Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: Evidence for direct 5-HT receptor modulation

Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan Lars

doi:10.1016/j.euroneuro.2013.10.011

Cited by 97Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: Evidence for direct 5-HT receptor modulation

Jensen, Jesper Bornø, du Jardin, Kristian Gaarn, Song, Dekun, Budac, David, Smagin, Gennady, Sanchez, Connie, Pehrson, Alan Lars·2014·European Neuropsychopharmacology

DOI 10.1016/j.euroneuro.2013.10.011

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Abstract

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.

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Vortioxetine has been shown to promote memory, cognition and executive functions in a variety of animal models.
“It has also been shown to promote memory, cognition and executive functions in a variety of animal models.13,14”
From A Randomized Controlled Study of Efficacy and Cognitive Function Improvement of Vortioxetine and Escitalopram in Patients with Depression in Chinese Han Nationality (2024) · cites this paper as [14]

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MethodResult
Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats
Gasull-Camós, J., Tarrés-Gatius, M., Artigas, F., & Castañé, A. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.7 · Cited by 60 · see citing works
5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway
Sui, H. X., Xu, H., Ji, Q., Liu, X., Zhou, L., Song, H., Zhou, X., Xu, Y., Chen, Z., Cai, J., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4543 · Cited by 60 · see citing works
Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory
Bétry, 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 · see citing works
“Using this task, it was also recently reported that the SSRI escitalopram and the SNRI duloxetine failed to restore 5-HT depletioninduced deficits in the object recognition at doses corresponding to full SERT occupancy whereas vortioxetine was active, suggesting that vortioxetine's receptor activities contributes to i…”
Self-citation
Vortioxetine: a review of efficacy, safety and tolerability with a focus on cognitive symptoms in major depressive disorder
Al-Sukhni, M., Maruschak, N. A., & McIntyre, R. S. (2015) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2015.1046836 · Cited by 58 · see citing works
“Vortioxetine demonstrated a reversal of this induced impairment in rats as assessed by the novel object recognition and Y-maze spontaneous alteration (spatial memory) tests [33,34].”
BackgroundMethod
A review of the clinical efficacy, safety and tolerability of the antidepressants vilazodone, levomilnacipran and vortioxetine
Deardorff, W. J., & Grossberg, G. T. (2014) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2014.960842 · Cited by 49 · see citing works
“The SSRI escitalopram and SNRI duloxetine were unable to reverse memory impairments induced by 5-HT depletion, showing that vortioxetine’s effect on serotonin receptors is likely essential [89].”
Background
Chemical update on the potential for serotonin 5-HT6 and 5-HT7 receptor agents in the treatment of Alzheimer’s disease
Kucwaj‐Brysz, K., Baltrukevich, H., Czarnota-Łydka, K., & Handzlik, J. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2021.128275 · Cited by 48 · see citing works
S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression
du Jardin, K. G., Liebenberg, N., Cajina, M., Müller, H. K., Elfving, B., Sanchez, C., & Wegener, G. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00978 · Cited by 47 · see citing works
“5-HT depletion was produced by pre-treating FSL rats with pCPA, 86 mg/kg/day, or vehicle for 3 consecutive days, as earlier shown to be an optimal depletion paradigm (Jensen et al., 2014).”
MethodResult
Effect of vortioxetine on cognitive impairment in patients with major depressive disorder: a systematic review and meta-analysis of randomized controlled trials
Huang, 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
“…various antidepressant agents thus far assessed, evidence for a positive, direct effect across multiple cognitive domains is strong for vortioxetine but relatively weak for other SSRI agents, serotonin-norepinephrine reuptake inhibitors, or bupropion (Jensen et al., 2014; McIntyre et al., 2015).”
Background
Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression
Taciak, P., Lysenko, N., & Mazurek, A. P. (2017) · Pharmacological Reports · doi:10.1016/j.pharep.2017.07.011 · Cited by 39 · see citing works
“Additionally, this drug has been reported to enhance memory in rats [108] and reverse memory impairment induced by central serotonin depletion [109].”
Background
Vortioxetina: una nueva alternativa en el trastorno depresivo mayor
Salagre, E., Grande, I., Solé, B., Sánchez‐Moreno, J., & Vieta, E. (2017) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2017.06.006 · Cited by 40 · see citing works
Vortioxetine ameliorates motor and cognitive impairments in the rotenone-induced Parkinson's disease via targeting TLR-2 mediated neuroinflammation
Samur, D. N., Akçay, G., Yıldırım, S., Özkan, A., Çeker, T., Derin, N., Tanrıöver, G., Aslan, M., Ağar, A., & Özbey, G. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.108977 · Cited by 39 · see citing works
Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission
Pehrson, A. L., Jeyarajah, T., & Sánchez, C. (2015) · CNS Spectrums · doi:10.1017/s1092852915000486 · Cited by 36 · see citing works
Self-citation
Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine
Stahl, S. M. (2015) · CNS Spectrums · doi:10.1017/s1092852915000346 · Cited by 36 · see citing works
Chronic vortioxetine treatment improves the responsiveness to an acute stress acting through the ventral hippocampus in a glucocorticoid-dependent way
Brivio, P., Corsini, G., Riva, M. A., & Calabrese, F. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.02.006 · Cited by 33 · see citing works
Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT1A Receptor with 5-HT3 Receptor Inhibition in Rats
Okada, M., Okubo, R., & Fukuyama, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246235 · Cited by 32 · see citing works
“Furthermore, the potentials of the cognitive enhancing action of vortioxetine have also been demonstrated [6,7].”
Background
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
Pharmacological Discrimination of Effects of MK801 on Thalamocortical, Mesothalamic, and Mesocortical Transmissions
Okada, M., Fukuyama, K., Nakano, T., & Ueda, Y. (2019) · Biomolecules · doi:10.3390/biom9110746 · Cited by 29 · see citing works
“The mesocortical serotonergic transmission contributes to improvement of depressive mood [61–63], and mesothalamic serotonergic transmission plays important roles in emotional perception via regulation of thalamocortical glutamatergic transmission [15,16,64].”
Background
Subchronic vortioxetine treatment –but not escitalopram– enhances pyramidal neuron activity in the rat prefrontal cortex
Riga, M. S., Teruel‐Martí, V., Sánchez, C., Celada, P., & Artigas, F. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.024 · Cited by 29 · see citing works
“…inhibitor of tryptophan hydroxylase pCPA (86 mg/kg free base, s.c.) was administrated daily during 4 consecutive days (from day 11 to day 14) in order to induce cognitive impairment through inhibition of 5-HT synthesis (du Jardin et al., 2014; Jensen et al., 2014; Wallace et al., 2014).”
Influential
Vortioxetine: A new alternative for the treatment of major depressive disorder
Salagre, E., Grande, I., Solé, B., Sánchez‐Moreno, J., & Vieta, E. (2018) · Revista de Psiquiatría y Salud Mental (English Edition) · doi:10.1016/j.rpsmen.2018.02.005 · Cited by 28 · see citing works
Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission
Pehrson, A. L., Pedersen, C. S., Tølbøl, K. S., & Sánchez, C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00162 · Cited by 29 · see citing works
“This analysis structure is similar to that used in previous studies with similar experimental designs (du Jardin et al., 2014; Jensen et al., 2014).”
BackgroundMethodResultInfluentialSelf-citation
Vortioxetine Prevents Lipopolysaccharide-Induced Memory Impairment Without Inhibiting the Initial Inflammatory Cascade
Alboni, S., Benatti, C., Colliva, C., Radighieri, G., Blom, J. M. C., Brunello, N., & Tascedda, F. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.603979 · Cited by 28 · see citing works
Effectiveness and Safety of Vortioxetine for the Treatment of Major Depressive Disorder in the Real World: A Systematic Review and Meta-Analysis
Li, 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 26 · see citing works
“The mechanism of cognitive improvement was thought to be related to the vortioxetine-induced elevation of serotonin levels and direct modulation of serotonin receptors (Jensen et al., 2014).”
Background
Vortioxetine promotes maturation of dendritic spines in vitro: A comparative study in hippocampal cultures
Waller, J. A., Chen, F., & Sánchez, C. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.12.012 · Cited by 25 · see citing works
Self-citation
New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine
Orsolini, L., Tomasetti, C., Valchera, A., Iasevoli, F., Buonaguro, E. F., Vellante, F., Fornaro, M., Fiengo, A. L. C., Mazza, M., Vecchiotti, R., et al. (2016) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2016.1173545 · Cited by 25 · see citing works
“Moreover, successive studies have also demonstrated that VRX, but not escitalopram or duloxetine, may restore memory impairment caused by serotonin depletion [116], and these effects are dose dependent and most likely rely on VRX modulation of 5-HT1a and 5-HT3 receptors [117].”
Background
Task- and Treatment Length–Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats
Pehrson, 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 · see citing works
“This is supported by evidence from a number of preclinical experiments (du Jardin et al., 2014; Jensen et al., 2014; Wallace et al., 2014; Li et al., Alan Pehrson, Arne Mørk, Gennady Smagin, Dekun Song, David Budac, Manuel Cajina, and Connie Sanchez were employees of Lundbeck Research USA while…”
BackgroundSelf-citation
A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One-Week Vortioxetine Treatment
Chen, 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 · see citing works
“A selective 5-HT1AR agonist (flesinoxan) and a selective 5-HT3 receptor antagonist (ondansetron) reversed memory impairments in 5-HT depleted rats (Jensen et al., 2014).”
Background
Effects of vortioxetine on biomarkers associated with glutamatergic activity in an SSRI insensitive model of depression in female rats
Hlaváčová, 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 · see citing works
“Observations such as significantly higher levels of the NR2A sub-unit of NMDA receptors in post mortem brains of depressed patients vs. healthy subjects (Karolewicz et al., 2009) are supportive of the construct validity of the TRP depletion model.”
Self-citation
Vortioxetine administration attenuates cognitive and synaptic deficits in 5×FAD mice
Jiang, L., Huang, G.-D., Feng, S., Wang, H., Zhang, C., & Yu, X. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05452-9 · Cited by 21 · see citing works
Vortioxetine Improves Brain Glymphatic System Function, Functional Connectivity, and Cognitive Functions in Major Depressive Disorder
Guo, Z., Tang, X., Zhong, S., Chen, G., Chen, P., Chen, C., Chen, R., Huang, L., Jia, Y., & Wang, Y. (2025) · Depression and Anxiety · doi:10.1155/da/1990117 · Cited by 20 · see citing works
“Compared with other antidepressants, vortioxetine has a distinctive pharmacological pro ﬁ le that may improve the impaired cognitive performance of patients with MDD [4, 5, 42].”
Vortioxetine for the treatment of major depressive disorder
Tritschler, L., Felice, D., Colle, R., Guilloux, J., Corruble, E., Gardier, A. M., & David, D. J. P. (2014) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2014.950655 · Cited by 21 · see citing works
“In addition, vortioxetine administration enhances cognitive performance [10] and dosedependently reverses serotonin depletion-induced memory deficits [29] in rats.”
BackgroundResult
Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats
Li, T., Guo, K., Qu, W., Han, Y., Wang, S., Lin, M., An, S., Li, X., Ma, S., Wang, T., et al. (2015) · Journal of Diabetes Investigation · doi:10.1111/jdi.12406 · Cited by 19 · see citing works
“5 mg/kg twice daily) according to Jensen et al.(15), and CDP-treated rats were intragastrically administered with CDP (10 mg/kg twice daily), whereas rats in the other groups were subcutaneously or intragastrically administered with an equivalent volume of normal saline or 0.”
MethodInfluential
Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers
Waller, 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 · see citing works
Self-citation
Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.
Feltmann, K., Konradsson‐Geuken, Å., Bundel, D. D., Lindskog, M., & Schilström, B. (2015) · Behavioral Neuroscience · doi:10.1037/bne0000100 · Cited by 17 · see citing works
“It is important to note that, although increased serotonergic transmission does not appear to be sufficient to improve object cognition, serotonin depletion impairs novel object recognition (Jensen et al., 2014), indicating that basal serotonergic transmission is necessary for recognition memory.”
Background
HILIC–MS Determination of Genotoxic Impurity of 2-Chloro-N-(2-Chloroethyl)Ethanamine in the Vortioxetine Manufacturing Process
Douša, M., Klvaňa, R., Doubský, J., Srbek, J., Richter, J., Exner, M., & Gibala, P. (2015) · Journal of Chromatographic Science · doi:10.1093/chromsci/bmv107 · Cited by 16 · see citing works
Comparing the Therapeutic Effects of Crocin, Escitalopram and Co-Administration of Escitalopram and Crocin on Learning and Memory in Rats with Stress-Induced Depression
Joodaki, M., Radahmadi, M., & Alaei, H. (2021) · Malaysian Journal of Medical Sciences · doi:10.21315/mjms2021.28.4.6 · Cited by 15 · see citing works
Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats
Riga, M. S., Sánchez, C., Celada, P., & Artigas, F. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108238 · Cited by 14 · see citing works
Role of 5-HT1A and 5-HT7 Receptors in Memory Regulation and the Importance of Their Coexpression: A Systematic Review
Briones-Aranda, A., Durán, D. M. F., Romero‐Nava, R., Corzo-Gómez, J. C., Cruz-Trujillo, R., Toalá-Sepúlveda, F., Del-Rio-Navarro, B. E., & Huang, F. (2025) · Biomolecules · doi:10.3390/biom15060762 · Cited by 13 · see citing works
Targeting the serotonergic system in the treatment of neurodegenerative diseases—emerging therapies and unmet challenges
Brüge, A., Ponimaskin, E. G., & Labus, J. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100071 · Cited by 12 · see citing works
Vortioxetine 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 · see citing works
“Interestingly, VORT restored Frontiers in Pharmacology | www.frontiersin.org 9 March 2018 | Volume 9 | Article 204 the memory impairment in NOR and spontaneous alterations induced by serotonin depletion in rats (Jensen et al., 2014).”
BackgroundSelf-citation
The protective effects of escitalopram on synaptic plasticity in the CA1 region of chronically stressed and non‐stressed male rats
Farahbakhsh, Z. Z., & Radahmadi, M. (2022) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.10224 · Cited by 11 · see citing works
“A study has emphasized the negative effects of escitalopram on cognitive performance (Jensen et al., 2014).”
Background
Utilization of Photochemically Induced Fluorescence Detection for HPLC Determination of Genotoxic Impurities in the Vortioxetine Manufacturing Process
Douša, M., Doubský, J., & Srbek, J. (2016) · Journal of Chromatographic Science · doi:10.1093/chromsci/bmw116 · Cited by 11 · see citing works
Neuroplasticity 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 · see citing works
“In 5-HT-depleted rats, vortioxetine, but not escitalopram or duloxetine, reversed deficits in the hippocampal-dependent novel object recognition task [17] and in the Y-maze spontaneous alternation spatial memory task [21].”
BackgroundSelf-citation
Protective role of functional food in cognitive deficit in young and senile rats
Attia, H. N., & Ahmed, K. A. (2020) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000522 · Cited by 11 · see citing works
“Serotonin or 5-hydroxytryptamine (5-HT) was also claimed to be involved in cognitive mechanisms such as learning, shortand long-term memory, both in the frontal CX and HC (Cifariello et al., 2008; Lapiz-Bluhm et al., 2009; Jensen et al., 2014).”
Background
Use of vortioxetine in different neurological fields: a systematic review and future perspectives
Verrienti, G., Colonna, I., & Raccagni, C. (2025) · Neurological Sciences · doi:10.1007/s10072-025-07987-1 · Cited by 9 · see citing works
Vortioxetine in the treatment of major depressive disorder
Baldwin, D. S., & Hanumanthaiah, V. B. (2015) · Future Neurology · doi:10.2217/fnl.14.69 · Cited by 9 · see citing works
Partial inhibition of catecholamine activity and enhanced responsiveness to NMDA after sustained administration of vortioxetine
Ebrahimzadeh, M. A., Mansari, M. E., & Blier, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.10.036 · Cited by 9 · see citing works
“…to the pro-cognitive effects of vortioxetine, which was reported to be ameliorated following vortioxetine administration in rats (du Jardin et al., 2014; Jensen et al., 2014; Mørk et al., 2013) and in patients with MDD (Katona et al., 2012; Mahableshwarkar et al., 2015; McIntyre et al., 2014).”
Background
Vortioxetine ameliorates anhedonic-like behaviour and promotes strategic cognitive performance in a rodent touchscreen task
Martis, L., Højgaard, K., Holmes, M. C., Elfving, B., & Wiborg, O. (2021) · Scientific Reports · doi:10.1038/s41598-021-88462-7 · Cited by 9 · see citing works
The efficacy of vortioxetine in the acute treatment of major depressive disorder: A systematic review and meta-analysis
Berardelli, 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 7 · see citing works
“The mechanism of cognitive improvement was thought to be related to the vortioxetineinduced elevation of serotonin levels and direct modulation of serotonin receptors (Jensen et al., 2014).”
Protective Effects of Long-Term Escitalopram Administration on Memory and Hippocampal BDNF and BCL-2 Gene Expressions in Rats Exposed to Predictable and Unpredictable Chronic Mild Stress
Marghmaleki, V. S., Radahmadi, M., Alaei, H., & Khanahmad, H. (2024) · Brain Science · doi:10.3390/brainsci14050420 · Cited by 7 · see citing works
“Conversely, there have been reports potential to improve memory consolidation under contrast, Jensen et al. (2014) examined the adverse [60].”
Background
Additional Reduction of Residual Symptoms with Aripiprazole Augmentation in the Patients with Partially Remitted Major Depressive Disorder
Shin, C., Pae, C., Kwak, K. P., Jeon, S. W., Jeong, H., Kim, J.-W., Lee, Y. J., Patkar, A. A., & Han, C. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.2.243 · Cited by 8 · see citing works
Propriétés pharmacologiques de la vortioxetine et leurs conséquences pré-cliniques
David, D. J. P., Tritschler, L., Guilloux, J., Gardier, A. M., Sánchez, C., & Raphaël Gaillard, B. (2016) · L Encéphale · doi:10.1016/s0013-7006(16)30015-x · Cited by 8 · see citing works
The rat hippocampal gliovascular system following one week vortioxetine and fluoxetine
Chen, F., Danladi, J., Ardalan, M., Nyengaard, J. R., Sánchez, C., & Wegener, G. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.11.008 · Cited by 7 · see citing works
The protective effects of escitalopram on chronic restraint stress-induced memory deficits in adult rats
Farahbakhsh, Z. Z., & Radahmadi, M. (2022) · Physiology and Pharmacology · doi:10.52547/phypha.26.1.9 · Cited by 7 · see citing works
Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity
Hillhouse, T. M., Merritt, C. R., Smith, D. A., Cajina, M., Sánchez, C., Porter, J. H., & Pehrson, A. L. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01024 · Cited by 7 · see citing works
Self-citation
Use of Hierarchical Carbon Nanofibers Decorated with NiCo Nanoparticles for Highly Sensitive Vortioxetine Determination
Smajdor, J., Zambrzycki, M., Paczosa‐Bator, B., & Piech, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314555 · Cited by 7 · see citing works
Acute dosing of vortioxetine strengthens event-related brain activity associated with engagement of attention and cognitive functioning in rats
Laursen, B., Bundgaard, C. H., Graversen, C., Grupe, M., Sánchez, C., Leiser, S. C., Sørensen, H. B. D., Drewes, A. M., & Bastlund, J. F. (2017) · Brain Research · doi:10.1016/j.brainres.2017.03.024 · Cited by 6 · see citing works
In vivo electrophysiological study of the targeting of 5‐HT3 receptor‐expressing cortical interneurons by the multimodal antidepressant, vortioxetine
Schweimer, J. V., Brouard, J. T., Li, Y., Sánchez, C., & Sharp, T. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15623 · Cited by 6 · see citing works
“Additionally, vortioxetine reversed memory impairment in 5-HTdepleted rodents (du Jardin et al., 2014; Jensen et al., 2014), and this effect was recapitulated by ondansetron (Pehrson et al., 2018).”
Background
Vortioxetine Reverses Impairment of Visuospatial Memory and Cognitive Flexibility Induced by Degarelix as a Model of Androgen Deprivation Therapy in Rats
Vaiana, A. M., Asher, A. M., Tapia, K., & Morilak, D. A. (2023) · Neuroendocrinology · doi:10.1159/000535365 · Cited by 4 · see citing works
“Acute administration of lower doses of 3 – 10 mg/kg vortioxetine was also effective behaviorally in rats, and produced fractional occupancy at high af ﬁ nity targets, similar to chronic dietary treatment at 24 mg/kg/day [30, 33].”
Background
A Randomized Controlled Study of Efficacy and Cognitive Function Improvement of Vortioxetine and Escitalopram in Patients with Depression in Chinese Han Nationality
Ye, X., Xu, P., Jiao, J., Zhao, H., Jin, K., Zhang, S., Pan, F., Chen, J., Jiang, H., Hu, J., et al. (2024) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s491768 · Cited by 3 · see citing works
Experimental Medicine in Psychiatry New Approaches in Schizophrenia, Depression and Cognition
Dawson, G. R. (2015) · Current topics in behavioral neurosciences · doi:10.1007/7854_2015_5016 · Cited by 3 · see citing works
Recovery of visual scotomas by vortioxetine in a patient with symptomatic occipital lobe epilepsy
Önder, H., Coşkun, A., & Goksungur, M. (2018) · Annals of Indian Academy of Neurology · doi:10.4103/aian.aian_291_17 · Cited by 3 · see citing works
The Discovery of the Antidepressant Vortioxetine and the Research that Uncovered Its Potential to Treat the Cognitive Dysfunction Associated with Depression
Bang‐Andersen, B., Olsen, C. K., & Sánchez, C. (2016) · doi:10.1002/9783527800315.ch9 · Cited by 3 · see citing works
Donepezil and α‐synuclein Constipation: A 60 Month Follow-Up
Lepkowsky, C. M. (2022) · POJ Clinical Case Reports · doi:10.32648/2639-3298/4/1/1 · Cited by 2 · see citing works
Comparing the Efficacy of Escitalopram with and without Crocin in Restoring I/O Functions and LTP within the Hippocampal CA1 Region of Stressed Rats
Joodaki, M., Radahmadi, M., & Alaei, H. (2024) · Advanced Biomedical Research · doi:10.4103/abr.abr_18_24 · Cited by 2 · see citing works
Treatment of Depression with Vortioxetine and Second Generation Antipsychotics During the Period of Remission Formation in Schizophrenia (Interim Data Analysis)
Reznik, A. M., Syunyakov, T., Mudrak, A. V., Zakharov, N. B., Popova, Z. B., Khoroshilova, A. N., Ig, K., Sayfulina, A. M., Eliseenko, A. M., Matvievskaya, T. K., et al. (2023) · Consortium Psychiatricum · doi:10.17816/cp3728 · Cited by 2 · see citing works
“…to be due to both a vortioxetine-induced increase in serotonin (due to inhibition of the serotonin transporter) and direct modulation of serotonin receptors, especially the 5-HT 3 block, which causes an increase in the hippocampal transmitters: glutamate, acetylcholine, and norepinephrine [32, 41].”
Background
Mental health update – update on depression with a focus on escitalopram
Skosana, P., Shirindza, N., & Abraham, V. (2024) · SA pharmaceutical journal. · doi:10.36303/sapj.0811 · Cited by 2 · see citing works
Donepezil and α-synuclein Constipation: A 36 Month Follow-Up
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“Vortioxetine was administered because it has demonstrated efficacy for reducing the symptoms of depression [42-55], anxiety [42, 56-57], and cognitive impairment [58-63].”
Method
Case Study 2
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Self-citation
Naringin ameliorates depressive-like behaviors in offspring rats induced by prenatal stress identified with metabolomic and network pharmacology analysis
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“Vortioxetine exerts 5-HT1D, 5-HT3, and 5-HT7 antagonism, 5-HT1B receptor partial agonism, 5-HT1A agonism, and SERT inhibition [4,16-17].”
Background
Donepezil and α-synuclein Constipation: A 48 Month Follow-Up
Lepkowsky, C. M. (2021) · POJ Clinical Case Reports · doi:10.32648/2639-3298/3/1/001 · Cited by 1 · see citing works
Multi-modality as a new pharmacological approach for treatment of depression: the role of vortioxetine La multimodalità come nuovo approccio nel trattamento della depressione: il ruolo di vortioxetina
Caraci, F., & Sciascio, G. D. (2015)
Serotonergic modulation of cognition
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The Potential Anti Stress-like Properties of Escitalopram on Improvement of Spatial Memory in Rats Subjected to Predictable and Unpredictable Chronic Mild Stress
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“[59] Therefore, it can depend on the reaction of the type of stress against escitalopram treatment with the same dose of medication.”
Changes in functional connectivity of the default mode network and thalamus may be a therapeutic mechanism for the treatment of major depressive disorder with vortioxetine
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P.2.d.003 The novel multimodal antidepressant Lu AA21004 improves memory performance in 5-HT depleted rats via 5-HT3 and 5-HT1A receptor mechanisms
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Self-citation
Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism
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Self-citation
P.2.g.004 Vortioxetine promotes maturation of dendritic spines – an in vitro study in hippocampal cultures
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Relative short-term efficacy and acceptability of agomelatine versus vortioxetine in adult patients suffering from major depressive disorder
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Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats
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Authors: Jensen, J. B., du Jardin, K. G., Song, D., Budac, D., Smagin, G., Sanchez, C., & Pehrson, A. L.
Affiliations: Lundbeck (United States) (US)
Corresponding author: Pehrson, Alan Lars
ORCID: Smagin, Gennady
Pehrson, Alan Lars
Venue: European Neuropsychopharmacology
Publisher: Elsevier BV
Published: 2014-01
Volume: 24
Issue: 1
Pages: 148-159
ISSN: 0924-977X (ISSN-L)
DOI: 10.1016/j.euroneuro.2013.10.011
OpenAlex: W2072080423
Cited by: 96
References: 51
Citations by year: 2026: 3 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 8 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 10 · 2017: 11 · 2016: 7 · 2015: 18 · 2014: 9
FWCI: 5.54
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Neuropsychopharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: H. Lundbeck A/S
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: vortioxetine, serotonin depletion, memory impairment, serotonin receptors, 5-HT transporter, selective serotonin reuptake inhibitors, escitalopram, duloxetine, fenfluramine, L-5-hydroxytryptophan, novel object recognition, spontaneous alternation, hippocampus, tryptophan hydroxylase inhibition
MeSH terms: Duloxetine Hydrochloride, Vortioxetine, Animals, Carbidopa, Disease Models, Animal, Dose-Response Relationship, Drug, Exploratory Behavior, Female, Hippocampus, 5-Hydroxytryptophan, Memory Disorders, Phenylalanine, Piperazines, Protein Binding, Serotonin, Sulfides, Thiophenes, Citalopram, Selective Serotonin Reuptake Inhibitors, Maze Learning, Rats, Long-Evans, Recognition, Psychology, Rats

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Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: Evidence for direct 5-HT receptor modulation

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