Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause.

OBJECTIVES: To analyse the effect of fezolinetant on patient-reported sleep disturbance and impairment in individuals with vasomotor symptoms (VMS) using pooled data from the SKYLIGHT 1 and 2 studies. STUDY DESIGN: The SKYLIGHT studies were phase-3, double-blind investigations. Individuals (≥40-≤65 years) who were assigned female at birth and seeking treatment of/relief from moderate-to-severe VMS were enrolled. Participants were randomised to receive placebo, fezolinetant 30 mg, or fezolinetant 45 mg during a 12-week treatment period. MAIN OUTCOME MEASURES: Sleep assessments: Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b), PROMIS Sleep-Related Impairment - Short Form 8a (PROMIS SRI SF 8a), and Patient Global Impression of Change/Severity in SD (PGI-C SD and PGI-S SD). Assessments were completed at baseline (except PGI-C SD), weeks 4 and 12. RESULTS: Overall, 1022 individuals were randomised and took ≥1 dose of study drug. PROMIS SD SF 8b results showed that improvements in sleep disturbance were observed for fezolinetant 30 and 45 mg versus placebo (week 12, least squares [LS] mean differences: -0.6 [95 % confidence interval [CI]: -1.7, 0.4] for 30 mg and -1.5 [-2.5, -0.5] for 45 mg). Similar improvements in sleep impairment were reported using the PROMIS SRI SF 8a (week 12, LS mean differences: -1.1 [95 % CI: -2.1, -0.1] for 30 mg and -1.3 [-2.3, -0.3] for 45 mg). For PGI-C SD at week 12, 33.6 % (98/292 participants) of the placebo group felt much/moderately better versus 40.1 % (110/274) and 51.0 % (154/302) of the fezolinetant 30 mg and 45 mg groups, respectively. For PGI-S SD at week 12, 44.0 % (129/293) of the placebo group had severe/moderate problems versus 41.1 % (113/275) and 36.6 % (111/303) of the fezolinetant 30 mg and 45 mg groups, respectively. The 12-week timeframe for this analysis was limited by the length of the placebo-controlled period. CONCLUSIONS: Fezolinetant had a beneficial effect on four measures of sleep disturbance and impairment following treatment for VMS.

A retrospective observational study of osteoporosis management after a fragility fracture in primary care.

In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. PURPOSE: A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. METHODS: A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. RESULTS: Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. CONCLUSION: In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures.

Psoriatic and psoriatic arthritis patients with and without jet-lag: does it matter for disease severity scores? Insights and implications from a pilot, prospective study.

Background: Jet-lag may affect air-travelers crossing at least two time-zones and has several health-care implications. It occurs when the human biological rhythms are out of synch with respect to the day-night cycle at the country destination. Its effect in psoriasis is missing. We aimed to evaluate the effect of Jet-lag in psoriatic patients' management. Methods: This is a prospective observational study that enrolled psoriatic patients that underwent a flight: patients who experienced jet-lag were compared to patients who did not experience jet-lag. Before the flight, a dermatologist recorded clinical and demographical data with particular attention to Psoriasis Area Severity Index (PASI) and Disease Activity in Psoriatic Arthritis (DAPSA). Patients performed Self-Administered Psoriasis Area Severity Index (SAPASI), the Dermatology Life Quality Index (DLQI) and the pruritus Visual Analog Scale (VAS) scores. After the flight, patients completed the SAPASI, DLQI and pruritus-VAS scores. Results: The sample recruited comprised of 70 psoriatic patients aged 42.4 ± 9.7 years (median 42.5 years). Thirty (42.9%) were males, mean BMI was 25.5 ± 2.2 kg/m2. Average disease duration was 15.2 ± 7.1 years, and 20 (28.6%) subjects had developed PsA. Average hours of flight were 5.4 ± 3.5 (median 3.5 h), with 34 (48.6%) subjects reporting jet-lag. At the multivariate regression analysis, the change in the SAPASI score resulted correlated with jet-lag (regression coefficient 1.63, p = .0092), as well the change in the DLQI score (regression coefficient = 1.73, p = .0009), but no change on the pruritus VAS scale was found. Conclusions: The present study suggests that jet-lag may influence disease severity and DLQI scores, but not itch in psoriatic patients.

Atypical presentation of NREM arousal parasomnia with repetitive episodes.

The case report describes a distinct variant of non-REM (Rapid Eye Movement) arousal parasomnia, sleepwalking type, featuring repetitive abrupt arousals, mostly from slow-wave sleep, and various automatisms and semi-purposeful behaviours. The frequency of events and distribution throughout the night presented as a continuous status of parasomnia ('status parasomnicus'). The patient responded well to treatment typically administered for adult NREM parasomnias, and after careful review of the clinical presentation, objective findings and treatment outcome, sleep-related epilepsy was ruled out in favour of parasomnia.

Underlying sleep pathology may cause chronic high fatigue in shift-workers.

About 20-25% of the population in primary healthcare settings complains of chronic fatigue but this symptom has been under-emphasized compared with sleepiness in clinical practice. Shift-workers are particularly vulnerable because of various fatigue-related personal and public morbidity and mortality. The goal of this cross-sectional study was to explore if fatigue severity could be used as an independent predictive tool to identify underlying sleep pathology. The 21 most-fatigued (study group) and 23 least-fatigued (control) miners were selected on the basis of the Fatigue Severity Scale (FSS), which was administered to 195 subjects in an underground mine in Timmins, a town in northern Ontario. The two groups were matched for age, gender, and body mass index (BMI). Mean FSS score for the most-fatigued subjects was 4.9 +/- 0.5 and the least-fatigued was 2.2 +/- 0.5 (P < 0.0001). The subjects from each group were studied polysomnographically to identify sleep disorders. The polysomnographic data in 15 of 21 (71.4%) of the most-fatigued subjects displayed significant sleep pathology compared with only three of 23 (13.0%) in the least-fatigued subjects. Based on Fisher's exact test, the difference between the two groups was highly significant (P < 0.0001). Also, in the total subject pool (n = 195), the correlation between subjective fatigue and sleepiness was not very strong (Pearson's r = 0.45), suggesting that these two symptoms can be independent phenomena. It is concluded that chronic high fatigue can be an independent manifestation of underlying sleep pathology, which warrants independent subjective and objective assessment.

Are there gender differences in the prescribing of hypnotic medications for insomnia?

Gender differences in the prescribing patterns of general classes of medications for insomnia were examined. The classes of medications included: zopiclone, antidepressants, benzodiazepines, antihistamines and no medication. The sample comprised a sub-set of respondents from 2620 questionnaires of the Canadian Multicentre Sleep Database. Respondents for this database were contacted through physicians, announcements in the media and local pharmacies. The results indicated that gender alone was not associated with differential prescribing for insomnia, nor was gender associated with patterns of medication use such as frequency of taking medication, length of use, taking more or less medication than prescribed or attempts to stop taking medication. Demographic factors were included in the analysis and age and marital status were associated with different prescribing patterns for men and women with insomnia. It is possible that physicians refer to stereotypic expectations when prescribing hypnotics.

Structure of lifestyle disruptions in chronic disease: a confirmatory factor analysis of the Illness Intrusiveness Ratings Scale.

BACKGROUND: The Illness Intrusiveness Ratings Scale (IIRS) measures the extent to which disease or its treatment or both interfere with activities in important life domains. Before comparing IIRS scores within or across groups it is crucial to determine whether a common underlying factor structure exists across patient populations. OBJECTIVE: To investigate the factor structure underlying the IIRS and evaluate its stability across diagnoses. METHODS: IIRS responses from 5,671 respondents were pooled from 15 separate studies concerning quality of life in eight patient groups: rheumatoid arthritis; osteoarthritis; systemic lupus erythematosus; multiple sclerosis; end-stage renal disease (maintenance dialysis); renal transplantation; heart, liver, and lung transplantation; and insomnia. Data were gathered by different methods (eg, interview, self-administered, mail survey) and in diverse contexts (eg, individual vs. group). RESULTS: Exploratory maximum-likelihood factor analysis identified three underlying factors in a randomly selected subset of respondents (n = 400), corresponding to "Relationships and Personal Development," "Intimacy," and "Instrumental" life domains. Confirmatory factor analysis corroborated the stability of this structure in an independent subsample (n = 2100). Complementary goodness-of-fit indices confirmed the consistency of the three-factor solution, corroborating that IIRS scores are uniquely defined across patient populations. Coefficient alpha was high for total and subscale scores. CONCLUSIONS: IIRS scores can be compared meaningfully within and across patient groups. Both total and subscale scores can be used depending on research objectives.

Bilateral primary breast lymphoma.

A primary breast lymphoma developed in a patient. After 139 months. she was diagnosed with a new primary breast lymphoma in the contralateral breast. The pathologic diagnosis in each tumor was non-Hodgkin's lymphoma, B-cell, diffuse large cell. Radiation therapy was effective in securing a clinical remission for both tumors.

A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome.

OBJECTIVE: The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. METHODS: Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. RESULTS: In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. CONCLUSIONS: Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.

Sleep and daytime sleepiness in retinitis pigmentosa patients.

OBJECTIVE: We examined sleep, daytime sleepiness and the ability to stay awake during the day in patients affected with retinitis pigmentosa (RP), to further delineate the role of photoreceptors in the circadian cycle. METHODS: Twelve individuals diagnosed with RP (40 +/- 8 years) And 12 normally sighted healthy individuals (39 +/- 7 years) matched for age, body mass index (BMI) and sex were selected for the study. Participants had their sleep recorded on two consecutive nights and were monitored on the two following days. On the first day, their ability to stay awake and on the second, their sleep propensity were assessed using the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT), respectively. Self-report measures were obtained using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Toronto Hospital Alertness Test (THAT). RESULTS: Subjective daytime sleepiness (ESS: 9 +/- 5 vs. 6 +/- 4, P=0.053) and objectively measured sleep propensity (MSLT: 10 +/- 5 vs. 17 +/- 3 min, P < 0.000) were significantly higher in RP patients than controls, whilst their alertness (THAT: 29 +/- 9 vs. 38 +/- 7, P=0.016) and ability to stay awake (MWT: 21 +/- 9 vs. 29 +/- 2 min, P=0.006) were significantly reduced. Retinitis pigmentosa participants had more disturbed nighttime sleep, with significantly more awakenings (arousal index: 14 +/- 8 vs. 8 +/- 6 h, P=0.039), and tended to have less rapid eye movement (REM) sleep (19 +/- 5 vs. 22 +/- 3%, P=0.094). CONCLUSION: Patients with RP have increased daytime sleepiness, reduced alertness and more disturbed nighttime sleep of poorer quality than their normally sighted counterparts, suggesting an influence of photoreceptor degeneration on the circadian cycle.

Knowledge of sleep apnea in a sample grouping of primary care physicians.

UNLABELLED: The purpose of this pilot study was to examine four groups of primary care physicians' knowledge of sleep apnea. METHODS: Using a 36-item questionnaire, we investigated how cognizant primary care physicians in Ontario, Canada, were of sleep apnea and its different symptoms. The questions covered incidence, diagnosis, treatment, and medical and social ramifications of sleep apnea. Sleep apnea surveys were administered to small groups of primary care physicians attending educational conferences or were distributed by mail to physicians who had previously referred patients to the sleep clinic. RESULTS: A total of 151 physicians responded to the survey. An overall average score of 69% was obtained on the questionnaire. CONCLUSIONS: This score suggests that the physicians sampled in this pilot study are relatively under-informed about the clinical features and medical and social ramifications associated with sleep apnea.

Sleep disturbances and psychiatric disorders associated with posttraumatic stress disorder in the general population.

The aim of the study was to assess sleep disturbances in subjects with posttraumatic stress disorder (PTSD) from an urban general population and to identify associated psychiatric disorders in these subjects. The study was performed with a representative sample of 1,832 respondents aged 15 to 90 years living in the Metropolitan Toronto area who were surveyed by telephone (participation rate, 72.8%). Interviewers used Sleep-EVAL, an expert system specifically designed to conduct epidemiologic studies of sleep and mental disorders in the general population. Overall, 11.6% of the sample reported having experienced a traumatic event, with no difference in the proportion of men and women. Approximately 2% (1.8%) of the entire sample were diagnosed by the system as having PTSD at the time of interview. The rate was higher for women (2.6%) than for men (0.9%), which translated into an odds ratio (OR) of 2.8 (95% confidence interval [CI], 1.3 to 6.1). PTSD was strongly associated with other mental disorders: 75.7% of respondents with PTSD received at least one other diagnosis. Most concurrent disorders (80.7%) appeared after exposure to the traumatic event. Sleep disturbances also affected about 70% of the PTSD subjects. Violent or injurious behaviors during sleep, sleep paralysis, sleep talking, and hypnagogic and hypnopompic hallucinations were more frequently reported in respondents with PTSD. Considering the relatively high prevalence of PTSD and its important comorbidity with other sleep and psychiatric disorders, an assessment of the history of traumatic events should be part of a clinician's routine inquiry in order to limit chronicity and maladjustment following a traumatic exposure. Moreover, complaints of rapid eye movement (REM)-related sleep symptoms could be an indication of an underlying problem stemming from PTSD.

Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.

OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.

Differentiating DSM-IV anxiety and depressive disorders in the general population: comorbidity and treatment consequences.

OBJECTIVE: To attempt, for the first time, to apply a positive and differential diagnosis process in the general population during interviews using DSM-IV classification to ascertain the profile and occurrence of concomitant mental disorders. METHOD: A representative sample of 1832 individuals aged 15 years or older living in the metropolitan area of Toronto were interviewed by means of telephone interviews. The participation rate was 72.8%. RESULTS: Overall, 13.2% (n = 242) of the sample had either a mood disorder (n = 127; 6.9%) or an anxiety disorder (n = 170; 9.3%) at the time of their interview. The prevalence was higher among women (16.5%) than among men (9.7%), with an odds ratio of 1.8. The comorbidity of mood and anxiety disorders was found in 3% (n = 55) of the sample. Less than one-third of respondents with a mood and/or anxiety disorder were being treated by a physician for a mental disorder. However, these individuals were greater consumers of health care services. Most of them consulted a physician an average of 5 times in the past year. Individuals on medication diagnosed with a mood and an anxiety disorder consulted a physician an average of 12 times in the past year. Only 13% of them were treated with antidepressants and under 9% with anxiolytics. CONCLUSIONS: More than 70% of subjects with a mood disorder also complained of insomnia. With the differential process, 12% of the subjects manifesting a full-fledged anxiety disorder were diagnosed with only a mood disorder because the anxiety occurred only in the course of the mood disorder. About two-thirds of the subjects diagnosed in this study were undiagnosed and untreated by their physician.

Interrelationships between nocturnal sleep, daytime alertness, and sleepiness: two types of alertness proposed.

The authors studied daytime sleepiness and alertness (based on the Multiple Sleep Latency Test [MSLT] and Maintenance of Wakefulness Test [MWT]) and nocturnal sleep in 22 patients with depression/anxiety and in 47 nondepressed patients with sleep apnea. The patients underwent two overnight sleep studies followed by daytime tests. In depressed patients, MWT scores correlated negatively with total sleep time and stage 3. MSLT scores correlated negatively with total sleep time and with sleep efficiency. Apneic patients showed a negative correlation between MWT results and amount of stage 1 sleep. MSLT results correlated positively with sleep onset latency on the preceding overnight sleep study. Thus, in depressed patients, there is a paradox that with more disturbed sleep there is greater daytime alertness. In contrast, the more disturbed the sleep is in sleep apnea patients, the more difficult it is to maintain daytime alertness.

Interactions of sleep and Parkinson's disease.

Sleep disruption represents an important, and clinically relevant facet of Parkinson's Disease [PD]. This review attempts to integrate the current knowledge regarding sleep alterations in PD by examining following: the nature of sleep disturbance in PD, the influence of antiparkinson medication on sleep parameters, the interaction of psychological conditions such as depression and anxiety with sleep, and possible beneficial aspects of sleep in PD. Special emphasis is placed on rapid eye movement sleep behavior disorder and the evidence of it heralding PD and related disorders.