clozapine

Question 1

6 indications de clozapine à part schizophrénie résistante

Answer 1

manie résistante (add)
psychose chez parkinson
agressivité
suicidalité
polydipsie psychogène
dyskinésie tardive

Question 2

traitement de non réponse a la clozapine

Answer 2

verifier adhérence

verifier niveaux plasmatiques et augmenter la dose (seuil minimal 350 ng/ml, aller ad 1000 ng/ml si toléré)

ajouter un AP avec D2 effect

ajouter ECT

Question 3

work up avant debuter clozapine

Answer 3

signes vitaux

BMI

constipation? smoking? seizures?

labs: FSC (neutro, eosino), E+/creat/liver/HbA1C/lipids

ECG (QT)

abd XR if needed

insciption au programme de suivi de clozapine

Question 4

QT correction error: how to estimate the true QT at rate >72/sec

Answer 4

current formula (Bazett) overestimates QT

Fridericia formula QTc=QT/racine cube du RR

Question 5

titration clozapine inpatient smoker/non smoker

Answer 5

titration pour smoker (non smoker - 50%)

se rendre à 200 en 1 sem et 400 en 2 sem

25-50-100-150-200

ensuite par increment de 50 mg (par 2-3 jours) ad 400

dosage clozapine 7 jours apres 400mg

Question 6

titration clozapine pour outpatient smoker/non smoker

Answer 6

doses pour smoker (non smoker - 50% de la dose)

ad 100 jour6

ad 200 jour12

ad 300 jour18

ad 400 jour24

dosage plasmatique 7 jours apres 300mg

Question 7

à quel delais d’attendre de la myocardite?

Answer 7

1-7 weeks after initiation of Tx, most cases - within 4 weeks

Question 8

monitoring after initiaion of clozapine

Answer 8

within 3 months - possible side effects

then - FSC

Question 9

8 side effects of clozapine

Answer 9

neutropenia

constipation - ileus

sedation

orthostasis - tachycardia

sialorrhea

seizure

metabolic syndrome

DRESS syndrome

Question 10

constipating medications - psychotrops

Answer 10

chlorpromazine +++

olanzapine

quetiapine >600

TCA

antiparkinsonian: cogentin, diphenhydramine

Question 11

constipating medications - non psychotrops

Answer 11

opiods

iron

Question 12

managing cholinergic rebound

Answer 12

si possible, baisser la dose par 100 mg die ad 100mg die

ensuite - par increments de 25 mg q 4-7 jours

if sleep disturbance - 25-50 mg benadryl HS

if abrupt d/c - strart cogentin (benztropine) at equivalent dose (50 mg clozapine in nonsmoker = 1 mg cogentin = 25 mg benadryl) for at least 2 weeks

Question 13

options pour pts parkinson sous clozapine si d/c

Answer 13

pimavanserin (nuplazid) - a first-in-class atypical antipsychotic that does not induce clinically significant antagonism of dopaminergic, adrenergic, histaminergic, or muscarinic receptors. It is the first FDA-approved drug indicated for the treatment of the hallucinations and delusions in PD-associated psychosis

possibly - quetiapine

ECT

Question 14

options pour pts parkinson sous clozapine si d/c

Answer 14

pimavanserin (nuplazid) - a first-in-class atypical antipsychotic that does not induce clinically significant antagonism of dopaminergic, adrenergic, histaminergic, or muscarinic receptors. It is the first FDA-approved drug indicated for the treatment of the hallucinations and delusions in PD-associated psychosis

possibly - quetiapine

ECT

Question 15

mechanisme d’action - clozapine

Answer 15

alpha 1 antagonist

H1 antagonist

M1 et M3 antagonism

norclozapine - agonist M1-M5 exept M3 (donne sialorrhea via agonisme muscarinique)

D2 antagost (low affinity)

5HT2A - inverse agonist

Question 16

conditions qui affectent le metabolisme de la clozapine (activité CYP 1A2)

Answer 16

tabagisme (hydrocarbons, pas la nicotine, CYP 1A2 inducers)

infections (augmentent niveaux de clozapine x3)

caffeine (heavy intake can increase clozapine level)

polymorphisme génétique

Question 17

vrai ou faux: individus avec la neutropénie ethnique bénigne sont plus grand risque de développer la neutropénie sévère

Answer 17

faux

Question 18

quand le risque de neutropénie est le plus élévé?

Answer 18

6 premiers mois

Question 19

quel est le temps de résolution de la neutropénie après la d/c de la clozapine?

Answer 19

12 jours (médiane)

Question 20

seuil neutrophiles pour débuter/continuer clozapine

Answer 20

ANC égal ou plus que 2000/mm3

BEN: 1000

Question 21

eosinophiles et clozaril: seuil d’alerte

Answer 21

700/mm3

Question 22

qui est à risque de BEN?

Answer 22

origine africaine

Question 23

première action si low ANC and no BEN

Answer 23

vérifier Rx (épival, ab + bcp autres très courants)

Question 24

US guidelines in case of low ANC under clozapine

Answer 24

if more than 1500 - continue

if 1000-1499 - continue

if moderate neutropenia (500-999) - interrupt and consult hematology

if severe neutropenia - d/c Tx and no rechallenge if risks>benefits

Question 25

vrai ou faux: lithium peux être utilisé comme prévention de neutropénie

Answer 25

oui, à doses autour de 300 HS

Question 26

clozapine induced constripation management

Answer 26

avoid opioids, iron and other cholinergic drugs start PEG (level 1) and docusate (no evidence) and stimulant (bisacodyl - moderate evidence) at the beginning of Tx do not use psyllium - exacerbates constipation

Question 27

vrai ou faux: mortalité d'ileus dépasse celle de neutropénie chez pts sous clozapine

Answer 27

vrai ileus - 15-27% neutropenie - 2.2-4.2%

Question 28

clozapine: how to manage sedation?

Answer 28

reduce dose if high adjunct aripiprazole or modafinil (if other methods failed - data weak)

Question 29

vrai ou faux: sedation is the cause no1 of clozarilTx discontinuation by pts

Answer 29

vrai

Question 30

Clozaril: management of orthostasis

Answer 30

fluid and salt intake slowing titration manage alpha 1 antagonists and antihypertensive drugs last method - fludrocortisone

Question 31

Clozaril: management of tachycardia

Answer 31

rule out orthostasis rule out other causes atenolol

Question 32

Clozaril: management of sialorrhea

Answer 32

atropine drops 1% (1st line) botulinum toxin-B (2nd line) amilsulpride or clonidine avoid anticholinergic - risk of ileus

Question 33

Clozapine: management of seizures

Answer 33

Do NOT stop clozapine Valproate - the most studied and recommended (risk of neutropenia/thrombocytemia/hyperNH3) manage as epilepsy

Question 34

Clozapine: management of metabolic effects

Answer 34

all patients are candidates for metformin (weight gain early) monitor BMI/lipid profile/Hb1Ac

Question 35

Clozapine: rate and onset of fever, myocarditis, interstitial nephritis, DRESS, cardiomyopathy

Answer 35

Fever - in 20%, within first 8 wks Myocarditis - up to 3% within the first 6-8 wks Intestitial nephritis, serosostis and DRESS - less common, within first 60 days Cardiomyopathy - many months after

Question 36

Clozapine: rate of incontinence and enuresis and their management

Answer 36

up to 40% early in Tx 20% - persistent manage other antipsychotics do not use anticholinergic

Question 37

vrai ou faux: si clozapine donne élevation des enzymes hépatiques il faut d/c

Answer 37

faux élevation x2 du baseline est normale chez 30%

Question 38

clozapine: rate and management of thrombocytopenia

Answer 38

3% no action needed unless less than 50K - risk of bleeding - d/c