Most
effective antipsychotics, typical as well as atypical, have affinities for the
DA D2 receptor high enough to suggest that they produce effective blockade of
these receptors in vivo. The model for atypical antipsychotic drug action
proposed by Meltzer et al. postulated that atypical antipsychotic drugs had to
have some D2 receptor blockade in vivo, although weaker than 5-HT2A
receptor blockade, to achieve a low EPS profile and, possibly, some of the other
advantages of clozapine.
An exception to this may be amperozide, with is a
potent 5-HT2A antagonist and DA reuptake inhibitor with very low affinity for
the D2 receptor. Recently, NRA0045, which has potent 5-HT2A, D4, and but no D2 or D3
receptor blockade has been found to have atypical antipsychotic properties.
Partial DA agonists, which may act as agonists at presynaptic DA receptors, and
antagonists at postsynaptic DA receptors are a new class of antipsychotic drugs
that has promise. Cartmell et al., (2000).
However,
clinical testing of these agents is just beginning, and current data support
only the view that they are atypical in the classic sense, i.e., they are
antipsychotic in preclinical or clinical testing at doses that produce weak or
absent EPSs. Other evidence of the importance of antagonism for atypical
antipsychotic drug activity will be discussed subsequently.
The
in vitro affinity of a drug at the DA D2 receptor is a useful predictor
of the dose that produces EPSs and control of positive symptoms for typical
neuroleptic drugs, although it does not do so for some atypical antipsychotic drugs,
e.g., ziprasidone. Furthermore, there is no agreement on how to determine the
doses used in such correlations because of the differences in dosage
requirements as a function of stage of illness, body mass index, and age. There
is little agreement even on the best dose for haloperidol, the most widely used
antipsychotic drug. A wide range of 2 to 15 mg/day has been suggested, far
removed from the 20 to 40 mg/day thought to be most effective in 1966. To date,
no clinically proven antipsychotic with the possible exception of amperozide
lacks significant D2 receptor antagonist properties.
As will be discussed, the
combination of D2 and 5-HT2A receptor blockade, in the right ratio, produces
some of the effects of clozapine and other atypical antipsychotic drugs in
rodents, e.g., increases DA efflux in the cortex and striatum of rats and
blockade of the conditioned avoidance response, an indication of antipsychotic
activity. There have been only limited tests of this hypothesis in humans,
mainly using ritanserin, which is a mixed 5-HT2A/2B/2C antagonist.
Nevertheless,
various comprehensive reviews of the action of the atypical antipsychotic drugs
have concluded that the combination of 5-HT2A, D2, and receptor blockade is the probable basis of their
antipsychotic action. The evidence for this hypothesis will be discussed subsequently.
Cartmell et al., (2000).
Counter
to the hypothesis of the importance of 5-HT2A receptor antagonism to the action
of clozapine and other atypical antipsychotic drugs is the proposal of Seeman
and Tallerico and Kapur and Seeman that the basis of atypical antipsychotics
may lie in their rapid dissociation from the DA D2 receptor and their
relatively easily displacement by surges of endogenous DA. It has also been
proposed that rapid and extensive displacement of clozapine and quetiapine from
binding sites accounts for the reported low occupancy of striatal D2 receptors
by these drugs. The authors also suggested that this might account for more rapid
relapse following clozapine and quetiapine withdrawal.
Although the evidence
cited for clozapine-induced relatively rapid relapse is robust, the evidence
with regard to quetiapine and rapid relapse has never been published and does
not accord with general clinical experience. Seeman and Tallerico found that
the affinity for and rate of dissociation of antipsychotics from the D2
receptor are highly correlated. Drugs with low affinity for the D2 receptor, e.g.,
clozapine and quetiapine, were found to have a higher dissociation rate
constant than drugs with higher affinity, e.g., haloperidol. Rapid dissociation
from the D2 receptor was reported to also permit easier displacement of
clozapine and quetiapine by endogenous DA, thereby avoiding side effects
related to DA receptor blockade such as EPSs and hyperprolactinemia. It was
also reported that olanzapine, risperidone, and sertindole, all of which are
well established as atypical antipsychotic drugs, are comparable comparable to
haloperidol in their rate of dissociation from the D2 receptor and are not
displaced by raclopride or iodobenzamide, as are clozapine and quetiapine.
Thus, this hypothesis could not explain the basis for their low EPSs. Moreover,
for these agents to achieve their antipsychotic action, they would have to be
less easily displaced from limbic and possibly cortical D2 receptors. There are
no data to support this selectivity with regard to displacement as yet.
Although there is evidence for higher occupancy of extrastriatal D2 receptors
by clozapine and quetiapine in patients with schizophrenia and for atypical
antipsychotic drugs that show more potent 5-HT2A receptor blockade in rodents,
the same appears to be true for olanzapine, which does not show the higher
off-rates of clozapine and quetiapine (R. Kessler and H. Meltzer, in preparation).
Because clozapine produces a greater increase in DA release in the cortex than
in the accumbens or striatum, at least in rodents and monkeys, clozapine might be
expected to produce greater occupancy of D2 receptors in these regions than the
cortex, but, as noted above, this is not the case.
It is also not clear how
this model could explain any of the advantages of clozapine with regard to efficacy
in neuroleptic-resistant patients or for cognition. (Cartmell et al., 2000). Studies
on the regulation of prefrontal cortical or limbic DA release also provide no
evidence that blockade of D2 receptors alone, regardless of degree of
occupancy, can mimic the effects of the multireceptor antagonists such as clozapine.
Pharmacologic analysis of this important model for the action of atypical
antipsychotic drugs on cognition and negative symptoms strongly supports the importance
of combined blockade of 5-HT2A, D2, and possibly receptors.