Letters to the Editor
Reply: Atypical Antipsychotics Mechanisms of Action
Dear Editor:
The basic principle proposed in my article (1) is that there are 2 groups
of antipsychotics (APs), those that bind tightly to the dopamine D2 receptor
and those that bind more loosely to the D2 receptor (2–4). The traditional
APs, which elicit parkinsonism, bind to the dopamine D2 receptor more tightly
than does dopamine to the high-affinity state of the D2 receptor. The newer,
atypical APs, which elicit less or no parkinsonism, bind to the dopamine
D2 receptor more loosely than does dopamine to the high-affinity state
of the D2 receptor (1). APs that are more loosely bound to D2 are able
to come off the receptor more quickly, as found by human brain positron
tomography with quetiapine and clozapine (4–7). This quality allows endogenous
dopamine to conduct normal neurotransmission over a matter of hours.
A look at clozapine and isoclozapine, as well as loxapine and isoloxapine,
supports this general principle of tightly bound and loosely bound types
of APs and their relation to EPSEs. For example, clozapine and isoclozapine
have identical affinities at the cloned muscarinic M1 receptor, the dopamine
D1 and D4 receptors, and the serotonin 1A and 2A receptors. However, isoclozapine has a tenfold higher affinity than clozapine for the human cloned D2 receptor
and correspondingly elicits catalepsy and hyperprolactinemia (7,8), in
contrast to clozapine. Similarly, while loxapine and isoloxapine have similar
affinities at the dopamine D3 and D4 receptors, and also at the 5-HT1A
and 5-HT2A receptors, isoloxapine has a twofold-to-tenfold lower affinity
for the D2 receptor than does loxapine. As a result, isoloxapine does not
lead to catalepsy or elevated prolactin (9), in contrast to loxapine.
Despite this basic underlying principle, however, there is no sharp clinical
division between typical and atypical APs: dosage-dependent parkinsonism
can occur with the moderately loosely bound APs such as olanzapine. Additional
factors are to be considered for each of the atypical APs, especially when
discussing the action of APs for L-DOPA psychosis in Parkinson’s disease
patients, as Dr Friedman properly points out. For example, Dr Friedman
notes that amoxapine, with its high dissociation constant of 20 nM (1),
ought to be an atypical AP—as in fact it is for patients with schizophrenia
(S Kapur, personal communication, 1999), but not for patients with Parkinson’s
disease (10). As outlined previously (1), the Parkinson putamen has only
2% or 3% of the normal amount of dopamine (11), and Parkinson’s disease
patients with L-DOPA psychosis should in principle receive one-thirtieth
the dosage of an atypical AP given to patients with schizophrenia. Because
the recommended AP dosage of amoxapine is 150 to 250 mg daily (12), the
starting dosage for Parkinson’s disease subjects ought, a priori, to be
about 6 mg daily. However, the amoxapine starting dosage was 12.5 mg daily
for the 3 patients tested by Sa and others (10). Although APs with dissociation
constants between 2 and 20 nM can elicit dosage-dependent parkinsonism,
the dissociation speed of the radio-labelled AP best predicts whether an
AP will be atypical. While it has been directly determined that [3H]clozapine,
[3H]-S-amisulpride and [3H]quetiapine are the APs most rapidly released
from the D2 receptor (1), [3H]amoxapine is not available for such studies.
It is not especially surprising that amoxapine avoids eliciting extrapyramidal
signs in schizophrenia patients but intensifies such signs in Parkinson’s
disease patients, because other atypical APs, such as olanzapine and risperidone,
also worsen parkinsonism in this patient group, as noted by Dr Friedman
and others (13,14). It appears, therefore, that APs with dissociation constants
between 2 nM and 20 nM can be atypical in patients with schizophrenia,
but not in patients with Parkinson’s disease, while APs with dissociation
constants above 20 nM (that is, clozapine, quetiapine, and melperone) are
atypical in both diseases. The different ranges correspond to the different
levels of endogenous dopamine, which is high in schizophrenia but very
low in Parkinson’s disease.
As for pimozide, there is no reason to expect it to be more atypical than
risperidone, because their dissociation constants are virtually identical
(1).
Concerning olanzapine, this drug does elevate prolactin (15,16). However,
while atypical APs avoid EPSEs, their propensity to elevate prolactin differs,
depending on their fat solubility (17). Hence, risperidone, with high fat
solubility and high affinity for the pituitary D2 receptor, readily elevates
prolactin. Conversely, quetiapine, with low fat solubility and low affinity
for D2, has little effect on prolactin.
Molindone and loxapine have dissociation constants in the range of 2 nM
to 20 nM for D2 and thus elicit dosage-dependent parkinsonism (1).
As for thioridazine, this compound has repeatedly been observed to cause
fewer EPSEs (18,19). Concerning the anticholinergic effects of thioridazine
and clozapine, these drugs have the same potent affinity as benztropine
for the M1 muscarinic-cholinergic receptor (that is, dissociation constants
of 3 nM) (20,21). Hence, clinical dosages of 200 to 400 mg daily of clozapine
or thioridazine are equivalent to giving a patient one hundredfold more
of the customary benztropine dosage of 2 mg twice daily. It is not surprising,
therefore, that clozapine would be clinically more effective than benztropine
in alleviating parkinsonism. As for the absence of systemic side effects
with clozapine (that is, dry mouth and blurred vision, although clozapine
does cause constipation), it is known that clozapine is a potent agonist
at the M4 muscarinic receptor (22). This agonist action may underly clozapine-induced
hypersalivation and the absence of systemic anticholinergic effects. In
addition, because clozapine has a tenfold range of different affinities
for the 5 different muscarinic receptors (21,22), the receptor basis for
the clinical cholinergic and anticholinergic actions of clozapine is not
obvious.
On the question of relevance of data for drugs binding in and out of the
striatum, the D2 percentage occupancy by a drug in the striatum is generally
identical to, or slightly lower than, the D2 occupancy for nonstriatal
brain regions, such as the cingulate cortex (23,24). Hence, data for the
striatum can be generalized to other brain regions. However, the data for
the speed of dissociation of [3H]APs from the human cloned dopamine D2
receptor (1) are obtained under artificial optimum laboratory conditions
and, therefore, only reflect the principles under study.
In summary, Dr Friedman is correct to point out that each atypical AP has
unique properties in addition to whether each has tight or loose binding
to the D2 receptor. We can conclude that APs that are atypical for schizophrenia
patients may not be sufficiently loosely bound to D2 to be atypical for
Parkinson’s disease patients. Clearly, APs must be extremely loosely bound
to D2 (as is the case with clozapine or quetiapine) to effectively treat
L-DOPA psychosis in dopamine-depleted Parkinson’s disease patients, without
enhancing their tremor, akinesia, and rigidity.
References
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2. Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998;3:123–34.
3. Seeman P, Tallerico T. Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon drug withdrawal of clozapine or quetiapine. Am J Psychiatry 1999;156:876–84.
4. Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?—a new hypothesis. Am J Psychiatry 2001;158:360–9.
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Philip Seeman, MD, PhD
Toronto, Ontario
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