Trazodone Mechanism of Action
Trazodone works through dual serotonergic mechanisms: it blocks serotonin reuptake at the presynaptic transporter (SERT) and simultaneously antagonizes postsynaptic 5-HT2A receptors, with the net effect on serotonergic transmission being the key to its antidepressant and anxiolytic properties. 1
Primary Pharmacological Mechanisms
Serotonergic Activity
- Trazodone selectively inhibits the serotonin transporter (SERT) with a binding affinity (Ki) of 367 nM, blocking reuptake of serotonin at the synaptic cleft and increasing serotonin availability 1
- Acts as a potent antagonist at 5-HT2A receptors (Ki = 35.6 nM), which is its strongest receptor binding action 1
- Also antagonizes 5-HT2B receptors (Ki = 78.4 nM) and 5-HT2C receptors (Ki = 224 nM) 1
- Functions as a partial agonist at 5-HT1A receptors (Ki = 118 nM), contributing to anxiolytic effects 1
The FDA explicitly states that the net result of this dual action on serotonergic transmission and its role in trazodone's antidepressant effect remains unknown, distinguishing it from pure SSRIs 1. This unique profile explains why trazodone avoids common SSRI side effects like sexual dysfunction, as the 5-HT2A antagonism counteracts the negative sexual effects of serotonin reuptake inhibition 2, 3.
Adrenergic Activity
- Antagonizes alpha-1 adrenergic receptors (Ki = 153 nM), which explains the risk of postural hypotension, particularly in elderly patients 1, 4
- Blocks alpha-2C adrenergic receptors (Ki = 155 nM) 1
Active Metabolite Formation
- 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 4, 1
- Less than 1% of an oral dose is excreted unchanged, indicating extensive metabolism 1
Clinical Implications of This Mechanism
Advantages Over Other Antidepressants
- Trazodone fundamentally differs from SSRIs/SNRIs because its primary mechanism is receptor antagonism combined with reuptake inhibition, rather than pure reuptake inhibition alone 4
- The 5-HT2A antagonism prevents SSRI-associated side effects including anxiety, insomnia, and sexual dysfunction that commonly occur with pure serotonergic agents 2
- Minimal anticholinergic activity compared to tricyclic antidepressants, making it better tolerated in elderly patients 4
Sedation Profile
- The American Academy of Sleep Medicine reports that somnolence/sedation with trazodone occurs at higher rates than with bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine 4, 5
- This pronounced sedation results from the combination of 5-HT2A antagonism, alpha-1 blockade, and H1 histamine receptor antagonism 6
Cardiovascular Considerations
- Alpha-1 adrenergic receptor antagonism explains the risk of postural hypotension, particularly problematic in elderly patients or those with cardiovascular disease 4
- QT interval prolongation and rare torsade de pointes can occur, though this is relatively uncommon 5, 4
Comparison to Related Mechanisms
Unlike SSRIs (which only block serotonin reuptake), trazodone's dual mechanism of reuptake inhibition plus 5-HT2A antagonism creates a distinct pharmacological profile 7. This differs fundamentally from SNRIs like venlafaxine and duloxetine, which inhibit both serotonin and norepinephrine reuptake without the receptor antagonism 7.
The mechanism also differs completely from tramadol/tapentadol, which are weak opioid agonists with serotonin/norepinephrine reuptake inhibition 4, 7.
Critical Pitfalls
- Do not confuse trazodone's classification as a "serotonin antagonist and reuptake inhibitor" (SARI) with pure SSRIs - the receptor antagonism component is therapeutically essential and explains its unique side effect profile 6, 2
- The CYP3A4 metabolism pathway means strong CYP3A4 inhibitors or inducers will significantly alter trazodone levels, requiring dose adjustments 1, 6
- Protein binding is 89-95%, which can lead to drug interactions with other highly protein-bound medications 1