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 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 D(1) and D(2) receptors, alpha(1)-adrenoceptors, histamine H(1) receptors, serotonin 5-HT(2) 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 D(2) 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 alpha(1)-adrenoceptor 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 receptor systems (i.e., dopamine D(1) receptor, alpha(1)-adrenoceptor and histamine H(1) receptor) and the incidence of dry mouth (r(s) = -0.50, -0.81 and -0.62, respectively).


CONCLUSIONS
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 D(2) receptor may not necessarily be associated with a lower incidence of extrapyramidal ADRs.
Sekine
Y
Y
Department of Pharmacy, Branch Hospital, Faculty of Medicine, University of Tokyo, 3-28-6 Mejirodai, Bunkyo-ku, Tokyo 112-8688, Japan. SEKINEYU-DIS@h.u-tokyo.ac.jp
Rikihisa
T
T
Ogata
H
H
Echizen
H
H
Arakawa
Y
Y
D016907:Adverse Drug Reaction Reporting Systems; D017109:Akathisia, Drug-Induced / Q000453:epidemiology; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000453:epidemiology; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000453:epidemiology; D015994:Incidence; D007700:Kinetics; D009127:Muscle Rigidity / Q000139:chemically induced / Q000453:epidemiology; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012894:Sleep Stages / Q000187:drug effects; D014202:Tremor / Q000139:chemically induced / Q000453:epidemiology; D014987:Xerostomia / Q000139:chemically induced / Q000453:epidemiology
D014150:Antipsychotic Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter