Evaluating the dose-dependent mechanism of action of trazodone by estimation of occupancies for different brain neurotransmitter targets

Abstract

Trazodone is a drug that was introduced in the clinic almost 40 years ago. It is licensed to treat depression, but it is also commonly used off-label to treat insomnia. A recent study shows that it could be promising in preventing neurodegeneration in mice, and clinical trials to assess its possible beneficial effects on dementia and Alzheimer's disease are expected to start soon in humans. In this study, we describe the dose-dependent pharmacology of trazodone by carrying out pharmacokinetic simulations aiming to predict the brain concentrations of trazodone for different drug-dosing regimens and calculating occupancy for 28 different targets for which published trazodone-binding data are available. Our study indicates that low doses of trazodone (typically 50 mg daily) should suffice to block specific receptors responsible for the hypnotic effect, and to provide the protective effect against neuroinflammation and neurodegeneration that could be beneficial in dementia. Higher doses are required for an antidepressant effect. The occupancy of specific receptors at therapeutic doses also explains peculiar side effects reported by patients treated with trazodone (e.g. dry-mouth, hypotension and priapism).

Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism

“…The efficacy of trazodone in activating 5-HT 1A ARs was about one third of that of the full agonist 5-CT with a potency in the low micromolar range, hence this action would occur at therapeutic concentrations of the drug [41]. The weak efficacy of trazodone in activating 5-HT 1A ARs is consistent with data obtained using 5-HT 1A receptor-stimulated [ 35 S]-GTPγS binding in rat hippocampal and cortical membrane preparations (≤ 20% at 30 μM) [21]).…”

“…Although the relative contribution of 5-HT 1A and α 1 -adrenoceptor effects in vivo cannot be fully mimicked in vitro as the actual degree of noradrenergic drive changes during wake-sleep cycle, the combined 5-HT 1A receptor agonist and α 1 -adrenoceptor antagonist effects of trazodone on these neurons could be relevant to its effects on sleep. At concentrations akin those present in human brain following administration of trazodone for sleep disorders [41], the dual action of trazodone could facilitate inhibition of serotonergic neuron firing in the phase of drowsiness when α 1 -adrenoceptor stimulation is lowered [53]. In addition, antagonism at α 1 -adrenoceptor is likely to dampen the effects of noradrenergic system reactivation that occurs during sleep thereby preventing insomnia-related microarousals [54].…”

<p>New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties</p>

“…An estimate receptor occupancy (RO) for NET, 5-HT 2B , and 5-HT 2C was calculated with the following equation: 23 , 24 …”

Treatment of Delirium in Older Persons: What We Should Not Do!

“…The supposed mechanisms of action include the low anticholinergic activity, the fact that it is less active as an inhibitor of noradrenaline and serotonin re-uptake than other drugs, and that decreases gamma-aminobutyric acid (GABA) release [57]. However, some authors emphasize a complex interaction between the GABAergic and serotoninergic systems for explaining the sedation and anxiolytic properties that accompany the antidepressant activity of trazodone [58]. The potential safety of low doses of trazodone as treatment for delirium is supported by its little effect on cardiac conduction, being better tolerated and more effective in major depressives simultaneously debilitated by significant cardiovascular disease [57,59].…”