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

Oggianu, Laura; Dato, Giorgio Di; Mangano, Giorgina; Rosignoli, Maria Teresa; McFeely, Savannah J.; Ke, Alice Ban; Jones, Hannah M.; Comandini, Alessandro

doi:10.1111/cts.13253

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…Additionally, although a single 8‐10 mg/kg dose of trazodone in dogs resulted in plasma concentrations that have been documented to cause HPA suppression in people after 1 hour, maximum plasma concentrations in dogs may occur later than 1 hour, 6 and the dose we administered was at the upper end of the dosing range. The effects observed in our study may be dose‐dependent because of variable receptor affinity for trazodone 23 . Follow‐up studies evaluating eACTH and cortisol at later timepoints reflecting maximum plasma concentrations are warranted in addition to studies evaluating both lower and higher doses of trazodone.…”

Section: Discussionmentioning

confidence: 88%

“…The effects observed in our study may be dose‐dependent because of variable receptor affinity for trazodone. 23 Follow‐up studies evaluating eACTH and cortisol at later timepoints reflecting maximum plasma concentrations are warranted in addition to studies evaluating both lower and higher doses of trazodone. Finally, our study investigated the influence of trazodone administration on the HPA axis in healthy dogs.…”

Section: Discussionmentioning

confidence: 99%

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The impact of single‐dose trazodone administration on plasma endogenous adrenocorticotropic hormone and serum cortisol concentrations in healthy dogs

Brown,

Lee‐Fowler,

Behrend

et al. 2023

Veterinary Internal Medicne

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BackgroundConditions affecting the hypothalamic‐pituitary‐adrenal (HPA) axis are common in dogs. Testing the function of the HPA axis includes measurement of endogenous adrenocorticotropic hormone (eACTH) and performance of an adrenocorticotropic hormone (ACTH) stimulation test. Trazodone is commonly administered to dogs to decrease stress. In humans, trazodone significantly decreases plasma cortisol concentration via alpha‐1 adrenergic activity.ObjectivesDetermine the influence of trazodone on eACTH and serum cortisol concentrations in healthy dogs.AnimalsFourteen healthy, adult, companion dogs.MethodsProspective, randomized placebo‐controlled study. Trazodone (8‐10 mg/kg) or placebo was administered PO 1 hour before eACTH measurement and ACTH stimulation testing. After a ≥7‐day wash‐out period, dogs received the opposite treatment. Differences in eACTH, pre‐ and post‐ACTH stimulation cortisol concentrations, and delta (difference between pre‐ and post‐ACTH) cortisol concentrations were analyzed using a paired t or signed‐rank test with a P < .05 significance level.ResultsThe eACTH concentrations were not significantly different (P = .23) between treatments. Similarly, no significant differences were found in the pre‐ACTH cortisol concentrations between treatments (P = .40). Post‐ACTH cortisol concentrations (P = .05) and delta cortisol concentrations (P = .04) were significantly lower when the dogs were treated with trazodone.ConclusionsPreliminary data suggest trazodone administration dampens the adrenocortical response to stimulation in healthy dogs. If similar effects are found in dogs with adrenal disease, the use of trazodone may affect diagnosis and clinical decision making in these populations.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

The impact of single‐dose trazodone administration on plasma endogenous adrenocorticotropic hormone and serum cortisol concentrations in healthy dogs

Brown,

Lee‐Fowler,

Behrend

et al. 2023

Veterinary Internal Medicne

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“…Trazodone doses between 25 and 150 mg do not achieve antidepressant activity but have hypnotic activity through antagonism of 5-HT 2a , H 1 , and α1 receptors. Estimates of brain receptor occupancy based on a pharmacokinetic model support the multimodal activity of trazodone, which may contribute to the rapid onset of its antidepressant action and its effectiveness for a variety of symptoms in depressed patients [ 24 ].…”

Section: Trazodonementioning

confidence: 99%

Role of trazodone in treatment of major depressive disorder: an update

Fagiolini,

González-Pinto,

Miskowiak

et al. 2023

Ann Gen Psychiatry

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Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist and reuptake inhibitor (SARI) antidepressant approved for major depressive disorder (MDD) in adults, has established efficacy that is comparable to other available antidepressants, and is effective for a range of depression symptoms, including insomnia, which is one of the most common and bothersome symptoms of depression. Also, trazodone’s pharmacodynamic properties allow it to avoid the side effects of insomnia, anxiety and sexual dysfunction often associated with selective serotonin reuptake inhibitor antidepressants. In this narrative review, we have summarized recent clinical trials and real-world data on trazodone, including the recently introduced once-daily formulation, which has single dose pharmacokinetic properties that maintain effective blood trazodone levels for 24 h, while avoiding concentration peaks associated with side effects. This, combined with a low incidence of weight gain, and sexual dysfunction, may improve adherence to treatment. The most common adverse effects of trazodone are somnolence, headache, dizziness and xerostomia. It has minimal anticholinergic activity but may be associated infrequently with orthostatic hypotension (especially in patients with cardiovascular disease or older adults), QT interval prolongation, cardiac arrhythmias, and rare episodes of priapism. The low liability for activating side effects, the efficacy on symptoms such as insomnia and psychomotor agitation and the rapid onset of action make it useful for many depressed patients, both in monotherapy at nominal dosages of 150–300 mg/day, and in combination with other antidepressants at lower dosages.

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

Oggianu

Dato

Mangano

et al. 2022

Clinical Translational Sci

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Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow different administration schedules and may be useful to facilitate patients’ compliance to the antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro and in vivo information on trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO) after single and repeated dosing of the IR formulation and repeated dosing of the OAD formulation in healthy subjects. Receptors included in the simulations were selected using static calculations of RO based on the maximum unbound brain concentration (Cmax,brain,u) of trazodone for each formulation and dosing scheme, resulting in 16 receptors being simulated. Seven receptors were simulated for the IR low dose formulation (30 mg), with similar tonset and duration of coverage (range: 0.09–0.25 h and 2.1–>24 h, respectively) as well as RO (range: 0.64–0.92) predicted between day 1 and day 7 of dosing. The 16 receptors evaluated for the OAD formulation (300 mg) showed high RO (range: 0.97–0.84 for the receptors also covered by the IR formulation and 0.73–0.48 for the remaining) correlating with affinity and similar duration of time above the target threshold to the IR formulation (range: 2–>24 h). The dose‐dependent receptor coverage supports the multimodal activity of trazodone, which may further contribute to its fast antidepressant action and effectiveness in controlling different symptoms in depressed patients.

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

Cited by 5 publications

References 16 publications

The impact of single‐dose trazodone administration on plasma endogenous adrenocorticotropic hormone and serum cortisol concentrations in healthy dogs

The impact of single‐dose trazodone administration on plasma endogenous adrenocorticotropic hormone and serum cortisol concentrations in healthy dogs

Role of trazodone in treatment of major depressive disorder: an update

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

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