Antidepressants and Depression Flashcards
epidemiology
5% adults with depression
leading cause of disability worldwide
US lifetime prevalence 20%
risk factors
2:1 F:M
native
1st deg relative
middle aged, stress, recent loss
chronic medical illness
personal hx of MDD and/or SUD
previous major depressive episodes
risk inc with number of episodes
Pathophysiology of MDD Neuroanatomical abnormalities
Multiple structures
overactive amygdala
overactive subgenual anterior cingulated cortex
decreased dorsolateral PFC activity
Pathophysiology of MDD Neurotransmitter involvement
Monoamine hypothesis
o 1950s development with noted dec of 5HT, NE, DA and noted MAOI and TPA improvement but missed delayed onset effect on mood and its relation to synaptic changes
Dysregulation hypothesis
o Accounts for delay in onset of antidepressant action and shows more than inc or dec in concentration
Chronic stress model
o Effect on hypothalamic (HPA) leads to secretion of glucocorticoid and cortisol which leads to neurogenesis in the hippocampus
DSM MDD
1 or more major depressive episodes with no hx of manic or mixed mood episodes
AND
5 or more of sx nearly every day for at least 2 wks
Depressed mood most of the time and on most days
Decreased interest or pleasure in daily activities most of the time and on most days
Significant changes in weight or appetite
Significant changes in sleep
Psychomotor agitation or retardation which is observable by others
Fatigue or decreased energy
Feelings of worthlessness or inappropriate guilt
Decreased concentration or difficulty making decisions
Recurrent thoughts of death, suicidal ideation without a specific plan, specific plan for committing suicide, or a suicide attempt
Clinical status
severity, psychotic features?
severity
- mild: 5 or 6 sx and minimal functional impairment
-severe: nearly all sx and significant impairment of functioning
can be present with psychotic features
clinical status
remission, chronic definition
remission: absence of significant sx for at least 2 months
chronic MDD: full criteria for major depressive episode for a minimum of 2 years
descriptive specifiers for MDD
Anxious distress
* Inc SI and worse outcome
* Tension, fear restless
Mixed features
* Mania but not criteria for specific but is RF for BP
Catatonic features
* Immobility etc
Melancholic features
* Severe depression
* Lack of stimuli
Atypical features
* Mood reactivity issue
* Weight, sleep
Peripartum onset
* During or after
Seasonal pattern
treatment by generation/class
1st gen
- TCA
-MAOI
2nd gen
-SSRI
-SNRI
-Buproprion
-Mirtazapine
- Trazodone
Newer
-Vilazodone
-Vortioxetine
SSRI MOA
inhibit presynaptic serotonin reuptake by interfering with 5HT transporter
SSRI side effects
Headache
wt gain
GI
sex
agitation/anxiety (when starting)
SSRI rx and initial dosing
Citalopram (Celexa ®): initial dose 20 mg PO once daily
- note QT prolong is dose dependent
Escitalopram (Lexapro ®): initial dose 10 mg PO once daily
Sertraline (Zoloft ®): initial dose 25-50 mg PO once daily
- QT
Paroxetine (Paxil ®): initial dose 20 mg PO once daily
- short half life
- higher risk discontinuation syndrome
Fluoxetine (Prozac ®)* : initial dose 20 mg PO once daily
- long half life
- QT
Fluvoxamine (Luvox ®) : initial 50 mg PO once daily
SNRI MOA
5HT receptors too BUT also inhibit NE reuptake (both by inhibition of transporters)
That leads to inc in 5HT and NE in the cleft
SNRI side effects
Same as SSRI
AND
hypertension
++ nausea/diarrhea
sweating
dry mouth
dizziness
fatigue
SNRI rx and initial dose
Duloxetine (Cymbalta ®): initial dose 40-60 mg PO once daily
- pain
-inhibits NE more than venlafaxine but that causes more dry mouth and constipation
Venlafaxine (Effexor ®): initial dose 37.5-75 mg PO once daily
- pain
- may inc cholestrol
Desvenlafaxine (Pristiq ®): initial dose 50 mg PO once daily
Levomilnacipran (Fetzima ®): initial dose 20 mg PO once daily
-recent approval
TCA MOA
Inhibit presynaptic 5HT and NE reuptake by inhibition of transporters which leads to inc in 5HT and NE in cleft
TCA AE
o Tertiary amine
More sedation and anticholinergic AE
5HT
o Secondary amine
More CV effect
Better tolerated
NE
overdose potential and cardiac effects
anticholinergic AE: confusion, constipation, wt gain, sedation
Tertiary amines (5HT) rx and initial dose
Amitriptyline (Elavil ®): initial dose 25-50 mg PO once daily
Imipramine (Tofranil ®): initial dose 25-50 mg PO once daily
Clomipramine (Anafranil ®): initial dose 25-50 mg PO once daily
Doxepin (Silenor ®): initial dose 25-50 mg PO once daily
Secondary amines (NE) rx and initial dose
Nortriptyline (Pamelor ®): initial dose 25 mg PO once daily
Desipramine (Norpramin ®): initial dose 25-50 mg PO once daily
Amoxapine (Asendin®): initial dose 25-50 mg PO 1-3 times daily
MAOI MOA
Irreversibly inhibit monoamine oxidase preventing metabolism of NE, 5HT, and dopamine
MAOI 2 types
MAO-A
MAO-B
MAOI drug interactions
amphetamines
carbamazepine
decongestants
ephedrine
dextromethorphan
MAOI AE
Cardiovascular side effects
–require dietary restrictions (aged meat/cheese, soy, or tyramine containing foods)
–Hypertensive crisis
MAOI rx and initial dose
Tranylcypromine (Parnate ®): initial dose 10-30 mg PO in divided doses
Phenelzine (Nardil ®): initial dose 15 mg PO 1-3 times daily
Isocarboxazid (Marplan ®): initial dose 10 mg PO twice daily
Selegiline transdermal (Emsam ®): initial dose 6 mg/24-hour patch once daily
Bupropion MOA
Inhibits DA and NE transporters, increasing dopamine and norepinephrine concentrations in the synapse
Bupropion initial dose
IR 100 mg PO twice daily
12-hour ER 150 mg PO once daily
24-hour ER 150 mg PO once daily
Bupropion AE
Insomnia (11-40%)
Activation/anxiety (2-30%)
Seizure (0.1% at approved doses), may be no higher than other antidepressants and close to incidence in general population.
–Highly dose related at > 600mg (2%)
–Consider risk of seizures in populations with substance use disorder, and history of head trauma
Hypertension (2.5-4.3%)
Less sexual dysfunction and weight gain
Mirtazapine (remeron) MOA
increases synaptic concentration of serotonin and norepinephrine through presynaptic alpha 2 antagonism
Also, a 5HT2 and 5HT3 antagonist and histamine-1 antagonist
Mirtazapine (remeron) initial dose
15mg PO qd
Mirtazapine (remeron) AE
Sedation (advise patient to take at bedtime)
Increased appetite
–may lead to weight gain
Hypertriglyceridemia
Liver toxicity and agranulocytosis (rare)
Trazodone and Nefazodone MOA
weak inhibition of presynaptic serotonin and norepinephrine reuptake (for nefazodone), 5HT2a antagonist, weak alpha-1 antagonist, and histamine-1 antagonist (trazodone > nefazodone)
Trazodone and Nefazodone initial dose
Trazodone: IR 50 mg PO twice daily or ER 150 mg PO once daily
Nefazodone: 100 mg PO twice daily
Trazodone and Nefazodone AE
Nefazodone
-Nausea (32%), headache (26%), dry mouth (25%)
-Hepatic failure (routine liver function test monitoring required)
Trazodone
-Somnolence, nausea (21%), dry mouth (14-33%), and dizziness (25%)
Vortioxetine (trintellix) MOA
Inhibition of 5HT reuptake
Serotonin 5HT3, 5HT1D, 5HT7 antagonism
Serotonin 5HT1a agonist
Vortioxetine (trintellix) initial dose
5-10mg PO qd
Vortioxetine (trintellix) AE
GI
Dry mouth
Sex dysfunction
Vilazodone (viibryd) MOA
inhibition of presynaptic 5-HT reuptake by inhibition of the 5-HT transporter
–leads to increased 5-HT in synaptic cleft
Also, a 5-HT1a partial agonist
May have some affinity for NE and DA transporters
Vilazodone (viibryd) initial dose
10mg PO qd
Vilazodone (viibryd) AE
GI
insomnia
MDD pos and neg for sedation
pos
- paroxetine
-mirtazapine
- trazodone
neg
-Buproprion
-fluoxetine
-sertraline
MDD pos and neg for weight gain
pos
- paroxetine
-mirtazapine
neg
-Buproprion
-Duloxetine
-fluoxetine
MDD pos and neg for bleeding risk
pos
-SSRI
neg
-Bupropion
-mirtazapine
MDD pos and neg for sex dysfunction
pos
- paroxetine
-venlafaxine
-sertraline
neg
-Buproprion
-mirtazapine
-vortioxetine
MDD pos and neg for hypertension
pos
-bupropion
-venlafaxine
neg
-SSRI
discontinuation syndrome
Flu like symptoms that occur after abrupt discontinuation of SSRI/SNRI, taper slow (except fluoxetine)
Star-D for depression
- Citalopram
- Switch
- Sertraline
- Bupropion
-Venlafaxine
-CBT - Augment
-Bupropion
-Buspirone
-CBT
2a
- venlafaxine
-Bupropion
- Switch
-mirtazapine
-nortyptiline - Augment
- Lithium
-Thyroid hormone
-largest and longest study
-compared acute and long term tx outcomes associated with steps
cumulative remission rate: 67%
APA 1st line and 2nd line
mild-mod
-psychotherapy +/- SSRI, SNRI, mirtaz, or bupro
mod-severe
- pharmacotherapy +/- psychotherapy
Psychotic features
- antidepressant + Antipsychotic
- ECT- severe depression
2nd
- switch but keep mono
- augment with antidepressant with diff mechanism
- quetapine
-psychotherapy
NICE guideline 1st
mild
-psychotherapy
mod-sev
-psych +/- pharma
severe
-ECT
CANMAT 1st line
1st
-SSRI, SNRI, and other newer agents based on safety and tolerability over TCAs or MAOIs
Psychotic features
-Antidepressant + Antipsychotic
CANMAT 1st line adjunctive
1st
-Aripiprazole, quetiapine, risperidone
Approach to tx of MDD 1-4 wks
Response
- full- maintain tx
-partial/none–assess adherence, inc as tolerated
if 50% reduction in sx cont at optimal dose and monitor at 6, 8, 12 wks
Approach to tx of MDD 4-8 wks
Response
- full- maintain tx
-partial/none–inc as tolerated, switch if no response at 8 wks, augment
MDD dx improvement: sleep
trazodone
mirtazapine
paroxetine
MDD dx improvement: concentration
bupropion
duloxetine
fluoxetine
MDD dx improvement: anxiety
sertraline
fluvoxamine
paroxetine
SNRI
MDD dx improvement: pain
SNRI
Rx choice based on
Past response (or family member response) to medication
Other psychiatric co-morbidities
Potential for drug interactions
Safety
Patient preference
Cost
patient education- counseling
When to start working
What to expect
Adverse side effects
Discontinuation syndrome
patient education- duration of therapy
1st episode – at least 6 months
2nd episode – at least 1 year
3rd episode – lifetime
new rx- Esketamine (spravato)
- Adjunct PO
- Black box noted
- For tx resistant
- REMS
- Expensive
new rx- brexanolone (zulresso)
- GABA- A
- Postpartum
- Infusion in facility
- Black box
- REMS
- Very expensive