Nadja Brandstätter

Nonorganic insomnia in generalized anxiety disorder. 1. Controlled studies on sleep, awakening and daytime vigilance utilizing polysomnography and EEG mapping.

Objective and subjective sleep and awakening quality as well as daytime vigilance of insomniac patients with generalized anxiety disorder (GAD) were investigated, as compared with normal controls. Forty-four outpatients (25 females, 19 males), aged 24-65 (mean 43) years, diagnosed with non-organic insomnia (ICD-10: F 51.0), related to mild GAD (F 41.1), with a Hamilton anxiety (HAMA) score of 22 +/- 6 and a Zung self-rating anxiety (SAS) score of 37 +/- 6 were included. After 1 adaptation night, sleep induction, maintainance and architecture were measured objectively by polysomnography, subjective sleep and awakening quality were assessed by self-rating scales and visual analog scales, objective awakening quality was measured by a psychometric test battery, and diurnal tiredness was measured by a 3-min vigilance-controlled EEG (V-EEG) and a 4-min resting EEG mapping. In polysomnography patients demonstrated-as compared with normals-significantly increased wake time during the total sleep period and more early-morning awakening, decreased total sleep and sleep efficiency. Subjective sleep quality was deteriorated as well, as were well-being, drive, mood, and wakefulness in the morning. In noopsychic performance, GAD patients did rather well in attention, concentration, attention variability, and numerical memory, while fine-motor activity and reaction time were deteriorated. In psychophysiology, critical flicker frequency was decreased in the morning, while muscle strength, blood pressure and pulse rate showed no differences. EEG mapping during the late morning hours (10.00-12.00 h) demonstrated hypervigilance in the V-EEG, while in the resting recording an increased sleep pressure was detected. The latter was correlated significantly to the SAS score, but less so to the observer-rated Hamilton anxiety score. Our findings suggest that CNS hypervigilance and hyperarousal, as actual symptoms of GAD, lead to nocturnal insomnia, which in turn may cause-as a consequence of sleep pressure not slept off-diurnal tiredness.

Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression

In a double-blind, placebo-controlled study, the antidepressant and vigilance-promoting properties of transdermal oestrogen in post-menopausal depression were investigated utilizing hormonal, syndromal and EEG mapping evaluations. Sixty-nine menopausal women, aged 45–60 years without previous hormonal replacement therapy, diagnosed as major depression without psychotic or suicidal symptoms (DSM-III-R criteria), were randomly assigned to a 3-month treatment with transdermal oestradiol [Estraderm TTS (ETTS) 50 µg, applied twice weekly] or placebo. No other psychoactive medication was allowed. After removal of protocol violators, 32 patients were evaluable in each group, which did not differ in age, height or weight. As five patients discontinued prematurely in both groups and in one placebo patient a post-drug EEG could not be obtained, 27 patients remained in the ETTS and 26 in the placebo group for efficacy analysis. While in the placebo group, oestradiol (E2) and follicle stimulating hormone (FSH) remained unchanged, E2 increased and FSH decreased significantly in the ETTS group. Syndromal evaluation showed a significant improvement in the Kupperman Index (KI) as well as Hamilton Depression Rating Scale (HAMD) in both groups, with no inter-group difference. However, EEG mapping demonstrated significant interdrug differences in brain function, mostly over the left temporal region. While ETTS patients showed an increase of alpha and alpha-adjacent theta activity and a decrease of beta activity, as well as an acceleration of the delta/theta centroid and a slowing of the alpha, beta and total power centroid, no changes occurred in the placebo-treated patients. These neurophysiological findings suggest improvement of vigilance by oestrogen, previously referred to as “mental tonic” effect. There were no changes, however, in the frontal alpha asymmetry index, reflecting left frontal hypo- and right frontal hyperactivation. Thus, this neurophysiological variable represents a state-independent marker for depression. The tolerability of ETTS was very good.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

Insomnia in Generalized Anxiety Disorder: Polysomnographic, Psychometric and Clinical Investigations before, during and after Therapy with a Long- versus a Short-Half-Life Benzodiazepine (Quazepam versus Triazolam)

Within a double-blind, comparative study on the effects of the long-half-life benzodiazepine (BDZ), quazepam, and the short-half-life BDZ, triazolam, on clinical symptomatology, sleep and anxiety of 45 patients with insomnia based on a mild to moderate generalized anxiety disorder (GAD) (ICD-9 code: 307.42-1, 300,0; ASDC-APSS-Code: A.2.a), we compared, in a first step at baseline, drug-free polysomnographic and psychometric data of 22 patients recorded in the laboratory (L-group) and 21 patients recorded by the Oxford Medilog 9000 system at home (H-group) with those of normal controls. Sleep efficiency, total sleep time, wake within total sleep period (middle insomnia) and wake before buzzer (late insomnia) were significantly deteriorated in both patient groups as compared with controls, while sleep induction time only differed significantly in home recordings. Regarding sleep architecture, stage (S)2 was reduced, S3 and S4 increased in the H-group only, while no intergroup differences were seen in S1, SREM and REM latency. Subjective sleep quality was reduced in both patient groups, but not awakening quality. Psychometric tests in the morning demonstrated for the noopsyche, only a significantly deteriorated psychomotor activity in both patient groups. In the thymopsyche, evening well-being and mood in the morning were reduced in both the L- and H-group, affectivity and morning well-being only in the H-group. The psychopharmacological part of the study was completed by 40 patients (there were 4 drop-outs in the triazolam, 1 in the quazepam group). They were treated after 1 week placebo with either 15-30 mg (median 15 mg) quazepam or 0.25-0.5 mg (median 0.25 mg) triazolam for 4 weeks, and thereafter for 2 weeks with placebo. Anxiety (rated by HAMA and SAS) improved significantly with both drugs and remained improved throughout 2 weeks post-drug placebo, with quazepam being slightly superior to triazolam. Polysomnography demonstrated a shortened sleep onset only after quazepam. Sleep efficiency improved after acute administration of both drugs, but the improvement was maintained by quazepam only (tolerance development with triazolam). Rebound insomnia was observed only in the 1st post-triazolam placebo night (significant intergroup difference based on confirmatory testing). S2 increased, S3 + S4 decreased under and after quazepam, which represents a normalization in home-recorded GAD patients. S1 decreased with both drugs, SREM only under quazepam. Subjective sleep quality behaved very similarly to objective sleep efficiency. Awakening quality improved after acute therapy with both drugs, somatic complaints only with quazepam.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Placebo-Controlled Sleep Laboratory Studies on the Acute Effects of Zolpidem on Objective and Subjective Sleep and Awakening Quality in Nonorganic Insomnia Related to Neurotic and Stress-Related Disorder

Recent investigations in our sleep outpatient clinic demonstrated that 30% of patients exhibited organic and 70% nonorganic sleep disorders, with 41% showing as an additional diagnosis neurotic, stress-related, and somatoform disorders, 31% affective disorders and 15% mental and behavioral disorders due to psychoactive substance use. Thus, the aim of the study was to investigate the acute effects of the imidazopyridine zolpidem on objective and subjective sleep and awakening quality in the largest of the above-mentioned groups. In this single-blind, placebo-controlled cross-over study, 15 patients (9 females and 6 males aged 51.1 + 11.3 years) diagnosed as having nonorganic insomnia (ICD–10: F 51.0) related to neurotic and stress-related disorders (F 1.1:12, F 41.2:2 and F 43.2:1) were included. Objective and subjective sleep and awakening quality measures were investigated in 3 subsequent nights in the sleep laboratory (adaptation, baseline/placebo and zolpidem 10 mg night), utilizing clinical, polysomnographic, psychometric and psychophysiological methods. The drug-free patients were matched according to age and sex with 15 normal healthy controls (age 51.2 + 11.8 years). Statistical analysis of polysomnographic variables demonstrated a significant lengthening of the total sleep period (TSP) and total sleep time (TST), an improvement in sleep efficiency and a shortening of sleep latencies after zolpidem as compared with placebo. These changes were opposite to the differences between patients and controls. Concerning sleep architecture, zolpidem increased the length of S4 and S3 + S4 as compared with placebo. Subjective sleep and awakening quality and the thymopsychic variables drive, mood, affectivity and wakefulness in the morning showed no significant changes, as a significant improvement had already occurred from the adaptation to the baseline/placebo night. Noopsychic variables (attention, concentration, attention variability, numerical memory, fine motor activity, reaction time measures) showed similar findings. Moreover, subjective sleep and awakening quality, thymopsychic and noopsychic measures during baseline/placebo recordings did not differ significantly from normative data (except for fine motor activity). Psychophysiological measures did not show any significant alterations either, except for a decrease in systolic blood pressure in the evening. Conclusion: As compared with placebo, zolpidem induced a significant improvement in objective sleep quality, mainly by increasing TSP, TST and sleep efficiency and shortening sleep latencies, thereby normalizing the disorder of initiating and maintaining sleep. Deep sleep stages S3 + S4 increased (although at baseline/placebo these stages did not differ from controls), while S1, S2 and SREM did not change significantly. Subjective sleep and awakening quality as well as thymopsychic and noopsychic performance in the morning mainly showed a placebo and ‘first- night effect’ phenomenon in these patients. Thus, the changes induced by zolpidem were somewhat different from those after classical benzodiazepines.