What is the mechanism of action for Trazodone (triazolopyridine antidepressant)?

From the Guidelines

Trazodone's mechanism of action is primarily through the inhibition of serotonin reuptake transporters (SERT), increasing serotonin levels in the brain, as well as acting as an antagonist at 5-HT2A and 5-HT2C serotonin receptors and alpha-1 adrenergic receptors. This unique combination of actions contributes to its antidepressant and sedative effects. Unlike many other antidepressants, trazodone has relatively weak effects on norepinephrine and dopamine reuptake 1. The medication's antagonism of alpha-1 adrenergic receptors and histamine H1 receptors contributes significantly to its sedative properties, which is why it's often prescribed for insomnia at lower doses (25-100 mg) than those used for depression (150-300 mg daily).

Some key points about trazodone's pharmacology include:

• Its relatively short half-life of 5-9 hours, which explains why it's typically taken at bedtime when used for sleep
• The medication's sedative effects usually begin within 30 minutes to an hour after ingestion, while its antidepressant effects may take several weeks to develop fully as the brain adapts to the altered serotonin signaling
• Trazodone's plasma concentration–clinical effectiveness relationship has not been clearly demonstrated, and therapeutic monitoring is not typically recommended, except in situations of noncompliance, nonresponse, adverse effects, or intoxication 1.

It's worth noting that the provided studies do not directly address the mechanism of action of trazodone, but rather its use in various clinical contexts, such as the treatment of alcohol dependence 1 and the monitoring of antidepressant levels 1. However, the information from these studies can still inform our understanding of trazodone's pharmacology and clinical use.

From the FDA Drug Label

The mechanism of trazodone’s antidepressant action is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist and the net result of this action on serotonergic transmission and its role in trazodone’s antidepressant effect is unknown. Trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors. Trazodone is also an antagonist at several other monoaminergic receptors including 5-HT2B (Ki = 78. 4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), α2C (Ki = 155 nM) receptors and it is a partial agonist at 5- HT1A (Ki = 118 nM) receptor.

The mechanism of action for trazodone is thought to be related to its enhancement of serotonergic activity in the CNS. It is a:

• Selective serotonin reuptake inhibitor (SSRI)
• 5HT2 receptor antagonist
• Antagonist at several other monoaminergic receptors, including 5-HT2B, 5-HT2C, α1A, and α2C
• Partial agonist at the 5-HT1A receptor However, the net result of these actions on serotonergic transmission and its role in trazodone’s antidepressant effect is unknown 2.

From the Research

Mechanism of Action of Trazodone

• Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs) 3, 4, 5.
• It has a wide pharmacodynamic profile, being an antagonist of 5-HT2A and 5-HT2C serotoninergic receptors, alpha1 and alpha2 adrenergic receptors, as well as H1 histaminergic receptors 4.
• In higher doses, it blocks the SERT serotonin transporter, which explains its wide therapeutic spectrum ranging from symptomatic treatment to monotherapy of depressive syndromes 4.
• Trazodone's mechanism of action is complex, with a double effect on the central 5-HT system: at low doses, it acts as a 5-HT antagonist, whereas at higher doses, it acts as a 5-HT agonist 6.
• The drug is metabolized by the CYP450 isoenzyme, mainly the 2D6 and 3A4, which requires its dose to be adjusted when administered simultaneously with other drugs influencing the activity of those isoenzymes 4.

Clinical Use and Efficacy

• Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants 3.
• It is well tolerated, with the most common adverse effects reported being drowsiness, headache, dizziness, and dry mouth 3, 4, 5.
• Trazodone has been found to be clinically useful in generalized anxiety disorder, agitation of patients with dementia and organic disorders, chronic pain disorders, alcohol and benzodiazepine dependence 5.
• The introduction of trazodone to the market may decrease the widespread use of benzodiazepines in antidepressive treatment 5.
• Meta-analyses have shown that trazodone and other 5HT2-receptor antagonists have comparable efficacy and tolerability to selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder 7.