Transcript Linking the Biology, Psychology and

How antipsychotics work:
Attaching to receptors and changing reality
Shitij Kapur
Institute of Psychiatry, King’s College London
Outline
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What is ‘psychosis’
A short introduction to a patient
Before we had effective medications
How they came about
How they work
Lets meet …
Antipsychotic treatments prior to 1951
The whirling chair
Insulin Coma
Artificial Hibernation
Radical new treatments for Schizophrenia
S
N
Cl
CH3
N
CH3
RP 4560
aka
CHLORPROMAZINE
aka
‘Largactil’
1950s
But, how do they work …
PET neuroreceptor imaging
Measures of interest
D2 receptors
[1.5 or 15 pmol/ml]
Radio-pharmaco-chemistry
11C- raclopride synthesis
Modeling of the TACs
Striatum
Cerebellum
Ratio method
PET Imaging after
11C- raclopride injection
Image Reconstruction
Dynamic Time Activity Curves
600
550
DETECTED ACTIVITY
Cyclotron
11C synthesis
500
450
400
350
Analytic models
90
50% Occupancy
  alotofmath
0
300
250
200
10
20
30
40
50
TIME
60
70
80
Region of Interest
Antipsychotics and D2 Occupancy
11C-Raclopride
PET Scan
Before
Treatment
Coregistered
MRI Scan
11C-Raclopride
PET Scan
Haloperidol
2 mg/d (74% Occ.)
Percent Responders (CGI)
D2 occupancy predicts clinical response
100
80
60
Non Responders
Responders
40
20
0
<65%
> 65%
Striatal D2 Occupancy
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
D2 occupancy predicts EPS/akathisia
Subjects with
EPS or akathisia
D2 Occupancy
78%
NO subject < 78%
showed EPS/akathisia
Individual Subjects
Kapur et al. American Journal of Psychiatry, 2000.
Good for science, but, does it make a difference for patients….
Knowledge of occupancy data has
lead to lower dose recommendations.
Dopamine D 2 receptor occupancy
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
Haloperidol plasma levels in ng/ml
1mg/d 2.5 mg/d
Data from Kapur et al. Psychopharmacology (131): 148-152, 1998.
5 mg/d
8
9
10
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?