[Consensus statement of the Austrian Sleep Medicine Society on the management of residual excessive daytime sleepiness in obstructive sleep apnea]. / Konsensus-Statement der Österreichischen Gesellschaft für Schlafmedizin (ÖGSM/ASRA) zum Management der residualen exzessiven Tagesschläfrigkeit (rETS) bei obstruktiver Schlafapnoe: Die SPAIN-Checkliste für den klinischen Alltag.

Background: Six to ten percent of patients with obstructive sleep apnea suffer from residual excessive daytime sleepiness (rEDS) despite adequate nocturnal positive airway pressure therapy or effective alternative treatment. The differential diagnosis of rEDS is an interdisciplinary challenge in clinical practice. Objectives: Development of a clear guideline for the detection, differential diagnostic considerations, and options for the continuing treatment of rEDS in clinical practice. Methods: MeSH analysis-based research and interdisciplinary consensus among specialists in internal medicine and pneumology, neurology, as well as psychiatry and psychotherapy. Results: The SPAIN checklist for systematic differential diagnostic exploration of rEDS with the parameters: S leep behavior, P sychological causes, A namesis of medication, I nternal causes and N eurological causes. Conclusions: rEDS should be recognized as a symptom worthy of treatment. It requires an interdisciplinary assessment and the individual adaptation of the treatment to the needs of the affected person.

Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis.

There is increasing evidence of a causal interaction between obstructive sleep apnea (OSA) and cerebrovascular disease. The aim of the study was to elucidate the relationship between the polysomnographically (PSG) measured severity of OSA and carotid atherosclerosis determined by ultrasonography and serum surrogate markers. 147 patients (102 males, 45 females) referred to our sleep laboratory for evaluation of snoring and sleep-disordered breathing were investigated. Carotid atherosclerosis was evaluated by serum analysis of high-sensitivity C-reactive protein (hs-CRP) and fibrinogen and four sonographic indices: intima-media thickness (IMT) of the common carotid artery (CCA), IMT from bulb to internal carotid artery (Bulb-ICA), combined IMT measurements from all segments and a plaque score (PlaS). Pearson correlation analysis, intergroup comparison (ANOVA), covariance analysis and a multiple regression were performed to assess the association between surrogate markers and respiratory variables. 44 patients had no OSA (apnea-hypopnea index AHI < 5/h), 27 mild (AHI 5-15), 25 moderate (AHI 15-30) and 51 severe OSA (AHI > 30). After adjusting for potential confounders, significant differences between the controls and all three OSA groups were observed in the CCA-IMT (p = 0.032) and in the PlaS between the controls and the severe group (p = 0.034). Multiple regression revealed the AHI as an independent predictor of CCA-IMT (p = 0.001) and combined IMT (p = 0.001), whereas the percentage of total sleep time with an oxygen saturation below 90 % was associated with Bulb-ICA IMT (p = 0.018) and hs-CRP (p = 0.015). OSA is associated with higher surrogate levels of cerebrovascular disease. Even mild OSA seems to predispose to early atherosclerosis.

Restless legs syndrome: a community-based study of prevalence, severity, and risk factors.

OBJECTIVE: To assess the prevalence and severity of restless legs syndrome (RLS) in the general community and to investigate its potential relationship with iron metabolism and other potential risk factors. METHODS: This was a cross-sectional study of a sex- and age-stratified random sample of the general population (50 to 89 years; n = 701). The diagnosis of RLS was established by face-to-face interviews; severity was graded on the RLS severity scale. Each subject underwent a thorough clinical examination and extensive laboratory testing. RESULTS: The prevalence of RLS was 10.6% (14.2% in women, 6.6% in men); 33.8% of all patients with RLS had mild, 44.6% had moderate, and 21.6% had severe disease expression. None had been previously diagnosed or was on dopaminergic therapy. Free serum iron, transferrin, and ferritin concentrations were similar in subjects with and without RLS. However, soluble transferrin receptor (sTR) concentrations were different in subjects with and without RLS (1.48 vs 1.34 mg/L; p < 0.001). Female sex and high sTR independently predicted the risk of RLS. CONCLUSION: This large survey confirms the high prevalence, female preponderance, and underrecognition of restless legs syndrome in the general community. Although two-thirds of patients had moderate to severe disease, none was on current dopaminergic therapy.

EEG-tomographic studies with LORETA on vigilance differences between narcolepsy patients and controls and subsequent double-blind, placebo-controlled studies with modafinil.

The aim of the present study was to identify brain regions associated with vigilance in untreated and modafinil-treated narcoleptic patients by means of low-resolution brain electromagnetic tomography (LORETA). 16 drug-free narcoleptics and 16 normal controls were included in the baseline investigation. Subsequently patients participated in a double-blind, placebo-controlled crossover study receiving a three-week fixed titration of modafinil (200, 300, 400 mg) and placebo. Measurements comprised LORETA, the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) obtained before and after three weeks' therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant inter-group differences in the resting (R-EEG), but not in the vigilance-controlled recordings (V-EEG). Subsequent univariate analysis revealed a decrease in alpha-2 and beta 1-3 power in prefrontal, temporal and parietal cortices, with the right hemisphere slightly more involved in this vigilance decrement. Modafinil 400 mg/d as compared with placebo induced changes opposite to the aforementioned baseline differences (key-lock principle) with a preponderance in the left hemisphere. This increase in vigilance resulted in an improvement in the MSLT and the ESS. LORETA provided evidence of a functional deterioration of the fronto-temporo-parietal network of the right-hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil on the left hemisphere, which is less affected by the disease.

Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome.

In a double-blind, placebo-controlled randomized crossover trial, the acute efficacy of a combination treatment of 100 mg regular-release (rr) and 100 mg sustained-release (sr) L-dopa/benserazide in RLS was investigated by means of sleep laboratory methods, with a subsequent open clinical follow-up for 4 weeks. 21 RLS patients classified according to ICSD and IRLSSG criteria were included; 18 completed the study. Objective sleep quality was determined by polysomnography (PSG) in 3 subsequent nights (adaptation/screening, placebo and drug night), subjective sleep and awakening quality was evaluated by rating scales, objective awakening quality by psychometric tests. Clinical follow-up consisted of daily ratings of subjective sleep and awakening quality (SSA) and VAS for RLS symptomatology ratings, completion of the RLS (IRLSSG) Scale weekly and the Zung Depression (SDS) and Anxiety (SAS) Scale, Quality of Life Index, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale before and after therapy. Acute L-dopa/benserazide significantly (p < 0.001) and markedly (75%) decreased the target variable PLM/h of sleep as well as all other RLS/PLM variables, but failed to improve objective sleep efficiency and subjective sleep quality in comparison to placebo. After 4 weeks of therapy, however, subjective sleep and awakening quality also improved significantly. While RLS/PLM measures showed an immediate significant and marked response to the combination therapy subjective sleep quality only improved after chronic treatment.

Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial.

OBJECTIVES: To assess the therapeutic efficacy of modafinil in the treatment of increased daytime sleepiness in patients with Parkinson's disease (PD). DESIGN: Double-blind, randomized, placebo-controlled crossover study with two 2-week treatment blocks, separated by a 2-week washout phase. SETTING: Tertiary Parkinson's disease care center and sleep laboratory at university hospital neurology department. PATIENTS: Fifteen patients with idiopathic PD and daytime sleepiness (Epworth sleepiness score (ESS) 10 or more). INTERVENTIONS: Administration of placebo or modafinil as a single morning dose in a randomized crossover order. The modafinil dose was 100 mg in the first, and 200 mg in the second treatment week. MEASUREMENTS AND RESULTS: At baseline and at the end of each treatment block, sleepiness was evaluated using subjective (perceived sleepiness with the ESS) and objective measures (maintenance of wakefulness test). Twelve patients completed the study (9 male, 3 female; mean age 65.0 +/- 7.6 years, mean disease duration 6.8 +/- 4.1 years). Epworth scores were significantly improved with modafinil (3.42 +/- 3.90) compared to placebo (0.83 +/- 1.99; p = 0.011). Latency to sleep in the maintenance of wakefulness test was not significantly altered by modafinil treatment: 10.9 (3-40)/15.1 (2.5-40) minutes before/after placebo and 12 (2.6-40)/17.8 (4.2-40) minutes before/after modafinil (p = 0.139) [data given as mean +/- standard deviation or median (range)]. CONCLUSIONS: The results of this study suggest that modafinil improves daytime sleepiness in PD patients, at least on a subjective or behavioral level. Modafinil treatment may be considered for EDS in PD patients, in whom otherwise treatable causes of Excessive Daytime Sleepiness (EDS) are absent.

Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome.

In a single-blind, placebo-controlled crossover trial, the acute efficacy of the dopamine agonist pramipexole was investigated in 11 restless legs syndrome (RLS) patients by sleep laboratory methods, with a clinical follow-up for 4 weeks. In 3 nights (pre-treatment, placebo and drug night), objective sleep quality was determined by polysomnography (PSG), subjective sleep and awakening quality by rating scales, objective awakening quality by psychometry. Clinical follow-up consisted of completion of the International RLS Study Group (IRLSSG) Scale, Zung Depression (SDS) and Anxiety (SAS) Scale, Quality of Life Index, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale. Concerning acute effects, an omnibus significance test for PSG variables demonstrated a global difference between placebo and pramipexole, but none between pre-treatment and placebo. Pramipexole 0.27 mg significantly decreased the target variable periodic leg movements (PLM)/h of sleep as well as all other RLS/PLM variables and improved objective sleep efficiency and subjective sleep quality as compared with placebo. In sleep architecture, sleep stages S1 and S2 and stage shifts increased, while slow-wave sleep and SREM decreased. After 4 weeks of therapy, the total scores of the IRLSSG questionnaire, sleep quality and daytime sleepiness, depression and quality of life also improved. Thus, acute pramipexole markedly reduced PLM measures and slightly improved objective and subjective sleep quality. Follow-up ratings showed a moderate improvement of RLS and sleep quality, and to a lesser extent of daytime sleepiness, depression and quality of life. The psychopathological findings as well as acute sleep architecture changes are reminiscent of those seen after activating antidepressants.

EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls.

OBJECTIVES: Investigation of daytime brain function, psychopathology, and objective and subjective sleep and awakening quality in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). METHODS: Thirty-three RLS and 26 PLMD patients free of psychotropic drugs were studied as compared with age- and sex-matched normal controls, utilizing electroencephalographic (EEG) mapping and clinical evaluations by the Zung Self-Rating Depression (SDS) and Anxiety Scale (SAS), the Quality of Life Index, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale. In a subsample of 12 RLS patients, 12 PLMD patients, and 12 controls, objective and subjective sleep and awakening quality were evaluated in two sleep laboratory nights (adaptation and baseline night). RESULTS: Scores of the PSQI, SDS, and SAS were found increased in both patient groups; RLS patients showed reduced quality of life, while in the PLMD group daytime sleepiness was increased. EEG mapping demonstrated findings characteristic of major depression in RLS patients and of generalized anxiety disorder in PLMD patients. Polysomnography showed a significant deterioration of sleep efficiency only for RLS patients, while nocturnal awakenings were increased in both patient groups. Concerning sleep architecture, both groups exhibited increased S1 and stage shifts and decreased S2, while only PLMD patients showed an increase in S4. The PLM/(h TST), the PLM/(h wake) and the PLMS-arousal index were significantly increased in both patient groups as compared with controls. Subjective sleep and awakening quality and thymopsychic measures were deteriorated in RLS. Morning mental performance and fine motor activity were deteriorated in both groups, reaction time only in RLS, numerical memory and attention variability only in PLMD. CONCLUSION: EEG mapping revealed neurophysiological correlates of depression and anxiety in RLS and PLMD, respectively, which were confirmed by self-ratings of symptoms.

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.

Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as compared with normals and acute effects of ropinirole.

Periodic limb movement disorder (PLMD) occurs in a variety of sleep disorders and can cause insomnia as well as hypersomnia with daytime somnolence. The aim of this study was to investigate 12 untreated PLMD patients as compared with 12 normal controls and to measure the acute effects of 0.5 mg ropinirole (Requip((R))) - a non-ergoline dopamine agonist - as compared with placebo. In three nights (adaptation, placebo, ropinirole night) objective and subjective sleep and awakening quality were evaluated. In the target variable 'periodic leg movements per hour of sleep' (PLM/(hTST)) PLMD patients showed an increased value of 42/h (normal 0-5/h) with a greater number of arousals due to periodic leg movements (PLM) in sleep. They further demonstrated an increased number of awakenings, sleep stage S1, S4, stage shifts and decreased S2, but there were no significant differences concerning total sleep time, sleep efficiency (SE), subjective sleep quality and morning measures of mood, drive and drowsiness. However, measures of attention variability, numerical memory, fine motor activity and reaction time performance were impaired. Ropinirole 0.5 mg was shown to significantly improve the index PLM/(hTST) by 64% and arousals due to PLM, increase spontaneous arousals, REM-latency, stage 2 and stage shifts and decrease SREM. In the morning attention variability was attenuated and numerical memory augmented. Thus, ropinirole improved some sleep architecture and early morning measures of performance but specifically all PLM variables, which suggests a dopaminergic pathogenesis in PLMD. Copyright 2001 John Wiley & Sons, Ltd.

Theophylline in snoring and sleep-related breathing disorders: sleep laboratory investigations on subjective and objective sleep and awakening quality.

The aim of the present investigation was to comparatively examine the effect of theophylline on various sleep-related breathing disorders of different severity. In a single-blind, placebo-controlled crossover study, 30 patients were polysomnographically diagnosed as suffering from primary snoring (n = 7), obstructive snoring (n = 12) or moderate sleep apnea (n = 11). Subsequent polysomnographic investigations included one baseline, one placebo and one theophylline (Respicur retard 400 mg, Byk Gulden, Konstanz, Germany) night. Subjective sleep and awakening quality was evaluated by means of a test battery completed in the morning. Concerning respiratory variables, theophylline was most effective in patients with moderate sleep apnea. Obstructive snorers only showed a tendency towards improvement and primary snorers remained unchanged. Sleep architecture generally remained unchanged in all three patient groups. Objective awakening quality was partly improved in primary snorers, obstructive snorers, as well as in moderate sleep apnea patients as compared with baseline, but not as compared with placebo. Regarding subjective sleep and awakening quality, only primary snorers and obstructive snorers showed an improvement, as compared with baseline while moderate sleep apnea patients remained unchanged. Based on intergroup comparison, we conclude that patients with moderate sleep apnea showed the most pronounced improvement in regard to respiratory events. Concerning sleep initiation and maintenance, sleep architecture and subjective sleep and awakening quality, no significant intergroup differences were found. Regarding objective awakening quality, attention showed a significantly greater improvement in primary than in obstructive snorers and sleep apnea patients, while motor performance was most improved in obstructive snorers.

Sleep laboratory studies in restless legs syndrome patients as compared with normals and acute effects of ropinirole. 1. Findings on objective and subjective sleep and awakening quality.

Although the restless legs syndrome (RLS) is a disorder with a relatively high prevalence rate (8% in Austria) and leads to insomnia and excessive daytime tiredness, there is a paucity of sleep laboratory data concerning objective and subjective sleep and awakening quality. Thus, the aim of this study was to investigate 12 untreated RLS patients as compared with 12 normal controls and subsequently measure the acute effects of 0.5 mg ropinirole (Requip((R))) - a nonergoline dopamine agonist - as compared with placebo. In 3 nights (adaptation, placebo, ropinirole night) sleep induction, maintenance and architecture were measured objectively by polysomnography, subjective sleep and awakening quality were assessed by self-rating scales and visual-analog scales, and objective awakening quality was evaluated by a psychometric test battery. In polysomnography, RLS patients demonstrated, as compared with normal controls, a decreased total sleep time (TST) and sleep efficacy, increased wakefulness during the total sleep period and frequency of nocturnal awakenings, increased sleep stage S1, decreased S2 and increased stage shifts. Subjective sleep quality tended to decrease, and morning well-being, mood, affectivity and wakefulness were deteriorated. In the noopsyche, fine motor activity and reaction time performance were deteriorated. Ropinirole 0.5 mg induced, as compared with placebo, an increase in TST, sleep efficacy, S2 sleep and stage shifts. In the morning, somatic complaints increased slightly, while fine motor activity and reaction time performance improved. Our findings suggest a key-lock principle in the diagnosis/treatment of RLS and a dopaminergic mechanism in its pathogenesis, which is supported by the data on periodic leg movements during sleep and arousals of the subsequent paper.

Sleep laboratory studies in restless legs syndrome patients as compared with normals and acute effects of ropinirole. 2. Findings on periodic leg movements, arousals and respiratory variables.

The restless legs syndrome (RLS) is a common sensorimotor disorder which leads to severe sleep disturbances and showed a prevalence of 7.9% in our sleep laboratory. The aim of this study was to investigate periodic leg movements (PLM), arousal and respiratory variables in 12 untreated RLS patients and to measure the acute effects of 0.5 mg ropinirole, a nonergoline dopamine agonist, as compared with placebo. In the target variable PLM/h of total sleep time (PLM/h TST), RLS patients showed an increased value of 40/h (normal 0-5/h). Further, we found an increased number of PLM (368), PLM/h of time in bed (49/h), PLM/h of REM sleep (11), PLM/h of non-REM sleep (46) and PLM/h awake (61). The arousal index was also increased (32/h; normal 0-25/h), as were arousals due to PLM. In the confirmatory part of our descriptive data analysis, ropinirole 0.5 mg significantly improved, as compared with placebo, the index PLM/h TST by 75%. In the descriptive part, all the other PLM variables were improved as well. Arousals due to PLM decreased, while spontaneous arousals increased. Respiratory variables, which had a priori been in the normal range, showed a slight but significant improvement after the dopamine agonist. Thus, 0.5 mg ropinirole significantly improved the target variable PLM/h TST, along with objective and subjective sleep quality and morning noopsychic performance, as described in the preceding paper. Our data encourage further sleep studies including all above-mentioned variables in a larger group of RLS/PLM during sleep patients as well as long-term efficacy trials.

[Daytime tiredness correlated with nocturnal respiratory and arousal variables in patients with sleep apnea: polysomnographic and EEG mapping studies]. / Tagesmüdigkeit korreliert mit nächtlichen Atmungs- und Arousal-Variablen bei Schlafapnoepatienten: Polysomnographische und EEG-Mapping-Untersuchungen.

There is evidence that daytime tiredness is caused by apnea/hypopnea with oxygen desaturation and/or by sleep fragmentation due to arousals. The aim of this study was to investigate objective and subjective sleep and awakening quality and daytime vigilance--objectified by midmorning mapping of vigilance-controlled EEG (V-EEG)--in sleep apnea patients (N: 18), as compared with age- and sex-matched normal controls (N: 18) as well as to correlate nocturnal respiratory distress and arousals to daytime brain function. Statistical analyses demonstrated a deterioration in subjective and objective sleep and awakening quality in apnea patients. Midmorning V-EEG mapping in apnea patients exhibited less total power, more delta and theta, less alpha and beta activity, as well as a slower dominant frequency and centroid of the total activity compared to controls, which suggests a vigilance decrement. The Spearman rank correlation between 6 polysomnographically registered respiratory variables and 36 diurnal quantitative EEG measures demonstrated the following: the higher the apnea, apnea-hypopnea, snoring and desaturation indices and the lower the minimum and average low oxygen saturation, the more pronounced was diurnal tiredness. Eleven arousal measures based on ASDA criteria showed the following significant correlations: the higher the nocturnal arousal index and the more arousals due to hypopneas, the greater was daytime tiredness. On the other hand, the greater the average frequency change during arousals and the more spontaneous arousals, the better was daytime vigilance. Our findings show that, in contrast to the lengthy Multiple Sleep Latency (MSLT) and Maintenance of Wakefulness (MWT) tests which evaluate sleep pressure under resting conditions conducive to sleep, V-EEG mapping provides a brief objective measure of a sleep apnea patient's daytime tiredness under conditions of wakefulness more appropriate to reflect the patient's everyday life.

Efficiency of continuous positive airway pressure versus theophylline therapy in sleep apnea: comparative sleep laboratory studies on objective and subjective sleep and awakening quality.

Sleep apnea is the most common sleep-related breathing disorder characterized by repetitive episodes of hypoxemia. Therapies include behavioral, surgical, orthodontic, pneumological, and pharmacological interventions. The aim of the present study was to compare the efficiency of pneumological therapy by nasal continuous positive airway pressure (CPAP) versus a pharmacological approach with theophylline (Respicur retard(R) 400 mg) on respiratory variables as well as objective and subjective sleep and awakening quality in patients with moderate sleep apnea measured by polysomnography and psychometry. Under CPAP therapy all respiratory variables improved and normalized, while under theophylline only the apnea-hypopnea index and the desaturation index improved but still did not return to normal values. Regarding sleep initiation and maintenance, CPAP therapy prolonged sleep latency and reduced movement time, while patients treated with theophylline showed reduced total sleep period, total sleep time and sleep efficiency. Sleep architecture demonstrated an increase in deep sleep and REM stages under CPAP therapy, and remained unchanged under theophylline. Concerning subjective sleep and awakening quality, both treatments improved well-being in the morning. Regarding objective awakening quality, reaction time performance was improved in both groups. In conclusion, CPAP treatment is more effective than theophylline regarding respiratory variables as well as the normalization of sleep maintenance and sleep architecture in sleep apnea patients.

Alcohol dependence: is carbohydrate-deficient transferrin a marker for alcohol intake?

We investigated %CDT (carbohydrate-deficient transferrin) in 92 ethanol-intoxicated alcohol-dependent patients after consecutive admission to hospital and followed the for 28 days under controlled conditions. At admission, 63% (58 patients) showed elevated CDT (> 2.5%) and 34 patients (37%) had normal CDT levels (< 2.5%). No correlation of the %CDT values to alcohol-related disabilities, severity of the withdrawal syndrome, alcohol-drinking pattern before admission, or several other factors was found. The sensitivity of GGT (gamma-glutamyl transferase) was 58% for the same group of patients. Levels of %CDT decreased during the 28 days following abstinence, whereby we could separate four statistically different groups of "CDT decrease'. In two of these groups, comprising most of the cases studied, normal %CDT levels were reached after 14 days of abstinence. Those patients with %CDT levels exceeding the upper normal level after 14 days of sobriety, showed a decrease during the following 14 days to levels of 2.55-2.61%.

Treatment of the alcoholic organic brain syndrome: double-blind, placebo-controlled clinical, psychometric and electroencephalographic mapping studies with modafinil.

In a double-blind study 40 abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS; ICD 9: 291.2) were treated for 6 weeks with either placebo or 200 mg modafinil b.i.d. Modafinil (CRL 40476) is a vigilance-promoting, putative central alpha 1-adrenergic agonist with a pharmacological profile quite different from that of amphetamine. Clinical investigations demonstrated that the spontaneous remission of the alcoholic OBS was augmented and accelerated by modafinil, which was found significant as compared with placebo by confirmatory statistics in the target variable, the Clinical Global Impression scale. The drug was well tolerated. Psychometric tests revealed significant improvement of the noopsyche after modafinil as compared with placebo, while the thymopsyche and psychophysiological measurements were not affected. Electroencephalographic mapping showed significant differences between the central effects of modafinil and placebo indicating an improvement of vigilance under modafinil. Typical vigilance-promoting properties were seen after acute drug administration, were less evident before the morning dose after chronic treatment but re-occurred after super-imposed daily drug administration. Thus, our clinical, psychometric and neurophysiological investigations in alcoholic OBS patients demonstrated a therapeutic effect of modafinil in the early phase of abstinence.

Efficacy and safety of moclobemide compared with imipramine in the treatment of major depressive disorder. Double-blind multicenter study, Austria.

In a double-blind, 4-week, prospective, randomized multicenter (17 centers) study we checked on the efficacy, tolerability and safety of moclobemide (300-600 mg/d) compared to imipramine (100-200 mg/d) in parallel groups of patients with a Major Depressive Episode (DSM III). The mean % reduction of the HAMD at the end of treatment was 51.7 in the moclobemide group and 52.1 in the imipramine group. The percentage of patients in whom efficacy was globally judged as "good" or "very good" was 62% in the moclobemide group and 60% in the imipramine group. There was no statistically significant difference in the efficacy in both groups but in some factors there was a trend for a better amelioration favoring moclobemide. The final overall physician's judgement of tolerability was "good" or "very good" in 83% of moclobemide patients and in 74% of imipramine patients. Adverse events were reported or observed in 56% of moclobemide patients and in 69% of imipramine patients. The number of mild, moderate and severe adverse events was higher in the imipramine group with a total of 286 versus 189. There was a statistically high significant difference considering the tolerability favoring moclobemide again. In this project the basic goal to find a substance with at least the same efficacy but a much better tolerability for sure got fulfilled.

On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: double-blind, placebo-controlled clinical, psychometric and neurophysiological studies.

1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.

Spontaneous and drug-induced remission of alcoholic organic brain syndrome: clinical, psychometric, and neurophysiological studies.

The spontaneous and drug-induced remission of alcoholic organic brain syndrome was studied in a double-blind, placebo-controlled trial. Forty patients with alcoholic organic brain syndrome (OBS) were randomly assigned to a 6-week treatment with either placebo or piridoxilate, a reciprocal salt between two stereoisomers of the glyoxylic acid-substituted piridoxine. Clinical, psychometric, and computer-assisted spectral analyses of the electroencephalogram (EEG) were carried out in weeks 0, 2, 4, and 6. Piridoxale-5-phosphate (PLP) blood level determination and laboratory investigations were performed before therapy and also in weeks 4 and 6. Both groups of patients demonstrated significant clinical improvement over 6 weeks of treatment, but the improvement in the piridoxilate-treated group was significantly greater than that in the placebo group. This conclusion was also confirmed by psychometric tests demonstrating a greater improvement in attention, concentration, attention variability, tapping, visual and numerical memory, and aftereffect (Archimedean spiral) in the piridoxilate than in the placebo group. Spectral analysis of the EEG showed an increase in alpha and a decrease in fast beta activities in both groups, while delta activity was attenuated only in the piridoxilate-treated group. The latter was found to be significantly correlated with the improvement in psychopathology. The present data confirm previous predictions about the encephalotropic and psychotropic properties of piridoxilate; these predictions were based on pharmaco-EEG trials in the elderly that suggested vigilance-improving qualities of piridoxilate. The reversible alcoholic OBS appears to be a suitable model for the assessment of therapeutic efficacy of nootropic drugs.