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Earlier investigations suggested an involvement of the right hemisphere and the left prefrontal cortex (PFC) in the pathogenesis of depression. This paper presents our own electroencephalographic (EEG) topography and low-resolution brain electromagnetic tomography (LORETA) data obtained in unmedicated depressed patients, and the effects of two representative drugs of non-sedative and sedative antidepressants, i.e., citalopram (CIT) and imipramine (IMI), as compared with placebo in normal subjects.Sixty female menopausal syndrome patients with the diagnosis of a depressive episode without psychotic symptoms as well as 30 healthy controls were investigated. Concerning the effects of antidepressants, normal healthy subjects received single oral doses of 20 mg CIT, 75 mg IMI and placebo p.o. A 3-min vigilance-controlled EEG and a 4-min resting EEG was recorded pre- and post-drug administration and analyzed by means of EEG mapping and LORETA.In the EEG mapping, depressed patients demonstrated a decrease in absolute power in all frequency bands, an augmentation of relative delta/theta and beta and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an acceleration of the alpha and beta centroid, which suggests vigilance decrements. In the alpha asymmetry index, they showed right frontal hyper- and left frontal hypoactivation correlated with the Hamilton Depression Score (HAMD). LORETA predominantly revealed decreased power in the theta and alpha-1 frequency band. Negative correlations between theta power and the HAMD were observed in the ventro-medial PFC, the bilateral rostral anterior cingulate cortex (ACC) and the left insular cortex; between alpha-1 power and the HAMD in the right PFC. In the EEG mapping of antidepressants, 20 mg CIT showed mainly activating, 75 mg IMI partly sedative properties. LORETA revealed that CIT increased alpha-2, beta-1, beta-2 and beta-3 power more over the right than over the left hemisphere. However, also a left temporal and frontal delta increase was observed.In conclusion, EEG topography and tomography of depressed menopausal patients demonstrated a right frontal hyper- and left frontal hypoactivation in the alpha asymmetry index as well as a vigilance decrease, with a right-hemispheric preponderance. Within antidepressants at least 2 subtypes may be distinguished from the electrophysiological point of view, a non-sedative and a sedative. LORETA identifies cerebral generators responsible for the pathogenesis of depression as well as for the mode of action of antidepressants.

Neuroimaging of sleep by means of low-resolution brain electromagnetic tomography (LORETA) can localize generators of electrical activity in the brain with high temporal resolution based on non-invasive multichannel EEG recordings. In 10 normal healthy subjects aged 20-35 years, delta waves in S4 as well as sleep spindles in S2 were marked visually. For these epochs, the spectral power density was calculated and LORETA was applied. For frequencies below 1 Hz (slow cortical oscillations), LORETA activity was maximal in posterior regions in the precuneus. In the delta frequency range of 1.6-4 Hz, LORETA activity was maximal in the medial prefrontal cortex and spread into the anterior cingulate and orbitofrontal cortex. For sleep spindles, LORETA revealed distributed sources in the prefrontal cortex, oscillating with a frequency below 13 Hz, and in the precuneus, oscillating with a frequency above 13 Hz. The observed LORETA sources are in accordance with recent results of local, use-dependent aspects of sleep. The enhanced delta activity in prefrontal regions is in line with hypotheses concerning the functional significance of slow-wave sleep. Moreover, the localized cortical brain regions have principal connections to adjacent parts of the dorsal thalamus where thalamic delta and spindle oscillations are generated.

The effects of S -adenosyl- l -methionine (SAMe)--a naturally occurring molecule with antidepressant properties--on event-related potentials (ERPs) were investigated in normal healthy volunteers (10 young subjects aged 22-33 years and 10 elderly subjects aged 56-71 years). In random order, they received infusions of 800 mg SAMe in 250 ml of isotonic solution, and placebo, administered over 30 min for 7 days, with a wash-out period of 3 weeks in between. ERP recordings were carried out before and 1 h after drug administration on days one and seven in a two-tone odd-ball paradigm. Independent of the subjects' age, standard N1 latency was shortened after SAMe as compared to placebo and target P300 latency was lengthened. As revealed by means of low-resolution brain electromagnetic tomography (LORETA), there was an increase in N2 source strength in the temporal gyri and in P300 source strength prefrontally, left more than right. These ERP findings suggest both excitatory and inhibitory drug effects on perceptual and central information processing resources, which is typical for imipramine-type antidepressants and in accordance with our pharmaco-EEG results. Moreover, LORETA demonstrated drug-induced source strength increases in the (left) prefrontal cortex, a brain region in which PET studies revealed reduced blood flow and metabolism in depressed patients.

Clinically well-defined diagnostic subgroups of mental disorders show EEG maps that statistically differ both from each other and from normal controls. Representative drugs of the main psychopharmacological classes induce--as compared with placebo--significant and typical changes in normal human brain function, which are opposite to the above-mentioned differences between psychiatric patients and normal controls. Thus, from the electrophysiological point of view, a key-lock principle may be seen in the diagnosis and treatment of mental disorders. This is supported by low-resolution brain electromagnetic tomography (LORETA), which identifies brain regions affected by psychiatric disorders and psychopharmacotherapeutic drugs.

Analyses of scalp-recorded sleep spindles have demonstrated topographically distinct slow and fast spindle waves. In the present paper, the electrical activity in the brain corresponding to different types of sleep spindles was estimated by means of low-resolution electromagnetic tomography. In its new implementation, this method is based on realistic head geometry and solution space is restricted to the cortical gray matter and hippocampus. In multichannel all-night electroencephalographic recordings, 10–20 artifact-free 1.25-s epochs with frontally, parietally and approximately equally distributed spindles were marked visually in 10 normal healthy subjects aged 20–35years. As a control condition, artifact-free non-spindle epochs 1–3s before or after the corresponding spindle episodes were marked. Low-resolution electromagnetic tomography demonstrated, independent of the scalp distribution, a distributed spindle source in the prefrontal cortex (Brodmann areas 9 and 10), oscillating with a frequency below 13Hz, and in the precuneus (Brodmann area 7), oscillating with a frequency above 13Hz. In extremely rare cases only the prefrontal or the parietal source was active. Brodmann areas 9 and 10 have principal connections to the dorsomedial thalamic nucleus; Brodmann area 7 is connected to the lateroposterior, laterodorsal and rostral intralaminar centrolateral thalamic nuclei. Thus, the localized cortical brain regions are directly connected with adjacent parts of the dorsal thalamus, where sleep spindles are generated.

Zusammenfassung: Vorliegende Studie basiert auf einer repräsentativen Untersuchung an 1000 Österreichern, die zu ihrem Schlafverhalten befragt wurden. Nächtliches Zähneknirschen gaben 4% an, es gab keine Geschlechtsunterschiede, jüngere Personen waren häufiger betroffen als ältere. Bruxismus zeigte keinen Zusammenhang mit psychopathologischen Symptomen, wie Ängstlichkeit oder Depressivität. Nur insgesamt 4 Personen berichteten, an Schlafwandeln zu leiden, dabei waren Männer häufiger betroffen. Sprechen im Schlaf wurde von 8% angegeben und 4% gaben an, unter Alpträumen zu leiden, bei beiden Schlafstörungen zeigten sich keine Geschlechts-oder Altersunterschiede. Beinunruhe beim Einschlafen wurde von 8% berichtet, ältere Personen und unregelmäßige Schnarcher zeigten sich häufiger betroffen

Summary In a double-blind, placebo-controlled study, the encephalotropic and psychotropic effects of tianeptine (TIA) — a new tricyclic antidepressant, enhancing serotonin reuptake — were investigated as compared with the serotonin reuptake inhibiting antidepressant, fluvoxamine (FLU), utilizing EEG mapping, psychometric and psychophysiological measures. 16 healthy volunteers (8 males, 8 females) aged 21–35 (man 27) years received randomized and at weekly intervals single oral doses of placebo, 12.5 and 25 mg TIA and 50mg FLU. EEG recordings, psychometric and psychophysiological tests and evaluation of pulse, blood pressure and side effects were carried out at 0,2,4,6 and 8 hours; blood sampling, in addition, at hour 1.

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.

Melatonin (MLT), a pineal hormone, has some sedative and hypnotic properties. To explore this effect further 20 young, healthy volunteers exposed to artificial insomnia participated in a double-blind, placebo controlled, parallel group design study. They slept in a sleep laboratory for several consecutive nights and were polygraphically monitored and subjected to a battery of psychometric tests and standardized self-report questionnaires each morning. One night all subjects received only placebo (21:00 hours) and on a second night half of them were subjected to placebo and half to MLT. On the later night blood MLT levels were measured. Polygraphic recordings revealed that MLT at bedtime decreased the time the subjects were awake before sleep onset (P<0.025), sleep latency (P<0.05), and the number of awakenings during the total sleep period (P<0.025), and increased sleep efficiency (P<0.05). In addition, it decreased sleep stage 1 (P<0.05) and increased sleep stage 2 (P<0.025). On the morning following the treatment most objective and subjective measures for awakening quality showed a trend towards improvement after MLT. One hour after its oral administration, serum MLT rose to a high pharmacological level (25817 pg/ml; median), but individual peak serum MLT levels varied by a factor of 300. From the data collected it is concluded that a single pharmacological dose of MLT exerts a hypnotic effect by accelerating sleep initiation, improving sleep maintenance and altering sleep architecture in a similar manner to anxiolytic sedatives; objective and subjective measures for awakening qualitiy indicate good tolerance of one dose of MLT without hangover problems on the following morning. Oral administration of crystalline MLT, however, results in high interindividual differences in absorption.

First-night effects (FNE) were comparatively investigated in patients with disorders in initiating and maintaining sleep (DIMS) associated with generalized anxiety disorder (GAD) in laboratory (n = 22) and home sleep polysomnography (n = 21). Patients had to be drug-free for at least 2 weeks prior to the first recording. Evaluation measures included 1) objective data on sleep initiation and maintenance; 2) sleep architecture based on polysomnographic recordings, analyzed visually according to the criteria of Rechtschaffen and Kales; 3) subjectively estimated sleep and awakening quality, assessed by a self-rating scale and visual analogue scales; 4) objective awakening quality as measured by a psychometric test battery; and 5) psychophysiological data, including critical flicker frequency, muscle strength, pulse, and blood pressure. Statistical analysis using multivariate analysis of variance (MANOVA) demonstrated multiple FNE in both groups regarding sleep efficiency, total sleep time, percentage of time in stage 2 sleep, percentage of time in stage 3/4 sleep, minutes of rapid eye movement (REM) sleep, and REM sleep latency. There was a group-by-night effect in the number of awakenings. There were no significant FNE regarding subjective sleep and awakening quality in either group. Differential adaptation effects were observed in attention and fine motor activity, with improvement in laboratory-recorded patients and deterioration in home-recorded patients. Differential findings also occurred in regard to evening blood pressure, with laboratory-recorded patients showing more adaptation.

Based on a double blind cross-over study, it was determined that schizophrenic patients who have more high frequency fast activity and a lesser degree of alpha and slow waves in computerized EEG before the treatment have a better therapeutic outcome to the major tranquilizer (neuroleptic) treatment. The correlation between pretreatment high frequency computer EEG measurements and better therapeutic outcome reached the level of statistical significance. “Therapy resistant” schizophrenic patients were characterized by a lesser degree of very fast beta activity, more alpha waves and slow waves, higher amplitudes in computer EEG, and a lesser degree of acute (florid) psychotic symptomatology but more “negative” symptoms such as motor retardation and blunted affect. One of the most striking results of the study is the finding that schizophrenic patients with certain psychopathological profiles also have similar computer EEG profiles.

In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic properties of a standard solution of diazepam (DZ) (ValiumR) were compared with those of a novel diazepam mixed-micelles solution (DZ MM) (Valium MMR) both after i.v. and i.m. application utilizing radioreceptor assay, quantitative pharmaco-EEG and brain mapping techniques as well as psychometric and psychophysiological methods. The local tolerance was studied as well. The subjects received randomized and, in weekly intervals, following injections (1) 10 mg DZ i.v. placebo i.m.; (2) 10 mg DZ MM i.v. placebo i.m.; (3) placebo i.v. 10 mg DZ i.m.; (4) placebo i.v. 10 mg DZ MM i.m.; (5) placebo i.v. placebo i.m. Blood sampling, EEG-recordings, psychometric and psychophysiological tests as well as tolerance evaluations were carried out at 0, ½ 1, 2, 4, 6 and 8 h. Blood level evaluation demonstrated after i.m. application a significantly shortened tmax, a higher Cmax and generally higher plasma concentrations in the first and second hour following the mixed-micelles solution than the standard formulation, which suggests better absorption of the former than the latter in the muscle. Subsequent to i.v. administration, lower blood levels were observed between 30 min and 2 h after DZ MM than DZ. Power spectral density analysis of the EEG resulted in typical anxiolytic-sedative pharmaco-EEG profiles after all 4 active substances as compared with placebo. However, there were significant inter-drug differences as far as topographic aspects (pharmaco-EEG maps) were concerned. DZ MM i.v. induced significantly more initial but also late delta augmentation, alpha attenuation and centroid slowing than DZ i.v. which suggests more sedative effects at those times. Following i.m. application, a significantly more pronounced deltaltheta attenuation, beta augmentation and centroid acceleration after DZ MM than DZ suggested more anxiolytic effects of the novcl than the standard formulation. Discriminant analysis of changes in 6 thymopsychic, 12 noopsychic and 17 psychophysiological variables demonstrated the best discrimination of the 4 substances based on thymopsychic effects. Considering the latter, all 4 active compounds differed significantly from placebo, with no inter-drug differences after i.v. application but a marked superiority of the novel mixed-micelles solution over the standard solution after i.m. application. Specifically, DZ MM i.m. induced more desactivation and affect-attenuation than DZ i.m. Moreover, there was a greater decrease in skin conductance (SCL) fluctuations, less decrease in amplitude changes of the pupillary response and less decrease in systolic blood pressure than after DZ i.m. After intravenous application, DZ MM induced less initial attention deficits, but greater decreases in attention variability and performance in mnestic, psychomotor and complex reaction tasks. Moreover, it decreased more SCL-fluctuations, speed and amplitude changes in pupillary response, increased more pulse rate but decreased less systolic blood pressure than the standard formulation. Anterograde amnesia was more pronounced after the mixed-micelles than the standard solution both after i.v. and i.m. administration. Local tolerance was excellent after i.v. and good after i.m. application with no inter-formulation differences.

In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic effects of a new imidazo-pyridine derivative, alpidem (SL80.0342) and the 1,4 benzodiazepine lorazepam were investigated utilizing quantitative EEG and psychometric testing. Ten normal volunteers received randomized (latin square) single oral doses of placebo, 25 mg, 50 mg and 100 mg alpidem and 2·5 mg lorazepam at weekly intervals. Blood level sampling, EEG recordings, evaluation of pulse, blood pressure and side-effects were carried out at 0, 1, 2, 4, 6 and 8 hours post drug; psychometric and psychophysiological investigations at the same time periods except for the first hour. Computer-assisted spectral-analysis of the EEG demonstrated an anxiolytic profile after both compounds, characterized by an increase of beta activity, decrease of alpha activity and acceleration of the centroid of the total activity and total beta activity. Total power was attenuated, delta activity augmented and the centroid of the combined delta and theta activities decreased. The latter changes were most pronounced after 2·5 mg lorazepam suggesting it is more sedative than alpidem. Dosetreatment efficacy calculations revealed 2·5 mg lorazepam as the most CNS-active compound, followed by 100 mg, 50 mg and 25 mg alpidem. Based on a multivariate analysis 2·5 mg lorazepam could be differentiated from placebo at all times, 100 mg alpidem in the first, second and fourth hours, 50 mg only in the second hour. Time-efficacy calculations showed a marked CNS effect after alpidem in the first hour with a peak in the second hour, a gentle decline to the fourth hour and thereafter a rapid decline up to the eighth hour. In contrast, 2·5mg lorazepam showed a slower rise in CNS activity which peaked in the fourth hour and declined slowly thereafter. These pharmacodynamic effects paralleled the blood level course of both compounds, as well as the time-course of psychometric changes. The latter were characterized by a deterioration in psychometer function after 2·5 mg lorazepam, which was less pronounced after 100 mg alpidem, while 50 mg and 25 mg showed no significant difference from placebo. Subjective ratings of mood showed a decrement which was most pronounced after 100 mg alpidem, less so after 50 mg, with no difference from placebo after 25 mg or lorazepam. Finally, there were no significant inter-drug differences with regard to psychophysiological variables.

In a double-blind, placebo-controlled, cross-over study, acute effects of suriclone — a cyclopyrrolone derivative — were investigated by means of topographic mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22–35 years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4 mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated in an auditory oddball paradigm before and 3 h after intake of each drug. In addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were recorded. After EOG minimization and artifact identification, the peak latencies of the spatial average were determined by an automatic procedure. Compared to placebo, no significant effects of the low and middle doses of suriclone on N1 amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg alprazolam to an even greater extent. While no consistent effects on P2 amplitude were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude was reduced only after the highest dosage of suriclone, but much more so after alprazolam. P300 latency was not affected significantly by suriclone, but a marked prolongation of P300 latency was observed after 1 mg alprazolam. Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an inhibitory influence on stimulus-induced cortical arousal. Concerning P300 effects, the used doses of suriclone were superior to 1 mg alprazolam, which seemed to have reduced cognitive information processing capacity and prolonged stimulus evaluation time. Self-rated well-being (adjective checklist) showed subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects after both 0.4 mg suriclone and 1 mg alprazolam.

Summary In a double-blind placebo-controlled cross-over study the encephalotropic and psychotropic properties of sertraline — a new potent and highly selective inhibitor of synaptosomal serotonin uptake — were studied along with blood levels of the parent drug and main metabolite in ten normal healthy volunteers. They received randomized at weekly intervals oral single doses of placebo, 100, 200 and 400 mg setraline and 100 mg zimelidine as reference drug. Blood sampling, EEG recordings, psychometric tests and evaluation of pulse, blood pressure and side-effects were carried out at the hours 0, 2, 4, 6, and 8. Blood level investigations demonstrated that sertraline is slowly absorbed with dose-dependent blood concentrations peaking in the 4th to 6th hour and remaining high thereafter, while the main metabolite, CP-53261 exhibited an even slower rise in plasma concentration up to the 8th hour. Computer-assisted spectral analysis of the EEG demonstrated slight effects of 100 mg zimelidine and 100 mg sertraline on human brain function, but moderate to marked effects after 200 and 400 mg sertraline as compared with placebo. Changes after 100 mg sertraline and the reference compound resembled the pharmaco-EEG profiles of antidepressants of the desipramine type and were indicative of some vigilance-improving properties while higher doses of sertraline induced alterations reminiscent of those after antidepressants of the imipramine type, thereby reflecting vigilance changes of the dissociative type. This neurophysiological conclusion was supported by the psychometric and psychophysiological data showing partly after 100 mg sertraline and zimelidine an improvement in psychometric performance, while 200 and 400 mg sertraline induced a deterioration of noopsyche and thymopsyche of the normal volunteers. Psychophysiological variables exhibited a dose-dependent change in CNS activation and a widening of the pupillary size. Time-efficacy calculations based on pharmacodynamic changes demonstrated maximal encephalotropic effects after 100 mg zimelidine in the 2nd to 4th hour, and after setraline in the 4th to the 6th hour, which is in agreement with the blood level data. Pulse, systolic and diastolic blood pressure showed no clinically relevant findings. Side-effects were non-existent to minimal after 100 mg zimelidine and sertraline, but marked after 200 and 400 mg sertraline characterized by nausea, vomiting, diarrhea, giddiness, restlessness, tremor and trismus.

Venlafaxine is a novel non-tricyclic antidepressant, which preclinically has demonstrated serotonin, norepinephrine, and dopamine reuptake inhibiting effects. In this study acute effects of single oral doses of placebo, 12.5 mg, 25 mg, and 50 mg venlafaxine on event-related potentials (ERPs), eye blink rate and mood were studied in 16 healthy subjects. ERPs were investigated in an auditory odd-ball paradigm before as well as 3 h after each drug intake. In addition to 17 EEG leads, vertical and horizontal EOGs were recorded. After EOG minimization and visual artefact rejection the peak latencies of the spatial average were determined by an automatic procedure. The applied methods of data acquisition, artefact processing, objective component determination and statistical analysis were successful in describing acute effects of venlafaxine on ERPs in normals. NI and P2 latencies were not affected. An increase in P2 amplitude in the relevant central and frontal regions was seen, reflecting some effect on automatic information processing. Stimulus evaluation time was not affected, as P300 latency remained unchanged. P300 amplitude was not affected at the relevant central and parietal region. Blink rate was not changed. By means of the adjective checklist a dose-dependent decrease of “extroversion” and “high spirits” and an increase of “introversion” was observed. Our findings suggest that venlafaxine affects human information processing less than would be expected from the more centrally inhibiting classical antidepressants.

In a double-blind, double dummy, placebo-controlled study, the encephalotropic, psychotropic and pharmacodynamic properties of a new controlled-release form of diazepam (Valium CR) and the standard 5 mg tablets were compared by means of quantitative EEG and psychometric analysis methods.Ten patients exhibiting emotional and vegetative lability, nervousness and phobias, with an elevated neuroticism score (Eysenck), were recruited for the study.They were treated according to a crossover design with placebo, 15 mg diazepam CR and 3×5 mg diazepam with a 3-day wash-out interval between each administration period.They all received one tablet t.i.d. (8 a.m., 2 p.m. and 8 p.m.) and one capsule in the evening (8 p.m.).The main difference between the two forms of diazepam can be illustrated by the fact that in the morning, i.e. 8 hours after the evening medication, the increase in the anxiolytic drug effect on the CNS was consistently greater, to a statistically significant degree, during the Valium CR schedule than during the 5 mg tablet schedule. This was the case even after chronic administration of the drug over 5 days.The two forms of diazepam also differed with regard to their acute effects on attention, CFF and CNS activation. Attention deteriorated significantly less after the administration of the controlled-release forms than after 3 × 5 mg diazepam (3 hours after the morning medication). CFF was significantly more augmented in the morning after 5 mg diazepam than after 15 mg diazepam CR. There were no significant psychotropic inter-drug differences after chronic administration.The absence of clinically relevant changes in pulse rate, systolic and diastolic blood pressure and side-effects indicates extremely good tolerance of both forms of diazepam by neurotic patients.

In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM IIIR criteria criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multi-infarct dementia (MID), based on computed tomography and Hachinski scores (≤49 SDAT, ≥7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 × 30 mg nicergoline (NIC) or 2 × 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC, SDAT/PLAC, MID/NIC, MID/PLAC; 4 × 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable — the Clinical Global Impression (CGI) — a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (χ2=4.1,P=0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (χ2=7.96,P<0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment, while opposite changes occurred in PLAC-treated SDAT and MID patients. The differences between PLAC and NIC reached the level of statistical significance. Event-related potential (ERP) recordings demonstrated a significantly shortened P300 latency under NIC treatment in both SDAT and MID patients, while there was a trend towards lengthening under PLAC. Thus, nicergoline improved vigilance and information processing at the neurophysiological level, which leads at the behavioural level to clinical improvement both in degenerative and vascular dementia.

Amantadine is generally used in the prophylaxis of infection with influenza A, in the treatment of Parkinson's disease and in the treatment of neuroleptic side effects. In this study acute effects of amantadine infusions on event-related potentials (ERP) were studied in 20 mildly demented patients diagnosed according to DSM-III-R criteria. Each patient was treated, in randomized order, with 0.2 g amantadinesulfate in 500 ml NaCl and 500 ml NaCl placebo, i.v. over one hour with an interval of two weeks inbetween. ERPs were investigated in an auditory odd-ball paradigm before as well as 5 hours after the infusion. In addition to 17 EEG records, vertical and horizontal EOGs were recorded. After EOG-minimization and visual artifact rejection the peak latencies of the spatial average were determined by an automatic procedure. There was no effect of amantadine on ERP latencies. N 1 of the non-target showed a trend towards amplitude augmentation, P2 amplitude was reduced. As compared to placebo, P300 amplitude of targets was significantly augmented by 3.1 μV (30% of pre-treatment value), confirming the hypothesis that amantadine may influence the P300 amplitude in the sense of an improved availability of cognitive processing resources.

Summary In a double-blind placebo-controlled study, the encephalotropic, psychotropic, pharmacodynamic and pharmacokinetic properties of 2 new substances, clovoxamine (a 5-HT and NE re-uptake inhibitor) and fluvoxamine (a selective 5-HT inhibitor) were investigated utilizing quantitative pharmaco-EEG, psychometric and blood level analyses. Ten normal volunteers received randomized and in weekly intervals oral single doses 50 mg, 75 mg and 125 mg clovoxamine, 75 mg fluvoxamine, placebo and as reference drug 75 mg imipramine. Quantitative EEG, psychometric data, pulse, blood pressure, side effects and pharmacokinetic data were studied at the hours 0, 2, 4, 6 and 8. Plasma levels of both substances peaked in the 4th to 6th hour and declined slowly thereafter. Digital computer period analysis of the EEG demonstrated after clovoxamine only minor changes characterized by an increase of fast beta-activities suggesting slight activating qualities of the drug. On the other hand 75 mg fluvoxamine and especially 75 mg imipramine produced marked CNS changes characterized by a concomitant increase of slow and fast activities and a decrease of alpha-activity. However, 75 mg fluvoxamine induced less augmentation of slow activity than imipramine indicating less sedative properties of fluvoxamine than the standard reference drug. Psychometric tests demonstrated after 50 and 75 mg clovoxamine and 75 mg fluvoxamine an increase in attention, attention variability, concentration, CFF and after-effect in the Archimedean Spiral (indicating central activation), further an improvement in mood and affectivity as compared with placebo, while 125 mg clovoxamine and 75 mg imipramine produced an increase in reaction time, deterioration of mood and affect and psychomotor activity. The latter changes were observed also after other antidepressants in normals. Pharmacodynamic investigations regarding dose-efficacy and time-efficacy relations based on both EEG and psychometric parameters revealed that 75 mg imipramine was the most effective compound, followed by 75 mg fluvoxamine and 125 mg, 75 mg and 50 mg clovoxamine. The peak effect of clovoxamine and fluvoxamine was observed around the 6th hour, while 75 mg imipramine was maximally effective between the 2nd and the 4th hours. Side effects were minimal after clovoxamine (interestingly euphoria in 3 subjects), while tiredness was seen in 5 out of 10 subjects after 75 mg fluvoxamine and in 8 out of 10 subjects after 75 mg imipramine. There were no clinically relevant changes in pulse, systolic and diastolic blood pressure.

Summary The clinical efficacy of fluvoxamine (DU 23000)-the first selective serotonin re-uptake inhibitor of the new class of 2-aminoethyloximethers of aralkylketones was investigated in endormorphous depressed patients during 5 weeks treatment with mean daily dosages of approximately 150 mg DU 23000. A marked and statistically significant improvement of the overall and detailed psychopathology was noted by means of the Global Clinical Impression and Hamilton Rating Scale as early as in the first week of drug administration. Bipolar patients tended to improve more than unipolar ones, retarded depressions more than agitated ones. An additional anxiolytic medication was occasionally required. The drug was well tolerated. Psychometric and laboratory findings did not show any significant changes. The findings are discussed in the light of the indolamine hypothesis of depression.

In a double-blind, placebo-controlled trial human brain function and mental performance as well as the antihypoxidotic properties of nicergoline were studied utilizing blood gas analysis, EEG brain mapping and psychometry. Hypoxic hypoxidosis was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 16 healthy volunteers. They received randomized after an adaptation session placebo, 10 mg, 30 mg and 60 mg nicergoline (NIC). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 hrs oral drug administration. Blood gas analysis demonstrated a drop in PO2 from 95 to 35 and 34 mm Hg in the 14 and 23 min of inhalation, respectively. PCO2 decreased too (38 to 34 and 34 mm Hg), while pH increased (7.39 to 7.44 and 7.44). Base excess increased (−0.6 to 0.6 and 0.4) while standard bicarbonate decreased (24.4 to 24.1 and 23.8 mmol/l). Thus, blood gases remained stable between the 14 and 23 min of hypoxia during which time the neurophysiological and behavioral evaluations were carried out. EEG brain mapping exhibited an increase in delta/theta activity mostly over the parietal, temporal and central regions (left more than right), while alpha activity decreased (mostly over the parietal, central, frontal, frontotemporal and temporo-occipital regions). 30 and 60 mg NIC attenuated this deterioration of vigilance. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymospsyche which was mitigated by NIC. Based on 13 psychometric variables, the hypoxia-induced performance decrement was on the overall (2nd–8th hr) 43% after placebo as compared with pretreatment normoxic values, while only 29, 24 and 31% after 10, 30 and 60 mg nicergoline, respectively. The difference between placebo and the optimal dosage of nicergoline 30 mg reached the level of statistical significance (p<0.01, multiple Wilcoxon).