What is the recommended treatment protocol for major depressive disorder using Trazodone (antidepressant)?

Trazodone Treatment Protocol for Major Depressive Disorder

Indication and Selection

Trazodone is FDA-approved for treating major depressive disorder in adults and should be selected among second-generation antidepressants based on its favorable adverse effect profile, particularly its benefits for depression-associated insomnia and lack of sexual dysfunction, rather than superior efficacy. 1, 2

• Trazodone demonstrates comparable antidepressant efficacy to SSRIs, SNRIs, and tricyclic antidepressants, with no evidence supporting superior effectiveness of any single second-generation antidepressant over another 2, 3
• The drug's unique mechanism as a serotonin antagonist and reuptake inhibitor (SARI) provides advantages over SSRIs by avoiding common side effects including insomnia, anxiety, and sexual dysfunction 3, 4
• Selection should prioritize trazodone when patients present with depression accompanied by insomnia or psychomotor agitation, as it effectively addresses these specific symptom clusters 4, 5

Dosing Protocol

Start trazodone at 150 mg daily and titrate to a therapeutic range of 150-300 mg/day for outpatients, with maximum doses of 400 mg/day for outpatients or 600 mg/day for hospitalized patients under close monitoring. 2, 6

• Administer trazodone shortly after a meal or light snack to optimize absorption and tolerability 1
• The once-daily prolonged-release formulation (trazodone controlled-release) maintains therapeutic blood levels for 24 hours while avoiding concentration peaks associated with side effects 3, 4
• Tablets should be swallowed whole or broken in half along the score line; do not crush or chew 1
• For elderly patients, use lower doses within the 75-400 mg/day range due to increased risk of orthostatic hypotension 5, 7

Monitoring Schedule

Begin monitoring patient status, therapeutic response, and adverse effects within 1-2 weeks of treatment initiation, with particularly close surveillance for suicidal ideation during the first 1-2 months. 2, 8

• Assess for emergence of agitation, irritability, unusual behavioral changes, or worsening depression at each visit, as these may indicate increased suicide risk 2, 1
• Monitor specifically for drowsiness/somnolence, headache, dizziness, and dry mouth, which are the most common adverse effects 3, 4
• In elderly patients and those with cardiovascular disease, closely monitor for orthostatic hypotension, cardiac arrhythmias, and QT interval prolongation 4, 7
• Watch for rare but serious adverse effects including priapism (requiring immediate medical attention) 3, 6
• Use standardized assessment tools such as the Patient Health Questionnaire-9 (PHQ-9) or Hamilton Depression Rating Scale (HAM-D) to quantify response, defined as ≥50% reduction in measured severity 2, 8

Response Assessment and Treatment Modification

If adequate response is not achieved within 6-8 weeks of initiating therapy, modify treatment by adjusting dose, switching agents, or adding combination therapy. 2, 8

• Expect initial therapeutic response within 1-2 weeks, with full efficacy typically achieved by 4 weeks of treatment 4, 6
• One-third of inpatients and one-half of outpatients demonstrate significant therapeutic response by the end of the first week 6
• If drowsiness is problematic, consider adjusting the dose or timing of administration rather than discontinuing effective therapy 1
• No evidence supports preferring one second-generation antidepressant over another as second-line therapy; selection should be based on adverse effect profiles and patient-specific factors 2

Treatment Duration

Continue trazodone for 4-9 months after achieving satisfactory response in patients with a first episode of major depressive disorder; for patients with two or more episodes, extend maintenance treatment to at least 1 year or longer. 2, 8

• The continuation phase (4-9 months post-remission) prevents relapse, defined as symptom return during acute or continuation phases 2, 8
• The maintenance phase (beyond 9 months) prevents recurrence, defined as a new distinct depressive episode 2, 8
• For chronic depression, treatment duration should extend well beyond standard 9-month recommendations to reduce recurrence risk 8
• Never discontinue trazodone abruptly; taper gradually under medical supervision to avoid withdrawal symptoms 1

Contraindications and Drug Interactions

Do not use trazodone concurrently with monoamine oxidase inhibitors (MAOIs) or within 2 weeks of MAOI discontinuation. 1

• Avoid concurrent use with medications that increase serotonin levels (triptans, SSRIs, SNRIs, St. John's Wort, tryptophan) due to serotonin syndrome risk 1
• Exercise caution when combining with NSAIDs, aspirin, or warfarin due to increased bleeding risk 1
• Trazodone is metabolized primarily by CYP3A4 and CYP2D6; adjust doses when co-administering with inhibitors or inducers of these enzymes 5
• Monitor closely when used with other CNS depressants, antipsychotics, lithium, or medications affecting cardiac conduction 1, 6

Special Populations

In elderly patients, initiate trazodone at lower doses (75-300 mg/day maximum) and monitor closely for orthostatic hypotension and falls. 5, 7

• Pregnancy: Discuss risks and benefits; consider enrollment in the National Pregnancy Registry for Antidepressants (1-844-405-6185) 1
• Breastfeeding: Trazodone passes into breast milk; discuss alternative feeding options with patients 1
• Cardiovascular disease: Use with caution due to risks of orthostatic hypotension, arrhythmias, and QT prolongation; consider baseline ECG 4, 7
• Hepatic or renal impairment: Dose adjustment may be necessary due to altered drug metabolism 1

Combination Therapy Considerations

For chronic depression, combine trazodone with psychotherapy (particularly cognitive behavioral therapy) for optimal outcomes, as combination treatment is more effective than monotherapy. 8

• Lower doses of trazodone (50-100 mg) can be used adjunctively with other antidepressants to address persistent insomnia without compromising the primary antidepressant's efficacy 4, 5
• When used in combination, trazodone's sedating properties at lower doses complement activating antidepressants like SSRIs or bupropion 5