Mechanism of Action and Side Effects of Trazodone
Trazodone is a serotonin receptor antagonist and reuptake inhibitor (SARI) that works through multiple mechanisms, primarily enhancing serotonergic activity in the CNS while also antagonizing specific serotonin receptors. 1
Mechanism of Action
- 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 1
- It also antagonizes several other monoaminergic receptors including 5-HT2B (Ki = 78.4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), and α2C (Ki = 155 nM) receptors 1
- Trazodone functions as a partial agonist at 5-HT1A (Ki = 118 nM) receptors 1
- The complex action on the serotonergic system explains its therapeutic effects and its unique side effect profile compared to other antidepressants 2
- Trazodone is extensively metabolized, with less than 1% excreted unchanged in urine; it is metabolized via CYP3A4 to m-chlorophenylpiperazine (mCPP), an active metabolite 1
Side Effects
Common Side Effects
- The most common side effects include drowsiness/somnolence (highest incidence compared to other antidepressants), headache, dizziness, and dry mouth 1, 3
- Gastrointestinal disturbances such as nausea, vomiting, and diarrhea may occur 1, 2
- Trazodone is associated with higher rates of somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine 4
Serious Side Effects
- Serotonin syndrome - symptoms include agitation, hallucinations, coordination problems, fast heartbeat, tight muscles, trouble walking, sweating, fever, nausea, vomiting, and diarrhea 1
- QT interval prolongation and potential for torsade de pointes, though this is relatively rare 5, 1
- Orthostatic hypotension, particularly in elderly patients or those with heart disease, due to its antagonism of alpha-1 adrenergic receptors 1, 3
- Priapism (prolonged erection lasting more than 6 hours) has been reported as a rare but serious side effect 1, 3
- Hyponatremia (low sodium in blood) can occur, with symptoms including headache, weakness, confusion, memory problems, and unsteadiness 1
- Visual problems including eye pain, changes in vision, and swelling or redness around the eye 1
Advantages in Side Effect Profile
- Minimal anticholinergic activity compared to tricyclic antidepressants, making it potentially better tolerated in elderly patients 6, 3
- Unlike SSRIs, trazodone typically does not cause sexual dysfunction or significant weight gain due to its unique pharmacodynamic profile 3, 7
- Trazodone's sedative properties can be beneficial for patients with depression and comorbid insomnia 7
Precautions and Drug Interactions
- Caution is required in patients with premature ventricular contractions due to potential cardiovascular effects 6
- Trazodone is 89-95% protein-bound in plasma, which may affect drug interactions 1
- The drug is metabolized by CYP3A4, requiring dose adjustments when administered with other medications that influence this enzyme's activity 2
- Concurrent use with other serotonergic medications increases the risk of serotonin syndrome 1
- Alcohol and other CNS depressants should be avoided as they may enhance the sedative effects of trazodone 1
Clinical Applications
- Trazodone is FDA-approved for major depressive disorder in adults 1
- It is commonly used off-label at lower doses (25-100 mg) for insomnia 6
- It may be used for agitation in dementia at initial doses of 25 mg per day, with a maximum of 200-400 mg per day in divided doses 6
- Trazodone has shown efficacy in reducing nightmare frequency in PTSD at a mean dose of 212 mg/day 6
Trazodone's unique pharmacological profile makes it particularly useful for patients with depression who also experience insomnia, while avoiding some of the common side effects associated with SSRIs such as sexual dysfunction and insomnia 7.