STEPTRACKERPHARMACOLOGY + PSYCHIATRY | PSYCHIATRY | HIGH-YIELD REVIEW

Antidepressants

All antidepressants raise monoamine signaling; they differ in which transmitters, which other receptors they hit, and therefore which side effects patients feel.

FOCUS ON
SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram): first-line for depression, anxiety, OCD, PTSD, bulimia, PMDD; 4–6 weeks for effect. Adverse: sexual dysfunction, GI upset, SIADH/hyponatremia, bleeding (with NSAIDs), QT (citalopram), activation/suicidality in young people, discontinuation syndrome (paroxetine). SNRIs (venlafaxine — ↑ BP; duloxetine — neuropathic pain, fibromyalgia). TCAs (amitriptyline, nortriptyline, imipramine, clomipramine, desipramine): block NE/5-HT reuptake + anticholinergic, α1, H1 → overdose: wide QRS, arrhythmia, seizures, coma → sodium bicarbonate. MAOIs (phenelzine, tranylcypromine, selegiline patch): atypical depression; tyramine crisis; serotonin syndrome. Atypicals: bupropion (NE/DA; smoking cessation; no sexual side effects; seizures — avoid in bulimia/anorexia), mirtazapine (α2 antagonist; weight gain, sedation), trazodone (insomnia; priapism), vortioxetine, vilazodone. Esketamine (NMDA), brexanolone/zuranolone (postpartum). Serotonin syndrome: hyperthermia, clonus, hyperreflexia, agitation, diarrhea → cyproheptadine.
CLASS · DRUGS
MECHANISM
USES
ADVERSE
SSRIs
sertraline, fluoxetine, escitalopram, paroxetine
Block SERT
MDD, GAD, panic, OCD, PTSD, bulimia, PMDD, social anxiety
Sexual dysfunction, GI, hyponatremia, bleeding, insomnia, QT (citalopram)
SNRIs
venlafaxine, desvenlafaxine, duloxetine, milnacipran
Block SERT and NET
MDD, GAD, neuropathic pain, fibromyalgia, stress incontinence (duloxetine)
↑ BP (venlafaxine), sweating, discontinuation syndrome
TCAs
amitriptyline, nortriptyline, imipramine, clomipramine
Block NET and SERT + M, α1, H1, Na⁺ channels
Neuropathic pain, migraine prevention, enuresis (imipramine), OCD (clomipramine)
Anticholinergic, orthostasis, sedation, weight gain, QT; lethal in overdose
MAOIs
phenelzine, tranylcypromine, isocarboxazid
Irreversible MAO-A/B inhibition
Atypical or refractory depression
Hypertensive crisis with tyramine (aged cheese, wine); serotonin syndrome with SSRIs, meperidine, dextromethorphan
Bupropion
NE and DA reuptake inhibitor
MDD, smoking cessation, ADHD (off-label)
Seizures (eating disorders, alcohol withdrawal), insomnia, ↓ appetite; no sexual dysfunction
Mirtazapine
α2 antagonist (↑ NE and 5-HT release), 5-HT2/3 and H1 block
MDD with insomnia or weight loss, elderly
Sedation, weight gain, ↑ cholesterol
Trazodone · nefazodone
5-HT2A antagonist, weak SERT block, α1 and H1 block
Insomnia (low dose)
Priapism, orthostasis · nefazodone hepatotoxicity
Vortioxetine · vilazodone
SERT block + 5-HT receptor modulation
MDD
Nausea; less sexual dysfunction
Esketamine
NMDA antagonist (nasal)
Treatment-resistant depression, acute suicidality
Dissociation, ↑ BP; supervised dosing
Brexanolone · zuranolone
GABA-A positive allosteric modulators (neurosteroids)
Postpartum depression
Sedation, loss of consciousness (IV)
Serotonin syndrome
Excess 5-HT (combinations: SSRI + MAOI, linezolid, tramadol, triptans, meperidine)
Within 24 h: fever, clonus, hyperreflexia, mydriasis, diarrhea
Stop drugs, benzodiazepines, cyproheptadine
Washout before MAOI switch
Fluoxetine long half-life (norfluoxetine)
5 weeks after fluoxetine; 2 weeks for most others
Prevents serotonin syndrome

Mechanism — TCA overdose

Na⁺ channel blockWide QRS → VT
AnticholinergicDelirium, hyperthermia, retention
α1 blockHypotension
Sodium bicarbonateNa⁺ load + alkalinization reverse channel block

QRS > 100 ms predicts seizures; > 160 ms predicts ventricular arrhythmia.

Choosing by side-effect profile

PATIENT ISSUE
FAVOR
AVOID
Sexual dysfunction
Bupropion, mirtazapine
SSRIs
Insomnia, weight loss
Mirtazapine
Bupropion
Seizure disorder, bulimia
SSRIs
Bupropion
Pregnancy
Sertraline
Paroxetine (cardiac defects)

How it's tested

COMMON CONFUSIONSerotonin syndrome is fast (hours) with clonus and hyperreflexia; NMS is slow (days) with lead-pipe rigidity and bradyreflexia, after dopamine blockers.
THE TRAPAntidepressants in a patient with undiagnosed bipolar disorder can trigger mania — screen for prior manic episodes.
YOUR APPROACHDiagnosis → SSRI default → adjust by comorbidity and side effects → check combinations for serotonin excess.

If you see… think…

Overdose with wide QRS, seizures, dry skin → TCA → sodium bicarbonate
Hypertensive crisis after cheese and wine → MAOI + tyramine
Seizure in a bulimic patient on antidepressant → bupropion
Painful prolonged erection → trazodone
Antidepressant also used for smoking cessation → bupropion
Antidepressant for diabetic neuropathy and depression → duloxetine
Hyponatremia in elderly woman on new antidepressant → SSRI-induced SIADH
Clonus, fever, diarrhea after adding linezolid to SSRI → serotonin syndrome
Weight gain and sleepiness on antidepressant → mirtazapine
Bedwetting treatment (TCA) → imipramine