1. Choosing an Antipsychotic
REFRENCES

3. primary
dopamine
deficiency
D2
receptor
blockad
e
increase in
negative and
secondary cognitive
dopamine symptoms
deficiency
mesocortical pathway
10-11 Stahl S M, Essential
Psychopharmacology (2000

4. Mechanism of Action of Antipsychotic Drugs
Dopaminergic Pathways
Goals: Presynaptic
Dopaminergic Neuron
To quiet hyperactive DA
neurons that mediate
psychosis
Autoreceptor
To trigger underactive DA
neurons that mediate Antipsychotic drug
negative and cognitive
symptoms Postsynaptic receptor
To preserve physiologic
function in DA neurons that
regulate movement and Postsynaptic neuron
prolactin secretion

5. Older and newer antipsychotics show, in
general, approximately the same efficacy
in countering symptoms of auditory and
visual hallucinations, delusional thoughts,
and incoherent speech.

6. Difference Between Low and
High States
•The dissociation constant (K) of dopamine for the high-
affinity state of the D2 receptor is between 1.7 and 1.8nM.
•The traditional antipsychotics generally have dissociation
constants lower than 1.75 nM.
•Virtually all of the atypical antipsychotics have dissociation
constants that are higher than 1.75 nM.
•Some antipsychotics with dissociation constants between
1.8 and 10 nM can exhibit dose-dependent extrapyramidal
signs (EPS)
•Antipsychotics with dissociation constants higher than 20
nM (clozapine, quetiapine, remoxipride) are bound so
loosely that they never elicit

7. Relevant Occupancy
When fewer than 60% of receptors are occupied (ie,
when sub threshold doses are prescribed or when
medication is not taken as prescribed), the symptoms of
psychosis return

8. • Motor Side Effects
At 80% occupancy of D2, most people will begin to experience
these adverse motor effects. (However, patients on the new
atypical compound, aripiprazole, may not exhibit parkinsonism
even with 90% occupation of D2 receptors.[8] This drug needs to
be studied more thoroughly than has been possible thus far.

9. • Why Psychotic Symptoms Wane With Age

10. • Why Higher Doses Are Required Over
Time

11. • Does 65% Occupancy Need to Be
Maintained Full Time?

12. • How to Prevent Tardive Dyskinesia
With First-Generation Drugs

13. How to Prevent the Negative Syndrome
Secondary to Antipsychotic Treatment ?

14. • What Is the Advantage of Tight
Binding?

15. • Treating Patients Who Are Undergoing
Stress

16. • Treating Patients Who Have EPS

17. • Treating First Episodes

18. • Treating Nonadherent Patients

19. • Treating Women

20. • Treating Cardiac Patients or Those
With a Family History of Cardiac
Disease

21. • Treating Patients With a Family History
of Osteoporosis

22. • Treating Patients With a Family History
of Diabetes

23. • Treating Treatment-Refractory Patients

24. • Treating Patients With Sexual
Dysfunction

25. • Avoiding Obesity

26. Differences among Antipsychotic
Drugs
• All effective antipsychotic drugs block D2 receptors
• Chlorpromazine and thioridazine
– block α1 adrenoceptors more potently than D2 receptors
– block serotonin 5-HT2 receptors relatively strongly
– affinity for D1 receptors is relatively weak
• Haloperidol
– acts mainly on D2 receptors
– some effect on 5-HT2 and α1 receptors
– negligible effects on D1 receptors
• Pimozide and amisulpride†
– act almost exclusively on D2 receptors

27. Differences among Antipsychotic
Drugs
• Clozapine
– binds more to D4, 5-HT2, α1, and histamine H1
receptors than to either D2 or D1 receptors
• Risperidone
– about equally potent in blocking D2 and 5-HT2
receptors
• Olanzapine
– more potent as an antagonist of 5-HT2 receptors
– lesser potency at D1, D2, and α1 receptors
• Quetiapine
– lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors

28. Differences among Antipsychotic
Drugs
• Clozapine, olanzapine and quetiapine
– potent inhibitors of H1 histamine receptors
– consistent with their sedative properties
• Aripiprazole
– partial agonist effects at D2 and 5-HT1A
receptors

29. Conclusion
• In summary, conventional antipsychotic drugs
bind tightly to the dopamine D2 receptors,
thereby eliciting EPS, elevated prolactin, and
tardive dyskinesia. The newer atypical
antipsychotic drugs attach more loosely to the
D2 receptors, thus resulting in less or no EPS,
no elevation of prolactin, and no risk of tardive
dyskinesia. Good clinical practice involves using
both types of medication at different times,
depending on the specific needs of the patient.