What is the recommended dosage and treatment approach for Trazodone (antidepressant) in patients with major depressive disorder?

Trazodone for Major Depressive Disorder

For major depressive disorder, trazodone should be initiated at 150 mg/day and titrated to an effective antidepressant dose of 150-300 mg/day, taken shortly after a meal or light snack, with the option to use the once-daily controlled-release formulation to improve tolerability and adherence. 1, 2, 3

FDA-Approved Indication and Dosing

• Trazodone is FDA-approved specifically for the treatment of major depressive disorder in adults 1
• The medication should be taken shortly after a meal or light snack to optimize absorption and reduce side effects 1
• Tablets can be swallowed whole or broken in half along the score line, but should not be chewed or crushed 1

Therapeutic Dosing Strategy

Antidepressant doses are typically 150-300 mg/day, which are substantially higher than the 25-100 mg doses commonly used off-label for insomnia. 2, 3

• Maximum tolerated doses can reach 300-400 mg/day in elderly patients and up to 600 mg/day in younger adults 4
• The once-daily controlled-release formulation (trazodone CR) maintains therapeutic blood levels for 24 hours while avoiding concentration peaks associated with side effects 2
• Lower doses (75-150 mg) may be used when combining trazodone with other antidepressants for augmentation, but these subtherapeutic doses do not constitute adequate monotherapy for major depression 5, 3

Monitoring and Treatment Response

Begin assessment of therapeutic response and adverse effects within 1-2 weeks of initiation, with treatment modification required if adequate response is not achieved within 6-8 weeks. 5, 6

• Response is defined as ≥50% reduction in depressive symptom severity measured by validated tools like PHQ-9 or HAM-D 5, 6
• Close monitoring for increased suicidal thoughts is critical during the first 1-2 months of treatment, particularly in young adults under age 25 7, 1
• If drowsiness occurs, the dose or timing may need adjustment rather than discontinuation 1

Treatment Duration

Continue treatment for 4-9 months after achieving remission for a first depressive episode; patients with two or more episodes require maintenance treatment of at least 1 year or longer. 5, 6

• Do not discontinue trazodone abruptly without consulting the prescriber, as this can cause withdrawal symptoms 1
• The continuation phase (4-9 months post-remission) is essential to prevent relapse, while the maintenance phase prevents recurrence of new episodes 5, 6

Clinical Advantages and Patient Selection

Trazodone's unique pharmacodynamic profile makes it particularly valuable for depressed patients with prominent insomnia, anxiety, or psychomotor agitation, as it avoids the activating side effects and sexual dysfunction common with SSRIs. 8, 2, 3

• Trazodone demonstrates comparable antidepressant efficacy to tricyclics, SSRIs, and SNRIs in clinical trials 8, 2
• The drug has minimal anticholinergic activity, low risk of weight gain, and low incidence of sexual dysfunction compared to SSRIs 2, 3
• Rapid onset of action on symptoms like insomnia and agitation makes it useful for acute symptom relief 2

Important Safety Considerations and Contraindications

Do not use trazodone within 2 weeks of MAOI therapy in either direction, and exercise caution in patients with cardiovascular disease or QT prolongation. 1

• Common adverse effects include somnolence/sedation, headache, dizziness, and dry mouth 8, 2
• Orthostatic hypotension risk is elevated in elderly patients and those with pre-existing heart disease, requiring careful monitoring 8, 4
• Rare but serious events include priapism (requiring immediate medical attention), cardiac arrhythmias, and QT prolongation 8, 2
• Trazodone is relatively safe in overdose compared to tricyclic antidepressants 4

Drug Interactions

Avoid concurrent use with other serotonergic agents (SSRIs, SNRIs, triptans, tramadol, St. John's Wort) due to serotonin syndrome risk 1

• Trazodone is metabolized primarily by CYP3A4 and CYP2D6, requiring dose adjustment when combined with inhibitors or inducers of these enzymes 9
• Use caution with anticoagulants (warfarin), NSAIDs, and aspirin due to increased bleeding risk 1

Special Populations

• In elderly patients, start with lower doses and titrate more cautiously due to increased risk of orthostatic hypotension and falls 4
• Pregnancy: Discuss risks/benefits and consider enrollment in the National Pregnancy Registry for Antidepressants (1-844-405-6185) 1
• Trazodone passes into breast milk; discuss feeding options with patients 1

Combination Therapy

When used as augmentation with another full-dose antidepressant (particularly SSRIs), trazodone at lower doses (50-150 mg) can address treatment-resistant insomnia, though this does not constitute adequate monotherapy for depression 5