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Mechanism Of Action

The mechanism of trazodone's antidepressant action is not fully understood, but is thought to be related to its potentiation of serotonergic activity in the CNS.


Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin and acts as an antagonist at 5-HT-2A/2C serotonin receptors.

Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.

Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.


Steady state AUC of Trazodone is equivalent after administration of Trazodone 100 mg immediate release (IR) three (3) times a day (mean ± SD AUCss = 33058 ± 8006 ng*h/mL) and Oleptro 300 mg once daily (mean ± SD AUCss = 29131 ± 9931 ng*h/mL) for one week. Steady State Cmax and Cmin of trazodone were not equivalent after administration of trazodone 100 mg IR 3 times a day (mean ± SD Cmax,ss = 3118 ± 758 ng/mL, Cmin,ss = 843 ± 274 ng/mL) and Oleptro 300 mg once daily (mean ± SD Cmax,ss = 1812 ± 621 ng/mL, Cmin,ss = 674 ± 355 ng/mL) for one week.


Trazodone is well absorbed after oral administration, without selective localization in any tissue. Following single-dose administration of Oleptro 300 mg tablets under fasting conditions, a mean peak trazodone plasma concentration (Cmax) of 1188 ± 362 ng/mL was reported at a median Tmax of 9 hours post-dose. When Oleptro 300 mg tablets are taken shortly after ingestion of a high-fat meal, Cmax increases by about 86% compared to taking it under fasting conditions. However, AUC0-∞ and Tmax are not significantly affected by food.

Oleptro tablets are dose proportional following single-dose administration of doses ranging from 75 mg to 375 mg as intact or bisected tablets.


In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.


Elimination is predominantly renal, with 70 to 75% of an oral dose being recovered in the urine within the first 72 hours of ingestion. Following single-dose administration of Oleptro 300 mg tablets, a mean apparent terminal half-life of 10 hours was reported.

Protein Binding

Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

Clinical Studies

The efficacy and safety of Oleptro were established from trials of the immediate release formulation as well as a randomized, double-blind, two-arm study comparing the efficacy and safety of Oleptro and placebo in the treatment of unipolar major depressive disorder.

The Oleptro trial was a multi-center, parallel-design study of outpatients meeting DSM-IV criteria for major depressive disorder (MDD). This study consisted of a Baseline Phase (screening and washout) and a double-blind Randomized Phase (randomization to Oleptro (n=206) or placebo (n=206)). The total study duration, including washout of prohibited medications, was approximately 11 weeks; the total duration of the randomized treatment phase was 8 weeks (titration: 2 weeks and treatment: 6 weeks). Rescue medication for MDD was not allowed during the study.

Patients were between 18 and 80 years of age. Of this population, 25 patients were 65 years old or older. The mean age of the population was 44 years; 64% were female.

The primary efficacy endpoint in this study was change from baseline in HAMD-17 total score.

A statistically significant difference in the HAMD-17 score was demonstrated at 8 weeks between the Oleptro group and the placebo group.

Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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