What are the uses, dosing, and precautions for Trazodone (antidepressant medication) in an adult or geriatric patient with a history of major depressive disorder, anxiety disorders, or insomnia, and potential comorbidities such as heart disease, liver disease, or seizures?

Trazodone: Clinical Uses, Dosing, and Precautions

FDA-Approved Indication

Trazodone is FDA-approved exclusively for the treatment of major depressive disorder (MDD) in adults, not for insomnia. 1

Primary Clinical Use: Major Depressive Disorder

Efficacy in Depression

• Trazodone demonstrates comparable antidepressant efficacy to SSRIs, SNRIs, and tricyclic antidepressants in treating MDD. 2
• The medication is particularly effective for depression accompanied by insomnia, anxiety, and psychomotor agitation, with rapid onset of action. 3
• Trazodone avoids the sexual dysfunction, insomnia, and anxiety commonly associated with SSRI antidepressants due to its unique serotonin receptor antagonist and reuptake inhibitor (SARI) mechanism. 4, 3

Dosing for Depression

• Therapeutic doses range from 150-300 mg/day for monotherapy in adults, with maximum doses up to 400 mg/day. 4, 3
• In elderly patients, maximum tolerated doses are 300-400 mg/day, requiring lower starting doses. 5
• Trazodone should be taken shortly after a meal or light snack to optimize absorption and reduce side effects. 1
• The tablet should be swallowed whole or broken in half along the score line; do not crush or chew. 1

Off-Label Use: Insomnia

Guideline Position on Insomnia

The American Academy of Sleep Medicine explicitly recommends AGAINST trazodone for sleep onset or maintenance insomnia, stating that harms outweigh benefits. 6

Despite widespread off-label use at low doses (25-100 mg) for insomnia, clinical trials show only modest improvements in sleep parameters with no improvement in subjective sleep quality. 6

Alternative Insomnia Treatments

• First-line: Cognitive Behavioral Therapy for Insomnia (CBT-I) before any medication. 6
• First-line pharmacotherapy: Short/intermediate-acting benzodiazepine receptor agonists (eszopiclone, zolpidem, zaleplon) or ramelteon. 6
• Second-line: Low-dose doxepin 3-6 mg for sleep maintenance. 6

Combination Therapy Strategy

With Other Antidepressants

Combining trazodone with mirtazapine or SSRIs is supported for treatment-resistant depression, particularly when insomnia is prominent. 7, 8

• Trazodone 50-150 mg at bedtime can augment SSRI/SNRI therapy to address insomnia and sexual dysfunction. 7, 9
• When combining with mirtazapine, start mirtazapine at 15 mg at bedtime while continuing trazodone at current dose, monitoring for excessive sedation in the first 1-2 weeks. 8
• This combination targets multiple neurotransmitter systems, potentially improving efficacy while using lower doses of each agent. 8

Critical Safety Precautions

Cardiovascular Risks

• Orthostatic hypotension occurs particularly in elderly patients and those with pre-existing heart disease. 4, 5, 3
• QT interval prolongation and cardiac arrhythmias have been reported, requiring caution in patients with cardiovascular disease. 4, 3
• Despite these risks, trazodone has been successfully used in patients with depression and pre-existing cardiovascular disease when monitored appropriately. 5

Serious Adverse Events

• Priapism is a rare but serious adverse effect requiring immediate medical attention and drug discontinuation. 4, 5, 3
• Serotonin syndrome risk increases when combined with MAOIs, SSRIs, SNRIs, triptans, tramadol, or St. John's Wort. 1
• Do not use trazodone within 2 weeks of MAOI therapy in either direction. 1

Common Adverse Effects

• Somnolence/sedation, headache, dizziness, and dry mouth are the most frequently reported side effects. 4, 3
• Drowsiness is common; if problematic, consider dose adjustment or timing modification. 1
• Minimal anticholinergic activity compared to tricyclic antidepressants, making it better tolerated in elderly patients. 5, 3

Special Population Considerations

Geriatric Patients

Use trazodone with caution in elderly patients, starting with lower doses and monitoring closely for orthostatic hypotension, falls, and cognitive impairment. 1, 5

• Elderly patients may be at greater risk for clinically significant hyponatremia with serotonergic antidepressants. 1
• Maximum tolerated doses in elderly are typically 300-400 mg/day versus 600 mg/day in younger adults. 5

Hepatic and Renal Impairment

Trazodone has not been formally studied in hepatic or renal impairment; use with caution and consider dose reduction. 1

Pregnancy and Lactation

• No definitive evidence of teratogenicity in humans, but consider risks of untreated depression during pregnancy. 1
• Women who discontinue antidepressants during pregnancy are more likely to experience relapse of major depression. 1
• Trazodone passes into breast milk; weigh developmental benefits of breastfeeding against maternal need for medication. 1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established; trazodone is not recommended for children. 1

• Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients. 1

Suicide Risk Monitoring

Black Box Warning

Antidepressants, including trazodone, may increase suicidal thoughts or actions in children, teenagers, and young adults within the first few months of treatment. 1

Required Monitoring

• Monitor closely for new or worsening depression, suicidal thoughts, unusual behavior changes, especially during initial treatment and dose changes. 1
• Patients with bipolar disorder or family history of bipolar illness/suicidal behavior are at higher risk. 1
• Schedule frequent follow-up visits, particularly in the first few weeks of treatment. 1

Drug Interactions

Major Interactions to Avoid

• MAOIs: Contraindicated within 2 weeks in either direction due to serotonin syndrome risk. 1
• Linezolid and intravenous methylene blue also contraindicated. 1

Significant Interactions Requiring Monitoring

• Triptans, SSRIs, SNRIs, tricyclics, lithium, buspirone, antipsychotics: Increased serotonin syndrome risk. 1
• Warfarin: Monitor INR closely due to potential bleeding risk. 1
• NSAIDs and aspirin: Increased bleeding risk. 1
• Phenytoin: Potential for altered anticonvulsant levels. 1
• CYP3A4 and CYP2D6 inhibitors/inducers: May require dose adjustment. 10

Discontinuation

Never stop trazodone abruptly; taper gradually to avoid withdrawal symptoms and rebound depression. 1

• Discuss all treatment changes with healthcare provider before implementing. 1
• Successful treatment should continue for 4-9 months after achieving remission in first-episode depression. 8

Common Clinical Pitfalls to Avoid

• Using trazodone as first-line treatment for insomnia when guideline-recommended alternatives exist. 6
• Failing to monitor for orthostatic hypotension in elderly or cardiac patients. 5, 3
• Combining multiple serotonergic agents without considering serotonin syndrome risk. 1
• Using adult doses in elderly patients without appropriate dose reduction. 5
• Neglecting to implement or continue CBT-I when treating comorbid insomnia. 6, 7
• Assuming treatment failure before allowing adequate trial duration of 6-8 weeks. 8