What is Trazodone (an antidepressant medication)?

What is Trazodone?

Trazodone is a second-generation antidepressant classified as a Serotonin Receptor Antagonist and Reuptake Inhibitor (SARI) that is FDA-approved for treating major depressive disorder in adults, though it is most commonly prescribed off-label at low doses (25-100 mg) for insomnia due to its potent sedative properties. 1, 2

Mechanism of Action

• Trazodone works by selectively inhibiting serotonin reuptake and antagonizing 5-HT2A serotonin receptors, though the exact mechanism of its antidepressant effect remains incompletely understood 2

• The drug also antagonizes alpha-1 adrenergic receptors, which contributes to its sedating effects and risk of orthostatic hypotension 2

• Trazodone is extensively metabolized by CYP3A4 into an active metabolite called m-chlorophenylpiperazine (mCPP), which is a more potent serotonin reuptake inhibitor than the parent compound 2, 3

Clinical Applications

FDA-Approved Use

• Approved for major depressive disorder in adults at therapeutic doses of 150-300 mg/day (up to 400 mg/day outpatient, 600 mg/day inpatient with monitoring) 2, 3, 4

• Demonstrates comparable antidepressant efficacy to tricyclic antidepressants, SSRIs, and SNRIs in clinical trials 5, 6, 7

Off-Label Use (Most Common)

• Low-dose trazodone (25-100 mg) is one of the most commonly prescribed medications for insomnia in the United States, particularly in patients with depression 5, 1, 3

• The American Academy of Sleep Medicine classifies trazodone as a "sedating low-dose antidepressant" that may be considered when insomnia accompanies comorbid depression or after other treatment failures 5, 8

• Important caveat: Low-dose trazodone for insomnia does NOT constitute adequate treatment for major depression 5, 1

Advantages Over Other Antidepressants

• Minimal anticholinergic activity compared to tricyclic antidepressants like doxepin and amitriptyline (no dry mouth, constipation, urinary retention) 5, 1, 8, 4

• Lower toxicity in overdose compared to first-generation antidepressants 1, 8

• Avoids common SSRI side effects including insomnia, anxiety, and sexual dysfunction 6, 7

• Effective for treating insomnia associated with depression, unlike SSRIs which often worsen sleep 6, 4, 7

• May have faster onset of action with some patients responding within the first week of treatment 3

Side Effects and Safety Profile

Common Adverse Effects

• Drowsiness/somnolence/sedation (most common) 1, 6, 7
• Headache 1, 7
• Dizziness 1, 7
• Dry mouth (xerostomia) 1, 7

Serious but Rare Adverse Effects

• Orthostatic hypotension, particularly in elderly patients or those with cardiovascular disease 6, 7
• Priapism (rare but requires immediate medical attention) 1, 7
• QT interval prolongation and cardiac arrhythmias 6, 7
• Suicidal thoughts or actions (FDA black box warning for all antidepressants in children, teenagers, and young adults) 2

Low Risk Profile

• Minimal weight gain 4, 7
• Low risk of sexual dysfunction 4, 7
• Minimal anticholinergic effects 4, 7

Dosing and Administration

• For depression: 150-300 mg/day (therapeutic antidepressant dose) 4, 7
• For insomnia (off-label): 25-100 mg at bedtime 5, 1
• Should be taken shortly after a meal or light snack to optimize absorption 2
• Tablets can be swallowed whole or broken in half along the score line, but should not be chewed or crushed 2
• Peak plasma levels occur approximately 1 hour after dosing on an empty stomach or 2 hours after dosing with food 2

Drug Interactions and Contraindications

• Contraindicated with MAOIs (must wait 2 weeks after stopping either medication before starting the other) 2
• Caution with other serotonergic medications due to risk of serotonin syndrome (SSRIs, SNRIs, triptans, tramadol, St. John's Wort) 2
• Metabolized by CYP3A4, so interactions possible with CYP3A4 inhibitors or inducers 2

Clinical Pearls

• The sedative effects occur at much lower doses (25-100 mg) than those required for antidepressant effects (150-300 mg) 1, 3

• Trazodone is 89-95% protein bound and extensively metabolized with less than 1% excreted unchanged in urine 2

• May be particularly useful for patients with depression accompanied by insomnia, anxiety, or psychomotor agitation 4, 7

• A prolonged-release once-daily formulation (Oleptro) is available in the United States, which may improve tolerability and adherence 6