title: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors.
abstract: This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.
authors.affiliation: Department of Pharmacology, University of Toronto, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Seeman
authors.forename: T
authors.initials: T
authors.lastname: Tallerico
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000145:classification / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001667:Binding, Competitive; D018680:Cholinergic Antagonists / Q000493:pharmacokinetics; D003024:Clozapine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000145:classification / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D008024:Ligands; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D011485:Protein Binding; D011605:Psychoses, Substance-Induced / Q000188:drug therapy / Q000209:etiology; D011618:Psychotic Disorders / Q000188:drug therapy*; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012008:Recurrence; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
chemical_list: D014150:Antipsychotic Agents; D018680:Cholinergic Antagonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007980:Levodopa; D003024:Clozapine; D004298:Dopamine