MS2 Lecture Sean Conrin MD Antipsychotic Agents MS2 Lecture Sean Conrin MD

Contents Psychosis and Schizophrenia The Framework Anti-psychotics 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) Primary Psychotic Illness Psychosis Primary Mood Disorder Medical and Substance Psychosis is like a fever! (It can happen for a number of reasons)

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

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

Hypothalamus and Pituitary

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

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 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

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

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

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 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!

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 This helps to reduce the total d2 blockade and avoids eps and tardive. Leads to cardiometabolic effects

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 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.