Selective Serotonin Reuptake Inhibitors

General Principles

  • The selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for major depressive disorder, anxiety disorders, posttraumatic stress disorder, and other psychiatric conditions.
  • The SSRIs have generally supplanted older antidepressants as first-line agents in depression due to their safety profile in therapeutic use and overdose.
  • Most SSRIs have similar pharmacologic and toxicologic profiles, with two important exceptions:
    • Citalopram is more dangerous in overdose than other SSRIs. Citalopram poisoning tends to produce more cardiotoxicity (QRS and QT prolongation) and seizures than poisoning by other SSRIs.
    • Fluoxetine has active metabolites and a very long half-life. Initiation of other serotonergic medications (especially MAO inhibitors—see below) too soon after fluoxetine discontinuation carries a risk of serotonin syndrome (see below).


  • The SSRIs inhibit serotonin reuptake via the SERT transporter on the presynaptic neuron terminal, thus increasing the amount and persistence of serotonin in the synaptic cleft and enhancing serotonergic signaling.
    • Unlike other antidepressants, the SSRIs have limited effects on any other receptor, channel, or pump.

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