How antipsychotics work:Attaching to receptors and changing reality

Shitij Kapur

Institute of Psychiatry, King’s College London

Outline

• 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

Artificial Hibernation

Insulin Coma

The whirling chair

Radical new treatments for Schizophrenia

1950s

S

N Cl

NCH3

CH3

RP 4560aka

CHLORPROMAZINEaka

‘Largactil’

But, how do they work …

PET neuroreceptor imaging

Cyclotron11C synthesis

Radio-pharmaco-chemistry11C- raclopride synthesis Image Reconstruction

PET Imaging after11C- raclopride injection

10 20 30 40 50 60 70 80TIME

200

250

300

350

400

450

500

550

600

DE

TE

CT

ED

AC

TIV

ITYD2 receptors

[1.5 or 15 pmol/ml]Ratio method

Analytic modelsalotofmath

0

90

Striatum

Cerebellum

50% Occupancy

Region of InterestDynamic Time Activity CurvesModeling of the TACsMeasures of interest

Antipsychotics and D2 Occupancy

11C-Raclopride PET Scan

Coregistered MRI Scan

BeforeTreatment

Haloperidol2 mg/d (74% Occ.)

11C-Raclopride PET Scan

Farde – Karolinska, Wong – Hopkins, Others and Kapur Lab 1990s

D2 occupancy predicts clinical response

Striatal D2 Occupancy

<65% > 65%

Pe

rce

nt R

esp

on

de

rs (

CG

I)

0

20

40

60

80

100

Non RespondersResponders

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

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%

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

Knowledge of occupancy data has lead to lower dose recommendations.

Data from Kapur et al. Psychopharmacology (131): 148-152, 1998.

0 1 2 3 4 5 6 7 8 9 10

Haloperidol plasma levels in ng/ml

0

10

20

30

40

50

60

70

80

90

100

Do

pam

ine

D2

rece

pto

r o

ccu

pan

cy

1mg/d 2.5 mg/d 5 mg/d

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?