Trazodone (Desyrel)

Trazodone (Tradename: Desyrel) is a Serotonin Antagonist and Reuptake Inhibitor (SARI).

History
  • Trazodone is a close relative of nefazodone (Serzone), a medication that was discontinued due to hepatoxicity.
  • At low doses (<150 mg) trazodone has:
    • Serotonin (5-HT) receptor antagonism
      • 5-HT2A (majority)
      • 5-HT2C (minority)
    • Histamine (H1) receptor antagonism
    • Alpha 1 (α1) receptor antagonism
    • The antagonism of 5-HT2A, α1, and H1, causes sedation at any dose. However, trazodone has very weak serotonin reuptake transporter (SERT) or 5-HT2C antagonism properties at low doses. This explains why at low doses, trazodone is ineffective as an antidepressant, but can be used as a non-habit forming sedative, and is also safe to combine with MAOIs
  • At high doses (150 to 600 mg per day) trazodone:
    • Actually “becomes an antidepressant” because trazodone basically inhibits 5-HT2A receptors at any dose, but to get an “antidepressant effect,” the dose needs to be much higher to start recruiting SERT inhibition (which increases serotonin levels).
  • One of the other unique things about trazodone is it has no sexual dysfunction side effects, this is because antidepressant-induced sexual dysfunction is thought to be due to 5HT2A stimulation (agonism), thus trazodone does the reverse of this.

Why Trazodone Is Not A Great Antidepressant

As mentioned above, for trazodone to work as an antidepressant, the dose must be sufficiently high for it to reach its potent serotonin reuptake (SERT) inhibition properties. Unfortunately, at these high doses, it also means its' H1 antihistamine and α1 antagonist properties are also maximized. It was found that patients at these high doses were very, very sedated, making it a terrible antidepressant! However, clinicians later discovered that trazodone actually works well as a hypnotic at low doses, due to it still having α1 and H1 antagonism, and some 5-HT2A antagonism.
  • Half-life = ~8 to 10 hours
  • Tmax = ~60 minutes, delayed to 2.5 hours when taken with food
  • 25-600mg (up to 200mg frequently used for sedation)

Extensive CYP450 3A4 metabolism

Main drug interactions extensive CYP450 3A4 metabolism

Contraindications concomitant use with a monoamine oxidase inhibitor (MAOi), IV methylene blue, linezolid may lead to increased risk of serotonin syndrome, concomitant use with saquinavir/ritonavir

Nausea, headache, somnolence, blurred vision, fatigue, prolonged QT, rare seizures, hypotension, dizziness, dry mouth & , sedation, GI

  • Priapism (due to α1 blockade)