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Last updated: July 27, 2021

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Antidepressants are used primarily to treat major depressive disorder (MDD), although they are also indicated for the treatment of many other neuropsychiatric conditions. The most widely used classes of antidepressants are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs). Most of these drugs work by increasing levels of serotonin, norepinephrine, or dopamine within the synaptic cleft. SSRIs are the first-line treatment for the vast majority of patients with depression because of their efficacy and favorable side-effect profile. While MAOIs and TCAs also have a high degree of efficacy, they are no longer widely used because of their undesirable side-effect profiles. Serotonin syndrome may occur as a complication of serotonergic antidepressant use; TCA toxicity is also possible, as is antidepressant discontinuation syndrome, which is caused by abrupt withdrawal or dose reduction of an antidepressant taken for ≥ 4 weeks.

Overview of antidepressants
Agents Indications Mechanism of action Adverse effects Contraindications Interactions
St. John's Wort
Selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, citalopram)
Serotonin norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, duloxetine)
Tricyclic antidepressants (TCAs) Secondary amines (e.g., nortriptyline, desipramine)
  • Tertiary amines should be avoided in elderly individuals.
Tertiary amines (e.g., amitriptyline, imipramine)
Serotonin antagonist and reuptake inhibitors (SARIs; e.g., trazodone)
  • Inhibition of H1, α1, and postsynaptic 5-HT2 receptors as well as serotonin reuptake → serotonin levels
Monoamine oxidase inhibitors (MAOIs; e.g., tranylcypromine, phenelzine, selegiline)
Atypical antidepressants Mirtazapine
  • Hypersensitivity [4]
Bupropion [5]
  • Concomitant MAOI use [6]
  • Hypersensitivity
  • Transdermal nicotine: ↑ adverse events
  • 5-HT1A receptor stimulation

Antidepressants increase the risk of suicidal thoughts and suicidality in children, adolescents, and young adults < 24 years with major depressive disorder.

The side effects of SSRIs are: Serotonin syndrome, Stimulation of the CNS (agitation), Reproductive dysfunctions in males, and Insomnia.

To avoid serotonin syndrome, SSRIs should be discontinued at least two weeks before starting an MAOI. Particular caution should be observed with fluoxetine, which should be discontinued at least five weeks before MAOI treatment begins.

Think “traZzzoBONE” to remember the adverse effects of sedation (Zzz...) and priapism!

Mirtazapine [10]

Mirtazzzapine makes you sleepy (Zzz...).

Bupropion [11]

Buproprion is not associated with sexual dysfunction or weight gain. It is contraindicated in patients with seizure and eating disorders.

Vilazodone [12]

Vortioxetine [13]


VareniCliNe makes you Very Clean from Nicotine.

To remember the members of the MAO inhibitor class, think: “MAO thought capitalism was the PITS” (Phenelzine, Isocarboxazid, Tranylcypromine, Selegiline).

Overview of tricyclic antidepressants

Physostigmine should not be given to patients with suspected TCA overdose because it can precipitate cardiac arrest!

Secondary amines are generally better tolerated than tertiary amines, especially in elderly patients.

The side effects of TCAs are: Tremor, Cardiovascular adverse effects, Anticholinergic adverse effects, Sedation, and Seizures.

Tricyclic antidepressant toxicity

The three Cs of tricyclic poisoning: Convulsions, Coma, and Cardiac conduction abnormalities (prolonged QTC).

Antidepressant discontinuation syndrome [16][17]

  • Description: symptoms caused by abrupt withdrawal or dose reduction of antidepressants taken for ≥ 4 weeks
  • Clinical features
  • Timing
    • Typically occurs within 3 days after drug cessation
    • Symptoms usually subside within 1–2 weeks
  • Diagnosis: is primarily based on history and clinical features.
  • Treatment: Restart antidepressant therapy at the original dose and begin tapering slowly.

To remember the main clinical features of antidepressant discontinuation syndrome, think: FINISH (Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal).

Serotonin syndrome [18]

Serotonin syndrome causes HARM: Hyperthermia, Autonomic instability, Rise in blood pressure, and Myoclonus.

Drug-induced hyperthermia

Differential diagnosis of drug-induced hyperthermia [18][19]
Characteristics Serotonin syndrome Neuroleptic malignant syndrome Malignant hyperthermia Anticholinergic toxicity
Causative agents
  • < 24 h
  • Days to weeks
  • Minutes–24 h
  • < 24 h
Clinical features Symptoms of autonomic dysfunction
Changes in neuromuscular activity
  • None: normal reflexes and tone
Altered mental status
  • Confusion possible
Laboratory findings
  • Nonspecific
  • Nonspecific

To differentiate between serotonin syndrome and the rest of drug-induced hyperthermia conditions remember that only SErotonin Shakes your Extremities (myoclonus and hyperreflexia, mostly of the lower limbs)

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  2. DESYREL® (trazodone hydrochloride) tablets, for oral use.
  3. PARNATE® (tranylcypromine) tablets, for oral use.
  4. REMERON (mirtazapine) tablets.
  5. WELLBUTRIN XL (bupropion hydrochloride extended-release) tablets for oral use.
  6. VIIBRYD (vilazodone HCl) Tablets for oral administration.
  7. BuSpar® (buspirone HCl, USP).
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  19. Trazodone.
  20. Amitriptyline. Updated: December 1, 2017. Accessed: April 10, 2018.
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