Depression/Anxiety Flashcards
3 monoamines
dopamine
seratonin
norepinephrine
inhibitors of monoamine uptake: 4 examples
SSRI
SNRI
NDRI
TCA
SSRI
selective serotonin reuptake inhibitors
SNRIs
serotonin and norepinpheinr reuptake inhibitors
NDRIs
norepinephrine and dopamine reuptake inhibitors
TCA
tricyclic anti depressants
MAOI stands for
monoamine oxidase inhibitors
NDRI example
duloxetine
etiology of MDD: monoamine hypothesis
deficiency in the amount or function of 5HT/Serotonin, norepinephrine, and or dopamaine.
etiology of depression: neurotrophic hypothesis
deficiency in neurotrophic factors, especially BDNF (brain derived neurotrophic factor)
in depression or chronic stress, you’ll have a decrease in (2)
synapses
BDNF
increased dendritic arbors is associated with
increased bdnf
most proximal cause of depressive symptoms
neural apoptosis in hippocampus/pre frontal cortex
stress mechanisms underlying neural apoptosis
- sustained high levels of cortisol which promotes neural apoptosis
- excessive glutamate levels which are high enough to be cytotoxic. leads to apoptosis.
what counteracts this neural apoptosis contributing to depressive symptoms?
monoamines and neurotrophic factors
monoamines and their receptors counteract cytotoxic effects of stress. what do they promote?
genes which facilitate neurogenesis in hippocampus, producing an anti depressant response.
depression results in an imbalance of opposing signals.
too much _____ or _____
too little _____, _____, and or ______
too much glutamate or cortisol
or too little norepinephrine, serotonin, and or BDNF.
the way to counter depression is to reduce _______ or increase _______
reduce stress related signaling
increase monoamine NTs or BDNF
antidepressant strategy
increase synaptic concentrations of norepinephrine / serotonin in the hippocampus and prefrontal cortex
if an antidepressant strategy is increase synaptic concentrations of norepinephrine / serotonin in the hippocampus and prefrontal cortex, how can we go about doing that? (3)
- inhibit reuptake of the monoamines once released from presynaptic neurons
- prevent degradation of the monoamines once released
- block pre synaptic forms of negative feedback regulation
anti depressants may also work by mimicking the actions of
NE / serotonin and postsynaptic receptors (beta adrenergic or serotonin 1A receptors)
time course of response: anti depressants
initial response: 1-3 weeks
max response: 12 weeks
when can an anti depressant be considered failed?
after 1 month with no success
selecting an anti depressant is
patient specific. they’re nearly all the same efficacy.
early treatment management of the patient on anti depressant
assess for suicidal tendencies
SSRI drugs (6)
fluoxetine paroxetine citalopram escitalopram sertraline fluvoxamine
action of SSRI
selectively inhibiting the serotonin reuptake transporter SERT
efficacy of SSRIs is attributed to
subsequent actions of elevated 5HT at 5HT1A receptors
5HT 1A receptor activation
anti depressant response
AEs of SSRIs are all serotonin mediated. They are (4)
nausea
agitation
insomnia
sexual dysfunction
AE of nausea from SSRI is due to which receptor activation
5HT3
sexual dysfunction is due to activation of what receptor in SSRI use?
5HT2
drug interactions with SSRIs can be due to
their inhibition of the metabolism of other drugs
risk of overdose with SSRI is
low
SSRIs must not be combined with
MAOIs
SSRIs are potent inhibitors of
CYP 2D6
SSRIs inhibit which transporter
SERT
which serotonin receptors are particularly problematic when stimulated re: adverse effects?
5HT2
5HT3
which other SSRIs inhibit metabolism of other drugs the most?
fluoxetine
paroxetine
which SSRIs probduce active metabolites?
fluoxetine
sertraline
stimulating 5HT14 in the wrong region of the brain
leads to undesired effects
by inhibiting CYP 1D6 AND 3A4, SSRIs can
increase plasma concentrations of many drugs
which SSRI has the longest half life?
fluoxetine
half life of fluoxetine’s metabolite’s half life?
3 days
washout period
t1/2 of med’s active metabolites.
SSRIs have high Vd because
lipophilic
SSRI with high protein binding, like fluoxetine, plus phenytoin
could cause phenytoin toxicity because they’d compete for protein binding and there would be more free phenytoin circulating
anti depressant actions of SSRIs are similar in efficacy and time course to
TCAs
acute toxicity/cardiotoxicity in anti depressant use is seen more in/less in which drugs?
more often in MAO Is and TCAs
less often in SSRIs
SSRI side effects
nausea
insomnia
sexual dysfunction
sedation in antidepressants is seen more in/less in
more in TCAs
less in SSRIs
SSRIs + MAOIs in comvination
risk for serotonin syndrome
serotonin syndrome s/s
tremor
hyperthermia
CV collapse
paroxetine or fluoxetine in combination with TCAs
should not be combined.
these SSRIs inhibit CYP2D6 –> inc risk for TCA toxicity
which SSRIs are FDA approved for adolescents?
fluoxetine
escitalopram
With regards to pregnancy, SSRIs are mainly
category C
which SSRI do you want to avoid the most in pregnancy?
paroxetine - category D
SSRIs may also treat (6)
GAD panic social anxiety OCD premenstrual dysphoric syndrome PTSD
interactions between hydrocodone and fluoxetine or paroxetine
hydrocodone is a prodrug converted by CYP2D6 into hydromorphone, a much more potent opioid. fluoxetine or paroxetine will inhibit CYP2D6, which may decrease pain relief in those taking hydrocodone.
SNRIs (4)
duloxetine
venlafaxine
desvenlafaxine
milnacipran
desvenlafaxine
active metabolite of venlafaxine, can be prescribed on its own
SNRIs inhibit which transporters?
SERT
NET
the antidepressant effects of SNRIs are due to
activating 5HT1a receptors
activating beta adrenergic receptors
adverse effects of SNRIs are similar to SSRIs, plus
dose related elevation of bp
risk of SSRI/SNRI overdose is
low
SNRIs cannot be used in combo with
MAOIs
why do you get elevated bp with SNRI?
activation of alpha adrenergic receptors in vasculature
SNRIs have a greater affinity for
SERT
Are SNRIs more efficacious than SSRIs or TCAs?
no
inhibiting SERT and NET leads to
increases in serotonin and norepinephrine signaling
bioavailability of SSRI and SNRIs
pretty good
half life of SNRIs is ____ than SSRIs
shorter
active metabolites / washout periods SNRIs
not a concern
protein binding of SNRIs
varies between the drugs
duloxetine protein binding as compared to other SNRIs
much higher, 90%
if you’re concerned about drug:drug interactions but need to prescribe an anti depressant, what would be a good choice?
venlafaxine or milnacipran SNRIs because of low protein binding
SNRIs are mainly metabolized by _____ except for
CYP 2D6
except for desvenlafaxine
metabolism of desvenlafaxine
phase II - conjugation
SNRIs noradrenergic related adverse effects
inc bp
tachy
CNS activation
like SSRIs, SNRIs may also be used to treat
anxiety disorders
fibromyalgia
neuropathic pain
SNRIs are thought to help fibromyalgia and neurpathic pain, unlike SSRIs, because of
increased noradrenergic signaling
TCA examples (5)
amitryptaline clomipramine dose-in imipramine trimipramine
why have TCAs fallen out of of favor (2)
not very well tolerated in regards to AE
risk for fatal cardiac arrhythmia with high doses
TCA MoA
inhibit 5HT and NE uptake
antidepressant effects of TCAs can be attributed to
effects on 5HT1a receptors and beta adrenergic receptors
TCAs and active metabolites
they do have active metabolites that work at 5HT and norepinephrine receptors, but their affinity may defer. you can have varied response to TCAs depending on the active metabolites.
why aren’t TCAs as well tolerated as SSRIs/SNRIs?
they affect additional receptors unrelated to therapeutic efficacy
what other receptors do TCAs antagonize, unrelated to therapeutic efficacy? (3)
muscarinic acetylcholine receptors
histamine H1 receptors
alpha1 adrenergic receptors
TCA half lives
long
TCA washout periods
important to pay attention to bc they do have active metabolites with long half lives
TCa protein binding
high
TCA lipophilicity
high
metabolite half lives of TCAs as compared to just the half life of TCAs
longer
washout period of TCA
long because of active metabolite half lives
TCAs are metabolized by
CYP 2D6
poor metabolizers of CYP 2D6 can have a _ fold difference in plasma conch
30 fold difference
what actions are warranted to avoid toxicity when a pt who is a PM of CYP2D6 is taking a TCA?
plasma level monitoring
dose reduction
a`
AEs of TCAs r/t to antagonism of muscarinic receptors (4)
dry mouth
blurred vision
constipation
urinary retention
AEs of TCA r/t antagonism of H1 histamine receptors? (2)
sedation
weight gain
A Es of TCAs r/t antagonism of alpha1 adrenergic receptors (1)
postural hypotension
potentially fatal A E of TCAs, particularly in overdose?
ventricular dyshythmias
therapeutic index of TCA
narrow
TCAs are only prescribed in 1 week intervals, why?
because they may be used for suicide in OD
drug interactions and TCAs
likely to cause adverse effects bc they rely on CYPs
TCAs potentiate the effects of (2)
alcohol
anesthetic
TCAs interfere with the actions of _____ and may require _____
anti hypertensive drugs
may require dose adjustments up, as TCAs can cause hypertension
efficacy and time course of TCAs as compared to SSRI and SNRI
identical
at the present time, TCAs are used if
depression is unresponsive to more commonly used agents like SSRIs or SNRIs
TCAs and chronic or neuropathic pain
efficacy
first choice for patient with depression and chronic pain and what is your next choice if they don’t respond to it?
1st - SNRI
2nd - TCA
acute TCA overdose s/s (3)
confusion
mania
cardiac dysrhythmias
TCAs are likely to interact with drugs which
are metabolized by, inhibit, or induce CYPs
(3) things that TCAs will interact with
alcohol
anesthetics
MAOIs
monoamine receptor antagonists (2)
mirtazapine
trazodone
monoamine receptor antagonist MoA
mirtazapine antagonizes 5HT2c and 5HT3 receptors, while also blocking a2 adrenergic receptors
mirtazapine differs in its anti depressant response because it blocks __&__ instead of activating _______.
blocks 5HT2c and 5HT3 instead of activating 5HT1a.
how do monoamine receptor antagonists, like mirtazapine, work? (2)
activation of 5HT2c and 5HT3 is actually depressive, so blocking them is anti depressive.
they also block a2 adrenergic receptors on NE and 5HT terminals, increasing the amount of NE and 5HT available for release to synaptic cleft.
what non therapeutic receptors do monoamine receptor antagonists also bind to and block, and what is the effect?
histamine h1 receptors, resulting in sedation.
MAOI for depression are
no longer preferred
how do MAOIs work
irreversibly bind to monoamine oxidase and inhibit it, preventing metabolism/breakdown of NE, 5HT, and DA in the brain.
MAOI effectiveness as compared to TCAs and SSRIs/SNRIs
as effective but more hazardous
MAOIs will be considered for depression if
a patient is treatment resistant
MAOIs are irreversible inhibitors of
MAO A and MAO B
MAOI dietary restrictions
need to restrict tyramine
risk for HTN crisis
seizure risk and MAOIs/SSRIs/SNRIs
seizure threshold is lowered
adverse effects of MAOIs
CNS stimulation
orthostatic hypotension
if you eat tyramine rich foods on an MAOI
htn crisis
why is tyramine so dangerous on an MAOI?
inhibiting MOA in the liver makes tyramine able to enter the systemic circulation. when tyramine hits NE containing terminals in the CNS, it causes a massive dump of NE. this increases sympathetic tone to the point of htn crisis and possibly death.
atypical antidepressant example
buproprion
MoA of buprioprion
binds to and inhibits NET and DAT, increasing NE and DA signaling.
also functions as a partial agonist of nicotinic Act receptors, underlying its efficacy for smoking cessation.
bupropion is a derivative of
amphetiamine
most notable adverse effect of buproprion
seizure
choosing an antidepressant is based on (6)
cost availability adverse effects drug interactions pt history of response pt preference
choosing an anti depressant for an individual with depression who is also having insomnia
choose mirtazapine bc of sedating effects
avoid SSRI bc of excitatory effects
if a patient is depressed and experiencing extreme fatigue, what would be a good choice?
buproprion
if a patient is experiencing depression and decrease in libido, which would be 2 better anti depressant choices?
bupropion (atypical)
mirtazipine (monoamine receptor antagonist)
most commonly prescribed first line agent in MDD
SSRI
second or third line choices are
TCAs
MAOIs
non pharmacological approaches may be preferred to
MAOIs
patient teaching for antidepressants
3-4 week lag time exists between initiation of therapy and measurable therapeutic response
if a pt doesn’t respond to a given antidepressant after a 12 week trial, what is the reasonable next step?
stopping and switching to another antidepressant, but you have to be mindful of washout periods in this instance
if a partial response is observed on an SSRI or SNRI,
other drugs can be added concomitantly
what is a typical maintenance treatment phase of antidepressants?
6-12 months
when is lifelong treatment advisable? (2)
if a patient has experienced 2-3 separate episodes of major depression
if a patient is chronically depressed
why don’t we withdraw antidepressants once remission occurs?
because they’re still at risk for relapse. the 6-12 month maintenance is recommended. you want to avoid episodes of MD because they get more severe as they come and treatment resistance becomes more likely with each episode.
the most safe anti depressants in pregnancy (3)
fluoxetine (SSRI)
citalopram (SSRI)
TCAs
antidepressants and breastfeeding
benefits of breastfeeding outweigh the risks of infant antidepressant exposure
blackbox warning for antidepressants in children and young adults
increased risk in suicidality
patients on antidepressants should be monitored
at least twice a year to assess if the drug is still needed or if the dose needs adjustment
withdrawing of antidepressants
needs to be a slow, supervised taper over months or longer to minimize withdrawal symptoms like rebound anxiety/depression
early warning signs of relapse and what you should do
insomnia
avoiding social engagement
adjust or restart treatment
for those who are treatment resistant, what are non pharm treatment options? (3)
vagus nerve stimulation
ECT
transcranial magnetic stimulation
new generation of anti depressants being introduced in clinical practice
NMDA receptor antagonist (ketamine)
how does ketamine work?
rapidly increases glutamate levels in the brain by blocking NMDA receptors on gaba terminals.
when you block glutamate signaling on a gaba terminal,
you reduce gaba release at the synapse. this increases glutamate signaling at the synapse, resulting in an increase of glutamate and brain neurotrophic signaling. this is all anti depressant.
doses of ketamine for anti depression
much lower than doses taken recreationally
ketamine’s antidepressant effect is
rapid
obstacles to using ketamine as an antidepressant
abuse liability
potential for dissociative effects
esketamine
intranasal ketamine
first FDA approved fast acting antidepressant
therapeutic onset of esketamine
hours
prescribed doses of esketamine can produce
sedation inattention dissociation abuse potential suicidal behaviors
to prevent abuse of esketamine, it is only available
at approved treatment centers. it cannot be taken home. patients go 2-3 times a week to get their treatment under supervision.
brexanolone
what is it
new FDA Approved Drug for postpartum depression
allopregnanolone, a neuroactive metabolite of progesterone which typically drops right after delivery (this triggers depression/anxiety for some women). when given as a continuous IV over 60 hours immediately after delivery. goal is to reduce or prevent PPD.
adverse effects of brexanolone
sedation headache dizziness dry mouth hot flashes LOC
blackbox warning: brexanolone
for LOC
need to be supervised while on this med
drugs used in anxiety disorders (5)
SSRI SNRI benzodiazepines buspirone beta blockers
types of anxiety disorders (5)
GAD OCD panic disorder PTSD social anxiety disorder
if acute relief is needed for anxiety, what is the drug of choice and for how long?
benzodiazepine
2-4 weeks
if adequate acute response is not achieved in 2-4 weeks of benzodiazepine for anxiety, what will you try next?
SSRI or SNRI
if SNRI or SSRI doesn’t provide an adequate for anxiety,
switch to another SSRI/SNRI
or switch to a different agent
benzodiazepines bind to
gaba-A receptors
benzos and barbiturates both
bind to and potentiate the effects of gaba
if your benzodiazepine expresses an alpha 1 unit,
sedation
if your benzodiazepine expresses an alpha 2 and 3 subunit,
decreased anxiety
alpha 1 subunits
sedation
alpha 2 and alpha 3 subunits
decrease anxiety
other general effects from benzos (3)
anti convulsant activity
hypnosis
anterograde amnesia
advantages of benzos for treating anxiety. (3)
rapid action
high therapeutic index
little or no induction of liver enzymes, so lower risk for drug interactions in terms of phase I metabolism
disadvantages of benzos (4)
impairment of psychomotor performance
amnesia
dependence/withdrawal after long term treatment
rebound anxiety after short term treatment
what to worry about after long term treatment of benzos
dependence
withdrawal
what to worry about after short term benzo treatment
rebound anxiety
pharmacokinetic considerations of benzos
long half lives
metabolites with long half lives
desmethyldiazepam
active metabolite of multiple benzos which has a very long half life. It then is metabolized to oxazepam, which is also active.
complicated metabolism of benzos
some have active metabolites who then have their own active metabolites. there are potentially many different wash out periods that we need to be aware of.
if hepatic function is compromised in a patient who needs benzos
you’d want to select a benzo that only undergoes phase II metabolism. ie: lorazepam
buspirone vs benzo
reduces symptoms of anxiety less effectively than benzos but has no risk of dependence
MoA buspirone (2)
mysterious
likely blocks 5HT1a autoreceptors, increasing 5HT signaling in the brain
stimulates 5HT1a post synaptic receptors as a partial agonist
Buspirone can be used as an adjunct
to SSRI/SNRIs if they’ve experienced only partial response. Its MoA allows an anti depressant effect as well.
buspirone duration of onset
longer than benzos
similar to SSRIs
