Correlations between in vitro affinity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions

Objective: This study was performed to determine whether in vitro affinitie s of currently available antipsychotics toward dopamine or other neuronal r eceptor systems are associated with their in vivo incidence of central and peripheral adverse drug reactions (ADRs). Methods: For 17 antipsychotic drugs available in Japan, the clinical incide nces of 7 different types of drug-induced ADRs (i.e., akathisia, dyskinesia , tremor, rigidity, drowsiness, hypotension and dry mouth) were obtained fr om both post-marketing ADR databases and the investigational clinical trial s of eight pharmaceutical companies. Affinity constants (K-i) of the respec tive drugs toward dopamine D-1 and D-2 receptors, alpha(1)-adrenoceptors, h istamine H-1 receptors, serotonin 5-HT2 receptors and muscarinic cholinocep tors, determined using rat brain synaptosomes, were obtained from the liter ature. Relationships between in vitro receptor-binding properties and in vi vo incidences of the respective types of antipsychotic-related ADRs were an alyzed using Spearman's rank correlation. Results: Significant (P < 0.05) correlations were observed between the K-i values for dopamine D-2 receptor and the clinical incidences of akathisia a nd dyskinesia (r(s) = -0.68 and -0.66, respectively). Significant (P < 0.05 ) correlations were also observed between the K-i values for alpha(1)-adren oceptor and histamine H-1 receptor and the incidence of drowsiness (r(s) = -0.65 and -0.55, respectively), and between the K-i values for three recept or systems (i.e., dopamine D-1 receptor, alpha(1)-adrenoceptor and histamin e H-1 receptor) and the incidence of dry mouth (r(s) = -0.50, -0.81 and -0. 62, respectively). Conclusion: Preclinical receptor-binding data of antipsychotic drugs toward central dopamine and other ancillary neurotransmitter systems may be usefu l for predicting not only in vivo antipsychotic potency but also clinical i ncidence of akathisia and dyskinesia for this class of agents. Newly develo ped antipsychotic drugs with more potent and selective antagonistic activit y against the dopamine D-2 receptor may not necessarily be associated with a lower incidence of extrapyramidal ADRs.