1. Psychopharmacology: Anti-psychotic Medications
Brian Ladds, M.D.

2. Outline Role of dopamine in psychosis Dopamine pathways
Dopamine receptors
Anti-psychotic medication
Mechanism of action
Classification
Side effects

3. Schizophrenia: The Dopamine Hypothesis
Chance discovery:
Chlorpromazine (Thorazine) reduced psychosis
It was found to block the effects of dopamine
The “dopamine hypothesis” posits that the development of schizophrenia involves an overactive dopamine system in the brain

4. Dopamine One of the key neurotransmitters in the brain, together with:
other ‘monoamine’ neurotransmitters:
norepinephrine, serotonin, acetylcholine
and the commonest neurotransmitters:
glutamate, GABA
Dopamine is released by a relatively small number of neurons, but serves important regulatory functions

6. Dopamine Pathways Several different dopamine pathways
all originate in the mid-brain
2 of the main clusters of nuclei are:
Ventral Tegmental Area (VTA)
meso-limbic/meso-cortical pathway
Substantia nigra
nigro-striatal pathway

7. Dopamine Pathways VTA (ventral tegmental area):
Mesolimbic & mesocortical pathways
projects to limbic system and to the pre-frontal cortex
primary path for production of psychosis
target for anti-psychotic medications
blockade of the post-synaptic dopamine receptors

8. Dopamine Pathways Substantia nigra: Nigro-striatal pathway
projects to the striatum (caudate and putamen)
anti-psychotic medications block the post-synaptic dopamine receptor in the striatum causing motoric side effects (e.g., rigidity and tremors)

9. Dopamine Pathways Arcuate and peri-ventricular nuclei:
Tubero-infindibular pathway
project to the pituitary
inhibits prolactin release
some anti-psychotic medications cause increased prolactin release (by blocking dopamine) and cause galactorrhea

10. Dopamine Receptors D-2 receptors
main site of action for the anti-psychotic effect of many medications
clinical potency for many of the older conventional anti-psychotic medications correlates with their affinity for the post-synaptic D-2 receptor

11. Dopamine Receptors D-3 and D4 receptors
May also be involved in the actions of some of the newer “atypical” anti-psychotic medications
These receptors are present more in limbic areas than in striatum
Therefore there are less motoric side effects with the newer “atypical” medications

12. Anti-psychotic Medication: Mechanism of Action
Anti-psychotic medications all involve blockade of the post-synaptic D-2 dopamine receptor
The therapeutic actions of the newer “atypical” anti-psychotic medications:
May also involve blockade of other types of dopamine receptors, and,
blockade of certain post-synaptic serotonin receptors

13. Anti-psychotic Medication: Classification
Conventional (typical) medications
vs. “atypical” anti-psychotic medications
Affinity for the D-2 receptor is related to clinical potency (especially for the conventional meds)
high affinity -> low dose
e.g., haloperidol (Haldol), fluphenazine (Prolixen)
low affinity -> high dose
e.g., chlorpromazine (Thorazine), thioridazine (Mellaril)

14. Side Effects
Low potency anti-psychotic medication (e.g., chlorpromazine) cause more of the non-motoric side effects
sedation (H-1 blockade)
hypotension (alpha-adrenergic blockade)
anti-cholinergic

15. Anti-cholinergic Side Effects
Blurred vision
Urinary retention
Constipation
Dry mouth
(Confusion)

16. Side Effects
High potency anti-psychotic medication (e.g., haloperidol) cause more of the neurological and motoric side effects
EPS TD
NMS

17. Extra-pyramidal Symptoms
Parkinsonian-like symptoms
“Parkinson’s Disease” = too little dopamine
due to degeneration of dopaminergic neurons
bradykinesia
rigidity
shuffling gait
tremor

18. EPS cont.’ Dystonia: sudden spasms of head/neck muscles
Akathisia: restlessness
subjective and/or objective

19. EPS: Causes and Treatment
Nigro-striatal pathway finely regulates initiation and coordination of movements
DA inhibits acetycholine release in the striatum
Anti-psychotic medications block DA in striatum causing too much Ach there and thus EPS

20. EPS: Treatment
Treatment with anti-cholinergic medication decreases EPS
benztropine (Cogentin)
diphenhydramine (Benadryl)

21. Tardive Dyskinesia
Involuntary choreo-athetoid movements of mouth, tongue, and other muscles
generally irreversible
after chronic use (> 3 months) of anti-psychotic
10-20% of patients on conventional AP after 1 year get TD
usually mild, but can be severe
elderly and women at highest risk
etiology: upregulation of striatal D-2 receptor

22. Neuroleptic Malignant Syndrome
NMS
fever
muscular rigidity
autonomic instability
tachycardia
increased blood pressure
fluctuating levels of consciousness
Rare, but has 20% mortality
Males and younger people are at higher risk

23. “Atypical” Anti-psychotic Meds
Clozapine (Clozaril)
Risperidone (Risperidal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)

24. “Atypical” Anti-psychotic Meds
Efficacy:
Generally comparable to conventional meds
May have some superior effects
Clozapine helps where conventional meds fail
They may help more with “negative symptoms”
Side effect profile:
Superior to conventional meds
Little EPS, less TD, less sedation, less anti-cholinergic
Some may cause EKG changes, weight gain, or increase in serum glucose

25. “Atypical” Anti-psychotic Meds
May have different mechanism of action
? more DA blockade in mesolimbic pathway
including more D-3 and D-4 ?
? weak D-2 antagonists, esp. in striatum
Minimal EPS
?? Increases DA in frontal cortex ??
? Improves negative symptoms

26. Clozapine Clozapine agranulocytosis 1% weekly cbc tests
approved only for treatment-refractory schizophrenia seizure risk 3-5%, dose-dependant