EEG and blood level of the potential antidepressant paroxetine after a single oral dose to normal volunteers

The quantitative electroencephalogram (EEG) and plasma concentration of the antidepressant paroxetine were monitored in five normal volunteers after a single oral dose of 70 mg paroxetine and placebo. Peak plasma concentration occurred 4–6 h post-dose. Placebo had little effect on the EEG but the effects of paroxetine were statistically significant at 6 h post-dose. The EEG changes after treatment consisted of a decrease in delta and theta activity (< 8 Hz) and increase in beta activity (>12 Hz). These changes were still evident 72 h after treatment. The EEG profile obtained with 70 mg paroxetine is similar to that reported for other antidepressant 5-HT uptake inhibitors, but dissimilar to the classical, sedative antidepressants.     

EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug

The pharmacologic profile of flutroline, a tetrahydro--carboline compound, predicts and antipsychotic compound with greater potency and longer duration than established clinical antipsychotic compounds. In normal male volunteers, it elicited EEG, behavioral, and plasma prolactin release profiles similar to established antipsychotic compounds. Peak activity occurred in 4–5 h. But the clinical activity projected from these studies is one-fifth that of haloperidol. In relation to the available clinical findings, the pharmaco-EEG data are better predictors of the clinical activity of flutroline than its preclinical profile.     

EEG profiles of fenfluramine,amobarbital and dextroamphetamine in normal volunteers

A quantitative EEG study in volunteer adults was undertaken to distinguish single oral administrations of 50 and 100 mg amobarbital, 10 mg dextroamphetamine, 40 mg fenfluramine and placebo. Four hour EEG recordings were monitored by frequent auditory reaction time tasks. The EEG changes were measured by digital computer period analysis.In the analysis, each drug was distinguished from placebo, and from each other, with the best discriminations for 50 mg amobarbital and dextroamphetamine, and the poorest discrimination of fenfluramine from 50 mg amobarbital.These observations are consistent with the clinical pharmacology of the compounds and suggest further applications of quantitative EEG for the classification of psychoactive drugs.Aided, in part, by USPHS grants MH-11358, 13003 and 13358; the Psychiatric Research Foundation of Missouri, Smith Kline and French Laboratories and A. H. Robins, Inc.This report summarizes data of a second quantitative EEG study undertaken in 1965–1966. Earlier progress reports dated April 1965 and May 1967 are available.The cooperation of Connie Hickman, B.S.E.E. and the nursing and technical staff of the Missouri Institute of Psychiatry are gratefully acknowledged.     

Controlled clinical investigation of trimeprazine as a sleep-inducer in normal subjects

Summary The effects of acute introduction and withdrawal of trimeprazine (Vallergan), an antihistaminic phenothiazine derivative with known sedative effects, were investigated by a single blind polygraphic study in 8 healthy volunteers. A baseline placebo was given on Nights 1–3, followed either by 10 mg or 20 mg of the drug on Nights 4–6, and then withdrawal effects were recorded on Nights 7–9. The subjective effects of the drug and EEG sleep variables were determined on these nights. The results showed that the drug might have had dose related effects. REM-sleep was increased by 10 mg doses, which also caused an increase in SW sleep. There was no significant change after the 20 mg dose. Significant REM rebound was not observed after withdrawal of either dose. These characteristics may be of value in the treatment of certain aspects of sleep disturbances.Partly supported by grant from Pharma Rhodia Laboratories, Denmark     

Diurnal variation in the quantitative EEG in healthy adult volunteers

AIMS: To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population. METHODS: This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking. RESULTS: Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for theta (4. 75-6.75 Hz), alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05). CONCLUSIONS: These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made.     

The effects of alcohol and atropine on EEG and behavior in the rabbit

Electroencephalographic (EEG) activity was recorded from hippocampus and neocortex of rabbits. It was found that movement, movement-related 6–12 Hz rhythmical slow actvity (RSA), and movement-related neocortical desynchronization were unaffected by intravenous atropine sulfate but depressed by ethyl alcohol (ethanol). Slower 4–8 Hz immobility-related RSA and immobility-related neocortical desynchronization produced by sensory stimulation (visual, auditory, tactle, vestibular) were relatively unaffected by ethanol even at high (0.1–0.2 g-%) blood alcohol levels, but were abolished by atropine sulfate. The results provide evidence for the idea of two pharmacologically separable cortical activating systems and suggest that ethanol has a greater effect on noncholinergic than cholinergic systems.     

EEG changes after fluphenazine enanthate and decanoate based on analog power spectra and digital computer period analysis

Quantitative EEG investigations, using an analog frequency analyzer and digital computer period analysis, were carried out following single parenteral injection of two long-acting fluphenazine derivatives, decanoate and enanthate. Both quantitative methods of analysis demonstrated that fluphenazine decanoate and enanthate produce significant EEG alterations which are similar to changes induced both by fluphenazine hydrochloride and by other known major tranquilizers (EEG profile of major tranquilizers). Maximum EEG changes occurred during the first week after enanthate, while they occurred during the second week following decanoate injection. These findings confirmed the metabolic and behavioral studies in animals regarding the long action of both compounds and, in particular, they demonstrated that the activity of fluphenazine decanoate is longer in duration than fluphenazine enanthate.Supported, in part, by the Psychiatric Research Foundation of Missouri and the Squibb Institute for Medical Research, New Brunswick, N.J. 08903. Presented, in part, at The 7 th Congress of Collegium Internationale Neuropsychopharmacologicum, August 11–13, 1970, Prague.     

Bretazenil modulates sleep EEG and nocturnal hormone secretion in normal men

Preclinical data suggest that the imidazo-diazepinone derivative bretazenil (Ro 16-6028) has anxiolytic and anticonvulsant properties with only weak sedative effects. We examined the influence of oral administration of 1 mg bretazenil on the sleep EEG and the concomitant nocturnal secretion of cortisol, growth hormone and prolactin in ten healthy young men. After bretazenil we found a significant increase in stage 2 sleep and a significant reduction in stage 3 sleep. REM latency was prolonged. Spectral analysis of sleep-EEG power revealed a decrease in delta and in theta power and an increase in sigma power. We found no significant influence on sleep onset latency or on intermittent wakefulness. Bretazenil prompted a significant decrease in cortisol secretion and a significant increase in prolactin release. It had no major influence on growth hormone secretion.     

The effects of haloperidol on the EEG spectrum

A placebo-controlled study with six normal volunteers was carried out using 1 mg haloperidol IM. In some EEG frequency bands, the power density due to haloperidol appeared to increase or decrease depending on the subject. Nevertheless, if the results of the six subjects are taken together, the effects of haloperidol are in agreement with the literature. No correlation was found between plasma concentration of haloperidol and EEG response. Some methodological problems are discussed.     

EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline

Three hallucinogens (d-lysergicacid diethylamide (LSD), mescaline, psilocybin) and two cannabinoid derivatives (tetrahydrocannabinol (THC), synhexyl) were tested for their long-term effects on the EEG of the cat. The drug-induced alterations in the EEG frequency spectrum were "drug-specific" in the sense that they would be statistically unlikely to occur during sleep-waking behavior. The two classes of compounds produced distinctly different EEG effects which were remarkably similar within each class. The duration of activity and relative potencies were consistent with those obtained by other measures, both in cats and in other species including man.     

Reassessing morphine effects in cats: II. Protracted effects on sleep-wakefulness and the EEG

Adult cats were implanted with standard electrodes to record EEG, EOG, and EMG. After 15 days, morphine sulphate or saline placebo was given IP at 0.5, 1.0, 2.0, 3.0 mg/kg, at least 15 days apart. Cats were continuously recorded for 72 hr postinjection. Wakefulness, drowsiness, NREM and REM sleep percentages were scored from polygraphic features and statistically analysed. There was a dose-dependent suppression of NREM and REM sleep for at least 6 hours postmorphine, with a progressive sleep recovery thereafter. During the insomnia period there was an EEG/behavioral dissociation where bursts of high-voltage waves were seen over a background of desynchrony; meanwhile the animal was first aroused although quiet and later showed stereotypic behavior. There was a prolonged NREM sleep rebound which started later at the higher doses. A significant, relatively brief REM sleep rebound was seen only at the lowest dose. The latency for NREM and REM sleep onset was also dose-dependent. Possible brain sites of morphine actions and similarities with effects in other species are discussed.     

A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults

A 25-night single-blind cross over design was employed to determine the long-term effects of clozapine on the sleep patterns of six normal young adults. Subjects received 12.50 mg placebo on the first and last five nights, whereas on the intermediate 15 nights 12.5 mg clozapine was administered. The subjects slept in the laboratory on the third and fourth nights to obtain baseline recordings, and on the eight, twelfth, sixteenth, and twentieth nights to determine the effects of clozapine on sleep variables. Recordings on nights 21 and 25 were used to assess withdrawal effects. Percentage stage 1 sleep and indices of body movements during sleep were significantly reduced, suggesting that clozapine may have sleep-inducing properties. There was no significant rebound of stage REM sleep during drug withdrawal despite a small but significant reduction in stage REM during drug administration. Numerous side effects, indicative of sleepiness, were reported on the mornings following drug administration, and there was evidence of a rapid tolerance to clozapine. These findings may limit the efficacy of clozapine as an hypnotic agent over an extended period of time. Further research on insomniac subjects is therefore indicated.     

EEG effects of subcutaneous and intracerebroventricular injections of arginine vasopressin in the rat

Several studies have suggested that arginine vasopressin (AVP) may act centrally as a neurohormone or neuromodulator to produce electrophysiological and behavioral effects. However, there are few reports of EEG effects of AVP in unanesthetized, behaving animals. In the present study the EEG effects of behaviorally relevant subcutaneous (SC) doses of AVP (6 g/kg) known to raise blood pressure were compared to behaviorally relevant intracerebroventricular (ICV) doses (0.1–1.0 ng) and multiple toxic ICV doses (1.0 g) of AVP. Central injections of toxic doses of AVP produced behavioral arrest, bodily barrel rolling, and EEG slowing, but did not induce electrographic signs of seizure activity. Comparison of the spectral characteristics of the EEG revealed some similarities in the distribution of power between SC and the 1.0 ng ICV dose; whereas ICV doses of 0.1 and 0.5 ng produced power distributions that were different from those seen following saline or SC doses of AVP. The similarities in EEG activity between SC injections and the 1.0 ng ICV dose suggest a common brain state may be induced by the two routes of administration in those dose ranges.     

Diphenylhydantoin potentiates the EEG and behavioural effects induced by N-methyl-D-aspartate antagonists in rats

The N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors are involved in the electrical and behavioural generalization of epileptiform activity within the brain. In rats, both competitive and non-competitive NMDA antagonists induce three dose-dependent stages of EEG patterns: 1) increase in cortical desynchronization periods; 2) increase in amplitude of cortical high frequency (20–30 Hz), low voltage (30–50 µV) background activity; 3) appearance of cortical slow (2–3 Hz) wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive behavioural effects such as stereotypy (circling, head weaving) and ataxia. In the present study, the influence of the prototypic anticonvulsant diphenylhydantoin (DPH) has been tested on the EEG and behavioural effects induced by the non-competitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) and by the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755). Even though DPH (up to 100 mg/kg IP) did not markedly affect basal cortical EEG activity, at doses of 10–100 mg/kg IP it potentiated all the EEG effects induced by the NMDA antagonists. These data support involvement of NMDA neurotransmission in the pharmacological effects of DPH.     

EEG correlates of acute nicotinic and muscarinic cholinergic blockade: separate and combined administration of mecamylamine and scopolamine in normal human subjects

Anticholinergic drugs have been proposed as a possible acute model for human electroencephalographic (EEG) studies focused on dementia but the interactive effects of muscarinic and nicotinic cholinergic receptor system blockade on the regulation of electrocortical activity has yet to be examined. EEG recordings were carried out in 15 normal subjects before and after the double-blind acute administration of a placebo, a centrally acting nicotinic blocker (20 mg of mecamylamine), a centrally acting muscarinic blocker (0·6 mg of scopolamine) and a combination dose of mecamylamine and scopolamine. Mecamylamine decreased absolute and relative beta power and increased relative theta power. Scopolamine increased relative power in both theta and beta frequency bands. Mecamylamine produced greater theta increments than scopolamine, while combined administration of the two central blockers induced changes similar to that observed with mecamylamine administered alone. Results are discussed in relation to electrocerebral activity in normal and pathological aging. © 1997 John Wiley & Sons, Ltd.     

EEG effects of physostigmine and choline chloride in humans

Seventeen normal volunteers received either 0.5 mg, 1.5 mg, or 2.5 mg physostigmine i.v. in a placebo-drug-placebo single-blind design. EEG was recorded simultaneously and analyzed by computerized spectral analysis. Eleven healthy elderly volunteers (mean age=69.1 years) with mild memory impairment were treated with placebo, followed by oral choline chloride (either 8 g/day for 3 weeks, or 16 g/day for 1 week), and then, again, placebo. Recordings of spontaneous EEG and EEG event-related potentials (contingent negative variation) were obtained during both placebo and choline treatments. The larger doses of physostigmine produced an increase in low frequency activity and a slowing of the peak alpha frequency. Oral choline chloride had no effect on the EEG as measured by spectral analysis, but appears to have differential effects on contingent negative variation (CNV) amplitude and reaction time, depending upon the initial CNV amplitude.     

Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers

Trospium chloride and oxybutynin are two antimuscarinergic agents used in the treatment of unstable bladder, urge incontinence, combined stress urge incontinence and detrusor hyperreflexia. The possibility that these two drugs produce changes in central nervous electrical activity was examined in an open, prospective, phase I study involving 12 volunteers.Quantitative evaluation of the multichannel electroencephalogram obtained from young healthy volunteers showed statistically significant decreases in alpha and beta₁ activity after oxybutynin, but not after intravenous or oral administration of trospium chloride. The biological activity of both drugs was ascertained by continuous simultaneous recording of the heart rate. A decrease in heart rate was detected after oral administration of oxybutynin, and an increase was seen after i.v. administration of trospium chloride.The results suggest that trospium chloride is less likely to produce central nervous adverse effects than to oxybutynin.     

Differential clonidine effects on EEG following lesions of the dorsal and median raphe nuclei in rats

The effects of clonidine on EEG activity and gross behavior were studied in rats with electrolytic lesions of the median (MR) and dorsal (DR) raphe nuclei. Lesioned animals showed significant depletion in forebrain serotonin concentrations. Clonidine (0.1 mg/kg and 0.2 mg/kg IP) produced synchronization in cortical EEG pattern and markedly increased alpha and theta activities in unlesioned animals. Clonidine treatment resulted also in a sedative response. In MR lesioned rats clonidine effect upon EEG was significantly reduced and, additionally, sedative response was not seen. On the other hand clonidine effect on EEG was markedly increased in rats with lesioned DR. These results are discussed on the basis of possible interaction between serotonergic and noradrenergic neurons in the brain.     

卒中后癫痫患者的视频脑电监测与动态脑电监测分析

目的比较视频脑电监测与动态脑电监测对卒中后癫痫的检查效果。方法回顾性分析视频脑电监测与动态脑电监测的卒中后癫痫的患者资料各40例。结果脑梗死患者55例,AEEG组21例,部分性发作6例(28.6%),全面性发作11例(52.4%),VEEG组34人,部分性发作19例(55.9%),全面性发作10例(29.4%),两组经统计学分析,P<0.05为有统计学差异。结论 VEEG检查对部分性发作有较高的准确性。有条件的患者应尽量安排VEEG检查。     

Analysis of sleep EEG microstructure in subchronic paroxetine treatment of healthy subjects

Paroxetine is a selective and potent serotonin reuptake inhibitor and its efficacy for the treatment of depression has been proven. Under acute and subchronical treatment regimens, disturbances of the regular sleep pattern are a reported side effect of the drug. The present study was therefore performed to investigate the impact of subchronic treatment with the selective serotonin reuptake inhibitor paroxetine on the microstructure of the sleep EEG. The study especially addressed the question of subchronic effects of paroxetine medication (30 mg/day) in eight healthy male volunteers in a double blind, placebo-controlled crossover design. Conventional sleep EEG parameters and a spectral power analysis for different sleep stages after 4 weeks of treatment were computed. Additionally, the correlation of certain EEG rhythms across the night was calculated in order to detect subtle dynamical EEG alterations, not necessarily obvious when regarding conventional EEG analysis. Although we could not detect any alterations of the spectral power values in certain frequency bands either during NREM nor during REM sleep following subchronic paroxetine medication, the dynamical EEG attributes across the night revealed a significant enhancement of the correlation between certain EEG rhythms mainly during NREM sleep. Received: 18 July 1996 /Final version: 19 February 1997