Antipsychotics Flashcards
name the first antipsychotic… when was it introduced
chlorpromazine –> 1955
*antipsychotics considered the single greatest advance in the treatment of mental disorders
names of the psychiatrists who introduced chlorpromazine as the first antipsychotic
pierre deniker
jean delay
*french
what dopaminergic pathway to antipsychotics target to treat the positive symptoms of schizophrenia
mesolimbic
list the 4 key dopaminergic pathways that antipsychotics affect
mesocortical
mesolimbic
nigrostriatal
tuberoinfundibular
what areas does the mesocortical pathway connect
prefrontal cortex
to the
ventral tegmental areas
what areas does the mesolimbic pathway connect
nucleus accumbens
to the
ventral tegmental area
what areas does the nigrostriatal pathway connect
substantia nigra
to the
basal ganglia (striatum)
what areas does the tuberoinfundibular pathway connect
hypothalamus–arcuate (infundibular) nucleus
to the
hypothalamus–median eminence
why do we care about the MESOCORTICAL pathway in schizophrenia
DECREASED dopamine leads to NEGATIVE SYMPTOMS
cognitive symptoms are also thought to be due to a HYPOACTIVE mesocortical pathway
why do we care about the MESOLIMBIC pathway in schizophrenia
INCREASED dopamine leading to POSITIVE symptoms
**same pathway for nicotie-reward
why do we care about the NIGROSTRIATAL pathway in schizophrenia
also gets blocked by antipsychotics leading to EPS and akathesia
why do we care about the TUBEROINFUNDIBULAR pathway in schizophrenia
the decrease of dopamine in this pathway (thru use of antipsychotics) can cause elevated PROLACTIN
what is the regular role of dopamine in the tuberoinfundibular pathway
to tonically inhibit prolactin release
where is the tuberoinfundibular pathway found
entirely in the hypothalamus
what is the physiologic action of the normal mesolimbic pathway
motivation
emotion
reward
what is the physiologic action of the normal mesocortical pathway
cognition and executive function (dorsolateral PFC)
emotion and affect (ventromedial PFC)
the nigrostriatal system contains what % of the brains dopamine
about 80%
what two structures make up the striatum
caudate and putamen
what is the physiologic action of the normal nigrostriatal pathway
motor planning
(dopaminergic neurons stimulate purposeful movement)
the therapeutic action of an antipsychotic occurs when what % of brain dopamine (D2) receptors are occupied
65-85%
what happens when more than 80% of D2 receptors are occupied
hyperprolactinemia
parkinsonism
*CAN happn
what factors influence the likelihood of a patient experiencing EPS (or other side effects)
% receptor occupancy + amount of time the antipsychotic remains bound to the receptor
does serum level of antipsychotics correlate to brain receptor occupancy?
no–> due to the blood brain barrier
name an antipsychotic that remains bound to D2 receptors for quite a long time?
name two antipsychotics that are bound to D2 receptors for only a very short time
haldol–> bound for about 38 min
clozapine, quetiapine–> bound for about 15 seconds (“kiss and run hypothesis”)
*suggested reason for why haldol has more EPS than clozapine and quetiapine
what does antipsychotic “potency” describe
affinity for dopamine receptor
what is the relationship between antipsychotic potency and anticholinergic action? why do we care?
all low potency antipsychotics are also more anticholinergic (anti-muscarinic) –> this means low potency antipsychotics have “built in” benztropine
(as benztropine is also anticholinergic med)
list high potency antipsychotics
haloperidol
risperidone
flupenthixol
paliperidone
fluphenazine
pimozide
list medium potency antipsychotics
loxapine
olanzapine
zuclopenthixol
ziprasidone
perphenazine
aripiprazole
list low potency antipsychotics
chorpromazine
quetiapine
methotrimeprazine
clozapine
amisulpride
what is a schema to best understand the most prominent side effects associated with high vs low potency antipsychotics
high potency–> higher risk of EPS and hyperprolactinemia
(due to higher affinity for D2); relatively less sedating (lower affinity for H1 receptor)
low potency–> more anticholergic symptoms and more sedating + more constipation (due to more anticholinergic and H1 binding); relatively fewer EPS
how are MOST antipsychotics metabolized
by CYP 2D6 and 3A4
clozapine and olanzapine are also metabolized by which CYP enzyme? (in addition to 3A4 and 2D6)
1A2
which population has increased CYP metabolism of antipsychotic medications
mediterranean
when did SGAs begin to arise
1990s
name the trial that showed SGAs were no more effective that FGAs
CATIE trial
GENERALLY speaking, what is the difference between SGAs and FGAs
FGAs–> higher D2 receptor occupancy–> higher risk of causing EPS
SGAs–> lower D2 occupancy–> lower risk of EPS
*some considerations i.e risperidone which acts like an SGA at low doses but like an FGA at higher doses, due to its high potency
is the FGA/SGA distinction really useful?
not really–> distinction is more historical than black and white
more important to look at individual antipsychotics potency, receptor profile, and pharmacokinetics rather than if FGA/SGA
state whether the following is low, mid or high potency:
haloperidol
high
state whether the following is low, mid or high potency:
quetiapine
low
state whether the following is low, mid or high potency:
clozapine
low
state whether the following is low, mid or high potency:
aripiprazole
mid
state whether the following is low, mid or high potency:
zuclopenthizol
mid
state whether the following is low, mid or high potency:
paliperidone
high
state whether the following is low, mid or high potency:
risperidone
high
state whether the following is low, mid or high potency:
olanzapine
mid
state whether the following is low, mid or high potency:
loxapine
mid
state whether the following is low, mid or high potency:
methotrimeprazine
low
state whether the following is low, mid or high potency:
ziprasidone
mid
state whether the following is low, mid or high potency:
fluphenazine
high
state whether the following is low, mid or high potency:
amisulpride
low
list common FGAs
methotrimeprazine
haldol
chlorpromazine
loxapine
zuclopenthixol
flupentixol
perphenazine
list common SGAs
risperidone
paliperidone
aripiprazole
brexpiprazole
lurasidone
olanzapine
quetiapine
ziprasidone
clozapine
amisulpride
pimavanserine
asenapine
how quickly do most people begin responding to antipsychotics
within a week
which antipsychotic has the lowest rehospitalization rate
clozapine
how has understanding shifted recently in terms of recommended treatment length for those with first episode psychosis
compared to standard maintenance treatment regimen, dose reduction or supervised d/c of antipsychotic during early phases of first episode psychosis may lead to HIGHER RELAPSE rate INITIALLY but IMPROVED LONG TERM OUTCOMES
*study has been criticized though
other studies have suggests that up to 40% of those with first episode psychosis may achieve good outcomes with either low or no doses of antipsychotics
what remains the most evidenced based practice for those with first episode schizophrenia
for the majority of patients, relapse rates are greater than 80% with med-discontinuation after several years
which medications have the lowest rates of relapse in schizophrenia
clozapine and LAIs
how does treatment with an LAI change risk of rehospitalization risk compared to those treated with oral equivalents
for those on LAIs, risk is 20-30% of those on oral equivalents
should you switch FGA LAI to SGA LAI if the patient is doing well on FGA LAI?
no–> this switch (assuming they are doing well on FGA LAI) puts them at higher risk of treatment discontinuation and weight gain
is treatment with multiple antipsychotic agents generally recommended?
what combo of meds recently suggested superiority over monotherapy?
generally, NOT recommended–> generally does not improve clinical response, should try and keep to/switch to monotherapy
*one cohort study recently showed superiority of CLOZAPINE + ARIPIPRAZOLE vs clozapine alone
list FGA LAIs available
haloperidol decanoate
fluphenazine decanoate
flupenthixol decanoate
zuclopenthixol decanoate
dose of haloperidol decanoate IM
50-200mg IM q3-4 weeks
dose of zuclopenthixol decanoate IM
200-500mg IM q1-4 weeks
list SGA LAIs available
aripiprazole monohydrate–> abilify maintenna
aripiprazole lauroxil–> aristada
olanzapine pamoate–> zyprexa
paliperidone palmitate (multiple formulations)–> invega sustenna, xeplion, invega trinza
risperidone microspheres–> risperidone consta
formulations of aripiprazole monohydrate (maintenna) available
300mg, 400mg
admin qmonthly
what is a consideration when starting abilify maintenna
requires 2 weeks of oral dosing (“oral bridging”) with oral abilify
formulations avail. of paliperidone palmitate (invega sustenna)
39 mg, 78mg, 117mg, 156 mg, 234 mg (prefilled syringes)
admin qmonthly
*oral supplementation not necessary
formulations avail. of risperidone consta
12.5mg, 25mg, 37.5mg, 50mg
what is a consideration when starting risperidone consta
requires period of 3 week overlap with oral risperidone
how do you switch antipsychotics
no difference in clinical outcome if maintain on old antipsychotic while introducing the new one, vs stopping the old one and introducing the new one immediately
for those on antipsychotics, when should you monitor:
electrolytes
initiation
as clinically indicated thereafter
for those on antipsychotics, when should you monitor:
fasting plasma glucose
initiation
1 mo if clinically indicated
3 months after initiation
annually thereafter
for those on antipsychotics, when should you monitor:
HbA1C
initiation
at 3 months
annually thereafter
for those on antipsychotics, when should you monitor:
lipid panel
initiation
1 mo if clinically indicated
3 months after initiation
annually thereafter
for those on antipsychotics, when should you monitor:
BMI
at initiation
at 1 month, 3 months, then annually
for those on antipsychotics, when should you monitor:
BP
initiation
1 mo if clinically indicated
3 months after initiation
annually thereafter
for those on antipsychotics, when should you monitor:
EPS exam
at initiation, 1 mo, 3 mo, and annually thereafter
for those on antipsychotics, when should you monitor:
endocrine function history (gynecomastia, galactorrhea, libido)
at initiation, 3 mo, then annually
for those on antipsychotics, when should you monitor:
prolactin
if clinically indicated
for those on antipsychotics, when should you monitor:
ECG (Qtc monitoring)
at initiation if clinically indicated
at 3 mo if on multiple QTc prolonging meds
annual if clinically indicated (could also reasonably just do it annually)
for those on antipsychotics, when should you monitor:
smoking history
initiation, 3 mo, annually thereafter
what are the “main” side effects of antipsychotics
EPS
sexual side effects
anticholinergic SEs (i.e sedation)
cardiovascular SEs
what causes the EPS and sexual side effects associated with antipsychotics
potent dopamine receptor blockade
what causes the anticholinergic side effects like sedation with antipsychotics
histaminergic and muscarinic receptor blockade
what causes the cardiovascular side effects of antipsychotics
anticholinergic effects and adrenergic blockade
who introduced the concept of Neuroleptic Induced Dopamine Supersensitivity Psychosis (DSP)
psychiatrist Guy Chouinard in 1980
what is the hypothesis behind DSP
chronic antipsychotic use leads to the upregulation of dopamine (D2) receptors in the BASAL GANGLIA –>
tardive dyskinesias + tolerance of increasing doses of antipsychotic –>
rebound psychosis could occur with reduction or discontinuation of the antipsychotic (separate from underlying illness)
why is the idea of DPS controversial?
could be iatrogenic
list side effects associated with antipsychotics
- metabolic syndrome
- constipation
- sedation
- hyperprolactinemia
- amenorrhea
- sexual dysfunction
- hypotension
- tachycardia
- QTc prolongation
- SIADH + hyponatremia
- sialorrhea
first line management for constipation due to antipsychotic use?
use of an osmotic agent–> PEG and/or stimulant laxative such as Senna
*patients on clozapine should have regular bowel monitoring
what determines the degree of sedation associated with an antipsychotic
affinity of the antipsychotic for the H1 receptor
*generally, low potency antipsychotics are more sedating than higher potency and atypicals are more sedating than typicals
rank the following four antipsychotics from most to least sedating (by H1 receptor affinity):
quetiapine
olanzapine
risperidone
clozapine
most:
clozapine
olanzapine
quetiapine
risperidone
least
how do you manage sedation due to antipsychotics
reduce dose or consider a switch to higher potency antipsychotic
how might you manage amenorrhea in those on antipsychotics
(hyperprolactinemia can result in amenorrhea)
METFORMIN can restore menstruation in obese women with amenorrhea by restoring sex hormone levels and decreasing insulin resistance
what causes the sexual dysfunction associated with antipsychotics
dopamine blockade and hyperprolactinemia
management of sexual dysfunction associated with antipsychotics
sildenafil can be considered
what causes the hypotension associated with antipsychotics
thought to be caused by anticholinergic effects and/or alpha-1 adrenorececptor blockade
management of hypotension associated with antipsychotics
consider adjusting dose
increasing hydration
change to less anticholinergic agent (ie switch from low to high potency)
how do antipsychotics increase the risk of QTc prolongation/ventricular arrthymias
blockade of potassium channels and prolongation of QTc
is hyponatremia common with antipsychotic use
no, its rare
how are antipsychotics thought to cause hyponatremia
increase AVP release despite normal plasma osmolality–> SIADH–> hyponatremia
why do we care about hyponatremia in psychiatry
can cause neuropsychiatric symptoms
acute onset hyponatremia can cause delirium and acute behavioural changes
diagnosis of SIADH may be delayed for psychiatric patients
what are the four general etiologies of hyponatremia
- too much water in (water intox)
- too little water going out (too much ADH–> SIADH–> can be due to psych meds like antipsychotics)
- too little sodium in (“tea and toasters”)
- too much sodium going out (multiple causes like diuretics or diarrhea)
symptoms of hyponatremia
nausea
vomiting
anorexia
disorientation
headache
fatigue
weakness
irritability
lethargy
confusion
muscle cramps
what is first line treatment of SAIDH
fluid restriction
what other type of psych med in particular is known to have SIADH as a potential side effect
antidepressants (especially in elderly)
what does the QT interval represent
the length of cardiac repolarization (i,e time for ventricles to contract and relax)
why do we care about the QT interval being long
causes heterogeneity in electrical phasing in different ventricular structures of the heart–>
can cause events like ventricular extrasystole and torsades
what affects the risk of QT prolongation of a particular med
likely dose related
is QTc “enough” to determine cardiac risk from QT prolonging medications?
its a good general indicator but can be imprecise for determining risk of torsades
best to combine QTc with T wave morphology to better predict risk (i.e involve cardio)–> some people with QTc above recommended limits can still take meds that alter cardiac repolarization without developing torsades
under what limit is QTc generally considered normal, and no referral to cardio is recommended (unless other risk factors) when considering starting a QTc prolonging med like antipsychotics
under 440ms for men
under 470ms for women
at what QTc might you consider reducing dose of QTc prolonging med, or switching to drug of lower effect? would you refer to cardio?
440-500ms for men
470-500ms for women
consider referral to cardio
once make changes to med, repeat ECG
at what QTc do we really sit up and take notice and refer to cardio
above 500ms for both men and women
*repeat the ECG
*stop suspected QT-prolonging agents and switch to drug with less QT effects
*refer to cardio
under what conditions would you refer to cardio when starting antipsychotics, even if QT normal
if abnormal T wave morphology
above what limit is QTc considered “prolonged”
above 470ms for men
above 480ms for women
list risk factors for QTc prolongation
- female gender
- use of meds primarily metabolized by CYP 3A4 (greater risk for drug-drug interactions)
- older age (above 65)
- eating disorders
- heart disease
- electrolyte disturbances (hypokalemia, hypomagnesemia)
- renal impairment
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
loxapine
low
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
brexpiprazole
no effect
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
risperidone
moderate to high
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
paliperidone
low
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
lurasidone
no effect
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
haloperidol
moderate
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
olanzapine
moderate
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
clozapine
low
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
aripiprazole
low
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
quetiapine
moderate
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
asenapine
low
indicate whether the following antipsychotic is felt to have no effect, low effect, moderate effect or high effect on QTc interval:
amisulpride
moderate
what medication used to treat OUD has high effect on QTc? (ie tends to prolong Qtc)
methadone
what illicit substance is also a QTc prolonging agent
cocaine
if patient is on antipsychotic and QTc is getting prolonged, what antipsychotic might you switch to instead?
aripiprazole or lurasidone
what should you do if your patients ECG comes back with QTc above 500ms
order Mg and K+ levels
if these levels are LOW, replace and redo ECG
*try to keep K+ above 4 and Mg above 1.0 if you’re worried about QTc prolongation
how do antipsychotics affect seizure threshold
lower it
which typical antipsychotic has the highest risk of inducing seizures
chorpromazine
which typical antipsychotics have a lower risk of seizures
haldol
pimozide
trifluoperazine
fluphenazine
which atypical antipsychotic is most commonly associated with seizures
clozapine
which atypical antipsychotic has the lowest risk of inducing seizures
risperidone
why must antipsychotics be used only carefully in the elderly
ALL antipsychotic agents are associated with increased risk of MORTALITY in the elderly
–> also increased incidence of cerebrovascular events
how might you adapt use of antipsychotics for use in elderly
make sure benefits outweigh risks
use lower doses
slower titration schedule
periodic reassessment for need for med
must you alter Rx for antipsychotics in those with renal impairement
all FGAs can be used with caution without dose adjustment
SGAs must be titrated carefully
must you alter Rx for antipsychotics in those with hepatic impairement
no dose adjustment needed for FGAs but recommend initiation at lowest dose
SOME antipsychotics should be avoided in those with hepatic impairment
which FOUR antipsychotics should be avoided in those with hepatic impairement
asenapine
lurasidone
paliperidone
risperidone
name the only two antipsychotics that are FDA risk category B (safe for use in pregnancy, but limited human data available) for use in pregnancy
I.e the two “safest” antipsychotics for use in pregnancy according to the FDA
lurasidone
clozapine
are antipsychotics excreted in breast milk
all are either proven or presumed to be excreted in breast milk
apart from lurasidone and clozapine, are any other antipsychotics considered safe in pregnancy according to the FDA
no–> all others are considered “category C–> not safe for use in pregnancy, use only if benefits outweigh the risks”
do antipsychotics change brain structure
controversial
in 2020–> first study showing OLANZAPINE changes brain structure (showed 1.2% loss in cortical volume over 36 weeks olanzapine exposure, which is 2x yearly loss of cortical thickness in older adults) –> findings have been challenged
is there a difference in all cause mortality between those on oral, injection or placebo antipsychotics in those with schizophrenia?
no difference
what effect do antipsychotics seem to have on mortality?
in what population is this different?
antipsychotic use, particularly clozapine, seems to lead to LOWER mortality
**population based studies show risk of increased all cause mortality in NON ELDERLY patients with DEPRESSION who are treated with SGA augmentation
