What type of medication is trazodone?

Trazodone: A Second-Generation Antidepressant with Sedative Properties

Trazodone is a second-generation antidepressant classified as a Serotonin Receptor Antagonist and Reuptake Inhibitor (SARI) that is FDA-approved for the treatment of major depressive disorder in adults, but is also commonly used off-label as a hypnotic for insomnia due to its sedative properties. 1

Pharmacological Classification and Mechanism of Action

• Trazodone belongs to the class of second-generation antidepressants known as Serotonin Receptor Antagonists and Reuptake Inhibitors (SARIs) 2, 3
• Its mechanism of action involves both selective serotonin reuptake inhibition and antagonism at 5-HT2A and 5-HT2C receptors 4, 5
• Trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors 4
• It also antagonizes alpha 1-adrenergic receptors, which may contribute to its side effect of postural hypotension 4
• Trazodone is metabolized via CYP3A4 to an active metabolite, m-chlorophenylpiperazine (mCPP), which has more potent serotonin reuptake inhibition than the parent compound 5

Clinical Uses

FDA-Approved Indication

• Trazodone is FDA-approved for the treatment of major depressive disorder (MDD) in adults 4
• Therapeutic antidepressant dosages typically range from 150-300 mg/day 3, 6

Common Off-Label Uses

• Low-dose trazodone (typically 25-100 mg) is one of the most commonly prescribed medications for insomnia, particularly in patients with depression 1
• Used as a sedating agent for sleep disturbances in various conditions, including PTSD-related nightmares 1
• May be used as an adjunctive treatment for anxiety symptoms associated with depression 1

Advantages Over Other Antidepressants

• Unlike many SSRIs, trazodone does not typically cause insomnia, anxiety, or sexual dysfunction 2, 6
• Has minimal anticholinergic activity compared to tricyclic antidepressants like doxepin and amitriptyline 1
• Lower toxicity in overdose compared to first-generation antidepressants (tricyclics and MAOIs) 1
• Particularly beneficial for patients with depression and comorbid insomnia 6

Side Effects and Safety Considerations

• Most common adverse effects include drowsiness/sedation, headache, dizziness, and dry mouth 2, 3
• Other potential side effects include orthostatic hypotension (particularly in elderly patients or those with heart disease) 2
• Rare but serious adverse effects may include:
  • QT interval prolongation and cardiac arrhythmias 2, 3
  • Priapism (rare but requires immediate medical attention) 1, 3
  • Suicidal ideation (particularly in young adults, as with all antidepressants) 4

Formulations and Dosing

• Available as immediate-release tablets 4
• A prolonged-release once-daily formulation (TzCOAD) has been developed to potentially improve tolerability 2
• For depression: typically dosed at 150-300 mg/day (maximum outpatient dose 400 mg/day) 5
• For insomnia (off-label): typically dosed at lower ranges (25-100 mg) 1, 5
• Should be taken shortly after a meal or light snack to improve absorption and reduce side effects 4

Comparison to Other Antidepressant Classes

• Trazodone is categorized as a second-generation antidepressant along with SSRIs, SNRIs, and other novel agents 1
• Studies have shown comparable antidepressant efficacy to other classes including tricyclic antidepressants, SSRIs, and SNRIs 2
• Unlike SSRIs, trazodone has a low risk of causing insomnia, anxiety, or sexual dysfunction 6
• Unlike many other antidepressants, trazodone has minimal impact on weight gain 3, 6

Clinical Pearls

• Trazodone's onset of action for depression is typically 1-2 weeks, with full efficacy at 4-6 weeks 5
• When used for insomnia, effects may be noticed on the first night of treatment 5
• The sedative effects of trazodone occur at lower doses than those required for antidepressant effects 1, 5
• Low-dose trazodone for insomnia does not constitute adequate treatment for major depression 1
• Trazodone should not be abruptly discontinued; gradual tapering is recommended 4

In summary, trazodone is a versatile second-generation antidepressant with a unique pharmacological profile that makes it particularly useful for patients with depression and comorbid insomnia. Its sedative properties have led to widespread off-label use as a hypnotic, while its favorable side effect profile regarding sexual function and weight gain distinguishes it from many other antidepressants.