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