Vortioxetine for cognitive enhancement in major depression: From animal models to clinical research
Open accessAbstract
Objectives: Vortioxetine, has already shown its efficacy in the acute and long-term treatment of MDD, and its interest in the prevention of relapse. The aim of this study was to review the current status of knowledge regarding cognitive effects of vortioxetine. Methods: We conducted a review of key data obtained from preclinical behavioral models and clinical trials in MDD focusing on vortioxetine-induced cognitive changes. Results: In animal, acute and chronic administration of vortioxetine improved performance on objective measures that cover a broad range of cognitive domains. In human, vortioxetine appears as a useful treatment option in patients with MDD, especially in the presence of cognitive dysfunction. Conclusion: Vortioxetine constitutes a promising treatment for treatment of cognitive impairment in MDD, but its place in the therapeutic armamentarium still need to be determined.
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Robust evidence exists regarding the use of vortioxetine to treat mood-related symptoms of depression and slowed processing speed, and it is the only FDA-cleared psychotropic medication to treat both.
“Robust evidence exists regarding the use of vortioxetine to treat mood-related symptoms of depression and slowed processing speed (Bennabi et al., 2019;Frampton, 2016;Harrison et al., 2016;Mahableshwarkar et al., 2015;McIntyre et al., 2014), and it is the only FDA-cleared psychotropic medication to treat both.”
From Neurocognitive effects of theta burst stimulation for treatment-resistant depression in adults: A systematic review and recommendations for future research (2025) · cites this paper as Bennabi et al., 2019
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“1 Edited by: Colin T. Dourish, P1vital Limited, United Kingdom Reviewed by: Paul Moser, Independent Researcher, Toulouse, France John Edward Harrison, King's College London, United Kingdom *Correspondence: Bennabi Djamila dbennabi@chu-besancon.fr Specialty section: This article was submitted to Psychopharmacology, a s…”
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“In addition to its antidepressant effects, vortioxetine has demonstrated cognitive-enhancing properties in humans in seven short-term RCTs (6–12 weeks) (26–35), three meta-analyses (28, 30, 38), and one open-label trial (62), wherein cognitive function was the primary outcome of interest.”
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“In two other studies, in female Long–Evans rats, acute administration of vortioxetine restored memory performance deficits induced by 5-HT depletion (14, 15).”
BackgroundResultGuilloux, J., Mendez‐David, I., Pehrson, A. L., Guiard, B. P., Repérant, C., Orvoën, S., Gardier, A. M., Hen, R., Ebert, B., Miller, S., et al. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.014 · Cited by 117 · cited 6× · see citing works
“, 2019 (36) Double blind RCT MDD (81) Vortioxetine 10 mg (41) vs.”
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Ekman, M., Granström, O., Omérov, S., Jacob, J., & Landén, M. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.03.003 · Cited by 101 · see citing works
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Efficacy of Vortioxetine on Cognitive Functioning in Working Patients With Major Depressive Disorder
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BackgroundNeurogenesis and antidepressant action
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“, 2014 (16) Male Sprague–Dawley rats with 5-HT depletion exposed to chronic intermittent cold stress Acute injections of vehicle or vortioxetine at 10 mg/kg immediately prior to behavioral test (i.”
BackgroundMethodJensen, J. B., du Jardin, K. G., Song, D., Budac, D., Smagin, G., Sanchez, C., & Pehrson, A. L. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.10.011 · Cited by 96 · cited 3× · see citing works
“To sum up, in animal studies, vortioxetine appears to have beneficial effects on depression-related behavior and cognitive deficits that are distinct from those of SSRIs and serotoninnorepinephrine reuptake inhibitors (15, 19, 41, 44, 45).”
MethodResultDale, E., Zhang, H., Leiser, S. C., Xiao, Y., Lu, D., Yang, C. R., Plath, N., & Sanchez, C. (2014) · Journal of Psychopharmacology · doi:10.1177/0269881114543719 · Cited by 93 · cited 3× · see citing works
“Other mechanisms have been suggested, such as the facilitating effects of vortioxetine on LTP and on neurogenesis levels in the hippocampus (17, 24, 50).”
BackgroundLu, Y., Ho, C. S. H., McIntyre, R. S., Wang, W., & Ho, R. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.06.007 · Cited by 90 · cited 1× · see citing works
“Vortioxetine, but not fluoxetine, also increases hippocampal brain–derived neurotrophic factor levels in healthy rats (57), as well as in rats subjected to chronic unpredictable mild stress (an animal model of depression) (58).”
BackgroundSmith, J. E. T., Browning, M. D., Conen, S., Smallman, R. P., Buchbjerg, J. K., Larsen, K. G., Olsen, C. K., Christensen, S. R., Dawson, G. R., Deakin, J. F. W., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.104 · Cited by 90 · see citing works
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“They found that vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of Flinders Sensitive Line rats in the object recognition task irrespective of 5-HT tone (19).”
BackgroundResultInfluentialVortioxetine: A review of the pharmacology and clinical profile of the novel antidepressant
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“, partial agonism at 5-HT1B receptors, agonism at 5-HT1A, and antagonist properties at 5-HT1D, 5-HT3, and 5-HT7 receptors) (10).”
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“, 2015 (18) Healthy middle-aged C57BL/6 female mice (11 months old) Ad libitum access to vortioxetineinfused food (0.”
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“In humans, PET studies using 5-HT transporter ligands to quantify the 5-HT transporter occupancy in the brain across different dose levels indicate that the mean 5-HT transporter occupancy is approximately 50% at 5 mg/ day and 65% at 10 mg/day and increases to above 80% at 20 mg/ day (34, 72).”
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“(31) observed improvements in DSST and UPSA-B performance in a small sample of patients with inadequate response to SSRI or SNRI (selective noradrenalin reuptake inhibitor) monotherapy treated with flexible doses of either vortioxetine or escitalopram.”
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“In humans, PET studies using 5-HT transporter ligands to quantify the 5-HT transporter occupancy in the brain across different dose levels indicate that the mean 5-HT transporter occupancy is approximately 50% at 5 mg/ day and 65% at 10 mg/day and increases to above 80% at 20 mg/ day (34, 72).”
BackgroundVortioxetine for depression in adults
Koesters, M., Ostuzzi, G., Guaiana, G., Breilmann, J., & Barbui, C. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011520.pub2 · Cited by 67 · see citing works
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“Of interest, in line with recent findings suggesting that the targeting of inflammatory signaling pathways is an interesting strategy to improve the responsiveness of unipolar depressive patients, an RCT conducted by Fourrier and colleagues (74) will explore the effects of vortioxetine as an add-on strategy with 400 m…”
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“To sum up, in animal studies, vortioxetine appears to have beneficial effects on depression-related behavior and cognitive deficits that are distinct from those of SSRIs and serotoninnorepinephrine reuptake inhibitors (15, 19, 41, 44, 45).”
BackgroundResultWhich cognitive domains are improved by treatment with vortioxetine?
Harrison, J. E., Lophaven, S., & Olsen, C. K. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw054 · Cited by 59 · cited 2× · see citing works
“(61) studied which specific domains vortioxetine improves and demonstrated a procognitive effect in vortioxetinetreated patients at 8 weeks, even after correcting for a change in depression severity.”
BackgroundBétry, C., Etiévant, A., Pehrson, A., Sánchez, C., & Haddjeri, N. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.12.002 · Cited by 59 · cited 4× · see citing works
“(17)], this improvement was observed through a neurogenesisindependent mechanism.”
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“Interestingly, a recent RCT investigated the efficacy of vortioxetine on cognitive functions in Alzheimer disease patients with depressive symptoms and reported significant improvement in most of the cognitive tests applied (75).”
BackgroundChokka, P. R., Bougie, J. K., Proulx, J., Tvistholm, A. H., & Ettrup, A. (2019) · CNS Spectrums · doi:10.1017/s1092852919000786 · Cited by 55 · see citing works
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“Eskelund and collaborators (59) examined, in Sprague–Dawley and Flinders Sensitive Line rats, the effects of vortioxetine and other antidepressants (fluoxetine and ketamine) on various tryptophan metabolites in different brain regions and plasma.”
BackgroundThe US Food and Drug Administration’s Perspective on the New Antidepressant Vortioxetine
Zhang, J., Mathis, M. V., Sellers, J. W., Kordzakhia, G., Jackson, A. J., Dow, A. L., Yang, P., Fossom, L. H., Zhu, H., Patel, H., et al. (2014) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14r09164 · Cited by 38 · cited 1× · see citing works
“In pooled analyses of randomized trial data, higher rates of positive response and successful remission following treatment with vortioxetine were observed when compared with placebo, which supported its approval by the US Food and Drug Administration and the European Medicines Agency (12).”
ResultLevada, O. A., & Troyan, A. S. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.03.040 · Cited by 35 · cited 2× · see citing works
“In addition to its antidepressant effects, vortioxetine has demonstrated cognitive-enhancing properties in humans in seven short-term RCTs (6–12 weeks) (26–35), three meta-analyses (28, 30, 38), and one open-label trial (62), wherein cognitive function was the primary outcome of interest.”
BackgroundStahl, S. M. (2015) · CNS Spectrums · doi:10.1017/s1092852915000358 · Cited by 33 · cited 2× · see citing works
“The distinctive serotoninergic properties of vortioxetine in the hippocampus and prefrontal cortex, in comparison to SSRIs that stimulate every 5-HT receptor, are likely an important feature of its cognitive activity (69).”
BackgroundNierenberg, A. A., Loft, H., & Olsen, C. K. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.02.006 · Cited by 32 · cited 3× · see citing works
“Surprisingly, only one RCT investigated the effects of the interventions on cognition in a remitted state of MDD (35).”
BackgroundInfluentialdu Jardin, K. G., Müller, H. K., Sánchez, C., Wegener, G., & Elfving, B. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.05.029 · Cited by 31 · cited 1× · see citing works
“Furthermore, a growing number of studies also indicate that vortioxetine modulates molecular targets that are related to neuroplasticity (53).”
BackgroundIs major depression a cognitive disorder?
Fossati, P. (2018) · Revue Neurologique · doi:10.1016/j.neurol.2018.01.365 · Cited by 30 · see citing works
Pehrson, A. L., Pedersen, C. S., Tølbøl, K. S., & Sánchez, C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00162 · Cited by 29 · cited 4× · see citing works
“In another study, the same team (23) demonstrated that either acute or subchronic vortioxetine administration attenuates phencyclidine (an N-methyl--aspartate [NMDA] receptor antagonist)–induced deficits in attentional set shifting performance and that both ondansetron (a selective 5-HT3 receptor antagonist) and escit…”
BackgroundInfluentialDale, E., Grunnet, M., Pehrson, A. L., Frederiksen, K., Larsen, P. H., Nielsen, J., Stensbøl, T. B., Ebert, B., Yin, H., Lu, D., et al. (2017) · Brain Research · doi:10.1016/j.brainres.2017.12.025 · Cited by 27 · see citing works
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“Interestingly, in vivo studies of the rat prefrontal cortex showed that effects on modulation of GABAergic and glutamatergic neurotransmission occur at doses across the clinically relevant dose range (5–20 mg/day) (50, 66, 68).”
BackgroundWaller, J. A., Chen, F., & Sánchez, C. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.12.012 · Cited by 25 · cited 2× · see citing works
“Enhanced release of glutamate in the prefrontal cortex and hippocampus enhances LTP (a cellular mechanism of learning and memory (67)) and promotes maturation of dendritic spines as shown in vitro in hippocampal cultures (56).”
BackgroundPehrson, A. L., Hillhouse, T. M., Haddjeri, N., Rovera, R., Porter, J. H., Mørk, A., Smagin, G. N., Song, D., Budac, D. P., Cajina, M., et al. (2016) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.233924 · Cited by 24 · cited 4× · see citing works
“Escitalopram (20) DSST RAVLT TMT-B Vortioxetine > escitalopram for RAVLT”
BackgroundInfluentialChen, F., Danladi, J., Ardalan, M., Elfving, B., Müller, H. K., Wegener, G., Sánchez, C., & Nyengaard, J. R. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy022 · Cited by 24 · cited 1× · see citing works
“Vortioxetine, but not fluoxetine, also increases hippocampal brain–derived neurotrophic factor levels in healthy rats (57), as well as in rats subjected to chronic unpredictable mild stress (an animal model of depression) (58).”
BackgroundHlaváčová, N., Li, Y., Pehrson, A. L., Sánchez, C., Bermúdez, I., Csanova, A., Ježová, D., & Franklin, M. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.07.008 · Cited by 23 · cited 3× · see citing works
“Since paroxetine, an SSRI, had almost no impact in this animal model of depression, the observations reported in the two studies mentioned above confirm the hypothesis that vortioxetine’s antidepressant activity may involve mechanisms beyond SERT inhibition (43, 60).”
BackgroundResultIn vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity
Kugathasan, P., Waller, J. A., Westrich, L., Abdourahman, A., Tamm, J. A., Pehrson, A. L., Dale, E., Gulinello, M. E., Sánchez, C., & Li, Y. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881116667710 · Cited by 22 · cited 1× · see citing works
“Indeed, it has been shown that vortioxetine exerts, in addition to direct effects on serotonin, indirect effects on multiple neurotransmitters such as noradrenergic, histaminergic, cholinergic, GABAergic, and glutamatergic systems (demonstrated in both in vitro and in vivo studies) (10, 51, 52).”
BackgroundFreeman, M. P., Cheng, L. J., Moustafa, D., Davies, A. C., Sosinsky, A. Z., Wang, B. H., Petrillo, L. F., Hogan, C. S., & Cohen, L. S. (2017) · Annals of Clinical Psychiatry · doi:10.1177/104012371702900407 · Cited by 22 · cited 4× · see citing works
“, 2017 (32) Open-label study 8 weeks 21 early postmenopausal and perimenopausal women with MDD Vortioxetine DSST CPFQ Cogstate test Improvement in DSST and CPFQ No improvement in Cogstate test scores”
BackgroundInfluentialHatherall, L. C., Sánchez, C., & Morilak, D. A. (2016) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw105 · Cited by 20 · cited 2× · see citing works
“, 2017 (21) Male Sprague–Dawley rats exposed to chronic stress (intermittent cold stress, social defeat, immobilization, swim stress) Vortioxetine was administered in the diet prepared to contain 0.”
BackgroundMethodWaller, J. A., Tamm, J. A., Abdourahman, A., Pehrson, A. L., Li, Y., Cajina, M., & Sánchez, C. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2016.11.014 · Cited by 20 · cited 1× · see citing works
“They also found that chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers (55).”
BackgroundLi, Y., Sánchez, C., & Gulinello, M. E. (2017) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx004 · Cited by 18 · cited 9× · see citing works
“Indeed, vortioxetine was still able to enhance mobility in the tail suspension test and in the FST, to reduce consumption latency in the novelty-induced hypophagia test, and to promote proliferation and survival of subgranular-zone hippocampal stem cells, despite less interaction with SERT in these mice (45).”
BackgroundInfluentialNackenoff, A. G., Simmler, L. D., Baganz, N. L., Pehrson, A. L., Sánchez, C., & Blakely, R. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00038 · Cited by 15 · cited 4× · see citing works
“To sum up, in animal studies, vortioxetine appears to have beneficial effects on depression-related behavior and cognitive deficits that are distinct from those of SSRIs and serotoninnorepinephrine reuptake inhibitors (15, 19, 41, 44, 45).”
BackgroundMethodResultInfluentialEffects of sertraline, duloxetine, vortioxetine, and idazoxan in the rat affective bias test
Refsgaard, L. K., Haubro, K., Pickering, D. S., Stuart, S. A., Robinson, E. S. J., & Andreasen, J. T. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4407-6 · Cited by 12 · cited 7× · see citing works
“Placebo (48) DSST TMT-A TMT-B Stroop test SRT”
BackgroundMethodInfluentialVortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism
Felice, D., Guilloux, J., Pehrson, A. L., Li, Y., Mendez‐David, I., Gardier, A. M., Sánchez, C., & David, D. J. P. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00204 · Cited by 12 · cited 3× · see citing works
“Other mechanisms have been suggested, such as the facilitating effects of vortioxetine on LTP and on neurogenesis levels in the hippocampus (17, 24, 50).”
BackgroundMethodRatajczak, P., Kus, K., Zaprutko, T., Szczepański, M., Rusowicz, S., & Nowakowska, E. (2019) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2019-002 · Cited by 11 · cited 2× · see citing works
“Lastly, a small number of studies were from and/or sponsored by Lundbeck, which represents a significant limitation (36, 47, 48).”
BackgroundNeuroplasticity pathways and protein-interaction networks are modulated by vortioxetine in rodents
Waller, J. A., Nygaard, S. H., Li, Y., du Jardin, K. G., Tamm, J. A., Abdourahman, A., Elfving, B., Pehrson, A. L., Sánchez, C., & Wernersson, R. (2017) · BMC Neuroscience · doi:10.1186/s12868-017-0376-x · Cited by 11 · cited 2× · see citing works
“For example, Waller and collaborators (54) have shown that neuroplasticity pathways, and protein-interaction networks are modulated by vortioxetine in rodents.”
BackgroundFranklin, M., Hlaváčová, N., Li, Y., Bermúdez, I., Csanova, A., Sánchez, C., & Ježová, D. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.008 · Cited by 4 · cited 5× · see citing works
“The involvement of tryptophan metabolism and the modulation of LTP as well as the increase in neurogenesis levels and brain-derived neurotrophic factor levels in the hippocampus could also potentially explain vortioxetine’s unique procognitive action (60, 68).”
BackgroundResultInfluentialFranklin, M., Hlaváčová, N., Li, Y., Bermúdez, I., Csanova, A., Sánchez, C., & Ježová, D. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.12.010 · Cited by 2 · see citing works
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Hack, L. M., Tozzi, L., Zenteno, S., Olmsted, A. M., Hilton, R. A., Jubeir, J., Korgaonkar, M. S., Schatzberg, A. F., Yesavage, J. A., O'Hara, R. M., et al. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.18411 · Cited by 121 · see citing works
Effects of chronic stress on cognitive function – From neurobiology to intervention
Girotti, M., Bulin, S. E., & Carreno, F. R. (2024) · Neurobiology of Stress · doi:10.1016/j.ynstr.2024.100670 · Cited by 142 · see citing works
“…mood improvement, their impact on cognitive symptoms remains negligible (Rosenblat et al., 2015; Shilyansky et al., 2016), except for vortioxetine (Bennabi et al., 2019), a multi-modal drug that is the only FDA-approved antidepressant for which the prescribing information mentions enhancements in…”
De Diego-Adeliño, J., Crespo, J. M., Mora, F., Neyra, A., Iborra, P., Gutiérrez-Rojas, L., & Salonia, S. F. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2022.2019705 · Cited by 67 · see citing works
“A comprehensive review delves into it [36].”
BackgroundInfluentialCaruso, G., Grasso, M., Fidilio, A., Torrisi, S. A., Musso, N., Geraci, F., Tropea, M. R., Privitera, A., Tascedda, F., Puzzo, D., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.809541 · Cited by 49 · see citing works
“Acute and long-term treatments with the new multimodal antidepressant vortioxetine (VTX) improve cognitive function in preclinical models of depression (Bennabi et al., 2019).”
BackgroundHuang, I.-C., Chang, T.-S., Chen, C., & Sung, J.-Y. (2022) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac054 · Cited by 41 · see citing works
“Vortioxetine can influence multiple cognitive domains, such as attention, orientation, executive function and concentration (Harrison et al., 2016; Bennabi et al., 2019; Cumbo et al., 2019).”
BackgroundAdamo, D., Pecoraro, G., Coppola, N., Calabria, E., Aria, M., & Mignogna, M. D. (2020) · Oral Diseases · doi:10.1111/odi.13602 · Cited by 41 · see citing works
Mortensen, J. K., & Andersen, G. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1880566 · Cited by 41 · see citing works
“It has thus been suggested that this drug may be a promising alternative in depressed patients with cognitive dysfunction [30].”
BackgroundSantos‐García, D., Losada, M. G. A., Hernando, I. C., Cabo, I., Baña, R. M. Y., Redondo, R. A., González, J. M. P., Bartolomé, C. C., Painceiras, M. J. F., Alvarado, M. C. Í., et al. (2022) · Brain Sciences · doi:10.3390/brainsci12111466 · Cited by 31 · see citing works
“The efficacy of vortioxetine on cognition has been mainly linked to its action on synaptic serotonin levels via the inhibition of the serotonin (5-HT) transporter (SERT), but its cognition-enhancing properties are hypothesized to also be mediated by other mechanisms such as the release of acetylcholine [60].”
BackgroundSteiner, S., Fehrer, A., Hoheisel, F., Schoening, S., Aschenbrenner, A. C., Babel, N., Bellmann–Strobl, J., Finke, C., Fluge, Ø., Froehlich, L., et al. (2023) · Autoimmunity Reviews · doi:10.1016/j.autrev.2023.103452 · Cited by 33 · see citing works
Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: a review and update
Adamo, D., Calabria, E., Coppola, N., Pecoraro, G., & Mignogna, M. D. (2021) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253211034320 · Cited by 32 · see citing works
Cognition and serotonin in Parkinson's disease.
Frouni, I., Kwan, C., Belliveau, S., & Huot, P. (2022) · Progress in Brain Research · doi:10.1016/bs.pbr.2022.01.013 · Cited by 25 · see citing works
Vortioxetine improves cognition in mild cognitive impairment
Tan, S. N., & Tan, C. S. C. (2021) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000376 · Cited by 26 · see citing works
“Besides inhibiting the serotonin transporter and modulating various serotonin receptors, vortioxetine has indirect effects on other systems, including the dopaminergic, noradrenergic and histaminergic systems (Bennabi et al., 2019).”
BackgroundLi, Z., Liu, S., Wu, Q., Li, J., Yang, Q., Wang, X., Peng, P., Wang, Q., Liu, Y., Li, M., et al. (2023) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyad018 · Cited by 25 · see citing works
“, 2015), and multiple cognitive domains, including attention, orientation, executive function, and concentration (Harrison et al., 2016; Bennabi et al., 2019; Cumbo et al., 2019).”
BackgroundŠagud, M., Perković, M. N., Dvojkovic, A., Jakšić, N., Vuksan‐Ćusa, B., Živković, M., Kušević, Z., Mihaljević-Peleš, A., & Pivac, N. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05790-2 · Cited by 23 · see citing works
Yoldi‐Negrete, M., Gill, L.-N., Olivares, S., Lauzière, A., Désilets, M., & Tourjman, V. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.08.005 · Cited by 24 · see citing works
McDonnell, C., Dunphy-Doherty, F., Rouine, J., Bianchi, M., Upton, N., Sokolowska, E., & Prenderville, J. A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.599588 · Cited by 23 · see citing works
Xue, L., Bocharova, M., Young, A. H., & Aarsland, D. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.06.003 · Cited by 18 · see citing works
Poggini, S., Banqueri, M., Albanese, N. C., Golia, M. T., Ibáñez, F. G., Limatola, C., Fuhrmann, M., Lalowski, M. M., Tremblay, M., Maggi, L., et al. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114295 · Cited by 18 · see citing works
Emery, S., Häberling, I. S., Berger, G. E., Baumgartner, N., Strumberger, M. A., Albermann, M., Nalani, K., Schmeck, K., Erb, S., Bachmann, S., et al. (2020) · Nutrients · doi:10.3390/nu12123630 · Cited by 16 · see citing works
Nastić, K., Pecikoza, U. B., Labudović‐Borović, M., Kotur‐Stevuljević, J., Micov, A. M., Jovanović, A., Tomic´, M. A., & Stepanović-Petrović, R. M. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115360 · Cited by 15 · see citing works
Association between depression and incident dementia: Longitudinal findings from the share study
Veronese, N., Smith, L., Koyanagi, A., Soysal, P., Mueller, C., Errera, C. M., Vassallo, G., Vernuccio, L., Catanese, G., Solmi, M., et al. (2024) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.6121 · Cited by 14 · see citing works
“43 We also found that the association between depression and dementia was significant only in Mediterranean countries and in Israel: we do not know the specific reason of this finding, but we can argue that some geographical differences could be moderators of our findings.”
Ciani, M., Rigillo, G., Benatti, C., Pani, L., Blom, J. M. C., Brunello, N., Tascedda, F., & Alboni, S. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240705143649 · Cited by 14 · see citing works
Riga, M. S., Sánchez, C., Celada, P., & Artigas, F. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108238 · Cited by 14 · see citing works
Key considerations in the pharmacological management of treatment-resistant depression
Yavi, M., Henter, I. D., Park, L. T., & Zarate, C. A. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1951225 · Cited by 14 · see citing works
“processing speed, verbal learning, and recall domains [10].”
BackgroundEvaluation of the effect of vortioxetine on pain threshold by hot-plate test in mice
İnaltekin, A., & Kıvrak, Y. (2021) · Nöro Psikiyatri Arşivi · doi:10.29399/npa.27462 · Cited by 13 · see citing works
Mariano, R. S., Coldibeli, B., Ceravolo, G. S., & Sartori, E. R. (2023) · Journal of Electroanalytical Chemistry · doi:10.1016/j.jelechem.2023.117962 · Cited by 13 · see citing works
Cuomo, A., Aguglia, A., Berardis, D. D., Ventriglio, A., Gesi, C., & Fagiolini, A. M. (2024) · Annals of General Psychiatry · doi:10.1186/s12991-024-00505-1 · Cited by 13 · see citing works
“Positron emission tomography (PET) studies using 5-HT transporter ligands (11 C-MADAM or 11 C-DASB) demonstrated that 5-HT transporter occupancy in the raphe nuclei is around 50% at 5 mg/day, 65% at 10 mg/day, and over 80% at 20 mg/day [22].”
BackgroundZhang, Y., Lai, S., Zhang, J., Wang, Y., Zhao, H., He, J., Huang, D., Chen, G., Qi, Z., Chen, P., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.01.272 · Cited by 11 · see citing works
Hack, L. M., Jubeir, J., Hilton, R. A., Tozzi, L., Boyar, L., Zhang, X., Lyons, T., Jo, B., O'Hara, R. M., Schatzberg, A. F., et al. (2025) · Nature Mental Health · doi:10.1038/s44220-025-00510-7 · Cited by 11 · see citing works
“The standard drug development pipeline in psychiatry has produced only one FDA-approved therapy specifically addressing cognitive deficits in depression: vortioxetine 13 .”
Danielak, D. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1880567 · Cited by 11 · see citing works
“unique properties, such as enhancing cognitive function [8,9].”
BackgroundSiwek, M., Gorostowicz, A., Bosak, M., & Dudek, D. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.852042 · Cited by 10 · see citing works
“…for cognitive dysfunctions in MDD patients—it has been observed to improve cognition (both objectively and subjectively) independently of the alleviation of depression severity and to induce greater improvement in different cognitive domains compared to other antidepressants (Bennabi et al., 2019).”
ResultÜnal, G. Ö., Doğuç, D. K., Öztürk, K. H., Erkılınç, G., Dönmez, F., Kıran, E. D., & Yüceer, R. O. (2024) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2024.2308268 · Cited by 10 · see citing works
“According to preclinical and clinical studies, VOR is a good alternative with its antidepressant effect as well as pro-cognitive effects in memory, cognitive and executive dysfunctions caused by depression [6,7].”
BackgroundMethodSegura‐Garcìa, C., Rania, M., Carbone, E. A., de Filippis, R., Aloi, M., Caroleo, M., Grasso, G., Calabrò, G., Fazia, G., Staltari, F. A., et al. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.635502 · Cited by 10 · see citing works
“Other researchers reported significant differences in these tests after treatment with VTX (91); nonetheless, it is known that positive outcomes of treatment on cognitive functioning are bigger among those patients occupationally active independently of the improvement of depression (90), whilst our different results…”
ResultBerardelli, I., Rogante, E., Formica, F., Iannazzo, R., mammoliti, A. V., Riccioni, R., Veizi, S., McIntyre, R. S., & Pompili, M. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811241309612 · Cited by 8 · see citing works
“…positive influences on psychomotor speed, delayed recall (Rosenblat et al., 2015), and multiple cognitive domains, including attention, orientation, executive function, and concentration, all symptoms often present in acute MDD (Bennabi et al., 2019; Cumbo et al., 2019; Harrison et al., 2016).”
Effects of Vortioxetine on Sleep Architecture of Adolescents with Major Depressive Disorder
Mlyncekova, Z., Hutka, P., Višňovcová, Z., Ferencová, N., Kovacova, V., Macejova, A., Tonhajzerová, I., & Ondrejka, I. (2023) · Clocks & Sleep · doi:10.3390/clockssleep5040042 · Cited by 8 · see citing works
“…it is suggested that, mostly through antagonism on the 5-HT 3 receptor, it has a significant procognitive effect via modulation of neurotransmission in the medial prefrontal cortex and via enhancement of neurogenesis and neurotrophic processes in the hippocampus, as found in animal models [24].”
MethodEffect of a 5-HT7 Receptor Antagonist on Reversal Learning in the Rat Attentional Set-Shifting Test
Hrnjadovic, A., Friedmann, J., Barhebreus, S., Allen, P. J., & Kocsis, B. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00554 · Cited by 8 · see citing works
Chakrabarty, T., McInerney, S. J., Torres, I. J., Frey, B. N., Milev, R. V., Müller, D. J., Rotzinger, S., Kennedy, S. H., Lam, R. W. M., & the CAN-BIND Investigator Team (2021) · CNS Drugs · doi:10.1007/s40263-021-00793-1 · Cited by 8 · see citing works
Recent advances in the psychopharmacology of major depressive disorder
Alexander, L., & Young, A. H. (2022) · BJPsych Advances · doi:10.1192/bja.2022.14 · Cited by 8 · see citing works
“Vortioxetine may additionally have bene fi cial effects beyond its action to improve mood: it seems to be effective in improving psychomotor speed, executive function, memory, attention and behavioural fl exibility in depression (Bennabi 2019).”
Recent Developments in Pharmacotherapy of Depression: Bench to Bedside
Shad, M. U. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13050773 · Cited by 8 · see citing works
Liu, X., Liu, R., Sun, Y., Wang, H., Wang, H., Wang, T., Ma, Y., Li, X., Wang, Q., Su, Y., et al. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01848-9 · Cited by 7 · see citing works
Adamo, D., Canfora, F., Pecoraro, G., Leuci, S., Coppola, N., Marenzi, G., Ottaviani, G., Rupel, K., Pellegrini, L., Aria, M., et al. (2025) · Current Neuropharmacology · doi:10.2174/1570159x22999240729103717 · Cited by 7 · see citing works
“This dual functionality is significant for enhancing neuroplasticity and improving the regulation of mood and cognitive func-tions—areas often impacted by chronic pain conditions [12, 55, 56].”
Vortioxetine Induced Hypomania: A Case Presentation and Review of the Literature
Tunç, A. E. B., & Tunç, S. (2022) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2022.20.2.394 · Cited by 6 · see citing works
Yuluğ, B., Ayyıldız, S., Sayman, D., Karaca, R., İpek, L., Çankaya, Ş., Salar, A. B., Ayyıldız, B., Mikutta, C. A., Yağcı, N., et al. (2024) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12450 · Cited by 6 · see citing works
“35,52 Xiong et al. identified decreased gray matter volume in the anterior pulvinar as a trait-marker of depression, 14 a phenomenon which was subsequently reversed with antidepressant therapy.”
BackgroundGarcía‐Alberca, J. M., de la Guía, P., Gris, E., Mendoza, S., de la Rica, M. L., Barbancho, M. Á., Lara, J. P., & Blanco‐Reina, E. (2024) · Journal of Personalized Medicine · doi:10.3390/jpm14090918 · Cited by 5 · see citing works
“It is thought that vortioxetine’s multimodal activity is responsible for its effects on cognitive function [19,22,29], with potential mechanisms including increased glutamate neurotransmission and neuroplasticity in regions such as the prefrontal cortex [19,27].”
BackgroundWang, L., Wang, M., Zhao, C., Jian, J., & Qiao, D. (2023) · BMC Psychiatry · doi:10.1186/s12888-023-04625-y · Cited by 4 · see citing works
“MDD is thought to be a complex polygenetic disorder in which both genetic and environmental factors are involved in its onset and development [11, 12].”
InfluentialEliaçık, S., & Kaya, A. E. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1398417 · Cited by 4 · see citing works
Neural oscillations induced by gamma sensory entrainment in cognitive biotype of depression
Shi, X., Wang, H., Zhao, Y., Wang, C., Qi, Y., Gao, M., Wei, M., & Wang, G. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1586075 · Cited by 3 · see citing works
Frycz, B. A., Dutsch-Wicherek, M., Płaza, O., Szulc, A., Bijata, M., Włodarczyk, J., & Dzwonek, J. (2026) · Pharmacological Reports · doi:10.1007/s43440-026-00827-9 · Cited by 2 · see citing works
Tangen, Ä., Veldman, E. R., Svensson, J. E., Tiger, M., Nord, M., Sorjonen, K., Andersson, M., Plavén‐Sigray, P., Varrone, A., Halldin, C., et al. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac084 · Cited by 3 · see citing works
“…on vortioxetine, a serotonin reuptake inhibitor with 5-HT 1B agonist activity (Bang-Andersen et al., 2011; Yang et al., 2019), have indicated beneficial effects on psychomotor speed and executive control compared with selective serotonin reuptake inhibitors in MDD patients (Bennabi et al., 2019).”
Samaryn, E., Galińska-Skok, B., Nobis, A., Zalewski, D., Maciejczyk, M., Gudowska-Sawczuk, M., Mroczko, B., Zalewska, A., & Waszkiewicz, N. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12227049 · Cited by 3 · see citing works
“Moreover, vortioxetine has been developed to treat cognitive dysfunctions [35].”
BackgroundZajecka, J., Laufer, O., Peremen, Z., Sholtes, D., Mackey, I., Baumeister, C., White, A., Geva, A. B., & Issachar, G. (2024) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2024.100732 · Cited by 3 · see citing works
Badr, B., Gailani, H. A., Alkhoori, S. A., Butt, H., Daher, M., Dheyaa, B., Hindy, N. E., Eid, M., Elsaadouni, N., Faia, V., et al. (2024) · Annals of General Psychiatry · doi:10.1186/s12991-024-00526-w · Cited by 3 · see citing works
“Animal models demonstrated that vortioxetine has pro-cognitive activities, significantly improving cognitive deficits and memory impairment [18].”
BackgroundHutnyan, M., & McClintock, S. M. (2025) · Transcranial Magnetic Stimulation · doi:10.1016/j.transm.2025.100088 · Cited by 2 · see citing works
Smith, A. L. W., Hamilton, S., Murphy, S. E., Cowen, P. J., & Harmer, C. J. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06770-6 · Cited by 2 · see citing works
“…medication that combines serotonin reuptake inhibition with 5-HT 1A receptor agonism, has beneficial effects on cognition in MDD (Mahableshwarkar et al. 2015; Bennabi et al. 2019) and to a greater extent than treatment with a selective serotonin reuptake inhibitor (SSRI) alone (Sagud et al. 2021).”
Alcalá, J. Á., Dorado, V. O., Herrera, G. D. P. A., Chamón, S. L., & Molinera, V. G. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1568777 · Cited by 2 · see citing works
Hirsch, D., Reed, J., Naqvi, A., Ngor, A., Dugan, L., Costa, K., Ganasi, R. S., Truman, K. A., Danovitch, I., IsHak, W. W., et al. (2025) · CNS Drugs · doi:10.1007/s40263-025-01248-7 · Cited by 2 · see citing works
“It functions as a serotonin modulator and stimulator, primarily through inhibition of the serotonin transporter and modulation of various serotonin receptors, including 5-HT1A agonism and 5-HT3 antagonism [126].”
Psychiatric rehabilitation and cognitive deficit for treatment-resistant depression
Cheng, C., & Jeng, J. (2023) · Progress in brain research · doi:10.1016/bs.pbr.2023.02.006 · Cited by 2 · see citing works
Cuomo, A., Barillà, G., Cattolico, M., Pardossi, S., Mariantoni, E., Koukouna, D., Carmellini, P., & Fagiolini, A. M. (2024) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2024.2333394 · Cited by 2 · see citing works
Vortioxetine: a comprehensive update on a new-generation antidepressant
Evren, C. (2021) · Dusunen Adam The Journal of Psychiatry and Neurological Sciences · doi:10.14744/dajpns.2021.00115 · Cited by 2 · see citing works
“Finally, a review also reported that vortioxetine appeared to be a useful and promising treatment option in MDD patients with cognitive dysfunction, but its role in treatment needs to be further clarified (77).”
BackgroundNg, C. G., Abousheishaa, A. A., Low, S.-Y., Zainal, N. Z., Thong, K. S., Awaluddin, A., Loo, T. H., Yacob, S., Jaafar, N. R. N., Taib, N. I. A., et al. (2023) · Asian Pacific Journal of Cancer Prevention · doi:10.31557/apjcp.2023.24.8.2583 · Cited by 2 · see citing works
“Its combined effect on SERT and 5-HT receptors has been suggested to significantly improve attention, executive function, learning, processing speed, and memory (Lundbeck, 2018) and enhance neurogenesis and plasticity-promoting effects (Bennabi et al., 2019).”
BackgroundCognitive impact in bipolar disorder
Bourin, M. (2019) · Archives of Depression and Anxiety · doi:10.17352/2455-5460.000042 · Cited by 2 · see citing works
Potter, W. Z., & Cuthbert, B. N. (2021) · Springer eBooks · doi:10.1007/978-3-030-62351-7_14 · Cited by 1 · see citing works
Chronic α5‐ GABA ‐A Receptor Potentiation Promotes Mouse Adult Hippocampal Neurogenesis
Prévot, T. D., Marcotte, M. D., David, D. J. P., Mendez‐David, I., Mian, M. Y., Cook, J. M., Guilloux, J., & Sibille, E. L. (2025) · Hippocampus · doi:10.1002/hipo.70019 · Cited by 1 · see citing works
“…et al. 2018; Olivas-Cano et al. 2023; Sachs and Caron 2014) and other antidepressants, such as venlafaxine (Belovicova et al. 2017), vortioxetine (Bennabi et al. 2019; Felice et al. 2018), paroxetine (Jahromi Malberg 2004) increase AHN in the adult brain, little is known about GABAergic drugs…”
Dølven, S., Moroń, M., Eriksen, I., Toft, J. E. G., & Semkovska, M. (2025) · Neuropsychology Review · doi:10.1007/s11065-025-09686-2 · Cited by 1 · see citing works
Memory in Psychiatric Disorders: A Review
Gurrieri, R., Gambini, M., Russomanno, G., Mucci, F., Carbone, M. G., Sità, G., Pescini, E., Stagi, S., Casucci, A. C., Mastrogiacomo, D., et al. (2025) · Life · doi:10.3390/life15121926 · Cited by 1 · see citing works
“Within antidepressant strategies, the multimodal serotonergic agent vortioxetine has repeatedly shown advantages on processing speed and learning/working memory in major depression, with effects that appear only partly mediated by mood improvement [308,309].”
Arai, K., Nonaka, M., Shimada, S., & Nakamura, M. (2023) · Psychiatry and Clinical Neurosciences Reports · doi:10.1002/pcn5.158 · Cited by 1 · see citing works
“Although the benefits of vortioxetine have been noted and include improved cognitive function 9 and low dropout rates, 10 Most symptoms of the jitteriness/anxiety syndrome appeared within 2 weeks of antidepressant initiation; however, only mania/ hypomania was present in the second month.”
BackgroundCognitive dysfunction: An important feature of major depressive disorder
Duan, D.-X., Li, X., Yang, L., Wang, W., & Zhu, H. (2023) · Neurons and Neurological Disorders · doi:10.58489/2836-8851/011 · Cited by 1 · see citing works
Carreno, F. R., & Frazer, A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00044-x
Mechanisms of action and clinical effects of vortioxetine
Петрова, Н. Н., & Mukhin, A. A. (2022) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202212206284
The Analgezic Effect of Vortioxetine on somatic and visceral Pain using the mouse models
Fotache, P. A., Pelin, A.-M., Georgescu, C., Bucă, B. R., & Mititelu-Tarțău, L. (2022) · Journal of Pharmaceutical Negative Results · doi:10.47750/pnr.2022.13.s04.168
“In this experimental model, which evaluate the paw`s animal reactivity to thermal noxious stimulation, it was considered that: the increases in the latency for the mouse to avoid the thermal noxious paw stimulation are indicative of analgesia, while decreases of the latency response are indicative of hyperalgesia [23,…”
BackgroundMethodJaywant, A. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.01.024
Derakhshan, D., Lipsman, N., Feinstein, A., LEVITT, A. J., Eizenman, M., Rabin, J. S., & Giacobbe, P. (2025) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2025.1696560
Голубев, С. А. (2026) · Психиатрия психотерапия и клиническая психология · doi:10.34883/pi.2026.17.1.007
Xu, H., Fan, H., Ding, E.-H., Hou, P., Jiang, B., & Zhu, W.-B. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1837566
“Notably, the superior efficacy of the higher dose (20 mg/kg) Frontiers in Pharmacology frontiersin.org across both behavioral and molecular endpoints mirrors clinical observations where vortioxetine exhibits dose-dependent therapeutic effects, particularly on cognitive symptoms often refractory to SSRIs (Bennabi et al…”
Influential
- Authors
- Bennabi, D., Haffen, E., & Van Waes, V.
- Affiliations
- Inserm (FR)
- Corresponding author
- Bennabi, Djamila
- ORCID
- Bennabi, Djamila
- Venue
- Frontiers in Psychiatry
- Publisher
- Frontiers Media SA
- Published
- 2019-11-06
- Volume
- 10
- Pages
- 771-771
- ISSN
- 1664-0640 (ISSN-L)
- PMC
- PMC6851880
- OpenAlex
- W2984384647
- Cited by
- 75
- References
- 79
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 14 · 2023: 15 · 2022: 11 · 2021: 15 · 2020: 4 · 2019: 1
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- vortioxetine, major depressive disorder, cognitive enhancement, cognitive impairment, animal models of depression, behavioral models, antidepressant effects, relapse prevention
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