Expert Opinion on Drug Safety ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieds20 Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review Javier De Diego-Adeliño, José Manuel Crespo, Fernando Mora, Adrián Neyra, Pedro Iborra, Luis Gutiérrez-Rojas & Selman F. Salonia To cite this article: Javier De Diego-Adeliño, José Manuel Crespo, Fernando Mora, Adrián Neyra, Pedro Iborra, Luis Gutiérrez-Rojas & Selman F. Salonia (2022) Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review, Expert Opinion on Drug Safety, 21:5, 673-690, DOI: 10.1080/14740338.2022.2019705 To link to this article: https://doi.org/10.1080/14740338.2022.2019705 © 2021 The Author(s). Published by Informa Published online: 29 Dec 2021. UK Limited, trading as Taylor & Francis Group. Submit your article to this journal Article views: 13475 View related articles View Crossmark data Citing articles: 8 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieds20 EXPERT OPINION ON DRUG SAFETY 2022, VOL. 21, NO. 5, 673–690 https://doi.org/10.1080/14740338.2022.2019705 REVIEW Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review Javier De Diego-Adeliño a, José Manuel Crespob, Fernando Mora c , Adrián Neyrad, Pedro Iborra e , Luis Gutiérrez- Rojas f and Selman F. Saloniag a Department of Psychiatry, Hospital de La Santa Creu I Sant Pau, Institut d’Investigació Biomèdica Sant Pau (Iib-sant Pau), Universitat Autònoma de Barcelona (Uab), Centro de Investigación Biomédica En Red de Salud Mental (Cibersam), Spain; bDepartment of Psychiatry, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain; cDepartment of Psychiatry, Hospital Universitario Infanta Leonor, Madrid, Spain; dDepartment of Psychiatry, Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain; eDepartment of Psychiatry, San Juan University Hospital, Alicante, Spain; f Department of Psychiatry, San Cecilio University Hospital, Granada, Spain; gDepartment of Psychiatry, CSM Yecla-Jumilla, Spain ABSTRACT ARTICLE HISTORY Introduction: Vortioxetine is a multimodal-acting antidepressant that provides improvements on Received 25 March 2021 cognitive function aside from antidepressants and anxiolytic effects. Vortioxetine has been found to Accepted 14 December 2021 be one of the most effective and best tolerated options for major depressive disorder (MDD) in head-to- KEYWORDS head trials. Antidepressant; cognition; Areas covered: The present review intends to gather the most relevant and pragmatic data of efficacy; interactions; major vortioxetine in MDD, specially focusing on new studies that emerged between 2015 and 2020. depressive disorder; Expert opinion: Vortioxetine is the first antidepressant that has shown improvements both in depres­ neurotransmission; sion and cognitive symptoms, due to the unique multimodal mechanism of action that combine the pharmacology; safety; 5-HT reuptake inhibition with modulations of other key pre- and post-synaptic 5-HT receptors (agonism vortioxetine of 5-HT1A receptor, partial agonism of 5-HT1B receptor, and antagonism of 5-HT3, 5-HT1D and 5-HT7 receptors). This new mechanism of action can explain the dose-dependent effect and can be respon­ sible for its effects on cognitive functioning and improved tolerability profile. Potential analgesic and anti-inflammatory properties observed in preclinical studies as well as interesting efficacy and toler­ ability results of clinical studies with specific target groups render it a promising therapeutic option for patients with MDD and concomitant conditions (as menopause symptoms, pain, inflammation, apathy, sleep and/or metabolic abnormalities). 1. Introduction monoamine oxidase inhibitors (MAOI), which are assumed to Major Depressive Disorder (MDD) is one of the most common have superior efficacy at least in severe, hospitalized and/or psychiatric disorders worldwide [1]. It encompasses a variety of treatment-resistant patients [9,10] but are also associated with changes in emotional, cognitive, vegetative and behavioral more tolerability and toxicity concerns. These problems are dimensions, including depressed mood, diminished interests related to non-desired antagonistic effects on histaminergic, and/or pleasure, concentration and/or memory problems, inde­ muscarinic and α-adrenergic receptors, and also to the cisiveness, guilty and hopelessness feelings, suicidal thoughts, increased tyramine sensitivity in the case of MAOI [11,12]. anxiety, pain or psychosomatic complaints, fatigue, psychomo­ Thus, selective reuptake inhibitors (SSRIs), mainly targeting tor inhibition and changes in appetite and sleep patterns, with the serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT), a significant psychosocial impact [2]. Impaired cognitive func­ have become the most prescribed first-line antidepressants tion ─one of the most common residual symptoms in MDD [3], besides serotonin/norepinephrine reuptake inhibitors (SNRIs), has been repeatedly related to negative outcomes [4,5]. which block both 5-HT and norepinephrine (NE) transporters Epidemiological studies suggest that less than a half of MDD [13]. Others act by inhibiting NE or both NE and dopamine patients will recover without suffering new episodes and at transporters (such as reboxetine and bupropion, respectively). least 15% of them will have a chronic unremitting course By contrast, other atypical antidepressants include antagoniz­ [6,7]. Therefore, it is not surprising that MDD has become one ing actions on 5-HT postsynaptic receptors with very weak or of the leading contributors to disability worldwide and a non- no inhibiting effects on 5-HT transporter, such as trazodone - negligible cause of premature mortality [8]. which blocks 5-HT2 and partially 5-HT1A receptors-, mirtaza­ Although other neurobiological systems are being studied pine and mianserine—which block 5-HT2, 5-HT3 and pre- as potential new therapeutic targets, nowadays, monoamine- synaptic α2-adrenergic receptors- or even agomelatine— based antidepressants represent the main therapeutic tool for which is a melatoninergic agonist and a selective 5-HT2C MDD. These include the ‘classical’ tricyclic antidepressants and antagonist-. Besides their effects enhancing monoaminergic CONTACT Luis Gutiérrez-Rojas gutierrezrojas@ugr.es San Cecilio University Hospital, Granada, Spain © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 674 J. DE DIEGO-ADELIÑO ET AL. 2. Pharmacological profile and preclinical studies Article highlights Vortioxetine is orally administered once daily at 5–20 mg ● Vortioxetine is a multimodal-acting antidepressant specifically doses (either as tablets or drops) and is slowly absorbed designed to inhibit serotonin reuptake and interact with several serotonin receptors exerting modulatory effects on multiple neuro­ with an absolute bioavailability of 75%. It has a linear and transmitter systems. dose proportional pharmacokinetics, with a mean terminal ● Is the first antidepressant drug with proven efficacy in improving half-life of approximately 66 h, and steady-state plasma con­ cognitive symptoms of depression and is the only antidepressant agent showing evidence of a positive effect on multiple cognitive centration generally achieved within 2 weeks of dosing. No domains. dose adjustments are needed for age, gender, any grade of ● Is useful in symptoms as anhedonic, psychical symptoms, sleep renal or hepatic dysfunction [23–25]. Food does not appear to disturbances, and suicidal ideation. ● Vortioxetine has shown no clinically relevant effect on blood pres­ affect vortioxetine’s absorption [23,24,26]. Although alcohol sure, ECG parameters including the QTcF interval, does not increase intake is not advised during antidepressant treatment, coad­ lipid or cholesterol, and showed a decrease in glycosylated hemoglo­ ministration with vortioxetine was well-tolerated with no rele­ bin suggesting amelioration in metabolic control with vortioxetine. ● Vortioxetine has a mean terminal half-life of approximately 66 h, vant pharmacokinetic or pharmacodynamic interactions [26]. which is long enough to avoid the presence of discontinuation Vortioxetine is extensively metabolized through oxidation symptoms following abrupt discontinuation of treatment with via cytochrome P450 isozymes (CYP), mainly CYP2D6 but also vortioxetine. CYP3A4/5, CYP2A6, CYP2C9, and CYP2C19. CYP2D6 metabo­ This box summarizes key points contained in the article. lism converts vortioxetine to its principal inactive metabolite (Lu AA34443), which remains in plasma over 72 h [23–25]. It is extensively metabolized by the liver (99%), so very small amounts of drug are excreted in urine (<1%) [23–25]. synaptic transmission, all these antidepressants induce Vortioxetine is the first so-called multimodal 5-HT agonist changes in intracellular signaling pathways, key gene expres­ and antagonist AD, with different functional activities at dif­ sion and neural plasticity presumably related to their efficacy ferent 5-HT neuronal targets including blockade of SERT, [14]. Unfortunately, their mechanisms of action are not always agonism of 5-HT1A receptor, partial agonism of 5-HT1B recep­ so selective and they cause undesirable adverse-effects (AE). tor, and antagonism of 5-HT3, 5-HT1D and 5-HT7 receptors [27]. SSRIs and SNRIs, to varying degrees, are associated with sexual The potency rank order measured in rat brains was 5-HT3 dysfunction, nausea, insomnia, sweating, somnolence, fatigue > SERT>5-HT1B>5-HT1A≈5-HT7. Therapeutic doses (5–20 mg/ and weight-gain, emotional blunting and, in case of abrupt day) in humans correspond to 50 to >80% SERT occupancy. withdrawal, can produce dizziness, nausea, anxiety or irritabil­ Considering 5-HT1A and 5-HT7 receptor affinities in humans are ity [15]. Noradrenergic antidepressants are better tolerated in >10-fold higher than in rats, 5-HT3 receptors and SERT would terms of sexual functioning; however, they can be associated be occupied at lower doses while also 5-HT1B, 5-HT1A and 5- with insomnia, anxiety, agitation, tachycardia or hypertension HT7 receptors at higher doses [27]. [16]. Mirtazapine and trazodone, commonly used in combina­ Preclinical studies suggest that vortioxetine may exert its tion with other antidepressants for their sleep-promoting and antidepressant activity by modulating neurotransmission in anxiolytic effects, can cause sedation, dizziness, weight-gain or multiple systems, including 5-HT, NE, dopamine, acetylcholine, even metabolic abnormalities [17–19]. Therefore, there is histamine, glutamate, and gamma-aminobutyric acid (GABA) a need for new treatments with more selective mechanisms systems [27]. Vortioxetine produced antidepressant-like of action, better efficacy, safety and tolerability profiles. responses and stimulated hippocampal neurogenesis in Vortioxetine is already approved for the treatment of MDD an SERT Met172 mouse model, in which 5-HT reuptake inhibi­ in 83 countries, including US, Europe, Canada, Chile, China, tory potency for antidepressants is seriously impaired [28]. It Japan, Mexico, Argentina, South Korea, Turkey, Australia, Hon demonstrated that vortioxetine’s effects on other targets Kong, Singapore, and South Africa. This differs from other beyond SERT inhibition are crucial to explain its efficacy. This antidepressants on their particular multimodal profile, com­ was also underscored by studies using the progesterone with­ bining the 5-HT reuptake inhibition with modulations of other drawal [29] and the tryptophan depletion [30] models of key pre- and post-synaptic 5-HT receptors [20]. These addi­ depression in which regular 5-HT antidepressants have tional targets differentiate vortioxetine from other SSRIs and shown to be ineffective. Vortioxetine, but not an SSRI or an SNRIs and can be responsible for its further effects on cogni­ SNRI showed antidepressant-like effects in both models tive functioning and improved tolerability profile [20,21]. [29,30]. Moreover, even without having a recognizable affinity Vortioxetine has been thoroughly investigated and more for glutamate receptors, vortioxetine reversed biochemical data are available each year supporting its efficacy and safety changes produced by tryptophan depletion, including several in MDD. In a meta-analysis comparing the 21 newest antide­ markers of glutamatergic activity [30]. Vortioxetine’s antago­ pressants for the acute treatment of MDD, vortioxetine was nistic effects on 5-HT3 receptors in GABAergic interneurons found to be one of the most effective and best tolerated can attenuate the inhibitory control over prefrontal pyramidal option in head-to-head clinical trials (CT) [22]. Other indirect cells and may underlie these findings [31]. comparisons have underlined its good balance of efficacy and Glutamatergic signaling and neuroplasticity attain signifi­ tolerability [21]. Current review intends to gather all relevant cant roles in depression pathophysiology and antidepressant studies of vortioxetine in MDD, specially focusing on those response [32]. Postmortem studies revealed smaller size and emerged between 2015 and 2020. density of neurons and loss of glial cells and dendrites in EXPERT OPINION ON DRUG SAFETY 675 frontal cortex and hippocampus of MDD patients [33], being brain levels of the anti-inflammatory cytokine IL-4 and an altered expression of synaptic-function-related genes decreased the hippocampal expression of the transcription a possible explanation [34]. An acute administration of vortiox­ factor NF-kB p65 that induces pro-inflammatory and oxidative etine (but not fluoxetine or ketamine) transiently increased the effects [42]. Vortioxetine could have superior anti- expression of several genes involved in neuroplasticity and in inflammatory properties than other antidepressants and its serotoninergic and glutamatergic neurotransmission in the rat use in patients displaying inflammatory abnormalities are cur­ frontal cortex [32]. In another study, vortioxetine, contrary to rently on-going [43,44]. fluoxetine, induced positive changes in spine number and In summary, its differential action on several 5-HT targets density and dendritic morphology in the rat hippocam­ and the ability to modulate a wide range of neurotransmitters pus [35]. confers vortioxetine not only antidepressant but also pro- A thorough review suggested that the blockade of 5-HT3 cognitive effects, as well as promising further analgesic and receptor is one of the crucial vortioxetine’s properties for the anti-inflammatory properties [39,40,45]. cognitive improvements observed in preclinical studies [36]. This would increase glutamatergic and serotoninergic trans­ mission as well as pyramidal neurons firing in the forebrain, 3. Therapeutic efficacy which seems crucial in facilitating cognitive processing. The The efficacy of vortioxetine in MDD has been established in agonism of 5-HT1A receptors, the partial agonism of 5-HT1B many short (6–8 weeks) and long-term (up to 52 weeks) stu­ receptors and the antagonism of 5-HT7 receptors by vortiox­ dies, with broad beneficial effects on emotional, anxious, phy­ etine can also contribute to these effects. Moreover, down­ sical, and cognitive symptoms. Specifically, effects of stream modulation of several neurotransmitters such as vortioxetine have been evaluated against placebo and active dopamine, NE, acetylcholine or histamine in the medial pre­ comparators such as venlafaxine, duloxetine, agomelatine, frontal cortex, as well as the enhancement in neurogenesis escitalopram or paroxetine. and neurotrophic processes in the hippocampus, can be addi­ tional mechanisms contributing to the vortioxetine’s procog­ nitive profile. Vortioxetine has also shown to cause spectral 3.1. General antidepressant effects changes in quantitative electroencephalography (qEEG) which A meta-analysis 1 favors the treatment. For acceptability: OR< 1 favors the treatment. Reproduced from Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10,128):1357–1366. DOI: 10.1016/S0140-6736(17)32,802–7. memory, and processing speed. These can be present among subjective cognitive deficits at week 12 strongly correlated patients with recurrent episodes but also among those with changes in work productivity at week 12 and 52 and indepen­ their first depressive episode [49] and frequently persist after dently predicted subsequent functioning outcomes. To wit, remission [3]. patients on vortioxetine who perceived cognitive function A meta-analysis [50] showed that antidepressants overall improvements also improved their workplace productivity had a positive effect on psychomotor speed domain[[and [56]. Interestingly, findings from previously mentioned delayed recall, but, after removing vortioxetine from the ana­ FOCUS study, demonstrated that vortioxetine’s cognitive- lysis, statistical significance for the former vanished. In the enhancing effects in both subjective and objective functioning analyses, vortioxetine displayed the largest effect size on psy­ measures were even more pronounced on working patients, chomotor speed, executive control and cognitive control particularly in those whose job places higher demands on domains. In another meta-analysis, vortioxetine obtained the executive functioning [57]. largest improvements in Digit Symbol Substitution Test During the last few years, the pro-cognitive benefits of (DSST), a neurocognitive test that integrates several domains vortioxetine has been tested by other randomized CT focused affected in MDD patients. Among all investigated antidepres­ on patients with cognitive residual symptoms and partially or sant classes, multimodal-acting vortioxetine was the only one fully remitted MDD [48], as well as on patients with inade­ that provoked significant changes on that task (Figure 2) [51]. quate response to SSRI or SNRI and persisting cognitive com­ Indeed, vortioxetine has shown direct cognitive-enhancing plaints [58]. In these cases, numerical differences favoring effects in a multi-domain fashion both in older and younger vortioxetine vs SSRI were seen across different secondary depressed adults with MDD. A post-hoc analysis of data from cognitive endpoints but primary outcomes were not met. one of the largest placebo-controlled vortioxetine CT (FOCUS A comprehensive review delves into it [36]. study, n = 602), showed that it resulted in general and multi- As previously announced, enhanced glutamatergic trans­ domain benefits on cognitive performance, including executive mission in prefrontal cortex through 5-HT3 or 5-HT7 antagon­ function, attention/speed of processing and memory domains ism, or 5-HT1A and 5-HT1B agonism, downstream effects on [52]. A meta-analysis revealed that vortioxetine, but not dulox­ other neurotransmitter systems or hippocampal neuroplasti­ etine, significantly improved cognitive function compared to city elicited by vortioxetine can underlie positive cognitive placebo. Moreover, a post-hoc analysis of data from an CT includ­ effects observed in CT [36]. Subtle spectral changes with ing arms with vortioxetine and duloxetine [53], showed that, vortioxetine have been described by means of qEEG [59]. although both outperformed placebo on depressive symptom A functional MRI study demonstrated direct effects of vortiox­ improvements, only vortioxetine led to robust effects on func­ etine on fronto-limbic networks and executive function, tional capacity. The more the baseline functional impairment, the regardless of its antidepressant effects [60]. Soon after more the functional improvement with vortioxetine. Remarkably, 2 weeks, vortioxetine reduced neural activity in regions typi­ changes in cognitive and functional capacity were direct and cally over-active in acute MDD (i.e. dorsolateral prefrontal independent of antidepressant effects [53,54]. cortex and hippocampus) in relation to a decrease on subjec­ Cognitive dysfunction in MDD plays a key role in work- tive cognitive complaints and executive functioning tasks. related disability. In the so-called AtWoRC study, vortioxetine Overall, it showed direct effects on fronto-limbic networks yielded substantial long-term improvements in mood, cogni­ and cognitive function, regardless of its antidepressant effects. tive and function in a large sample of gainfully employed While age-related cognitive decline affects function and patients with acute MDD [55,56]. Positive changes in quality in the eldest, depressed mood is one of the most EXPERT OPINION ON DRUG SAFETY 677 a * TCA MAOI SSRI SNRI Vortioxetine ** -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 b Nortriptyline Desipramine Phenelzine Escitalopram Fluoxetine Citalopram Sertraline Duloxetine Vortioxetine -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 Figure 2. Standardized effect size relative to placebo. Standardized mean difference vs placebo, A: by class analysis and B: by treatment analysis. MAOI: Monoamino oxidase Inhibitors; SSRI: Selective Serotonin Reuptake Inhibitors; SNRI: Selective Serotonin–noradrenaline Reuptake Inhibitor; TCA: Tricyclic Antidepressants; * p < 0.05; ** p < 0.01. Reproduced from Baune BT, Brignone M, Larsen KG. A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients With Major Depressive Disorder. Int J Neuropsychopharmacol. 2018;21(2):97–107. Copyright (2017), with permission from Oxford University Press. DOI: 10.1093/ijnp/pyx070 common neuropsychiatric symptoms in Alzheimer’s disease functional assessments and on some cognitive outcome mea­ but data about antidepressants’ efficacy in those patients is sures. They were compared to patients who refused to take scarce [61]. Vortioxetine associated to a cognitive training antidepressants so findings have to be interpreted with the program produced greater improvements on global cognitive greatest caution. performance compared with placebo and cognitive training in Overall, vortioxetine is the first antidepressant with proved a CT with participants aged ≥65 years suffering from age- efficacy in improving multiple cognitive domains impaired in related cognitive decline without MDD, although differences MDD and it should be particularly considered for the treat­ only reached statistical significance at week 12 [62]. In an ment of MDD with prominent cognitive symptoms [66]. open-label study of patients with Alzheimer’s disease and associated depressive symptomatology, vortioxetine showed 3.3. Other specific symptom domain effects superior improvements compared to other antidepressants on a variety of cognitive domains and depressive symptoms [63]. Although pro-cognitive and general antidepressant effects of Undoubtedly, larger double-blind randomized CT are required vortioxetine in MDD have been already proved, several studies to confirm these promising observations. have focused on other specific symptom domains of consider­ Post-stroke depression is a common and serious complica­ able clinical importance such as anhedonia, physical symp­ tion [64]. To our knowledge, there was only an exploratory toms, sleep disturbances or suicidal ideation. study evaluating efficacy of vortioxetine in patients with ischemic stroke and mild-to-moderate depression [65]. 3.3.1. Anhedonia Patients on vortioxetine displayed robust and significantly Anhedonia, defined as an impaired capacity to experience or higher improvements on depressive symptoms, motor deficits, anticipate pleasure, is, together with depressed mood, one of 678 J. DE DIEGO-ADELIÑO ET AL. Figure 3. Change from baseline in SHAPS and MADRS anhedonia factor scores with vortioxetine. SHAPS: Snaith-Hamiltom Pleasure Scale; MADRS: Montgomery Åsberg Depression Rating Scale.Reproduced from Cao B, Park C, Subramaniapillai M, et al. The Efficacy of Vortioxetine on Anhedonia in Patients With Major Depressive Disorder. Front Psychiatry. 2019;10:17. DOI: 10.3389/fpsyt.2019.00017. the core symptoms that can lead to the diagnosis of a MDD on depression-related physical symptoms, namely fatigue or [2]. It is estimated to be present up to 70–75% of patients with low energy, somatic anxiety such muscle tension, headaches acute MDD and is associated with poor prognosis and sub­ or other pain complaints, genital symptoms and sleep, appe­ optimal response [67,68]. An open-label CT of 100 patients tite, or weight disturbances, among many others [73]. These with MDD treated with vortioxetine (10–20 mg/day, flexible symptoms are frequently present in the acute episode of MDD doses) demonstrated a clear and significant improvement in but are also common residual chronic symptoms and they are this particular symptom domain. Improvement in anhedonia often associated with comorbid anxiety disorders, exerting after vortioxetine treatment was correlated with functional a negative impact on clinical and prognostic outcomes [74]. recovery and quality of life (Figure 3) [67]. In fact, amelioration Vortioxetine demonstrated a broad symptom relief in patients of anhedonia with vortioxetine had a direct beneficial impact with MDD, including in those with high levels of anxiety, on social functioning, independent from global antidepressant showing significant improvements in most of the physical effects. symptoms assessed (Figure 4) [73]. Although subjective measures of anhedonia and objective Effects of vortioxetine on sleep disturbances and sleep measures of motivation and reward processing could repre­ quality associated with MDD have been studied in more sent dissociable domains of the same psychopathological depth in another open-label 8-week clinical trial of 92 phenomenon, a study revealed that cognitive performance depressed patients treated with flexible doses of vortioxetine at the end of a treatment period with vortioxetine in (10–20 mg/day) [75]. Vortioxetine doubled and tripled the a cohort of patients with MDD highly correlated with the proportion of patients without insomnia and the proportion willingness to expend effort for hard task rewards. Since it is of good sleepers, respectively, at the end of the follow-up. By just an analysis of cross-sectional data, inferences should be contrast, the percentage of patients with moderate-to-severe drawn with caution, but the current results would suggest that insomnia decreased after 8 weeks of treatment with vortiox­ pro-cognitive properties of vortioxetine might be linked to etine. Of note, improvements in sleep quality were correlated putative positive effects on reward and hedonic proces­ with an overall improvement of depressive symptoms and sing [69]. they were predictive of antidepressant response. On the other hand, emotional blunting, a closely related A retrospective analysis of the vortioxetine’s effects on sleep concept that encompass feelings of detachment or reduced disturbances in MDD by another observational study found emotional responses, has also been described as a common that benefits of vortioxetine on sleep quality and depressive subjective AE in patients treated with SSRIs with a significant symptoms were maintained after 6 months [76]. impact on their daily functioning and quality of life [70,71]. In fact, treatment-emergent insomnia and treatment- A preliminary report showed that vortioxetine produced sig­ emergent somnolence after treatment with vortioxetine nificant reductions of depressive symptoms in a sample of 143 seems to be rare and rates are much lower than with other patients with MDD and associated emotional blunting who antidepressants such as SSRIs or SNRIs [77]. Clinical and had failed to respond to an adequate trial of SSRI o SNRI. After preclinical polysomnographic studies have shown that SSRIs 8 weeks of treatment with vortioxetine, the mean change from can facilitate wakefulness producing acute and long-term baseline in OQD total score was −29.8 (p < 0.0001) with REM sleep suppression and reduction in REM onset latency significant changes from week 1, and 50% of the patients [78]. Both of these effects are believed to be related with the reported no more blunting of their emotions in answer to increased synaptic 5-HT levels promoted by reuptake inhibi­ the standardized screening question [72]. tion and their actions on 5-HT1A receptors, but 5-HT3 recep­ tors appear to play an additional crucial role. Two 3.3.2. Physical-symptoms and sleep disturbances interrelated polysomnographic studies with healthy volun­ A meta-analysis using data from five short-term placebo- teers and rats, respectively, demonstrated that the antago­ controlled studies was aimed to establish its potential benefits nistic properties of vortioxetine on 5-HT3 receptors are EXPERT OPINION ON DRUG SAFETY 679 Item 16 *** Item 14 *** Item 13 * Item 12 *** Item 11 * Item 6 ** *** Item 5 ** *** Item 4 -0.40 -0.30 -0.20 -0.10 0.00 0.10 VOR 10 mg VOR 5 mg Figure 4. Change from baseline in HAM-D single items at week 6/8. * p < 0.05; ** p < 0,01; *** p < 0,001. Results as difference to placebo. HAM-D: Hamilton Depression Scale. Item 4 – Insomnia Early: complains of occasional difficulty falling asleep, i.e. more than ½ hour, or complains of nightly difficulty falling asleep. Item 5 – Insomnia Middle: patient complains of being restless and disturbed during the night or waking during the night. Item 6 – Insomnia Late: waking in early hours of the morning but goes back to sleep or unable to fall asleep again if getting out of bed. Item 11 – Anxiety Somatic: physiological concomitants of anxiety, such as gastrointestinal – dry mouth, wind, indigestion, diarrhea, cramps, belching, cardiovascular (palpitations, headache), respiratory (hyperventilation, sighing, urinary frequency, sweating). Item 12 – Somatic Symptoms-Gastrointestinal: loss of appetite but eating without staff encouragement, heavy feelings in abdomen, difficulty eating without staff urging, requests or requires laxatives or medication for bowels or medication for GI symptoms. Item 13 – Somatic Symptoms-General: heaviness in limbs, back or head, backaches, headache, muscle aches, loss of energy and fatigability. Item 14 – Genital Symptoms: symptoms such as loss of libido or menstrual disturbances. Item 16 – Loss of Weight: probable weight loss associated with present illness or definite (according to patient) weight loss. Reproduced from Cronquist MC, Florea I, Lindsten A, et al. Efficacy of vortioxetine on the physical symptoms of major depressive disorder. J Psychopharmacol. 2018;32(10):1086-97. DOI: 10.1177/0269881118788826. crucial to explain the good profile of vortioxetine in sleep precludes the possibility of capture the possible anti-suicidal architecture in comparison with paroxetine [78,79]. benefits of vortioxetine or any other antidepressant in such Furthermore, vortioxetine’s blocking effects on 5-HT7 recep­ kind of studies, so data from epidemiological naturalistic stu­ tors can provide additional benefits since antagonist agents dies will be greatly welcomed. of these receptors have demonstrated to counteract SSRI- induced micro-arousals, a probable correlate of the sleep 3.4. Anxiety and other psychiatric comorbidities fragmentation induced by SSRI in some patients [80,81]. Coexistence of MDD and anxiety is common and more difficult 3.3.3. Suicidal ideation to treat than MDD alone. A meta-analysis of data from up to Epidemiological and longitudinal observational studies with 2165 depressed patients who presented with significant high real-world patients and real-world clinical settings clearly sup­ levels of anxiety (i.e. Hamilton Anxiety Rating Scale score ≥ 20) port the beneficial effects of antidepressants on suicide idea­ in 10 randomized short-term CT of vortioxetine vs placebo, tion and suicide behavior in MDD [82,83]. However, indicated that vortioxetine was also efficacious among this a controversy over presumed suicidal effects of antidepres­ population [87]. A dose-related effect favoring vortioxetine sants persist since questionable interpretations of data from was observed in most sub-analyses, suggesting than increas­ CT in children and adolescents led the U.S. Food and Drug ing doses of vortioxetine can effectively reduce both depres­ Administration to issue a black box warning about a potential sion and anxiety severity in patients with MDD and high increased risk of suicidal thoughts and suicidal behaviors anxiety levels. associated with antidepressants [84,85]. MDD and social anxiety disorder (SAD) are often associated, Nevertheless, post-hoc analyses of data from 10 short-term causing higher disability and poorer prognostic outcomes randomized, placebo-controlled studies and 3 additional long- than MDD alone with an increased risk of recurrence, chronic term open-label extension studies of up to 52 weeks duration course and suicide behavior [88]. Only a small double-blind, showed that vortioxetine was not associated with an increased placebo-controlled CT of vortioxetine at (20 mg/day) with 40 risk of suicidal ideation or suicidal behavior in adults with patients with comorbid MDD and SAD has been published so MDD [86]. It is also worth to mention that suicidal ideation is far [89]. Robust and significant reductions on dimensional a common exclusion criterion in placebo-controlled CTs and it measures for depression and social anxiety were observed 680 J. DE DIEGO-ADELIÑO ET AL. although differences on response and remission rates did not quality of life and cognitive performance. A more recent reach the required statistical level. observational retrospective 6-months study comparing effi­ Given the high prevalence of psychological trauma history cacy of vortioxetine vs paroxetine in postmenopausal in patients with MDD and the risk of suboptimal treatment women with MDD showed that both antidepressants were response among them, effects of vortioxetine were also effective in significantly reducing depressive symptoms, but explored in a meta-analysis centered on adults with MDD while paroxetine achieved greater severity reduction and, sur­ who reported childhood or recent trauma [90]. More than prisingly, better performance on a cognitive screening tool at 60% of patients in the 5 CT included reported history of either the end of the study, vortioxetine showed significantly super­ childhood or recent trauma and almost 30% reported both. ior efficacy in reducing menopausal symptoms [98]. There Vortioxetine still showed clear significant clinical benefits on were baseline differences that could affect the results, since depressive symptoms, anxiety, and overall functioning in this all patients receiving vortioxetine had needed to switch from population. Patients with any trauma randomized to placebo other previous antidepressant compared to only 12.5% of were 2.8 times to relapse than patients that blindly continued patients in paroxetine, which could explain superiority of par­ vortioxetine. oxetine on cognitive performance. Apparently, vortioxetine On the other hand, depression is the most common psy­ offer a good profile to treat MDD during menopausal and chiatric complication of alcohol use disorder and their co- perimenopausal period but further well-designed studies occurrence is accompanied with greater clinical burden and need to be conducted in this field. poorer prognostic outcomes than either single disorder [91]. Coincidence of MDD and general medical comorbidities is Additionally, as previously mentioned, vortioxetine has proved more the norm than the exception in current clinical practice, to be safe and well-tolerated after alcohol consumption [26] not only among older adult patients. It is associated with and could be even administered without restrictions in increased symptom severity, lower treatment adherence, patients with any grade of hepatic dysfunction [23,24]. In decreased quality of life, poorer outcomes and even higher this regard, preliminary clinical evidence proposes vortioxetine risk of mortality [99]. as a useful antidepressant for patients with both MDD and Several lines of research suggest a bidirectional relationship alcohol use disorder as part of an integrated therapeutic- between MDD and diabetes. While diabetes is a risk factor for rehabilitation program. In a retrospective analysis of two well- the development and recurrence of depression, MDD clearly matched clinical samples, vortioxetine demonstrated similar increased the risk of developing type 2 diabetes and is asso­ antidepressant effects among depressed patients with and ciated with poorer glycemic control, lower treatment adher­ without alcohol use disorder [92]. Depression remission rates ence and worse prognostic outcomes among patients with after 6 months of treatment were 45.6% and 57.1%, respec­ diabetes [100]. Treating depression can improve treatment tively. Interestingly, significant improvements also emerged adherence and glycemic levels in patients suffering from for both groups on anxiety scores, anhedonia, functioning both conditions but some antidepressants can negatively and quality of life-related measures, cognitive performance impact on glucose metabolism [101]. Fifty subjects with type and subjective cognitive complaints. 2 diabetes and moderate-to-severe MDD were randomized to receive vortioxetine (10 mg/day) versus sertraline (75 mg/day) for 8 weeks in a single-blind pilot study. In accordance with common compliance issues in these patients, withdrawal rate 3.5. Older people, menopause, and non-psychiatric was high (mainly due to non-adherence to antidepressants or comorbidities to follow-up visits) and only data from 21 participants that MDD among the older people is a public health problem of finished the CT (12 assigned to vortioxetine and 9 to sertraline) increasing concern that is more often presented with several was analyzed. Vortioxetine and sertraline lead to similar and psychiatric and nonpsychiatric disorders, along with higher consistent remission rates as well as improvements on dia­ rates of disability [93]. Antidepressant’s efficacy has been betes-related stress at the end of the study. However, only repeatedly called into question in older patients [93,94]. patients treated with vortioxetine showed significant reduc­ A post-hoc analysis of data from 1508 patients aged between tions in body weight, waist circumference, glycosylated hemo­ 55 and 88 years (mean age 62.4 years) who had participated in globin and triglycerides while these remain unchanged or 12 placebo-controlled CT with vortioxetine showed that vor­ even increased in patients treated with sertraline [102]. tioxetine 5–20 mg/day is also efficacious and well-tolerated in Perhaps, partial agonism of vortioxetine on 5-HT1B receptors, such population [95,96]. which can inhibit food intake and satiety and improve glucose Due to hormonal fluctuations, menopausal transition is tolerance [103,104]. a critical period for the onset of MDD in women. Menopause Depressed mood is one of the most common non-motor is often associated with vasomotor symptoms such as hot symptoms in patients with Parkinson’s Disease, with flashes and night sweats, but it could be also accompanied a reported prevalence of 30–40% overall, and is associated by fatigue, sleep disturbance, anxiety and depressive symp­ with rapid progression of motor and cognitive symptoms, as toms and cognitive complaints [97]. In an open-label study well as with worse quality of life. A 3-month clinical trial was conducted with perimenopausal and early postmenopausal designed to assess the efficacy of vortioxetine (10–20 mg/day) women with MDD, antidepressant response to vortioxetine in 150 patients with Parkinson’s Disease and comorbid MDD. was remarkable, with statistically significant improvements of Findings presented in a preliminary report showed that vor­ depression and anxiety symptoms, climacteric complaints, tioxetine was able to improve depression severity without EXPERT OPINION ON DRUG SAFETY 681 Favors Favors Favors Favors comparator vortioxetine vortioxetine comparator -16.8% 12.1% (-41.1%, 7.5%) Citalopram (-0.3%, 24.5%) -10.7% 18.3% (-27.8%, 6.4%) Bupropion SR (6.4%, 30.1%) -7.2% 12.3% (-24.3%, 9.9%) Venlafaxine XR (0.8%, 23.8%) -14.4% 12.1% Sertraline (3.1%, 21.1%) (-29.9%, 1.1%) -11.0% Agomelatine 3.6% (-19.4%, -2.6%) (-1.1%, 8.3%) 20 10 0 -10 -20 -30 -40 -50 40 30 20 10 0 -10 Risk difference (%) Risk difference (%) for remission for withdrawals due to AEs Risk difference (95% CI), vortioxetine versus comparator. AE: adverse event. Figure 5. Risk difference for remission and for withdrawal due to AEs. Risk difference (95% CI), vortioxetine versus comparator. AE: adverse event. Reproduced from Brignone M, Diamand F, Painchault C, et al. Efficacy and tolerability of switching therapy to vortioxetine versus other antidepressants in patients with major depressive ® disorder. Curr Med Res Opin. 2016;32(2):351–66. Copyright Clearance Center’s RightsLink service, with permission from Taylor & Francis. DOI: 10.1185/03007995.2015.1128404. significant worsening of motor symptoms and with a good symptomatology at follow-up but patients treated with vor­ safety profile [105]. Idiopathic REM sleep behavior disorder tioxetine showed faster improvements and significantly higher (RBD), a parasomnia characterized by loss of muscular atonia rates of response (96.6%) and remission (83.3%) at the end of during REM sleep and the emergence of complex motor the study, with very good tolerability. behaviors, has been described as a robust prodromal marker Therefore, unique attributes of vortioxetine render it of Parkinson’s disease and other synucleinopathies. a promising therapeutic option for several non-psychiatric Antidepressants can also trigger RBD, but this can also be disorders that are accompanied by pain, inflammation, apathy, associated with an increased risk of this kind of neurodegen­ sleep and/or metabolic abnormalities besides prominent erative illnesses [106]. Clonazepam and melatonin are two of depressive and anxiety symptoms. Anyhow, most of these the most recommended treatments in RBD disorder, although initial encouraging findings have to be confirmed in double- use of clonazepam in the older people and in patients with blind controlled studies. cognitive impairment has to be carefully considered due to safety concerns. By contrast, utility of paroxetine has also been 3.6. Inadequate response to first-line antidepressant suggested although is controversial since it has been useful in treatment some cases, but it can even worsen symptoms in others [107]. Burning mouth syndrome (BMS) is a disabling chronic idio­ According to the evidence gathered, vortioxetine has become pathic intraoral pain condition that is accompanied with an additional first-line option for acute MDD in adults, as it can a remarkable psychological distress increasing the risk of anxi­ be found in a recently updated clinical guideline [65]. But ety and depressive disorders. Since several neuropathic, cen­ efficacy of vortioxetine has also been studied among patients tral brain and inflammatory abnormalities have been who had failed to respond adequately to an SSRI or SNRI described underlying BMS, the use of antidepressants is gain­ therapy in an 8-week double-blind CT published by ing momentum with these patients and vortioxetine’s profile Montgomery and colleagues [109]. Two systematic reviews make it particularly indicated for both the alleviation of pain have evaluated the benefits of switching to vortioxetine by and the psychiatric comorbidities. Adamo published a first combining both direct and indirect comparisons with other open-label pilot study showing promising results in a sample antidepressants [110,111]. Vortioxetine as switch therapy of 30 patients with BMS and symptoms of anxiety and depres­ showed significant advantages in terms of efficacy, function­ sion treated with vortioxetine. Posteriorly, the same group ing, and quality of life outcomes compared to agomelatine. report the results of a larger and long-term (n = 150, Indirect analyses demonstrated that vortioxetine can also pro­ 12 months follow-up) open-label randomized study compar­ duce numerically higher remission rates and lower withdrawal ing the effectiveness and tolerability of vortioxetine (15 mg/ rates due to AE compared to other antidepressants such as day) with other four commonly prescribed SSRIs and SNRIs bupropion, citalopram, sertraline or venlafaxine (Figure 5). (paroxetine sertraline, escitalopram, and duloxetine) [108]. All In a brief ecological study, Tegin found a positive correla­ antidepressants decreased pain, anxiety, and depressive tion between minimal effective vortioxetine’s doses observed 682 J. DE DIEGO-ADELIÑO ET AL. in CT and the defined daily doses (DDD) of antidepressants in 4. Safety/Tolerability the countries where these trials were performed [112]. DDD Side effects of vortioxetine are different from other commonly can be assumed as a rough estimate of antidepressant expo­ used antidepressants, according to its low incidence of sleep sure in the source populations but it may not reflect the real disturbances, sexual dysfunction, weight gain, cardiovascular antidepressant use among studies participants. Therefore, alterations or discontinuation symptoms. As it has been dis­ findings should be interpreted with caution but, from cussed before, sleep disruptions (namely insomnia, initial a clinical practical perspective, it would imply that higher insomnia, middle insomnia, hyposomnia, sleep disorder, dys­ doses of vortioxetine are recommended in patients with pre­ somnia, poor quality sleep or terminal insomnia) were uncom­ vious antidepressant exposure. mon in published CT among patients receiving vortioxetine Nevertheless, switching antidepressant is one of the most [77], and beneficial effects on sleep quality and continuity has widely used strategy in patients who experience inadequate been observed with vortioxetine in contrast to other conven­ response or intolerable effects to SSRI or SNRI therapy tional antidepressants [75]. [113,114] and converging evidence suggests vortioxetine as Treatment-emergent sexual dysfunction (TESD) is com­ an appropriate second-line option in MDD. monly associated with antidepressants such as SSRIs and SNRIs and a common reason for treatment withdrawal among patients with MDD [120]. A pooled analysis of 7 short- 3.7. Functioning outcomes and cost-utility term CT compared the general incidence of TESD between vortioxetine, placebo and/or duloxetine in patients without Several studies have investigated functional impairment in sexual dysfunction at baseline. The results found that vortiox­ patients with MDD, which can negatively affect many aspects etine has TESD rates not significantly different from placebo, of daily life, including school, work, interpersonal relationships, while duloxetine presented a significantly higher TESD risk and overall social functioning. A meta-analysis of the data versus both placebo and vortioxetine (Table 2) [121]. from 9 short-term studies to determine the effect of vortiox­ In order to avoid confounding effects of MDD or other etine on overall patient functioning using Sheehan Disability medical comorbidities, independent effects of vortioxetine Scale (SDS), found that vortioxetine 5–20 mg for 6–8 weeks on sexual functioning were evaluated in a double-blind trial improved overall patient functioning, and vortioxetine 10 and with a large sample of healthy volunteers receiving either 20 mg demonstrated significant improvement in SDS total vortioxetine 10 mg/day or 20 mg/day, paroxetine 20 mg/day score, and functional remission compared to placebo [115]. or placebo. No significant differences of TESD were observed In another study, evaluating the effect of vortioxetine on over­ between placebo and vortioxetine at any dose although all functionality using the University of California, San Diego a trend toward dose-relationship was observed. Participants Performance-Based Skills Assessment (UPSA, performance on paroxetine showed significantly more TESD than partici­ measures of functional capacity), found that vortioxetine pants on placebo and a higher proportion of them experi­ demonstrated a significantly greater improvement compared enced a clinically meaningful decline in sexual functioning with placebo, supporting the clinical effect of vortioxetine in (44.6%) compared to those treated with vortioxetine 10 mg/ functional capacity [116]. day (23.5%, p = 0.004) and vortioxetine 20 mg/day (38%, but Given that functional recovery together with symptomatic only with a marginal significance p = 0.068) [122]. remission are the therapeutic objectives of antidepressant ther­ Switching to another efficacious and better tolerated anti­ apy, Cronquist and colleagues evaluated the combined effect of depressant is one of the most suitable strategies for patients vortioxetine on depressive symptoms and functional capacity in with TESD who need to continue antidepressant treatment 602 adult patients with MDD from a placebo-controlled, dulox­ but there are very few controlled studies that have addressed etine-referenced study, using the Montgomery Åsberg this question [123]. A double-blind randomized 8-week CT Depression Rating Scale (MADRS) and UPSA score. They found published by Jacobsen compared the benefits of switching that treatment with vortioxetine retrieved more patients classi­ from an SSRI (citalopram, paroxetine or sertraline) to flexible fied as dual responders and therefore vortioxetine demon­ doses (10–20 mg) of either vortioxetine or escitalopram in strated a robust combined effect on depressive symptoms and a sample of 447 patients with MDD in remission who suffered functional capacity in patients with MDD [117]. from TESD [121,124]. Patients treated with vortioxetine The disease burden of MDD is significant in some countries, achieved significantly greater improvements in sexual func­ and therefore a cost-utility analysis of treatments is needed to tioning compared to those treated with escitalopram (the choose the optimal treatment. Soini assessed the cost-utility SSRI with the safest profile in terms of sexual AE [120]). analyses of vortioxetine versus relevant comparators (agome­ Benefits were evident in all explored phases (i.e. desire, arousal latine, bupropion SR, citalopram, duloxetine, escitalopram, ser­ and orgasm) and antidepressant efficacy was also maintained. traline, and venlafaxine XR) in MDD patients with inadequate It is well known that increased levels of 5-HT after SERT response to previous antidepressants and found that vortiox­ blockade reduce sexual functioning, but not all 5-HT receptors etine was less costly and more effective versus all compara­ play the same role in modulating sexual behavior [125]. tors. Therefore, vortioxetine was considered a cost-effective Preclinical studies showed that vortioxetine’s agonistic effects treatment option and the greater effectiveness associated on 5-HT1A receptors could counteract the sexual AE induced with vortioxetine is an important driver for the cost savings by SERT inhibition and explain its reduced sexual side and quality of life gains accrued with vortioxetine [118,119]. effects [126]. EXPERT OPINION ON DRUG SAFETY 683 Table 2. Spontaneously reported AEs related to sexual dysfunction. Placebo Vortioxetine total Duloxetine 60 mg (n = 2230) (n = 3377) (n = 907) Incidence of any sexual AEs 23 (1.0) 74 (2.2) 52 (5.7) Incidence of sexual AEs by gender Males Females Males Females Males Females (n = 789) (n = 1441) (n = 1166) (n = 2261) (n = 281) (n = 626) Any sexual AE 13 (1.6) 10 (0.7) 44 (3.9) 30 (1.3) 40 (14.2) 12 (1.9) Libido decreased 8 (1.0) 6 (0.4) 18 (1.6) 19 (0.8) 15 (5.3) 2 (0.3) Orgasm abnormal 1 (0.1) 3 (0.2) 7 (0.6) 7 (0.3) 9 (3.2) 2 (0.3) Anorgasmia 0 1 (<0.1) 5 (0.4) 6 (0.3) 3 (1.1) 7 (1.1) Ejaculation delayed 2 (0.3) 0 6 (0.5) 0 11 (3.9) 0 Loss of libido 0 0 4 (0.4) 2 (<0.1) 0 1 (0.2) Erectile dysfunction 3 (0.4) – 5 (0.4) – 13 (4.6) – Vulvovaginal dryness – 0 – 3 (0.1) – 0 Ejaculation disorder 0 – 2 (0.2) – 2 (0.7) – Sexual dysfunction 1 (0.1) 0 2 (0.2) 0 1 (0.4) 1 (0.2) Disturbance in sexual arousal 0 0 0 1 (<0.1) 0 0 Orgasmic sensation decreased 0 1 (<0.1) 0 1 (<0.1) 0 0 Ejaculation failure 1 (0.1) 0 0 0 2 (0.7) 0 Results in n (%). Number (percentage) of patients in each treatment group who spontaneously reported AEs related to sexual dysfunction (data pooled from 10 trials in major depressive disorder and 4 trials in generalized anxiety disorder). AE: adverse event. Reproduced from Jacobsen PL, Mahableshwarkar AR, Palo WA, et al. Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major ® depressive disorder or generalized anxiety disorder: a pooled analysis. CNS Spectr. 2016;21(5):367–78. Copyright Clearance Center’s RightsLink service, with permission from Elsevier. DOI: 10.1017/S1092852915000553. Safety and tolerability of higher dosages of vortioxetine prolonged by several antidepressants and psychotropics). In was evaluated in a 52-week open-label study of patients long-term treatment studies, no new types of TEAE emerged, with MDD. Long-term treatment with vortioxetine at dosages and the mean weight gain was 0.7–0.8 kg. According to other of 15 or 20 mg once daily was safe and well tolerated, being previously referred reviews [21,22] vortioxetine showed nausea and headache the most common treatment emergent a remarkable tolerability and safety profile compared to AE (TEAE) (≥10%) [127]. other antidepressants in the treatment of MDD. Meta- Several meta-analyses have evaluated general safety and analyses that have used indirect treatment comparisons tolerability profile of vortioxetine. Two of them focused on among antidepressants based on CT of switching therapy placebo-controlled CT using fixed doses of 10 mg/day or after a failed first-line treatment attempt in MDD, showed 20 mg/day of vortioxetine, respectively [128,129]. Significant that withdrawal rates because of an AE were significantly differences compared to placebo were only evident for nausea lower for vortioxetine than for sertraline, venlafaxine or bupro­ and constipation in meta-analysis assessing safety of 10 mg/ pion [111]. In direct comparisons between vortioxetine and day, and for nausea and dry mouth in that assessing 20 mg/ agomelatine, only nausea was significantly more associated to day. Another more comprehensive review included data from vortioxetine (16.2%) than agomelatine (9.1%), but the first still 11 short-term (6–8 weeks) and 5 long-term (up to 52 weeks) had a statistically significant lower probability of withdraw controlled-studies of vortioxetine 5–20 mg/day compared to treatment due to TEAE compared with the latter (5.9% vs both placebo and active-comparator arms, namely venlafaxine 9.5%, respectively) [110]. 225 mg/day and duloxetine 60 mg/day [130]. As can be seen Although incidence of nausea with vortioxetine seems not in Table 3, it showed that withdrawal rates due to TEAE for to be higher than with other antidepressants (see Table 3), it is vortioxetine at different doses (4.5–7.1%) were slightly higher the most common TEAE leading to withdrawal in CT and compared to placebo (3.6%) but lower compared to venlafax­ shows a dose–effect relationship [130]. Nauseas are commonly ine (14.2%) or duloxetine (8.8%) in short-term studies. Patients transient, mild to moderate in intensity and typically occurred treated with vortioxetine showed no clinically relevant within the first week of treatment. But approximately 10% of changes on body weight, heart rate, blood pressure and on patients on 10–20 mg/day dose reported nausea at the end of clinical laboratory (including lipid and cholesterol) or electro­ 6–8 week CT [23]. It has also been reported that incidence of cardiogram parameters, including QTcF interval (which can be nausea in patients who had switched therapy to vortioxetine Table 3. Analysis of treatment-emergent AEs. Vortioxetine Vortioxetine Vortioxetine Vortioxetine Duloxetine Placebo 5 mg/day 10 mg/day 15 mg/day 20 mg/day Venlafaxine 225 mg/day 60 mg/day (n = 1817) (n = 1013) (n = 894) (n = 449) (n = 662) (n = 113) (n = 753) Patients withdrawn due to TEAEs 65 (3.6) 46 (4.5) 43 (4.8) 35 (7.8) 47 (7.1) 16 (14.2) 66 (8.8) Patients with TEAEs 1052 (57.9) 657 (64.9) 546 (61.1) 309 (68.8) 433 (65.4) 85 (75.2) 571 (75.8) Insomnia 73 (4.0) 52 (5.1) 33 (3.7) 9 (2.0) 22 (3.3) 18 (15.9) 61 (8.1) Sexual dysfunction 18 (1.0) 16 (1.6) 16 (1.8) 7 (1.6) 12 (1.8) 14 (12.4) 34 (4.5) Nausea 148 (8.1) 212 (20.9) 208 (23.3) 140 (31.2) 184 (27.8) 38 (33.6) 257 (34.1) Results in n (%). Data pooled from 11 short-term studies. AE: adverse event; TEAEs: treatment-emergent adverse events. Reproduced from Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016;30(3):242-52. Copyright (2016), with permission from SAGE Publications. DOI: 10.1177/0269881116628440. 684 J. DE DIEGO-ADELIÑO ET AL. is lower than in treatment-naïve individuals who received 5. Interactions vortioxetine for the first time [110]. Vortioxetine is primarily metabolized by the CYP2D6 enzyme Antidepressant-induced nausea is thought to be [24], but there are also other CYP enzymes involved in its mediated via 5-HT3 receptor activation in either the brain metabolism. Therefore, there may be potential drug–drug and/or the gut [131], and eventual desensitization of these interactions with drugs that are substrates of the same CYP receptors would dissipate nauseas within few days. enzymes [24]. These effects have been evaluated in studies Vortioxetine’s potent antagonism of 5-HT3 receptors should with healthy volunteers. provide it with a neutral gastrointestinal profile from the Co-administration of vortioxetine has no effects on the phar­ beginning. However, basic research has proven that vortiox­ macokinetics (PK) of warfarin, rifampicin, fluconazole, diazepam, etine’s inhibitory activity at 5-HT3 receptors differs from midazolam, caffeine, tolbutamide, ethinyl estradiol, levonorges­ other competitive antagonists, and it might induce a brief trel, aspirin, ethanol, or lithium [24,26,137]. Multiple doses of initial agonistic response [132]. Accordingly, some case- vortioxetine showed no substantial effects on the PK of caffeine reports have suggested splitting daily dosage or even com­ (CYP1A2 substrate), tolbutamide (CYP2C9 substrate) and mida­ bining with a different 5-HT3 antagonist as mirtazapine to zolam (CYP3A4/5 substrate), and minimal or negligible effects prevent the onset of nauseas [133]. On the other hand, 5- on the PK of dextromethorphan (CYP2D6 substrate), bupropion HT3 antagonists such as ondansetron or granisetron, com­ (CYP2B6 substrate) and omeprazole (CYP2C19 substrate), which monly used to treat chemotherapy-induced emesis, are actu­ indicates that vortioxetine was not a relevant inhibitor or indu­ ally much better preventing vomiting than nausea and the cer of any of these CYP enzymes [24]. physiopathological mechanisms underlying nausea appear much harder to describe than those underlying vomiting A study conducted with healthy subjects tried to determine [134]. Beyond 5-HT3 receptors, there is evidence for an the incidence of PK and pharmacodynamic alterations of vor­ involvement of many other types of 5-HT receptors on tioxetine co-administered with ethanol, diazepam, and lithium emesis, including 5-HT1A, although their role is difficult to in three separated substudies. None of the PK parameters of understand. In fact, some 5-HT1A agonists appear to have any assayed substances suffered modifications due to the antiemetic properties but others, like buspirone or repino­ combined administration with vortioxetine. Regarding phar­ tan, can really cause nausea and vomiting [135]. macodynamics, the co-administration of vortioxetine together Interestingly, in post-hoc analyses of the study of Jacobson with ethanol or diazepam did not entail more deleterious [124], it was observed that nausea rates in patients pre­ effects on psychomotor or cognitive performance than admin­ viously treated with an SSRI, although transient, were sig­ istration of ethanol or diazepam alone [26]. nificantly higher in those switching to vortioxetine (ranging Another study with healthy subjects also explored the 20–29.2%) than to escitalopram (ranging 3.3–6.1%). potential existence of interactions between vortioxetine Desensitization of 5-HT3 receptors in such patients can be and several inductors, inhibitors, and substrates of different presupposed; therefore, it is reasonable to conclude that, type of P450 cytochrome (CYP). Vortioxetine did not modify besides its particular 5-HT3 binding pattern, other vortioxe­ the PK parameters of any of the other drugs, such as rifam­ tine’s mechanisms of action, like 5-HT1A agonism, could be picin, fluconazole, omeprazole, bupropion and ethinyl estra­ involved in transient treatment induced nausea associated diol/levogestrel. However, maximum concentrations and with this multimodal acting AD. AUC of vortioxetine significantly increased after co- Sudden interruption of treatment with SSRIs or SNRIs can administration with bupropion and were decreased after co- yield the onset of several emotional (worsening mood and administration with rifampicin [137]. It would mean that, if anxiety) and/or physical symptoms (flu-like and shock-like the combination of vortioxetine and bupropion is consid­ complaints, dizziness, sleep disturbances, etc.) which is often ered clinically appropriate for a certain patient with MDD, known as ‘discontinuation’ or ‘withdrawal’ syndrome [136]. It then the dose of vortioxetine should be reduced by half. is often mild and transient but sometimes is more intense and Conversely, the combination of vortioxetine with rifampicin long-lasting and can be misidentified as signs of relapse. They may require an increase of the vortioxetine dose up to three are commonly related to agents with shorter half-lives and times the original dose [24]. high potency, such as venlafaxine and paroxetine [136]. The increased risk of bleeding and hemorrhagic stroke Vortioxetine therapy can be interrupted abruptly since its associated to the use of SSRIs and SNRIs is well known [138], long terminal half-life (approximately 66 h) makes it particu­ being even higher in the older people and in combination larly safe to avoid the emergence of a discontinuation with antithrombotic, platelet antiaggregant or nonsteroidal syndrome. antiinflammatory drugs (NSAID). A placebo-controlled trial In summary, the more frequent TEAE of vortioxetine are comparing co-administration of aspirin, warfarin and vortiox­ nausea and vomiting, both usually transitory and dose depen­ etine, did not show relevant modifications in the PK para­ dent. Data from CT with vortioxetine showed a low incidence of meters, nor in the coagulation times or the international sleep disruption, sexual dysfunction and discontinuation syn­ normalized ratio (INR). However, the absence of risks may drome, with neither relevant cardiovascular nor weight altera­ not be ruled out considering the sample size used in this tions, and with beneficial effects on sleep quality. Therefore, study, and the concomitant use should be done with caution vortioxetine displays fairly benign safety and tolerability profiles. until more safety studies are available [139]. EXPERT OPINION ON DRUG SAFETY 685 Antidepressant agents are often prescribed to women with duloxetine, and vortioxetine had the largest improvements in breast cancer; however, as tamoxifen is a standard of care in cognitive function versus other antidepressants (citalopram, breast cancer and some antidepressants are substrates or escitalopram, nortriptyline, phenelzine, and sertraline). inhibitors of the tamoxifen metabolic pathway, there may be Vortioxetine demonstrated long-term benefits in working interactions when prescribed simultaneously, so that tamox­ patients with MDD. ifen may become less effective or null. A review of basic and Vortioxetine showed significant improvements in depres­ clinical evidence for choosing an antidepressant agent in sive symptoms associated to improvements in sleep. women receiving tamoxifen, concluded that citalopram, des­ Considering that sleep impairment is a frequent comorbid venlafaxine, escitalopram, milnacipran and vortioxetine were symptom in patients affected by MDD, vortioxetine could be the antidepressants with fewer AE and better global pro­ considered for treating depressive symptoms and improving file [140]. sleep quality in patients with MDD and insomnia. On the other hand, effect of food intake on exposure to Vortioxetine has demonstrated efficacy in the treatment of vortioxetine was also evaluated as co-administration of med­ MDD associated with menopause, diabetes, Parkinson's, ications and food can affect by reducing, delaying, increasing, Alzheimer's and acute ischemic stroke. accelerating, or having no effect on drug absorption, and the Nausea was the most commonly associated AE with results found no food effect on PK [23]. a dose–effect relationship. However, meta-analyses have shown that withdrawal rates because of an AE were signifi­ cantly lower for vortioxetine than for sertraline, venlafaxine, or 6. Summary and Conclusions bupropion. Intrinsic factors such as age, gender, ethnicity, body size, and Vortioxetine has shown low rates of sexual dysfunction in hepatic and renal impairment has no clinically meaningful MDD CT. Vortioxetine is one of the antidepressants with low­ effects on vortioxetine exposure. Food intake or alcohol con­ est incidence of TESD, with rates of sexual dysfunction not sumption does not affect exposure to vortioxetine, although it significantly different from placebo (for doses up to 15 mg), is not recommended during treatment with antidepressants, lower rates of TESD than duloxetine and paroxetine, and sig­ as it may make some symptoms worse and impair evolution. nificantly greater improvements in sexual dysfunction when Vortioxetine is a multimodal-acting antidepressant specifi­ switching from SSRIs/SNRIs to vortioxetine than to escitalo­ cally designed to inhibit serotonin reuptake and interact with pram (possibly because the agonistic effects on 5-HT1A). several serotonin receptors (agonism of 5-HT1A receptor, par­ Both in short-term (6–8 weeks) and long-term (up to tial agonism of 5-HT1B receptor, and antagonism of 5-HT3, 5- 52 weeks) studies, vortioxetine had no effect relative to pla­ HT1D and 5-HT7 receptors), exerting modulatory effects on cebo on clinical laboratory parameters, body weight, heart multiple neurotransmitter systems (as NE, dopamine, acetyl­ rate or blood pressure, and showed no clinically relevant effect choline, histamine, glutamate, and GABA systems). on ECG parameters, including the QTcF interval. MDD is characterized by multiple debilitating symptoms, Vortioxetine does not increase lipid or cholesterol, showed spanning emotional, physical, and cognitive domains, with an improvement in biochemical parameters, and in type 2 serious consequences for patient’s psychosocial and occupa­ diabetes patients showed a decrease in glycosylated hemo­ tional functioning. Efficacy has been proved for vortioxetine in globin, suggesting amelioration in metabolic control with short-term and long-term treatment of MDD, with broad ben­ vortioxetine. eficial effects on emotional, physical, and cognitive symptoms. Vortioxetine has a mean terminal half-life of approximately Therefore, vortioxetine may enhance functional recovery 66 h, which is long enough to avoid the presence of disconti­ which is the ultimate treatment goal for patients with MDD. nuation symptoms following abrupt discontinuation of treat­ Vortioxetine is an efficacious treatment choice for ment with vortioxetine. depressed patients with anxious symptoms. Vortioxetine is not an inducer or inhibitor for several CYP Vortioxetine has demonstrated its efficacy in MDD patients substrates, which means that it has a low potential for drug– in several studies, being more effective than placebo and with drug interactions, and therefore can be used with most of the similar efficacy to that observed in duloxetine and venlafaxine. usual drugs. However, caution should be taken until more In a systematic review and meta-analysis vortioxetine was safety studies are available. found to be one of the most effective and best tolerated option in head-to-head CT. 7. Expert opinion Vortioxetine is the first antidepressant drug with proven efficacy in improving cognitive symptoms of depression and is Vortioxetine is a novel antidepressant with multimodal activity the only antidepressant agent showing evidence of a positive and high-affinity for SERT and several 5-HT receptor subtypes, effect on multiple cognitive domains as attention, processing which provide clinical advantages to other existing speed, executive function, learning, and memory. antidepressants. Vortioxetine has shown be useful in symptoms as anhedo­ This review, focused on the available evidences of vortiox­ nic, psychical symptoms, sleep disturbances and suicidal etine, supports its short (6–8 weeks) and long-term (up to ideation. 52 weeks) antidepressant efficacy and tolerability in a broad Vortioxetine significantly improved cognition, independent range of settings in MDD patients. Efficacy has been proved of depressive symptoms. The improvements on cognition for vortioxetine with broad beneficial effects on emotional, observed with vortioxetine were not apparent with physical, and cognitive symptoms. Specifically, vortioxetine 686 J. DE DIEGO-ADELIÑO ET AL. has evidenced improvements in cognitive domains of atten­ expectation on future studies about its potential effects on tion, processing speed, executive function, learning, and mem­ other symptoms and comorbid pathologies. ory. Efficacy has also been suggested in patients with MDD for sexual dysfunction, physical symptoms (flu-like and shock-like Funding complaints, dizziness, sleep disturbances, etc.), anxiety, social functioning, sleep disturbances, anhedonia, emotional blunt­ This paper was not funded. ing, and menopausal transition, and even in depressed patients with Parkinson’s Disease and with type 2 diabetes, and post-ictus among others. Vortioxetine has also shown Declaration of interests analgesic and anti-inflammatory properties. The unique attri­ J De Diego-Adeliño was supported by the Catalan Intensification butes of vortioxetine render it a promising therapeutic option Programme (PERIS, SLT008/18/00207; Generalitat de Catalunya). He has for several non-psychiatric disorders that are accompanied by received consultancy and/or lecture honoraria from Lundbeck, Pfizer, Neuraxpharm, Janssen and Esteve in the last 5-years, none of them with pain, inflammation, apathy, sleep and/or metabolic abnormal­ direct relation to this work. JM Crespo has received consultancy and/or ities besides prominent depressive and anxiety symptoms. lecture honoraria from Lundbeck, Angelini, Casen Recordati, Esteve and Although some antidepressants have shown improvements Janssen in the last 5-years, none of them with direct relation with this in cognitive function in patients with MDD, most of the anti­ work. F Mora has received consultancy and/or lecture honoraria from depressants have not shown an effect on cognition. However, Lundbeck, Pfizer, Sandoz-Novartis, Baxter, Janssen, Neuraxpharm, Lilly, MSD and Takeda in the last 5-years, none of them with direct relation vortioxetine is the first antidepressant that has shown to this work. A Neyra has received consultancy and/or lecture honoraria improvements both in depression and cognition. from Lundbeck, Pfizer and Janssen in the last 5-years, none of them with Furthermore, the positive effects of vortioxetine in cognition direct relation to this work. P Iborra has been consultant or has received are independent of its beneficial effects on depressive symp­ honoraria from Lundbeck. L Gutiérrez-Rojas has received consultancy toms, due to the unique multimodal mechanism of action of and/or lecture honoraria from Lundbeck, Pfizer, Novartis, Janssen, Neuraxpharm, and Otsuka in the last 5-years, none of them with direct vortioxetine. Cognitive improvements observed with vortiox­ relation to this work. SF Salonia has been a consultant or has received etine were not apparent with duloxetine in head-to-head CT, honoraria from Servier, Lundbeck, Janssen, Esteve and Pfizer. The authors and vortioxetine had the largest cognitive-enhancing effects have no other relevant affiliations or financial involvement with any in indirect comparisons with other antidepressants (citalo­ organization or entity with a financial interest in or financial conflict pram, escitalopram, nortriptyline, phenelzine, and sertraline). with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or 8The long elimination half-life of vortioxetine allows admin­ options, expert testimony, grants or patents received or pending, or istration of once daily doses which is more convenient for royalties. patients and promotes treatment compliance. It also allows abrupt discontinuation with no presence of discontinuation symptoms, and therefore vortioxetine can be discontinued Reviewer disclosures whenever needed. Vortioxetine had shown lower withdrawal A reviewer on this manuscript has disclosed that they are/have been rates than other antidepressants. a consultant and/or a speaker and/or have received research grants Regarding tolerability, the side effects of vortioxetine are from Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo, Doc different from conventional antidepressants, being the most Generici, Glaxo Smith Kline, Italfarmaco, Lundbeck,Janssen, Mylan, frequent AE nausea and vomiting, with a transitory and dose- Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, and Vifor. All other peer reviewers on this manuscript have no relevant finan­ dependent effect. Data from CT with vortioxetine showed cial or other relationships to disclose. a low incidence of sleep disruption, sexual dysfunction, and discontinuation syndrome, and beneficial effects on sleep quality. Importantly, vortioxetine does not increase lipid, ORCID cholesterol or glycemic levels and has a low incidence of Javier De Diego-Adeliño http://orcid.org/0000-0001-9708-2441 cardiovascular and alterations, with no clinically relevant Fernando Mora http://orcid.org/0000-0003-4698-1679 effect on ECG parameters, including the QTcF interval. The Pedro Iborra http://orcid.org/0000-0001-9041-0983 procognitive action together with the low incidence of som­ Luis Gutiérrez-Rojas http://orcid.org/0000-0003-0082-2189 nolence and other cardiovascular alterations support that vortioxetine can be a good alternative to be considered in References elder patients with MDD. Vortioxetine has also been sug­ gested as an effective alternative for switching treatment in Papers of special note have been highlighted as either of interest (•) or of patients with MDD with inadequate response to SSRIs and considerable interest (••) to readers. SNRIs. 1. Gutiérrez-Rojas L, Porras-Segovia A, Dunne H, et al. Prevalence and correlates of major depressive disorder: a systematic review. Braz Vortioxetine has been demonstrated to be a cost-effective J Psychiatry. 2020;42(6):657–672. treatment option in patients with MDD versus other widely 2. American Psychiatric Association. Diagnostic and statistical manual used antidepressant treatments such as agomelatine, bupro­ of mental disorders. 5th. APA. 2013. DSM–5. https://www.psychia pion XR, citalopram, duloxetine, escitalopram, sertraline, and try.org/psychiatrists/practice/dsm venlafaxine XR. In summary, the benefits of vortioxetine rela­ 3. Bora E, Harrison BJ, Yücel M, et al. Cognitive impairment in euthy­ mic major depressive disorder: a meta-analysis. Psychol Med. tive to other antidepressants have been broadly evidenced in 2013;43(10):2017–2026. terms of efficacy, tolerability, and cost-effectiveness. 4. Etkin A, Patenaude B, Song YJ, et al. A cognitive-emotional biomar­ Vortioxetine has been recently launched and there is a high ker for predicting remission with antidepressant medications: EXPERT OPINION ON DRUG SAFETY 687 a report from the iSPOT-D trial. Neuropsychopharmacology. 2015;40(6):1332–1342. ® 23. US Food and Drug Administration. Trintellix (formerly Brintellix ) Medication guide (revised 07/2019). 2020. [cited 2021 Dec 20]. ® 5. Jaeger J, Berns S, Uzelac S, et al. Neurocognitive deficits and Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ disability in major depressive disorder. Psychiatry Res. 2006;145 label/2019/204447s018lbl.pdf (1):39–48. 24. Chen G, Højer AM, Areberg J, et al. Vortioxetine: clinical pharma­ 6. Eaton WW, Shao H, Nestadt G, et al. Population-based study of first cokinetics and drug interactions. Clin Pharmacokinet. 2018;57 onset and chronicity in major depressive disorder. Arch Gen (6):673–686. Psychiatry. 2008;65(5):513–520. 25. Chen G, Nomikos GG, Affinito J, et al. Effects of intrinsic factors on 7. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from the clinical pharmacokinetics of vortioxetine. Clin Pharmacol Drug major depressive disorder during 15 years of observational Dev. 2018;7(8):880–888. follow-up. Am J Psychiatry. 1999;156(7):1000–1006. 26. Chen G, Nomikos GG, Affinito J, et al. Lack of effect of vortioxetine 8. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of on the pharmacokinetics and pharmacodynamics of Ethanol, disease attributable to mental and substance use disorders: find­ Diazepam, and Lithium. Clin Pharmacokinet. 2016;55(9):1115-1127. ings from the global burden of disease study 2010. Lancet. 27. Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant 2013;382(9904):1575–1586. with multimodal activity: review of preclinical and clinical data. 9. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic Pharmacol Ther. 2015;145:43–57. antidepressants: a meta-analysis of efficacy and tolerability. J Affect 28. Nackenoff AG, Simmler LD, Baganz NL, et al. Serotonin Disord. 2000;58(1):19–36. transporter-independent actions of the antidepressant vortioxetine 10. Thase ME, Rush AJ. When at first you don’t succeed: sequential as revealed using the SERT Met172 mouse. ACS Chem Neurosci. strategies for antidepressant nonresponders. J Clin Psychiatry. 2017;8(5):1092–1100. 1997;58(Suppl 13):23–29. 29. Li Y, Raaby KF, Sánchez C, et al. Serotonergic receptor mechanisms 11. David DJ, Gourion D. Antidépresseurs et tolérance: déterminants et underlying antidepressant-like action in the progesterone withdra­ prise en charge des principaux effets indésirables[Antidepressant wal model of hormonally induced depression in rats. Behav Brain and tolerance: determinants and management of major side Res. 2013;256:520–528. effects]. Encephale. 2016;42(6):553–561. 30. Hlavacova N, Li Y, Pehrson A, et al. Effects of vortioxetine on 12. Wille SM, Cooreman SG, Neels HM, et al. Relevant issues in the biomarkers associated with glutamatergic activity in an SSRI insen­ monitoring and the toxicology of antidepressants. Crit Rev Clin Lab sitive model of depression in female rats. Prog Sci. 2008;45(1):25–89. Neuropsychopharmacol Biol Psychiatry. 2018;82:332–338. 13. Bauer M, Pfennig A, Severus E, et al. Task force on unipolar depres­ 31. Riga MS, Sánchez C, Celada P, et al. Involvement of 5-HT3 receptors sive disorders. World Federation of Societies of Biological in the action of vortioxetine in rat brain: focus on glutamatergic Psychiatry (WFSBP) guidelines for biological treatment of unipolar and GABAergic neurotransmission. Neuropharmacology. depressive disorders, part 1: update 2013 on the acute and con­ 2016;108:73–81. tinuation treatment of unipolar depressive disorders. World J Biol 32. Du Jardin KG, Müller HK, Sanchez C, et al. A single dose of vortiox­ Psychiatry. 2013;14(5):334–385. etine, but not ketamine or fluoxetine, increases plasticity-related 14. Artigas F, Bortolozzi A, Celada P. Can we increase speed and gene expression in the rat frontal cortex. Eur J Pharmacol. efficacy of antidepressant treatments? Part I: general aspects and 2016;786:29–35. monoamine-based strategies. Eur Neuropsychopharmacol. 2018;28 33. Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evi­ (4):445–456. dence for neuronal and glial prefrontal cell pathology in major 15. Carvalho AF, Sharma MS, Brunoni AR, et al. The safety, tolerability depression. Biol Psychiatry. 1999;45(9):1085–1098. and risks associated with the use of newer generation antidepres­ 34. Kang HJ, Voleti B, Hajszan T, et al. Decreased expression of sant drugs: a critical review of the literature. Psychother synapse-related genes and loss of synapses in major depressive Psychosom. 2016;85(5):270–288. disorder. Nat Med. 2012;18(9):1413–1417. 16. Whiskey E, Taylor D. A review of the adverse effects and safety of 35. Chen F, Du Jardin KG, Waller JA, et al. Vortioxetine promotes early noradrenergic antidepressants. J Psychopharmacol. 2013;27 changes in dendritic morphology compared to fluoxetine in rat (8):732–739. hippocampus. Eur Neuropsychopharmacol. 2016;26(2):234–245. 17. Henssler J, Bschor T, Baethge C. Combining antidepressants in 36. Bennabi D, Haffen E, Van Waes V. Vortioxetine for cognitive acute treatment of depression: a meta-analysis of 38 studies includ­ enhancement in major depression: from animal models to clinical ing 4511 patients. Can J Psychiatry. 2016;61(1):29–43. research. Front Psychiatry. 2019;10:771. 18. Wichniak A, Wierzbicka A, Walęcka M, et al. Effects of antidepres­ • This article summarizes the importance of the cognitive func­ sants on sleep. Curr Psychiatry Rep. 2017;19(9):63. tion in patients with major depressive disorder 19. Song HR, Kwon YJ, Woo YS, et al. Effects of mirtazapine on patients 37. Leiser SC, Pehrson AL, Robichaud PJ, et al. Multimodal antidepres­ undergoing naturalistic diabetes treatment: a follow-up study sant vortioxetine increases frontal cortical oscillations unlike esci­ extended from 6 to 12 months. J Clin Psychopharmacol. 2015;35 talopram and duloxetine–a quantitative EEG study in rats. Br (6):730–731. J Pharmacol. 2014;171(18):4255–4272. 20. Alvarez E, Perez V, Artigas F. Pharmacology and clinical potential of 38. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. vortioxetine in the treatment of major depressive disorder. J Clin Invest. 2010;120(11):3779–3787. Neuropsychiatr Dis Treat. 2014;10:1297–1307. 39. Zuena AR, Maftei D, Alemà GS, et al. Multimodal antidepressant 21. Citrome L. Vortioxetine for major depressive disorder: an indirect vortioxetine causes analgesia in a mouse model of chronic neuro­ comparison with duloxetine, escitalopram, levomilnacipran, sertra­ pathic pain. Mol Pain. 2018;14:1744806918808987. line, venlafaxine, and vilazodone, using number needed to treat, 40. Talmon M, Rossi S, Pastore A, et al. Vortioxetine exerts number needed to harm, and likelihood to be helped or harmed. anti-inflammatory and immunomodulatory effects on human J Affect Disord. 2016;196:225–233. monocytes/macrophages. Br J Pharmacol. 2018;175(1):113-124. 22. Cipriani A, Furukawa TA, Salanti G, et al., Comparative efficacy and 41. Köhler CA, Freitas TH, Maes M, et al. Peripheral cytokine and acceptability of 21 antidepressant drugs for the acute treatment of chemokine alterations in depression: a meta-analysis of 82 adults with major depressive disorder: a systematic review and studies. Acta Psychiatr Scand. 2017;135(5):373–387. network meta-analysis. Lancet. 391(10128): 1357–1366. 2018. 42. Tomaz VS, Chaves Filho AJM, Cordeiro RC, et al. Antidepressants of •• Current metanalysis on the efficacy and tolerability of 21 dif­ different classes cause distinct behavioral and brain pro- and ferent antidepressants in patients with major depressive anti-inflammatory changes in mice submitted to an inflammatory disorder. model of depression. J Affect Disord. 2020;268:188–200. 688 J. DE DIEGO-ADELIÑO ET AL. • Summary of the anti-inflammatory effects produced by anti­ 58. Vieta E, Sluth LB, Olsen CK. The effects of vortioxetine on cognitive depressants on Central Nervous System dysfunction in patients with inadequate response to current anti­ 43. Fourrier C, Sampson E, Mills NT, et al. Anti-inflammatory treatment depressants in major depressive disorder: a short-term, rando­ of depression: study protocol for a randomised controlled trial of mized, double-blind, exploratory study versus escitalopram. vortioxetine augmented with celecoxib or placebo. Trials. 2018;19 J Affect Disord. 2018;227:803–809. (1):447. 59. Nissen TD, Laursen B, Viardot G, et al. Effects of vortioxetine and 44. Talmon M, Chaudhari RD, Suryavanshi H, et al. Design, synthesis escitalopram on electroencephalographic recordings - and biological evaluation of vortioxetine derivatives as new COX-1/ a randomized, crossover trial in healthy males. Neuroscience. 2 inhibitors in human monocytes. Bioorg Med Chem. 2020;28 2020;424:172-181. (23):115760. 60. Smith J, Browning M, Conen S, et al. Vortioxetine reduces BOLD 45. Salagre E, Grande I, Solé B, et al. Vortioxetina: una nueva alternativa signal during performance of the N-back working memory task: en el trastorno depresivo mayor.[Vortioxetine: a new alternative for a randomised neuroimaging trial in remitted depressed patients the treatment of major depressive disorder]. Rev. Psiquiatr Salud and healthy controls. Mol Psychiatry. 2018;23(5):1127–1133. Ment (Barc.). 2018;11(1):48–59. 61. Orgeta V, Tabet N, Nilforooshan R, et al. efficacy of antidepressants 46. Thase ME, Mahableshwarkar AR, Dragheim M, et al., A for depression in Alzheimer’s Disease: systematic review and meta- meta-analysis of randomized, placebo-controlled trials of vortiox­ analysis. J Alzheimers Dis. 2017;58(3):725–733. etine for the treatment of major depressive disorder in adults. Eur 62. Lenze EJ, Stevens A, Waring JD, et al. Augmenting computerized Neuropsychopharmacol. 26(6): 979–993. 2016. cognitive training with vortioxetine for age-related cognitive • Metanalysis on the clinical efficacy of vortioxetine in patients decline: a randomized controlled trial. Am J Psychiatry. 2020;177 with major depressive disorder. (6):548–555. 47. Furukawa TA, Cipriani A, Cowen PJ, et al. Optimal dose of selective 63. Cumbo E, Cumbo S, Torregrossa S, et al. Treatment Effects of serotonin reuptake inhibitors, venlafaxine, and mirtazapine in Vortioxetine on Cognitive Functions in Mild Alzheimer’s Disease major depression: a systematic review and dose-response Patients with Depressive Symptoms: a 12 Month, Open-Label, meta-analysis. Lancet Psychiatry. 2019;6(7):601–609. Observational Study. J Prev Alzheimers Dis. 2019;6(3):192–197. 48. Nierenberg AA, Loft H, Olsen CK. Treatment effects on residual 64. Paolucci S. Advances in antidepressants for treating post-stroke cognitive symptoms among partially or fully remitted patients depression. Expert Opin Pharmacother. 2017;18(10):1011-1017. with major depressive disorder: a randomized, double-blinded, 65. Strelnikova IA, Svetkina AA, YuD M, et al. Experience with vortiox­ exploratory study with vortioxetine. J Affect Disord. 2019;250:35-42. etine in the treatment of post-stroke depression. Nevrologiya, neir­ 49. Lee RS, Hermens DF, Porter MA, et al. A meta-analysis of cognitive opsikhiatriya, psikhosomatika = Neurology. Neuropsychiatry, deficits in first-episode major depressive disorder. J Affect Disord. Psychosomatics. 2020;12(1):45–49. 2012;140(2):113–124. 66. Kennedy SH, Lam RW, McIntyre RS, et al., Canadian network for 50. Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of mood and anxiety treatments (CANMAT) 2016 clinical guidelines antidepressants in major depressive disorder: a systematic for the management of adults with major depressive disorder: review and meta-analysis of randomized clinical trials. section 3. pharmacological treatments. Can J Psychiatry. 61(9): Int J Neuropsychopharmacol. 2015;19(2):yv082. 540–560. 2016. • Metanalysis and systematic review of the antidepressant effect •• Canadian clinical guidelines on pharmacological management on cognitive symptoms of depression of patients with major depressive disorder. 51. Baune BT, Brignone M, Larsen KG. A network meta-analysis 67. Cao B, Park C, Subramaniapillai M, et al. The efficacy of vortioxetine comparing effects of various antidepressant classes on the on anhedonia in patients with major depressive disorder. Front digit symbol substitution Test (DSST) as a measure of cognitive Psychiatry. 2019;10:17. dysfunction in patients with major depressive disorder. 68. Franken IH, Rassin E, Muris P. The assessment of anhedonia in Int J Neuropsychopharmacol. 2018;21(2):97–107. clinical and non-clinical populations: further validation of the 52. Harrison JE, Lophaven S, Olsen CK. Which Cognitive Domains are Snaith-Hamilton Pleasure Scale (SHAPS). J Affect Disord. 2007;99 Improved by Treatment with Vortioxetine? (1–3):83–89. Int J Neuropsychopharmacol. 2016 May 26;19(10):yw054. 69. Subramaniapillai M, Mansur RB, Zuckerman H, et al. Association 53. Jacobson W, Zhong W, Nomikos GG, et al. Effects of vortioxetine on between cognitive function and performance on effort based deci­ functional capacity across different levels of functional impairment sion making in patients with major depressive disorder treated in patients with major depressive disorder: a University of with Vortioxetine. Compr Psychiatry. 2019;94:152113. California, San Diego Performance-based Skills Assessment (UPSA) 70. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting asso­ analysis. Curr Med Res Opin. 2020;36(1):117–124. ciated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emo­ 54. McIntyre RS, Harrison J, Loft H, et al., The effects of vortioxetine on tional responses? Int J Neuropsychopharmacol. 2002;5(2):147–151. cognitive function in patients with major depressive disorder: a 71. Price J, Cole V, Goodwin GM. Emotional side-effects of selective meta-analysis of three randomized controlled trials. serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. Int J Neuropsychopharmacol. 19(10): yw055. 2016. 2009;195(3):211–217. •• Metanalysis of randomized clinical trials published on the 72. Fagiolini A, Florea I, Loft H, et al. Effectiveness of vortioxetine on efficacy of vortioxetine on cognitive function of patients with emotional blunting in patients with major depressive disorder with major depression. inadequate response to SSRI/SNRI treatment. J Affect Disord. 55. Chokka P, Bougie J, Rampakakis E, et al. Assessment in work 2021;283:472–479. productivity and the relationship with cognitive symptoms 73. Cronquist MC, Florea I, Lindsten A, et al. Efficacy of vortioxetine on (AtWoRC): primary analysis from a Canadian open-label study of the physical symptoms of major depressive disorder. vortioxetine in patients with major depressive disorder (MDD). CNS J Psychopharmacol. 2018;32(10):1086-1097. Spectr. 2019;24(3):338–347. 74. Jaracz J, Gattner K, Jaracz K, et al. Unexplained painful physical 56. Chokka P, Bougie J, Proulx J, et al. Long-term functioning outcomes symptoms in patients with major depressive disorder: prevalence, are predicted by cognitive symptoms in working patients with pathophysiology and management. CNS Drugs. 2016;30 major depressive disorder treated with vortioxetine: results from (4):293–304. the AtWoRC study. CNS Spectr. 2019;24(6):616–627. 75. Cao B, Park C, Rosenblat JD, et al. Changes in sleep predict changes 57. McIntyre RS, Florea I, Tonnoir B, et al. Efficacy of vortioxetine on in depressive symptoms in depressed subjects receiving vortioxe­ cognitive functioning in working patients with major depressive tine: an open-label clinical trial. J Psychopharmacol. 2019;33 disorder. J Clin Psychiatry. 2017;78(1):115–121. (11):1388–1394. EXPERT OPINION ON DRUG SAFETY 689 76. Liguori C, Ferini-Strambi L, Izzi F, et al. Preliminary evidence that double-blind randomized controlled trials with antidepressants. vortioxetine may improve sleep quality in depressed patients with J Affect Disord. 2012;141(2–3):103–115. insomnia: a retrospective questionnaire analysis. Br J Clin 95. Nomikos GG, Tomori D, Zhong W, et al. Efficacy, safety, and toler­ Pharmacol. 2019;85(1):240–244. ability of vortioxetine for the treatment of major depressive dis­ 77. Doghramji K, Jangro WC. Adverse effects of psychotropic medica­ order in patients aged 55 years or older. CNS Spectr. 2017;22 tions on sleep. Psychiatr Clin North Am. 2016;39(3):487–502. (4):348-362. 78. Leiser SC, Iglesias-Bregna D, Westrich L, et al. Differentiated effects 96. Agüera-Ortiz LF. Tratamiento actual de la depresión en el anciano: of the multimodal antidepressant vortioxetine on sleep architec­ un foco en la vortioxetina.[Current treatment of depression in the ture: part 2, pharmacological interactions in rodents suggest a role elderly: a focus on vortioxetine]. Psicogeriatria. 2020;10(Supl 1):S1– of serotonin-3 receptor antagonism. J Psychopharmacol. 2015;29 S9. (10):1092–1105. 97. Freeman MP, Cheng LJ, Moustafa D, et al. Vortioxetine for major 79. Wilson S, Højer AM, Buchberg J, et al. Differentiated effects of the depressive disorder, vasomotor, and cognitive symptoms asso­ multimodal antidepressant vortioxetine on sleep architecture: part ciated with the menopausal transition. Ann Clin Psychiatry. 1, a pharmacokinetic/pharmacodynamic comparison with paroxe­ 2017;29(4):249–257. tine in healthy men. J Psychopharmacol. 2015;29(10):1085-1091. 98. Callegari C, Ielmini M, Caselli I, et al. Paroxetine versus vortioxetine 80. Bonaventure P, Kelly L, Aluisio L, et al. Selective blockade of for depressive symptoms in postmenopausal transition: 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmis­ a preliminary study. Psychopharmacol Bull. 2019;49(1):28–43. sion, antidepressant-like behavior, and rapid eye movement sleep 99. Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic dis­ suppression induced by citalopram in rodents. J Pharmacol Exp eases, and decrements in health: results from the World Health Ther. 2007;321(2):690–698. Surveys. Lancet. 2007;370(9590):851–858. 81. Shelton J, Bonaventure P, Li X, et al. 5-HT7 receptor deletion 100. Fiore V, Marci M, Poggi A, et al. The association between diabetes enhances REM sleep suppression induced by selective serotonin and depression: a very disabling condition. Endocrine. 2015;48 reuptake inhibitors, but not by direct stimulation of 5-HT1A (1):14–24. receptor. Neuropharmacology. 2009;56(2):448–454. 101. Roopan S, Larsen ER. Use of antidepressants in patients with 82. Simon GE, Savarino J. Suicide attempts among patients starting depression and comorbid diabetes mellitus: a systematic review. depression treatment with medications or psychotherapy. Am Acta Neuropsychiatr. 2017;29(3):127–139. J Psychiatry. 2007;164(7):1029–1034. 102. Tovilla-Zárate CA, Pérez-Mandujano A, Ramírez-González IR, et al. 83. Simon GE, Savarino J, Operskalski B, et al. Suicide risk during Vortioxetine versus sertraline in metabolic control, distress and antidepressant treatment. Am J Psychiatry. 2006;163(1):41–47. depression in Mexican patients with type 2 diabetes. Ann Transl 84. Khan A, Khan S, Kolts R, et al. Suicide rates in clinical trials of SSRIs, Med. 2019;7(22):656. other antidepressants, and placebo: analysis of FDA reports. Am 103. Lee MD, Kennett GA, Dourish CT, et al. 5-HT1B receptors modulate J Psychiatry. 2003;160(4):790–792. components of satiety in the rat: behavioural and pharmacological 85. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibi­ analyses of the selective serotonin1B agonist CP-94,253. tors (SSRIs) and suicide in adults: meta-analysis of drug company Psychopharmacology (Berl). 2002;164(1):49–60. data from placebo controlled, randomised controlled trials sub­ 104. Nonogaki K, Kaji T. Pharmacological stimulation of serotonin mitted to the MHRA’s safety review. BMJ. 2005;330(7488):385. 5-HT1B receptors enhances increases in plasma active 86. Mahableshwarkar AR, Affinito J, Reines EH, et al. Suicidal ideation glucagon-like peptide-1 levels induced by dipeptidyl peptidase-4 and behavior in adults with major depressive disorder treated with inhibition independently of feeding in mice. Diabetes Metab. vortioxetine: post hoc pooled analyses of randomized, 2015;41(5):425–428. placebo-controlled, short-term and open-label, long-term exten­ 105. Russo M, Carrarini C, Dono F, et al. Vortioxetine treatment of sion trials. CNS Spectr. 2019;14:1–11. depression in Parkinson’s disease[abstract]. Mov Disord. 2019; 34 87. Baldwin DS, Florea I, Jacobsen PL, et al. A meta-analysis of the (suppl 2). [cited 2021 Dec 20]. Available from https://www.mdsab efficacy of vortioxetine in patients with major depressive disorder stracts.org/abstract/vortioxetine-treatment-of-depression-in- (MDD) and high levels of anxiety symptoms. J Affect Disord. parkinsons-disease/ 2016;206:140–150. 106. Postuma RB, Gagnon JF, Tuineaig M, et al. Antidepressants and • Metanalysis on the efficacy of vortioxetine in patients with REM sleep behavior disorder: isolated side effect or neurodegen­ depression and comorbid high levels of anxiety erative signal? Sleep. 2013;36(11):1579–1585. 88. Blanco C, Nissenson K, Liebowitz MR. Social anxiety disorder: recent 107. Aurora RN, Zak RS, Maganti RK, et al. Best practice guide for the findings in the areas of epidemiology, etiology, and treatment. Curr treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med. Psychiatry Rep. 2001;3(4):273–280. 2010;6(1):85–95. 89. Liebowitz MR, Careri J, Blatt K, et al. Vortioxetine versus placebo in 108. Adamo D, Pecoraro G, Coppola N, et al. Vortioxetine versus other major depressive disorder comorbid with social anxiety disorder. antidepressants in the treatment of burning mouth syndrome: an Depress Anxiety. 2017;34(12):1164–1172. open-label randomized trial. Oral Dis. 2020;27(4):1022–1041. 90. Cronquist MC, Florea I, Loft H, et al. Efficacy of vortioxetine in 109. Montgomery SA, Nielsen RZ, Poulsen LH, et al. A randomised, patients with major depressive disorder reporting childhood or double-blind study in adults with major depressive disorder with recent trauma. J Affect Disord. 2020;263:258–266. an inadequate response to a single course of selective serotonin 91. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor co-occurrence of substance use disorders and independent mood treatment switched to vortioxetine or agomelatine. Hum and anxiety disorders: results from the national epidemiologic Psychopharmacol. 2014;29(5):470–482. survey on alcohol and related conditions. Arch Gen Psychiatry. 110. Thase ME, Danchenko N, Brignone M, et al. Comparative evalua­ 2004;61(8):807–816. tion of vortioxetine as a switch therapy in patients with major 92. Di Nicola M, Pepe M, Panaccione I, et al. Effect of vortioxetine in depressive disorder. Eur Neuropsychopharmacol. 2017;27(8):773- subjects with major depressive and alcohol use disorders: a 781. 6-month retrospective analysis. CNS Spectr 2020 1–9 10.1017/ 111. Brignone M, Diamand F, Painchault C, et al. Efficacy and tolerability S109285292000173X of switching therapy to vortioxetine versus other antidepressants 93. Oslin DW, Datto CJ, Kallan MJ, et al. Association between medical in patients with major depressive disorder. Curr Med Res Opin. comorbidity and treatment outcomes in late-life depression. J Am 2016;32(2):351–366. Geriatr Soc. 2002;50(5):823–828. 112. Tegin C, Tegin G, El-Mallakh RS. Effective vortioxetine dose varies 94. Kok RM, Nolen WA, Heeren TJ. Efficacy of treatment in older with extent of antidepressant use across countries. depressed patients: a systematic review and meta-analysis of Psychopharmacol Bull. 2018;48(1):26-39. 690 J. DE DIEGO-ADELIÑO ET AL. 113. Garcia-Toro M, Medina E, Galan JL, et al. Treatment patterns in possible roles of direct receptor modulation. Neuropharmacology. major depressive disorder after an inadequate response to first-line 2017;121:89–99. antidepressant treatment. BMC Psychiatry. 2012;12(1):143. 127. Jacobsen PL, Harper L, Chrones L, et al. Safety and tolerability of 114. Goldberg JF, Freeman MP, Balon R, et al. The American society of vortioxetine (15 and 20 mg) in patients with major depressive clinical psychopharmacology survey of psychopharmacologists’ disorder: results of an open-label, flexible-dose, 52-week extension practice patterns for the treatment of mood disorders. Depress study. Int Clin Psychopharmacol. 2015;30(5):255–264. Anxiety. 2015;32(8):605–613. 128. Zheng J, Wang Z, Li E. The efficacy and safety of 10 mg/day 115. Florea I, Loft H, Danchenko N, et al. The effect of vortioxetine on vortioxetine compared to placebo for adult major depressive dis­ overall patient functioning in patients with major depressive order: a meta-analysis. Afr Health Sci. 2019;19(1):1716–1726. disorder. Brain Behav. 2017;7(3):e00622. 129. Behzadifar M, Dehghan H, Saki K, et al. Evaluation efficacy and 116. Mahableshwarkar AR, Zajecka J, Jacobson W, et al. A randomized, safety of Vortioxetine 20 mg/d versus placebo for treatment placebo-controlled, active-reference, double-blind, flexible-dose major depressive disorder: a systematic review and meta-analysis study of the efficacy of vortioxetine on cognitive function in of randomized controlled trials. Pharmacology & Pharmacy. 2015;6 major depressive disorder. Neuropsychopharmacology. 2015;40 (4):221. (8):2025–2037. 130. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of 117. Cronquist MC, Loft H, McIntyre RS. Vortioxetine improves sympto­ vortioxetine: analysis of data from randomized placebo-controlled matic and functional outcomes in major depressive disorder: trials and open-label extension studies. J Psychopharmacol. a novel dual outcome measure in depressive disorders. J Affect 2016;30(3):242–252. Disord. 2018;227:787–794. 131. Coupland NJ, Bailey JE, Potokar JP, et al. 5-HT3 receptors, nausea, 118. Soini E, Hallinen T, Brignone M, et al. Cost-utility analysis of vortiox­ and serotonin reuptake inhibition. J Clin Psychopharmacol. 1997;17 etine versus agomelatine, bupropion SR, sertraline and venlafaxine (2):142–143. XR after treatment switch in major depressive disorder in Finland. 132. Ladefoged LK, Munro L, Pedersen AJ, et al. Modeling and muta­ Expert Rev Pharmacoecon Outcomes Res. 2017;17(3):293–302. tional analysis of the binding mode for the multimodal antidepres­ 119. Young AH, Evitt L, Brignone M, et al. Cost-utility evaluation of sant drug vortioxetine to the human 5-HT3A receptor. Mol vortioxetine in patients with major depressive disorder experien­ Pharmacol. 2018;94(6):1421–1434. cing inadequate response to alternative antidepressants in the 133. Crapanzano C, Politano A, Amendola C, et al. Vortioxetine-induced United Kingdom. J Affect Disord. 2017;218:291–298. nausea and its treatment: a case report. Archives of Clinical 120. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related Psychiatry (São Paulo). 2021;47(5):160–161. to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29 134. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and (3):259–266. vomiting by cannabinoids. Br J Pharmacol. 2011;163 121. Jacobsen PL, Mahableshwarkar AR, Palo WA, et al. Treatment- (7):1411–1422. emergent sexual dysfunction in randomized trials of vortioxetine 135. Johnston KD, Lu Z, Rudd JA. Looking beyond 5-HT(3) receptors: for major depressive disorder or generalized anxiety disorder: a review of the wider role of serotonin in the pharmacology of a pooled analysis. CNS Spectr. 2016;21(5):367–378. nausea and vomiting. Eur J Pharmacol. 2014;722:13–25. 122. Jacobsen P, Zhong W, Nomikos G, et al. Paroxetine, but not vor­ 136. Fava GA, Benasi G, Lucente M, et al. Withdrawal symptoms after tioxetine, impairs sexual functioning compared with placebo in serotonin-noradrenaline reuptake inhibitor discontinuation: sys­ healthy adults: a randomized, controlled trial. J Sex Med. 2019;16 tematic review. Psychother Psychosom. 2018;87(4):195–203. (10):1638–1649. 137. Chen G, Lee R, Højer AM, et al. Pharmacokinetic drug interactions 123. Montejo AL, Prieto N, de Alarcón R, et al. Management strategies involving vortioxetine (Lu AA21004), a multimodal antidepressant. for antidepressant-related sexual dysfunction: a clinical approach. Clin Drug Investig. 2013;33(10):727–736. J Clin Med. 2019;8(10):1640. 138. Schäfer W, Princk C, Kollhorst B, et al. Antidepressants and the risk 124. Jacobsen PL, Mahableshwarkar AR, Chen Y, et al. Effect of vortiox­ of hemorrhagic stroke in the elderly: a nested case-control study. etine vs. escitalopram on sexual functioning in adults with Drug Saf. 2019;42(9):1081–1089. well-treated major depressive disorder experiencing ssri-induced 139. Chen G, Zhang W, Serenko M. Lack of effect of multiple doses of sexual dysfunction. J Sex Med. 2015;12(10):2036–2048. vortioxetine on the pharmacokinetics and pharmacodynamics of 125. Olivier JDA, Olivier B. Antidepressants and sexual dysfunctions: aspirin and warfarin. J Clin Pharmacol. 2015;55(6):671–679. a translational perspective. Curr Sex Health Rep. 2019;11(3):156–166. 140. Me IO, Gaete GL. Antidepressants agents in breast cancer patients 126. Li Y, Pehrson AL, Oosting RS, et al. A study of time- and using tamoxifen: review of basic and clinical evidence. Rev Med sex-dependent effects of vortioxetine on rat sexual behavior: Chil. 2016;144(10):1326–1335.