Antidepressants

Question 1

SSRIs

Answer 1

• Fluoxetine, citalopram, escitalopram, paroxetine, sertraline
• MOA
• highly selective blockade of SERT
• little effect on NET
• Effects
• acute increase of serotonergic synaptic activity
• slower changes in several signaling pathways and neurotrophic activity
• Clinical
• major depression, anxiety disorders, panic disorder, OCD, PTSD, perimenopausal vasomotor symptoms, bulimia
• Kinetics, tox, int.
• t_1/2 15-75h, oral activity
• tox: well tolerated but cause sexual dysfunction, risk of serotonin syndrome with MAOIs
• int: some CYP inhibition (fluoxetine 2D6, 3A4; paroxetine 2D6)

Question 2

SNRIs

Answer 2

• Duloxetine, venlafaxine, levomilnacipran
• MOA
• moderately selective blockade of NET and SERT
• Effects
• acute increase in serotonergic and adrenergic synaptic activity, otherwise like SSRIs
• Clinical
• major depression, chronic pain disorders, fibromyalgia, perimenopausal symptoms
• Kinetics, tox, int.
• tox: anticholinergic, sedation, hypertension (venlafaxine)
• int: some CYP2D6 inhibition (duloxetine, desvenlafaxine), CYP3A4 interactions with levomilnacipran

Question 3

TCAs

Answer 3

• Imipramine, many others
• MOA
• mixed and variable blockade of NET and SERT
• Effect
• like SNRIs plus significant blockade of ANS and histamine receptors
• Clinical
• major depression unresponsive to other drugs, chronic pain disorders, incontinence, OCD (clomipramine)
• Kinetics, tox, int.
• long t_1/2, CYP substrates, active metabolites
• tox: anticholinergic, α-blocking effects, sedation, weight gain, arrythmias, seizures in overdose
• int: CYP inducers and inhibitors

Question 4

Nefazodone, trazodone

Answer 4

• 5-HT receptor modulators
• MOA
• inhibition of 5-HT_2A receptor
• nefazodone also blocks SERT weakly
• Effects
• trazodone forms m-cpp that blocks 5-HT_2A,2C receptors
• Clinical applications
• major depression, sedation and hypnosis (trazodone)
• Kinetics, tox, int.
• relatively short t_1/2, active metabolites
• tox: modest α- and H₁ blockade (trazodone)
• int: nefazodone inhibits CYP3A4

Question 5

Vortioxetine

Answer 5

• 5-HT receptor modulator
• MOA
• antagonist at 5-HT₃, 5-HT₇, 5-HT_1D
• partial agonist at 5-HT_1B
• agonist at 5-HT_1A
• inhibits SERT
• Effects
• complex modulation of serotonergic systems
• Clinical
• major depression
• Kinetics, tox, int.
• extensively metabolized via CYP2D6 and glucuronic acid conjugation
• tox: GI disturbances, sexual dysfunction
• int: additive with serotonergic agents

Question 6

Tetracyclics, unicyclic

Answer 6

• Bupropion, amoxapine, maprotiline, mirtazapine
• MOA
• increased NE and dopamine activity (bupropion)
• NET>SERT inhibition (amoxapine, maprotiline)
• increased release of NE, 5-HT (mirtazapine)
• Effects
• presynaptic release of catecholamines but no effect on 5-HT (bupropion)
• amoxapine and maprotiline resemble TCAs
• Clinical
• major depression, smoking cessation (bupropion), sedation (mirtazapine), amoxapine & maprotiline rarely used
• Kinetics, tox, int.
• extensive metabolism in liver
• tox: lowers seizure threshold (amoxapine, bupropion); sedation and weight gain (mirtazepine)
• int: CYP2D6 inhibitor (bupropion)

Question 7

MAOIs

Answer 7

• Phenelzine, tranylcypromine, selegiline
• MOA
• blockade of MAO-A and MAO-B (phenelzine, nonselective)
• MAO-B irreversible selective MAO-B inhibition (low-dose selegiline)
• Effects
• transdermal formulation of selegiline achieves levels that inhibit MAO-A
• Clinical
• major depression unresponsive to other drugs
• Parkinson’s disease (selegiline)
• Kinetics, tox, int.
• very slow elimination
• tox: hypotension, insomnia
• int: hypertensive crisis with tyramine, other indirect sympathomimetics, serotonin syndrome with serotonergic agents, meperidine