Antipsychotics Part II (includes Clozapine) Flashcards
how might you describe clozapine as an antipsychotic
“last line”
low potency
highly anticholinergic
what is the risk of EPS with clozapine
very low incidence
what is the major metabolite of clozapine
norclozapine
what is the affinity of clozapine for the D2 receptor
second lowest (quetiapine is lowest)
what antipsychotic is indicated in parkinsons dissease psychosis/dementia psychosis
clozapine
compared to placebo, what is the risk of EPS with clozapine
risk of EPS with clozapine is same as placebo
there are only two psychotropic medications that have been shown clinically to reduce the risk of suicide–what are they
clozapine
lithium
what is the starting dose of clozapine
25-50mg po daily OR 12.5 mg qHS or BID
can be titrated 25-50mg per day up to 300mg
how do you titrate clozapine (doses)`
25-50mg po daily, increasing by 25-50mg daily until 300mg
then after 300mg, titration should not exceed more than 25mg each day
once at daily doses of 400, 500, 600, 700 etc… should maintain at each interval for AT LEAST TWO WEEKS before moving on
how should you titrate clozapine if going above doses of 500mg
consider increasing the dose by 25-50mg ONLY every two weeks
what is the maximum dose of clozapine
900mg (canadian guidelines say 600mg)
what is considered an adequate trial of clozapine
minimum 8 weeks
preferably 12 weeks
(reaching a minimum dose of 400mg per day)
what two formulations are available for clozapine
oral or liquid
what physical exams should be done before starting clozapine
height
weight
waist circumference
BP
HR
what lab work should be ordered before starting clozapine
CBC + differential
fasting glucose
AST, ALP, ALT
lipid panel
HbA1c
CRP
Lytes and Cr
high sensitivity troponin I
baseline ECG
b-HCG
in which populations do clozapine plasma levels tend to be LOWER compared to plasma levels in others at a similar dose
plasma levels tend to be lower in:
younger patients
males
smokers
in what population does clozapine plasma levels tend to be HIGHER compared to others on a similar dose
plasma levels tend to be higher in:
asians
when should you take the blood sample to most accurately assess clozapine plasma level
either right before morning dose or 10-12 hours post-dose if only one dose taken per day
what is the mechanism of action of clozapine
loosely blocks dopamine D2 receptors–> reduces positive symptoms of psychosis and stabilizes affective symptoms
blocks serotonin 5HT-2A receptors–> enhancement of dopamine release in certain brain regions and thus reducing motor side effects–> possibly improves cognitive and affective symptoms
also interacts with H1, M1, alpha-1 receptors
what receptors does clozapine interact with
D2
5HT-2A
M1
H1
alpha-1
list 4 indications for clozapine use
treatment resistant schizophrenia (HC/FDA approved)
reduction in risk of recurrent suicidal behaviour in patients with schizophrenia or schizoaffective disorder (FDA approved)
treatment resistance bipolar disorder
tardive dyskinesia (practical indication)
how long does it take to see the effect of clozapine
some people respond within one week
recommended to wait at least 4-6 weeks but not considered resistant until adequate trial of 12 weeks long
some patients require up to 16-20 weeks to show good response
after what dose of clozapine should doses be divided
above 300mg should be divided
after how many missed doses of clozapine do you need to restart at a lower dose
after 2 missed days need to re-initiate at lower dose
if its been less than 48 hours since last clozapine dose, what do you do for the next dose?
resume previous dose
if its been 48-72 hours since last clozapine dose, what do you do for the next dose?
re-initiate at starting/lower dose
if its been 72 hours or more since last clozapine dose, what do you do for the next dose?
re-titrate from starting dose
Stahl’s suggests that asian patients need what % of the dose of clozapine compared to caucasian patients
about HALF
how often should you do vitals when initiating clozapine
at least daily, including orthostatic vitals
how often do you need to do CBC+ diff (ANC) when on clozapine
weekly x 6 months
then q2weeks x 6 months
then q4 weeks INDEFINITELY
how often do you need to do CRP + troponin when on clozapine
weekly x first 4 weeks
how often do you need to do fasting glucose and lipids when on clozapine
q3-6 months
how often do you need to do ECG when on clozapine
at least one once reach steady state + if any clinical indication
how often do you need to do clozapine + norclozapine levels when on clozapine
once target dose reached
consider when patient unwell/has infection or starts or stops smoking
target ratio above 2
what other psychotropic medication can improve clozapine:norclozapine ratio
fluvoxamine
why do we care about the clozapine: norclozapine ratio
?better efficacy and decreased side effects
norclozapine is thought to be more responsible for side effects like sedation etc
what are target clozapine levels
350-600ng/mL
= 1070-1800nmol/L
some patients may need levels above 600ng/mL for adequate response
some sources indicate levels up to 1000ng/mL are not unsafe and should be pursued in non-responders
above what clozapine level does risk of adverse drug reactions increase
1000ng/mL (= 3100nmol/L)
what is the expected metabolic ratio of clozapine: norclozapine in a nonsmoking male
1.32
what dose of clozapine would you expect to need to reach a clozapine level of 350ng/mL in a:
female smoker
435mg/day
what dose of clozapine would you expect to need to reach a clozapine level of 350ng/mL in a:
female non smoker
265mg/day
what dose of clozapine would you expect to need to reach a clozapine level of 350ng/mL in a:
male smoker
525mg/day
what dose of clozapine would you expect to need to reach a clozapine level of 350ng/mL in a:
male nonsmoker
325mg/day
*basically, you need higher doses of clozapine if they’re male, and if they’re a smoker
why might looking at the metabolic ratio between clozapine and norclozapine be helpful
to understand presence of an inducer or an inhibitor
if ratio is low (ie more norclozapine than expected) then there is probably an inducer present or they are a CYP 1A2 ultra rapid metabolizer
if the ratio is high (i.e less norclozapine than expected) but not too high (i.e between 1.7-3.0) then likely presence of weak inhibitor or they are CYP poor metabolizers
if ratio is very high (i.e above 3) then there is likely presence of a strong inhibitor or viral or bacterial illness
list 9 common side effects of clozapine
sedation (usually transient)
dizziness
hypotension
hypersalivation (or dry mouth)
tachycardia
constipation (can be lethal)
metabolic effects
sexual dysfunction
nocturnal enuresis (21% risk)
(also nausea, GERD, transaminitis, fever)
what change in HR can be expected with clozapine
increase of 10-20 bpm
what is the average weight gain associated with clozapine
5-8kg on average
1/5 will gain 10% of body weight
about 60-75% of people will gain weight
like 5 rare but serious possible side effects of clozapine
agranulocytosis (/neutropenia)
myocarditis
seizures
NMS
EPS
what is the risk of agranulocytosis with clozapine
about 1% risk
what is the risk of myocarditis with clozapine
1-5% risk in some studies
?overestimate
what is the risk of seizures with clozapine
5% risk at 500mg/day dose
describe how a clozapine overdose would present
arrhythmias
excess salivation
respiratory depression
altered state of consciousness
MAY BE LETHAL
first line treatment for clozapine induced sialorrhea
orally applied anticholinergics (so as not to increase constipation risk)
ATROPINE 1% drops
ipratropium 0.6% spray (under tongue)
can consider low dose terazosin before glycopyrrolate if oral applied meds dont wory
why is clozapine more constipating than other antipsychotics
because strong anticholinergic, antihistaminic and anti 5HT3
what is the mean colon transit time for food/feces in someone on clozapine compared to normal
normal = 23 h
on clozapine = 105 h
how to manage constipation associated with clozapine
minimize other anticholinergics
encourage exercise, hydration, dietary fiber (20g)
stool softeners like docusate and osmotic/stimulant laxatives
*avoid bulk forming laxatives
how much does the risk of seizures with clozapine increase when you go from doses below 300mg to above 600mg
below 300mg = 1% risk
300-600mg = 2.7% risk
above 600mg = 4.4 % risk
*EEG abnormalities without seizures are common
how do you manage seizures with clozapine
reduce dose of clozapine
anti-epileptic medications
what % of cases of myocarditis on clozapine occur in the first month
about 88% (average is 17days)
how might myocarditis related to clozapine present
“flu like” symptoms
fever
tachy (if they’re not tachy, they dont have myocarditis–> but may have tachy without myocarditis)
chest pain (50%)
SOB (35%)
what lab findings would you expect in myocarditis
elevated ESR/CRP
elevated CK
elevated BNP
elevated troponin
what is the gold standard for diagnosis of myocarditis
echo and cardiac MRI
what is the sensitivity and specificity of elevated troponin for myocarditis
sensitivity 83%
specificity 91%
under what conditions should you stop clozapine if myocarditis is suspected
if CRP is above 100
if troponin is 2x upper limit of normal
how do you manage clozapine related myocarditis after diagnosis
stop clozapine
do serial troponins, ECG and echo
follow up ECG in 2-4 weeks then q6months
what is “agranulocytosis”
absence of granulocytes–> neutro-, eosino- and basophils
what is “benign ethnic neutropenia”
individuals of african heritage may have lower baseline neutrophils
can consult heme (then call company line and have monitoring parameters adjusted)
what are the “green” “yellow” and “red” parameters for clozapine based on
neutrophil and WBC count
are monitoring for possible agranulocytosis
what is the WBC level associated with “green” status for clozapine monitoring
WBC above 3.5 x 10^9/L
what is the neutrophil level associated with “green” status for clozapine monitoring
neutrophils above 2
what action should be taken if someone falls in the “green” zone for clozapine monitoring
continue clozapine and continue current frequency of blood test
what is the WBC level associated with “yellow” status for clozapine monitoring
WBC below 3.5
what is the neutrophil level associated with “yellow” status for clozapine monitoring
neutrophils below 2
what do you do if someone falls in the “yellow” zone of clozapine monitoring
continue clozapine
monitor CBC at least TWICE WEEKLY until back to green
what is the “flashing yellow” zone of clozapine monitoring
yellow drop–> basically a downward trend but not yet out of green zone officially
WBC less than 4 with WBC fall of 3x10^9/L in the last four weeks
OR
neutrophils less than 2.5 with neutrophil fall of 1.5 in the last four weeks
what should you do if someone falls in the “flashing yellow” zone of clozapine monitoring
continue clozapine
monitor CBC at least twice weekly unitl back to green
what is the WBC level associated with “red” status for clozapine monitoring
WBC below 2
what is the neutrophil level associated with “red” status for clozapine monitoring
neutrophils below 1.5
what should you do if someone falls in the “red” zone on clozapine monitoring
stop clozapine
monitor daily for vitals and signs of infection
repeat CBC in 24 hours to confirm low neutrophils
if remains confirmed, d/c clozapine
admit to ER if patient has symptoms of infection
what will happen if a patient falls into the yellow zone on clozapine monitoring
lab will call patient
if patient has fever, they go to hospital
what enzyme if responsible for the major metabolism of clozapine
CYP 1A2
what other CYP enzymes are involved in clozapine metabolism apart from CYP 1A2
3A4
2D6
2C19
what other psychiatric medication should be used cautiously with clozapine
fluvoxamine
it is a 1A2 inhibitor
why does cigarette smoke decrease clozapine levels
it is a CYP 1A2 inducer
like four common medications that are CYP 1A2 inhibitors (and thus increase clozapine levels)
fluvoxamine
caffeine
ciprofloxacin
oral contraceptivecs
list 3 common meds/substances that are CYP1A2 inducers (and thus decrease clozapine levels)
smoking
carbamazepine
omeprazole
list 9 contraindications to clozapine treatment
hypersensitivity to clozapine
myeloproliferative disorder
uncontrolled epilepsy
hx agranulocytosis or severe granulocytopenia
CNS depression
paralytic ileus
acute liver disease (with nausea, jaundice, anorexia) or progressive liver failuer
unable to undergo blood tests
severe cardiac disease (this is a relative contraindication)
what is the bioavailability of clozapine? is it affected by food?
27-50%
not affected by food
what is the time to peak concentration of clozapine
2.5 h
(range is 1-6 h)
does clozapine undergo first pass metabolism
yes–> significant in the gut and liver
what is the half life of clozapine
12h (range is 4-66h)
can you use clozapine in cases of renal or liver failure
must use with caution
what is the response rate for people with schizophrenia with:
1. clozapine
- high dose olanzapine
- other antipsychotics
- clozapine = above 40%
(30% after 3 mo and 60% if maintained) - high dose olanzapine = 0-7%
- other = less than 5%
what should you be aware of and monitoring for is discontinuing clozapine
- rebound psychosis
–may occur unless very slowly tapered
–taper by 100mg/week or slower - cholinergic rebound
–occur in 1-4 days
–N/V, diarrhea, sweating, urinary urgency, anxiety, delirium
–tx with anticholinergics (i.e benztropine)
how does the TRIPP working group recommend approaching clozapine refectory schizophrenia
for positive sx–> raise clozapine level above 350ng/mL–>
consider addition of 2nd antipsychotic (best evidence–though sparse–for ABILIFY PO, or amisulpride)
–>or ECT
for negative sx–> consider addition of antidepressant i.e citalopram (not specifically investigated)
can also augment with CBT and psychosocial interventions
has safety/efficacy been established for clozapine in kids
no–> preliminary research suggests efficacy for early-onset treatment resistant schizophrenia
what risk category is clozapine for pregnancy/lactation
risk level B
(animal studies do not show adverse effects but no controlled studies in humans)
what is “morning pseudoneutropenia”
a physiologic pronounced diurnal variation in circulating neutrophils some people have
if WBC low in AM, repeat in PM before changing clozapine treatment
what blood parameters are considered “critical” for clozapine monitoring? what do you do in this case?
WBC below 1
neutrophils below 0.5
place patient in protective isolation with close observation
physician must watch for signs of infection
do you have to restart monitoring regimen if more than 3 days of clozapine are missed
yes–> its basically starting the whole thing over
how long do clozapine induced fevers usually last
2-3 days in first month of treatment
*make sure to rule out NMS or myocarditis
list 3 antipsychotics that have “no effect” on QTc
brexpiprazole
cariprazine
lurasidone
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
aripiprazole
low
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
risperidone
moderate-high
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
quetiapine
moderate
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
olanzapine
moderate
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
loxapine
low
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
clozapine
low
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
haloperidol
moderate
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
asenapine
low
state whether the following antipsychotic has low, moderate or high effect on QTc prolongation:
paliperidone
moderate
