Title: Dopamine And Antipsychotic Drug Action Revisited H.M. Jones and L.S.Pilowsky British Journal of Psychiatry (2002) Presented by Dr Ashraf Azmy
1Dopamine And Antipsychotic Drug Action Revisited
H.M. Jones and L.S.Pilowsky British Journal of
Psychiatry (2002)PresentedbyDr Ashraf Azmy
2- Some pharmacological facts which are important in
understanding the antipsychotic drug action - The more potently a drug binds to the receptor,
the more effective it is at competing for binding
sites. - The greater the potency a drug has for the
receptor, the lower the concentration required
before all available receptor sites are occupied
or blocked. - The affinity (termed Kd or Ki )for the receptor
is a function of the rate of drug association
and dissociation from the receptor.It is measured
as the concentration of drug required to block
half the total receptor population. - High affinity drugs have low Kd values. These
drugs are better at occupying receptors.Receptor
occupancy is also determined by the rate of
association and dissociation of the drug at the
receptor and the concentration of endogenous
neurotransmitter at the receptor.
3Dopaminergic pathway and receptor physiology
4- Dopamine (DA) systems arise from 2 primary
midbrain clusters ventral tegmental area (A10),
substantia nigra (A9) A separate
tuberinfundibular pathways runs from hypothalamic
neurons to the pituitary gland. The DA receptor
family separates into two major subtypes D1
like(D1D5)and D2- like (D2,D3, D4) Receptor
cloning has identified two isoforms of the D2
receptor (D2 short and D2 long) which are
differently localized. The neurochemical
anatomy of dopamine differed in cortical and
striatal regions and it appears that DA
concentration , receptor regulation and D2-like
receptor subtype density vary greatly between
striatal and extrastriatal regions.
5DA receptors and antipsychotic drug action
6The D2 receptor blockade hypothesisEffective
antipsychotic drugs have at least some degree of
antagonism of the D2 receptors. The observation
that antipsychotic drug affinity for the D2
receptor and the average daily dose required to
control symptoms were directly correlated, led to
confirmation that it was a major site of action
of drugs. Efforts to treat partly or poorly
responsive patients revolving around mega dose
antipsychotic therapy questioned the usefulness
of this approach.
7Re-evaluation of the dopamine hypothesis of
antipsychotic drug action
8- In 80s and 90s the simple understanding of the
linear relation between the D2 receptor blockade
and the clinical action was reversed by powerful
new research tools, which forced re-evaluation of
the role of D2 receptor in antipsychotic drug
action. - Receptor imaging using PET and SPECT showed that
12 different typical antipsychotics had only
65-85 occupancy at D2 receptors. Did D2
occupancy also correlate with clinical benefit?? - Some patients had levels of central D2 receptor
blockade in excess of 90 but they failed to
benefit from the treatment. This finding obviated
the explanation that poor clinical effect was the
result of low brain penetration of increased
was-out of typical antipsychotics in treatment
resistant individuals. Indeed, some patients who
responded well to treatment showed remarkably low
level of D2 block. These data attributed greatly
to the consensus that high-dosage antipsychotic
treatment in the main, unhelpful in the treatment
of poorly responsive schizophrenia.
9- Finally, clozapine,( who has modest affinity for
D2 receptor in vitro) had consistently low levels
of D2 blockade (20 - 60) in association with
excellent clinical response, even in patients
previously poorly responsive to standard
high-dosage typical antipsychotic drug therapy.
10The central primacy of dopamine to antipsychotic
action
11- The notion that D2 receptor occupancy was central
to therapeutic response never went away.
Compounds that lack modest activity at these
sites are therapeutically inactive. - Studies showed that symptom reduction and
side-effect induction could be fitted to a
threshold model of striatal D2 receptor
occupancy. In a study of patient with first
episode schizophrenia , it was found that
striatal D2 receptor occupancy values exceeding
65 predicted clinical benefit, values exceeding
72 predicted hyperprolactinaemia and values
exceeding 78 predicted motor side-effects.
12- Furthermore, individual responses to similar
degrees of D2 occupancy may vary(undefined
pharmacogenetic characteristics underlying
dopaminergic tone). - It is pertinent to this point that
hyperprolctinaemia occurred in 80 of women and
24 of men despite similar level of D2 occupancy.
- Another study showed that women developed
symptomatic hyperprolactinaemia at half the
chlorpromazine equivalent dose of that in
men(approx. 250 mg chlorpromazine equivalents).
13- For the clinician maintaining patients within a
therapeutic window of 7-15 D2 occupancy is not
straightforward, especially when prescribing
haloperidol, since doses as low as 2.5 mg result
in a wide variation in striatal D2/D3
occupancy(38-87).
14Dopamine transmission is abnormal in schizophrenia
15- Increased striatal D2 receptor density was
reported by some authors, (could be
questioned).Classical antipsychotic therapy
could. In itself , cause D2 receptor
upregulation. - Imaging studies (PET and SPECT) could control for
this confound by studying never-treated people
with schizophrenia. These studies did not, on the
whole, support increased striatal D2 receptor
density in schizophrenia although the possibility
that endogenous DA concentration was abnormal
remained untested in vivo.
16- Studies using 123I(iodobenzamide SPECT)suggest
that DA transmission was disrupted in
schizophrenia. Other studies showed aberrant
response in people with schizophrenia to a drug
that elevated DA levels. - Following amphitamine administration , mean
occupancy of striatal DA receptors by
amphetamine-stimulated endogenous DA release was
approximately doubled in the patient group
compared with the control group - These data provided concrete proof of disturbed
DA control, at least in some people with
schizophrenia.
17- Overactive phasic DA transmission in limbic
regions(including the amygdala and nucleus
accumbens) could account for misinterpretation of
innocuous external stimuli(resulting in
delusions) and improper filtering of
perceptions(causing hallucination). - Blockade of D2 receptor sin these regions would
help control the positive symptoms of
schizophrenia. - In cortical areas(especially frontal and
prefrontal)regions, tonic DA transmission is
relatively underactive, resulting in disrupted
executiv efunctions, poverty of thought, speech
and action, and love motivation. Antipsychotic
occupancy of D2 receptors in these regions would
worsen these negative features.
18Re-evaluation of the dopamine hypothesis(cont.)
- This evidence prompted a careful
re-interpretation of the importance of D2
receptor blockade to therapeutic efficacy. Other
receptor systems were probed as potential sites
of antipsychotic drug action. Most notable of
these was the 5HT2 receptor subclass. - The ratio of 5 HT2A to D2 receptor affinity was
the major determinant of a drugs likelihood to
behave as an atypical antipsychotic. Studies
using PET and SPET found that many atypical
antipsychotic including clozapine, olanzapine,
risperidone and quetiapine, shared a stikingly
high degree of 5 HT2A receptor occupancy gt90over
their entire dose range. This is unsurprising
given that olanzepine, risperidone and quetiapine
were developed on the basis of their high
5HT2AD2 receptor affinity profiles. - Further studies revealed that pure 5HT2A receptor
occupancy alone is unlikely to be sufficient to
determine clinical efficacy for antipsychotic
drugs
19- These finding meshes with the data that atypical
antipsychotic drugs (esp clozapine and
quetiapine) exhibit cortically selective D2
receptor occupancy at clinically useful dose in
vivo. This effect is not seen for standard doses
of typical antipsychotic drugs. - Drugs with modest affinity for D2 receptors
exhibit this effect robustly across their whole
dose range, whereas atypical drugs with higher
affinity for the D2 receptor (e.g. risperidone)
display dose-dependent limbic selectivity. - Regionally selective DA action of atypical
antipsychotic drugs is supported by both
electrophysiological and animal studies.
20How much D2 blockade is too much
21- Imaging studies reveal that striatal D2 receptor
occupancy by atypical drugs changes considerably
over a 24 hr period, even in steady state. - Owing to low affinity for the D2 receptor (driven
by fast dissociation off the receptor)
clozapine and quetiapine exhibit transient high
D2 receptor occupancy (just not exceeding the
threshold required to induce adverse movement or
hormonal side-effects) which decline to very low
levels over a 24 h period. - This suggests that low affinity drugs, with
modest effects at D2 receptors, may antagonise
the system in a manner that preserves
physiologically responsive endogenous DA
transmission across a wide dose range. The effect
may presumably also be achieved by higher
affinity drugs that are cleared rapidly from the
synapse, or given at doses producing low synaptic
concentrations of the drug. - These data so not explain the discrepancy between
the rapid D2 receptor blockade induced by
antipsychotic drugs and the gradual remission of
psychotic symptoms over several days or weeks.
This delay could result from longer-term effects
of antipsychotic drugs on bran plasticity,
including synaptogenesis.
22Smart antipsychotic drugs
23- Effective less-toxic treatment of schizophrenia
is the regionally sensitive stabilization of
dopamine function, and not DA paralysis induced
by classical antipsychotic drugs. - This selective targeting could come about by
exploiting behaviour intrinsic to compound with
low D2 affinity, by designing compounds selective
for DA receptor subtypes found at grater
densities in limbic or cortical regions( e.g.
D3)or by modulating DA release through action at
alternative systems( e.g 5HT sigma and glutamate
receptor sits). - Agents with specific action at presynaptic D3
autoreceptors controlling central DA release may
offer more physiological modulation of DA than
conventional antagonists.
24 Thank you