Major Depressive Disorder (MDD) Flashcards
What is major depressive disorder?
low mood, characterized by feelings of sadness, emptiness or irritability and accompanied by other somatic or cognitive changes that significantly affect the individuals capacity to function
How much does genetics come in to play for MDD?
twin studies show 40-50% heritability
what is the monoamine hypothesis of MDD?
dysfunction in monoamine production
dysregulation in monoamine activity
what are monoamines?
serotonin, norepinephrine, dopamine
What is the neuroplasticity hypothesis of MDD?
downstream effects lead to altered cell growth and adaptation leading to lower levels of BDNF
What is BDNF?
brain derived neurotrophic factor: growth factor that regulates survival of neurons, important for structural integrity and neuroplasticity
According to the neuroplasticity hypothesis, which drugs are needed to help depression?
drugs that restore balance to glutamate/GABA
How might endocrine and immune system abnormalities cause depression?
increased plasma cortisol, increased peripheral cytokine concentrations
chronic stress model – involves the HPA axis
how might structural and functional alterations in brain regions involving emotional processing cause depression?
reduced volume or hyperactivity in prefrontal cortex, cingulate cortex, hippocampus, amygdala
What percent do personality disorders play a role in depression?
30%
What amount of people with depression have other medical comorbidities?
85%
What are the emotional, neurovegetative and neurocognitive symptoms of depression according to the DSM?
emotional:
depressed mood
anhedonia
feelings of worthlessness or guilt
suicidal ideation, plan or attempt
neurovegetative:
fatigue or loss of energy
sleep increase or decrease
weight or appetite increase or decrease
neurocognitive:
decreased ability to think or concentrate or indecisiveness
psychomotor retardation or agitation
How many symptoms of depression according to the DSM-5 are needed to be considered severe?
nearly all symptoms, significant functional impairment or motor impairment
What criteria must be met to be diagnosed with depression according to the DSM-5?
(A) at least 5 symptoms, at least 1 symptom must be depressed mood or anhedonia; present nearly every day for at least a 2 week period
(B) symptoms cause clinically significant distress or impairment in social, occupational, or other areas of functioning
(C) episode is not attributable to direct physiologic effects of a substance of another medication
(D) MDD is not better explained by a different mental illness
(E) there has never been a manic or hypomanic episode
What does SIG: E. CAPS stand for?
symptoms of depression:
Sleep changes: increase during day or decreased sleep at night
Interest (loss): of interest in activities that used to interest them
Guilt (worthless): depressed elderly tend to devalue themselves
Energy (lack): common presenting symptoms (fatigue)
Cognition/concentration: reduced cognition and/or difficulty concentration
Appetite (wt. loss); usually declined, occasionally increased
Psychomotor: agitation (anxiety) or retardations (lethargic)
Suicide/death preocp.
What is MDD with anxious distress?
MDD diagnosis PLUS 2+ of: tension, worried, restlessness, afraid of losing control, impaired concentration
not a full anxiety diagnosis
What is MDD with mixed features?
subthreshold mania/hypomania
MDD diagnosis PLUS 3+ symptoms of mania most days
What is MDD with catatonic features?
MDD diagnosis PLUS 2+ of: catalepsy, excessive purposeless motor activity, extreme negativism, peculiar voluntary movements, echopraxia
What is MDD with melancholic features?
Severe form of depression
MDD diagnosis PLUS 3+ of: nonreactive “empty” mood, increase morning severity, early morning awakening, psychomotor agitation or retardation, significant weight loss, excessive guilt
What is MDD with atypical features?
MDD diagnosis with reactive mood, oversleeping, overeating, leaden paralysis, sensitive to rejection
What is Peripartum onset depression?
MDD during pregnancy or within 4 weeks postpartum
What is MDD with psychotic symptoms?
MDD diagnosis with delusions or hallucinations
What is dysthymia?
Persistent depressive disorder
depressive mood for 2 or more years with symptoms free period no greater than 2 months
2+ additional depressive symptoms (not full criteria for MDD)
no MDD episode in first 2 years of onset – depressive episodes can be superimposed after
What is substance/medication induced depressive episode?
prominent, persistent disturbance in mood predominates the clinical picture with diminished interest in almost all activities
symptoms develop or shortly after substance intoxication or withdrawal and the substance is known to cause disturbance
How do you rule out Bipolar depression when diagnosing MDD?
completely mood disorders questionnaire to rule out history of mania/hypomania
How to rule out anxiety when diagnosing MDD?
complete GAD-7
may co-occur with MDD
What is part of the differential diagnosis of MDD?
Bipolar depression
anxiety (no co-occur)
substance use disorder (may co-occur)
another medical condition
grief
PMS
irritable or labile emotions
feeling sad
What prescription medications might cause depression?
CV agents: clonidine, methyldopa, reserpine
anticonvulsants: phenobarbital, topiramate, vigabatrin
hormonal agents: corticosteroids, GnRH agonists, tamoxifen
immunologic: IFN alpha
other: benzos, BB (?), opioids, anti-thyroid
which standardized rating scales for MDD can be completed by the patient?
PHQ-9, QIDS, Beck depression inventory
Which standardized rating scales for MDD are administered by a physician?
QIDS (also a self administered version), HAM-D, MADRS
What questions are on PHQ-9?
- little interest or pleasure in doing things
- feeling down, depressed, or hopeless
- trouble falling or staying asleep, or sleeping too much
- feeling tired or having little energy
- poor appetite or overeating
- feeling bad about yourself - or that you are a failure or have let yourself or your family down
- trouble concentrating on things, such as reading the newspaper or watching TV
- moving or speaking so slowly that other people could have noticed? or the opposite - being so fidgety or restless that you have been moving around a lot more than usual
- thoughts that you would be better off dead or hurting yourself in some way
What does your PHQ-9 score mean?
20-27 = severe
15-19 = moderately severe
10-14 = moderate
5-9 = minimal
<5 = no symptoms
what improvement in PHQ-9 score is considered a response to treatment? what is considered remission?
Response = 50% or more reduction in score
remission = score 5 or lower
What questions are on the PHQ-2?
- little interest or pleasure in doing things
- feeling down, depressed or hopeless
What is considered a positive score for the PHQ-2
3+
what is the lifetime risk of suicide in untreated MDD?
20%
what are suicide risk factors?
IS PATH WARM
Ideation
Substance use
Purposelessness
Anxiety
Trapped (feelings of no way out)
Hopelessness
Withdrawal
Anger
Recklessness
Mood changes (dramatic)
What is the response rate to antidepressants vs response to placebo?
40-60% to antidepressants; 30-50% to placebo
T or F
response/remission declines with each subsequent treatment trial
True
what percentage of people will experience a recurrance?
25-40% in 2 years, 50-80% have more than one episode in lifetime
What is considered a partial remission?
continued presence of some symptoms but full criteria not met
What is the difference between remission and recovery?
full remission is the absence of significant symptoms and recovery is full remission for at least 2 months
what is the difference between a relapse and a recurrance?
a relapse is a new episode before recovery, and a recurrence is new episode any time after achieving recovery
What is considered chronic depression?
full criteria for MDD met for a minimum of 2 years
What is considered to be treatment resistance?
episode that has failed to response to 2 separate trials of different antidepressants of adequate dose and duration
What are some predictors of remission?
female sex, white race, employment, higher level of education, higher income
what is the goal of acute treatment?
symptom remission and restoration of premorbid functioning within 8-12 weeks
prevent hard ongoing
restore optimal functioning within 8-12 weeks
what HAM-D scores are considered remission? response?
remission: HAM-D score 7 or less
response: HAM-D 50% or more reduced from baseline
What is the goal with maintenance treatment of MDD?
prevent recurrences of mood episode
What are some non pharm treatments of MDD?
positive lifestyle changes
natural products
psychological treatment
neurostimulation
physical interventions: acupuncture, massage, yoga
bright light therapy
music therapy
spiritual care
vagal nerve stimulation
What is St. John’s Worts MOA in MDD?
weak non selective MAO, inhibits 5-HT, NE, DA transporter
What is St. John’s Wort used for?
monotherapy for mild to moderate depression symptoms
what are some AE’s of St. John’s Wort?
GI upset, sexual dysfunction, photosensitivity
increases risk of serotonin syndrome, bleeding
lots of drug interactions
What is S-Adenosyl Methionine used for?
adjunct for mild-moderate symptoms
What are some AE’s of S-Adenosyl-Methionine?
GI upset, flatulence, dry mouth
how might omega-3 fatty acids work in depression?
3-PUFA deficiency has been shown to be associated with depression
What is Omega-3 fatty acids used for?
monotherapy or adjunct to antidepressants
What is Folate L-methylfolate used for?
adjunct for antidepressants
When is psychological treatment used as monotherapy?
mild depression
What severity of depression is psychological treatment recommended in?
All
T or F
Psychological treatment is not found to be as successful as antidepressants in treating depression
False
What is transcranial magnetic stimulation (TMS)?
magnetic fields are used to stimulate nerve cells in regions of the brain involved in mood regulation and depression
What is TMS used for?
refractory depression
How long is the course of TMS treatment?
4-6 weeks
What are some AE’s of TMS?
headache, scalp discomfort
what is electroconvulsive therapy (ECT)?
electrodes placed on various scalp regions
electrical charge is applied to stimulate the brain and produce a seizure while patient under general anesthetic
seizure lasts 1 minute
what is ECT used for?
severe depression, depression with psychosis or catatonic features, severe SI
how long is the course of ECT treatment?
6-12 treatments
what medications should be minimized/avoided during ECT treatment?
anticonvulsant medications
benzos
lithium
buproprion
what are some AE’s of ECT?
confusion during post-ictal period
impaired memory after procedure
headache
muscle ache
What are the two landmark papers on MDD?
Cipriani network meta-analysis
STAR*D
what did the Cipriani show?
no strong evidence to conclude that any antidepressant is superior in efficacy
which antidepressants do meta-analyses show have the best efficacy/tolerability profile?
sertraline, escitalopram, vortioxetine, venlafaxine, mirtazapine
what did the STAR*D trial show?
no difference in remission rates or times to remission:
between medication strategies (switch or augmentation) at any treatment level
between any of the switching options between any of the augmenting options in step 2-4
between switch to CT vs meds or augment with CT vs meds
longer time to remission, greater number of treatment steps = higher relapse rates
prognosis better for those achieving remission prior to follow-up phase compared to those with adequate response without remission
no difference between remission/response between primary or psychiatric care setting
What is the success rate upon first treatment of antidepressants?
30% remission
10-15% show no response
what is the symptom response rate across all antidepressant trials?
40-60%
According to CANMAT, what is the 2nd line intervention to no response to antidepressants?
switch to alternate antidepressant
TMS
ECT
light therapy
omega-3
according to CANMAT, what is the 2nd line intervention to partial response to antidepressants?
augment with 1st line adjunct (aripiprazole, quetiapine, risperidone)
adjunctive exercise
light therapy, yoga, SAMe
adjunct St. John’s Wort, omega-3
According to CANMAT what are 3rd line interventions (AKA treatment resistance)?
augment with other AD or different med: brexpiprazole, buproprion, lithium, mirtazapine, modafinil, olanzapine, triiodothyronine, TCAs, MAOIs, ketamine
neurostimulation mono treatment or augmentation
adjunctive acupuncture
what are the patient factors to take into account while selection an antidepressant?
clinical features and dimensions
comorbid conditions
response and side effects during previous use of antidepressants
patient perference
according to CANMAT what are the first line antidepressants?
SSRIs: sertraline, escitalopram, fluoxetine, citalopram, paroxetine
SNRIs: duloxetine, venlafaxine
Mirtazapine
Buproprion
how many remit after first treatment? second? fourth?
1 = 1/2
2 = 1/3
4 = 2/3
what is the MOA of SSRIs?
inhibition of presynaptic 5-HT reuptake by inhibition of the 5-HT transporter CNS neurons (reuptake inhibition/transporter inhibition) = increased 5-HT in synaptic cleft
What is the onset of action of SSRIs?
1st few days: decrease agitation and anxiety, improved sleep and appetite
1-3 weeks: increased activity and sex drive, improved self-care, concentration, memory, thinking, movements
2-4 weeks: relief of depressed mood, return of experiencing pleasure, fewer hopeless feelings, subsiding suicidal thoughts
what are some AEs of SSRIs?
HANDS:
Headache
Anxiety
Nausea
Diarrhea and other GI upset
Sleep disturbances: insomnia or sedation
anticholinergic: dry mouth, constipation, blurred vision
sexual dysfunction
emotional blunting/detachment
tremor, yawning, sweating, enuresis
What is SIADH?
syndrome of inappropriate antidiuretic hormone secretion
body makes too much antidiuretic hormone (vasopressin)
causes body to retain too much water
What are some causes of SIADH?
pain, vomiting, CNS injury, inflammation, lung injury, carbamazepine, opioids, SSRIs, NSAIDs, SNRIs, mirtazapine
what are the s/sx’s of SIADH?
lethargy, change in mental status, Na <135 mEq/L, hyperosmolar urine (>300 mosmol/kg)
what is the management of SIADH?
usually inpatient care, d/c offending agent, water restrictions
what are some precautions with SSRIs?
increased risk of suicide in children, adolescents, and young adults <24 years old
increased fracture risk and decreased bone mineral density (especially elderly)
citalopram, escitalopram have dose dependent risk of QTc prolongation
which SSRIs seem to be most sedating?
mild sedation: sertraline and citalopram
most: paroxetine
Which SSRI has the most weight gain?
paroxetine
which SSRI is the most stimulating?
fluoxetine
Which SSRI has the longest half life?
fluoxetine
Which SSRIs have the highest rates of nausea/diarrhea?
fluvoxamine and sertraline
which SSRI has been shown to be the least tolerable?
fluvoxamine
which SSRIs have the most DIs?
fluoxetine, paroxetine, fluvaoxamine
what are some DIs of SSRIs?
NSAIDs, antiplatelets, anticoagulants: increased bleeding risk secondary to decreased platelet aggregation effects of SSRIs
serotonergic agents: increased risk of serotonin syndrome
which SSRI has better bioavailability with food?
sertraline
which SSRIs form active metabolites? when would this be a concern?
fluoxetine, citalopram and sertraline
concern if liver cannot metabolize these efficiently
What is the dosing of SSRIs?
all taken once daily
what is the MOA of vorioxetine?
serotonin reuptake inhibitor
5HT1A receptor agonist
5HT1B receptor partial agonist
5HT3+7 5Ht1D receptor agonist
what are some AE’s of vortioxetine?
headache, nausea, vomiting, diarrhea, sexual dysfunction
seems to be better tolerated than other ADs
Which SNRIs are available in Canada?
venlafaxine
desvenlafaxine
duloxetine
levomilnacipran (not first line)
what is the MOA of SNRIs?
inhibit presynaptic 5-HT and NE reuptake by inhibiting 5-HT and NE transporters in CNS neurons
T or F
SSRIs are thought to be more antidepressive and more pro-cognitive compared to SNRIs
False
SNRIs are thought to be more antidepressive and more pro-cognitive than SSRIs
what does of venlafaxine binds to only 5-HT? which does binds to both 5-HT and NE?
only 5-HT = <150 mg/day
NE and 5-HT = >150 mg/day
T or F
at high doses, venlafaxine inhibits DA transport?
True
at doses >450 mg/day it weakly inhibits DA transporter
which SNRIs have equal affinity for NE and 5-HT?
duloxetine and desvenlafaxine
what is the onset of action of SNRIs?
1st few days: decreased agitation and anxiety, improved sleep and appetite
1-3 weeks: increased activity and sex drive, improved self-care, concentration, memory, thinking, movements
2-4 weeks: relief of depressed mood, return of experiencing pleasure, fewer hopeless feelings, subsiding suicidal thoughts
What are the AE’s of SNRIs?
similar to SSRIs
“HANDS”
anticholinergic like effects (dose related): related to increased NE - dry mouth, constipation, sedations, urinary retention
sexual dysfunction
SIADH
risk of serotonin syndrome, AD-induced suicidality
dose related increased BP and HR and sweating due to NE action
less emotional blunting than SSRIs
T or F
SNRIs are associated with increased risk of fractures
False
which SNRIs have more risk of sexual dysfunction?
venlafaxine similar rates of SSRIs
desvenlafaxine and duloxetine less than SSRIs
Which SNRI has the highest SIADH risk?
venlafaxine
T or F
SNRIs are not effected by food
True
T or F
you do not have to adjust SNRI dose in renal impairment
False
which SNRIs are hepatically metabolized?
venlafaxine and duloxetine
what are some DIs with SNRIs?
CYP interactions:
duloxetine: moderate inhibitor and substrate
venlafaxine: weak inhibitor and substrate
desvenlafaxine: no significance
NSAID, antiplatelets, anticoagulants - caution only: increased bleeding risk secondary to decreased platelet aggregation effects serotonin reuptake inhibition (less risk than SSRIs)
serotonergic agents: increased risk of serotonin syndrome
what are some precautions with SNRIs?
duloxetine CI in narrow angle glaucoma
increased suicide risk if <24 years
monitor for increased BP
caution if history of HTN or narrow angle glaucoma
avoid abrupt withdrawal
duloxetine: avoid in hepatic impairment or heavy ETOH use; risk of urinary retention
which SNRI has the worst withdrawal symptoms?
venlafaxine
which SNRI is particularly useful for menopausal vasomotor symptoms?
desvenlafaxine
what is the MOA of bupropion
inhibits NE and DA transporters increasing concentrations in the synapses
T or F
bupropion has effects on 5-HT
False
T or F
bupropion is similar in structure to amphetamine
True
in what situations may bupropion be beneficial?
useful in patients with psychomotor retardation, hypersomnia, ADHD type symptoms
can be used to augment SSRI or SNRI in treatment resistant cases
much less risk of sexual dysfunction and in some cases may alleviate symptoms when used as adjunct
possibly useful in stimulant use disorder to reduce illicit use and cravings
What are some AEs with bupropion?
activating: agitation, insomnia, tremor and anxiety - may need to avoid if hx of anxiety
sweating due to NE reuptake inhibition
GI upset
psychosis/exacerbation of psychosis
urticaria and anaphylactoid reactions
seizures: dose dependent
how is bupropion activated?
metabolized in liver by CYP2B6 to active metabolite hydroxybupropion
T or F
Bupropion is renally eliminated
true
dose adjustments may be needed in renal impairment
What are some DIs of bupropion?
Zyban: same drug
concurrent MAOI therapy CI: hypertensive crisis
potent CYP2D6 inhibitor
What is the difference between bupropion SR and bupropion XL?
SR = OD or BID dosing
XL = OD dosing
what are some CIs of bupropion?
seizure disorder
eating disorders
abrupt discontinuation of alcohol or sedatives
what are some precautions with bupropion?
increased risk of suicide if <24 years
precaution in:
dependence on opioids, cocaine, stimulants
concurrent use of seizure threshold lowering drugs
head trauma history
HTN
unstable CVD/CAD
psychosis
anxiety
insomnia
overdose lethality
what is the MOA of mirtazapine?
antagonism at 5-HT2a, 5-HT2c, 5-HT3, a2-adrenergic, H1
what does antagonism of presynaptic central alpha2 adrenergic autoreceptors in mirtazapine use do?
increased release of NE and 5HT
at what dose does mirtazapine need to be at to cause antagonism of a2-adrenergic autoreceptors?
> 15 mg/day
what is 5HT2a/2c receptor antagonism linked to in mirtazapine use?
linked to lower anxiety, antidepressive, pro-cognitive
lower 5HT related AEs
what is 5HT3 receptor antagonism linked to in mirtazapine use?
lower GI side effects (helps relieve N/V)
What is H1 receptor antagonism linked to in mirtazapine use?
sedation, weight gain
at what dose does mirtazapine antagonize histamine receptors?
doses <30 mg
in what situations might mirtazapine be useful?
useful as monotherapy and adjunctive treatment
consider patients with insomnia, anxiety, reduced appetite
benefit for antipsychotic induced akathisia
possibly useful in stimulant intoxication or opioid withdrawals
What are some AEs with mirtazapine?
CNS: sedation
endocrine: increased TGs and weight gain due to increased appetite
GU: less sexual dysfunction
which antidepressants have the least sexual dysfunction?
bupropion and mirtazapine
T or F
half life of mirtazapine is significantly longer in men compared to women
false
significantly longer in women
T or F
mirtazapine dose needs to be adjusted in renal AND hepatic impairment
False
but use with caution as it may accumulate
What is the typically dosing on mirtazapine?
initially: 15 mg PO HS
may increase q1-2 weeks up to a max of 45mg PO HS
What dose of mirtazapine is best to balance andepression and insonmia?
around 22.5mg
what are some precautions in mirtazapine?
increased suicide risk if <24 years
caution:
agranulocytosis cases reported (rare)
orthostasis
hyponatremia in elderly
What are CANMATs second line agents?
TCAs: amitriptyline, clomipramine, noritryptaline, etc.
SNRI: levomilnacipran
reversible MAOI: moclobemide
Serotonin reuptake inhibitor/5Ht2 antagonist: trazodone
atypical antipsychotic: quetiapine
serotonin reuptake inhibitor/5HT1a partial agonist: vilazodone
which TCAs are available in Canada?
tertiary amines:
amitriptyline
clomipramine
doxepin
imipramine
secondary amines:
notritryptaline
desipramine
what is the MOA of TCAs?
inhibit presynaptic 5HT and NE reuptake by inhibiting 5HT and NE transporters in CNS neurons
T or F
tertiary amine TCAs have more NE activity while secondary amine TCAs have more 5HT activity
false
the opposite is true
T or F
secondary amines are typically better tolerated
true
in which situations might TCAs by useful in?
MDD with:
insomnia
anxiety
chronic, non-cancer pain (low back, neuropathic)
migraines/headaches
OCD (clomipramine)
what are some CIs with TCAs?
acute MI, heart block, CHF
severe liver impairment
what are some conditions where TCAs should be taken with caution?
any CVD
suicidal ideation (limit quantity dispensed)
QT prolongation
seizure history/risk
risk of harm associated with anticholinergic effects
elderly
bipolar disorder
what are some AEs of TCAs
common: sedation, anticholinergic, CV
CV effects:
cardiotoxicity is primary mechanism of OD
orthostatic hypotension
tachycardia
right bundle branch block
QT prolongation
weight gain
tremors
sexual dysfunction
urine discolouration (amitriptyline)
rash; anticonvulsant hypersensitivity cross reaction (rare)
seizures, SIADH, fractures
T or F
TCAs have a high risk of lethal OD
true
what are some DIs on TCAs?
many potential interactions related to additive CNS depression, serotonin activity, neurotoxicity w lithium, seizure risk, arrhythmias
most are substances of CYP2D6
clomipramine: 1A2
what is the MOA of trazodone?
weak inhibitor of SERT and NET
5HT2a and 2c (doses 200mg or more) receptor antagonism
antagonism at a1 adrenergic receptors and H1 histamine receptors
what are some AEs of trazodone?
CNS: dizziness, sedation, headache, akathisia, myalgia, tremor
CV: orthostatic hypotension, syncope, prolonged QT interval, arrhythmias, CI is recent or acute MI
GI: nausea, constipation, dry mouth
rare: can cause priaprism, sexual dysfunction, seizures, suicidal ideation, serotonin syndrome, bleeding
what is the dosing of trazodone in MDD?
initial: 50 mg BID taken after a meal
may be increased by 50mg/d every 3-7 days
usual dose range: 200-400mg
what is the dosing of trazodone for a sedative?
50-200 mg HS
what are some DIs of trazodone?
CYP 3A4 inducers or inhibitors
antihypertensives: trazodone causes hypotension
what is the MOA of quetiapine?
antagonism of 5HT1 and 2, D1 and2, H1, a1 and 2
what is the dosing of quetiapine in MDD?
start at 50 mg PO daily
increase to 150mg PO on day 3
usual dose range = 150-300mg/day
max daily dose for MDD = 300-600mg
what are the reversible MAOIs available in canada?
moclobemide
what is the MOA of reversible MAOIs?
short acting reversible inhibition of MAO-A to decrease metabolism of 5HT, NE and DA
what are the irreversible MAOIs available in canada?
selegiline, phenelzine, tranycypromine
what is the dosing of moclobemide?
300mg/d div into 2 doses
at what dose of moclobemide is specificity for MAO-A lost? what are the consequences of this?
over 600mg/d
caution regarding tyramine is required
which foods are rich in tyramine?
cheese, wine, meats, chocolate, smoked, pickled foods
what happens in tyramine overdose?
increased NE leading to a hypertensive crisis
how long before starting an MAOI must you stop taking other ADs?
2 weeks
fluoxetine: 5 weeks
T or F
MAOIs must be stopped for at least 2 days prior to local or general anesthesia
true
what are some AEs of moclobemide?
tachycardia, hypotension, sleep disturbance, agitation, nervousness, anxiety
less common: N/V/D, sexual dysfunction, anticholinergic effects
what is the MOA of irreversible MAOIs?
nonspecifically irreversibly binds MAO-A and MAO-B
what are some CIs for irreversible MAOIs?
pheochromocytoma
concurrent use of serotonergic or sympathomimetic agents
tyramine containing foods
d/c at least 10 days prior to surgery
what are some important DIs of irreversible MAOIs?
antihistamines
opioids
carbamazepine
linezolid
methylene blue
stimulants
which receptors/channels does ketamine inhibit?
NMDA
HCN channels
calcium channels
voltage gated sodium channels
BK channels
which receptors/channels does ketamine activate?
opioid receptors
AMPA receptors
GABAa receptors
what does inhibition of NMDA in ketamine use do?
dissociative anesthesia, amnesia
analgesia, inhibited sensory perception
what does activation of opioid receptors in ketamine use do?
central antinociception; potential acute euphoric effects
what does activation of AMPA receptors in ketamine use do?
rapid antidepressant effects
which receptor is responsible for the antidepressant effect of ketamine?
AMPA
what is the MOA of ketamine in MDD?
chronic stress theory
chronic stress induces neuronal remodeling and glial deficit –> results in decreased glutamate reuptake, increased extrasynaptic glutamate, leads to excitotoxicity –> in prefrontal cortex this leads to neuronal synaptic hypoconnectivity (decreased dendritic length and synaptic density/strength) –> decrease in certain receptors and synaptic strength
ketamine upregulates neurotrophic signaling –> increased synthesis and restoration or synaptic connectivity in the prefrontal cortex
what is the official indication of racemic ketamine?
anesthesia
what is the official indication of esketamine?
intranasal spray for TRD
what is the official indication of arketamine?
no official indication
shows promise for more potent and longer lasing antidepressant effects with fewer side effects
what are some AEs of ketamine at TRD doses?
CNS: dissociation, dizziness, feeling drunk, sedation, headache, anxiety, vertigo, cognitive impairment
GU: frequent daytime urination, dysuria, ulcerative or interstitial cystitis
dermatological: hyperhidrosis
CV: increased BP/HR
GI: nausea
how do you manage nausea and stomach upset as a side effect of ADs?
divided doses/decrease SSRI dose if patient is stable
take the medication with small amount of food
ginger (?)
which antidepressants are the worse for nausea as a side effect?
venlafaxine > SSRI > bupropion > moclobemide > mirtazapine
which SSRI is linked to the highest rates of constipation?
paroxetine
what is the association of AD use and suicidality across different age groups?
> 18: possible association
18-24: ambiguous
25-64: neutral to protective
64: possible protective effect
which ADs have an increased frequency of sexual side effects?
SSRIs, SNRIs, TCAs
what are the 5 possible management strategies for sexual side effects of ADs?
- no intervention
- decrease dose
- drug holidays or eliminating doses for a few days prior to sex
- using medication to adjunct sexual s/e
- switching AD (bupropion or mirtazapine)
which ADs are at the highest risk for QT prolongation?
TCAs at highest risk
citalopram, escitalopram, venlafaxine, desvenlafaxine and mirtazapine
T or F
serotonin syndrome is not life threatening
False
what is the triad of symptoms with serotonin syndrome?
mental status change: confusion, agitation, lethargy, coma
autonomic hyperactivity: hyperthermia, tachycardia, mydriasis, diaphoresis, nausea and vomiting, diarrhea
neuromuscular abnormalities: hyperkinesia, hyperflexia, trismus, myclonis, cogwheel rigidity
how long after changing a drug or dose will serotonin syndrome occur?
6-24 hours
what is the treatment for serotonin syndrome?
supportive, d/c serotonergic agents (usually resolve within 24-72 hours)
cyproheptadine (serotonin antagonist): 12 mg once, followed by 2 mg q2h until sx resolve
what are the causes of serotonin syndrome?
antidepressants: MAOIs, TCAs, venlafaxine, st Johns wort
other: linezolid, DM, meperidine, tramadol, opioids
which are the worst ADs for discontinuation syndrome?
venlafaxine and paroxetine
at what duration of treatment do you have a higher risk for discontinuation syndrome?
> 6-8 weeks
which SSRI has the lowest risk of discontinuation syndrome and why?
fluoxetine because of its long t1/2
what are the symptoms of discontinuation syndrome?
FINISH
Flu like sx: fatigue, lethargy, malaise, muscle aches
Insomnia
Nausea
Imbalance
Sensory disturbances: paresthesia, electric shock sensations
Hyperarousal: anxiety, agitation
how long after stopping ADs does discontinuation syndrome occur?
24-72 hours
how long does discontinuation last for?
1-2 weeks
may persist for weeks to months for some pts
what do you do if symptoms of discontinuation syndrome occur during treatment what do you do?
consider restarting at original dose and taper slowly
what can you do if a slow taper off SSRIs is not well tolerated?
consider substituting fluoxetine
how often should you follow up with patients after they start ADs?
week 1-4: follow up q1-2 weeks
week 2-8: follow up q2-4 weeks
suicidal ideation: ensure someone is monitoring daily until resolved
when is it best to augment vs switch in treatment nonresponse?
if no response: switch
if partial response: augment
what is the definition of treatment resistant depression?
lack of improvement (<20% decrease in depression scores) following adequate trials of 2 or more AEs
What options do you have with TRD?
switch to another AD - again
may choose to use augmentation therapy
or combining ADs
how do you switch between SSRIs and SNRIs?
can switch directly
similar MOA but will still often cross taper
How would you switch from another AD to an MAOI?
“wash out” period of 2 weeks
5 days in fluoxetine
What are the first line adjunct medications options in MDD?
2nd generation antipsychotics (aripiprazole, quetiapine, risperidone, olanzapine, brexpiprazole)
what are the second line adjunct medication options in MDD?
bupropion
mirtazapine
lithium
T3
what are the third line adjunct medication options in MDD?
lisdexamphetamine
TCAs
Describe lithium as an adjunct therapy in TRD
has AD effect and is one of the most investigated augmented strategies
should see response by 3-4 weeks: if patient responds continue the combo for at least 6-9 months
describe thriiodothyronine (T3) as an adjunct therapy in TRD
improves and accelerates AD effects in some studies
25-50 mcg/day is recommended and rarely affects peripheral thyroid measures at this dose
recommended trial is 2 weeks at 50mcg
describe atypical antipsychotics as adjunct therapy in TRD
augmentation with olanzapine, quetiapine and risperidone as well as aripiprazole and brexpiprazole
usually at lower doses than for schizophrenia or bipolar
what are the 3 phases of treatment in MDD?
response
continuation
maintenance
when does the acute phase of MDD move into the continuation phase?
with clinically significant improvement in sx (preferably remission of sx)
who is maintenance phase treatment of MDD recommended for?
pts with chronic sx or with a hx of 3 or more depressive episodes
what is the general rule for AD use in elderly?
start low, go slow and use less drugs
consider maintenance therapy
which ADs are on the BEERS list?
SSRIs, SNRIs, TCA, mirtazapine
which ADs are best in elderly?
duloxetine
bupropion
sertraline
which ADs are indicated for children <18?
none approved by HC
FDA: fluoxetine, escitalopram
off label: sertraline, citalopram
which ADs should be avoided in children?
SNRIs and TCAs
what is the preferred treatment of mild depression in pregnancy?
psychotherapy
what is the treatment of moderate to severe treatment of depression in pregnancy?
use lowest effective dose
agents with few metabolites, higher protein binding, few DIs
which ADs are used in pregnancy?
SSRIs first: most safely with sertraline, citalopram and escitalopram
paroxetine has risk of cardiac malformations of fetus
which ADs are used during breast feeding?
citalopram, nortriptyline, sertraline and paroxetine are first line
breast feeding not a CI to any AD
