Antidepressants Flashcards
Drug Induces Depression
Antihypertensive and cardiovascular
Sedative hypnotics
anti-inflammatory and analgesics
steroids
Risk of recurrence of depression
1 episode: 50-6-%
2 episodes: 70%
3 episodes: 90%
Biogenic amine hypothesis of depression
Reserpine causes depression by depleting NE and 5HT from vesicles
Neuroendocrine hypothesis of depression
overactivity of hypothalamic-pituitary adrenal axis causes an elevation of cortisol releasing factor which increases depression symptoms (causes insomnia, anxiety, decreased appetite and libido)
Neurotrophic hypothesis of depression
Brain-derived neurotrophic factor (BDNF) is decreased when experiencing pain and stress (so we want to increase BDNF levels to treat depression Sx)
BDNF has ‘antidepressant’ activity in animals
BDNF is important for neuronal connections
Integration of hypotheses of depression
- HPA and steroid abnormalities regulate BDNF levels
- Hippocampal glucocorticoid receptors are activated by cortisol during stress (decreasing BDNF)
- chronic activation of monoamine receptors increase BDNF signaling (through neurotrophic pathway)
- chronic activation of monoamine receptors leads to down regulation of HPA axis (through neuroendocrine)
Delayed therapeutic response of antidepressants
SSRI will cause an immediate increase of 5HT in brain, but clinically the effect will not affect depression symptoms for days or weeks
Mechanism of MAOIs
- NE and 5HT are normally degraded by monoamine oxidase
- increased amount of NE and 5HT packaged in vesicles because inhibiting monoamine oxidase
- causes depolarization and release, so we have more monoamines to activate pre and post synaptic receptors
- MAO -A breaks down 5HT & NE
- MAO-B breaks down dopamine
MAO inhibitors (drugs)
Non-selective: (irreversible)
- Phenelzine (nardil)
- Tranylcypromine (parnate)
MAO-B selective: (reversible)
- selegiline
MAO-A selective: (reversible)
- moclobemide (manerix)
MAOIs pearls
- Severe side effects: headache, drowsiness, dry mouth, weight gain, orthostatic hypotension, sexual dysfunction
- hypertensive crisis
- interactions with: TCAs, SSRIs, L-DOPA, cold preparations, diet pills
- avoid foods with Tyramine (ex. cheese, sour cream, liver, sausage, pepperoni, avocados, bananas, figs, soy sauce, ginseng)
- avoid St. John’s wort with MAOIs bc of its MAOI activity
Tricyclic antidepressants
Intication: depression, panic disorder, chronic pain, enuresis
overdose/toxicity: depressed patients more likely to be suicidal (bc have enough energy from drugs before therapy ‘kicks in’ so often self harm)
Tertiary Amines (TCA)
- 1st class of TCAs
- inhibit NE and 5HT reuptake via NET and SERT
- antihistamine, antimuscarinic, antiadrenergic activity
- SE: sedation, autonomic SE, weight gain
Drugs:
- imipramine (tofranil) - metabolized to desipramine - for enuresis and ADHD
- amitriptyline (elavil) - metabolized to nortriptyline
- clomipramine - used of OCD
- doxepin
Secondary Amines (TCA)
- 2nd class of TCAs
- better NET inhibitors than SERT
- SE: less sedation, anticholinergic, autonomic, weight gain, cardiovasular effects than tertiary amines
Drugs:
- desipramine (norpramin)
- nortriptyline (pamelor)
- maprotiline (ludiomil)
SSRI mechanism
- Seretonin transporters pumps are blocked, which increases the amount of 5HT in the synapse, 5HT stays in the synapse longer and remains active longer
- uses: depression, alcoholism, OCD, enuresis, PTSD, eating disorders, social phobias, panic, PMDD, GAD
- SE: N/V, headache, sexual dysfunction, anxiety, insomnia, tremor
SSRI drugs
- fluoxetine (prozac)
- fluvoxamine (luvox)
- paroxetine (paxil)
- sertraline (zoloft)
- citalopram (celexa)
- escitalopram oxalate (lexapro)
SSRI discontinuation syndrome
“brain zaps”. dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo
Serotonin syndrome
when given with MAOIs, TCAs
- also metoclopramide, tramadol, triptans, st john’s wort
- symptoms: hyperthermia, muscle rigidity, restlessness, myoclonus, sweating, shivering, seizures
- treatment: discontinuation of medication and management of symptoms, serotonin antagonists, BZDs to control myoclonus
SSRI + 5HT1A partial agonists
vilazodone (viibryd)
-reduced sexual SE vs pure SSRIs
-similat 5HT1A action to aripiprazole and buspirone
votrioxetine (brintellex)
Tetracyclic and Unicyclic
- maprotiline (ludiomil) - NET inhibitor
- amoxapine (ascendin) - NET inhibitor, D2 antagonist
- mirtazapine (remeron) - a2 antagonist, 5HT2 & 5HT3 antagonist, H1 antagonish
- bupropion (wellbutrin) - DAT inhibitor, NET & SERT inhibitor, also treats GAD, Zyban for smoking cessation
SNRIs
Venlafaxine (effexor)
- NET & SERT inhibitors
- treats GAD and panic disorder
Desvenlafaxine (pristiq)
- NET & SERT inhibitor
- treatment of vasomotor symptoms associated with menopause
duloxetine (cymbalta)
- NET & SERT inhibitor
- treats GAD and peripheral neuropathy
milnacipran (ixel)
- NET & SERT inhibitor
- approved for fibromayalgia
levomilnacipran (fetzima)
-active enantiomer of milnacipran
-NET & SERT inhibitors
Norepinephrine selective reuptake inhibitors
reboxetine (vestra, edornax)
-possibly less side effects than prozac
atomoxetine (straterra)
-used for ADHD
Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs)
- “triple blockers”
Rapidly acting antidepressants: NMDA Antagonists
- ketamine- subanaesthetic doses
- scopolamine (muscarinic & NMDA antagonist)
- Lanicemine - “low trapping”
clinically used NMDA antagonists
ketamine
eskatamne (spravato) - in conjunction with oral antidepressant
- CNS effects: depression, drug interactions
- intranasal based dosing
Postpartum depression (PPD)
- SSRIS (fluoxetine and paroxetine) and venlafaxine
- Brexanolone - allopregnanolone levels increase in pregnancy and return to normal postpartum. Brexanolone resensitizes GABA-A receptors which makes membrane potential back to normal so decreases PPD.
DSM 5 Diagnostic critetia of depression
- at least one of the symptoms must be depressed mood or loss of interest or pleasure in doing things
S - sleep (insomnia/hypersomnia)
I - interest decreased
G - guit/worthlessness
E - energy loss/fatigue
C - concentration difficulties
A - appetite change (increase or decrease)
P - psychomotor agitation/retardation
S - suicidal ideation
citalopram (celexa)
- SSRI
- dose-dependent QTc prolongation
- substrate of 2C19 and 3A4
escitalopram (lexapro)
- SSRI
- pure S-enantiomer of citalopram
- substrate of 2C19
fluoxetine (prozac)
- SSRI
- long half life (96-144 hrs)
- activating potential
- 2D6 inhibitor, 3A4 inhibitor
fluvoxamine (luvox)
- SSRI
- inhibitor of 1A2, 2C19
- indicated for OCD treatment
paroxetine
- SSRI
- MUST taper due to anticholinergic effects
- weight gain, sedation
- septal wall defect risk to the fetus
- inhibitor 2D6, 2B6
sertraline (zoloft)
- SSRI
- more GI upset than other antidepressants
- inhibitor 2C19, 2D6, 3A4
SSRI - adverse effects/key points
- onset of action is 1-2 weeks
- 4-6 weeks until full dose response observed
- increased bleed risk (platelet inhibition)
- weight gain (paroxetine)
- hyponatremia especially in elderly
- weight loss (fluoxetine)
- sexual dysfunction
desvenlafaxine (pristiq)
- SNRI
- active metabolite of venlafaxine
- dose-limiting SE: nausea
- no major CYP interactions
duloxetine (cymbalta)
- SNRI – go to SNRI
- slow titration of divided dosing to help with nausea
- FDA warning for hepatotoxicity
- inhibitor 2D6
levomilnacipran (fetzima)
- SNRI
- must adjust in renal impairment or strong 3A4 inhibitors
- 3A4 substrate
milnacipran (savella)
- SNRI
- indicated for fibromyalgia
- renal dosage adjustments
SNRI adverse effects/key points
- onset is 1-2 weeks but clinical benefit 4-6
- useful in pain syndrome, musculoskeletal pain, fibromyalgia, and neuropathic pain
- blood pressure elevation
- nausea
- duloxetine: obtain LFTs at baseline and when symptomatic or every 6 months
venlafaxine (effexor)
- SNRI
- must be >150mg per day to have NE effects
- 2D6 inhibitor at higher doses
- substrate 2D6 and 3A4
TCAs
- blockade of reuptake transporter (DAT, SERT, NET) which inhibits the reuptake of serotonin, NE, and DA
- amitriptyline (elavil) - tertiary amine
– used low doses for neuropathi pain
MAO inhibitors
- not commonly used
- old antidepressants but super effective
- must have 2 weeks washout period before switching antidepressants
- all require tyramine diet except selegiline patch
- caution due to hypertensive crisis and serotonin syndrome
selegiline patch
- selective MAO-B inhibitor at low doses
- tyramine diet NOT required with this patch
TCAs adverse effects/key points
- most often used for neuropathic syndromes than depression – amitriptyline or nortriptyline
- CNS: sedation, reduced seizure threshold, confusion
- anticholinergic: blurred vision, urinary retention, constipation
- cardiovascular: orthostatic hypotension, tachycardia
- other: weight gain, sexual dysfunction
mirtazapine (remeron)
- presynaptic a2 blockade as well as 5HT2, 5HT3, and H2 blockade (can be combined with SSRI/SNRI)
- sedation and increased appetite occur with doses less than 15mg/day
- agranulocytosis, increased cholesterol
- can be used with SSRI/SNRI
buproprion (wellbutrin)
- dopamine and norepinephrine reuptake inhibitor
- stimulating - insomnia, appetite suppression
- XL dosing for depression
- 2D6 inhibitor
- CI in active seizure
trazadone (desyrel)
- SSRI but also impacts 5HT1 and 1
- high dose needed for depression
- Drug interactions: trazadone –3A4, 2D6
- SE: orthostatic hypotension, risk of priapism
vilazodone (viibryd)
- SSRI with 5HT1A agonism (helps proviod anxiolytic effects)
- do not use in combo with SSRI/SNRI
- take with food bc nausea
- bioavailability increases with food
- 3A4 substrate
vortioxetine (trintellix)
- SSRI + 5HT1A agonist + 5HT3 antagonist
- do not use in combo with SSRI/SNRI
- possibly less sexual dysfunction
- 2D6 substrate
- nausea
Serotonin syndrome treatment
- stop the offending agent + supportive care
- potentially could use serotonin blockers (cyproheptadine)
Antidepressant withdrawal syndrome
- common with ALL antidepressants EXCEPT fluoxetine
- not life threatening but extremely uncomfortable (so we should slowly taper when discontinuing)
- antidepressants with anticholinergic activity should be tapered no matter what
augmentation agents (for depression)
antipsychotics
lithium
anticonvulsants
pindolol
triiodothryonine
benzodiazepines
buspirone
atomoxetine
atypical antipsychotics (add on for depression)
- dosing is lower for depression than other states
- FDA approved: aripiprazole, brexpiprazole, cariprazine, quetipine
Antidepressants for Post-partum
- allosteric modulators of alloprenanolone
- brexanolone - iv only
- zuranolone - oral dose
Antidepressants for treatment resistant depression
Esketamine nasal spray - NMDA receptor antagonist
overall key counseling points for depression
- may take 2-4 weeks to see benefit
- abrupt discontinuation may lead to antidepressant withdrawal syndrome
- possible increase in suicidal thinking in first few weeks of therapy
