Chapter 7: treating mood disorders Flashcards
what is classified as a “response”
at least 50% reduction in symptoms
what are the 6 SSRIs
fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
citalopram (Celexa)
escitalopram (Lexapro)
what is the SPARI used in clinical practice
Vilazodone (Viibryd)
what does SPARI stand for
serotonin partial agonist reuptake inhibitor
what are the 5 SNRIs
venlafaxine (Effexor)
desvenlafaxine (Pristiq)
duloxetine (Cymbalta)
milnacipran (Toledomen)
levomilnacipran (Fetzima)
what does NDRI stand-for and what is the NDRI used in clinical practice
Norepinephrine-dopamine reuptake inhibitor
Buproprion (Wellbutrin)
what is agomelatine (Valdoxen) used for
exerts antidepressant effect by correcting circadian rhythm by acting as a substitute melatonin
mechanism of action for agomelatine (Valdoxen)
agonist at melatonin 1 (MT1) and 2 (MT2)
antagonist at 5HT2C
4 principle mechanisms of action for mirtazapine
antagonism of 5HT2A, 5HT2C, a2-adrenergic, H1 receptors
what does SARI stand for and what are the SARIs used in clinical practice
serotonin antagonist reuptake inhibitors
nefazodone (Dutonin)
trazadone (Deseryl)
5 mechanisms of action for vortioxetine
inhibits SERT
antagonist ar 5HT3 and 5HT7
agonist at 5HT1A
weak partial agonism at 5HT1B/1D
name of the neuroactive steroid used in clinical practice
brexanolone
drugs most often used as augmentation agents in treatment-resistant unipolar depression
olanzapine/fluoxetine combo
quetiapine (seroquel)
aripiprazole (abilify)
brexpiprazole (rexulti)
cariprazine (Vraylar)
second line monotherapies for treatment-resistant depression
tricyclics
MAOIs
what is 1st line treatment for bipolar disorder
serotonin/dopamine blocker rather than monoamine inhibitor
drugs typically prescribed as 1st line treatment for bipolar disorder
olanzapine-fluoxetine combo
quetiapine (seroquel)
lurasidone (Latuda)
cariprazine (Vraylar)
what is the “classic” mood stabilizer
Lithium
how are anticonvulsants categorized as mood stabilizers
“mania minded” (tx/stabilize from above)
“depression minded” tx/stabilize from below
anticonvulsants proven effective in bipolar disorder
valproic acid (Depakote)
carbamazepine (Tegretol)
lamotrigine (Lamictal)
is monotherapy or combination therapy the standard for treating bipolar disorder
combination therapy
what % of SERTs need to be occupied to achieve antidepressant effect with SSRIs
80-90%
how do SSRIs work in general (common to all 6)
serotonin levels rise d/t SERT blockade.
There is an immediate increase of serotonin in the somatodendritic area which causes stimulation of 5HT1A autoreceptors. 5HT1A receptors downregulate (desensitized) after prolonged exposure to increased 5HT levels (correlates with time to therapeutic effect). Once autoreceptors are desensitized the neuron is disinhibited and releases 5HT at the axon terminal. Eventually, postsynaptic 5HT receptors desensitize which reduces side effects as tolerance develops
what is the only SSRI approved for treatment of eating disorders
fluoxetine (Prozac)
what is the mechanism of action of fluoxetine (Prozac) other than SERT inhibition
5HT2C antagonism
what neurotransmitters are increased by 5HT and 5HT2C antagonism
norepinephrine and dopamine
is 5HT2C antagonism generally activating or sedating
activating (energizing for increased concentration/attention)
half-life and available dosing options for fluoxetine
2-3 days
once daily or once weekly (active metabolite has a half-life of 2-3 weeks
binding profile of sertraline (Zoloft)
SERT inhibition with weaker DAT inhibition and σ1binding
binding porperties of stimulants like cocaine and meth
high-impact DAT inhibition
“well-oft”
adds weak DAT inhibition of wellbutrin and zoloft together
binding profile of paroxetine
NET and muscarinic inhibition and enzyme nitric oxide synthase
withdrawal rxns for paroxetine (Paxil)
akathisia, restlessness, GI symptoms, dizziness, tingling
binding properties of fluvoxemine (Luvox)
5HT inhibition and σ1binding properties (agonist)
what is Fluvoxamine approved for
OCD, not depression
available dosing options for fluvoxemine
IR (BID)
ER (QD)
one of the better tolerated SSRIs that are favorable for the elderly
Citalopram (Celexa)
enantiomers of citalopram
S and R
function of R enantiomer in citalopram
mild antihistaminic properties
activity may interfere with S enantiomer’s ability to inhibit SERT
whats important to remember about dosing citalopram
high doses can cause QTc prolongation
advantages of escitalopram over citalopram
only contains S enantiomer
no high dose restriction
removes antihistaminic properties
BEST tolerated SSRI
escitalopram
drugs typically used to augment SSRIs/SNRIs to add 5HT1A partial agonism
buspirone
aripiprazole/brexpiprazole/cariprazine
quetiapine
SPARI binding of buspirone
5HT1A partial agonist
SPARI binding profile of aripiprazole, brexpiprazole, cariprazine
5HT1A/D2 partial agonist
SPARI binding profile of quetiapine
5HT/D2 antagonist w/ 5HT1A partial agonist properties
how does wellbutrin work
occupation of SERT and 5HT1A receptors increase 5HT in somatodendritic area. This causes 5HT1A autoreceptors to downregulate/desensitize after prolonged exposure to increased levels of 5HT. downregulated autoreceptors to increased neuronal firing and 5HT release at axon terminal
binding profile of vilazodone
SERT inhibition with 5HT1A partial agonism
what is an advantage of SNRIs over SSRIs
ability to treat pain
where do SNRIs increase dopamine levels and how do they do it
in the PFC
NET inhibition increases the diffusion radius of NET. There are not very many DATs in the PFC so dopamine uses NET for reuptake. When NET is inhibited it increases dopamine levels in PFC
which SNRI is approved for fibromyalgia but not depression
milnacipran
which enzyme converts venlafaxine to its active metabolite desvenlafaxine
2D6
Is venlafaxine more potent for SERT or NET
SERT. Dose-dependent NET inhibition
which enzyme is desvenlafaxine a substrate for
2D6
Is desvenlafaxine more potent for SERT or NET
SERT
Is duloxetine more potent for SERT or NET
SERT (slightly)
Should duloxetine be dosed daily or BID
BID at first then transition to daily once patient is tolerant of dose
which of mirtazapine’s mechanisms of action increases the downstream release of dopamine in the PFC
antagonism of 5HT2A
also improves sleep
what is the result of mirtazapine’s 5HT2C antagonism
enhanced release of norepinephrine and dopamine
what is the MAIN mechanism of action for mirtazapine
a2-adrenergic antagonism
how does mirtazapine’s a-2 adrenergic antagonism work
a2 are norepinephrine auto receptors so when they are blocked, norepinephrine can’t shut itself off and release is increased
which SNRI is approved for fibromyalgia but not depression
milnacipran
which of mirtazapine’s mechanisms of action enhances the release of norepinephrine and dopamine in the PFC
antagonism of 5HT2C
what is the main mechanism of action of mirtazapine
antagonism of a2 adrenergic receptors
this makes it so norepinephrine cannot turn itself off at its autoreceptors on noradrenergic neurons
where are 5HT3 receptors usually located
on GABA interneurons
how doe 5HT3 antagonist action work
when serotonin stimulates it it causes GABA to inhibit whatever neuron is downstream from it
Is 5HT3 antagonism activating or sedating
always activating
mechanism of action for nefazadone
5HT2A antagonism (robust)
5HT2C antagonism (weaker)
SERT inhibition
why is nefazadone not really used anymore
liver toxicity
what is the difference between high and low doses of trazodone
hypnotic at low doses (5HT2A blockade), antidepressant at higher doses
Is 5HT2A action generally activating or sedating
sedating
Mechanism of action of vortioxetine
SERT inhibition
5HT3 and 5HT7 antagonism
5HT1A antagonism
cognitive domains treated by vortioxetine
attention
executive function
memory
processing speed
what happens with SERT inhibition and 5HT1B/D (vortioxetine)
5HT1B/D autoreceptors typically turn off 5HT, when they are not inhibited it increases 5HT more than just SERT inhibition alone
SERT inhibition and 5HT3 antagonism (vortioxetine)
Removes GABAs inhibition of dopamine and acetylcholine neurons causing increased neurotransmitter release
SERT inhibition and 5HT7 antagonism
Prevents GABA from inhibiting downstream neurotransmitters resulting in increased serotonin in the PFC
what does brexanolone typically treat
postpartum depression (60-hour continuous infusion)
what are the typical augmenting agents for treatment-resistant unipolar depression
olanzapine-fluoxetine combo
quetiapine
aripiprazole
brexpiprazole
cariprazine
What binding property of brexpiprazole contributes to efficacy for agitation in dementia
a1 antagonism
How does brexpiprazole enhance dopamine release in the PFC
simultaneous a1 and 5HT2A blockade (antagonism)
what is California rocket fuel
NRI with mirtazapine
how does California rocket fuel work
blocks serotonin/norepinephrine reuptake
disinhibits serotonin and norepinephrine release
How do you achieve triple monoamine action with an attention to dopamine
stimulant/modafinil (DAT inhibitor)
with SNRI
2nd line therapy for treatment-resistant depression
TCAs
MAOIs
Lethal dose of a TCA
1 month supply
TCAs are very effective for depression. What is their downfall
side effects
what are TCA side effects caused by
blockade of:
muscarinic cholinergic receptors
H1 histamine receptors
a1 adrenergic receptors
VSSCs
Class of medication for MAOIs
irreversible enzyme inhibitors
enzyme activity only returns when another one is synthesized in 2-3 weeks
MAOA
enzyme that preferentially metabolizes monoamines associated with depression (5HT/NE)
MAOI and tyramine
may develop HTN crisis after ingesting tyramine (especially cheese) since tyramine causes NE release that is destroyed by MAOA. When that is inhibited NE is not destroyed and BP rises
5HT/DA blockers used for bipolar
olanzapine-fluoxetine combo
quetiapine
lurasidone
cariprazine
1st line treatment for bipolar
5HT/DA blocker
what is olanzapine-fluoxetine combo approved for
schizophrenia
bipolar mania
treatment-resistant unipolar depression
bipolar depression
how does olanzapine-fluoxetine combo work in bipolar
antagonism of 5HT2A/5HT2C responsible for antidepressant action
D2 antagonism keeps antidepression from spilling over into mania
what is quetiapine approved for
schizophrenia
bipolar mania
bipolar depression
augmenting SSRI/SNRI for tx-resistant depression
how does quetiapine work in bipolar
antagonist at 5HT2A. 5HT2C, and a2
agonism at 5HT1A
D2 antagonism keeps it from spilling over into mania
what is Lurasidone NOT approved for
bipolar mania
what med is most often prescribed for bipolar depression
lurasidone
what is cariprazine approved for
bipolar mania and depression
what receptors does cariprazine work at
partial agonist at D3, D2, 5HT1A
what sets cariprazine apart from other D2/5HT blockers used for bipolar
highly potent action at D3 as a partial agonist
how potent is cariprazine’s action at D3
more potent than dopamine itself
anticonvulsants used in bipolar disorder
valproic acid (depakote)
carbamazepine (tegretol)
lamotrigine (Lamictal)
what are the three hypotheses for valproic acid’s mechanism of action
-inhibits VSSCs
boost action of neurotransmitter GABA
-regulating downstream signal transduction cascades
typical side effects of valproic acid
hair loss, weight gain, sedation, metabolic disturbance, tremor
what warnings does valproic acid have
bone marrow suppression, liver, pancreatic, and fetal toxicities
what risks does valproic acid pose to women of childbearing age
amenorrhea, polycystic ovaries, hyperandrogenism, obesity, insulin-resistance
what tests should you order when starting valproic acid
pregnancy test, LFTs, platelet count
What enzyme is induced by carbamazepine
3A4
What additional indication is carbamazepine useful for
neuropathic pain
