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Trazodone

Trazodone hydrochloride

Desyrel Oleptro Trittico Trazorel Molipaxin

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Updated: December 06, 2025

Overview

Trazodone is an antidepressant medication primarily used to treat major depressive disorder (MDD). It belongs to the serotonin antagonist and reuptake inhibitor (SARI) class, with unique multimodal pharmacological actions. Originally developed in the 1960s, trazodone has gained additional popularity for off-label use in insomnia management due to its sedative properties. Unlike many antidepressants, it generally has minimal anticholinergic effects but carries specific risks including priapism and orthostatic hypotension.

Drug Class

Serotonin antagonist and reuptake inhibitor (SARI) Second-generation antidepressant Phenylpiperazine compound

Mechanism of Action

Multimodal mechanism involving: • Potent antagonism of 5-HT2A and 5-HT2C receptors • Moderate inhibition of serotonin reuptake (SERT) • Weak α1-adrenergic receptor blockade • Moderate histamine H1 receptor antagonism • Weak serotonin 5-HT1A receptor agonism This combination enhances serotonergic transmission while blocking specific serotonin receptors, resulting in antidepressant and sedative effects.

Pharmacokinetics

Absorption: Well absorbed orally (80-85%), food increases bioavailability by 20% Distribution: Extensive tissue distribution, Vd ~0.8-1.4 L/kg, 89-95% protein bound Metabolism: Hepatic via CYP3A4 to active metabolite m-chlorophenylpiperazine (mCPP) Excretion: Primarily renal (70-75%), 20% fecal Half-life: Biphasic - initial 3-6 hours, terminal 5-9 hours (prolonged in elderly)

Pharmacodynamics

Central nervous system: • Antidepressant effects via serotonergic modulation • Sedation through H1 receptor antagonism Cardiovascular system: • α1-blockade causes orthostatic hypotension Genitourinary system: • 5-HT2A/α1 blockade may cause priapism Therapeutic effects typically appear within 1-2 weeks, with full effect at 4-6 weeks.

Indications

• Major depressive disorder (FDA-approved) • Insomnia (off-label, particularly for sleep maintenance) • Anxiety disorders (off-label adjunct) • Augmentation in treatment-resistant depression • Post-traumatic stress disorder (PTSD) sleep disturbances (off-label)

Contraindications

Absolute: • Hypersensitivity to trazodone • Concurrent MAOI use or within 14 days • History of priapism Relative: • Recent myocardial infarction • Cardiac arrhythmias • Severe hepatic impairment • Angle-closure glaucoma • History of bipolar disorder

Dosage & Administration

Major depressive disorder: Initial: 150 mg/day in divided doses Maintenance: 150-400 mg/day (max 600 mg/day) Dose increments: Increase by 50 mg/day every 3-7 days Insomnia (off-label): 25-100 mg at bedtime Geriatric patients: Start with 25-50 mg at bedtime Administration: Take shortly after meal to reduce dizziness

Special Populations

Pediatric: Not FDA-approved <18 years; limited data Geriatric: Start low (25-50 mg), increased fall risk Renal impairment: CrCl <30 mL/min - reduce dose by 50% Hepatic impairment: Child-Pugh B/C - reduce dose by 50%

Adverse Effects

Common (>10%): • Sedation/somnolence (40%) • Dry mouth (25%) • Dizziness/lightheadedness (20%) • Nausea (15%) Serious (<1%): • Priapism (1:6000 males) • Serotonin syndrome • QT prolongation • Suicidal ideation • Orthostatic hypotension

Drug Interactions

• MAOIs: Risk of serotonin syndrome • CYP3A4 inhibitors (ketoconazole, ritonavir): Increase trazodone levels • CYP3A4 inducers (carbamazepine): Decrease trazodone levels • CNS depressants: Additive sedation • Warfarin: Altered anticoagulation • Digoxin: Increased digoxin levels

Warnings & Precautions

• Black box warning: Increased risk of suicidal thinking/behavior in children/young adults • Priapism risk (medical emergency) • QT prolongation risk, especially with preexisting cardiac conditions • Serotonin syndrome potential • Orthostatic hypotension monitoring • Activation of mania/hypomania

Pregnancy & Lactation

Pregnancy: FDA Category C • Animal studies show adverse effects • Limited human data - use only if benefit justifies risk Lactation: Excreted in breast milk • Infant plasma levels ~6% of maternal • Consider risk/benefit, monitor infant for sedation

Monitoring Parameters

• Mental status/suicidal ideation • Blood pressure (orthostatic changes) • Liver function tests (baseline and periodic) • ECG in high-risk patients • Sexual function assessment • Signs of serotonin syndrome • Therapeutic response (4-6 weeks)

Patient Counseling

• Take with food to reduce dizziness • Avoid alcohol and CNS depressants • Report persistent erections (>4 hours) immediately • Rise slowly from sitting/lying position • Do not stop abruptly • May cause daytime drowsiness • Therapeutic delay: 1-4 weeks for antidepressant effect

Storage & Stability

• Store at 20-25°C (68-77°F) • Protect from moisture • Keep in original container • Stable in oral suspension for 14 days refrigerated

Clinical Pearls

• Lower doses (25-150 mg) often sufficient for insomnia • Morning dosing may reduce daytime sedation • Consider splitting doses for better GI tolerance • Gradual taper recommended (reduce by 25-50 mg weekly) • Effective alternative for patients with SSRI sexual dysfunction • Monitor for serotonin syndrome when combining with other serotonergic agents

References

• UpToDate: Trazodone Drug Information • FDA Prescribing Information: Desyrel (trazodone hydrochloride) • Stahl SM. Essential Psychopharmacology (4th ed) • Goodman & Gilman's: The Pharmacological Basis of Therapeutics (14th ed) • Fagiolini A, et al. CNS Drugs. 2012;26(12):1033-49