Antidepressants

SSRIs

Escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

• Inhibit SERT, leading to increased serotonin activity at 5-HT1A receptors

• Can cause nausea d/t increased serotonin at 5-HT3 and sexual dysfunction d/t 5-HT2

• Working memory issues

SSRI interactions

Fluoxetine, paroxetine, setraline especially

• Mainly actions on CYP2D6 and CYP3A4

• Fluoxetine has a LONG WASHOUT period, have to wait 5 half lives (4-6 weeks) between drugs

• Lipophilic

• Highly protein bound

SSRI concerns

• Serotonin syndrome with MAOIs → tremor, hyperthermia, cardiovascular collapse

• Paroxetine/fluoxetine can increase toxicity of TCAs d/t CYP2D6 inhibition

• Fluoxetine and escitalopram are approved in children/adolescents

• Some can interfere with prodrug opioids (hydrocodone, hydromorphone)

• Paroxetine- avoid in pregnancy

SNRIs

Venlafaxine, desvenlafaxine, duloxetine, milnacipran

• Inhibit both SERT (serotonin) and NET→ more NE at B-adrenergic receptors!

• Can cause nausea, agitation, insomnia, and elevation of blood pressure

• Avoid MAOIs

SNRI interactions

• Duloxetine- Short wash out, high protein binding

• Venlafaxine- Fewer drug interactions (low protein binding, active metabolite from CYP2D6)

• Desvenlafaxine- Not metabolized by CYPS but by conjugation → watch renal function!

SNRI considerations

• Noradrenergic effects such as hypertension, tachycardia, CNS activation

• Minimal drug interactions

• Also used to treat anxiety disorders and functional/neuropathic pain through increased noradrenergic signaling in the spinal cord

Tricyclic Antidepressants

Amitryptaline, clompramine, doxepin, impramine, trimipramine

• Inhibit SERT and NET, like SNRIs

• Also antimuscarinic/cholinergic, antihistamine (H1), and alpha-1 adrenergic receptors

• Lipophilic, narrow therapeutic windows, long washouts

TCA side effects

• Anticholinergic: dry mouth, blurry vision, constipation, urinary retention

• Antihistamine: sedation, weight gain

• Anti alpha-1 adrenergic: postural hypotension

• Can cause VENTRICULAR DYSRHYTHMIAS in overdose- no more than a week of pills at a time!

TCA interactions

• Rely on hepatic/CYP metabolism so many drug interactions

• Potentiate the effects of alcohol and anesthetic agents

• Interfere with antihypertensives, MAOIs

Mirtazapine

Monoamine receptor antagonist: Blocks 5-HT2C and 5-HT3 receptors, blocking depressant effects and increasing serotonin release

• Also block alpha-2 receptors, inhibiting feedback loop

• NO 5HT1A activity

• More sedating

Trazodone

Monoamine receptor antagonist: Blocks 5-HT2A and 5-HT2C receptors, inhibits serotonin uptake

• Block depressant effect

• Also antihistamine (H1) effects- sedating, take at night

MAOIs

Phenelzine, Selegiline

• Inhibits MAO, which metabolizes serotonin, norepinephrine, dopamine

• IRREVERSIBLE inhibition of MAO-A and MAO-B

  • Lower seizure threshold, orthostatic hypotension, hypertensive crisis

Hypertensive crisis

Dietary tyramine → promotes release of NE from sympathetic neurons → no MAO, can’t breakdown → hypertension, headache, confusion, diaphoresis, stroke, death

Bupropion

Atypical antidepressant

• Binds to NET/DAT, partial nicotinic agonist

• Stimulating, can cause agitation

  • Lowers seizure threshold

Bupropion, mirtazapine

LEASE sexual side effects

Safe antidepressants in pregnancy

Fluoxetine, citalopram, TCAs

Ketamine

NMDA receptor antagonist: Inhibits GABA signaling → rapid increase in glutamate → increase BDNF → increase neurogenesis, synapse repair

• Nasal spray- fast acting, but expensive, potential for abuse

• Side effects- dissociation, inattention, suicidality

Brexanolone

• Neuroactive metabolite, allopregnanolone

• Increases GABA-gated Cl currents leading to hyperpolarization (inhibitory response)

• Had to be given as a 60-hour infusion with constant observation

Benzodiazepines

• Sedation, hypnosis with a1 subunits

• Anxiolysis with a2 and a3 units

• Anticonvulsant, hypnosis, amnesia

• Rebound anxiety!

• Long half lives

• Urinary excretion

Buspirone

• Blocks 5-HT1A autoreceptors and stimulates 5-HT1A postsynaptic receptors

  • Partial agonist, adjunct antidepressant

  • Time to effect longer, similar to SSRIs