Testing Drugs for Impaired Brain Function in Old Age: On the Effects of a Single Dose of Bifemelane using Topographic Mapping of EEG and Event-Related Potentials (P300) and Psychometric Measurements in Healthy Elderly Subjects

Abstract

Clinical studies have demonstrated that bifemelane hydrochloride [4-(0-benzylphenoxy)-N-methylbutylamine hydrochloride] can improve cognitive functions in patients with various types of dementia. To elucidate specific mechanisms which may underlie the clinical benefit, the effects of bifemelane were investigated by means of computerized electroencephalography (EEG), event-related potentials (P300) and psychometry. Eighteen healthy elderly subjects, aged between 60 and 73 years, were included in a double-blind, placebo-controlled crossover study. Each subject received a single dose of 150 mg bifemelane or placebo with an interval of 1 week in between. EEG and psychometric investigations were carried out before and 2, 4, 6, and 8 h after drug administration, ERP investigations only before and 3 h after drug administration. Descriptive data analysis of the EEG showed that 150 mg bifemelane accelerated the centroid of the total frequency band, induced a significant reduction of the absolute delta + theta power and increased the absolute beta power most markedly 6 h after drug intake. Topographic analyses of ERP amplitudes showed that bifemelane did not effect ERP amplitudes. While N1, P2 and N2 latencies were not changed after bifemelane, P300 latency was shortened significantly. Psychometric investigations did not show significant or consistent effects on noopsychic and thymopsychic functions. In conclusion, bifemelane affected EEG in the sense of improved vigilance. The reduction of P300 latency may be interpreted as accelerated stimulus evaluation time, therefore indicating a beneficial effect of bifemelane on cognition at this stage of information processing. (Ogawa et al., 1992a). Moreover, bifemelane given before ischemia antagonizes learning deficits in rats (Tobe et al., 1986). Concerning bifemelane actions that may be related to cognition enhancing activity, electrophysiological studies support cholinomimetic activity (Tobe et a/., 1981;Egawa et al., 1987;Okuyama and Aihara, 1988 The authors speculated that bifemelane may act both as a metabolic activator and a vasodilator. In a study with 10 patients with Alzheimer-type dementia and 10 patients with multi-infarct dementia, eight subjects out of 20 were regarded as responders after a 3-month treatment period with a daily dosage of 150 mg bifemelane (Shigeta et al., 1993a,b). As the frequency of small rapid eye movements in the EOG increased significantly only in responders, and as only responders demonstrated a significant reduction in amplitude of the 6.0-8.0 Hz EEG frequency band, the authors concluded that part of the intellectual improvement in the patients resulted from an increased level of arousal. KEYWhile the ultimate goal in the evaluation of nootropic drugs lies in the demonstration of clinically relevant changes (Amaducci et al., 1990; Advisory Committees to the German Federal Health Office, 1992), computerized electrophysiological methods like topographic mapping of the electroencephalogram (EEG) may allow classification as well as the evaluati...