Can trazodone and amitriptyline (tricyclic antidepressant) be used concomitantly?

From the Guidelines

Trazodone and amitriptyline can be used together, but this combination should only be taken under close medical supervision due to the increased risk of serotonin syndrome and other adverse effects. Both medications are used to treat depression and other conditions, but they work through similar mechanisms affecting serotonin levels in the brain. When combined, they can increase the risk of serotonin syndrome, a potentially serious condition characterized by agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and in severe cases, seizures or loss of consciousness, as reported in a study on serotonin syndrome 1. Additionally, both medications can cause drowsiness, dizziness, and low blood pressure, so these side effects may be amplified when taken together.

Some key points to consider when using this combination include:

• Monitoring for signs of serotonin syndrome, such as mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 1
• Reporting any unusual side effects promptly to the healthcare provider
• Avoiding alcohol and other central nervous system depressants while on this combination
• Never adjusting the dosage of either medication without consulting the healthcare provider first
• Considering the potential for behavioral activation/agitation, mania/hypomania, and sexual dysfunction, as reported in a study on SSRIs 1

It's essential to weigh the benefits against the risks for each individual situation, as the efficacy of low-dose sedating antidepressants, such as trazodone and amitriptyline, is relatively weak when used alone, and no specific agent is recommended as preferable to the others in this group 1. Factors such as treatment history, coexisting conditions, specific side effect profile, cost, and pharmacokinetic profile may guide the selection of a specific agent.

From the FDA Drug Label

1. 2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including Trazodone Hydrochloride Tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i. e., MAOIs [see CONTRAINDICATIONS (4), DRUG INTERACTIONS (7.1)].

The use of trazodone and amitriptyline together may increase the risk of serotonin syndrome, a potentially life-threatening condition.

• Key points:
  • Trazodone and amitriptyline are both serotonergic drugs.
  • Concomitant use of these drugs may increase the risk of serotonin syndrome.
  • Patients should be monitored for signs and symptoms of serotonin syndrome, such as mental status changes, autonomic instability, and neuromuscular symptoms.
  • If serotonin syndrome occurs, treatment with trazodone and amitriptyline should be discontinued immediately, and supportive symptomatic treatment should be initiated 2.
  • It is also mentioned in another study that, patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome 2.

From the Research

Combination of Trazodone and Amitriptyline

• The combination of trazodone and amitriptyline has been studied in various clinical trials, with some studies suggesting that it may be effective in treating depression 3.
• However, other studies have raised concerns about the potential risks of serotonin syndrome when combining these two medications, particularly when used in combination with other serotonergic agents 4, 5.
• A study published in the Journal of Clinical Psychopharmacology found that the concurrent use of two or more drugs that enhance central nervous system serotonin activity can produce the serotonin syndrome, a potentially life-threatening complication of treatment with psychotropic drugs 5.
• Another study published in the Journal of Pharmacy Practice reported a case of serotonin syndrome precipitated by the rapid titration of sertraline and trazodone in the setting of risperidone use, highlighting the importance of careful dosing and monitoring when combining these medications 4.

Efficacy and Safety

• A double-blind study published in Pharmacopsychiatria found that trazodone had sedative and some anxiolytic properties but only negligible antidepressant efficacy compared to amitriptyline 3.
• A study published in Psychopharmacology found that trazodone was as effective as amitriptyline, mianserin, and dothiepin in treating depression, with no significant differences in efficacy between the four treatments 6.
• However, the study also found that trazodone was associated with a lower incidence of side effects compared to the other medications 6.

Prescribing Patterns

• A retrospective chart review published in the Journal of Clinical Psychiatry found that patients prescribed trazodone were older and more likely to have a history of unresponsiveness to other antidepressants compared to those prescribed amitriptyline 7.
• The study also found that initially prescribed daily doses of trazodone were often below the recommended starting dose, while starting daily doses for amitriptyline were more adequate relative to the recommended daily dose 7.