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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