The atypical antipsychotics risperidone, clozapine and olanzapine differ regarding their sedative potency in rats.
The atypical antipsychotics risperidone, clozapine and olanzapine were studied for their ability to antagonise apomorphine-induced stereotypy and to affect electroencephalographic (EEG) activity in rats. The compounds antagonised apomorphine-induced stereotypy with ED(50)s of 0.15 mg/kg s.c. for risperidone, 0.42 mg/kg s.c. for olanzapine and 1.3 mg/kg s.c. for clozapine. At a dose close to that required for apomorphine antagonism (0.16 mg/kg s.c.), risperidone induced only minor changes in EEG power spectral activity. At a higher dosage (0.63 mg/kg s.c.) it increased the power density in the high frequency range (9.8-18.6 Hz), characteristic of a sedative-like effect. Olanzapine and clozapine caused a dose-dependent increase in power density in all frequency bands. These effects were already present at doses (0.04 and 0.16 mg/kg s.c., respectively) 10 times below those required for apomorphine antagonism. The effects increased dose-dependently and were pronounced at the doses required for apomorphine antagonism. These results in rats are in agreement with the clinical observation that risperidone has less propensity for inducing sedation at therapeutic dose levels than olanzapine and clozapine.
Ahnaou
A
A
Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica N.V., Department of CNS Discovery Research, Beerse, Belgium. aahnaou@prdbe.jnj.com
Megens
A A H P
AA
Drinkenburg
W H I M
WH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines; D003024:Clozapine / Q000494:pharmacology; D016292:Procedural Sedation; D018491:Dopamine Agonists / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D005583:Fourier Analysis; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018967:Risperidone / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects*; D013997:Time Factors
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D004338:Drug Combinations; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D010890:Pirenzepine; D003024:Clozapine; D018967:Risperidone; D001058:Apomorphine; D000077152:Olanzapine