Antipsychotic Agents MS2 Lecture Sean Conrin MD
Feb 24, 2016
Antipsychotic Agents
MS2 Lecture
Sean Conrin MD
Contents
Psychosis and Schizophrenia The Framework
• Neuroanatomy• Circuits• Important Neurotransmitters
Anti-psychotics• Dopamine Hypothesis• Typical Antipsychotics• Atypical Antipsychotics• Side Effects
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 (?)
Psychosis is like a fever!(It can happen for a number of reasons)
Psychosis
Primary Psychotic Illness
Primary Mood DisorderMedical and Substance
DSM V - SchizophreniaA – 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
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
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)
The Brainstem Midbrain
“Meso” Substantia-Nigra Dopamine
Pons Contains Locus
Coeruleus (NE) Medulla
Pyramids (EPS!) Raph Nuclei
Located throughout brainstem
Serotonin
Hypothalamus and Pituitary
Basal Ganglia
The Brain Has a “Few” Connections
These are the main connections involving dopamine Limbic System Cortex Tubero
Mesocortical (cognition)Mesolimbic (hallucinations)Nigrostriatal (movement)Tuberoinfundibular (prolactin)
Typicals 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
Clozapine 1989 Risperidone 1993 Olanzapine 1996 Quetiapine 1997 Ziprasidone 2001 Aripiprazole 2002 Asenapine 2009 Iloperidone 2009 Lurasidone 2010
Atypical Antipsychotic Release Dates
Name Average Cost
Aripiprazole $576
Chlorpromazine $38
Clozapine $278
Haloperidol $14-21
Paliperidone $532
Quetiapine $549
Risperidone $256
Ziprasidone $538
Monthly Cost of Antipsychotic Medications (From Consumer Reports 2009)
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
High vs Low Potency Potency
- 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!
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
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
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
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”
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
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
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