The Pharmacology of Second Generation Neuroleptics

1
The Pharmacology of Second Generation Neuroleptics
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Structure of Serotonin
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Distribution of Serotonin
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Combined Serotonin and Dopamine Pathways
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Receptor Binding Affinities of Three Atypical
Antipsychotics
(No data available for a2-receptors)
Kasper, Data fromSchotte et al., 1996
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Neuroleptic Receptor Pies
Ziprasidone
Risperidone
Sertindole
Haloperidol
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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
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Using Imaging Tools to Develop Rational Dosing
Strategies
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D2 Receptor Binding

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

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Haloperidol and D2 Occupancy
11C-Raclopride PET Scan
11C-Raclopride PET Scan
Coregistered MRI Scan
Before Treatment
Haloperidol 2 mg/d (74 Occ.)
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D2 Occupancy Predicts Clinical Response
D2 occupancy predicts response on CGI (p lt
0.001) Predicts change in positive symptoms (p
0.07)
Kapur et al. Am. J Psychiatry, 2000
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D2 Occupancy Predicts EPS/akathisia
Subjects with EPS or akathisia
78
NO subject lt 78 showed EPS/akathisia
Kapur et al. American Journal of Psychiatry, 2000.
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D2 Occupancy Predicts Prolactin Elevation
2 of 15 show prolactin elevation below 72D2
5 of 6 show prolactin elevation above 72D2
D2 occupancy predicts prolactin elevation (F1,20
7.3, p lt 0.01)
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Risperidone 5-HT2 D2 Occupancy
Threshold for EPS
Threshold for Response
EPS
Kapur, Zipursky and Remington, American Journal
of Psychiatry, 1999.
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Olanzapine 5-HT2 D2 Occupancy
EPS Prolactin ?
EPS and/or prolactin elevation
Kapur, Zipursky and Remington, American Journal
of Psychiatry, 1999.
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Practical Aspects of Treatment
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Practical Issues

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

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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

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Psychosocial Treatments
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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