What class of antidepressant medication is Trazodone (serotonin antagonist and reuptake inhibitor)?

Trazodone Drug Classification

Trazodone is classified as a Serotonin Antagonist and Reuptake Inhibitor (SARI), which is distinct from other major antidepressant classes. 1, 2

Pharmacological Mechanism

• Trazodone has a unique dual mechanism of action as both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist 1
• The drug selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors 1
• Trazodone also antagonizes several other receptors including 5-HT2B, 5-HT2C, α1A, α2C, and acts as a partial agonist at 5-HT1A receptors 1, 3
• This complex pharmacodynamic profile distinguishes trazodone from other antidepressant classes such as SSRIs, SNRIs, and tricyclic antidepressants 2, 4

Classification in Treatment Guidelines

• Trazodone is categorized as a second-generation antidepressant in clinical practice guidelines, alongside SSRIs, SNRIs, and SSNRIs 5
• Unlike first-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors), second-generation antidepressants like trazodone have similar efficacy but lower toxicity in overdose 5
• In insomnia treatment guidelines, trazodone is specifically classified as a "sedating low-dose antidepressant" that may be considered when insomnia is accompanied by comorbid depression 5

Clinical Applications

• Trazodone's primary FDA-approved indication is for major depressive disorder (MDD) in adults 1, 3
• Due to its sedating properties, trazodone is commonly prescribed off-label at lower doses for insomnia 5, 2
• Guidelines note that trazodone has little or no anticholinergic activity compared to other antidepressants like doxepin and amitriptyline 5
• Unlike other antidepressants, trazodone is not associated with sexual dysfunction or weight gain, which are common side effects of SSRIs 2, 3

Important Distinctions from Other Antidepressants

• Trazodone's classification as a SARI distinguishes it from SSRIs, SNRIs, and other antidepressant classes 2, 6
• While SSRIs primarily work by inhibiting serotonin reuptake, trazodone's additional antagonism of 5-HT2A and 5-HT2C receptors contributes to its unique therapeutic profile 6, 4
• This receptor profile explains why trazodone lacks some common SSRI side effects (like sexual dysfunction and insomnia) but has increased sedative properties 2, 3

Common Side Effects and Safety Considerations

• The most common adverse effects of trazodone include drowsiness/sedation, headache, dizziness, and dry mouth 2, 3
• Other potential adverse effects include orthostatic hypotension (particularly in elderly patients), QT interval prolongation, and rare occurrences of priapism 2, 3
• Trazodone is metabolized primarily by CYP3A4 and CYP2D6 enzymes, requiring dose adjustments when used with medications affecting these enzymes 6

In summary, trazodone belongs to the Serotonin Antagonist and Reuptake Inhibitor (SARI) class of antidepressants, with a unique pharmacological profile that distinguishes it from other antidepressant classes such as SSRIs, SNRIs, and tricyclic antidepressants.