% of the original SOF study and 64% of participants seen at this visit. Data were collected for a mean of 4 consecutive 24-hour periods. Sleep parameters measured objectively included total sleep time, sleep efficiency (SE), sleep latency, wake after sleep onset (WASO), and nap time. All analyses were adjusted for potential confounders (age, clinic site, race, BMI, cognitive function, physical activity, depression, anxiety, education, marital status, age at menopause, alcohol use, prior hysterectomy, and medical conditions).</p> <p>Results</p> <p>Actigraphy measurements were available for 424 current, 1,289 past, and 1,410 never users of HT. Women currently using HT had a shorter WASO time (76 vs. 82 minutes, P = 0.03) and fewer long-wake (≥ 5 minutes) episodes (6.5 vs. 7.1, P = 0.004) than never users. Past HT users had longer total sleep time than never users (413 vs. 403 minutes, P = 0.002). Women who never used HT had elevated odds of SE <70% (OR,1.37;95%CI,0.98-1.92) and significantly higher odds of WASO ≥ 90 minutes (OR,1.37;95%CI,1.02-1.83) and ≥ 8 long-wake episodes (OR,1.58;95%CI,1.18-2.12) when compared to current HT users.</p> <p>Conclusions</p> <p>Postmenopausal women currently using HT had improved sleep quality for two out of five objective measures: shorter WASO and fewer long-wake episodes. The mechanism behind these associations is not clear. For postmenopausal women, starting HT use should be considered carefully in balance with other risks since the vascular side-effects of hormone replacement may exceed its beneficial effects on sleep.</p

GABAergic Gene Expression in Postmortem Hippocampus from Alcoholics and Cocaine Addicts; Corresponding Findings in Alcohol-Naïve P and NP Rats

BACKGROUND:By performing identical studies in humans and rats, we attempted to distinguish vulnerability factors for addiction from neurobiological effects of chronic drug exposure. We focused on the GABAergic system within the hippocampus, a brain region that is a constituent of the memory/conditioning neuronal circuitry of addiction that is considered to be important in drug reinforcement behaviors in animals and craving and relapse in humans. METHODOLOGY:Using RNA-Seq we quantified mRNA transcripts in postmortem total hippocampus from alcoholics, cocaine addicts and controls and also from alcohol-naïve, alcohol preferring (P) and non-preferring (NP) rats selectively bred for extremes of alcohol-seeking behavior that also show a general addictive tendency. A pathway-targeted analysis of 25 GABAergic genes encoding proteins implicated in GABA synthesis, metabolism, synaptic transmission and re-uptake was undertaken. PRINCIPAL FINDINGS:Directionally consistent and biologically plausible overlapping and specific changes were detected: 14/25 of the human genes and 12/25 of the rat genes showed nominally significant differences in gene expression (global p values: 9×10⁻¹⁴, 7×10⁻¹¹ respectively). Principal FDR-corrected findings were that GABBR1 was down-regulated in alcoholics, cocaine addicts and P rats with congruent findings in NSF, implicated in GABAB signaling efficacy, potentially resulting in increased synaptic GABA. GABRG2, encoding the gamma2 subunit required for postsynaptic clustering of GABAA receptors together with GPHN, encoding the associated scaffolding protein gephryin, were both down-regulated in alcoholics and cocaine addicts but were both up-regulated in P rats. There were also expression changes specific to cocaine addicts (GAD1, GAD2), alcoholics (GABRA2) and P rats (ABAT, GABRG3). CONCLUSIONS/SIGNIFICANCE:Our study confirms the involvement of the GABAergic system in alcoholism but also reveals a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction. Finally, the results of this study have therapeutic implications

The sleep EEG spectrum is a sexually dimorphic marker of general intelligence

The shape of the EEG spectrum in sleep relies on genetic and anatomical factors and forms an individual “EEG fingerprint”. Spectral components of EEG were shown to be connected to mental ability both in sleep and wakefulness. EEG sleep spindle correlates of intelligence, however, exhibit a sexual dimorphism, with a more pronounced association to intelligence in females than males. In a sample of 151 healthy individuals, we investigated how intelligence is related to spectral components of full-night sleep EEG, while controlling for the effects of age. A positive linear association between intelligence and REM anterior beta power was found in females but not males. Transient, spindle-like “REM beta tufts” are described in the EEG of healthy subjects, which may reflect the functioning of a recently described cingular-prefrontal emotion and motor regulation network. REM sleep frontal high delta power was a negative correlate of intelligence. NREM alpha and sigma spectral power correlations with intelligence did not unequivocally remain significant after multiple comparisons correction, but exhibited a similar sexual dimorphism. These results suggest that the neural oscillatory correlates of intelligence in sleep are sexually dimorphic, and they are not restricted to either sleep spindles or NREM sleep

Sleep disturbances in an arctic population: The Tromsø Study

<p>Abstract</p> <p>Background</p> <p>Prevalence estimates for insomnia range from 10 to 50% in the adult general population. Sleep disturbances cause great impairment in quality of life, which might even rival or exceed the impairment in other chronic medical disorders. The economic implications and use of health-care services related to chronic insomnia represent a clinical concern as well as a pronounced public health problem. Hypnotics are frequently prescribed for insomnia, but alcohol and over-the-counter sleep aids seem to be more widely used by insomniacs than prescription medications. Despite the complex relationship between insomnia and physical and mental health factors, the condition appears to be underrecognized and undertreated by health care providers, probably due to the generally limited knowledge of the causes and natural development of insomnia.</p> <p>Methods/Design</p> <p>The Tromsø Study is an ongoing population-based cohort study with five previous health studies undertaken between 1974 and 2001. This protocol outlines a planned study within the sixth Tromsø Study (Tromsø VI), aiming at; 1) describing sleep patterns in a community-based sample representative of the general population of northern Norway, and 2) examining outcome variables of sleep disturbances against possible explanatory and confounding variables, both within a cross-sectional approach, as well as retrospectively in a longitudinal study – exploring sleep patterns in subjects who have attended two or more of the previous Tromsø studies between 1974 and 2009. First, we plan to perform a simple screening in order to identify those participants with probable sleep disturbances, and secondly to investigate these sleep disturbances further, using an extensive sleep-questionnaire. We will also collect biological explanatory variables, i.e. blood samples, weight, height and blood pressure. We plan to merge data on an individual level from the Tromsø VI Study with data from the Norwegian Prescription Database (NorPD), which is a national registry including data for all prescription drugs issued at Norwegian pharmacies. Participants with sleep disturbances will be compared with pair-matched controls without sleep disturbances.</p> <p>Discussion</p> <p>Despite ongoing research, many challenges remain in the characterization of sleep disturbances and its correlates. Future mapping of the biological dimensions, natural history, as well as the behavioral and drug-related aspects of sleep disturbances in a representative population samples is clearly needed.</p