Extended-release Trazodone in Major Depressive Disorder: A Randomized, Double-blind, Placebo-controlled Study

Abstract

Objective: To investigate the efficacy, safety, and clinical benefit of a once-daily formulation of trazodone (Trazodone Contramid((c)) OAD) in the treatment of major depressive disorder.

Design/participants: In this double-blind study, 412 patients with major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were randomized 1:1 to receive either Trazodone Contramid OAD (150 to 375mg) or placebo. Treatment was titrated over two weeks to each individual optimal dose. Patients then continued six weeks of treatment; further dose adjustments were allowed based on efficacy and tolerability.

Measurements: The primary end point was change in the 17-item Hamilton Depression Rating Scale total score from baseline to last study visit. Secondary end points included Hamilton Depression Rating Scale responders/remitters, change in Montgomery-Asberg Depression Rating Scale, Clinician and Patient Global Improvement Scales, and quality of sleep.

Results: From the end of titration to the end of the six-week treatment period, the mean maximum daily dose of the intent-to-treat population was 310mg for the active group and 355mg for the placebo group. There was a statistically significant difference between trazodone and placebo on the mean HAMD-17 score (-11.4 vs. -9.3, P=0.012). A significant difference was present as early as Week 1 and was maintained at all subsequent study visits. Many secondary end points supported these findings, including improvements in quality of sleep. The most frequent adverse events were the same for both the treatment and placebo groups: headache and somnolence. There were no serious adverse events that were considered related to treatment. There were no clinically significant electrocardiogram or laboratory abnormalities.

Conclusions: The trazodone Contramid formulation was more effective than placebo in major depressive disorder and was well tolerated.

Keywords: Hamilton Depression Rating Scale; Major depressive disorder; antidepressant; extended release; placebo-controlled trial; serotonin-2 antagonist/reuptake inhibitor (SARI); trazodone.

Figures

Figure 1

Study design

1. The number of days in the screening phase was determined by washout time of patient's previous medications.

2. Patients who could not tolerate the 150 mg dose had to exit the study.

3. Patients who could not tolerate the next dose after trying it for at least 2 days could decrease to the previous dose. In rare cases, if the patient was unable to tolerate the higher dose after trying it for at least 1 day, the dose could be decreased to the previous level. Patients were allowed to decrease their dose only once during the titration period.

4. Patients had to stay at the final titration dose until the end of titration.

Figure 2

Study flowchart Patient requests included reasons for discontinuation other than adverse events or lack of efficacy.

Figures 3A–C

HAMD-17 outcomes

Figures 3A–C

HAMD-17 outcomes

Figures 3A–C

HAMD-17 outcomes

Figure 4

Distribution of responses for quality of sleep measures of the modified ITT/LOCF population. *response distribution significantly different from placebo, P

Figure 4

Distribution of responses for quality of sleep measures of the modified ITT/LOCF population. *response distribution significantly different from placebo, P

Figure 4

Distribution of responses for quality of sleep measures of the modified ITT/LOCF population. *response distribution significantly different from placebo, P