Pharmaco-EEG profile of maroxepine: third example to discuss the predictive value of pharmaco-electroencephalography in early human pharmacological evaluations of psychoactive drugs.
This publication forms the third part of a critical evaluation of pharmaco-EEG applications as an instrument for assessing the profile of action of psychoactive drugs based on the trial results of three new psychoactive test substances: savoxepine, levoprotiline and maroxepine. After the presentation, in Parts I (savoxepine) and II (levoprotiline), of trial substances for which compatible results were obtained in the pharmaco-EEG model and in the clinical studies, a case with discrepant and less predictive results has been presented, and on this basis the limitations of the pharmaco-EEG model in the evaluation of therapeutic efficacy are discussed. The substance examined in this report, the tetracyclic dibenzoxepine derivative, maroxepine, produced prominent central effects in pharmacological studies which pointed to a bipolar profile of action, i.e., the EEG showed similarities both to antidepressants and antipsychotics. The pharmaco-EEG effects of maroxepine were investigated in a randomised, double-blind study in 15 young healthy male subjects and compared with those of placebo and the reference substances, chlorpromazine and imipramine. The experimental design was a cross-over uncompleted block design with five consecutive trial days one week apart. The pharmaco-EEG was recorded from the occipito-temporal and frontocentral regions before, 3 and 6 h after application of 2.5 mg and 5.0 mg maroxepine, 75 mg chlorpromazine, 75 mg imipramine and placebo. The selected target variables for descriptive statistical evaluation were the Spectral Difference Index (SDI), the absolute and relative power values in seven predetermined frequency bands within the range 1.5 to 30.0 Hz, the dominant frequency (6.0 to 18.0 Hz) and the alpha slow-wave index (ASI). The results show that maroxepine has a potent central nervous action and a strong sedative potential. The EEG effects consisted of a shift to the left of the relative power spectrum of the occipital lead, accompanied by an increase in the absolute beta power in the frontocentral region. Discriminative inspection of the profiles of EEG changes, induced by maroxepine and the reference drugs, revealed closer similarity of maroxepine with chlorpromazine than with imipramine. Maroxepine showed vigilance-decreasing features like imipramine. This is one condition to be able to interfere with depressive illness. The underlying hypothesis is that depressive illness is based on affective and vigilance disturbance. Maroxepine furthermore showed the typical neuroleptic-like shift from resting alpha to resting subalpha (theta F band) which we assume related to the anti-productive properties of neuroleptics in schizophrenia.(ABSTRACT TRUNCATED AT 400 WORDS)
Herrmann
W M
WM
Department of Clinical Psychiatry, Free University of Berlin, Germany.
Schärer
E
E
Wendt
G
G
Delini-Stula
A
A
D000328:Adult; D002746:Chlorpromazine / Q000494:pharmacology; D002908:Chronic Disease; D003984:Dibenzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales; D011597:Psychomotor Performance / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy
D003984:Dibenzazepines; D007099:Imipramine; D002746:Chlorpromazine; C068397:maroxepin