Can trazodone trigger mania in patients?

Can Trazodone Trigger Mania?

Yes, trazodone can trigger mania or hypomania, particularly in patients with bipolar disorder. The FDA label specifically warns about the "activation of mania/hypomania" as a potential adverse reaction with trazodone use. 1

Mechanism and Risk Factors

• Trazodone, like other antidepressants, can precipitate a mixed/manic episode in patients with bipolar disorder when used to treat a depressive episode 1
• Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with antidepressants, including trazodone 1
• The risk appears to be higher in patients with:
  • Pre-existing bipolar disorder 1, 2
  • Personal or family history of mania or hypomania 1
  • Use of higher antidepressant doses rather than lower doses used for sleep 2

Clinical Evidence

• Multiple case reports have documented trazodone-induced mania in both bipolar and unipolar depressed patients 3, 4
• The manic symptoms typically resolve when trazodone is discontinued or the dose is reduced 3, 4
• The risk of switching to mania appears to be related primarily to doses recommended for antidepressant treatment, especially when administered without mood-stabilizer co-therapy 2
• Low doses of trazodone used for hypnotic or sedative effects were observed to cause mania only in patients with other risk factors for switching 2

Recommendations for Clinical Practice

• Screen patients for any personal or family history of bipolar disorder, mania, or hypomania prior to initiating treatment with trazodone 1
• Consider that a manic episode precipitated by an antidepressant is characterized as substance-induced per DSM-IV-TR 5
• For patients with known bipolar disorder who require trazodone:
  • Use lower doses when possible (such as when prescribed for insomnia rather than depression) 2
  • Always combine with a mood stabilizer 2
  • Standard therapy for bipolar disorder typically includes lithium, valproate, and/or atypical antipsychotic agents 5

Risk Mitigation

• Monitor patients closely for signs of activation or mania, particularly early in treatment and with dose increases 5
• Be aware that behavioral activation/agitation (motor or mental restlessness, insomnia, impulsiveness, talkativeness, disinhibited behavior, aggression) may be difficult to distinguish from mania/hypomania 5
• Behavioral activation typically occurs early in treatment (first month) or with dose increases, whereas mania may appear later 5
• Behavioral activation usually improves quickly after dose decrease or discontinuation, whereas mania may persist and require more active pharmacological intervention 5

Special Considerations

• Parenteral trazodone may be a suitable option in patients at high risk of treatment-emergent mania, according to limited evidence 6
• When treating insomnia in patients with bipolar disorder, low doses of trazodone may be considered as an alternative to hypnotics, but should be used with caution 2
• Trazodone should be avoided in patients with a history of bipolar depression due to risk of mania, similar to SSRIs 5