1. How antipsychotics work: Attaching to receptors and changing reality
Shitij Kapur
Institute of Psychiatry, King’s College London

2. Outline What is ‘psychosis’ A short introduction to a patient
Before we had effective medications
How they came about
How they work

3. Lets meet …

4. Antipsychotic treatments prior to 1951
The whirling chair
Insulin Coma
Artificial Hibernation

5. Radical new treatments for Schizophrenia
RP 4560
aka
CHLORPROMAZINE
‘Largactil’
1950s 5

6. But, how do they work … 6

7. PET neuroreceptor imaging
Cyclotron
11C synthesis
Radio-pharmaco-chemistry
11C- raclopride synthesis
PET Imaging after
11C- raclopride injection
Image Reconstruction
Measures of interest
Modeling of the TACs
Dynamic Time Activity Curves
Region of Interest
D2 receptors
[1.5 or 15 pmol/ml]
Ratio method
Analytic models
50% Occupancy

9. Antipsychotics and D2 Occupancy
11C-Raclopride
PET Scan
11C-Raclopride
PET Scan
Coregistered
MRI Scan
Before
Treatment
Haloperidol
2 mg/d (74% Occ.)
Farde – Karolinska, Wong – Hopkins, Others and Kapur Lab 1990s

10. D2 occupancy predicts clinical response
D2 occupancy predicts response on CGI (p < 0.001)
Predicts change in positive symptoms PANSS (p = 0.07)
Kapur et al. Am. J Psychiatry, 2000

11. 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.

12. Good for science, but, does it make a difference for patients….

13. Knowledge of occupancy data has lead to lower dose recommendations.
Data from Kapur et al. Psychopharmacology (131): , 1998.

14. What we know and what we don’t
What we know now
That antipsychotics act on the dopamine D2 receptor
That you need to block a certain threshold ~ 60%
That if you block too many, you get side-effects
What we still don’t know
Why do some patients not get better even though we do block the receptors?
Why does blocking a receptor change your ideas?