Limited Efficacy of Caffeine and Recovery Costs During and Following 5 Days of Chronic Sleep Restriction.

Objectives: To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Methods: Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Results: Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Conclusions: Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management.

Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

Assessment of buccal aerosolized midazolam for pediatric conscious sedation.

AIM: To assess the acceptance and efficacy of aerosolized midazolam through buccal mucosa for conscious sedation. METHODS: Thirty-five children aged 2-6 years with Grade I and II Frankl behavior rating scale were selected for various dental procedures under local anesthesia. Initially behavior-shaping procedures were used and Houpt behavior scoring was recorded. Thereafter, midazolam was administered using a spray through buccal mucosa and scores for acceptance of drug and behavior after sedation were recorded. The data were compiled and a Wilcoxon signed ranks test was used to assess the difference in behavior before and after the sedation. RESULTS: Eighty-three percent of the patients accepted the drug without any complaint. A statistically significant improvement was seen in the Houpt scores before and after drug administration (P < 0.001). CONCLUSIONS: Buccal aerosolized midazolam can be used successfully for pediatric conscious sedation.

Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer: a prospective analysis using the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module.

BACKGROUND: A prospective longitudinal study to profile patient-reported symptoms during radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) for head and neck cancer was performed. The goals were to understand the onset and trajectory of specific symptoms and their severity, identify clusters, and facilitate symptom interventions and clinical trial design. METHODS: Participants in this questionnaire-based study received RT or CCRT. They completed the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module before and weekly during treatment. Symptom scores were compared between treatment groups, and hierarchical cluster analysis was used to depict clustering of symptoms at treatment end. Variables believed to predict symptom severity were assessed using a multivariate mixed model. RESULTS: Among the 149 patients studied, the majority (47%) had oropharyngeal tumors, and nearly one-half received CCRT. Overall symptom severity (P < .001) and symptom interference (P < .0001) became progressively more severe and were more severe for those receiving CCRT. On multivariate analysis, baseline Eastern Cooperative Oncology Group performance status (P < .001) and receipt of CCRT (P < .04) correlated with higher symptom severity. Fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food were more severe for those receiving CCRT. Both local and systemic symptom clusters were identified. CONCLUSIONS: The findings from this prospective longitudinal study identified a pattern of local and systemic symptoms, symptom clusters, and symptom interference that was temporally distinct and marked by increased magnitude and a shift in individual symptom rank order during the treatment course. These inform clinicians about symptom intervention needs, and are a benchmark for future symptom intervention clinical trials.

Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety.

OBJECTIVE: There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. METHODS: Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. RESULTS: Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. CONCLUSION: Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies.

A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

Modeling sleep data for a new drug in development using markov mixed-effects models.

PURPOSE: To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models. METHODS: Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability. RESULTS: Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. CONCLUSION: The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.

Multinomial logistic functions in markov chain models of sleep architecture: internal and external validation and covariate analysis.

Mixed-effect Markov chain models have been recently proposed to characterize the time course of transition probabilities between sleep stages in insomniac patients. The most recent one, based on multinomial logistic functions, was used as a base to develop a final model combining the strengths of the existing ones. This final model was validated on placebo data applying also new diagnostic methods and then used for the inclusion of potential age, gender, and BMI effects. Internal validation was performed through simplified posterior predictive check (sPPC), visual predictive check (VPC) for categorical data, and new visual methods based on stochastic simulation and estimation and called visual estimation check (VEC). External validation mainly relied on the evaluation of the objective function value and sPPC. Covariate effects were identified through stepwise covariate modeling within NONMEM VI. New model features were introduced in the model, providing significant sPPC improvements. Outcomes from VPC, VEC, and external validation were generally very good. Age, gender, and BMI were found to be statistically significant covariates, but their inclusion did not improve substantially the model's predictive performance. In summary, an improved model for sleep internal architecture has been developed and suitably validated in insomniac patients treated with placebo. Thereafter, covariate effects have been included into the final model.

Joint modeling of performance and subjective reporting to assess sensitivity to drug-induced sleepiness.

In an NASA ground study, two forms of cognitive tests were evaluated in terms of their sensitivity to sleepiness induced by the drug promethazine (PMZ). Performance for the two test modes (Y(1) and Y(2)), PMZ concentration, and a self-reported sleepiness using the Karolinska Sleepiness Scale (KSS) were monitored for 12 h post dose. A problem arises when using KSS to establish an association between true sleepiness and performance because KSS scores are discrete and also because they tend to concentrate on certain values. Therefore, we define a latent sleepiness measure X as an unobserved continuous random variable describing a subject's actual state of sleepiness. Under the assumption that drug concentration affects X, which then affects Y(1), Y(2), and KSS, we use Bayesian methods to estimate joint equations that permit unbiased comparison of the performance measures' sensitivity to X. The equations incorporate subject random effects and include a negativity constraint on subject-specific slopes of performance with respect to sleepiness.

Multinomial logistic estimation of Markov-chain models for modeling sleep architecture in primary insomnia patients.

Hypnotic drug development calls for a better understanding of sleep physiology in order to improve and differentiate novel medicines for the treatment of sleep disorders. On this basis, a proper evaluation of polysomnographic data collected in clinical trials conducted to explore clinical efficacy of novel hypnotic compounds should include the assessment of sleep architecture and its drug-induced changes. This work presents a non-linear mixed-effect Markov-chain model based on multinomial logistic functions which characterize the time course of transition probabilities between sleep stages in insomniac patients treated with placebo. Polysomnography measurements were obtained from patients during one night treatment. A population approach was used to describe the time course of sleep stages (awake stage, stage 1, stage 2, slow-wave sleep and REM sleep) using a Markov-chain model. The relationship between time and individual transition probabilities between sleep stages was modelled through piecewise linear multinomial logistic functions. The identification of the model produced a good adherence of mean post-hoc estimates to the observed transition frequencies. Parameters were generally well estimated in terms of CV, shrinkage and distribution of empirical Bayes estimates around the typical values. The posterior predictive check analysis showed good consistency between model-predicted and observed sleep parameters. In conclusion, the Markov-chain model based on multinomial logistic functions provided an accurate description of the time course of sleep stages together with an assessment of the probabilities of transition between different stages.

Joint modeling of dizziness, drowsiness, and dropout associated with pregabalin and placebo treatment of generalized anxiety disorder.

Dizziness and drowsiness are cited as being predictors of dropout from clinical trials for the medicine pregabalin. These adverse events are typically recorded daily on a four point ordinal scale (0 = none, 1 = mild, 2 = moderate, 3 = severe), with most subjects never reporting either adverse event. We modeled the dizziness, drowsiness, and dropout associated with pregabalin use in generalized anxiety disorder using piecewise Weibull distributions for the time to first non-zero dizziness or drowsiness score, after which the dizziness or drowsiness was modeled with ordinal regression with a Markovian element. Dropout was modeled with a Weibull distribution. Platykurtosis was encountered in the estimated random effects distributions for the ordinal regression models and was addressed with dynamic John-Draper transformations. The only identified predictor for the time to first non-zero dizziness or drowsiness score was daily titrated dose. Predictors for dropout included creatinine clearance and maximum daily adverse event score. Tolerance to adverse events over time was modeled by including a non-stationary component for the dizziness ordinal Markov regression while the piecewise Weibull distributions allowed a change point in the median time to first non-zero dizziness or drowsiness score.

The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study.

The surge in dopamine in ventral striatal regions in response to drugs of abuse and drug-associated stimuli is a final common pathway of addiction processes. GABA B agonists exert their effects indirectly, by quieting dopaminergic afferents. The ability of the GABA B agonist, baclofen to ameliorate nicotine and drug motivated behavior is established within the animal literature, however its potential to do so in humans is understudied, particularly with respect to its possible utility as a smoking cessation agent. We conducted a nine-week double-blind placebo-controlled pilot trial of baclofen for smoking reduction (N=30/group) in smokers contemplating, but not quite ready to quit. Baclofen was titrated upwards to 20mg q.i.d. over a period of twelve days. The primary outcome measure was the number of cigarettes smoked per day (CPD). A significant group by time effect of medication was observed. Baclofen was superior to placebo in reducing CPD (beta=0.01, t=1.97, p<0.05). The most common side effect reported during baclofen treatment is transient drowsiness, however there were no differences between groups in mild, moderate, or severe sedation. Craving was significantly lowered at end of treatment in all smokers (p<0.02). Retention did not differ between groups. In line with a multitude of preclinical studies examining the effects of baclofen on drug-motivated behavior, baclofen reduced CPD. In agreement with other studies examining craving and drug use, reductions in CPD were accompanied by a reduction in craving, a major motivator underlying continued smoking and relapse. These preliminary results demonstrate provisional evidence of the utility of baclofen to aid in smoking cessation and indicate further investigation.

The use of a clinical utility index to compare insomnia compounds: a quantitative basis for benefit-risk assessment.

The use of a clinical utility index (CUI) was proposed in order to compare two calcium channel alpha2delta ligands that were in development for the treatment of insomnia. The important attributes included in the CUI were two measures of residual sedation and five measures of efficacy (wake after sleep onset, sleep quality, sleep latency, and sleep stages (stage 1 and stages 3-4)). Dose-response analyses were conducted on each end point, and a sensitivity analysis was conducted to determine a clinically meaningful difference in CUI. Nonparametric bootstrap parameters were used to build confidence intervals (CIs). Peak CUI (80% CI) was 0.345 (0.25-0.43), observed at a dose of approximately 30 mg with the lead compound and 0.436 (0.35-0.52) observed at >600-mg dose for the backup. Although CUI was slightly greater for the backup, peak CUI values were observed at doses that were not considered viable, and therefore development of the ligand was discontinued. The use of the CUI allowed an efficient, quantitative, and transparent decision.

Phase 1A safety assessment of intravenous amitriptyline.

UNLABELLED: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. PERSPECTIVE: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.

An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults.

BACKGROUND AND PURPOSE: This randomized, double-blind, placebo-controlled study assessed the efficacy and safety of eszopiclone, a non-benzodiazepine hypnotic agent, in healthy adults using the first-night effect model of transient insomnia. PATIENTS AND METHODS: A total of 436 healthy, normal sleeping participants were randomized to receive either eszopiclone 1, 2, 3, or 3.5mg, or placebo. Efficacy and next-morning effects were evaluated via polysomnography (PSG), Digit Symbol Substitution Test (DSST), and self-report. RESULTS: Patients treated with eszopiclone had significantly less PSG latency to persistent sleep (all doses except 1mg; P< or =0.0001), wake time after sleep onset (all doses; P< or =0.05) and number of awakenings (3 and 3.5mg doses; P<0.005), and greater sleep efficiency (all doses; P< or =0.02) compared with placebo. Self-reported efficacy results were similar to PSG. Self-reported morning sleepiness scores were significantly better for eszopiclone 3 and 3.5mg compared with placebo (P<0.05). Treatment was well tolerated by patients, and the most common treatment-related adverse event was unpleasant taste. CONCLUSIONS: In this model of transient insomnia, all doses of eszopiclone were more effective than placebo and were well tolerated by patients.

Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used as the first-line treatment for depression. Information regarding their side effects is mostly based on controlled clinical trials. METHOD: Patients who received an SSRI for a new or recurrent case of depression (ICD-9 code 296.2 or 311) between December 15, 1999, and May 31, 2000 were interviewed by telephone 75 to 105 days after initiation of SSRI therapy. Using closed-ended questions, investigators asked patients if they experienced any of 17 side effects commonly associated with SSRIs, how bothersome they were, and what their duration was. Prescribing physicians completed a written survey providing their estimates about frequency of side effects associated with SSRIs and how bothersome those side effects are. RESULTS: Of 401 patients who completed the phone interview, 344 patients (86%) reported at least 1 side effect, and 219 patients (55%) experienced 1 or more bothersome side effect(s). The most common bothersome side effects were sexual dysfunction and drowsiness (17% each). While most side effects first occurred within the first 2 weeks of treatment, the majority of patients were still experiencing the same side effects at the time of interview, most notably blurred vision (85%) and sexual dysfunction (83%). Overall, physicians (N = 137) significantly underestimated the occurrence of the 17 side effects explored, and they tended to underrate how bothersome those side effects were to their patients. CONCLUSION: Side effects associated with SSRIs are common and bothersome to patients. Treatment-emergent side effects tend to persist during the first 3 months of treatment.

Subjective assessment of the effects of CNS-active drugs on sleep by the Leeds sleep evaluation questionnaire: a review.

The Leeds sleep evaluation questionnaire (LSEQ) comprises ten self-rating 100 mm line analogue questions concerned with sleep and early morning behaviour. A literature search identified 83 studies in peer-reviewed journals that reported the use of the LSEQ for psychopharmacological investigations of drug effects on self-reported aspects of sleep. High internal consistency and reliability of the questionnaire have been demonstrated. Findings from studies involving a variety of psychoactive agents indicated that the LSEQ was able to quantify subjective impressions of sleep and waking and the effects of drugs in healthy volunteers, depressed and insomnia patients. In accordance with their known activity profile nocturnal administration of sedative hypnotic agents and antihistamines induced dose-related improvements in self-reported ease of getting to sleep, and quality of sleep but a decrease in alertness and behavioural integrity the following morning. Psychostimulants, on the other hand, impaired subjective ratings of sleep and increased early morning alertness. Antidepressants and certain anxiolytic agents improved both self-reported sleep aspects and early morning alertness. Treatment effects measured by the LSEQ corresponded to those measured for the same drugs by other assessment methods. These data indicate that the LSEQ is a robust and reliable instrument for psychopharmacological evaluations. Self-evaluations of sleep, as obtained by the LSEQ, can therefore provide consistent and meaningful measures for estimating the effectiveness of sleep modulators and sedative-hypnotic drugs.

[Assessment of efficacy and tolerability of mirtazapine treatment of patients with depression]. / Ocena skutecznosci i tolerancji leczenia mirtazapina u pacjentów z rozpoznaniem zaburzen depresyjnych.

The paper presents results of the study on the efficacy and tolerability of mirtazapine treatment of patients with depression. The study was open and conducted in three centers. 65 out- and in-patients with diagnosis of depression was included. 50% reduction of the score in the HAM-D scale was obtained in 57%, according to MADRS scale--in 61% patients. Side effects were reported in 49% patients. The most frequent side effects were: drowsiness, fatigue, anxiety, sleepiness, weight increase, headache. The results of the study are comparable with other mirtazapine studies.