Trazodone as a Multimodal and Multifunctional Antidepressant
Substances with multiple therapeutic effects, often depending on the dose, can be described as multifunctional. In low doses, trazodone has hypnotic effects, while its effective antidepressant action is evident at higher doses. This can be more frequently utilized now thanks to a modified-release formulation, which has the potential to improve the tolerability of antidepressant doses of trazodone.
Effects of Trazodone Depending on Dose
At lower doses (25–150 mg), trazodone exhibits hypnotic effects through the blockade of serotonin 5-HT2A receptors, to which it has high affinity. Additionally, lower doses of the drug also block histamine H1 and adrenergic α1 receptors, which supports its hypnotic effect. Trazodone has a slightly lower affinity for these receptors than for 5-HT2A receptors.
Within the group of antidepressants, trazodone belongs to the so-called SARIs – serotonin antagonist and reuptake inhibitors. However, to inhibit the serotonin transporter (SERT) and induce an antidepressant effect, full therapeutic doses (150–300 mg) are required. At these doses, antagonism also occurs at adrenergic α2 and serotonin 5-HT2C receptors, which contributes to its antidepressant effect. The antagonism at 5-HT2C receptors is especially typical for many commonly used antidepressants (e.g., mirtazapine or tricyclic antidepressants).
How is Trazodone Different from SSRIs?
In antidepressant doses, trazodone blocks SERT just like serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). Unlike them, however, it concurrently blocks 5-HT2A and partially 5-HT2C receptors. The agonistic action of endogenous serotonin on these receptors is the reason for the side effects of SSRIs and SNRIs, such as anxiety, sleep disorders, and sexual dysfunction. Although long-term administration of SSRIs and SNRIs leads to desensitization of these receptors, alleviating these issues for many patients, some may continue to experience sleep disorders or sexual dysfunction, complicating depression treatment.
The combination of SERT inhibition and antagonism at 5-HT2A/2C receptors observed with trazodone leads to an antidepressant effect without the typical side effects of SSRIs/SNRIs. This antagonistic action can also help in treating insomnia and anxiety accompanying depression and can be utilized when combining antidepressants to improve their efficacy and tolerability.
Immediate or Extended Release of Trazodone?
Trazodone has a relatively short biological half-life. Administering the drug at a low dose and in an immediate-release form leads to rapid peak plasma concentration and a relatively quick decline. For its hypnotic effect, this is ideal, helping to improve both sleep onset and maintenance without affecting the REM phase and without morning sluggishness.
For antidepressant indications, immediate release of trazodone and a quick rise and fall in plasma concentration are less suitable, as it results in sub-therapeutic antidepressant concentrations for part of the day and, conversely, causes sedation. An extended-release formulation could be the solution. Administering 300 mg of trazodone in an extended-release tablet once daily maintains sufficient concentration and minimizes sedation-inducing fluctuations in drug levels.
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Source: Stahl S. M. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr 2009; 14 (10): 536–546, doi: 10.1017/s1092852900024020.
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