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

Abstract

Objective: This study was performed to determine whether in vitro affinities of currently available antipsychotics toward dopamine or other neuronal receptor 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 incidences of 7 different types of drug-induced ADRs (i.e., akathisia, dyskinesia, tremor, rigidity, drowsiness, hypotension and dry mouth) were obtained from both post-marketing ADR databases and the investigational clinical trials of eight pharmaceutical companies. Affinity constants (K _i) of the respective drugs toward dopamine D₁ and D₂ receptors, α₁-adrenoceptors, histamine H₁ receptors, serotonin 5-HT₂ receptors and muscarinic cholinoceptors, determined using rat brain synaptosomes, were obtained from the literature. Relationships between in vitro receptor-binding properties and in vivo incidences of the respective types of antipsychotic-related ADRs were analyzed using Spearman's rank correlation.

Results: Significant (P < 0.05) correlations were observed between the K _i values for dopamine D₂ receptor and the clinical incidences of akathisia and dyskinesia (r _s = −0.68 and −0.66, respectively). Significant (P < 0.05) correlations were also observed between the K _i values for α₁-adrenoceptor and histamine H₁ receptor and the incidence of drowsiness (r _s=−0.65 and −0.55, respectively), and between the K _i values for three receptor systems (i.e., dopamine D₁ receptor, α₁-adrenoceptor and histamine H₁ 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 useful for predicting not only in vivo antipsychotic potency but also clinical incidence of akathisia and dyskinesia for this class of agents. Newly developed antipsychotic drugs with more potent and selective antagonistic activity against the dopamine D₂ receptor may not necessarily be associated with a lower incidence of extrapyramidal ADRs.