Which antidepressant is associated with the highest risk of developing serotonin syndrome?

Venlafaxine, an atypical antidepressant that primarily functions as a serotonin-norepinephrine reuptake inhibitor (SNRI), has a higher potential for inducing serotonin syndrome compared to the other listed options. This risk is particularly notable at higher doses, as venlafaxine's mechanism increases the levels of serotonin substantially, thereby heightening the risk of overlapping with other serotonergic agents, which could lead to the development of serotonin syndrome.

Serotonin syndrome is characterized by a triad of symptoms that can include altered mental status, autonomic instability, and neuromuscular abnormalities. The risk of this potentially life-threatening condition increases with the dosage and when venlafaxine is used in combination with other serotonergic drugs.

While citalopram, fluoxetine, and sertraline are selective serotonin reuptake inhibitors (SSRIs), and can also contribute to serotonin syndrome, venlafaxine's mechanism of action and the impact on serotonin levels generally place it at a higher risk. This distinction helps in understanding why venlafaxine is often highlighted in discussions about medication-related serotonin syndrome.