1. The Pharmacology of Second Generation Neuroleptics

2. Structure of Serotonin

3. Distribution of Serotonin

4. Combined Serotonin and Dopamine Pathways

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

6. Neuroleptic Receptor PiesD1 D2
5-HT2A
5-HT1A A1 A2 H1
Muscarinic
Clozapine
Olanzapine
Quetiapine
Sertindole
Ziprasidone
Risperidone
Haloperidol

7. In Humans the Effects Are a Function of Dose
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
5-HT2 D2 D2

8. Using Imaging Tools to Develop Rational Dosing Strategies

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

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

12. 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

13. 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.

14. 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)

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

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

17. Practical Aspects of Treatment

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

19. 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

20. Psychosocial Treatments

21. 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