WPA The Pharmacology of Second Generation Neuroleptics.
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Transcript of WPA The Pharmacology of Second Generation Neuroleptics.
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The Pharmacology of The Pharmacology of Second Generation Second Generation
NeurolepticsNeuroleptics
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Structure of SerotoninStructure of Serotonin
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Distribution of SerotoninDistribution of Serotonin
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Combined Serotonin and Combined Serotonin and Dopamine PathwaysDopamine Pathways
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Receptor Binding Affinities Receptor Binding Affinities of Three Atypical Antipsychoticsof Three Atypical Antipsychotics
Kasper, Data from:Schotte et al., 1996
Olanzapine
5-HT2A
5-HT2C
AChM
H1
1
D210
1
0.1
0.01
0.001
0.0001
D2
5-HT2A
5-HT2C
AChM
H1
2 1
Risperidone
10
1
0.1
0.01
0.001
0.0001
Clozapine
5-HT2A
5-HT2C
AChM
H1
2 1
D210
1
0.1
0.01
0.001
0.0001
(No data availablefor 2-receptors)
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Neuroleptic Receptor Neuroleptic Receptor PiesPies
ClozapineClozapine OlanzapineOlanzapineQuetiapineQuetiapineDD11
DD22
5-HT5-HT2A2A
5-HT5-HT1A1A
AA11
AA22
HH11
MuscarinicMuscarinic
ZiprasidoneSertindole Risperidone Haloperidol
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Receptor-pies Reflect an Abstract Concept In Humans the Effects Are a Function of Dose
5-HT2
5-HT2D2
D2
B B B BB
BB
B
B
B
B
B
B
BB
BB B B B B B B B B B B B B
J J J J J J J JJ
JJ
J
J
J
J
J
JJ
JJ J J J J J J J J J
0
10
20
30
40
50
60
70
80
90
100
Dose of the S2/D2 medication
5-HT2 5-HT2
5-HT2
D2D2
D2
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Using Imaging Tools to Using Imaging Tools to Develop Rational Develop Rational Dosing StrategiesDosing Strategies
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D2 Receptor BindingD2 Receptor Binding
•The ligand C11-The ligand C11-Raclopride is Raclopride is injected prior to injected prior to PET study.PET study.Areas of high Areas of high uptake (high D2 uptake (high D2 occupancy) are occupancy) are shown in red.shown in red.
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Haloperidol and D2 Occupancy
11C-Raclopride PET Scan
Coregistered MRI Scan
BeforeTreatment
Haloperidol2 mg/d (74% Occ.)
11C-Raclopride PET Scan
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DD22 Occupancy Predicts Clinical Occupancy Predicts Clinical
ResponseResponse
Striatal D2 Occupancy
<65% > 65%
Per
cent
Res
pond
ers
(CG
I)
0
20
40
60
80
100
Non RespondersResponders
Kapur et al. Am. J Psychiatry, 2000
D2 occupancy predicts response on CGI (p < 0.001)Predicts change in positive symptoms (p = 0.07)
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DD22 Occupancy Predicts EPS/akathisia Occupancy Predicts EPS/akathisia
Individual Subjects
D2
Occ
up
ancy
Subjects withEPS or akathisia
NO subject < 78%showed EPS/akathisia
Kapur et al. American Journal of Psychiatry, 2000.
78%
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DD22 Occupancy Predicts Occupancy Predicts
Prolactin ElevationProlactin Elevation
30 40 50 60 70 80 90 100
Dopamine D 2 Receptor Occupancy
0
20
40
60
80
100
120
Pro
lac
tin
Le
ve
ls (
ng
/ml)
D2 occupancy predicts prolactin elevation (F1,20 = 7.3, p < 0.01)
2 of 15 show prolactin
elevation below 72%D2
5 of 6 show prolactin
elevation above 72%D2
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0 2 4 6 8 10 12Risperidone dose mg/day
0
10
20
30
40
50
60
70
80
90
100
Re
ce
pto
r O
cc
up
an
cy
(%
)
D2 Occupancy5-HT2 Occupancy
Risperidone 5-HTRisperidone 5-HT22 & D & D22
OccupancyOccupancy
EPS
Threshold for Response
Threshold for EPS
Kapur, Zipursky and Remington, American Journal of Psychiatry, 1999.
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0 10 20 30 40 50Olanzapine dose mg/day
0
10
20
30
40
50
60
70
80
90
100
Rec
epto
r O
ccu
pan
cy (
%)
LegendD2 data5-HT2 data
Olanzapine 5-HTOlanzapine 5-HT22 & D & D22
OccupancyOccupancy
EPS + Prolactin *
EPS and/or prolactin elevation
Kapur, Zipursky and Remington, American Journal of Psychiatry, 1999.
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Practical Aspects Practical Aspects of Treatmentof Treatment
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Practical IssuesPractical Issues
• DosageDosage• Use of AnticholinergicsUse of Anticholinergics• Oral vs. Depot NeurolepticsOral vs. Depot Neuroleptics• Reducing or Discontinuing Reducing or Discontinuing
MedicationMedication• Long-term OutcomeLong-term Outcome• Early interventionEarly intervention
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Can Early Intervention Can Early Intervention Prevent Disease Prevent Disease
Progression?Progression?• Early diagnosis is difficultEarly diagnosis is difficult• It is also hampered by stigmaIt is also hampered by stigma• There is minimal to no evidence There is minimal to no evidence
for a direct toxic brain effect of for a direct toxic brain effect of untreated psychosisuntreated psychosis
• However, the psychological However, the psychological impact of untreated psychosis impact of untreated psychosis may be significantmay be significant
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Psychosocial Psychosocial TreatmentsTreatments
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Psychosocial StrategiesPsychosocial Strategies• Facilitation of pharmcotherapyFacilitation of pharmcotherapy• Token economy systemToken economy system• Carer-based stress managementCarer-based stress management• Living skills trainingLiving skills training• Social case managementSocial case management• Educational Techniques and Family Educational Techniques and Family
TherapyTherapy• Cognitive-Behavioral InterventionsCognitive-Behavioral Interventions• Sustaining the benefitsSustaining the benefits