Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action

Abstract

Background Most antidepressants have a delayed onset of action and must be administered for several weeks to generate therapeutic effects. Trazodone is a serotonin antagonist and reuptake inhibitor approved for the treatment of major depressive disorder. The once-a-day (OAD) formulation of trazodone has an improved tolerability profile compared to its conventional formulations. In this study, we systematically reviewed the evidence available for the antidepressant efficacy and early improvement in depressive symptoms with trazodone OAD treatment. Method We conducted a PubMed database search for randomized controlled trials published from 2005 to 2020. Results Two studies, a placebo-controlled and an active-comparator (venlafaxine extended-release or XR) study were found. Both the studies demonstrated that trazodone exhibits antidepressant activity at a starting dose of 150 mg/day and results in statistically significant greater reduction in Hamilton Depression Rating Scale (HAM-D17) scores within 1 week of starting treatment compared to placebo or venlafaxine XR (P < .05). Trazodone also resulted in significant early improvement in the HAM-D17 sleep disturbance factor compared to placebo or venlafaxine XR at day 7 (P < .05). This clinical effect is supported by in vitro proprietary data for the affinity of trazodone for different target receptors. Activity at these receptors may underlie trazodone’s fast antidepressant action. Conclusions Trazodone, if properly dosed, can be an effective antidepressant with early onset of action and good tolerability. Future studies designed to specifically evaluate onset and timing of improvement of depressive symptoms remain necessary to confirm and extend these results.

Estimation of brain receptor occupancy for trazodone immediate release and once a day formulations

“…1 Trazodone acts as a potent antagonist of the serotonin (5-HT) receptors 5-HT 2A and shows moderate affinity to 5-HT 1A , 5-HT 2C , and 5-HT 7 receptors, acting as a weak agonist for the first one and as a weak antagonist for the following two receptors. 2 Trazodone also shows moderate affinity for the serotonin transporter SERT. Moreover, it was demonstrated that trazodone binds with high affinity to adrenergic receptors, where it acts blocking α 1 -adrenoceptors and moderately antagonizing α 2 -adrenoceptors.…”

“…Trazodone acts as a potent antagonist of the serotonin (5‐HT) receptors 5‐HT 2A and shows moderate affinity to 5‐HT 1A , 5‐HT 2C , and 5‐HT 7 receptors, acting as a weak agonist for the first one and as a weak antagonist for the following two receptors 2 . Trazodone also shows moderate affinity for the serotonin transporter SERT.…”

Serotonergic metamodulation of mGlu23 receptors, a new mechanism for pain management: the case of trazodone

“…Since its introduction in therapy in the early 1970s, trazodone (TZD) hydrochloride has been used for the treatment of depression and often administered in association with other antidepressants to patients with insomnia. The drug is well tolerated, with a favorable pharmacokinetic profile and convenient pharmacodynamic characteristics [1][2][3][4][5][6]. It is commonly referred to as a serotonin receptor antagonist and serotonin reuptake inhibitor (SARI) [7], although its potency to block the 5-HT reuptake is lower than that of other specific serotonin reuptake inhibitors (SSRIs), such as citalopram and fluoxetine [8].…”

“…It is commonly referred to as a serotonin receptor antagonist and serotonin reuptake inhibitor (SARI) [7], although its potency to block the 5-HT reuptake is lower than that of other specific serotonin reuptake inhibitors (SSRIs), such as citalopram and fluoxetine [8]. The most likely effect accounting for its antidepressant activity is the antagonistic action at serotonergic receptors, particularly the 5-HT2A and the 5-HT2C receptors [1,6,9].…”

“…The simultaneous inhibition of serotonin transporters (SERTs) and of the 5-HT2A/5-HT2C receptors leads to a synergistic action which potentiates the antidepressant activity and improves the tolerability, reducing some of the side effects exerted by classic antidepressants, including insomnia and anxiety [2,6]. TZD also antagonizes the 5-HT2B receptors, although less efficiently than the 5-HT2A ones and has a partial agonistic activity towards the 5-HT1A receptors [1]. Furthermore, it interacts with noradrenergic α1 receptors, but has minimal antagonistic activity on cholinergic and histaminergic H1 receptors [6].…”