Trazodone once-a-day: A formula for addressing challenges in antidepressant safety and tolerability

Psychotropic drug properties can vary across different formulations of a compound. Trazodone is a multifunctional drug that exemplifies this phenomenon. Although it is a serotonin reuptake inhibitor, trazodone is a significantly more potent blocker of serotonin 5-HT2A receptors. It also acts as an antagonist at several other 5-HT receptors and acts as a partial agonist at 5-HT1A receptors. Additional targets of trazodone blockade include histamine H1 receptors and alpha-1 adrenergic receptors. Trazodone's newer once-a-day (OAD) formulation is thought to have improved safety and tolerability over earlier formulations due to release kinetics that avoid the multiple higher peaks in plasma concentrations observed with earlier formulations. Here, we systematically reviewed the clinical data from randomized controlled trials (RCTs). We performed a PubMed and Cochrane Library database search for RCTs on trazodone OAD that either included placebo or active comparator controls or used a crossover design with at least one additional treatment. Three studies met inclusion criteria. Trazodone OAD was compared to placebo in one study, to venlafaxine extended-release (XR) in another, and to trazodone immediate-release in an additional study. Trazodone OAD demonstrated a favorable safety and tolerability profile across studies and was associated with low levels of sexual dysfunction and weight gain. It improved sleep disturbance scores and was associated with time point-dependent improvements in anxiety/somatization scores on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) as compared to placebo or venlafaxine XR, suggesting that it does not tend to promote anxiety or insomnia. Trazodone OAD represents a well-tolerated treatment for MDD patients who are concerned by anxiety symptoms and are seeking to minimize adverse drug effects involving sexual dysfunction, weight gain, and psychomotor activation.