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