Trazodone: A Comprehensive Overview
Trazodone is a second-generation antidepressant belonging to the serotonin receptor antagonist and reuptake inhibitor (SARI) class, primarily used for treating major depressive disorder, with significant off-label use for insomnia due to its sedating properties. While approved for depression, trazodone is now more commonly prescribed for insomnia than for its original indication, with strong evidence supporting its efficacy for sleep disorders at lower doses than those used for depression. 1
Mechanism of Action
Trazodone works through multiple mechanisms:
- Selective serotonin reuptake inhibition (SSRI)
- Antagonism at 5-HT2A receptors (Ki = 35.6 nM)
- Antagonism at 5-HT2B (Ki = 78.4 nM) and 5-HT2C (Ki = 224 nM) receptors
- Partial agonism at 5-HT1A receptors (Ki = 118 nM)
- Antagonism at α1-adrenergic receptors (Ki = 153 nM) and α2C receptors (Ki = 155 nM) 2
This unique pharmacological profile distinguishes trazodone from pure SSRIs and contributes to both its therapeutic effects and side effect profile.
FDA-Approved Indications
- Major Depressive Disorder (MDD) in adults 2
Common Off-Label Uses
- Insomnia (primary and secondary) 3, 1
- Anxiety disorders
- Nightmare disorder in PTSD patients 3
- Agitation in dementia 3
Dosing
- Depression: 150-300 mg/day (therapeutic range) 4
- Insomnia: 25-100 mg at bedtime (lower doses) 3, 1
- Agitation/Mood stabilization: Initial dose 25 mg/day, maximum 200-400 mg/day in divided doses 3
Efficacy
For Depression
Trazodone has demonstrated comparable antidepressant efficacy to:
- Tricyclic antidepressants (TCAs)
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin-norepinephrine reuptake inhibitors (SNRIs) 5
For Insomnia
- Particularly effective for sleep disorders in depressed patients
- Often used as an alternative to benzodiazepines and Z-drugs
- Improves sleep quality, reduces sleep latency, and increases total sleep time 1
For Nightmares in PTSD
- In a retrospective study of veterans, trazodone decreased nightmare frequency from 3.3 to 1.3 nights/week at a mean dose of 212 mg/day 3
Advantages Over Other Antidepressants
- Less likely to cause sexual dysfunction compared to SSRIs 5
- Minimal weight gain 4
- Beneficial for insomnia (unlike SSRIs which can worsen sleep) 5
- Low anticholinergic activity 3, 4
Common Side Effects
Serious Adverse Effects (Less Common)
- Orthostatic hypotension (particularly in elderly or those with heart disease)
- QT interval prolongation (rare)
- Cardiac arrhythmias (rare)
- Priapism (rare but serious)
- Suicidal ideation (as with other antidepressants) 2, 4
Special Populations
Elderly
- Lower starting doses recommended
- Increased risk of orthostatic hypotension
- Generally well-tolerated compared to other antidepressants 4
Patients with Insomnia
- Lower doses (25-100 mg) are effective
- May be preferred over benzodiazepines due to less risk of dependence 1
Drug Interactions
- MAOIs: Contraindicated within 14 days of MAOI use
- CYP3A4 inhibitors: May increase trazodone levels
- Other CNS depressants: May enhance sedative effects
- Warfarin: Monitor for increased anticoagulant effects 2
Clinical Considerations
- Trazodone should be taken shortly after a meal or light snack to improve absorption
- Sedative effects make it suitable for bedtime dosing
- May be used in combination with other antidepressants to address insomnia 2
- When used for insomnia, trazodone has advantages over benzodiazepines including less risk of dependence and fewer cognitive effects 3
Monitoring
- Monitor for improvement in depressive symptoms using standardized scales
- Assess for orthostatic hypotension, especially in elderly patients
- Watch for emergence of suicidal thoughts, particularly when initiating therapy
- Regular follow-up within 1-2 weeks of initiation is recommended 3
Trazodone represents a valuable option in the psychopharmacological armamentarium, particularly for patients with depression accompanied by insomnia or for those who cannot tolerate the activating side effects of SSRIs.