Mechanism of Action: How Trazodone Causes Sleepiness
Trazodone induces sleepiness primarily through antagonism of 5-HT2A serotonin receptors, with additional contributions from alpha-1 adrenergic receptor blockade and antihistaminic effects. 1
Primary Mechanism: Serotonin Receptor Antagonism
The sedating effects of trazodone are predominantly mediated through its potent antagonism at 5-HT2A receptors (Ki = 35.6 nM), which is distinct from its antidepressant mechanism. 1 This 5-HT2 receptor blockade is the main pathway through which trazodone promotes sleep, particularly by increasing slow-wave (deep) sleep duration. 2
Dual serotonergic action: Trazodone functions as both a selective serotonin reuptake inhibitor (SSRI) with Ki = 367 nM and a 5-HT2 receptor antagonist, but the antagonism at 5-HT2A receptors is significantly more potent and primarily responsible for sedation. 1
Additional serotonin receptor effects: Trazodone also antagonizes 5-HT2B (Ki = 78.4 nM) and 5-HT2C (Ki = 224 nM) receptors, and acts as a partial agonist at 5-HT1A receptors (Ki = 118 nM), which may contribute to its overall sleep-promoting effects. 1
Secondary Mechanisms Contributing to Sedation
Alpha-1 adrenergic receptor antagonism (Ki = 153 nM) contributes to sedation and is also associated with orthostatic hypotension, a significant side effect. 1 This adrenergic blockade adds to the overall sedating profile but is not the primary mechanism.
Alpha-2C receptor antagonism (Ki = 155 nM) provides additional sedating effects through modulation of noradrenergic transmission. 1
Clinical Implications of the Mechanism
Sleep architecture effects: Unlike hypnotics that decrease slow-wave activity in sleep EEG, trazodone increases the duration of deep sleep (stages 3+4), which patients associate with better subjective sleep quality. 2, 3
Timing considerations: The mechanism requires trazodone to be administered at least 1 hour before bedtime for sleep onset insomnia, as it is less effective than hypnotics for falling asleep but very effective for sleep maintenance. 2
Dose-response relationship: The sedating effects occur at lower doses (25-100 mg) than those required for antidepressant action, suggesting that 5-HT2A antagonism dominates at these doses while serotonin reuptake inhibition requires higher concentrations. 4, 5
Important Caveats
The mechanism differs fundamentally from hypnotics: While benzodiazepine receptor agonists work through GABAA receptors and other sedative antidepressants primarily block H1 histamine receptors, trazodone's 5-HT2A antagonism represents a distinct pharmacological pathway. 2 This difference explains why trazodone increases rather than decreases deep sleep.
Tolerance does not develop: The serotonergic mechanism does not lead to tolerance or REM rebound on discontinuation, unlike benzodiazepines. 5
Metabolic considerations: Trazodone is extensively metabolized by CYP3A4 to m-chlorophenylpiperazine (mCPP), an active metabolite that may contribute to both therapeutic and adverse effects. 1