Early Effect of Once-a-Day Trazodone in the Treatment of Major Depressive Disorder

Trazodone Once-a-Day

The antidepressant trazodone is available in a controlled-release formulation that ensures controlled release of the drug over 24 hours, allowing for a single daily dose (OAD – once a day). Thanks to better tolerability, this dosing is associated with better patient compliance.

Analyzed Data

A trio of Italian and American authors published a systematic review this year focusing on the clinical efficacy of once-a-day trazodone in MDD, and particularly on its early efficacy within 7 days of starting therapy. Included were randomized controlled trials published from 2005 to 2020 found in the PubMed database, which evaluated the effects of once-a-day trazodone in patients with major depressive disorder. Formulations with different pharmacokinetic profiles were not included in the review.

The compared parameters were the average total score on the Hamilton Depression Rating Scale (HAM-D17) and within its individual domains, the size of the cohort at each visit, the incidence of adverse events reported in ≥ 5% of patients, and the rate of premature therapy discontinuation.

Data from 2 double-blind studies were analyzed, and both showed the effectiveness of the antidepressant action of once-a-day trazodone at an initial dose of 150 mg/day. One of the studies compared once-a-day trazodone with placebo, the other with extended-release venlafaxine (venlafaxine XR).

Study Findings

Once-a-Day Trazodone vs. Placebo

The results of the study with 412 participants indicate that trazodone exhibited antidepressant activity in patients with MDD at an initial dose of 150 mg/day and led to a statistically significant improvement in HAM-D17 scores within 1 week of starting treatment compared to placebo: –5.6 points for once-a-day trazodone vs. –3.9 points for placebo (95% confidence interval [CI] –2.4 to –0.4; p < 0.05). This corresponded to a 24% reduction in the average score on day 7 of treatment for once-a-day trazodone and a 17% reduction for placebo.

Once-a-Day Trazodone vs. Venlafaxine XR

In the study involving 324 patients, a faster onset of the antidepressant effect was demonstrated for once-a-day trazodone (dose 150 mg/day in week 1) than for venlafaxine XR (dose 75 mg/day in week 1). HAM-D17 score improvements were as follows: –4.3 points for once-a-day trazodone vs. –3.5 points for venlafaxine XR (95% CI –1.5 to –0.2; p < 0.05). This corresponded to an 18% reduction in the average score on day 7 of treatment for once-a-day trazodone and a 15% reduction for venlafaxine XR. At the end of the study (day 56), venlafaxine XR was more effective than once-a-day trazodone in the intention-to-treat (ITT) population of all randomized patients, but in the per-protocol (PP) population, both therapies were comparably effective. The intensity of the depressive disorder decreased from moderate to mild in both groups.

Safety

In both studies, adverse events in the trazodone arms were mostly mild to moderate in intensity. The most common were headaches, drowsiness, dizziness, dry mouth, and nausea. Serious adverse events occurred in only 3 cases in each study. The most common reasons for discontinuing trazodone were dizziness, sedative effects, and QT interval prolongation.

Conclusion

The early effect of an antidepressant is considered a predictive marker of a sustainable therapeutic response, while its absence predicts therapeutic failure. According to this systematic review with the once-a-day formulation and studies with other formulations, trazodone is associated with an early onset of action faster than that of active comparators. At a dose of 150 mg/day, it inhibits the serotonin transporter (SERT) and has affinity for several subtypes of serotonin receptors, adrenergic receptors α₁ and α₂, and very low affinity for histamine H₁ receptors. The early onset of action is likely due to the synergy of these pharmacological actions according to the authors of the systematic review.

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Source: Albert U., Lamba P., Stahl S. M. Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action. CNS Spectr 2021; 26 (3): 232–242, doi: 10.1017/S1092852921000304.