Introduction
Trazodone hydrochloride is an antidepressant medication belonging to the serotonin antagonist and reuptake inhibitor (SARI) class. Originally developed in the 1960s and FDA-approved in 1981, trazodone has established itself as a versatile psychotropic agent with both antidepressant and sedative properties. While primarily indicated for major depressive disorder, its off-label use for insomnia has become widespread in clinical practice.
Mechanism of Action
Trazodone exerts its therapeutic effects through multiple mechanisms. It primarily acts as a serotonin receptor antagonist and reuptake inhibitor (SARI), specifically:
- Potent antagonism of 5-HT2A and 5-HT2C receptors
- Moderate inhibition of serotonin reuptake
- Antagonism of α1-adrenergic receptors (contributing to sedative effects and orthostatic hypotension)
- Weak histamine H1 receptor blockade (contributing to sedative effects)
Unlike many antidepressants, trazodone has minimal affinity for muscarinic cholinergic receptors, resulting in a lower incidence of anticholinergic side effects.
Indications
FDA-approved indications:- Major depressive disorder (MDD)
- Insomnia (particularly sleep maintenance insomnia)
- Anxiety disorders
- Adjuvant therapy in chronic pain conditions
- Augmentation strategy in treatment-resistant depression
Dosage and Administration
Depression:- Initial dose: 150 mg/day in divided doses
- May increase by 50 mg/day every 3-4 days
- Maximum dose: 400 mg/day for outpatients, 600 mg/day for inpatients
- Usually administered in divided doses with larger portion at bedtime
- Typical dose: 25-100 mg at bedtime
- Lower doses (25-50 mg) often effective for sleep initiation
- Geriatric patients: Initiate with lower doses (25-50 mg at bedtime)
- Hepatic impairment: Reduce dose by 25-50%
- Renal impairment: Use with caution; no specific dosage adjustment recommended
- CYP2D6 poor metabolizers: Consider lower starting doses
Pharmacokinetics
Absorption: Well absorbed orally, bioavailability approximately 85% Distribution: Volume of distribution ~1.5 L/kg; 89-95% protein bound Metabolism: Extensive hepatic metabolism via CYP3A4 (major) and CYP2D6 (minor) Elimination: Half-life 5-9 hours (biphasic elimination); primarily renal excretion (75%) with some fecal elimination Active metabolite: m-chlorophenylpiperazine (mCPP) with serotonergic activityContraindications
- Hypersensitivity to trazodone or any component of the formulation
- Concomitant use with MAOIs or within 14 days of MAOI therapy
- Patients who have experienced priapism with previous trazodone use
Warnings and Precautions
Boxed Warning: Suicidal thoughts and behaviors in children, adolescents, and young adults Cardiovascular: Risk of QT prolongation; use caution in patients with cardiac disease Priapism: Requires immediate medical attention (reported incidence 1:6000 men) Orthostatic hypotension: Particularly in elderly patients Serotonin syndrome: Risk increased with concomitant serotonergic drugs Activation of mania/hypomania: In patients with bipolar disorder Discontinuation syndrome: Taper gradually when discontinuing after prolonged use CNS depression: May impair mental/physical abilities required for hazardous tasksDrug Interactions
Major interactions:- MAOIs: Risk of serotonin syndrome (contraindicated)
- Strong CYP3A4 inhibitors (ketoconazole, ritonavir): Increase trazodone levels 2-4 fold
- Other serotonergic agents: Increased serotonin syndrome risk
- CNS depressants: Additive sedation
- Digoxin, phenytoin: Trazodone may increase levels
- Warfarin: May increase anticoagulant effect
- Antihypertensives: Additive hypotensive effects
- Dopamine antagonists: Increased risk of extrapyramidal symptoms
Adverse Effects
Common (>10%):- Sedation/somnolence (40%)
- Dizziness/lightheadedness (20%)
- Dry mouth (15%)
- Headache (10%)
- Nausea (10%)
- Constipation
- Blurred vision
- Fatigue
- Orthostatic hypotension
- Confusion (especially elderly)
- Priapism (medical emergency)
- Serotonin syndrome
- Suicidal ideation
- QT prolongation
- Arrhythmias
- Hyponatremia/SIADH
- Mania/hypomania
Monitoring Parameters
Baseline:- Comprehensive metabolic panel
- ECG (if cardiac risk factors present)
- Blood pressure (supine and standing)
- Depression severity assessment
- Therapeutic response and side effects at 2-4 week intervals
- Blood pressure monitoring, especially during dose titration
- Mood assessment for emerging suicidal thoughts
- Signs of serotonin syndrome
- Priapism screening in male patients
- Periodic liver function tests
- Weight changes
- Continued assessment of depression symptoms
Patient Education
Key points to discuss:- Take with food to minimize nausea
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying position to prevent dizziness
- Report persistent penile erections immediately (medical emergency)
- Do not stop abruptly without medical supervision
- May take 2-4 weeks for full antidepressant effect
- Sedation usually improves within first few weeks
- Use effective contraception; discuss pregnancy plans with provider
- Notify all healthcare providers of trazodone use
- Store at room temperature
- Keep in original container away from moisture
- Dispose of unused medication properly
References
1. FDA Prescribing Information: Trazodone Hydrochloride Tablets 2. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. Cambridge University Press; 2013. 3. Schatzberg AF, Nemeroff CB. The American Psychiatric Association Publishing Textbook of Psychopharmacology. 5th ed. American Psychiatric Association Publishing; 2017. 4. Jaffer KY, et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci. 2017;14(7-8):24-34. 5. Jayesuria P, et al. Trazodone: a review of its safety in the treatment of depression. Drug Saf. 2016;39(1):43-55. 6. Micromedex Solutions. Trazodone monograph. Truven Health Analytics; 2023. 7. Lexicomp Online. Trazodone monograph. Wolters Kluwer; 2023.
Note: This monograph provides general information and should not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.