CANMAT Guidelines: Depression Part 2 (pharmacology) Flashcards
effective dosing range for citalopram
20-40mg
effective dosing range for escitalopram
10-20mg
effective dosing range for fluoxetine
20-60mg
effective dosing range for fluvoxamine
100-300mg
effective dosing range for paroxetine
20-50mg
effective dosing range for sertraline
50-200mg
effective dosing range for venlafaxine
75-225mg
effective dosing range for desvenlafaxine
50-100mg
effective dosing range for duloxetine
60mg
effective dosing range for milnacipran
100mg
effective dosing range for buproprion
150-300mg
effective dosing range for mirtazapine
15-45mg
effective dosing range for mianserin
60-120mg
effective dosing range for vortioxetine
10-20mg
effective dosing range for agomelatine
25-50mg
list 3 factors that predict poorer response to AD therapy
increasing age
anxiety
longer episode
*age, sex, race, ethnicity do NOT predict outcomes with a specific AD
have differences in AD effectiveness (between different ADs) been shown for the following subtype:
melancholic
no differences reliably noted
have differences in AD effectiveness (between different ADs) been shown for the following subtype:
psychotic depression
AD + AP combo is better than either alone for treating psychotic depression
have differences in AD effectiveness (between different ADs) been shown for the following subtype:
atypical
no differences reliably noted
have differences in AD effectiveness (between different ADs) been shown for the following subtype:
mixed features
lurasidone or ziprasidone monotherapy (over placebo… not comparison to other ADs)
have differences in AD effectiveness (between different ADs) been shown for the following subtype:
anxious
no differences reliably shown though consider using AD that has evidence in treatment of anxiety as well
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
cognitive dysfunction
VORTIOXETINE–> largest effect on processing speed, executive control, cognitive control
duloxetine–> largest effect on delayed recall
SSRIs, buproprion, duloxetine, moclobemide–> may improve learning and memory and executive function
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
sleep disturbance
agomelatine
mirtazapine
trazodone
quetiapine
*all but agomelatine have side effects including daytime somnolence and sedation
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
pain
SNRIs, especially DULOXETINE
there are no comparative studies for fatigue or low energy
what are the principles of pharmacotherapy in MDD per the CANMAT guidelines
list patient factors to consider when choosing and antidepressant
clinical features and dimensions
comorbid conditions
response and side effects of previous ADs
patient preference
list medication factors to consider when choosing an antidepressant
comparative efficacy
comparative tolerability
potential drug interactions
simplicity of use
cost and availability
what medication or combo of meds should you choose for someone with MDD and:
anxious distress
antidepressant with efficacy in GAD
(no differences between SSRI, SNRI, buproprion)
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
catatonic features
benzodiazepines
–> no ADs have been studied
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
melancholic features
no specific antidepressants have demonstrated superiority–> TCAs and SNRIs have been studied
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
atypical features
no specific antidepressants have demonstrated superiority
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
with psychotic features
AP + AD combo
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
mixed features
lurasidone
ziprasidone
*no comparative studies done
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
with seasonal pattern
no specific ADs have demonstrated superiority–> SSRIs, agomelatine, buproprion, meclobemide have been studied
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
with cognitive dysfunction
level 1 evidence for VORTIOXETINE
also buproprion, duloxetine, SSRIS (level 2) and moclobemide (level 3)
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
with sleep disturbances
level 1 evidence for AGOMELATINE
mirtazapine, quetiapine, trazodone have level 2
have differences in AD effectiveness (between different ADs) been shown for the following symptom clusters in MDD:
with somatic symptoms
level 1 evidence for DULOXETINE (PAIN) and BUPROPRION (FATIGUE)
level 2 evidence for other SNRIs (pain), SSRIs (fatigue), and duloxetine (for energy)
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
agolematine and sertraline
AGOMELATINE superior over sertaline
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
paroxetine, citalopram, reboxetine
CITALOPRAM superior over paroxetine and reboxetine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
milnacipran and fluoxetine
FLUOXETINE superior over milnacipran
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
SSRIS as a class, venlafaxine, mirtazapine
MIRTAZAPINE superior over SSRIs as a class and venalfaxine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
fluoxetine and paroxetine
PAROXETINE superior over fluoxetine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
sertraline and fluoxetine
SERTRALINE superior over fluoxetine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
escitalopram and citalopram
ESCITALOPRAM superior over citalopram
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
fluoxetine and venlafaxine
VENLAFAXINE superior over fluoxetine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
escitalopram and duloxetine
ESCITALOPRAM over duloxetine
which of the following groups/pairs of ADs have shown superiority in efficacy based on meta-analyses:
fluoxetine and escitalopram
ESCITALOPRAM over fluoxetine
what have the differences in response rate generally been between ADs in head to head trials
modest–> 5-6%
list the 4 ADs that have level 1 evidence for superior efficacy per the CANMAT guidelines
escitalopram
mirtazapine
sertraline
venlafaxine
list the 2 ADs that have level 2 evidence for superior efficacy based on the CANMAT guidelines
agomelatine
citalopram
is there any AD that can be cited as demonstrating superior functional improvement?
no
which AD seems to have lower rates of sexual side effects
buproprion
(also vortioxetine, agomelatine, desvenlafaxine, mirtazapine, vilazodone)
which ADs seem to have higher rates of sexual side effects
escitalopram
paroxetine
are there clear differences in tolerability of ADs?
no–> based on product monographs
(*Dr. Rhandawa’s lecture I recall indicating that vortioxetine may be better tolerated)
what is the relationship between ADs and suicide risk
for SSRIs in adolescents–> DOUBLE the risk of suicide w SSRI use but this was based on OBSERVATIONAL studies (use caution; black box warning… no specific ADs, caution in all)
in adults (above age 25) and the elderly (above age 65), ADs seem to show decreased suicidal ideation + acts/attempts
in adults, risk may be DECREASED by as much as 40% and in elderly may be by as much as 50% with use of SSRIs
which 3 ADs have been most implicated with QTC prolongation
citalopram
escitalopram
quetiapine
what is the association between ADs and QTc prolongation/torsades
torsades is often idiosyncratic, unclear associations
per systemic review, can occur even at therapeutic dose and torsades can occur even with normal QTc
most cases had additional risk factors –> without additional risk factors, VERY LOW RISK with SSRIs/ADs
with which AD should you monitor LFTs
agomelatine–> can icnrease liver enzymes and there is sporadic toxic hepatitis
(uncommon with other ADs)
list 4 other possible adverse consequences of SSRI use
- increased falls
- increased fractures–> highest risk within first 6 weeks of exposure to SSRI
- hyponatremia
- inhibited platelet aggregation–> increased risk of GI bleeding
what population is particularly as risk of SSRI associated hyponatremia
elderly patients with other risk factors
what can increase the risk of GI bleed in patients taking SSRIs
NSAIDs–> concomittant NSAID use increases risk of GI bleed by 2x
what is one way to significantly reduce the risk of GI bleed in patients taking SSRIs
acid suppressing drugs
list 19 possible side effects of antidepressants
- nausea
- constipation
- diarrhea
- dry mouth
- headaches
- dizziness
- somnolence
- nervousness
- anxiety
- agitation
- insomnia
- fatigue
- sweating
- asthenia
- tremor
- anorexia
- increased appetite
- weight gain
- male sexual dysfunction
list 3 ADs associated in particular with the following side effect:
nausea
fluvoxamine
venlafaxine IR and XR
what AD is particularly associated with headaches as a side effect
buproprion both SR and XL
(also venlafaxine and fluvoxamine)
what are some of the most common side effects of ADs
nausea, dry mouth, headaches, sexual dysfunction, insomnia or somnolence
which AD is associated with somnolence in particular
mirtazapine
which ADs in particular might you want to mention side effects of nervousness/agitation
fluoxetine
venlafaxine and fluvoxamine to a lesser extent
main side effects of the following AD:
escitalopram
nausea
sexual dysfunction
main side effects of the following AD:
fluvoxamine
nausea++
constipation
dry mouth
headaches
dizziness
somnolence
insomnia
main side effects of the following AD:
venlafaxine
nausea ++
dry mouth
headaches
dizziness
somnolence
nervousness
insomnia
sweating
male sexual dysfunction
main side effects of the following AD:
mirtazapine
increased appetite
increased weight gain
somnolence++
dry mouth
constipation
main side effects of the following AD:
vortioxetine
nausea
are there differences in efficacy or tolerability between extended and immediate release versions of ADs
no–> may consider extended release if there are adherence/compliance issues
what level of bioequivalence is required between generic and branded medications in the US and Canada
80-125% bioequivalence
is there a difference between generic and branded meds?
generic are safe and reliable for MOST patients however–> consider the risk/benefit for switching patient who is benefitting from branded med
what is the primary metabolic pathway for ADs
CYP 450 metabolic pathway in the liver
name two ADs that are primarily metabolized via the CYP 1A2 pathway
agomelatine
duloxetine
*should not be coadministered with agents that inhibit the CYP1A2 pathway
name two non psych medications that are potent inhibitors of the CYP1A2 pathway
cimetidine
ciprofloxacin
*note that fluvoxamine is also a potent CYP3A4 inhibitor
name an AD that is primarily metabolized by CYP3A4
vilazodone
name a common non psych medication that is a potent inhibitor of the CYP3A4 pathway
ketoconazole
*note that fluvoxamine is also a potent CYP3A4 inhibitor
name 3 ADs that are potent CYP pathway inhibitors
fluoxetine
paroxetine
fluvoxamine
which CYP enzyme foes fluoxetine inhibit
CYP2D6
which CYP enzyme does paroxetine inhibit
CYP 2D6
which CYP enzyme does fluvoxamine inhibit
CYP 1A2, 2C19, 3A4
name 3 ADs that are moderate CYP inhibitors–which CYP enzyme do they inhibit
buproprion
duloxetine
sertraline
all inhibit 2D6
*these drug drug interactions are RARELY clinically relevant except at higher doses
is there any consistent evidence of P-glycoprotein interactions with antidepressants (or antipsychotics)
no
why is the P-glycoprotein system important
important component of the blood brain barrier and the intestinal barrier and affects efflux of medications (including psychotropic, cardiac and cancer agents)
what drug combinations are particular risk for serotonin syndrome
when serotonergic or sympathomimetic drugs are combined with MAOIs like moclobemide and selegiline
SS is rare except in overdose but can occur with use of multiple serotonergic agents (i.e SSRIs, SNRIs, tramadol)
list 5 antidepressants that have MINIMAL or LOW potential for drug-drug interactions
citalopram
desvenlafaxine
escitalopram
mirtazapine
venlafaxine
list 7 antidepressants that have MODERATE potential for drug-drug interactions
agomelatine
buproprion
duloxetine
levomilacipran
sertraline
vilazodone
vortioxetine
list 5 antidepressants that have HIGHER potential for drug-drug interactions
fluoxetine
fluvoxamine
paroxetine
selegiline
moclobemide
list 1 antipsychotic with MINIMAL or LOW potential for drug drug interactions
paliperidone
list 3 antipsychotics with MODERATE potential for drug drug interactions
aripiprazole
olanzapine
risperidone
list 3 antipsychotics with HIGHER potential for drug drug interactions
clozapine
lurasidone
quetiapine
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
citalopram
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
aripiprazole
moderate
2D6 + 3A4 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
fluoxetine
higher potential
2D6 + 2C19 inhibitor
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
vortioxetine
moderate
2D6 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
desvenlafaxine
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
duloxetine
moderate
2D6 inhibitor
1A2 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
quetiapine
higher potential
3A4 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
paroxetine
higher potential
2D6 inhibitor
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
agomelatine
moderate
1A2 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
buproprion
moderate
2D6 inhibitor
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
mirtazapine
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
paliperidone
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
sertraline
moderate
2D6 inhibitor
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
fluvoxamine
higher potential
1A2 + 2C19 + 3A4 inhibitor
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
clozapine
higher potential
3A4 and 1A2 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
escitalopram
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
venlafaxine
minimal/low
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
selegiline
higher potential
MAO inhibitor cautions
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
lurasidone
higher potential
3A4 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
levomilnacipran
moderate
3A4 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
olanzapine
moderate
1A2 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
risperidone
moderate
2D6 + 3A4 substrate
state whether the following agent has minimal/low, moderate or higher potential for drug drug interactions
if moderate or higher potential, state which part of the CYP system is relevant (i.e which enzyme) and in what way (substrate or inhibitor):
moclobemide
higher potential
MAO inhibitor cautoins
is routine pharmacogenetic testing recommended (for CYP enzymes)
no because data on utility of these tests is still lacking
may be helpful in certain situations–> i.e inabilty to tolerate minimum dose = ? poor metabolizer?/ repeated failure to respond to high doses may suggest rapid metabolizer
is drug level monitoring recommended for 2nd gen ADs?
no–> poor correlation between blood levels and clinical response
only useful really to detect nonadherence
inhibition of CYP 1A2 would increase serum levels of which psych meds?
agomelatine
clozapine
duloxetine
olanzapine
risperidone
inhibition of CYP 1A2 would increase serum concentrations of what important non-psych. meds
warfarin
theophylline
naproxen
caffeine
inhibition of CYP 2C19 would increase serum levels of which non- psych meds?
propanolol
warfarin
omeprazole
antiepileptics like phenobarbital
antiarrhythmics
inhibition of CYP 2D6 would increase serum levels of which psych meds?
TCAs
olanzapine
risperidone
vortioxetine
inhibition of CYP 2D6 would increase serum levels of which non psych meds?
tramadol
opioids (reduces effect)
beta blockers
tamoxifen (reduces effect)
inhibition of CYP 3A4 would increase serum levels of which psych meds?
haloperidol
methadone
vilazodone
quetiapine
levomilnacipran
inhibition of CYP 3A4 would increase serum levels of which non psych meds?
HIV protease inhibitors
statins
antihistamines
antiarrhythmics
immune modulators like tacrolimus
tamoxifen
sildenafil
macrolide antibiotics like erythromycin
what is the definition of “early improvement” on an AD trial? why do we care?
defined as more than 20-30% reduction from baseline in depression rating scale after 2-4 weeks
correlated with response and remission at 6-12 weeks
*lack of early improvement at 2-4 weeks also predictor of later AD nonresponse/nonremission
what should you do if someone does not show early improvement at an AD at 2-4 weeks
increase the dose if medication is tolerated
if med not tolerated then should switch to a different AD
why should you not stop an AD within 6 months of starting it
high risk of relapse/recurrence if stopped within 6 months
how long should you continue an AD
6-9 months after symptomatic remission
continue for AT LEAST 2 years if has risk factors for recurrence
what is a mnemonic to remember antidepressant discontinuation symptoms
FINISH
Flu like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbance
Hyperarousal
which two ADs are most likely to give people discontinuation syndrome
paroxetine
venlafaxine
which two ADs are least likely to give people discontinuation syndrome
fluoxetine
vortioxetine
(longer half lives)
what % of people will develop discontinuation syndrome if stop ADs abruptly
40% approx
*recommend slowly tapering dose over several weeks
what should you do if someone has a partial response or no response to initial AD
ensure treatment OPTIMIZATION
–> reevaluate dx, consider treatment issues
i.e ?subtherapeutic dose, ?inadequate tx duration, ?poor adherence
consider psychotherapy + neurostim approaches
was is the definition of partial response to an AD
25-49% reduction in symptoms
(no response is less than 25% reduction in symptoms)
what is the definition of “treatment resistant depression”
inadequate response to two or more antidepressants
does NOT consider adjunctive strategies or partial vs no response
is there evidence guiding whether, after inadequate response to AD monotherapy, you should switch within SSRI class vs non-SSRI class?
insufficient evidence
is there evidence guiding whether, after inadequate response to AD monotherapy, you should switch pursue ongoing AD monotherapy vs atypical antipsychotic augment?
low quality evidence for superiority of atypical antipsychotic augment strategy
is there evidence guiding whether, after inadequate response to AD monotherapy, there is a particular atypical antipsychotic you should use vs other adjuncts?
insufficient evidence
is there evidence to support switching AD nonresponders to another antidepressant?
yes, there is evidence for good response and remission rates with switching
*HOWEVER–> few studies comparing switch strategy with continuing current AD for longer, and a systematic review suggested that there was no difference in response or remission rates between switch and continuing strategies
if you’re switching antidepressants, which one do you pick?
guidelines recommend ideally switching to an AD with “superior efficacy”
(though there is some evidence noted in the guidelines that there may be some benefit to switching AD class if does not respond to initial AD)
list the 3 FIRST LINE meds for adjunctive therapy in MDD
aripiprazole (2-15mg)
risperidone (1-3mg)
quatiapine (150-300mg)
all level 1 evidence
list the 7 SECOND LINE meds for adjunctive therapy in MDD
level 1 evidence:
brexpiprazole
olanzapine
lithium
level 2 evidence:
buproprion
mirtazapine/mianserin
modafinil
triiodothyronine
list the 4 THIRD LINE meds/classes for adjunctive therapy in MDD
TCAs (level 2)
other antidepressants
others stimulants
ziprasidone
(all level 3)
name an experimental med that could be used adjunctively in tx of MDD
ketamine (0.5mg/kg single IV dose)
name a med that is NOT recommended as adjunctive treatment for MDD
pindolol (level 1 negative evidence)
which class of med has the most consistent evidence for efficacy in adjunctive tx of MDD
atypical antipsychotics
did adverse event rates differ from placebo in RCTs examining modafinil as adjunctive treatment for MDD
no they were about the same
*to date, other stimulants seem to have negative studies
according to a network meta-analysis of 48 RCTs, which 4 medications were more effective than placebo as adjunctive strategies for MDD treatment
aripiprazole
quetiapine
lithium
T3 (triiodothyronine)
*stronger efficacy for aripiprazole and quetiapine
should you combine ADs at initiation of treatment
no–> increased side effects and not clear benefit for efficacy
wait to see if responds to monotherapy then consider augmentation/switch etc
how did T3 compared to lithium as an adjunctive agent for MDD
T3 was better tolerated and had lower dropout rates compared to lithium
what factors would make you consider switching meds (instead of adding adjunctive treatment) when treating MDD
this is the first trial of antidepressant
initial AD was poorly tolerated
no response to initial AD
there is more time available to wait for a response
patient prefers to switch
what factors would make you consider adding an adjunctive agent rather than switching agents in the treatment of MDD
there have been 2 or more AD trials
initial AD is well tolerated
there has been a partial response to the initial AD
less time is available to wait for a response (i.e more severe or impairing sx)
patient prefers to add on
there are specific/residual symptoms or side effects that can be targeted
what systems are being targeted by evolving novel treatments for MDD
glutamate system
endocannabinoid system
what experimental meds for MDD target the glutamate system
ketamine
esketamine
lanicemine
memantine
list 5 novel/experiemental treatments for MDD
ketamine/esketamine
memantine
targeting endocannabinoid system
adjunctive celecoxib
cariprazine
pramipexole