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3 diagnosis
At least 1 + symptom and 1 other symptoms
Over 6 months
No evidence of Drug induced or mood disorders
3 domains of major symptoms
Positive
Negative
Cognitive defects
4 positive symptoms
Hallucinations, Delusions
Disorganized speech/formal thought disorder
Disorganized/bizarre/tanatonic behavior
4 negative symptoms
Alogia
Affective blunting
Anhedonia
Avolition/amotivational
4 cognitive defects
Tangentiality
Incoherence
Looseness of Associations
Neologisms
4 theories of psychotic disorders
Dopamine hypothesis
Serotonin
Glutamate
Neurodevelopmental
What's glutamate hypothesis
NMDA antagonists cause negative symptoms and cognitive defects
What's Nigrostriatal pathway? What's DA do?
Motor control.
Increase in DA causes PA
2 endocrine pathways
Tuberoinfundibular
Tuberohypophyseal
DA decrease prolactin release
3 therapeutic indications for antipsychotic agents
Psychotic disorders
neurologic disease
Motion sickness
4 neurologic diseases
tourette's syndrome
Huntington's disease
Lesch-Nyhan
Dementia/alzheimer's
Parkinson disease caused by what receptor?
D2 antagonists
Drug treatment works best for acute episodes of?
+ symptoms
How long would it take to have full efficacy?
Acute episode responds faster or slower?
2-6 weeks
Faster
Slowly tapering the dose would increase or decrease relap?
Avoid what kind of SE?
decrease
Extrapyramidal SE
What do D2 like receptor subtype antagonism do to + symptoms?
Decrease + symptoms via decreasing NAC DA signaling
What do D2 like receptor subtype antagonism do to - symptoms?
Worsen - symptoms due to decrease PFC signaling
4 MOA of SE
D2 like antagonism
A 1 antagonists
Antimuscarinic
H1 receptor blockade
3 SE D2 like antagonism causes?
Parkinson like symptoms initially
TD with prolong treatment
Gynecomastia: increase prolactin
3 SE caused by A 1 antagonists
Dizziness
Postural Hypotension
Reflex tachycardia
5 SE caused by antimuscarinic activities
Blurred vision, Dry mouth, Contipations
Relieves initial parkinsonism
Worsen TD
H1 receptor blockade causes? (2)
Sedation
Weight gain due to 5 HT2C
High potency drugs cause more or less Parkinsonian SE?
More SE vs other SE's
order of 5 receptors
D2
Musc
A1
H1
5HT
2 drugs with low potency
Chlorpromazine
Thioridazine
Potency for Chlorpromazine
+
++
+++
+++
+
Thioridazine has same potency as?
With higher affinity for
Chlorpromazine
Muscarinics
5 drugs with mid potency
Chlorprothixene
Perphenazine
Prochlorperazine
Triflupromazine
Acetophenazine
Affinity of chlorprothixene
2
2
2
3
Affinity of Perphenazine
2
2
1
2
Affinity of Prochlorperazine
2
1
1
1
TRiflupromazine has same affinity as?
Without affinity for?
as prochlorperazine
No H1 and 5HT
Affinity of Acetophenazine
2 for D2
+/- for A1
+ for H1
4 drugs with high potency for D2
Thiothixene
Trifluoperazine
Loxapine
Pimozide
2 drugs with very high potency for D2
Haloperidol
Fluphenazine
Affinity of Thiothixene
3
1
1
1
+/-
Affinity of Trifluoperazine
3
1
1
1
Affinity of Loxapine
3
1
2
2
2A
Affinity of Pimozide
3
0
+/-
1
1
Affinity of Haloperidol
4
+/-
+/-
+/-
2A
Affinity of fluphenazine
4
1
2
1
4 extrapyramidal SE
parkinson like
Dystonia
Akathisia
Tardive Dyskinesia
5 symptomos of parkinson-like
catatonia
Motor rigidity
Tremor
Bradykinesia
Parkinson like caused by? what med could help to decrease this SE
caused by D2 blockade
L-dopa decreases SE but also decreases therapeutic effects
What's dystonia? caused by?
Involuntary muscle contractions that cause bizarre and uncontrolled movements of face, neck and tongue
D2 blockade
What's Akathisia? caused by?
severe restlessness and agitation
NOT caused by D2 blockade
What's Tardive dyskinesia/ related by?
Movements are continuous during walking
Related to increased dose and increased duration of treatment
What 2 drugs could increase TD severity?
anticholinergics
L dopa
4 symptoms of signs and symptoms of TD
Chewing licking movements
Tongue protrusions
Limb movements
4 pathogenesis of TD
D2 receptor hypersensitivity
D2 subtype theory
GABA hypothesis
ABnormal D2/D1 ratio
D2 receptor hypersensitivity theory
Continuous exposure to DA antagonists causes increased receptor number or increased sensitivity to DA
GABA hypothesis
Decreased striatal GABA activity
Abnormal D2/D1 ratio theory
D1 agonists cause more TD if D2 receptors blocked
3 treatment options for TD
Drug holidays
discontinue antipsychotic treatment
Switch to atypical antipsychotic
What's the drawback of drug holidays
Decrease dose until symptoms decrease may return more severe even at lower dose
Characteristics of atypical antipsychotics
less potent for extrapyramidal and prolactin SE
More efficacy, less sedation, cognitive impairment, catalepsy, less TD with prolonged use
2 proposed mechanisms of atypical antipsychotics
Subregional selectivity of receptor subtype population
Dose response separation between therapeutic and motor effects
receptors in the Frontal cortex
Striatum
NAC
FCTX: 90% D3/4
Striatum 90% D2
NAC 70% D2 30% D3
Blockade of frontal cortex 5HT-2 receptors stops
serotonin inhibition of mesocortical dopamine
How much D2 receptor occupancy causes Akathisia
55-65%
How much D2 receptor occupancy causes EPS
80%
how much D2 occupancy is required for a typical drug to work?
70%
how much D2 occupancy does an atypical drug require?
20%
8 agent non specific SE
Weight gain, impaired glucose tolerance, hyperlipidemia, Stroke, Seizure, HTN, increased mortality in elderly with dementia, EPS, malignant syndrome
5 Symptoms of malignant syndrome
Catatonia, stupor, fever, unstable BP, myoglobinemia
MOA of malignant syndrome
unknown but related to DA receptor antagonism
How to treat malignant syndrome
stop therapy and give dantrolene or bromocriptine
SE of clozapine
agranulocytosis
Blocks K channel- QT prolongation
Ziprasidone
sertindole
thioridazine
2 SE of risperidone and paliperidone
Increased risk of stroke
Worst EPS and gynecomastia of atypical class
SE of olanzapine
Risk of stroke
Worst weight gain
SE of Lurasidone
Less EPS
Effective for depression and anxiety
SE of aripiprazole
increase risk of stroke
First 6 Atypical drugs
Clozapine,
Risperidone, paliperidone, iliperidone,
Olanzapine
Quetiapine
last 6 atypical drugs
Ziprasidone, Lurasidone
Aripiprazole, Asenapine
Sertindole, Zotepine
Affinity for Clozapine
D2-4, 1
3
1
3
2A,C
Affinity for risperidone
D2-4
0
2
1
2A,C
Affinity for Olanzapine
D2-4
3
1
1
2A,C
Affinity for Quetiapine
D1,2
+/-
2
1
part 1A,2
Affinity for ziprasidone
D2,3
-
+
+
2A,C,1D part 1A
Affinity for Lurasidone
D2
-
-
-
7, 2A, 1A agonist
affinity for aripiprazole
Part D2
-
-
-
2, part 1A
Affinity for Asenapine
D3
-
+
+
2, part 1A
Affinity for Sertindole
D2-4
-
+
-
2, part 1A
Affinity for Zotepine
D1,2
-
NE-T
2
2A,C
2 atypical drugs with high antimuscarinic activity
clozapine
olanzapine
the only atypical drug with high sedation property
clozapine
atypical drug that binds to 5HT7
lurasidone
2 atypical drugs that bind to NE-T
ziprasidone
Zotepine