The reintroduction of clozapine, the prototype of atypical antipsychotics,
in the late 1980s has led to significant advances in the pharmacological ma
nagement of schizophrenia. Since then, there has been a rapid development o
f novel "atypical" antipsychotic agents that have been pharmacologically mo
deled, to a certain extent, after their predecessor clozapine, As with all
antipsychotics, there is variability among individuals in their response to
these "atypical" drugs. Pharmacogenetics can provide a foundation for unde
rstanding this interindividual variability in antipsychotic response. This
review first provides a rationale for the pharmacogenetic investigation of
this variable trait. Studies of pharmacokinetic and pharmacodynamic factors
of antipsychotic therapy are considered in the development of this rationa
le, Next, the molecular genetic techniques used to study this interindividu
al variation in response are described. This is followed by a review and di
scussion of the published studies examining genetic factors involved in clo
zapine response. From this, several recommendations for future pharmacogene
tic investigations of antipsychotic response are proposed. Although still i
n its early stages, psychiatric pharmacogenetics should provide a basis for
individualized pharmacotherapy of schizophrenia, and may also lead to the
development of newer, more efficacious antipsychotic agents. Biol Psychiatr
y 2000;47:252-266 (C) 2000 Society of Biological Psychiatry.