Mechanism of action
Trazodone exerts its therapeutic effects through multiple receptor interactions. It functions as a serotonin reuptake inhibitor (SRI), increasing synaptic serotonin availability in the central nervous system. However, unlike selective serotonin reuptake inhibitors (SSRIs), trazodone also acts as a potent 5-HT2A receptor antagonist, which is thought to reduce anxiety, improve sleep architecture, and minimize sexual side effects commonly seen with SSRIs.
Additionally, trazodone blocks alpha-1 adrenergic receptors, leading to vasodilation and orthostatic hypotension, and antagonizes histamine H1 receptors, contributing significantly to its sedative properties. At therapeutic doses used for depression, trazodone weakly inhibits serotonin reuptake; at lower doses commonly used for insomnia, the antihistaminic and alpha-blocking effects predominate.
The active metabolite meta-chlorophenylpiperazine (mCPP) has serotonergic activity but is present in low concentrations and contributes minimally to clinical effects. The combination of serotonin modulation with sedative properties makes trazodone particularly useful in depressed patients with insomnia or anxiety.
- Trazodone is a SARI: inhibits serotonin reuptake and antagonizes 5-HT2A receptors
- Priapism is a rare but classic adverse effect; requires immediate discontinuation and urologic emergency care
- Commonly used off-label at low doses (25-100 mg) for insomnia due to H1 antagonism
- Orthostatic hypotension from alpha-1 blockade increases fall risk, especially in elderly
- Black box warning: increased suicidality risk in patients <25 years old
- Causes minimal sexual dysfunction compared to SSRIs; useful as SSRI augmentation
- Contraindicated with MAOIs (14-day washout); risk of serotonin syndrome with serotonergic drugs
- Metabolized by CYP3A4; levels increased by inhibitors (ketoconazole, ritonavir) and decreased by inducers (carbamazepine)
Indications
FDA-approved indications:
- Major depressive disorder (MDD)
Common off-label uses:
- Insomnia (primary or secondary), especially in patients with depression or substance use history
- Anxiety disorders
- Agitation in dementia
- Alcohol dependence (adjunctive)
- Fibromyalgia (adjunctive)
Trazodone is frequently prescribed off-label at low doses (25-100 mg at bedtime) for insomnia because it lacks the abuse potential and tolerance issues associated with benzodiazepines and Z-drugs. Its sedative effects make it particularly useful in patients who cannot tolerate or should avoid controlled substances. In depression, trazodone may be used as monotherapy or augmentation with SSRIs or SNRIs to address residual insomnia or sexual dysfunction.
Pharmacokinetics
- Absorption: Well absorbed orally; food increases bioavailability and reduces peak concentration variability
- Distribution: Highly protein-bound (89-95%); volume of distribution suggests extensive tissue distribution
- Metabolism: Hepatic via CYP3A4 to active metabolite mCPP and other inactive metabolites
- Elimination: Biphasic half-life of 3-6 hours for immediate-release formulations and 10-12 hours for extended-release; renal excretion (70-75% as metabolites), with smaller amounts in feces
- Time to peak: 1-2 hours (immediate-release), 4-5 hours (extended-release when taken on an empty stomach)
CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase trazodone levels significantly, while CYP3A4 inducers (e.g., carbamazepine, phenytoin) may reduce efficacy. Dosage adjustments may be required in hepatic impairment; use caution in renal impairment although specific adjustments are not well defined.
Adverse effects
Common adverse effects
- Sedation and drowsiness (very common, dose-dependent)
- Orthostatic hypotension and dizziness (due to alpha-1 blockade)
- Dry mouth (anticholinergic effect)
- Headache
- Nausea
- Blurred vision
Serious adverse effects
- Priapism: Painful erection lasting >4 hours; occurs in approximately 1 in 6,000 men. This is a urologic emergency requiring immediate intervention to prevent permanent erectile dysfunction. Trazodone should be discontinued immediately if prolonged or inappropriate erections occur.
- Cardiac arrhythmias: QT prolongation, ventricular arrhythmias (including torsades de pointes), especially in predisposed patients or those on multiple QT-prolonging drugs
- Serotonin syndrome: When combined with other serotonergic agents (SSRIs, SNRIs, MAOIs, linezolid, tramadol)
- Orthostatic hypotension with syncope: Risk of falls, particularly in elderly patients
- Hyponatremia/SIADH: More common in elderly patients
Other considerations
- Unlike SSRIs, trazodone causes minimal sexual dysfunction, making it useful as augmentation in SSRI-treated patients
- Weight gain is uncommon compared to other antidepressants
- Withdrawal syndrome can occur with abrupt discontinuation after prolonged use, though less severe than with SSRIs
Contraindications and warnings
Contraindications:
- Hypersensitivity to trazodone
- Concurrent use or within 14 days of MAO inhibitor therapy (risk of serotonin syndrome)
- Acute recovery phase following myocardial infarction
Black box warning:
- Suicidality in children, adolescents, and young adults: Like all antidepressants, trazodone carries an FDA black box warning for increased risk of suicidal thinking and behavior in patients under age 25, especially during the initial months of treatment or with dose changes. Close monitoring is essential.
Warnings and precautions:
- Cardiac disease: Use with caution; can prolong QT interval and cause arrhythmias
- Priapism risk: Educate all male patients about this risk and the need for immediate medical attention
- Bleeding risk: Serotonergic drugs may increase bleeding risk, especially when combined with NSAIDs, aspirin, or anticoagulants
- Angle-closure glaucoma: Pupillary dilation may trigger an attack in patients with anatomically narrow angles
- Bipolar disorder: May precipitate manic or hypomanic episodes; use with mood stabilizers if needed
- Hepatic/renal impairment: Reduce dose and monitor closely
- Elderly patients: Increased risk of orthostatic hypotension, falls, cognitive impairment, and hyponatremia
- Pregnancy: Category C; limited human data; use only if benefits outweigh risks
- Lactation: Excreted in breast milk; consider risks and benefits
Drug interactions
Major interactions:
- MAO inhibitors: Contraindicated; risk of serotonin syndrome with hypertensive crisis. Allow 14-day washout period.
- Other serotonergic agents (SSRIs, SNRIs, TCAs, tramadol, triptans, St. John's wort, linezolid): Increased risk of serotonin syndrome
- CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, grapefruit juice): Increase trazodone levels, enhance sedation and hypotension
- CYP3A4 inducers (carbamazepine, phenytoin, rifampin): Decrease trazodone efficacy
- CNS depressants (benzodiazepines, opioids, alcohol, barbiturates): Additive sedation and respiratory depression
- Antihypertensives: Enhanced hypotensive effects due to alpha-1 blockade
- QT-prolonging drugs (antiarrhythmics, antipsychotics, macrolides, fluoroquinolones): Increased risk of torsades de pointes
Moderate interactions:
- Anticoagulants and antiplatelet agents (warfarin, aspirin, NSAIDs): Increased bleeding risk
- Digoxin and phenytoin: Trazodone may increase serum levels; monitor closely
- Phosphodiesterase-5 inhibitors (sildenafil): May enhance hypotensive effects
Patients should be counseled to avoid alcohol, which potentiates sedation and orthostatic hypotension.
Clinical pearls
- Low-dose trazodone (25-100 mg) is one of the most commonly prescribed medications for insomnia in the United States, despite this being an off-label use. It is favored because it is non-controlled, non-addictive, and does not cause rebound insomnia.
- Trazodone is often used to augment SSRI therapy in patients with major depression who experience sexual dysfunction or persistent insomnia on SSRIs. The 5-HT2A antagonism may counteract SSRI-induced sexual side effects.
- Priapism is the classic high-yield adverse effect for exams. It occurs in approximately 1 in 6,000 male patients and requires emergency urologic intervention. Any episode of prolonged erection warrants immediate discontinuation.
- Taking trazodone with food reduces the peak plasma concentration spikes that contribute to dizziness and orthostatic hypotension, improving tolerability.
- Trazodone is not a first-line antidepressant due to its side-effect profile (especially sedation and orthostatic hypotension), but it remains useful in specific populations, particularly those with comorbid insomnia.
- Orthostatic hypotension is particularly problematic in the elderly, increasing fall risk and associated morbidity. Start with low doses and titrate slowly in older adults.
- Serotonin syndrome can occur when trazodone is combined with other serotonergic agents. Classic triad includes autonomic instability, neuromuscular abnormalities (hyperreflexia, clonus), and altered mental status.
- Trazodone does not cause significant weight gain or metabolic syndrome, unlike many other antidepressants (e.g., mirtazapine, TCAs, some atypical antipsychotics).
- For exam purposes, remember trazodone for depression with insomnia, and always associate it with priapism and orthostatic hypotension.
TrazoD-ONE: D for Depression and Drowsiness, ONE serious risk = priapism (prolonged erection)
Practice questions
1. A 68-year-old man with major depressive disorder is started on trazodone 50 mg at bedtime for depression with insomnia. Three days later, he presents to the emergency department after falling at home. His blood pressure is 138/82 mmHg supine and 98/60 mmHg standing. He reports feeling dizzy when he stands up quickly. Which property of trazodone is most likely responsible for this patient's presentation?
2. A 35-year-old man with depression treated with sertraline 100 mg daily reports persistent insomnia despite adequate response of his mood symptoms. His psychiatrist adds trazodone 50 mg at bedtime. Two weeks later, the patient develops agitation, diaphoresis, tremor, hyperreflexia, and confusion. His temperature is 38.9°C (102°F). Which of the following is the most likely diagnosis?
3. A 28-year-old man presents to the emergency department with a painful erection that has persisted for 6 hours. He reports starting a new medication for depression and insomnia one week ago. Physical examination confirms a rigid, painful erection. Which of the following medications is he most likely taking?
Frequently asked questions
How does trazodone work?
Trazodone works by inhibiting serotonin reuptake at presynaptic neurons and blocking postsynaptic 5-HT2A serotonin receptors, which increases serotonin neurotransmission while reducing anxiety and sexual side effects. It also antagonizes alpha-1 adrenergic and histamine H1 receptors, producing sedation and orthostatic hypotension. At lower doses used for insomnia, the antihistaminic effects predominate, while higher doses provide antidepressant activity through serotonin modulation.
What are the side effects of trazodone?
Common side effects include sedation, orthostatic hypotension, dizziness, dry mouth, headache, and nausea. Serious adverse effects include priapism (prolonged painful erection requiring emergency treatment), cardiac arrhythmias with QT prolongation, serotonin syndrome when combined with other serotonergic drugs, and syncope from severe orthostatic hypotension. Elderly patients are at increased risk for falls, hyponatremia, and cognitive effects. Unlike SSRIs, trazodone causes minimal sexual dysfunction.
Is trazodone a controlled substance?
No, trazodone is not a controlled substance. It has no abuse potential and is not classified as a scheduled drug by the DEA. This makes it a preferred option for treating insomnia in patients with substance use history or those at risk for benzodiazepine dependence. However, it still requires a prescription and should be used under medical supervision due to potential serious adverse effects like priapism and orthostatic hypotension.
Trazodone vs mirtazapine — what is the difference?
Both are sedating antidepressants used for depression with insomnia, but they have different mechanisms. Trazodone is a SARI that inhibits serotonin reuptake and blocks 5-HT2A receptors, while mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) that blocks alpha-2 adrenergic and 5-HT2/5-HT3 receptors. Mirtazapine commonly causes weight gain and increased appetite, whereas trazodone causes more orthostatic hypotension. Trazodone is associated with priapism; mirtazapine is not. Both are non-controlled alternatives to benzodiazepines for insomnia.
Can trazodone cause priapism?
Yes, trazodone can cause priapism, a prolonged and painful erection lasting more than 4 hours. This occurs in approximately 1 in 6,000 male patients and is considered a urologic emergency because it can lead to permanent erectile dysfunction if not treated promptly. The mechanism involves alpha-1 adrenergic blockade affecting penile vascular smooth muscle. All male patients should be counseled about this risk and instructed to seek immediate medical attention if they experience prolonged or inappropriate erections. Trazodone must be discontinued immediately if priapism occurs.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: N06AX05
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.