1 / 66

Dopamine stabilising drugs as antipsychotics

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)

braeden
Download Presentation

Dopamine stabilising drugs as antipsychotics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Dopamine stabilising drugs as antipsychotics Philip Strange University of Reading

  2. A Treatment Option for Schizophrenia and Bipolar I Disorder “Third generation antipsychotic” – “dopamine stabiliser”

  3. 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

  4. Dopamine stabilising drugs • Schizophrenia • Antipsychotic drugs • First and second generation • “Dopamine stabilisers” • Intrinsic efficacy of drugs • Intrinsic efficacy and antipsychotic drug action

  5. Schizophrenia • 1911 - Bleuler gave name to schizophrenia • “madness” • psychosis

  6. Ophelia (Millais) … poor Ophelia, divided from herself and her fair judgement without the which we are pictures or mere beasts … Shakespeare, Hamlet (~1601)

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

  8. The scream Edvard Munch

  9. 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

  10. Schizophrenia - symptoms • Course and prognosis varied

  11. Schizophrenia - aetiology • Environmental factors e.g. birth complications, viral infection, cannabis usage etc • Genetic factors • Identification of susceptibility genes e.g. neuregulin 1

  12. Treatment of Schizophrenia • Antipsychotic (neuroleptic) drugs • First generation drugs (chlorpromazine, haloperidol) • Second generation drugs (risperidone, quetiapine, olanzapine, amisulpride) • Treat positive symptoms

  13. 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

  14. Mechanisms of antipsychotic action • Effects on dopamine systems • Correlation between daily dose of drug and affinity at D2 dopamine receptor (Snyder, Seeman, 1976)

  15. D2-like receptors from cloning

  16. D2-like receptors from cloning

  17. Dopamine pathways in the brain nigrostriatal (movement) mesocorticolimbic (behaviour) tuberoinfundibular (prolactin)

  18. 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

  19. Dopamine neurotransmission Regulation of release via presynaptic receptors - Neurotransmitter taken back in to nerve terminal dopamine D2/D3 dopamine receptors

  20. Dopamine neurotransmission – effects of antipsychotic drug ~ 70% occupancy – reduce dopamine signalling Regulation of release via presynaptic receptors - dopamine D2/D3 receptors antagonists

  21. Role of serotonin receptors • 5-HT2A antagonism – suppression of EPS • 5-HT1A agonism – effects on cognitive symptoms, suppression of EPS

  22. 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?

  23. Problems with current antipsychotic drugs • Negative symptoms not treated • Side effect profile • Dopamine systems (prolactin) • Other systems (weight gain, metabolic, sexual dysfunction etc)

  24. Dopamine stabilising drugs? • Stabilise dopamine dysregulation (Carlsson) • Suppress excessive dopamine function • Reverse dopamine hypofunction • Better therapeutic and side effect profile

  25. 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

  26. 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

  27. Dopamine output and effects of drugs normal schizophrenia

  28. Dopamine output and effects of drugs normal schizophrenia antagonist drug

  29. Dopamine output and effects of drugs normal schizophrenia antagonist drug partial agonist drug

  30. Dopamine stabilisers (partial agonists) (-)-3-PPP (preclamol) aripiprazole bifeprunox UH-232

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

  32. 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

  33. Intrinsic efficacy of drugs? R + D RD effect • binding • affinity • effect • intrinsic efficacy

  34. Intrinsic efficacy scale + 0 - inverse agonist neutral antagonist agonist assesses potential for drug to have effect acute versus chronic effects?

  35. agonist R E a bg GTP response e.g. cAMP G protein-coupled receptors

  36. agonist R E a bg GTP response [35S]GTPgS binding [35S]GTPgS binding assay to assess drug intrinsic efficacy

  37. Stimulation of [35S]GTPgS binding (D2 dopamine receptor) dopamine bromocriptine CHO-D2 cell membranes

  38. Intrinsic efficacy scale + 0 - inverse agonist neutral antagonist agonist bromocriptine dopamine

  39. Inverse agonism assayed by inhibition of [35S]GTPgS binding D2-CHO membranes 10-15% response

  40. Inverse agonism assayed by inhibition of [35S]GTPgS binding P<0.05 for raclopride and sulpiride versus butaclamol

  41. Intrinsic efficacy scale + 0 - inverse agonist neutral antagonist agonist bromocriptine haloperidol clozapine sulpiride dopamine

  42. Dopamine stabilising drugs? • Aripiprazole, UH-232, (-)-3-PPP, bifeprunox

  43. Effects of dopamine and aripiprazole on [35S]GTPgS binding + Na+ - Na+

  44. Effects of dopamine and UH-232 on [35S]GTPgS binding + Na+ - Na+

  45. Effects of dopamine and (-)-3-PPP on [35S]GTPgS binding + Na+ - Na+

  46. Relative efficacy of dopamine stabilisers

  47. Relative efficacy of dopamine stabilisers

  48. Intrinsic efficacy scale + 0 - inverse agonist neutral antagonist agonist bromocriptine haloperidol clozapine sulpiride dopamine (-)-3-PPP aripiprazole/UH-232/bifeprunox

  49. 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

More Related