Major Depressive Disorder - Pharmacotx Flashcards
T or F: Antidepressant trials have shown that antidepressants have a huge impact upon MDD sx’s
F
There are large placebo effects in these trials > indicates unspecific factors are strongly involved in MDD tx
What kind of MDD has been studied the most in antidepressant trials?
mod-sev MDD
CANMAT 1st line SSRIs:
sertraline escitalopram citalopram fluoxetine paroxetine vortioxetine
What’s special about vortioxetine?
It’s an SSRI that also has 5-HT actions (i.e. it’s a serotonin MODULATOR)
What SSRI is NOT recommended by CANMAT as a first-line agent for MDD?
fluvoxamine (Luvox) > due to DIs and reduced tolerability
SSRI MOA?
Inhibit reuptake of 5-HT by inhibiting 5-HT transporters in CNS neurons
SSRI onset of action?
1st few days for decreased agitation and anxiety, improved sleep, and improved appetite.
1-3 wks: increased activity, increased sex drive, improved self care, conc, memory, thinking, movements
2-4 weeks on average for relief of depressed mood/anhedonia/hopeless feelings/suicidal thoughts
(can take up to 8 weeks for full effects)
SSRI AEs?
HANDS
h/a, anxiety (esp. when starting SSRI tx), nausea, diarrhea (and other GI upset), Sexual and sleep dysfn (insomnia, sedation, sexual dysfn [men and women])
SSRI’s most commonly assoc w/ sedation?
Sertraline, citalopram, and paroxetine
SSRIs assoc w/ wt gain?
Paroxetine
T or F: SSRIs are commonly assoc w/ wt gain.
F
What’s so special about fluoxetine?
It is the most stimulating SSRI and has a long half life (4-6 days)
Which SSRIs have the highest rates of N/D?
Fluvoxamine and sertraline
Which SSRI is assoc w/ the least amt of sexual dysfn?
Escitalopram
Which SSRI is the least tolerable overall?
Fluvoxamine
What life-threatening adverse effect are SSRIs assoc w/?
SIADH (syndrome of inappropriate ADH)
What is SIADH?
A condition where a lot of ADH is produced > causes lots of fluid retention > electrolyte dilution > hyponatremia/concentrated urine
Sx’s/signs of SIADH?
Lethargy, change in mental status, Na<130 mEq/L, hyperosmolar urine (>300 mOsm/kg)
Fluvoxamine’s inhibition of CYP1A2 is s.times strategically used to increase the levels of this drug.
clozapine (clozapine is metabolized by 1A2)
DIs of SSRI?
- NSAIDs, antiplatelets, anticoags
- SSRIs reduce platelet aggregation > increased bleeding risk - Serotonergic agents
- increased risk of serotonin syndrome
How does food affect SSRI absorption?
It doesn’t
There is ONE SSRI that is affected by food.
It’s sertraline; its F increases w/ food
How are SSRIs metabolized?
By CYP enzymes
These three SSRIs are metabolized into active metabolites by the liver.
- fluoxetine
- citalopram
- sertraline
How often are SSRIs taken per day?
OD
Are SSRIs safe in pregnancy?
Yes, as far as the evidence is concerned (no teratogenicity)
Which SSRI should be avoided during pregnancy?
Paroxetine
Why should paroxetine be avoided in pregnancy?
It’s assoc w/ most reports of pulmonary HTN and SSRI withdrawal (jitteriness, restlessness, irritability, tremors) [although, these are in fact seen w/ other SSRIs too]
Which SSRIs are safe in breastfeeding?
Sertraline and paroxetine (most research + low to undetectable levels)
Which SSRIs should be avoided in breastfeeding?
Fluoxetine (high levels in breast milk + prolonged half-life)
SSRI warnings:
- increased risk of suicide in children, adolescents, and young adults <24yrs
- reduced BMD and increased fracture risk
Which SSRI is assoc w/ QTc prolongation?
Citalopram
What is the max dose for citalopram in order to reduce the risk of QTc prolongation?
40mg
This SSRI is assoc w/ the most diarrhea and male sexual dysfn:
Sertraline
Which SSRI is most assoc w/ sedation?
paroxetine
T or F: SSRIs do not need to be tapered when being d/c’ed.
F (They SHOULD be tapered to avoid withdrawal sx’s)
What is vortioxetine (i.e. class of medication)?
It’s a serotonin modulator
1st line SNRIs (CANMAT)?
Duloxetine, Venlafaxine
2nd line SNRIs (CANMAT)?
Levomilnacipran
SNRI MOA?
Inhibits presynaptic 5-HT and NE reuptake in CNS neurons.
T or F: Venlafaxine can also work as an SSRI.
T
Minimum dose of venlafaxine for it to work as an SNRI.
150mg/day
Venlafaxine dosed at doses <150mg/day works as a what?
SSRI
Duloxetine vs. venlafaxine: which one inhibits NE transporter better?
Duloxetine
SNRI onset of action
SAME AS SSRIs!
1st few days for decreased agitation and anxiety, improved sleep, and improved appetite.
1-3 wks: increased activity, increased sex drive, improved self care, conc, memory, thinking, movements
2-4 weeks on average for relief of depressed mood/anhedonia/hopeless feelings/suicidal thoughts
(can take up to 8 weeks for full effects)
SNRI AEs
HANDS (like SSRIs)
h/a, anxiety (esp. when starting SSRI tx), nausea, diarrhea (and other GI upset), Sexual and sleep dysfn (insomnia, sedation, sexual dysfn [men and women])
Antichol effects (dose-related) [can’t pee/see/spit/shit, sedation]
Increased BP/HR (dose-related)
T or F: SSRIs must be tapered when d/c’ing, but SNRIs do not.
F (SNRIs must be tapered before d/c too)
SNRI vs SSRI: withdrawal sx’s are worse with which one?
SNRI
How does food affect SNRI absorption?
It doesn’t
Does kidney fn affect dosing of SNRIs?
Yes, dosing must be adjusted
T or F: Venlafaxine and duloxetine are excreted unchanged by the kidneys.
F (They’re metabolized hepatically first)
Duloxetine and venlafaxine are inhibitors and substrates for which CYP enzyme?
2D6
Besides CYP450 interactions, name 2 other DIs involving SNRIs
- NSAIDs/antiplatelets/anticoagulants (increased bleeding risk)
- Serotonergic agents (increased risk of serotonin syndrome)
SNRI warnings/precautions:
- narrow angle glaucoma
- HTN pts
- increased risk of suicide if <24yrs
- avoid abrupt withdrawal
1st line NDRI (CANMAT):
Bupropion (Wellbutrin)
Bupropion MOA
inhibits NE and DA transporters increasing concs in the synapses
T or F: Bupropion has some 5-HT effects at higher doses.
F
Bupropion (NDRI) onset
Similar to SSRIs/SNRIs
1st few days for decreased agitation and anxiety, improved sleep, and improved appetite.
1-3 wks: increased activity, increased sex drive, improved self care, conc, memory, thinking, movements
2-4 weeks on average for relief of depressed mood/anhedonia/hopeless feelings/suicidal thoughts
(can take up to 8 weeks for full effects)
What enzyme metabolizes bupropion?
CYP2B6
T or F: The metabolite of bupropion is nonactive
F (It’s also active - hydroxybupropion)
Bupropion route of elimination
Kidneys mainly (87%)
Brand name of bupropion used for MDD?
Wellbutrin
Brand name of bupropion used for smoking cessation?
Zyban
T or F: You cannot use Zyban for MDD - the brand must be changed to Wellbutrin.
F
They’re the exact same drug. If using Zyban for smoking cessation, it can also concurrently be used for MDD tx
If a patient is on Zyban for smoking cessation, and he is dx’ed with MDD, he can be put on Wellbutrin to tx it.
F
They are the SAME drug!
Bupropion inhibits this enzyme strongly
2D6
Common bupropion AEs
- Activating (ANXIETY, agitation, insomnia, tremor - due to NE)
- Sweating (due to NE)
- Reduced appetite/wt loss
- GI upset
- Psychosis (due to DA)
- Seizures
- Sexual dysfn (less so than SSRIs/SNRIs)
T or F: There’re no dosing adjustments needed for bupropion for renal/hepatic impairment.
F (dosing adjustments needed for impairment in either of those organs)
Bupropion contraindications?
- MAOI tx > causes hypertensive crisis
- seizures disorder
- eating disorder
- abrupt d/c of alcohol or sedatives (another risk factor for seizures)
What’s mirtazapine’s MOA?
central alpha-2-blocker > increased NE and 5HT release
5HT2 receptor blocker > lower anxiety
5HT3 receptor blocker > GI AEs
H1 histamine receptor blocker > sedation, wt gain
Where does mirtazapine fit in CANMAT’s MDD guidelines?
It’s another 1st line agent for MDD
Mirtazapine AEs
- sedation (lasts long)
- increased appetite > wt gain
- sig sexual dysfn (more than other antidepressants)
Mirtazapine onset?
Like SSRIs/SNRIs
1st few days for decreased agitation and anxiety, improved sleep, and improved appetite.
1-3 wks: increased activity, increased sex drive, improved self care, conc, memory, thinking, movements
2-4 weeks on average for relief of depressed mood/anhedonia/hopeless feelings/suicidal thoughts
(can take up to 8 weeks for full effects)
How is mirtazapine excreted?
75% renally excreted
T or F: Mirtazapine has no risk of serotonin syndrome, just like bupropion.
F (it causes more serotonin release from central neurons)
When should mirtazapine be taken?
At night due to its sedating effects
When should mirtazapine be taken?
At night due to its sedating effects
When does the sedative effect of mirtazapine begin to disappear?
30 mg
When is mirtazapine usually used?
When pts have insomnia and if wt gain is desired
T or F: Mirtazapine is dangerous in overdose
F
It’s pretty safe in overdose
Black box warning assoc w/ SSRIs, SNRIs, bupropion, AND mirtazapine?
Increased suicide risk for inds <24yrs
Agranulocytosis is assoc w/ which antidepressant?
Mirtazapine
Name the 2nd line agents recommended by CANMAT for tx of MDD
1. TCAs: Amitriptyline Clomipramine Nortriptyline (others) SNRI 2. Levomilnacipran Reversible MAOI 3. Moclobemide Serotonin reuptake inhibitor/5HT2 antagonist 4. trazodone Atypical antipsychotic 5. quetiapine Serotonin reuptake inhibitor/5HT1A partial agonist 6. Vilazodone
MOA of TCAs
Inhibit presynaptic 5HT and NE reuptake
MOA of TCAs is similar to this class of medication.
SNRI (reuptake of NE and 5HT is delayed)
What kind of TCAs have more 5HT reuptake inhibition (and hence more 5HT activity)?
Those w/ 3º amines
What kind of TCAs have more NE reuptake inhibition (and hence more NE activity)?
Those w/ 2º amines
Name a TCA with 3º amine.
amitriptyline
Name a TCA w/ 2º amine.
nortriptyline
What kind of TCA is better tolerated?
2º amine TCAs since they have more NE activity relative to 5HT activity
amitriptyline vs nortriptyline - which is better tolerated? Why?
Nortriptyline since it contains a 2ºamine, and hence has more NE activity.
What comorbidity should be considered before Rx’ing nortriptyline?
HTN (increased BP w/ increased NE activity)
What did the Cipriani paper tell us about amitriptyline?
It may be more effective than the other antidepressants.
Common AEs w/ TCAs
sedation, anticholinergic effects (reduced sweating, dry mouth, reduced urination, mydriasis, flushing, delirium and confusion, constipation), CV AEs, wt gain, sexual dysfn, urine discolouration (blue-green with amitriptyline)
What happens in TCA overdose?
It has potentially lethal cardiotoxic effects such as heart block or ventricular tachycardia
Trazodone MOA
Weak inhibition of 5HT and NE uptake
5HT2A antagonist
Alpha-1 and histamine-1 receptor antagonists (sedating)
How is trazodone mainly excreted?
Kidneys (75%)
How does food affect trazodone?
It enhances yet delays peak conc
CYP enzyme involved in trazodone metabolism
CYP3A4
Trazodone DIs
CYP3A4 inducers/inhibitors
Antihypertensives (due to alpha-1 blocking activity > hypotn)
Serotonergic meds
QT prolonging meds
Trazodone AEs
Dizziness, sedation, h/a, orthostatic hypotn, QT prolongation, N, constipation, dry mouth
Should trazodone be taken with a meal? Why or why not?
Yes > it delays peak conc > reduces AEs
What is trazodone usually used for?
sedation (NOT MDD usually due to AEs)
Quetiapine MOA
Antagonist at 5HT1, 5HT2, D1 and D2, H1 (sedation), alpha-1 and alpha-2 receptors
What kind of drug is quetiapine?
Atypical antipsychotic
Quetiapine has a usual dose range (150-300mg/day) and a max daily dose range (300-600mg/day). What’re ea. used for?
Usual daily dose range: MDD
Max daily dose range: psychotic depression (quetiapine is an atypical antipsychotic)
Which MAOI is often used in MDD pts (in Canada)?
Moclobemine
How does moclobemine differ from the other MAOIs?
It’s reversible (the other MAOIs are irreversible)
MAO-A preferentially metabolizes ______
5HT and NE (DA, but less than MAO-B)
MAO-B preferentially metabolizes ______
trace amines (like DA)
MAO-A and MAO-B both metabolize ______
DA and tyramine
Which MAO subtype has a larger effect on DA metabolism?
MAO-B
MOA of moclobemide?
Short-acting reversible inhibitor of MAO-A > reduces metabolism of 5HT, NE, and DA
At what dose of moclobemide do we begin to see tyramine rxns?
> 600mg/day
Why do we begin to see tyramine rxns after exceeding the daily max dose of moclobemide?
The drug loses its specificity to MAO-A
DI’s of moclobemide:
Serotonergic drugs, anesthesia
If taking a serotonergic drug, what should you do if you want to start an MAOI?
Stop the serotonergic drug 2 weeks before starting the MAOI
Why do we stop the serotonergic drug if starting an MAOI?
Avoid hypertensive rxn or serotonin syndrome
D/c THIS SSRI 5 weeks before starting MAOI. Why?
Fluoxetine > it has a longer t1/2
other SSRIs are stopped 2 weeks prior to MAOI initiation
Moclobemide main AEs
Nervousness/anxiety (due to NE and DA)
Antichol effects
Levomilnacipran - MOA?
SNRI
AEs of levomilnacipran
HANDS (like SSRIs)
h/a, anxiety (esp. when starting SSRI tx), nausea, diarrhea (and other GI upset), Sexual and sleep dysfn (insomnia, sedation, sexual dysfn [men and women])
Antichol effects (dose-related) [can’t pee/see/spit/shit, sedation]
Increased BP/HR (dose-related)
Vilazodone - MOA
Serotonin reuptake inhibitor/5HT1A partial agonist
3rd line tx’s for MDD
Irreversible MAOIs
Irreversible MAOIs - name the two drugs:
Phenelzine
Tranylcypromine
What do irreversible MAOIs do (MOA)?
Inhibit MAO-A and MAO-B > increase 5HT, NE, and DA concs in synapses
CANMAT 1st line SSRIs:
sertraline escitalopram citalopram fluoxetine paroxetine vortioxetine
1st line SNRIs (CANMAT)?
Duloxetine, Venlafaxine
1st line NDRI (CANMAT):
Bupropion (Wellbutrin)
Where does mirtazapine fit in CANMAT’s MDD guidelines?
It’s another 1st line agent for MDD
MOA of ketamine?
helps to rebalance glutamate levels in the CNS > reduces chronic excitatory stress on neurons
Major ketamine AE
Dissociation (50%!!)
