Radioreceptor Binding Profile of the Atypical Antipsychotic Olanzapine

Abstract

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

Chronic Olanzapine or Sertindole Treatment Results in Reduced Oral Chewing Movements in Rats Compared to Haloperidol

“…The motor response produced by these two new drugs mimics results with chronic clozapine administration in rats (Gunne et al 1982;Kakigi et al 1995). It is not entirely surprising that these two drugs demonstrate the same action on oral dyskinesias as clozapine, based upon their similar regional depolarization blockade of dopamine neurons, Fos activation pattern, and clinical motor side effect profile, despite their very different receptor affinity profiles (Bymaster et al 1996;Sanchez et al 1991).…”

“…The motor response produced by these two new drugs mimics results with chronic clozapine administration in rats (Gunne et al 1982;Kakigi et al 1995). It is not entirely surprising that these two drugs demonstrate the same action on oral dyskinesias as clozapine, based upon their similar regional depolarization blockade of dopamine neurons, Fos activation pattern, and clinical motor side effect profile, despite their very different receptor affinity profiles (Bymaster et al 1996;Sanchez et al 1991).The preclinical characteristic shared by olanzapine and sertindole that may predict their low motor side effect profile in human studies is their anatomic selectivity demonstrated in the depolarization blockade model (Grace et al 1997) and using Fos protein activation (Robertson et al 1994). Both olanzapine and sertindole relatively selectively affect dopamine neurons that innervate the limbic and frontal cortices (the A10 dopamine neurons) and leave relatively unaffected those dopamine neurons involved in the striatum (the A9 dopamine neurons) (Skarsfeldt 1995).…”

“…Olanzapine is a new antipsychotic drug developed by Lilly Laboratories, Inc., a thio[1,5]benzo-diazepine (Bymaster et al 1996). It has potent antipsychotic actions in schizophrenic psychosis, comparable to traditional neuroleptics, and is active against both positive and negative symptoms (Beasley et al 1996).…”

“…The difficulty of distinguishing types of antipsychotic-induced movements in rats, along with the limited oral distribution of the movements in rats, and disagreements about the anticholinergic suppressability of the rat movements, have maintained a proper skepticism about using this preparation without reservation as an animal model of human TD. In this report, we have attempted to expand the pharmacology of these rat dyskinesias by testing whether two of the new antipsychotic drugs, olanzapine and sertindole, which have known low acute motor side effect profiles in humans, would induce purposeless oral chewing in rats.Olanzapine is a new antipsychotic drug developed by Lilly Laboratories, Inc., a thio[1,5]benzo-diazepine (Bymaster et al 1996). It has potent antipsychotic actions in schizophrenic psychosis, comparable to traditional neuroleptics, and is active against both positive and negative symptoms (Beasley et al 1996).…”

Comorbidity Profile and Healthcare Utilization in Elderly Patients with Serious Mental Illnesses

“…It is possible that higher levels of comorbidity did exist in the seriously mentally ill patients but that they were under-identified by the attending physicians because information from caregivers is often lacking and these patients are difficult to evaluate. Antipsychotic medication has been associated with hypotension through its alpha-blocking properties (33, 34). As the seriously mentally ill were more likely to be receiving these medications it is possible that this accounts for some of the differences between the groups.…”