Double-blind, placebo-controlled, multiple-ascending-dose study on the pharmacodynamics of ABIO-08/01, a new CNS drug with potential anxiolytic activity. 1. EEG mapping, psychometric and tolerability findings.

In a double-blind, placebo-controlled, multiple-ascending-dose study, the encephalotropic and psychotropic properties of ABIO-08/01, a new potentially anxiolytic and nootropic isoxazoline, were studied in 16 young healthy males. In a randomized nonbalanced phase 1 study, they received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (washout period 8 days). EEG mapping and psychometry were carried out at hours 0, 1, 6 of day 1 (acute effect) and day 5 (subacute and superimposed effects). MANOVA/ Hotelling T(2) test demonstrated significant central effects of ABIO-08/01 versus placebo after acute, subacute and superimposed administration of all doses in the resting, vigilance-controlled and eyes-open EEG. Univariate analysis revealed activating patterns in the resting EEG (40 mg > 20 mg > 10 mg), and sedative patterns in the eyes-open EEG (10 mg > 20 mg > 40 mg). In the vigilance-controlled EEG, 40 mg of ABIO-08/01 induced activating patterns, whereas 10 mg induced sedative patterns. Concerning psychometry, ABIO-08/01 improved concentration (40 mg > 20 mg > 10 mg; activating effect) and deteriorated well-being (10 mg > 20 mg > 40 mg; sedative effect). Ten milligrams also improved reaction time performance and psychomotor activity. ABIO-08/01 is well-tolerated and is of interest in anxiety disorders.

Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy.

Low-resolution brain electromagnetic tomography (LORETA) showed a functional deterioration of the fronto-temporo-parietal network of the right hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil. The aim of this study was to determine the effects of modafinil on cognitive and thymopsychic variables in patients with narcolepsy and investigate whether neurophysiological vigilance changes correlate with cognitive and subjective vigilance alterations at the behavioral level. In a double-blind, placebo-controlled crossover design, EEG-LORETA and psychometric data were obtained during midmorning hours in 15 narcoleptics before and after 3 weeks of placebo or 400 mg modafinil. Cognitive investigations included the Pauli Test and complex reaction time. Thymopsychic/psychophysiological evaluation comprised drive, mood, affectivity, wakefulness, depression, anxiety, the Symptom Checklist 90 and critical flicker frequency. The Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) were performed too. Cognitive performance (Pauli Test) was significantly better after modafinil than after placebo. Concerning reaction time and thymopsychic variables, no significant differences were observed. Correlation analyses revealed that a decrease in prefrontal delta, theta and alpha-1 power correlated with an improvement in cognitive performance. Moreover, drowsiness was positively correlated with theta power in parietal and medial prefrontal regions and beta-1 and beta-2 power in occipital regions. A less significant correlation was observed between midmorning EEG LORETA and the MSLT; between EEG LORETA and the ESS, the correlation was even weaker. In conclusion, modafinil did not influence thymopsychic variables in narcolepsy, but it significantly improved cognitive performance, which may be related to medial prefrontal activity processes identified by LORETA.

Age-related cognitive decline in the menopause: effects of hormone replacement therapy on cognitive event-related potentials.

OBJECTIVE: Although epidemiological and clinical studies suggest that hormone replacement therapy (HRT) may protect against cognitive disorders and neurodegenerative diseases, the relation between estrogen and cognition in postmenopausal women remains controversial. METHODS: In a double-blind placebo-controlled, parallel group design study the effects of HRT with the estrogen-progestogen combination Presomen 1.25 compositum((R)) (1.25mg equine conjugated estrogens administered for 21 days plus the progestogen 5mg medrogeston given for 11 days) on event-related potentials (ERPs) in postmenopausal patients with age-related cognitive decline (DSM-IV code 780.9, ICD-10 code R 41.8) were investigated. After a pre-drug comparison with age-matched normal postmenopausal controls, 48 psychotropic drug-free patients aged 60 +/- 6 years were randomized to receive either placebo or verum for 4 months. ERPs were recorded before as well as on the 91-92 days of the study, which thus fell into the estrogen phase of the treatment during the fourth cycle. RESULTS: At baseline, patients showed a lengthening of P300 latency and an attenuation of P300 amplitudes as compared with normal controls. After HRT with Presomen, a significant shortening of P300 latency as compared with placebo was observed. CONCLUSIONS: The baseline P300 differences suggest that in the patient group the aging process was advanced, while after HRT with Presomen a significant improvement and normalization of information processing as indexed by P300 was observed.

Effects of hormone replacement therapy on perceptual and cognitive event-related potentials in menopausal insomnia.

The influence of a combined estrogen-progestin regimen (Climodien, Lafamme) on auditory event-related potentials (ERPs) was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3=estradiol valerate 2 mg+the progestin dienogest 3 mg, EV=estradiol valerate 2 mg, and placebo), followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg+dienogest 2 mg). Both the double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone odd-ball paradigm in 49 patients aged between 46 and 67 yr with the diagnosis of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1). Climodien reduced standard N1 and target P300 latencies as compared to placebo, while EV did not affect N1 latency but similarly reduced P300 latency. Climodien increased N1, P2 and P300 amplitudes dose-dependently, predominantly at frontal leads. Estrogen alone had only minor effects on ERP amplitudes. The shortening of standard N1 latency and enhancement of N1 and P2 amplitudes indicates a positive effect of Climodien on perceptual processing, most likely due to vigilance improvements also observed in EEG mapping. Concerning target P300, it seems that estradiol is responsible for the improvement in stimulus evaluation time, as reflected by the shortening of the peak latency, while dienogest seems to account for the improvement in cognitive information processing capacity, whereby 3 mg induced a more pronounced augmentation of P300 amplitudes than 2 mg. Based on the spatial distribution of this increase, it can be speculated that Climodien mainly affects the more frontally distributed P3a subcomponent, which is associated with attention and orientation. Furthermore, the observed changes in ERP-components are consistent with recent studies showing significant positive effects of hormone replacement therapy on cholinergic functions. Thus, Climodien seems to be of interest in preventing cognitive decline and treating cognitive disorders in postmenopausal women. Indeed, there is increasing evidence of beneficial effects of estrogen in dementia. Our present findings suggest that the estrogen effects may be augmented by dienogest.

Effect of rest on physicians' performance in an emergency department, objectified by electroencephalographic analyses and psychometric tests.

OBJECTIVE: The aim of the field study was to objectify physicians' vigilance, well-being, and cognitive performance in the course of 24-hr shifts with and without afternoon rest. SUBJECTS, SETTING, AND DESIGN: Eleven residents (four women, seven men; age, 33.5 +/- 4.7 yrs) were observed when doing two regular 24-hr shifts at the emergency department (randomized crossover design): one without rest, the other with a period of rest in the early afternoon (duration, 2:31 +/- 1:04 hrs) and the opportunity of having a nap (duration, 1:07 +/- 0:26 hrs, n = 6). Electroencephalography and psychometric tests were carried out at 8 am and at midnight. MEASUREMENTS: Measurements included subjective perception of workload, stress, and sleeping behavior; computer-analyzed electroencephalography; adjective checklist (Eigenschaftswörterliste 60 S, a self-rating scale); complex reaction time test; Pauli test (number of calculations during 3 mins); and numerical memory test. RESULTS: Electroencephalographic analyses showed a significant decrease in alpha power and a significant increase in beta power in the evening as compared with the morning on both days. The nocturnal increase observed in delta activity was significantly less pronounced in duties with rest than in duties without rest. Physicians felt deactivated at night. The Eigenschaftswörterliste 60 S indicated deactivation at night and a rest-induced activation in the subgroup that had taken the opportunity to sleep in the afternoon. Psychometric tests did not show any significant differences, neither between performance in the morning and evening nor between results with and without rest. CONCLUSION: As expected, electroencephalographic recordings showed nocturnal deactivation and a vigilance-promoting effect of the afternoon rest. These objective findings were in accordance with the results derived from self-rating scales. On the other hand, in short-lasting psychometric tests, performance was found unchanged after 16 hrs of routine work. In further studies, a discrimination between resting periods with and without sleep will be important.

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.

Nicergolina na demência senil do tipo Alzheimer e na demeência multi-infarto: um estudo clínico duplo-cego, controlado com placebo e de mapeamento do EEG/PRE / Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study

Num estudo duplo-cego controlado com placebo sobre a eficácia terapêutica e os efeitos centrais da nicergolina, um alcalóide do Ergot com açäo metabólica, antitrombótica e vasoativa, foram incluídos 112 pacientes com demência leve e moderada, diagnosticada de acordo com os critérios do DSM III-R (MMS 13-25), que viviam em lares para aposentados. Cinqüenta e seis deles foram subdiagnosticados como demência senil do tipo Alzheimer (DSTA), 56 como demência multi-infarto (DMI), com base em tomogafia computadorizada e em avaliaçöes de Hachinski (menor ou igual 49 DSTA, maior ou igual 7 DMI). Eles receberam, após um período de tratamento de duas semanas (placebo), randomizados por oitos semanas, 2 x 30 mg de nicergolina (NIC) ou 2 x 1 de placebo (PLAC) via oral...