Trazodone

• Major Depressive Disorder
• Insomnia
• Anxiety Disorders
• Sleep Disorders

Trazodone is a serotonin receptor antagonist and reuptake inhibitor (SARI) primarily used to treat major depressive disorder. It is also widely used off-label for insomnia due to its sedating properties at lower doses.

Mechanism of Action

Trazodone has multiple mechanisms:

• Serotonin reuptake inhibition: Blocks SERT, increasing synaptic serotonin
• 5-HT2A receptor antagonism: Blocks postsynaptic serotonin receptors
• 5-HT2C receptor antagonism: May contribute to antidepressant and weight effects
• Alpha-1 adrenergic antagonism: Contributes to sedation and orthostatic hypotension
• Histamine H1 antagonism: Contributes to sedation

The 5-HT2A antagonism combined with serotonin reuptake inhibition distinguishes SARIs from SSRIs.

Available Formulations

• Immediate-release tablets: 50 mg, 100 mg, 150 mg, 300 mg
• Extended-release tablets (Oleptro): 150 mg, 300 mg

Medical Uses

FDA-Approved Indication:

• Major depressive disorder

Common Off-Label Uses:

• Insomnia (most common off-label use)
• Anxiety disorders
• Fibromyalgia

Dosing Guidelines

Depression (Immediate-Release):

• Initial: 150 mg/day in divided doses
• Increase by 50 mg/day every 3-4 days
• Usual range: 150-400 mg/day in divided doses
• Maximum: 400 mg/day (outpatient), 600 mg/day (inpatient)

Depression (Extended-Release):

• Initial: 150 mg once daily at bedtime
• Increase by 75 mg every 3 days
• Maximum: 375 mg/day

Insomnia (Off-Label):

• 25-100 mg at bedtime
• Lower doses provide sedation without full antidepressant effects

Important Safety Information

Black Box Warning:

• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders

Contraindications:

• Concurrent use of MAOIs or within 14 days
• Known hypersensitivity to trazodone

Warnings and Precautions:

• Serotonin syndrome: Risk with other serotonergic drugs
• Priapism: Rare but serious; requires immediate medical attention
• Orthostatic hypotension: May cause falls, especially in elderly
• Cardiac arrhythmias: Use with caution in patients with cardiac disease
• Bleeding risk: May increase bleeding events
• Activation of mania/hypomania: Use with caution in bipolar disorder

Drug Interactions

• MAOIs: Contraindicated; risk of serotonin syndrome
• Serotonergic drugs (SSRIs, SNRIs, triptans, tramadol): Increased serotonin syndrome risk
• CYP3A4 inhibitors (ketoconazole, ritonavir): May increase trazodone levels
• CYP3A4 inducers (carbamazepine, phenytoin): May decrease trazodone levels
• CNS depressants (alcohol, benzodiazepines): Additive sedation
• Digoxin, phenytoin: Trazodone may increase their serum levels
• Warfarin: Monitor INR; may increase or decrease anticoagulation

Special Populations

• Hepatic Impairment: Use with caution; lower doses may be needed
• Renal Impairment: Generally no adjustment needed
• Elderly: Start with lower doses due to increased sensitivity and orthostatic hypotension risk
• Pregnancy: Limited data; use only if benefit outweighs risk
• Lactation: Present in milk; weigh benefits and risks
• Pediatric: Not approved; black box warning applies