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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Vortioxetine is an atypical antidepressant, acting as a serotonin modulator and stimulator (Alvarez et al. 2014; Citrome 2014; Dhir 2013; Garnock-Jones 2014; Pearce and Murphy 2014; Sanchez et al. 2015). It was approved in September 2013 by the FDA for the treatment of major depressive disorder in adults. Vortioxetine binds with high affinity to the human serotonin transporter (K1= 1.6 nM), but not to the norepineph-rine (Ki = 113 nM) or dopamine (Ki > 1000 nM) transporters (Bang-Andersen et al. 2011). Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50 = 5.4 nM). Vortioxetine binds to 5-HT3 with a Ki of 3.7 nM, 5-HT1A with a Ki of 15 nM, 5-HT7 with a Ki of 19 nM, 5-HT1D with a K, of 54 nM, and 5-HT1, with a Ki of 33 nM and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist; 5-HT1B receptor partial agonist; and 5-HT1A receptor agonist (Bang-Andersen et al. 2011). The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose proportional when vortioxetine is administered once daily (Dubovsky 2014). Absolute oral bioavailability is 75%. The drug reaches Cmax within 7 to 11 h postdosing, and its mean t1/β is ~66 h (Dubovsky 2014). Steady-state plasma concentrations are typically reached within 2 weeks. Vortioxetine is extensively metabolized primarily through oxidation via hepatic CYP2D6, 3A4/5, 2C19, 2C9, 2A6, 2C8, and 2B6 and subsequent glucuronic acid conjugation (Hvenegaard et al. 2012). CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite (Hvenegaard et al. 2012).
Pharmacological management of post-stroke depression: an update of the evidence and clinical guidance
Published in Expert Opinion on Pharmacotherapy, 2021
Janne Kaergaard Mortensen, Grethe Andersen
Several new antidepressants have been developed in the past years, but their use in post-stroke depression is yet to be studied. Vortioxetine, a serotonin modulator and stimulator, acting as a 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, a partial 5-HT1A and 5-HT1B receptor agonist and a 5-HT transporter inhibitor were approved by the American Food and Drug Administration in 2013 [29]. It has been studied in geriatric patients and evidence suggests it improves cognitive function, notably psychomotor speed, and executive function, independently of improvement in depressive symptoms. It has thus been suggested that this drug may be a promising alternative in depressed patients with cognitive dysfunction [30]. It has also been studied as a potential add-on treatment in SSRI-resistant major depressive disorder and appears to be relatively well tolerated [29,31].
Safety considerations for prescribing SSRI antidepressants to patients at increased cardiovascular risk
Published in Expert Opinion on Drug Safety, 2022
Janne Kaergaard Mortensen, Grethe Andersen
Patients with a history of stroke or myocardial infarction are likely to have one or more risk factors for QTc prolongation regardless of antidepressant treatment. They are, on average, older and have an increased risk of structural heart disease, other comorbidity and a greater risk of receiving co-medication with the potential of creating unwanted interactions. When treating patients at increased cardiovascular risk, which for all practical purposes would include all patients with previous MI and most patients with a history of stroke, special caution toward preventing QTc and TdP is warranted. Based on the FDA’s ‘thorough QT studies’ choosing a different SSRI than citalopram is often recommended. It should be noted, however, that there are no similar ‘thorough QT studies’ on the other SSRIs acquitting them from prolonging the QTc. The preference of certain other SSRIs is therefore primarily based on a lack of a documented effect on the QTc interval. Finally, it should be taken into consideration that the increased risk of depression associated with stroke and MI in itself may increase the risk of poor cardiac outcome. To abstain from treatment based on a theoretical concern of TdP could end up causing more harm to these patients. If a patient experiences unacceptable side effects or has no effect of treatment with an SSRI, there are several newer antidepressants to consider [30]. Vortioxetine a serotonin modulator and stimulator, acting as a 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, a partial 5-HT1A and 5-HT1B receptor agonist and a 5-HT transporter inhibitor has been studied in geriatric patients and appears to be relatively well tolerated [31]. More studies on the use of these newer antidepressants in patients at increased cardiovascular risk are warranted, however.
Considerations when selecting an antidepressant: a narrative review for primary care providers treating adults with depression
Published in Postgraduate Medicine, 2023
C. Brendan Montano, W. Clay Jackson, Denise Vanacore, Richard Weisler
4.4.1 Vilazodone and vortioxetine: Vilazodone and vortioxetine are more recent entries to the antidepressant space, and each may be considered a “serotonin modulator and stimulator” or multimodal antidepressant [12,51]. Vilazodone appears to have a lower risk of weight gain and sexual side effects than the SSRIs or SNRIs based on noncomparative trials [12,52,53]. Vilazodone should be taken with food to ensure adequate absorption, and a titrated dosing schedule is recommended to minimize GI effects that are frequently observed [48,53].