The Pharmacology of Second Generation Neuroleptics

Structure of Serotonin

Distribution of Serotonin

Combined Serotonin and Dopamine Pathways

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

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

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

Using Imaging Tools to Develop Rational Dosing Strategies

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

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

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

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.

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)

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

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

Practical Aspects of Treatment

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

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

Psychosocial Treatments

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