1. MS2 Lecture Sean Conrin MD
Antipsychotic Agents
MS2 Lecture
Sean Conrin MD

2. Contents Psychosis and Schizophrenia The Framework Anti-psychotics
Neuroanatomy
Circuits
Important Neurotransmitters
Anti-psychotics
Dopamine Hypothesis
Typical Antipsychotics
Atypical Antipsychotics
Side Effects

3. Psychosis – What is it? 1. Being “out of touch” with reality
2. Alternate definition similar to similar symptoms listed as part of diagnostic criteria.
Hallucinations (lack of insight)
Delusions
Disorganized/catatonic behavior
Negative symptoms (?)

4. Psychosis is like a fever! (It can happen for a number of reasons)
Primary Psychotic Illness
Psychosis
Primary Mood Disorder
Medical and Substance
Psychosis is like a fever! (It can happen for a number of reasons)

5. DSM V - Schizophrenia
A – Two or more for significant portion of a 1-month period. One must be of the first three
1. Delusions
2. Hallucinations
3. Disorganized Speech
4. Grossly disorganized/catatonic behavior
5. Negative symptoms
B – During this time, impairment in functioning in at least one domain

6. DSM V - Schizophrenia
C – Continuous signs of disturbance for at least 6 months (w/ one month of full criteria A symptoms) in the form of attenuated A, prodromal or negative symptoms.
D – Not part of another illness
E – No due to a substance or medical condition
F – If autism or communication disorder, only diagnose if prominent delusions or hallucinations are present for one month
Specifications for episode pattern
Specifications for severity (1-5 scale) of each symptom domain

7. Dopamine Hypothesis
In 1950’s discovery that Chlorpromazine administration led to less response to adverse stimuli in rats.
- Initially thought it was H1 effects
- Methylene Blue is also a phenothiazine
Gave it to humans and saw that it worked well
100 million have been treated at least (same scale as antibiotics)
Learned it’s main effect was on dopamine
Affects all dopamine pathways (good and bad)

8. The Brainstem Midbrain Pons Medulla Raph Nuclei “Meso”
Substantia-Nigra
Dopamine
Pons
Contains Locus Coeruleus (NE)
Medulla
Pyramids (EPS!)
Raph Nuclei
Located throughout brainstem
Serotonin

9. Hypothalamus and Pituitary

10. Basal Ganglia Caudate Putamen Globus Pallidus Thalamus
Subthalamic Nuclei
Lentiform = Putamen and Globus Pallidus
Striatum = Caudate and Putamen (nigrostriatal pathway)
So this area majorly important in movement/parkinsonism and side effects

11. The Brain Has a “Few” Connections
These are the main connections involving dopamine
Limbic System
Cortex
Tubero

12. Mesocortical (cognition)
Mesolimbic (hallucinations)
Nigrostriatal (movement)
Tuberoinfundibular (prolactin)

13. Typicals Atypicals Atypical, Atypical - Chlorpromazine
High Potency
- Haldol
- Fluphenazine
- Prochlorperazine
Low Potency
- Chlorpromazine
- Thioridazine (Retinitis Pigmentosa – buzzword alert)
Atypicals
Risperdal (functions like typical at higher doses)
Quetiapine (titrate so pt doesn’t fall)
Aripiprizole (partial D2 antag)
Ziprasidone (QT prolong)
Lurasidone (new)
Iloperidone (new – titrate to avoid falls)
Asenapine (new – dissolved under tongue)
Atypical, Atypical
Clozapine
- WBC/ANC monitoring for risk of agranulocytosis
- Indicated for suicidality in schizophrenia
- Most effective
Iloperidone – fanapt
Asenapine – saphris
Thioridazine – Mellaril
Prochlorperazine – compazine
Trifluoperazine - Stelazine

14. Atypical Antipsychotic Release Dates
Clozapine 1989
Risperidone 1993
Olanzapine 1996
Quetiapine 1997
Ziprasidone 2001
Aripiprazole 2002
Asenapine 2009
Iloperidone 2009
Lurasidone 2010

15. Monthly Cost of Antipsychotic Medications (From Consumer Reports 2009)
Name
Average Cost
Aripiprazole
$576
Chlorpromazine
$38
Clozapine
$278
Haloperidol
$14-21
Paliperidone
$532
Quetiapine
$549
Risperidone
$256
Ziprasidone
$538

16. Typical vs Atypical Refers to extrapyramidal symptoms
- Old vs New
- Cheap vs Expensive
EPS (1st gen > 2nd gen)
- Parkonsonism
- Tardive Dyskinesia
- Akathisia
- Dystonic Reaction
Cardiometabolic (2nd gen > 1st gen)
- Weight
- Glucose
- Lipids
- Cardiovascular

17. High vs Low Potency Potency High Potency (2-20mg)
- Refers to potency at D receptors
- Think ETOH (wine < potent than rum so you need less rum to have the same effect)
High Potency (2-20mg)
- More likely to cause EPS
Low Potency (100’s-2,000mg)
- More H1/Ach/Alpha blockade
Be able to identify High vs Low based on milligrams and say how they differ!

18. Dystonic Reactions
Nigrostriatal – D2 blockade leads to increased ACH. This causes inhibition of spontaneous movement and parkinson like symptoms.
Dystonias + parkinsonism
Benztropine – (cogentin) is an anti-cholinergic, this realigns the balance and decreases EPS
High vs Low Potency – Low potency drugs such as thioridazine have significant anticholinergic properties.
Compared to high potency, like haloperidol cause less eps

19. Tardive Dyskinesia
Tardive dyskinesia – prolonged blockade of D2 receptors leads to upregulation of D2 receptors.
Causes hyperexcitability: writhing tongue and hand movements,
5% per year on typicals
NOT FIXED BY BENZTROPINE!
AIMS
Antipsychotic

20. Akathisia Inner sense of restlessness
Can lead to increased violence or suicide
Can be treated with propranolol, some give benzos or anticholinergics (not as effective)
Often misclassified, especially in antidepressant trials and can be hard to recognize in DD or nonverbal patients.
Barnes Akathisia Scale

21. Anticholinergic Effects
“Red as a beet” (loss of sweating so vasodilation occurs)
“Dry as a bone” (loss of sweating)
“Hot as a hare” (loss of sweating)
“Blind as a bat” (pupillary constriction and effective accommodation blocked – blurry vision)
“mad as a hatter” (delirium/hallucinations)
“Full as a flask”

22. Atypicals Huh? – Basically low eps, and good(?) for negative symptoms
So? – Four proposed mechanisms
Serotonin/dopamine antagonism
D2 antagonism w/ rapid disassociation
D2 partial agonists
Serotonin partial agonists
This helps to reduce the total d2 blockade and avoids eps and tardive. Leads to cardiometabolic effects

23. So What’s the Deal?
Weight Gain – antipsychotic drugs act on hypothalamus and stimulate appetite. Antagonism of alpha adrenergic, dopamine, histamine 1, glutamate, muscarinic type 1, 5HT2A and 5HT2C
Some evidence regarding concurrent H1 and 5HT2C antagonism – Especially Problematic
Also – 2nd gens might work on peptides galanin, neuropeptide U and leptin

24. Atypical Antipsychotics and Weight Gain
10 weeks on drug
Ziprasidone 0.09 pounds
Haloperidol 1.1 pounds
Aripiprazole 1.6 pounds
Risperidone 4.4 pounds
Chlorpromazine 4.7 pounds
Olanzapine 7.8 pounds
Thioridazine 7.8 pounds
Clozapine 8.9 pounds
Bowl of icecream and a coke everynight can cause significant weight gain – 1 pound of fat/week and when you gain a pound of fat you gain a few pounds of water weight – small increase in appetite can lead to major effects.