Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling.

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT1A) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

The ameliorating effect of Rutin on hepatotoxicity and inflammation induced by the daily administration of vortioxetine in rats.

BACKGROUND: Vortioxetine (VORTX) is a potent and selective type of selective serotonin reuptake inhibitor (SSRI) that is mainly prescribed for treating major depression along with mood disorders as the first drug of choice. Limited previous findings have indicated evidence of liver injury and hepatotoxicity associated with daily VORTX treatment. Rutin (RUT), which is known for its antioxidant properties, has demonstrated several beneficial health actions, including hepatoprotection. Therefore the current study aimed to evaluate and assess the ameliorative effect of RUT against the hepatotoxic actions of daily low and high-dose VORTX administration. METHODS: The experimental design included six groups of rats, each divided equally. Control, rats exposed to RUT (25 mg/kg), rats exposed to VORTX (28 mg/kg), rats exposed to VORTX (28 mg/kg) + RUT (25 mg/kg), rats exposed to VORTX (80 mg/kg), and rats exposed to VORTX (80 mg/kg) + RUT (25 mg/kg). After 30 days from the daily exposure period, assessments were conducted for serum liver enzyme activities, hepatotoxicity biomarkers, liver antioxidant endogenous enzymes, DNA fragmentation, and histopathological studies of liver tissue. RESULTS: Interestingly, the risk of liver damage and hepatotoxicity related to VORTX was attenuated by the daily co-administration of RUT. Significant improvements were observed among all detected liver functions, oxidative stress, and inflammatory biomarkers including aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), albumin, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), glutathione S-transferase (GST), total protein, acid phosphatase, N-Acetyl-/ß-glucosaminidase (ß-NAG), ß-Galactosidase (ß-Gal), alpha-fetoprotein (AFP), caspase 3, and cytochrom-C along with histopathological studies, compared to the control and sole RUT group. CONCLUSION: Thus, RUT can be considered a potential and effective complementary therapy in preventing hepatotoxicity and liver injury induced by the daily or prolonged administration of VORTX.

Establishment of a 3D multicellular placental microtissues for investigating the effect of antidepressant vortioxetine.

The placenta is a unique organ with an active metabolism and dynamically changing physiology throughout pregnancy. It is difficult to elucidate the structure of cell-cell and cell-extracellular matrix interactions of the placenta in in vivo studies due to interspecies differences and ethical constraints. In this study, human umbilical cord vein cells (HUVEC) and human placental choriocarcinoma cells (BeWo) were co-cultured for the first time to form spheroids (microtissues) on a three-dimensional (3D) Petri Dish® mold and compared with a traditional two-dimensional (2D) system. Vortioxetine is an antidepressant with a lack of literature on its use in pregnancy in established cultures, the toxicity of vortioxetine was studied to investigate the response of spheroids representing placental tissue. Spheroids were characterised by morphology and exposed to vortioxetine. Cell viability and barrier integrity were then measured. Intercellular junctions and the localisation of serotonin transporter (SERT) proteins were demonstrated by immunofluorescence (IF) staining in BeWo cells. Human chorionic gonadotropin (beta-hCG) hormone levels were also measured. In the 3D system, cell viability and hormone production were higher than in the 2D system. It was observed that the barrier structure was impaired, the structure of intracellular skeletal elements was altered and SERT expression decreased depending on vortioxetine exposure. These results demonstrate that the multicellular microtissue placenta model can be used to obtain results that more closely resemble in vivo toxicity studies of various xenobiotics than other 2D and mono-culture spheroid models in the literature. It also describes the use of 3D models for soft tissues other than the placenta.

Vortioxetine Reverses Impairment of Visuospatial Memory and Cognitive Flexibility Induced by Degarelix as a Model of Androgen Deprivation Therapy in Rats.

INTRODUCTION: Androgen deprivation therapy (ADT) is a mainstay treatment for prostate cancer, but many patients experience cognitive impairment in domains mediated by the medial prefrontal cortex (mPFC) and hippocampus. Prostate cancer typically occurs in older patients (>65 years). As age is often accompanied by cognitive decline, it may impact the efficacy of any treatment aimed at restoring cognitive impairment induced by ADT. Vortioxetine, a multimodal antidepressant that improves cognition in depression, has been shown to be efficacious in elderly patients. Therefore, vortioxetine may improve cognition in older patients who experience cognitive decline after ADT. METHODS: Young (3 months) and middle-aged (13 months) rats were used to investigate the influence of age on treating ADT-induced cognitive decline. As our previous studies used surgical castration, we tested if vortioxetine would reverse cognitive deficits associated with more translationally relevant chemical castration using degarelix. Vortioxetine was given in the diet for 21 days. Animals underwent behavioral testing to assess visuospatial memory mediated by the hippocampus and cognitive flexibility mediated by the mPFC. We also investigated changes in afferent-evoked responses in these regions in middle-aged rats. RESULTS: Degarelix induced impairments in both visuospatial memory and cognitive flexibility that were reversed by vortioxetine. Vortioxetine also rescued afferent-evoked responses in the mPFC and hippocampus. However, modest age-related reductions in baseline visuospatial memory limited our ability to detect further decreases induced by degarelix in middle-aged rats due to a floor effect. CONCLUSION: These results suggest that vortioxetine may be a treatment option for older prostate cancer patients who experience cognitive decline after ADT.

Effects of vortioxetine on hippocampal-related cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment.

Advances in prostate cancer treatment have significantly improved survival, but quality of life for survivors remains an under-studied area of research. Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer and is used as an adjuvant for prolonged periods in many high-risk, localized tumors. More than half of patients treated with ADT experience debilitating cognitive impairments in domains such as spatial learning and working memory. In this study, we investigated the effects of androgen deprivation on hippocampal-mediated cognition in rats. Vortioxetine, a multimodal antidepressant, has been shown to improve cognition in depressed patients. Thus, we also tested the potential efficacy of vortioxetine in restoring impaired cognition after ADT. We further investigated mechanisms that might contribute to these effects, measuring changes in the circuitry and gene expression within the dorsal hippocampus. ADT via surgical castration induced impairments in visuospatial cognition on the novel object location test and attenuated afferent-evoked local field potentials recorded in the CA1 region of the dorsal hippocampus. Chronic dietary administration of vortioxetine effectively reversed these deficits. Castration significantly altered gene expression in the hippocampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that the hippocampus may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients who experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit-level plasticity-related mechanisms compromised by ADT.

A 6-Month Open-Label Study of Vortioxetine among Cancer Patients with Major Depressive Disorder (MDD).

OBJECTIVE: Vortioxetine is a monoaminergic drug with a novel multimodal mechanism of action. We investigated its efficacy on depressive symptoms, cognitive function, and quality of life among cancer patients. METHODS: In this multicenter, open-label, single-arm, observational study, patients received flexible doses of Vortioxetine for a period of six months. All participants were assessed at baseline and scheduled for monitoring at weeks 2, 4, 8, 12, 16, 20, and 24. Depression severity was assessed using Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale. The Perceived Deficiency Questionnaire (PDQ-5) assessed the perceived cognitive difficulties in concentration, executive functioning, and memory. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) was used to assess the patients' quality of life. Side effects of vortioxetine were monitored using the Antidepressant Side-Effect Checklist (ASEC). RESULTS: Patients experienced a reduction in MADRS scores from 29.89 ± 5.997 at baseline to 11.59 ± 4.629 by Week 24. The PDQ-5 scores showed significant change from Week-4, whereas the EORTC role, emotional, and cognitive functioning scores showed a significant change from Week 2 onwards. CGI-Severity scores decreased from a baseline of 4.39 ± 0.746 to 2.41 ± 1.085 by Week 24. During the 24-Weeks of therapy, around three-quarters of the patients (73.3%) had one or more adverse events reported on the ASEC. The most frequently reported TEAEs were dry mouth, insomnia, somnolence, and headache, with more than a 30% incidence rate. CONCLUSION: Vortioxetine seems promising in the management of depression and enhancement of cognitive function and quality of life of cancer patients with Major Depressive Disorder.
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YY1 (Yin-Yang 1), a transcription factor regulating systemic inflammation, is involved in cognitive impairment of depression.

AIM: Clinical and preclinical studies suggest that alterations in the peripheral and brain immune system are associated with the pathophysiology of depression, also leading to changes in local glucose metabolism in the brain. Here, the authors identified Yin-Yang 1 (YY1), a transcription factor closely associated with central and peripheral inflammation. METHODS: Plasma levels of YY1, interleukin (IL) 6, and IL-1ß in major depressive disorder (MDD) were collected before and after treatment with vortioxetine, and correlation with clinical and cognitive scores was studied. Chronic unpredictable mild stress was treated with vortioxetine. Micropositron emission tomography (microPET) was used to analyze glucose metabolism and mRNA, and the protein level of the YY1-nuclear factor κB (NF-κB)-IL-1ß inflammatory pathway were measured in related brain regions. RESULTS: Plasma levels of YY1 and IL-1ß were significantly increased in MDD and decreased after treatment with vortioxetine. Meanwhile, the level of YY1 in plasma was negatively correlated with cognitive functions in patients with MDD and positively correlated with the level of IL-1ß in plasma. Compared with the control group, in chronic unpredictable mild stress rats, (microPET) analysis showed that the decrease of glucose metabolism in the hippocampus, entorhinal cortex, amygdala, striatum, and medial prefrontal cortex was reversed after treatment. mRNA and protein level of related molecular in YY1-NF-κB-IL-1ß inflammatory pathway decreased in the hippocampus and was reversed by vortioxetine. CONCLUSION: The current study suggests that the YY1-NF-κB-IL-1ß inflammatory pathway may play an essential role in both mood changes and cognitive impairment in depression, and may be associated with changes in glucose metabolism in emotion regulation and cognition. These findings provide new evidence for the inflammatory mechanisms of depression.

Magnesium Potentiates the Vortioxetine's Effects on Physical Performances and Biological Changes in Exercise-Induced Stress in Rats.

Background and objectives: Vortioxetine (VRT) is a relatively new selective serotonin reuptake inhibitor (SSRI) antidepressant and serotonin receptor modulator, approved for the treatment of major depression and generalized anxiety disorder. Depression has been linked with psychomotor disengagement, oxidative stress burden and decreased blood levels of brain-derived neurotrophic factor (BDNF). In our study we performed the experimental investigation of VRT, magnesium and of their association on the rats' endurance capacity, motor behavior and blood biological disturbances in rats subjected to forced exercise in treadmill test. Materials and Methods: The substances were administered orally for 14 consecutive days, as follows: group 1 (control): distilled water 0.3 mL/100 g body; group 2 (Mg): magnesium chloride 200 mg/kg body; group 3 (VRT): VRT 20 mg/kg body; group 4 (VRT+Mg): VRT 20 mg/kg body + magnesium chloride 200 mg/kg body. Magnesium was used as positive control substance with known effects in treadmill test. The consequences of VRT treatment on glucose, cortisol, BDNF and oxidative stress biomarkers (superoxide-dismutase, malondialdehyde, glutathione-peroxidase, lactate dehydrogenase) were also assessed. Results and conclusions: The use of VRT resulted in an improvement in motor capacity and an increase of the rats' endurance to physical effort. The administration of VRT increased the serum BDNF levels and reduced the oxidative stress in rats subjected to physical effort. The association of magnesium potentiated the effects of VRT on physical performances, the antioxidant activity and the decreasing in serum stress markers in treadmill test in rats.

Hippocampal F3/Contactin plays a role in chronic stress-induced depressive-like effects and the antidepressant actions of vortioxetine in mice.

Depression is a very prevalent psychiatric disorder which threats nearly one in six of the population in this world. To date, the pathogenesis of depression remains elusive and is thought to depend on multiple factors in which chronic stress is critical. Currently, it has been demonstrated that besides monoaminergic dysfunction, depression is accompanied by several other important pathological phenomena such as impaired neurogenesis and decreased brain-derived neurotrophic factor (BDNF)-cAMP response element binding protein (CREB) signaling cascade in the hippocampus. F3/Contactin is a cell-adhesion molecule which has been reported to correlate with hippocampal neurogenesis and BDNF-CREB signaling. Here we assumed that F3/Contactin may be implicated in depression, and various methods including western blotting, immunofluorescence, virus-mediated gene transfer and chronic stress models of depression were adopted together. It was found that both chronic restraint stress (CRS) and chronic social defeat stress (CSDS) significantly decreased the expression of F3/Contactin in the hippocampus. Adeno-associated virus (AAV)-mediated over-expression of hippocampal F3/Contactin notably prevented the CRS-induced and CSDS-induced depressive-like behaviors in mice. Moreover, hippocampal F3/Contactin over-expression also fully reversed the CRS-induced and CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis of mice. Furthermore, administration of vortioxetine, a multimodal-acting antidepressant, fully ameliorated the inhibitory actions of both CRS and CSDS on the hippocampal F3/Contactin expression. In contrast, AAV-mediated knockdown of hippocampal F3/Contactin significantly abolished the protecting effects of vortioxetine against CRS and CSDS. Collectively, hippocampal F3/Contactin is implicated in depression and could be a novel antidepressant target.

Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action.

Vortioxetine is a novel atypical antidepressant with multimodal activity that has recently demonstrated efficacy against neuropathic pain. There is no published data about its analgesic properties in models characterized by peripheral inflammation and consequent pain pathway sensitization, nor data on its mechanism of antinociceptive action. This study aimed to investigate vortioxetine's antinociceptive/antihyperalgesic effects in trigeminal, visceral, and somatic inflammatory pain models, and provide evidence on its mechanism of action in the modulation of trigeminal nociception. Vortioxetine's effects on the nociceptive behavior in orofacial formalin test (OFT) and acetic acid-writhing test in mice and on mechanical hyperalgesia in carrageenan-induced paw inflammation in rats were examined following peroral single administration. The involvement of serotonergic/adrenergic/cholinergic/cannabinoid/adenosine receptors was evaluated in OFT by intraperitoneally treating mice with an appropriate antagonist immediately after vortioxetine application. We used antagonists of 5-HT1B/1D serotonergic (GR 127935), α1 -adrenergic (prazosin), α2 -adrenergic (yohimbine), ß1 -adrenergic (metoprolol), muscarinic (atropine), α7 nicotinic (methyllycaconitine), CB1 /CB2 cannabinoid (AM251 and AM630), and adenosine A1 (DPCPX) receptors. Vortioxetine dose-dependently reduced pain behavior in OFT and acetic acid writhing test, as well as inflammatory hyperalgesia in paw pressure test. All examined antagonists except prazosin dose-dependently inhibited vortioxetine's antinociceptive effects. In conclusion, vortioxetine exerted analgesic efficacy in trigeminal, visceral, and somatic inflammatory pain. The effect is at least in part mediated by 5-HT1B/1D serotonergic, α2 /ß1 -adrenergic, muscarinic and nicotinic cholinergic, CB1 /CB2 cannabinoid, and adenosine A1 receptors. These findings contribute to better understanding of the analgesic effect of vortioxetine and suggest its potential usefulness for inflammatory pain treatment.

Serotonergic Neurotransmission System Modulator, Vortioxetine, and Dopaminergic D2/D3 Receptor Agonist, Ropinirole, Attenuate Fibromyalgia-Like Symptoms in Mice.

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.

Pregnancy outcome after first trimester exposure to vortioxetine: A case series.

BACKGROUND: The objective of this study was to collect outcome after vortioxetine exposure during the first trimester of pregnancy in a case series. METHODS: Callers who were counseled by the Israeli Teratology Information Service (TIS) regarding vortioxetine exposure during pregnancy were prospectively collected and followed-up by telephone using a structured questionnaire. Outcomes were confirmed by a pediatrician with medical records in the neonatal period. RESULTS: Between 2016 and 2019, a total of 19 women were included in the TIS database after first trimester exposure to vortioxetine. Seventeen pregnancy follow-ups were obtained, while two pregnancies were lost to follow-up. Eleven pregnancies resulted in 12 live births with no malformations including one set of twins; there were three miscarriages, two terminations, and one stillbirth in week 22. One termination was performed due to prenatal diagnosis of acrania (the woman also took carbamazepine, folic acid and dipyrone), and the second due to fear of abnormalities after cystic hygroma was suspected at week 12 with nuchal translucency of 8.1 mm and no further cytogenetic testing. The twins were born in week 35. Two women continued using the medication until delivery; one of these women reported nursing her baby from birth to up to 1 year, while she continued taking vortioxetine. DISCUSSION: This case series provides preliminary outcome data on vortioxetine exposure in pregnancy. However, the small sample size calls for caution in the interpretation of results. Denominator-based studies are needed before conclusions can be drawn.

The rat hippocampal gliovascular system following one week vortioxetine and fluoxetine.

We have previously reported that vortioxetine, unlike the selective serotonin reuptake inhibitor fluoxetine, produces a rapid increase of dendritic spine number and Brain Derived Neurotrophic Factor (BDNF)-associated formation of synapses with mitochondrial support in the rat hippocampal CA1 and dentate gyrus. As a continuation of this line of research, and given the putative role of brain glial cells in mediating antidepressant responses the present study investigated early effects of vortioxetine on hippocampal microvasculature and Vascular Endothelial Growth Factor (VEGF) and astrocytes and microglia cells. Rats were treated for 1 week with vortioxetine (1.6 g/kg food chow) or fluoxetine (160 mg/L drinking water) at pharmacologically relevant doses. Stereological principles were used to estimate the number of ALDH1L1 positive astrocytes and Iba1 positive microglia cells, and the length of microvessels in subregions of hippocampus. VEGF protein levels were visualized with immunohistochemistry. Our results showed that vortioxetine significantly increased the number of ramified (resting) microglia and astrocytes accompanied by VEGF level elevation, whereas fluoxetine had no effect after 7 days treatment on these measures. Our findings suggest that astrocytes and microglia may have a role in mediating the pharmacological effects of vortioxetine in rats and that these effects are mediated through mechanisms that go beyond inhibition of the serotonin transporter and may target specific 5-HT receptors. It remains to be investigated whether these findings are relevant for the therapeutic effects of vortioxetine.

Synthesis of three-dimensional nickel ferrite nanospheres decorated activated graphite nanoplatelets for electrochemical detection of vortioxetine with pharmacokinetic insights in human volunteers.

An innovative electrochemical nanoprobe was developed for determination of vortioxetine (VORT), a serotonergic antidepressant drug, for the first time. The fabrication of the nanoprobe is based on decoration of a glassy carbon electrode with three-dimensional nickel ferrite nanospheres modified activated graphite nanoplatelets (3D NiFe2O4 NS/AGNP/GCE). The morphological characterization of the nanoprobe was carried out via scanning electron microscope (SEM), transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, energy dispersive X-ray spectroscopy (EDS), N2-adsorption-desorption isotherm, and powder X-ray spectroscopy (PXRD). In addition, the electrochemical behavior of the nanoprobe was described using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). A well-defined and irreversible peak at 0.82 V was seen at the surface of 3D NiFe2O4 NS/AGNP/GCE. The proposed nanoprobe exhibited outstanding electro-catalytic activity towards VORT oxidation. Under the optimized conditions, the anodic oxidation currents were linearly proportional to VORT concentration at the working range 1.8-90 nM with a LOD of 0.55 nM. The nanoprobe was used to determine VORT in pharmaceutical tablets and human plasma samples. Satisfactory recoveries and RSD percentages were obtained in the range 103.8-107.7% (RSD% = 2.7-3.1%) and 101.4-105.3% (RSD % = 2.8-3.4%) for tablets and plasma samples, respectively. Moreover, the method was used to monitor VORT during a pharmacokinetic study in human volunteers with satisfactory results. The 3D NiFe2O4 NS/AGNP/GCE shows excellent sensitivity, reproducibility, and selectivity towards VORT detection. The proposed electrode could be utilized as simple, rapid, and inexpensive sensing tool for routine analysis and during pharmacokinetic/pharmacodynamic investigations. Graphical abstract.

Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway.

Vortioxetine is a potent antagonist of the 5-hydroxytryptamine receptor and serotonin transporter and has been reported to function as an antidepressant in the treatment of major depressive disorder. However, its antitumor effects remain unclear. Here, we examined whether vortioxetine affects the characteristics of GC cells. Cell viability was measured by a colony formation assay and, in addition, cell invasion, migration and apoptosis assays were performed with a transwell assay and a flow cytometry assay. Protein levels were measured by western blotting. We found that vortioxetine inhibited the proliferation, invasion and migration abilities of AGS cells. Additionally, vortioxetine could induce apoptosis and autophagy by increasing the levels of Bax, active caspase-3/-9, Beclin-1 and light chain 3, as well as by downregulating Bcl-2 and P62. Further investigations indicated that vortioxetine regulated apoptosis and autophagy via activation of the phosphoinositide 3-kinase/AKT pathway. Taken together, our data suggest that vortioxetine has cytotoxic effects against GC AGS cells as a result of inhibiting proliferation, invasion and migration, as well as by inducing apoptosis and autophagy through the phosphoinositide 3-kinase/AKT pathway.

Adjunctive vortioxetine for SSRI-resistant major depressive disorder: a real-world chart review study

Objective: Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of treatment of major depressive disorder (MDD). However, non-response is common, often necessitating combination strategies. The present study assessed the efficacy of vortioxetine as an add-on therapy in patients with SSRI-resistant MDD. Methods: The charts of 36 adult outpatients with DSM-IV-TR MDD who had not achieved a response after at least 8 weeks of treatment with an SSRI were reviewed retrospectively. Subjects were treated with vortioxetine (5-20 mg/day) for 8 weeks added to the current SSRI. The main outcome measures were change from baseline in total Hamilton Scale for Depression (HAM-D) score and the rate of response (a 50% or greater reduction in HAM-D score and a Clinical Global Impression ‐ Improvement module [CGI-I] score of 1 or 2 at endpoint). HAM-D scores ≤ 7 were considered as remission. Additional outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Scale for Suicide Ideation (SSI). Results: 32 patients completed the 8 weeks of treatment. At 8 weeks, a significant reduction in HAM-D score was observed (p ≤ 0.001), with response obtained by 41.7% and remission by 33.3% of patients. Significant reductions in SHAPS and SSI were also observed (p ≤ 0.001 for both scales). Conclusions: Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression. However, the limitations of this study (such as small sample size, absence of randomization and control group, retrospective design, etc.) must be considered.

Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy.

Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1-10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1-15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings.

Pharmacological and non-pharmacological treatments for major depressive disorder in adults: A systematic review and network meta-analysis.

Depression has brought huge disease burden to the world. This systematic review aimed to compare the efficacy and safety of pharmacological and non-pharmacological treatments for major depressive disorder (MDD). We searched electronic databases with time range from 1990.1.1 to 2018.9.5. Randomized controlled trials (RCTs) including adult patients with MDD were eligible for inclusion. We conducted network meta-analyses using multivariate meta-analyses models under the frequency framework. Primary outcomes were efficacy (response rate) and safety (overall risk of adverse events). We estimated summary odds ratios (ORs) based on group-level data. 20,937 citations were identified, 91 trials comprising 10,991 participants were included in efficacy study, and 32 trials comprising 5245 participants were included in safety study. In terms of efficacy, all treatments studied (acupuncture, mirtazapine, herbal medicine, venlafaxine, physical exercise, cognitive-behavioral therapy (CBT), bupropion, fluoxetine, and vortioxetine) except for probiotics were significantly more effective than placebo. In terms of safety, bupropion, fluoxetine, venlafaxine, and vortioxetine were significantly less safe than placebo. Herbal medicine and mirtazapine had no significant difference in overall risk of adverse events compared with placebo. Acupuncture, CBT, physical exercise and probiotics were lack of eligible safety data.

Protective effects of vortioxetine in predator scent stress model of post-traumatic stress disorder in rats: role on neuroplasticity and apoptosis.

Post-traumatic stress disorder (PTSD) can be observed after a traumatic event. The effect of an antidepressant vortioxetine (Vrx) against PTSD is unknown. The aim of this study was to investigate the possible protective effect of Vrx in the predator scent-induced PTSD rat model. The rats were exposed to dirty cat litter for 10 min and the protocol was repeated 1 week later with clean cat litter as a trauma reminder. The rats received Vrx (10 mg/kg/p.o.) or saline (1 ml/kg/p.o.) during 7 days between two exposure sessions. Novel object recognition test, hole board test, and elevated plus maze were performed. The b-cell lymphoma (bcl-2)/bcl-2-associated X protein (bax) ratio, brain-derived neurotrophic factor (BDNF), caspase-3 and -9 expressions were detected using Western blotting in the amygdaloid complex, hippocampus, and frontal cortex. Our results indicate that increased freezing time and anxiety index in the stress-induced group is decreased with Vrx application. Vrx treatment improved deteriorated recognition memory in the stress-induced group. Decreased bcl-2/bax ratio and BDNF level and increased caspase-3 and -9 expressions in the stress group, improved with Vrx in the amygdala, and hippocampus. Decreased bcl-2/bax ratio and increased casp-3 and -9 expressions in the stress group are ameliorated with Vrx in frontal cortex. The level of BDNF was increased with Vrx in the frontal cortex. Increased damage scores in the amygdaloid complex, hippocampal CA3, and frontal cortex in the stress group ameliorated with Vrx treatment. Our results show that if vortioxetine is administered immediately after trauma, it reduces anxiety, cognitive and neuronal impairment and may be protective against the development of PTSD.