What is the mechanism of action of Trazodone (antidepressant medication)?

Mechanism of Action of Trazodone

Trazodone's antidepressant action is primarily due to its dual role as both a selective serotonin reuptake inhibitor (SSRI) and a potent antagonist at 5-HT2A/2C serotonin receptors, with the net effect on serotonergic transmission being the foundation of its therapeutic benefits. 1

Primary Pharmacodynamic Properties

Trazodone has a complex pharmacological profile that includes:

• Serotonergic activity:

  • Selective serotonin reuptake inhibition (Ki = 367 nM) 1
  • Potent antagonism at 5-HT2A receptors (Ki = 35.6 nM) 1
  • Antagonism at 5-HT2B receptors (Ki = 78.4 nM) 1
  • Antagonism at 5-HT2C receptors (Ki = 224 nM) 1
  • Partial agonism at 5-HT1A receptors (Ki = 118 nM) 1

• Adrenergic activity:

  • Antagonism at α1A receptors (Ki = 153 nM) 1
  • Antagonism at α2C receptors (Ki = 155 nM) 1

• Histaminergic activity:

  • Antagonism at H1 histaminergic receptors 2

Mechanism Explaining Therapeutic Effects

Trazodone belongs to the SARI (Serotonin Antagonists and Reuptake Inhibitors) class of antidepressants 3. Its antidepressant effect is thought to result from:

1. Enhancement of serotonergic activity in the CNS - though the exact mechanism is not fully understood 1

2. 5-HT2A/2C receptor antagonism - which may be more important for its antidepressant action than its serotonin reuptake inhibition 2

3. Partial 5-HT1A receptor agonism - contributing to anxiolytic properties 2

The combination of these actions results in a unique pharmacodynamic profile that distinguishes trazodone from pure SSRIs.

Mechanism Explaining Side Effects

Trazodone's receptor profile explains its common side effects:

• Sedation/Hypnotic effects: Mediated through H1 histaminergic receptor antagonism and α1-adrenergic receptor antagonism 2

• Postural hypotension: Associated with α1-adrenergic antagonism 2, 1

• Anxiolytic properties: Related to 5-HT2A and 5-HT2C receptor antagonism and partial 5-HT1A receptor agonism 2

Clinical Implications of Mechanism

Trazodone's complex mechanism results in:

• Fewer sexual dysfunction side effects compared to pure SSRIs due to its 5-HT2A/2C antagonism counterbalancing the sexual dysfunction often associated with serotonin reuptake inhibition 2, 3

• Minimal weight gain compared to other antidepressants 3

• Potentially faster onset of antidepressant action compared to other antidepressants, possibly due to its multiple receptor activities 2, 4

• Strong sedative properties making it useful for depression with insomnia 3

Metabolism and Pharmacokinetics

Trazodone is metabolized via oxidative cleavage by CYP3A4 to an active metabolite, m-chlorophenylpiperazine (mCPP) 1. It is extensively metabolized with less than 1% excreted unchanged in urine and is 89-95% protein bound at therapeutic concentrations 1.

Important Clinical Considerations

• Trazodone's mechanism differs from pure SSRIs like fluoxetine, as it acts primarily through 5-HT2/1C receptor antagonism rather than solely through serotonin reuptake inhibition 5

• The sedative effects make it particularly useful for depression with insomnia, but can be problematic when daytime alertness is required 3

• When taken with food, there may be an increase in the amount absorbed, a decrease in maximum concentration, and a lengthening in time to maximum concentration 1