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The Pharmacology of Second Generation Neuroleptics

The Pharmacology of Second Generation Neuroleptics. Structure of Serotonin. Distribution of Serotonin. Combined Serotonin and Dopamine Pathways. Risperidone. Clozapine. Olanzapine. D 2. D 2. D 2. 10 1 0.1 0.01 0.001 0.0001. 10 1 0.1 0.01 0.001 0.0001. 10 1 0.1 0.01 0.001

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The Pharmacology of Second Generation Neuroleptics

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  1. The Pharmacology of Second Generation Neuroleptics

  2. Structure of Serotonin

  3. Distribution of Serotonin

  4. Combined Serotonin and Dopamine Pathways

  5. Risperidone Clozapine Olanzapine D2 D2 D2 10 1 0.1 0.01 0.001 0.0001 10 1 0.1 0.01 0.001 0.0001 10 1 0.1 0.01 0.001 0.0001 AChM 5-HT2A AChM 5-HT2A AChM 5-HT2A H1 H1 H1 5-HT2C 5-HT2C 5-HT2C a2 a1 a2 a1 a1 Receptor Binding Affinities of Three Atypical Antipsychotics (No data available fora2-receptors) Kasper, Data from:Schotte et al., 1996

  6. D1 D2 5-HT2A 5-HT1A A1 A2 H1 Muscarinic Olanzapine Clozapine Quetiapine Neuroleptic Receptor Pies Ziprasidone Risperidone Sertindole Haloperidol

  7. Receptor-pies Reflect an Abstract Concept In Humans the Effects Are a Function of Dose D2 D2 5-HT2 D2 5-HT2 5-HT2 5-HT2 D2 5-HT2 D2

  8. Using Imaging Tools to Develop Rational Dosing Strategies

  9. D2 Receptor Binding • The ligand C11- Raclopride is injected prior to PET study. Areas of high uptake (high D2 occupancy) are shown in red.

  10. Haloperidol and D2 Occupancy 11C-Raclopride PET Scan 11C-Raclopride PET Scan Coregistered MRI Scan Before Treatment Haloperidol 2 mg/d (74% Occ.)

  11. D2 Occupancy Predicts Clinical Response D2 occupancy predicts response on CGI (p < 0.001) Predicts change in positive symptoms (p = 0.07) Kapur et al. Am. J Psychiatry, 2000

  12. D2 Occupancy Predicts EPS/akathisia Subjects with EPS or akathisia 78% NO subject < 78% showed EPS/akathisia Kapur et al. American Journal of Psychiatry, 2000.

  13. D2 Occupancy Predicts Prolactin Elevation 2 of 15 show prolactin elevation below 72%D2 5 of 6 show prolactin elevation above 72%D2 D2 occupancy predicts prolactin elevation (F1,20 = 7.3, p < 0.01)

  14. Risperidone 5-HT2 & D2 Occupancy Threshold for EPS Threshold for Response EPS Kapur, Zipursky and Remington, American Journal of Psychiatry, 1999.

  15. Olanzapine 5-HT2 & D2 Occupancy EPS + Prolactin * EPS and/or prolactin elevation Kapur, Zipursky and Remington, American Journal of Psychiatry, 1999.

  16. Practical Aspects of Treatment

  17. Practical Issues • Dosage • Use of Anticholinergics • Oral vs. Depot Neuroleptics • Reducing or Discontinuing Medication • Long-term Outcome • Early intervention

  18. Can Early Intervention Prevent Disease Progression? • Early diagnosis is difficult • It is also hampered by stigma • There is minimal to no evidence for a direct toxic brain effect of untreated psychosis • However, the psychological impact of untreated psychosis may be significant

  19. Psychosocial Treatments

  20. Psychosocial Strategies • Facilitation of pharmcotherapy • Token economy system • Carer-based stress management • Living skills training • Social case management • Educational Techniques and Family Therapy • Cognitive-Behavioral Interventions • Sustaining the benefits

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