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Antipsychotic Agents MS2 Lecture Sean Conrin MD. Contents  Psychosis and Schizophrenia  The Framework Neuroanatomy Circuits Important Neurotransmitters.

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Presentation on theme: "Antipsychotic Agents MS2 Lecture Sean Conrin MD. Contents  Psychosis and Schizophrenia  The Framework Neuroanatomy Circuits Important Neurotransmitters."— Presentation transcript:

1 Antipsychotic Agents MS2 Lecture Sean Conrin MD

2 Contents  Psychosis and Schizophrenia  The Framework 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) Psychosis Primary Psychotic Illness Primary Mood Disorder Medical and Substance

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 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  “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

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  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

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

15 NameAverage 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)

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

17 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!

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

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

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