What is the drug class and mechanism of action of Trazodone (serotonin antagonist and reuptake inhibitor)?

Trazodone: Drug Class and Mechanism of Action

Drug Classification

Trazodone is classified as a Serotonin Antagonist and Reuptake Inhibitor (SARI), a unique antidepressant class distinct from SSRIs, SNRIs, and tricyclic antidepressants. 1, 2, 3

• The SARI classification reflects trazodone's dual pharmacological actions that differentiate it from other antidepressant classes 2, 3
• It is a triazolopyridine derivative, structurally unrelated to other major antidepressant families 2, 4

Mechanism of Action

Primary Pharmacological Actions

Trazodone's antidepressant effect results from two principal mechanisms: selective serotonin reuptake inhibition combined with potent 5-HT2A receptor antagonism. 1, 5

The FDA label explicitly states that trazodone's mechanism is "related to its enhancement of serotonergic activity in the CNS" through being "both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist," though the net effect on serotonergic transmission and its role in antidepressant efficacy remains incompletely understood 1.

Specific Receptor Binding Profile

Trazodone demonstrates the following receptor affinities based on preclinical studies 1:

• 5-HT2A antagonism (Ki = 35.6 nM) - the most potent action and likely primary mechanism 1, 5
• Serotonin reuptake inhibition (Ki = 367 nM) - weaker than its receptor antagonism 1
• 5-HT2B antagonism (Ki = 78.4 nM) 1
• 5-HT2C antagonism (Ki = 224 nM) 1, 4
• 5-HT1A partial agonism (Ki = 118 nM) 1
• Alpha-1 adrenergic antagonism (Ki = 153 nM) - responsible for orthostatic hypotension risk 1, 2
• Alpha-2C adrenergic antagonism (Ki = 155 nM) 1, 4
• H1 histamine receptor antagonism - contributes to sedation 4, 6

Active Metabolite

• Trazodone undergoes oxidative cleavage via CYP3A4 to form m-chlorophenylpiperazine (mCPP), an active metabolite that is a more potent serotonin reuptake inhibitor than the parent compound 7, 1, 6
• Less than 1% of trazodone is excreted unchanged, indicating extensive metabolism 1

Clinical Implications of Mechanism

Advantages Over SSRIs

The American College of Physicians notes that trazodone's SARI mechanism "may overcome the tolerability issues that are often associated with" SSRIs, specifically avoiding common SSRI side effects of insomnia, anxiety, and sexual dysfunction 2, 3.

• The 5-HT2A antagonism counteracts the sexual dysfunction, insomnia, and anxiety that result from excessive 5-HT2A stimulation seen with pure SSRIs 2, 3
• This makes trazodone particularly useful for depressed patients with prominent insomnia or sexual dysfunction from prior SSRI trials 3, 6

Distinguishing SARI from SSRI Action

The critical distinction is that trazodone's most potent action is 5-HT2A receptor antagonism (Ki = 35.6 nM), not serotonin reuptake inhibition (Ki = 367 nM), which is the opposite profile of fluoxetine and other SSRIs. 1, 5

• This explains why trazodone is effective for depression but ineffective for obsessive-compulsive disorder and panic disorder, conditions where pure serotonin reuptake inhibition (as with fluoxetine) is required 5
• The receptor antagonism likely mediates trazodone's antidepressant effect, while the reuptake inhibition may be secondary 5

Sedation Mechanism

• The pronounced sedation results from combined H1 histamine receptor antagonism, 5-HT2A antagonism, and alpha-1 adrenergic blockade 4, 6
• The American Academy of Sleep Medicine reports that somnolence/sedation with trazodone occurs at higher rates than with bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine 8

Cardiovascular Effects

• Alpha-1 adrenergic receptor antagonism explains the risk of postural hypotension, particularly in elderly patients or those with cardiovascular disease 1, 2, 3
• QT interval prolongation and rare torsade de pointes can occur, though the mechanism is not fully elucidated 8, 2

Comparison to Other Antidepressant Classes

Trazodone differs fundamentally from 9:

• SSRIs/SNRIs: Trazodone was shown ineffective for low back pain, unlike duloxetine (an SNRI), because its primary mechanism is receptor antagonism rather than pure reuptake inhibition 9
• Tramadol/Tapentadol: These are weak opioid agonists with serotonin/norepinephrine reuptake inhibition, fundamentally different from trazodone's SARI mechanism 9
• Tricyclic antidepressants: Trazodone has minimal anticholinergic activity compared to TCAs, making it better tolerated in elderly patients 8, 2