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

Abstract

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.

Keywords: Activating effects; Adverse events; Antidepressants; Sexual dysfunction; Systematic review; Trazodone once-a-day (OAD).

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart The initial literature search for randomized controlled trials (RCTs) on once-a-day (OAD) trazodone formulation identified 58 PubMed and 41 Cochrane Library articles, 13 of which were duplicate articles. Of the 86 articles screened, only three met the eligibility criteria: RCTs that included a placebo, an active comparator, or crossover design to evaluate the safety and tolerability of trazodone OAD in either patients with major depressive disorder or healthy participants. Studies that only examined different doses of trazodone OAD were also excluded.

Fig. 2

Relative binding affinity of trazodone to monoamine receptors compared to serotonin transporter (SERT) Bars represent the log10 of the fold difference between trazodone's Kis for serotonin (5-HT), alpha adrenergic (alpha), and histamine H1 (H1) receptors vs the Ki for SERT derived from previously reported proprietary in vitro data (Albert et al., 2021; Mangano et al., 2020). The Ki of trazodone for each target is listed in nanomolar units. Trazodone has a greater than 10-fold higher affinity for 5-HT2A, alpha-1B, and 5-HT1D as compared with SERT. The other receptors are within an order of magnitude of SERT, with trazodone having a lower affinity for 5-HT2C and 5-HT7 than SERT.

Fig. 3

Model of hypothesized effects of the modulation of distinct serotonin receptors (A) Agonism of the serotonin (5-HT) receptor 5-HT1A is thought to be responsible for antidepressant activity, whereas agonism of 5-HT2A/2C/7 is believed to contribute to sleep disturbances, anxiety, and/or sexual dysfunction. These effects may be anticipated with general serotonin transporter (SERT) blockade. (B) Partial agonism of 5-HT1A may reduce sexual dysfunction. Antagonism of 5-HT2A/2C/7 is believed to reduce sleep disturbances, anxiety, and/or sexual dysfunction. These are pharmacodynamic features of trazodone that may help explain its safety and tolerability profile.