Dopamine And Antipsychotic Drug Action Revisited H.M. Jones and L.S.Pilowsky British Journal of Psychiatry (2002) Presented by Dr Ashraf Azmy - PowerPoint PPT Presentation

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Dopamine And Antipsychotic Drug Action Revisited H.M. Jones and L.S.Pilowsky British Journal of Psychiatry (2002) Presented by Dr Ashraf Azmy

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Title: Dopamine And Antipsychotic Drug Action Revisited H.M. Jones and L.S.Pilowsky British Journal of Psychiatry (2002) Presented by Dr Ashraf Azmy


1
Dopamine 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.

3
Dopaminergic 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. 

5
DA receptors and antipsychotic drug action
6
The 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.
7
Re-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.

10
The 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).

14
Dopamine 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.

18
Re-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.

20
How 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.

22
Smart 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
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