Insomnia disorder: clinical and research challenges for the 21st century.

BACKGROUND AND PURPOSE: Insomnia is a common and debilitating disorder that is frequently associated with important consequences for physical health and well-being. METHODS: An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field of insomnia and identified future priorities. RESULTS: The association of trajectories of insomnia with subsequent quality of life, health and mortality should be investigated in large populations. Prospective health economics studies by separating the costs driven specifically by insomnia and costs attributable to its long-term effects are needed. Ignoring the heterogeneity of insomnia patients leads to inadequate diagnosis and inefficient treatment. Individualized interventions should be promoted. More data are needed on both the impact of sleep on overnight effects, such as emotion regulation, and the potential compensatory effort to counteract diurnal impairments. Another gap is the definition of neurocognitive deficits in insomnia patients compared to normal subjects after chronic sleep loss. There are also a number of key gaps related to insomnia treatment. Expert guidelines indicate cognitive-behavioural therapy for insomnia as first-line treatment. They neglect, however, the reality of major healthcare providers. The role of combined therapy, cognitive-behavioural therapy for insomnia plus pharmacological treatment, should be evaluated more extensively. CONCLUSION: Whilst insomnia disorder might affect large proportions of the population, there are a number of significant gaps in the epidemiological/clinical/research studies carried out to date. In particular, the identification of different insomnia phenotypes could allow more cost-effective and efficient therapies.

Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension.

STUDY OBJECTIVES: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. METHODS: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. RESULTS: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P < .0001) at months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. CONCLUSIONS: Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919.

Cognitive remediation for depressed inpatients: Results of a pilot randomized controlled trial.

OBJECTIVE: Neurocognitive deficits that persist despite antidepressive treatment and affect social and vocational functioning are well documented in major depressive disorder. Cognitive training approaches have proven successful in ameliorating these deficits in other psychiatric groups, but very few studies have been conducted in unipolar depressive patients by now. In contrast to previous studies solely including outpatients, effects of a cognitive remediation intervention on neurocognitive functioning of depressed inpatients were assessed by the present study. METHOD: A randomized controlled trial was carried out with 46 depressed inpatients of a psychiatric hospital. Patients were randomly assigned to either a control group that received standard drug and non-drug (cognitive behavioural, occupational, sports, relaxation and music therapy) antidepressive treatment or a remediation group that additionally received 12 sessions of cognitive training for a total of 4 weeks (three sessions per week). An intent to treat analysis and a last observation carried forward method was used for data analyses. RESULTS: Patients of the remediation group demonstrated greater improvements in neurocognitive measures of verbal and nonverbal memory, working memory and executive function (Cohen's d effect sizes between .52 and .98). CONCLUSIONS: These results provide preliminary evidence that cognitive remediation interventions can be successfully applied also in psychiatric inpatients experiencing an acute depressive episode.

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. METHODS: Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N = 17, sham coil with the TBS protocol). RESULTS: There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. CONCLUSIONS: This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies.

Feasibility, safety and efficacy of transcutaneous vagus nerve stimulation in chronic tinnitus: an open pilot study.

OBJECTIVES: Vagus nerve stimulation represents an established treatment strategy for epilepsy and affective disorders. Recently, positive effects were also shown in animals and humans with tinnitus. Here we report the results of an open pilot study exploring feasibility, safety and efficacy of tVNS in the treatment of chronic tinnitus. STUDY DESIGN: Fifty patients with chronic tinnitus underwent tVNS in an open single-armed pilot study which was conducted in two phases applying two different stimulating devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as change in TQ (baseline vs. final visit in week 24). The study has been registered with clinicaltrials.gov (NCT01176734). RESULTS: Primary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8 points (phase 2) significant for the first study phase. Secondary analyses indicated a significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further systematic or significant effects. Adverse events included twitching and pressure at electrode placement site. The occurrence of one hospitalization because of palpations and the development of a left bundle branch block were considered as unrelated to the intervention. Cognitive testing revealed no significant changes. CONCLUSION: Our data demonstrate the feasibility of tVNS over a period of 6 months. There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS to be considered safe in patients without a history of cardiac disease.

Cognitive remediation improves cognition and good cognitive performance increases time to relapse--results of a 5 year catamnestic study in schizophrenia patients.

BACKGROUND: Cognitive deficits are stable features of schizophrenia that are linked to functional outcome. Cognitive remediation approaches have been proven successful in ameliorating these deficits, although effect sizes vary considerably. Whether cognitive deficits are serious predictors of clinical outcome is less clear. METHODS: Sixty patients suffering from schizophrenia were included in our sample, thirty of them received computer-assisted cognitive training, and thirty received occupational therapy. For a subsample of 55 patients, who could be traced over a period of five years after the end of the cognitive remediation intervention, time until first relapse and time in psychosis were determined retrospectively from their medical records. RESULTS: Cognitive remediation significantly improved problem solving, memory and attention with high effect sizes. Employment status, a post test verbal memory performance measure and a measure of executive functioning outperformed all other measures in the prediction of time to relapse, while allocation to treatment group outperformed all other variables in the prediction of both cognitive measures. CONCLUSIONS: Cognitive remediation of neurocognitive deficits thus makes sense in a twofold fashion: It enhances cognition directly and positively acts on clinical course indirectly via improved neurocognition. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004880.

The associations of insomnia with costly workplace accidents and errors: results from the America Insomnia Survey.

CONTEXT: Insomnia is a common and seriously impairing condition that often goes unrecognized. OBJECTIVES: To examine associations of broadly defined insomnia (ie, meeting inclusion criteria for a diagnosis from International Statistical Classification of Diseases, 10th Revision, DSM-IV, or Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition) with costly workplace accidents and errors after excluding other chronic conditions among workers in the America Insomnia Survey (AIS). DESIGN/SETTING: A national cross-sectional telephone survey (65.0% cooperation rate) of commercially insured health plan members selected from the more than 34 million in the HealthCore Integrated Research Database. PARTICIPANTS: Four thousand nine hundred ninety-one employed AIS respondents. MAIN OUTCOME MEASURES: Costly workplace accidents or errors in the 12 months before the AIS interview were assessed with one question about workplace accidents "that either caused damage or work disruption with a value of $500 or more" and another about other mistakes "that cost your company $500 or more." RESULTS: Current insomnia with duration of at least 12 months was assessed with the Brief Insomnia Questionnaire, a validated (area under the receiver operating characteristic curve, 0.86 compared with diagnoses based on blinded clinical reappraisal interviews), fully structured diagnostic interview. Eighteen other chronic conditions were assessed with medical/pharmacy claims records and validated self-report scales. Insomnia had a significant odds ratio with workplace accidents and/or errors controlled for other chronic conditions (1.4). The odds ratio did not vary significantly with respondent age, sex, educational level, or comorbidity. The average costs of insomnia-related accidents and errors ($32 062) were significantly higher than those of other accidents and errors ($21 914). Simulations estimated that insomnia was associated with 7.2% of all costly workplace accidents and errors and 23.7% of all the costs of these incidents. These proportions are higher than for any other chronic condition, with annualized US population projections of 274 000 costly insomnia-related workplace accidents and errors having a combined value of US $31.1 billion. CONCLUSION: Effectiveness trials are needed to determine whether expanded screening, outreach, and treatment of workers with insomnia would yield a positive return on investment for employers.

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.

BACKGROUND: Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. OBJECTIVES: Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. METHODS: Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3-10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). RESULTS: Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend toward shortening of the QRS complex after tVNS. CONCLUSION: To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.

Methodological aspects of clinical trials in tinnitus: a proposal for an international standard.

Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.

Insomnia, comorbidity, and risk of injury among insured Americans: results from the America Insomnia Survey.

STUDY OBJECTIVES: To estimate associations of broadly defined insomnia (i.e., meeting inclusion criteria for International Classification of Diseases, Tenth Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition (RDC/ICSD-2) diagnosis) with workplace/nonworkplace injuries controlling for comorbid conditions among workers in the America Insomnia Survey (AIS). DESIGN/SETTING: Cross-sectional telephone survey. PARTICIPANTS: National sample of 4,991 employed health plan subscribers (age 18 yr and older). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Broadly defined insomnia with duration of at least 12 mo was assessed with the Brief Insomnia Questionnaire (BIQ). Injuries in the 12 mo before interview were assessed with a standard self-report measure of injuries causing role impairment or requiring medical attention. Eighteen comorbid condition clusters were assessed with medical/pharmacy claims records and self-reports. Insomnia had significant gross associations (odds ratios, ORs) with both workplace and nonworkplace injuries (OR 2.0 and 1.5, respectively) in logistic regression analyses before controlling for comorbid conditions. The significant population attributable risk proportions (PARPs) of total injuries with insomnia was 4.6% after controlling for comorbid conditions. Only 2 other conditions had PARPs exceeding those of insomnia. The associations of insomnia with injuries did not vary significantly with worker age, sex, or education, but did vary significantly with comorbid conditions. Specifically, insomnia was significantly associated with workplace and nonworkplace injuries (OR 1.8 and 1.5, respectively) among workers having no comorbid conditions, with workplace but not nonworkplace injuries (OR 1.8 and 1.2, respectively) among workers having 1 comorbid condition, and with neither workplace nor nonworkplace injuries (OR 0.9 and 1.0, respectively) among workers having 2 or more comorbid conditions. CONCLUSIONS: The associations of insomnia with injuries vary with comorbid conditions in ways that could have important implications for targeting workplace interventions.

Hypothermia associated with antipsychotic drug use: a clinical case series and review of current literature.

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5-HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.

Can repetitive transcranial magnetic stimulation prolong the antidepressant effects of sleep deprivation?

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed for stabilizing the antidepressant effect of sleep deprivation (SD) by preventing the relapse after a night of recovery sleep. In this study, we aimed to replicate these data coming from a small pilot study in a larger patient sample. METHODS: Thirty-seven patients were randomly assigned to receive either active or sham rTMS on four consecutive days after one night of SD. The majority of the participants had experienced an antidepressant effect of SD in the past. At each rTMS session 1000 stimuli were applied over the left dorsolateral prefrontal cortex at 10 Hz with an intensity of 110% resting motor threshold. For sham stimulation, a sham-coil system was used. Treatment effects were assessed with a modified version of the Hamilton Depression Rating Scale and a self-report well-being scale (BfS) before SD, after SD, during rTMS and 3 days after rTMS. RESULTS: SD led to a highly significant reduction of depressive symptoms in the whole group as reflected by a mean Hamilton Depression Rating Scales score reduction of 56% (with omission of sleep items). In both the active and the sham-stimulated group, the symptom reduction remained stable for the whole observation period. No difference between active and sham rTMS was observed. CONCLUSIONS: SD is capable of inducing pronounced antidepressant effects. In contrast to a previous study, active rTMS was not superior to sham rTMS in stabilizing the antidepressant effects of SD, which was mainly due to a pronounced effect in the sham group in this study population.

Can Temporal Repetitive Transcranial Magnetic Stimulation be Enhanced by Targeting Affective Components of Tinnitus with Frontal rTMS? A Randomized Controlled Pilot Trial.

OBJECTIVES: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been investigated as a new treatment tool for chronic tinnitus during the last years and has shown moderate efficacy. However, there is growing evidence that tinnitus is not a pathology of a specific brain region, but rather the result of network dysfunction involving both auditory and non-auditory brain regions. In functional imaging studies the right dorsolateral prefrontal cortex has been identified as an important hub in tinnitus related networks and has been shown to particularly reflect the affective components of tinnitus. Based on these findings we aimed to investigate whether the effects of left low-frequency rTMS can be enhanced by antecedent right prefrontal low-frequency rTMS. STUDY DESIGN: Fifty-six patients were randomized to receive either low-frequency left temporal rTMS or a combination of low-frequency right prefrontal followed by low-frequency left temporal rTMS. The change of the tinnitus questionnaire (TQ) score was the primary outcome, secondary outcome parameters included the Tinnitus Handicap Inventory, numeric rating scales, and the Beck Depression Inventory. The study is registered in clinicaltrials.gov (NCT01261949). RESULTS: Directly after therapy there was a significant improvement of the TQ-score in both groups. Comparison of both groups revealed a trend toward more pronounced effects for the combined group (effect size: Cohen's d = 0.176), but this effect did not reach significance. A persistent trend toward better efficacy was also observed in all other outcome criteria. CONCLUSION: Additional stimulation of the right prefrontal cortex seems to be a promising strategy for enhancing TMS effects over the temporal cortex. These results further support the involvement of the right DLPFC in the pathophysiology of tinnitus. The small effect size might be due to the study design comparing the protocol to an active control condition.

Days-out-of-role associated with insomnia and comorbid conditions in the America Insomnia Survey.

BACKGROUND: Insomnia is highly prevalent and impairing but also highly comorbid with other chronic physical/mental disorders. Population-based research has yet to differentiate the role impairments uniquely associated with insomnia per se from those due to comorbidity. METHODS: A representative sample of 6791 adult subscribers to a large national US commercial health plan was surveyed by telephone about sleep and health. Twenty-one conditions previously found to be comorbid with insomnia were assessed with medical/pharmacy claims data and validated self-report scales. The Brief Insomnia Questionnaire, a fully structured, clinically validated scale, generated insomnia diagnoses according to inclusion criteria of DSM-IV-TR, ICD-10, and Research Diagnostic Criteria/International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition. The World Health Organization Disability Assessment Schedule-II assessed number of days in the past 30 when health problems prevented respondents from conducting their usual daily activities. Regression analyses estimated associations of insomnia with days-out-of-role controlling comorbidity. RESULTS: Insomnia was significantly associated with days-out-of-role (.90 days/month) in a gross model. The association was reduced when controls were introduced for comorbidity (.42 days/month). This net association did not vary with number or type of comorbid conditions but was confined to respondents 35+ years of age. Insomnia was one of the most important conditions studied not only at the individual level, where it was associated with among the largest mean days-out-of-role, but also at the aggregate level, where it was associated with 13.6% of all days-out-of-role. CONCLUSIONS: Insomnia has a strong net association with days-out-of-role that does not vary as a function of comorbidity.

Transcranial magnetic stimulation for the treatment of tinnitus: 4-year follow-up in treatment responders--a retrospective analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) over the temporal cortex has been proposed as a new approach for the treatment of tinnitus. Even if most studies have shown beneficial effects, there is only limited knowledge about clinical predictors for treatment response and about the duration of treatment effects. OBJECTIVE: In this study, we compared clinical characteristics of rTMS responders and nonresponders and assessed long-term outcome in the responder group. METHOD: Results from 235 patients, who were treated with rTMS because of chronic tinnitus were analysed. Patients received either a standard protocol of low-frequency rTMS (n = 188; 110% motor threshold, 1 Hz, 2000 stimuli/day) over the left temporal cortex or combined frontal and temporal rTMS (n = 47; 110% motor threshold, 1000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 1000 stimuli at 1 Hz left temporal cortex). Response criterion was defined as an improvement of at least 10 points in the tinnitus questionnaire (TQ) score between baseline and the follow-up assessment 90 days after treatment. RESULTS: For the entire study group there was a highly significant effect of treatment on the TQ score. Fifty patients (21.3%) were responders according to the above mentioned definition. The response criterion was fulfilled by 19.7% of the patients receiving left temporal rTMS and by 26% of the patients receiving combined rTMS. The only significant difference between responders and nonresponders was a higher baseline score of the TQ in the responder group. There were no significant differences in all other assessed patient parameters (gender, age, tinnitus duration, tinnitus laterality, motor threshold, handedness). Ninety days after treatment the average TQ reduction in the responder group was 18.2 points as compared with baseline. At the two long-term follow-up assessments (2.12 ± 1.17 years and 3.9 ± 1.17 years after treatment) the improvement in the responder group was still 14.2, respective 14.4 points. CONCLUSIONS: These data underscore the clinical relevance of rTMS in the treatment of tinnitus. A potential explanation for the observed long-lasting clinical effects is that rTMS interferes with tinnitus related neuronal activity and thus facilitates the intrinsic ability of the brain to restore normal function.

Insomnia and the performance of US workers: results from the America insomnia survey.

STUDY OBJECTIVES: To estimate the prevalence and associations of broadly defined (i.e., meeting full ICD-10, DSM-IV, or RDC/ICSD-2 inclusion criteria) insomnia with work performance net of comorbid conditions in the America Insomnia Survey (AIS). DESIGN/SETTING: Cross-sectional telephone survey. PARTICIPANTS: National sample of 7,428 employed health plan subscribers (ages 18+). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Broadly defined insomnia was assessed with the Brief Insomnia Questionnaire (BIQ). Work absenteeism and presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) were assessed with the WHO Health and Work Performance Questionnaire (HPQ). Regression analysis examined associations between insomnia and HPQ scores controlling 26 comorbid conditions based on self-report and medical/pharmacy claims records. The estimated prevalence of insomnia was 23.2%. Insomnia was significantly associated with lost work performance due to presenteeism (χ² (1) = 39.5, P < 0.001) but not absenteeism (χ² (1) = 3.2, P = 0.07), with an annualized individual-level association of insomnia with presenteeism equivalent to 11.3 days of lost work performance. This estimate decreased to 7.8 days when controls were introduced for comorbid conditions. The individual-level human capital value of this net estimate was $2,280. If we provisionally assume these estimates generalize to the total US workforce, they are equivalent to annualized population-level estimates of 252.7 days and $63.2 billion. CONCLUSIONS: Insomnia is associated with substantial workplace costs. Although experimental studies suggest some of these costs could be recovered with insomnia disease management programs, effectiveness trials are needed to obtain precise estimates of return-on-investment of such interventions from the employer perspective.

Nighttime insomnia symptoms and perceived health in the America Insomnia Survey (AIS).

STUDY OBJECTIVES: To explore the distribution of the 4 cardinal nighttime symptoms of insomnia-difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), and nonrestorative sleep (NRS)-in a national sample of health plan members and the associations of these nighttime symptoms with sociodemographics, comorbidity, and perceived health. DESIGN/SETTING/PARTICIPANTS: Cross-sectional telephone survey of 6,791 adult respondents. INTERVENTION: None. MEASUREMENTS/RESULTS: Current insomnia was assessed using the Brief Insomnia Questionnaire (BIQ)-a fully structured validated scale generating diagnoses of insomnia using DSM-IV-TR, ICD-10, and RDC/ICSD-2 inclusion criteria. DMS (61.0%) and EMA (52.2%) were more prevalent than DIS (37.7%) and NRS (25.2%) among respondents with insomnia. Sociodemographic correlates varied significantly across the 4 symptoms. All 4 nighttime symptoms were significantly related to a wide range of comorbid physical and mental conditions. All 4 also significantly predicted decrements in perceived health both in the total sample and among respondents with insomnia after adjusting for comorbid physical and mental conditions. Joint associations of the 4 symptoms predicting perceived health were additive and related to daytime distress/impairment. Individual-level associations were strongest for NRS. At the societal level, though, where both prevalence and strength of individual-level associations were taken into consideration, DMS had the strongest associations. CONCLUSIONS: The extent to which nighttime insomnia symptoms are stable over time requires future long-term longitudinal study. Within the context of this limitation, the results suggest that core nighttime symptoms are associated with different patterns of risk and perceived health and that symptom-based subtyping might have value.

Comparison of agomelatine and escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder patients.

Agomelatine, an MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, is known to have beneficial effects on subjective sleep in major depressive disorder patients. This international multicenter, randomized, double-blind study compared the effects of agomelatine (25-50 mg/day) and escitalopram (10-20 mg/day) on sleep polysomnographic parameters in major depressive disorder patients treated up to 24 weeks. A total of 138 outpatients were randomly allocated to agomelatine (n=71) or escitalopram (n=67). Treatment with agomelatine was associated with a reduction in sleep latency from week 2 onward. The difference between treatments was significant on all evaluations. Rapid eye movement latency was increased with escitalopram compared with agomelatine, with significant between-group differences at every visit. Agomelatine preserved the number of sleep cycles, whereas it was decreased with escitalopram with significant between-group differences at every visit. Assessments on visual analogue scales indicated that treatment with agomelatine improved morning condition, and reduced daytime sleepiness compared with escitalopram.17-item Hamilton depression rating scale total score was reduced in both groups, agomelatine was statistically noninferior to escitalopram at 6 weeks. Both treatments were well tolerated. This study showed that the clinical effects of agomelatine on sleep and wake parameters are different from that of escitalopram.

Determinants of depressive symptoms in narcoleptic patients with and without cataplexy.

The present prospective study assesses depressive symptoms in narcoleptic patients with (NC+) and without (NC-) cataplexy (46 women, 40 men) and age- and sex- matched healthy controls. Seventy patients were under treatment with stimulants and/or anticataplectics. All subjects completed the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale (SDS), the Global Impression of Severity of Depression (GSD), the Profile of Mood States (POMS) and Epworth Sleepiness Scale. Patients with narcolepsy were more depressed than controls (higher scores in BDI, GSD, SDS, and POMS [in the total score and in all subscale scores]); however, between the NC+ and NC- patient groups, no differences were found. Our study shows that the women and the patients using antidepressants and stimulants (combination) have a higher probability for depressive symptoms independent of the presence of cataplexy. The lack of difference between NC+ and NC- in the level of depression supports the assumption that the major psychosocial burden in narcolepsy is not necessarily associated with the presence of cataplexy.

Reduced intra-cortical inhibition after sleep deprivation: a transcranial magnetic stimulation study.

Sleep deprivation has multiple effects on brain function. It increases the risk for epileptic seizures both in healthy individuals and in patients with epilepsy. Furthermore it represents an effective antidepressive intervention with rapid onset. However, the mechanisms underlying these effects are still largely unknown. Transcranial magnetic stimulation (TMS) can be used as a non-invasive method for the measurement of motor cortex excitability. Here we used TMS for assessing sleep deprivation effects on cortical excitability in healthy individuals. Before and after 24 h of sleep deprivation, parameters of cortical excitability (resting motor threshold, short intracortical inhibition, intracortical facilitation, cortical silent period) were measured in a sample of 15 healthy volunteers (11 women, 4 men, aged between 21 and 30 years with a mean of 24.3±2.7 years). We detected a significant (p=0.042) reduction of short intracortical inhibition (SICI) after sleep deprivation. Motor threshold, intracortical facilitation and contralateral silent period remained unchanged. Our results confirm previous studies which have demonstrated changes of SICI after sleep deprivation. Our findings further suggest that the increased risk for epileptic seizures after sleep deprivation is mediated by a reduction of intracortical inhibition. Whether this mechanism is also involved in mediating the antidepressant effect of sleep deprivation has to be addressed by further studies in depressive patients.