Wolfgang Prause

Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): Acute placebo-controlled sleep laboratory studies with clonazepam

Restless legs syndrome (RLS) - a common sensorimotor disorder - and periodic limb movement disorder (PLMD) are currently treated with substances of four classes: dopaminergic agents, which are considered the drugs of choice, benzodiazepines, opioids and anticonvulsants. As their effects on sleep variables differ considerably, the aim of the present placebo-controlled sleep laboratory study was to measure the acute effects of 1 mg clonazepam on objective and subjective sleep and awakening quality in ten RLS and 16 PLMD patients, utilizing polysomnography (PSG) and psychometry. Descriptive data analysis demonstrated at the confirmatory level concerning three target variables that - as compared with placebo - clonazepam significantly improved objective sleep efficiency and subjective sleep quality in both patient groups, but failed to reduce the index PLM/h of sleep. At the descriptive level, in PLMD clonazepam improved PLM during time in bed, REM and wakefulness and showed more significant changes in various sleep and awakening measures than in RLS patients, though there were no significant inter-group differences. In conclusion, in both PLMD and RLS clonazepam exhibited acute therapeutic efficacy regarding insomnia, which is quite different from the mode of action of dopamine agonists.

Insomnia in depression: Differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone

Utilizing polysomnography (PSG) and psychometry, objective and subjective sleep and awakening quality was investigated in 11 drug-free patients (five females, six males) aged 35-75 years (mean age 54.1 +/- 11.4) suffering from nonorganic insomnia (F 51.0) related to a depressive episode (F 32) or recurrent depressive disorder (F 33). as compared with 11 age- and sex-matched normal controls (five females, six males) aged 36-75 years (mean age 53.0 +/- 13.5). PSG demonstrated decreased sleep efficiency, total sleep time (TST), total sleep period (TSP) and sleep stage S2, as well as increased wakefulness during TSP, early morning awakening, sleep latency to S1, S2, S3 and sleep stage S1 in depressed patients. Subjective sleep quality and the total score of the Self-Assessment of Sleep and Awakening Quality Scale (SSA) were deteriorated as were morning and evening well being, drive, mood and fine motor activity right. Evening and morning blood pressure, the O2 desaturation index and periodic leg movement (PLM) index were increased. In a subsequent acute, placebo-controlled cross-over design study, the acute effects of 100 mg of trazodone, a serotonin reuptake inhibitor with a sedative action due to 5-HT2 and alpha1 receptor blockade, were investigated in the patients. As compared with placebo, trazodone induced an increase in sleep efficiency (primary target variable), TST, TSP and SWS (S3 + S4), as well as a decrease in wakefulness during the TSP, early morning awakening and S2. There was no change in rapid eye movement (REM) sleep with the exception of an increase in the REM duration in minutes. Trazodone also caused an improvement in subjective sleep quality, affectivity, numerical memory and somatic complaints. All respiratory variables remained within normal limits. Critical flicker frequency and moming diastolic blood pressure were decreased. The present study demonstrated that depression induced significant changes in objective and subjective sleep and awakening quality, which were counteracted by 100 mg of trazodone, thus suggesting a key-lock principle in the treatment of depression.

On the Pharmacotherapy of Sleep Bruxism: Placebo-Controlled Polysomnographic and Psychometric Studies with Clonazepam

Objectives: Sleep bruxism (SB) is a parasomnia defined as a stereotyped movement disorder characterized by grinding or clenching of the teeth during sleep. Pathophysiologically, SB is the result of biological and psychosocial influences. Treatment comprises behavioral, orthodontic and pharmacological interventions. While benzodiazepines and muscle relaxants have been reported by clinicians to reduce bruxism-related motor activity, placebo-controlled studies are lacking. Thus, the aim of the present study was to investigate the acute effects of clonazepam (Rivotril®) as compared with placebo, utilizing polysomnography and psychometry. Method: Ten drug-free outpatients (6 females, 4 males), aged 46.5 ± 13.1 years, suffering from SB (ICD-10: F45.8; ICSD: 306.8) and having been treated by bite splints were included in the trial. Comorbidity was high: 7 patients presented nonorganic insomnia related to adjustment or anxiety disorders (5 patients) or depression (2 patients); all patients had a concomitant movement disorder (6 restless legs syndrome, 4 periodic leg movement disorder). After one adaptation night, patients received placebo and 1 mg clonazepam 1/2 hour before lights out in a single-blind, nonrandomized study design. Objective sleep quality was determined by polysomnography, subjective sleep and awakening quality by rating scales, objective awakening quality by psychometric tests. Clinical evaluation was based on the Pittsburgh Sleep Quality Index (PSQI), the Zung Depression (SDS) and Anxiety (SAS) Scales, the Quality of Life Index, the Epworth Sleepiness Scale and the International Restless Legs Syndrome Study Group (IRLSSG) Scale. Results: On admission, SB patients exhibited deteriorated PSQI, SAS, SDS and IRLSSG measures. As compared with placebo, 1 mg clonazepam significantly improved the mean bruxism index from 9.3 to 6.3/h of sleep. Furthermore, it significantly improved the total sleep period, total sleep time, sleep efficiency, sleep latency and time awake during the total sleep period, and increased stage 2 sleep and movement time. Periodic leg movements decreased significantly, while the apnea index and apnea-hypopnea index increased marginally, but remained within normal limits. Subjective sleep quality improved as well, while in mood, performance and psychophysiology no changes were observed. Conclusion: Acute clonazepam therapy significantly improved not only the bruxism index but also objective and subjective sleep quality, with unchanged mood, performance and psychophysiological measures upon awakening, suggesting good tolerability of the drug.

Quality of life in nonorganic and organic sleep disorders: I. Comparison with normative data

Zusammenfassung100 Schlaflaborpatienten (39 Frauen im Alter von 52±13 Jahren, 61 Männer im Alter von 53±10 Jahren) wurden im Vergleich zu 100 gesunden Personen hinsichtlich ihrer subjektiven gesundheitsbezogenen Lebensqualität untersucht.Erhoben wurde der Lebensqualitätsindex (Mezzich und Cohen) sowie objektive (Polysomnographie) und subjektive Schlaf- und Aufwachqualität (Psychometrie).Statistische Analysen (Mann-Whitney U-Test) zeigten eine signifikant reduzierte Lebensqualität bei Schlafstörungen, wobei die Verschlechterung bei nichtorganischen Schlafstörungen ausgeprägter war als bei organischen. In der Gruppe der nichtorganischen Schlafstörungen wiesen Patienten mit einer Hypersomnie stärkere Lebensqualitätseinbußen auf als jene mit Insomnie, innerhalb der organischen Schlafstörungen zeigten sich Apnoepatienten stärker beeinträchtigt als obstruktive Schnarcher.Bei schlafgestörten Patienten war die Lebensqualität in 7 von 10 grundlegenden Komponenten reduziert: körperliches Wohlbefinden, seelisches Wohlbefinden, für sich selbst Sorgen und selbständiges Funktionieren, berufliches Funktionieren, zwischenmenschliches Funktionieren, persönliche Erfüllung und Lebensqualität im allgemeinen. Keine Unterschiede zeigten sich in den Bereichen soziale Unterstützung, zufriedenstellende Lebensumwelt und geistige Erfüllung. Patienten mit nichtorganischen Schlafstörungen wiesen in den Dimensionen körperliches und seelisches Wohlbefinden und Lebensqualität im Allgemeinen signifikant schlechtere Werte auf als jene mit organischen Schlafstörungen. Patienten mit affektiven Störungen als Zusatzdiagnose zeigten eine stärker reduzierte Lebensqualität als jene mit Angststörungen.Untersuchungen bei 51 der 100 schlafgestörten Patienten ein Jahr nach dem Schlaflaboraufenthalt ergaben sowohl bei nichtorganischen (n=31) als auch bei organischen Schlafstörungen (n=20) eine signifikant bessere Lebensqualität als vor der Behandlung. Außerdem zeigten Patienten, die im Schlaflabor diagnostiziert und behandelt worden waren, niedrigere Rehospitalisierungsraten.SummarySubjective health-related quality of life (HRQoL) was investigated in 100 patients with disturbed sleep (39 women aged 52±13 years and 61 men aged 53±10 years) referred to the sleep laboratory and compared with HRQoL in 100 normal healthy adults. Measurements included the Quality of Life Index (QLI) (Mezzich and Cohen), and objective (polysomnographic) and subjective (psychometric) quality of sleep and awakening.Statistical analysis (Mann-Whitney U-test) showed HRQoL to be significantly reduced in sleep disorders (SDs), with a more pronounced reduction in nonorganic than in organic SDs. Patients with nonorganic hypersomnia were more disturbed than those with nonorganic insomnia. Within organic SDs, patients with apnea were more disturbed than those with obstructive snoring.Out of ten elementary HRQoL components, seven were disturbed in SDs: physical well-being, psychological well-being, self-care and independent functioning, occupational functioning, interpersonal functioning, personal fulfillment, and overall quality of life. No differences between patients and normal healthy subjects where found in the components social support, community and services support or spiritual fulfillment. Patients suffering from nonorganic SDs had significantly worse scores in physical and psychological well-being and overall quality of life than those with organic SDs. Patients with both SDs and additional diagnoses of affective disorders had more profoundly reduced HRQoL than those with anxiety disorders. Follow-up of 51 patients (31 with nonorganic SDs and 20 with organic SDs) one year after sleep laboratory investigation and subsequent treatment found significantly improved HRQoL compared with pre-treatment. Moreover, patients diagnosed and treated in the sleep laboratory showed lower re-hospitalization rates.

Sleep Disturbances in Somatoform Pain Disorder

Patients with chronic somatoform pain often complain about sleep disorders. However, sleep disorder/disturbances are not an integrated part of the somatoform disorders in the DSM-IV and the ICD-10. Sleep is important for recreation. Deprivation of deep sleep stages is experimentally linked to muscle pain. Therefore, sleep disorder may play an important part in the persistence of somatoform pain disorder. The aim of the study was to evaluate the frequency of sleep disorder in patients with somatoform pain disorder and to correlate it with comorbid depression, pain parameters and psychosocial parameters. Method: In this study, 147 patients (mean age: 48.8 years; SD: 11.0) with the diagnosis of a somatoform pain disorder were studied with regard to affective comorbidity, pain duration (months), maximum pain within the last month, minimum pain within the last month and medium pain within the last month, psychosocial disability within the last month and the presence of a sleep disorder. Results: Eighty-four percent of the patients had a sleep disorder. The patients with a sleep disorder had significantly higher maximum and medium pain, a significantly higher level of psychosocial disability and a significantly lower overall subjective well-being. The medium pain and psychosocial disability in leisure and social activities are significant predictors for sleep disorder. Conclusions: The presence of a sleep disorder may be a hint for higher pain intensity and a higher level of psychosocial disability. Sleep disorder may be a factor in the persistence and aggravation of pain as well as psychosocial disability. Therefore, sleep disorder should be integrated in the therapeutic targets. It is suggested that sleep disorder should be a diagnostic criterion in somatoform pain disorder.

Quality of life in nonorganic and organic sleep disorders: II. Correlation with objective and subjective quality of sleep and awakening

ZusammenfassungZielZiel der Studie war die Bestimmung von Korrelationen zwischen objektiven (Einund Durchschlafverhalten, Schlafarchitektur, Aufwachqualität, Psychophysiologie) und subjektiven Schlaf- und Aufwachqualitätsvariablen einerseits und subjektiver gesundheitsbezogener Lebensqualität andererseits bei 100 schlafgestörten Patienten.MethodikDie Bestimmung der objektiven Variablen erfolgte mittels polysomnographischer Ganznachtschlafaufzeichnungen. Zur Ermittlung der subjektiven gesundheitsbezogenen Lebensqualität wurde der Lebensqualitätsindex (QLI) nach Mezzich und Cohen eingesetzt, welcher den Patienten vor der Adaptationsnacht vorgelegt wurde. Weiters wurde die subjektive und objektive Schlafund Aufwachqualität (psychometrische Untersuchungen) am Abend vor und Morgen nach der Polysomnographie bestimmt.Ergebnisse63% der Patienten litten an nichtorganischen Schlafstörungen, wobei die nichtorganische Insomnie am häufigsten auftrat, bei 37% waren organische Schlafstörungen, insbesonders Schlafapnoe, diagnostiziert worden. Die subjektive gesundheitsbezogene Lebensqualität zeigte, vor allem bei nichtorganischen Schlafstörungen, eine starke Korrelation mit der subjektiven Schlaf- und Aufwachqualität. Mit den anderen erhobenen Variablen waren nur vereinzelt Korrelationen zu beobachten: So korrelierte in der Gesamtgruppe der Patienten die gesundheitsbezogene Lebensqualität mit dem Schlafstadium 2 und in der Gruppe der nichtorganischen Schlafstörungen mit der Aufmerksamkeitsleistung und psychophysiologischen Parametern (vor allem mit der Pulsfrequenz abends und morgens).KonklusionUnsere Ergebnisse lassen sowohl bei organischen als auch bei nichtorganischen Schlafstörungen nur auf einen geringen Zusammenhang zwischen objektiven Schlafvariablen und subjektiver gesundheitsbezogener Lebensqualität schließen. Die subjektiven Schlafvariablen jedoch zeigten vor allem bei nichtorganischen Schlafstörungen zahlreiche Korrelationen mit der subjektiven gesundheitsbezogenen Lebensqualität.SummaryObjectiveThe purpose of this study of 100 patients suffering from sleep-disorders was to determine correlations between their subjective health-related quality of life (HRQoL) and objective variables in sleep initiation and maintenance, sleep architecture, objective quality of awakening, psychophysiological parameters and subjective quality of sleep and awakening.MethodsObjective measurements were obtained from overnight diagnostic polysomnography. Subjective HRQoL was determined from the Quality of Life Index (QLI, Mezzich and Cohen) completed prior to the adaptation night. Other measurements included subjective and objective quality of sleep and awakening (psychometry) the evening before and morning after polysomnographic investigations.Results63% of the patients were suffering from nonorganic and 37% from organic sleep disorders (SDs). Within the first group, nonorganic insomnia predominated; within the second, sleep apnea.Subjective HRQoL correlated well with subjective sleep and awakening quality, especially in nonorganic SDs. There were only a few correlations of objective measurements with subjective HRQoL: in the total group of SD patients HRQoL correlated with sleep stage S2, and in nonorganic SDs with attention scores and psychophysiological measurements (mainly the pulse rate in the evening and morning).ConclusionOur findings suggest only a weak relationship between objective sleep variables and subjective HRQoL in both organic and nonorganic SDs. However, we found various significant correlations of HRQoL with subjective measurements of sleep, especially in nonorganic SDs.

Visualizing central effects of S-adenosyl-l-methionine (SAMe), a natural molecule with antidepressant properties, by pharmaco-EEG mapping

In a double-blind, placebo-controlled, cross-over study, the central effects of the natural molecule S-adenosyl-L-methionine (SAMe), or ademetionine (ADE), used in low doses as a nutraceutical and in higher doses as a pharmaceutical, were investigated by means of EEG mapping and psychometry. Ten young, normal healthy volunteers of both sexes, with a mean age of 25.2+3.9 yr received, in random order, infusions of 800 mg ADE in 250 ml of isotonic solution, and placebo consisting of 250 ml of isotonic solution administered over 30 min for 7 d, with a wash-out period of 3 wk in between. EEG recordings and psychometric tests were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 7. While there were no significant changes in psychometric findings, multivariate analyses of the EEG results based on MANOVA/Hotelling T 2 tests demonstrated significant encephalotropic effects of ADE compared to placebo. ADE-induced changes were characterized by a decrease in total power, an increase in absolute delta power and a decrease in absolute alpha and beta power, further by an increase in relative delta and beta power and a decrease in relative alpha power, a slowing of the delta/theta centroid, an acceleration of the alpha centroid as well as a slowing of the centroid of the total power spectrum. These changes are typical of classical antidepressants of the thymoleptic type such as imipramine and amitriptyline. Time-efficacy calculations demonstrated a significant central effect of ADE in the first hour after the first infusion, declining slowly until the third hour and thereafter steeply until the sixth hour; a further significant effect was after 1 wk of daily infusions and in the third hour after one superimposed infusion on day 7 of subacute treatment. Our pharmaco-EEG findings suggest both inhibitory and excitatory drug effects at the neurophysiological level, underlying the antidepressant properties well-documented in clinical trials.

Contents Vol. 36, 2003

Medical and Scientifi c Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant fl ow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specifi ed fee to the Copyright Clearance Center (see ‘General Information’).