How Trazodone Can Cause Depression

Trazodone is widely used for insomnia, and with good reason. Although lacking FDA-approval, it has a few advantages over the official hypnotics. It improves sleep quality and daytime functioning.¹ Its lack of reinforcing qualities makes it an appealing choice in substance use disorders. In sleep apnea, it’s one of the safer hypnotics; trazodone actually reduces the apnea-hypoxia index.² But trazodone is a complex medicine, and some patients can actually get more depressed.

Adolescents who take trazodone for sleep while on a serotonergic antidepressant are six times less likely to respond to the antidepressant and three times more likely to self harm. That was the case in a large, controlled trial of treatment-resistant depression.³ Hypnotic use was not controlled in that study, but the problems were not seen with other sleep medicines, and the finding was later confirmed in a naturalistic sample by a separate group.⁴

The mechanism behind this paradoxical effect involves a controversial metabolite of trazodone: meta-chlorophenylpiperazine (mCPP). This metabolite swings both ways; it can make depression better or worse. Abrupt rises in mCPP can cause dysphoria, anxiety, and even hallucinations. On the other hand, mCPP works as a partial serotonin agonist and can improve depression when it is titrated slowly and its levels are kept steady.⁵

To get rid of mCPP, the liver metabolizes it through CYP2D6. That means that potent CYP2D6 inhibitors can cause mCPP levels to spike. Those inhibitors include fluoxetine (Prozac) and paroxetine (Paxil), and it was these antidepressants that were associated with the worst responses to trazodone in the adolescent study. Adolescents may be more vulnerable to mCPP’s dysphoric effects, but it has been observed in adults as well.

Other potent CYP2D6 inhibitors are listed in the Table.

If what we know about mCPP is true, then the way to prevent this problem is to titrate trazodone slowly in patients who are on CYP2D6 inhibitors or are slow metabolizers at this enzyme. Pharmacogenetic testing can identify these metabolic differences, which are more common among African-Americans and Asians.⁷ Adolescents may be more vulnerable to mCPP’s dysphoric effects, but it has been observed in adults as well. It can also occur with nefazodone, another mCPP precursor. Even with a normal CYP2D6 enzyme, mCPP levels can still spike if trazodone is raised too quickly. That may explain why trazodone worked poorly as an antidepressant in the studies that titrated it aggressively, reaching 300 mg to 450 mg in the first week.⁸

These patients are at risk for dysphoric reactions on trazodone.

Trazodone is complicated, but people are far more complex. Not everyone will have a drop in their mood when there is a peak in mCPP, but it is something to look out for. When a patient calls with anxious, agitated symptoms after starting trazodone or nefazodone, they might have bipolar disorder, or they might just have too much mCPP. Stop the antidepressant and look for drug interactions or evidence of metabolic problems at CYP2D6. And, for good measure, check their Mood Disorder Questionnaire or Bipolarity Index. Trazodone has been known to trigger mania, even in the low doses used for sleep.⁹