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Dopamine stabilising drugs as antipsychotics. Philip Strange University of Reading. A Treatment Option for Schizophrenia and Bipolar I Disorder . “Third generation antipsychotic” – “dopamine stabiliser”. Top 10 best selling drugs 2006. Global sales ($ billion)

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dopamine stabilising drugs as antipsychotics
Dopamine stabilising drugs as antipsychotics

Philip Strange

University of Reading

slide2

A Treatment Option for Schizophrenia and Bipolar I Disorder

“Third generation antipsychotic” – “dopamine stabiliser”

top 10 best selling drugs 2006
Top 10 best selling drugs 2006

Global sales ($ billion)

Lipitor 13.6

Nexium 6.7

Seretide/Advair 6.3

Plavix 5.8

Norvasc 5.0

Aranesp 5.0

Zyprexa 4.7

Risperdal 4.6

Enbrel 4.5

Venlafaxine 4.0

dopamine stabilising drugs
Dopamine stabilising drugs
  • Schizophrenia
  • Antipsychotic drugs
    • First and second generation
    • “Dopamine stabilisers”
  • Intrinsic efficacy of drugs
  • Intrinsic efficacy and antipsychotic drug action
schizophrenia
Schizophrenia
  • 1911 - Bleuler gave name to schizophrenia
  • “madness”
  • psychosis
slide6

Ophelia (Millais)

… poor Ophelia, divided from herself and her fair judgement

without the which we are pictures or mere beasts …

Shakespeare, Hamlet (~1601)

schizophrenia7
Schizophrenia
  • Onset – adolescence/early adulthood
  • Lifetime risk 1%
  • Presentation of symptoms and outcome – varied
slide8

The scream

Edvard Munch

schizophrenia symptoms
Schizophrenia - symptoms
  • Positive symptoms – disordered thoughts, delusions, hallucinations
  • Negative symptoms – poverty of speech and thought, reduced movement, social withdrawal
  • Patients present with different combinations of symptoms
schizophrenia symptoms10
Schizophrenia - symptoms
  • Course and prognosis varied
schizophrenia aetiology
Schizophrenia - aetiology
  • Environmental factors e.g. birth complications, viral infection, cannabis usage etc
  • Genetic factors
  • Identification of susceptibility genes e.g. neuregulin 1
treatment of schizophrenia
Treatment of Schizophrenia
  • Antipsychotic (neuroleptic) drugs
    • First generation drugs (chlorpromazine, haloperidol)
    • Second generation drugs (risperidone, quetiapine, olanzapine, amisulpride)
  • Treat positive symptoms
side effects of antipsychotics
Side effects of antipsychotics
  • Extrapyramidal (motor) – acute dystonia, akathesia, parkinsonism, tardive dyskinesia
    • Seen more with First Generation (typical) antipsychotics
    • Seen less with Second Generation (atypical) antipsychotics
  • Actions at other receptors - sedation, weight gain, sexual dysfunction
mechanisms of antipsychotic action
Mechanisms of antipsychotic action
  • Effects on dopamine systems
  • Correlation between daily dose of drug and affinity at D2 dopamine receptor (Snyder, Seeman, 1976)
dopamine pathways in the brain
Dopamine pathways in the brain

nigrostriatal

(movement)

mesocorticolimbic

(behaviour)

tuberoinfundibular (prolactin)

therapeutic and side effects of antipsychotic drugs
Therapeutic and side effects of antipsychotic drugs
  • Therapeutic effects due to blockade of D2/D3 receptors in nucleus accumbens/olfactory tubercle
  • Extrapyramidal side effects due to blockade of D2/D3 receptors in caudate/putamen
dopamine neurotransmission
Dopamine neurotransmission

Regulation of release

via presynaptic receptors

-

Neurotransmitter

taken back in to nerve

terminal

dopamine

D2/D3 dopamine receptors

dopamine neurotransmission effects of antipsychotic drug
Dopamine neurotransmission – effects of antipsychotic drug

~ 70% occupancy – reduce

dopamine signalling

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

antagonists

role of serotonin receptors
Role of serotonin receptors
  • 5-HT2A antagonism – suppression of EPS
  • 5-HT1A agonism – effects on cognitive symptoms, suppression of EPS
dopamine in the brain in schizophrenia
Dopamine in the brain in schizophrenia
  • “Dopamine hypotheses” of schizophrenia
    • Increased dopamine function in limbic regions?
    • Dopamine release increased in psychosis (Laruelle)
  • Reduced dopamine function in cortex?
problems with current antipsychotic drugs
Problems with current antipsychotic drugs
  • Negative symptoms not treated
  • Side effect profile
    • Dopamine systems (prolactin)
    • Other systems (weight gain, metabolic, sexual dysfunction etc)
dopamine stabilising drugs25
Dopamine stabilising drugs?
  • Stabilise dopamine dysregulation (Carlsson)
  • Suppress excessive dopamine function
  • Reverse dopamine hypofunction
  • Better therapeutic and side effect profile
dopamine stabilising drugs26
Dopamine stabilising drugs?
  • Dopamine D2 partial agonists
  • Suppress excessive dopamine function without hypodopaminergia
  • Enhance reduced dopamine function?
  • e.g. (-)-3-PPP, UH-232, aripiprazole, bifeprunox
dopamine neurotransmission effects of partial agonist drug
Dopamine neurotransmission – effects of partial agonist drug

~ 90% occupancy –

inhibit dopamine - signal

depends on agonism of drug

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

dopamine output and effects of drugs29
Dopamine output and effects of drugs

normal

schizophrenia

antagonist

drug

dopamine output and effects of drugs30
Dopamine output and effects of drugs

normal

schizophrenia

antagonist

drug

partial agonist

drug

dopamine stabilisers partial agonists
Dopamine stabilisers (partial agonists)

(-)-3-PPP (preclamol)

aripiprazole

bifeprunox

UH-232

intrinsic efficacy of antipsychotics
Intrinsic efficacy of antipsychotics?
  • Antagonism/partial agonism?
  • Actions of drugs depend on more than just binding
  • Intrinsic efficacy of drugs
slide33

What is ligand efficacy?

  • Agonist: Ligand that binds to a receptor and produces a response
  • Partial agonist: Produces an effect less than the maximum
  • Antagonist: Ligand that binds but does not cause activation
  • Inverse Agonist: Binds and produces the opposite response to the agonist

Receptor Activity

log [Ligand] (M)

Full Agonist

Partial Agonist

Antagonist

Inverse Agonist

intrinsic efficacy of drugs
Intrinsic efficacy of drugs?

R + D RD effect

  • binding
  • affinity
  • effect
  • intrinsic efficacy
intrinsic efficacy scale
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

assesses potential for drug to have effect

acute versus chronic effects?

slide36

agonist

R

E

a

bg

GTP

response

e.g. cAMP

G protein-coupled receptors

slide37

agonist

R

E

a

bg

GTP

response

[35S]GTPgS

binding

[35S]GTPgS binding assay

to assess drug intrinsic efficacy

stimulation of 35 s gtp g s binding d 2 dopamine receptor
Stimulation of [35S]GTPgS binding (D2 dopamine receptor)

dopamine

bromocriptine

CHO-D2 cell membranes

intrinsic efficacy scale39
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

dopamine

inverse agonism assayed by inhibition of 35 s gtp g s binding41
Inverse agonism assayed by inhibition of [35S]GTPgS binding

P<0.05 for raclopride and sulpiride

versus butaclamol

intrinsic efficacy scale42
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

haloperidol

clozapine

sulpiride

dopamine

dopamine stabilising drugs43
Dopamine stabilising drugs?
  • Aripiprazole, UH-232, (-)-3-PPP, bifeprunox
intrinsic efficacy scale49
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

haloperidol

clozapine

sulpiride

dopamine

(-)-3-PPP

aripiprazole/UH-232/bifeprunox

intrinsic efficacy scale50
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

haloperidol

clozapine

sulpiride

dopamine

(-)-3-PPP

aripiprazole/UH-232/bifeprunox

System dependence of expression of intrinsic efficacy

intrinsic efficacy scale51
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

haloperidol

clozapine

sulpiride

dopamine

(-)-3-PPP

aripiprazole/UH-232/bifeprunox

dopamine stabilisers are very different drugs compared to conventional drugs

dopamine output and effects of drugs52
Dopamine output and effects of drugs

normal

schizophrenia

antagonist

drug

partial agonist

drug

+ inverse

agonism

clinical effects of the dopamine stabilising drugs
Clinical effects of the dopamine stabilising drugs?
  • Aripiprazole does not differ greatly from other atypical antipsychotic drugs for therapeutic effects
  • Low extrapyramidal side effects, similar to other atypicals
  • Reduced effects on prolactin and weight gain
intrinsic efficacy scale54
Intrinsic efficacy scale

+ 0 -

inverse

agonist

neutral

antagonist

agonist

bromocriptine

haloperidol

clozapine

sulpiride

dopamine

(-)-3-PPP

aripiprazole/UH-232/bifeprunox

dopamine receptor occupancy by dopamine
Dopamine receptor occupancy by dopamine

Predict need ~50%

occupancy by drug

to normalise dopamine

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 dopamine receptors

dopamine occupancy

~ 12% normally

~ 24 % in psychosis

(Laruelle)

dopamine neurotransmission receptor occupancy by drugs
Dopamine neurotransmission – receptor occupancy by drugs

occupancy:

olanzapine ~55%

(Frankle et al)

Counteracts excess

dopamine release in

psychosis

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

dopamine neurotransmission receptor occupancy by drugs57
Dopamine neurotransmission – receptor occupancy by drugs

occupancy:

aripiprazole ~90%

(Yokoi et al)

Receptor output

depends on intrinsic

efficacy of drug

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

dopamine neurotransmission receptor occupancy by drugs58
Dopamine neurotransmission – receptor occupancy by drugs

Receptor occupancy:

olanzapine ~55% + dopamine ~12%

versus

aripiprazole >90% + dopamine <2%

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

dopamine neurotransmission receptor occupancy by drugs59
Dopamine neurotransmission – receptor occupancy by drugs

Receptor occupancy:

olanzapine ~55% + dopamine ~12%

versus

aripiprazole >90% + dopamine <2%

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

Overall output may be similar

dopamine neurotransmission receptor occupancy by drugs60
Dopamine neurotransmission – receptor occupancy by drugs

Receptor occupancy:

olanzapine ~55% + dopamine ~12%

versus

aripiprazole >90% + dopamine <2%

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

Very dependent on intrinsic efficacy of drug

dopamine neurotransmission receptor occupancy by drugs61
Dopamine neurotransmission – receptor occupancy by drugs

Receptor occupancy:

olanzapine ~55% + dopamine ~12%

versus

aripiprazole >90% + dopamine <2%

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

High receptor occupancy may be more stable

extrapyramidal side effects
Extrapyramidal side effects

EPS are expected if occupancy by

conventional drugs exceeds 80%,

dopamine occupancy then is ~4%

Does the partial agonism of

aripiprazole prevent this

or is it the lack of

inverse agonism??

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

antipsychotic treatment longer term effects
Antipsychotic treatment - longer term effects

Inverse agonism of conventional

antipsychotics will lead to receptor

up-regulation and effects

on signalling systems

This will be absent

for the partial agonist

aripiprazole

Regulation of release

via presynaptic receptors

-

dopamine

D2/D3 receptors

conclusion
Conclusion
  • Consideration of intrinsic efficacy allows new insights into drug action
  • Dopamine stabilisers achieve similar end result to conventional antipsychotics
  • Aripiprazole may allow better control of psychosis
unresolved issues
Unresolved issues
  • Why is bifeprunox not more effective?
  • Why do some patients not respond to drugs?
  • Why do so many patients stop therapy on conventional antipsychotics?
  • Why do conventional antipsychotics stop working?
acknowledgements
David Roberts

Hong Lin

Sigmar Saisch

M Wood (GSK)

S Kapur (Toronto)

Acknowledgements