What is the recommended dosing schedule for trazodone in treating major depressive disorder, including starting dose, titration, maximum dose, and special considerations for elderly or hepatic impairment?

Trazodone Dosing for Major Depressive Disorder

For major depressive disorder, initiate trazodone at 150 mg/day in divided doses, increase by 50 mg/day every 3-4 days as tolerated, targeting 200-300 mg/day for outpatients (maximum 400 mg/day) or up to 600 mg/day for severely depressed inpatients, with the majority of the dose administered at bedtime to minimize daytime sedation. 1

Starting Dose and Initial Titration

• Begin with 150 mg/day in divided doses for the first few days to assess tolerability 1
• Administer trazodone shortly after a meal or light snack to improve absorption and reduce side effects 1
• The initial dose can be weighted toward bedtime (e.g., 50 mg morning, 100 mg bedtime) to leverage trazodone's sedating properties and reduce daytime drowsiness 2
• If drowsiness is problematic, either reduce the total daily dose or shift more of the dose to bedtime 1

Dose Escalation Schedule

• Increase by 50 mg/day every 3-4 days based on clinical response and tolerability 1
• Monitor for therapeutic response and adverse effects at each dose increment 1
• Target therapeutic range is 200-300 mg/day for most outpatients with major depression 2, 3
• Evidence suggests trazodone may be more effective at moderate doses (150-300 mg/day) rather than maximal doses; studies using rapid titration to 600 mg/day showed poorer responses than those using conservative dosing 3

Maximum Doses

• Outpatients: Do not exceed 400 mg/day in divided doses 1
• Inpatients (severely depressed): May use up to 600 mg/day in divided doses, though this should be reserved for more severe cases 1
• Higher doses (>400 mg/day) are better tolerated in younger patients compared to elderly patients 4

Optimal Dosing Strategy: Single Bedtime Dose

• After initial titration, transition to predominantly bedtime dosing (e.g., 150-300 mg as a single dose at bedtime) 2
• Studies demonstrate equal antidepressant efficacy between multiple daily doses and single bedtime dosing 2
• Single nighttime dosing produces better sleep with less daytime drowsiness, particularly during treatment initiation 2
• The 3-9 hour half-life of trazodone supports once-daily bedtime administration 2
• Differences in sedation between single and divided dosing diminish with continued administration 2

Special Population: Elderly Patients

• Maximum tolerated doses in elderly patients are 300-400 mg/day, compared to 600 mg/day in younger adults 4
• Elderly patients respond similarly to single bedtime dosing as younger patients 2
• Monitor closely for orthostatic hypotension, which occurs more frequently in elderly patients despite lower anticholinergic effects compared to tricyclic antidepressants 4

Special Population: Hepatic Impairment

• The provided evidence does not contain specific dosing adjustments for hepatic impairment
• Consider starting at lower doses and titrating more slowly in patients with liver disease, though no specific guidelines are provided in the available evidence

Timeline for Response

• Antidepressant effects typically require several weeks of treatment at therapeutic doses 5
• Some evidence suggests trazodone may produce statistically significant improvement in HAM-D17 scores within 1 week at 150 mg/day, particularly for sleep disturbance 5
• Full antidepressant efficacy generally requires 4-6 weeks at therapeutic doses 4

Maintenance and Dose Reduction

• Once adequate response is achieved, gradually reduce dosage with subsequent adjustments based on therapeutic response 1
• Continue maintenance therapy at the lowest effective dose that maintains remission 1

Drug Interactions Requiring Dose Adjustment

• With strong CYP3A4 inhibitors: Consider reducing trazodone dose based on tolerability 1
• With strong CYP3A4 inducers: Consider increasing trazodone dose based on therapeutic response 1

Discontinuation

• Gradually taper the dose rather than stopping abruptly to minimize withdrawal symptoms 1
• Adverse reactions may occur upon discontinuation 1

Critical Safety Considerations

• Screen all patients for personal or family history of bipolar disorder, mania, or hypomania before initiating trazodone 1
• Allow at least 14 days between discontinuing an MAOI and starting trazodone, and vice versa 1
• Monitor for orthostatic hypotension, arrhythmias, and priapism, particularly in elderly patients 4
• Trazodone is relatively safe in overdose compared to tricyclic antidepressants 4, 3

Common Pitfalls to Avoid

• Avoid rapid titration to maximal doses (600 mg/day), as this strategy has been associated with poorer therapeutic responses compared to conservative dosing 3
• Do not administer trazodone on an empty stomach, as taking it with food reduces side effects 1, 3
• Avoid multiple daytime doses when a single bedtime dose would suffice, as this increases daytime sedation without improving efficacy 2
• Do not exceed 400 mg/day in outpatients or 600 mg/day in inpatients 1