Schizophrenia and Antipsychotics

Question 1

Types of Schizophrenia

Answer 1

Paranoid, Disorganized, Catatonic, Undifferentiated, and Residual

• Schizophreniform disorder: early disease/first break
• Schizoaffective disorder: combined with bipolar
• Psychotic disorder due to general medical condition or substance abuse

Question 2

DSM-IV Criteria for Schizophrenia

Answer 2

1. Two or more of the following in a one month period: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms
2. Social/occupational dysfunction from above symptoms
3. Continuous signs of the disorder for 6 months
4. Exclude mood disorders with psychotic symptoms
5. Not due to medical disorder or substance abuse
6. If a history of pervasive developmental disorder is present (PDD), must have hallucinations/delusions for one month

Question 3

Positive vs Negative symptoms

Answer 3

Positive: hallucinations, delusions, disorganized speech, bizarre behaviors, psychomotor agitation

Negative: alogia, flattened affect, avolition, anhedonia, poverty of speech, psychomotor retardation

Question 4

Types of Schizophrenia symptoms

Answer 4

positive
negative
cognitive
mood symptoms
social and occupational dysfunction

Question 5

Pathophysiology of schizophrenia

Answer 5

Excess of dopamine leads to psychotic s/sx
DA hyperactivity in limbic system
DA hypofunctioning in prefrontal cortex
Decreased glutamate
NMDA receptor dysfunction

Question 6

Typical Antipsychotics (Neuroleptics/Conventional Antipsychotics)

Answer 6

High potency (eg Haldol), mid potency, and low potency (eg thorazine)

All of the above lower DA at all pathways

Question 7

Four DA Pathways

Answer 7

Mesolimbic- lower DA here, decrease positive symptoms :)
Nigrostriatal- lower DA here, create EPS :(
Mesocortical- lower DA here, increase negative symptoms :(
Turberoinfundibular- lower DA here = gynecomastia issues :(

Question 8

Typical Antipsychotic SE

Answer 8

sedation
anticholinergic
cardiac (QTc prolongation)
EPS
neuroleptic malignant syndrome
tardive dyskinesia

Question 9

Tardive Dyskinesia

Answer 9

post-synaptic DA blockade leads to hypersensitivity to DA
neuronal degeneration
20% of all patients per year with conventionals
risk factors: typical agents, elderly, women
presentation: irreversible involuntary movements, blinking, lip smacking, movements of the face, neck, back, trunk, and extremities

Question 10

Neuroleptic Malignant syndrome

Answer 10

0.2% of patients on conventionals
mortality is high, up to 20%

at risk: mood disorders, catatonia, lithium
about 1/3 of NMS cases develop again if re-challenged

diagnosis: treatment with APs within 7 days of onset (2-4 weeks for depots), hyperthermia, muscle rigidity, exclusion of other causes, and five of the following- change in mental status, tremor, tachycardia, labile BP, tachypnea or hypoxia, diaphoresis, incontinence, CPK elevation or myoglobinuria, metabolic acidosis
treat: manage with supportive care, remove DA blocking agent

Question 11

atypical antipsychotics: MOA

Answer 11

D2 and 5HT antagonists (block DA and 5HT)
mesolimbic selectivity for D2 antagonism (decrease SE)
5HT blocking works to decrease EPS and benefits negative s/sx
each drug works on many receptors and works differently

Question 12

Antipsychotic Receptor Activity

Answer 12

D1-5: relief of psychosis, EPS
5HT2: help suppress DA activity, protect from EPS, +weight gain
Alpha 1: orthostatic hypoTN, dizziness
M1: anticholinergic effects, protect against EP (drowsy, dizzy, dry mouth, blurred vision, constipation)
H1: +weight gain, drowsiness

Question 13

Olanzapine (Zyprexa)

Answer 13

DDI: CYP 1A2 substrate (cigarette smoking can decrease efficacy)

Question 14

Risperidone (Risperdal)

Answer 14

doses above 6mg/day begins to clinically look more like typical AP
DDI: CYP 2D6 major substrate, 34A minor substrate

Question 15

Quetiapine (Seroquel)

Answer 15

DDI: CYP 34A major, 2D6 minor
risk of lenticular formations (cataracts)
commonly used for sleep, anxiety, agitation, depression

Question 16

Ziprasidone (Geodon)

Answer 16

must take with food (affects absorption)
DDI: minimal CYP activity
monitor closely with other QTc prolongers (worse than other atypical APs, but better than even low potency typicals)

Question 17

Clozapine (Clozaril)

Answer 17

must start slowly, titrate over 2-3 weeks minimum
NOT a first-line agent due to multiple SE
DDI: CYP 1A major substrate, multiple other CYP interactions
cigarette smoking may decrease drug effect
some antidepressants may increase drug effect
use caution in seizure disorder
use with caution in combo with benzos due to respiratory depression
1% risk of agranulocytosis (must monitor WBC and ANC weekly for first six months of therapy, then continue less frequent monitoring; don’t initiate tx if WBC <2000)

Question 18

Aripiprazole (Abilify)

Answer 18

dopamine modulator (controls receptors to antagonize receptors when DA is increased and agonize receptors when DA is decreased)
antagonist at 5HT2A
partial agonist at 5HT1A
long half-life, good for non compliance
DDI: CYP 2D6 and 34A major substrates

Question 19

Paliperidone (Invega)

Answer 19

• newest availble, active metabolite of risperidone
• once daily dosing due to osmotic pump delivery system
• proposed to have less risk of EPS and prolactin elevation than risperidone, but need more data

Question 20

Atypical AP side effects

Answer 20

anticholinergic, orthostasis, sedation, weight gain, diabetes/metabolic syndrome, lipid abnormalities

clozapine (Clozaril) – olanzapine (Zyprexa) – risperidone (Risperdal) – quetiapine (Seroquel) – ziprasidone (Geodon) – aripiprazole (Abilify)

Question 21

Metabolic syndrome

Answer 21

any three of the following: 
abdominal obesity
hypertension
impaired fasting glucose
decreased HDL
elevated triglycerides

baseline screening and regular monitoring: personal/family hx, weight/BMI, waist circumference, blood pressure, fasting plasma glucose, FLP

Question 22

Depot APs

Answer 22

long acting injection, every few weeks
suspended in sesame oil to limit absorption
Haloperidol & fluphenazine (lower rate of EPS/TD than oral)
risperdal consta (new)

Question 23

Schizophrenia treatment guidelines

Answer 23

monotherapy of atypical antipsychotic
if fail, switch to another atypical or conventional
if fail, use clozapine
combo therapy as last resort

common to go through all atypicals before switching to typical AP or clozaril