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Introduction and objectiveSeveral studies revealed the therapeutic potential of vortioxetine (Vo) for pain. In this context, we aimed to evaluate the efficacy of Vo as a safe and tolerable novel pharmacologic agent in treating neuropathic pain (NP) in patients with major depressive disorder (MDD).Materials and methodsThe population of this cross-sectional prospective study consisted of all consecutive patients who were newly diagnosed with MDD by a neurology doctor at a psychiatric clinic and had NP for at least 6 months. All patients included in the sample were started on Vo treatment at 10 mg/day. They were assessed with Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), Douleur Neuropathique 4 Questions (DN4), Montreal Cognitive Assessment (MoCA), and Neuropathic Pain Impact on Quality of Life (NePIQoL) at the beginning of treatment and during the follow visits conducted at the end of the first, second and third months of the treatment. During these follow-up visits, patients were also queried about any side effects of Vo.ResultsThe mean age of 50 patients included in the sample, 76% of whom were female, was 45.8 ± 11.2 years. There was a significant reduction in patients’ NP complaints based on DN4 and S-LANNS, the subscales of NePIQoL, and significant improvement in MoCA. There was a significant reduction in patients’ NP complaints based on DN4 and S-LANNS scores and a significant improvement in scores of the subscales of NePIQoL and MoCA.ConclusionThe study’s findings indicate that Vo, with its multiple mechanisms of action, can effectively treat NP independently of its mood-stabilizing effect. Future indication studies for Vo are needed to establish Vo’s efficacy in treating NP.

Abstract Cenesthopathy is a rare syndrome characterized by strange bodily and oral sensations and is classified as a delusional disorder, somatic type, according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Cenesthopathy has been considered difficult to treat. However, to improve cenesthopathy, many pharmacotherapeutic options are reported, including antidepressants and antipsychotics. In this case report, vortioxetine significantly alleviated the distress of oral cenesthopathy in a patient with cerebral ischemia and depression without any adverse effects. To the best of our knowledge, this is the first report on the efficacy of vortioxetine in treating cenesthopathy. Though it is unclear why vortioxetine was effective for cenesthopathy in our case, we stated two possibilities for improving his oral cenesthopathy. When treating oral cenesthopathy in elderly patients, clinicians consider to be one of the options to prescribe vortioxetine.

Abstract Background Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. Methods This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. Results Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). Conclusion Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. Trial Registration NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Masaki Kato,1 Toshiaki Kikuchi,2 Koichiro Watanabe,3 Tomiki Sumiyoshi,4 Yoshiya Moriguchi,5 Daniel Oudin Åström,6 Michael Cronquist Christensen6 1Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan; 2Department of Neuropsychiatry, Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan; 3Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 4Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; 5Lundbeck Japan K.K, Tokyo, Japan; 6H. Lundbeck A/S, Valby, DenmarkCorrespondence: Yoshiya Moriguchi, Medical Affairs, Lundbeck Japan, K.K, Kamiyacho Prime Place 8F, 4-1-17 Toranomon, Minato-ku, Tokyo, 105-0001, Japan, Email yomo@lundbeck.comPurpose: Goal attainment scaling (GAS) has been proposed as a person-centric, semi-quantitative measure that assimilates achievement of individually set goals into a single standardized “goal attainment score” that can be compared at the population level. We aimed to examine the reliability and validity of the Japanese version of the GAS for depression (GAS-D) tool in assessing goal attainment in people living with major depressive disorder (MDD).Patients and Methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the GAS-D and other clinical rating scales at baseline and Weeks 8, 12 and 24.Results: Goal attainment was significantly associated with symptom severity as assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS) scale, confirming convergent validity. In particular, GAS-D scores were significantly related to MADRS total score at Weeks 12 and 24, indicating that improvements in overall symptom severity with vortioxetine treatment were likely to be reflected in the achievement of individualized treatment goals. With an intraclass correlation coefficient of 0.67 (95% CI 0.45– 0.82), the GAS-D also showed moderate test–retest reliability between Weeks 8 and 12 while proving independent of demographic characteristics.Conclusion: The results of this open-label study support the use of the GAS-D as a valid and sensitive outcome measure in the assessment of treatment response in MDD.Keywords: major depressive disorder, goal attainment scaling, goal setting, validation, vortioxetine

Background: Vortioxetine, known for its efficacy in treating depression through its effects on various neurotransmitters, has not been previously reported to induce syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Case Presentation: This case report describes a 74‐year‐old man with major depressive disorder who developed SIADH 1 week after starting treatment with vortioxetine. SIADH is characterized by symptoms such as headache, nausea, disorientation, and seizures, stemming from hyponatremia (123 mEq/L), without dehydration or edema. Vortioxetine was discontinued, and an alternative drug, mianserin, was initiated. The patient was restricted from drinking water due to hyponatremia. The serum Na concentration improved over time to within the normal range by the second week after admission. Conclusion: This is the first case report of vortioxetine‐induced SIADH. This report documents the first known case where vortioxetine, a medication for depression, caused a rare side effect: Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) in a 74‐year‐old male patient. Within a week of starting vortioxetine, the patient experienced symptoms like headache, nausea, confusion, and seizures, attributable to low blood sodium levels. Upon discontinuing vortioxetine and switching to another antidepressant, the patient's condition normalized within two weeks. This case highlights a significant association between vortioxetine and SIADH. [ABSTRACT FROM AUTHOR]

Abstract Background This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures (PROMs) in a real-world setting. Methods This retrospective chart review analyzed the care experiences of adult patients with a diagnosis of MDD from Parkview Physicians Group – Mind-Body Medicine, Midwestern United States. Patients with a prescription for vortioxetine, an initial baseline visit, and ≥ 2 follow-up visits within 16 weeks from September 2014 to December 2018 were included. The primary outcome measure was effectiveness of vortioxetine on depression severity as assessed by change in Patient Health Questionnaire-9 (PHQ-9) scores ~ 12 weeks after initiation of vortioxetine. Secondary outcomes included changes in depression-related symptoms (i.e., sexual dysfunction, sleep disturbance, cognitive function, work/social function), clinical characteristics, response, remission, and medication persistence. Clinical narrative notes were also analyzed to examine sleep disturbance, sexual dysfunction, appetite, absenteeism, and presenteeism. All outcomes were examined at index (start of vortioxetine) and at ~ 12 weeks, and mean differences were analyzed using pairwise t tests. Results A total of 1242 patients with MDD met inclusion criteria, and 63.9% of these patients had ≥ 3 psychiatric diagnoses and 65.9% were taking ≥ 3 medications. PHQ-9 mean scores decreased significantly from baseline to week 12 (14.15 ± 5.8 to 9.62 ± 6.03, respectively; p

Background: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. Methods: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. Results: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). Conclusion: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. Trial Registration: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021). [ABSTRACT FROM AUTHOR]

Background: Vortioxetine is efficacious and well tolerated in patients with major depressive disorder (MDD) and is available as an immediate-release tablet and oral drop solution. The oral drop solution may offer clinical benefits versus a tablet, such as the reduced risk of nausea, personalised dosing and ease of administration. Aims: To investigate the bioequivalence of vortioxetine 20 mg/mL oral drop solution versus a 20 mg immediate-release tablet. Methods: Healthy adults were randomised 1:1 to receive vortioxetine 20 mg oral drop solution or immediate-release 20 mg tablet after fasting on days 1 and 29 in an open-label, single-centre, single-dose crossover study. The area under the plasma concentration–time curve from 0 to 72 h (AUC0–72h) and maximum plasma concentration (C max) were analysed. Bioequivalence was concluded if the 90% CI for the oral drop solution-to-immediate-release tablet ratio for AUC0–72h and C max were contained within a range of 0.80−1.25. Results: Vortioxetine oral drop solution was bioequivalent to the tablet (n = 26; estimated AUC0–72h ratio 1.06 (90% CI: 1.03–1.10); C max ratio 1.01 (90% CI: 0.97–1.05)). A similar proportion of participants reported adverse events in each study arm but more headache events (7 vs 1) were reported with the oral drop solution versus tablet. The most common adverse event was nausea (16–23% of participants; all mild intensity). Conclusions: Vortioxetine oral drop solution is bioequivalent to immediate-release tablets. Oral drop solution provides an alternative to tablets and facilitates clinical benefit through individualised treatment, including gradual dose up-titration, for patients with MDD. [ABSTRACT FROM AUTHOR]

Treatment-emergent sexual dysfunction (TESD) is one of the most frequent and persistent adverse effects of antidepressant medication. Sexual dysfunction (SD) secondary to SSRIs occurs in >60% of sexually active patients and >80% of healthy volunteers, with this causing treatment discontinuation in >35% of patients. However, this factor is rarely addressed in routine examinations, and only 15–30% of these events are spontaneously reported. A strategy of switching to a different non-serotonergic antidepressant could involve a risk of relapse or clinical worsening due to a lack of serotonergic activity. Vortioxetine appears to have less impact on sexual function due to its multimodal mechanism of action. No studies have been published on the effectiveness of switching to vortioxetine in patients with poorly tolerated long-term antidepressant-related SD in naturalistic settings. Study objectives: To determine the effectiveness of switching to vortioxetine due to SD in a routine clinical practice setting. Methodology: observational pragmatic and naturalistic study to determine the effectiveness of the switch to vortioxetine (mean dosage 13.11 ± 4.03) in 74 patients aged 43.1 ± 12.65 (54% males) at risk of discontinuing treatment due to sexual dysfunction. The PRSexDQ*- SALSEX scale (* Psychotropic-Related Sexual Dysfunction Questionnaire) was applied at two moments: baseline visit and after 3 months of follow-up. Results: global Sexual Dysfunction (SD) measured with the SALSEX scale decreased significantly between the baseline visit (10.32; SD 2.73) and the follow-up visit (3.78; SD 3.68), p < 0.001. There was a significant improvement (p < 0.001) at the endpoint including decreased libido, delay of orgasm, anorgasmia and arousal difficulties in both sexes. After switching to vortioxetine, 83.81% of patients experienced an improvement in sexual function (43.2% felt greatly improved). Most patients (83.3%) who switched to vortioxetine continued treatment after the follow-up visit. A total of 58.1% of patients showed an improvement in depressive symptoms from the baseline visit. Conclusion: switching to vortioxetine is an effective and reliable strategy to treat patients with poorly tolerated previous antidepressant-related sexual dysfunction in real-life clinical settings. [ABSTRACT FROM AUTHOR]

Depressive symptoms are a customary finding in hospitalized patients, particularly those who are undergoing long hospitalizations, underwent major surgical procedures or suffer from high levels of multimorbidity and frailty. The patients included in this case series shared high degrees of frailty-complexity and were evaluated within the ordinary consultation and liaison psychiatry service of the University Hospital in Pisa, Italy, from September 2021 to June 2023. Patients were administered at least one follow-up evaluation after a week and before discharge. To relate this case series to the extant literature, a comprehensive systematic review of vortioxetine safety and efficacy was performed. None of the six patients included developed serious safety issues, but one patient complained of mild-to-moderate nausea for some days after the vortioxetine introduction. Five out of six patients exhibited at least a slight clinical benefit as measured by the clinical global impression scale. Of the 858 entries screened via Scopus and Medline/PubMed, a total of 134 papers were included in our review. The present case series provides preliminary evidence for vortioxetine's safety in this healthcare domain. The literature reviewed in this paper seems to endorse a promising safety profile and a very peculiar efficacy niche for vortioxetine in consultation and liaison psychiatry. [ABSTRACT FROM AUTHOR]

Background: This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures (PROMs) in a real-world setting. Methods: This retrospective chart review analyzed the care experiences of adult patients with a diagnosis of MDD from Parkview Physicians Group – Mind-Body Medicine, Midwestern United States. Patients with a prescription for vortioxetine, an initial baseline visit, and ≥ 2 follow-up visits within 16 weeks from September 2014 to December 2018 were included. The primary outcome measure was effectiveness of vortioxetine on depression severity as assessed by change in Patient Health Questionnaire-9 (PHQ-9) scores ~ 12 weeks after initiation of vortioxetine. Secondary outcomes included changes in depression-related symptoms (i.e., sexual dysfunction, sleep disturbance, cognitive function, work/social function), clinical characteristics, response, remission, and medication persistence. Clinical narrative notes were also analyzed to examine sleep disturbance, sexual dysfunction, appetite, absenteeism, and presenteeism. All outcomes were examined at index (start of vortioxetine) and at ~ 12 weeks, and mean differences were analyzed using pairwise t tests. Results: A total of 1242 patients with MDD met inclusion criteria, and 63.9% of these patients had ≥ 3 psychiatric diagnoses and 65.9% were taking ≥ 3 medications. PHQ-9 mean scores decreased significantly from baseline to week 12 (14.15 ± 5.8 to 9.62 ± 6.03, respectively; p < 0.001). At week 12, the response and remission rates in all patients were 31.0% and 23.1%, respectively, and 67% continued vortioxetine treatment. Overall, results also showed significant improvements by week 12 in anxiety (p < 0.001), sexual dysfunction (p < 0.01), sleep disturbance (p < 0.01), cognitive function (p < 0.001), work/social functioning (p = 0.021), and appetite (p < 0.001). A significant decrease in presenteeism was observed at week 12 (p < 0.001); however, no significant change was observed in absenteeism (p = 0.466). Conclusions: Using PROMs, our study results suggest that adults with MDD prescribed vortioxetine showed improvement in depressive symptoms in the context of a real-world clinical practice setting. These patients had multiple comorbid psychiatric and physical diagnoses and multiple previous antidepressant treatments had failed. [ABSTRACT FROM AUTHOR]

The relationship between depression and insomnia is bidirectional and both conditions need to be treated adequately, especially in a vulnerable neurodevelopmental stage of adolescence. This study aimed to evaluate the effects of antidepressant treatment using vortioxetine (VOR) on the sleep architecture of depressed adolescents by using video-polysomnography (v-PSG), which has not been researched before. The v-PSG was performed on 30 adolescent in-patients (mean age of 15.0 years ± 1.5 SD, 21 girls) treated with VOR (dosage of 10/15/20 mg/day) administered orally once a day, before and after VOR treatment. The evaluated parameters were conventional sleep parameters, sleep fragmentation parameters, and selected spectral power indices. Symptoms of depression and insomnia before and after the treatment period were evaluated using valid and reliable questionnaires (the Children´s Depression Inventory and the Athens Insomnia Scale). Depressed adolescents showed higher REM latency and decreased REM sleep percentage after treatment than before the treatment period (p = 0.005, p = 0.009, respectively). Our study revealed REM suppression (increased REM latency and reduced REM sleep percentage), indicating altered sleep architecture as a potential result of VOR treatment, which seems to be dose-dependent. [ABSTRACT FROM AUTHOR]

Background: Depression, one of the most significant mental disorders, is still poorly understood in terms of its pathogenetic mechanisms despite its well-recognized association with stress. Objectives: The current study's goal was to ascertain how the novel antidepressant drug vortioxetine (VOR) affected the BDNF (brain-derived neurotrophic factor), S100, amyloid β (Aβ), CREB (cAMP response element-binding protein), and NR2B, as well as its impact on depression-like behaviors, and tissue damage in an experimental rodent model of depression caused by chronic unpredictable stress. Methods: We employed twenty-eight Wistar albino male rats, and we randomly divided them into four groups, each consisting of 7 rats: control, CUMS (chronic unpredictable mild stress), CUMS+vortioxetine (CUMS+VOR), and CUMS+fluoxetine (CUMS+FLU). Sucrose preference and forced swimming tests (SPT and FST, respectively), PCR, ELISA, and histopathological and immunohistochemical evaluation were made on brains. Results: The behaviors of reduced immobility in the FST and increased sucrose preference were observed in the CUMS group and they improved in the groups treated with VOR and FLU. Compared with the control group, the group exposed to CUMS showed increased Aβ and decreased BDNF, CREB, and S-100 expressions, as well as neuronal degeneration (p<0.001). VOR and FLU treatment ameliorate the findings. Conclusions: This study demonstrated significant ameliorative effects of VOR in an experimental model of chronic unpredictable depression to reduce brain tissue damage and depression-like behaviors in rats. [ABSTRACT FROM AUTHOR]

Background: Identifying neurological biomarkers to aid with diagnoses and treatment effect evaluation of mood and cognitive symptoms in major depressive disorder (MDD) is an unmet need. This study explores the Brain Network Analytics (BNA) tool, which provides information on cortical patterns compared to a healthy normative group, for improving MDD management. Methods: BNA was used to extract event-related potentials (ERPs) from high-density EEG, and its clinical utility to assess the effects of vortioxetine on depression and cognition was evaluated. Twenty-five MDD subjects (20–65 years old) with cognitive dysfunction underwent an 8-week open-label treatment using vortioxetine. ERP data, generated during cognitive tasks, were collected at pre-treatment, two weeks and eight weeks into treatment. Correlations with MDD symptoms and cognitive functioning were investigated. Exploratory analyses assessed the differences in baseline and endpoint ERP characteristics between MDD subjects and matched controls (N = 41). Results: Compared to controls, MDD subjects exhibited increased baseline latencies of P200 and P3b ERP components, which normalized at treatment endpoint. P200 and P300 in the MDD group were correlated with clinical assessments, and indicated a pro-cognitive effect of vortioxetine independent of its antidepressant effect. Limitations: This study was limited by a small sample size and lack of a placebo condition. Conclusions: Our results suggest that the application of BNA can potentially support MDD diagnosis and monitor treatment efficacy across various symptom and functional domains. Further studies are warranted to explore the role of BNA in clinical research and practice.

Abstract Background We present a case report on the efficacy of the short‐term application of vortioxetine in managing winter depression in patients with seasonal bipolar disorder (BP). Standard treatment strategies for BP may not adequately address seasonal depressive symptoms during winter in patients with seasonal BP patterns. Depressive symptoms during winter may be linked to seasonal changes in serotonin transporter binding, such as a decrease in synaptic serotonin levels, necessitating alternative approaches. Although antidepressants, including vortioxetine, are effective in treating seasonal monopolar depression, their efficacy and safety in treating depression in patients with seasonal BP patterns remain unclear. Case Presentation This case report focuses on a 44‐year‐old male patient diagnosed with seasonal BP who had recurrent depressive episodes, specifically during winter. Notably, the patient had a significant decrease in recurrent episodes after short‐term seasonal vortioxetine use without inducing mania or rapid cycling. Conclusion Our study highlights the potential effectiveness of a seasonal, short‐term treatment strategy with antidepressants, including vortioxetine, for winter depression in individuals with BP.

Summary: Background: Major depressive disorder (MDD) is prevalent and disabling among older adults. Standing on its tolerability profile, vortioxetine might be a promising alternative to selective serotonin reuptake inhibitors (SSRIs) in such a vulnerable population. Methods: We conducted a randomised, assessor- and statistician-blinded, superiority trial including older adults with MDD. The study was conducted between 02/02/2019 and 02/22/2023 in 11 Italian Psychiatric Services. Participants were randomised to vortioxetine or one of the SSRIs, selected according to common practice. Treatment discontinuation due to adverse events after six months was the primary outcome, for which we aimed to detect a 12% difference in favour of vortioxetine. The study was registered in the online repository clinicaltrials.gov (NCT03779789). Findings: The intention-to-treat population included 179 individuals randomised to vortioxetine and 178 to SSRIs. Mean age was 73.7 years (standard deviation 6.1), and 264 participants (69%) were female. Of those on vortioxetine, 78 (44%) discontinued the treatment due to adverse events at six months, compared to 59 (33%) of those on SSRIs (odds ratio 1.56; 95% confidence interval 1.01–2.39). Adjusted and per-protocol analyses confirmed point estimates in favour of SSRIs, but without a significant difference. With the exception of the unadjusted survival analysis showing SSRIs to outperform vortioxetine, secondary outcomes provided results consistent with a lack of substantial safety and tolerability differences between the two arms. Overall, no significant differences emerged in terms of response rates, depressive symptoms and quality of life, while SSRIs outperformed vortioxetine in terms of cognitive performance. Interpretation: As opposed to what was previously hypothesised, vortioxetine did not show a better tolerability profile compared to SSRIs in older adults with MDD in this study. Additionally, hypothetical advantages of vortioxetine on depression-related cognitive symptoms might be questioned. The study's statistical power and highly pragmatic design allow for generalisability to real-world practice. Funding: The study was funded by the Italian Medicines Agency within the “2016 Call for Independent Drug Research”.

Masaki Kato,1 Toshiaki Kikuchi,2 Koichiro Watanabe,3 Tomiki Sumiyoshi,4 Yoshiya Moriguchi,5 Daniel Oudin Åström,6 Michael Cronquist Christensen6 1Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan; 2Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; 3Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 4Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; 5Lundbeck Japan K.K, Tokyo, Japan; 6H. Lundbeck A/S, Valby, DenmarkCorrespondence: Yoshiya Moriguchi, Medical Affairs, Lundbeck Japan, K.K, Kamiyacho Prime Place 8F, 4-1-17 Toranomon, Minato-ku, Tokyo, 105-0001, Japan, Email yomo@lundbeck.comPurpose: Originally developed in English, the Oxford Depression Questionnaire (ODQ) is a patient-reported scale specifically developed for assessing emotional blunting in people with major depressive disorder (MDD). We aimed to examine the reliability and validity of the Japanese version of the ODQ.Patients and methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the ODQ and other clinical rating scales at baseline and Weeks 8, 12 and 24.Results: One hundred and sixteen patients initiated vortioxetine and had ≥ 1 post-baseline visit. Directionally, the associations between ODQ scores and other clinical measures were as expected and demonstrated good concurrent validity. Factor analysis shows that the scale has a good fit for three factors. The Cronbach’s α coefficient was 0.912, and the scale also showed good test–retest reliability with intraclass correlation coefficients for the ODQ total score and domains ranging between 0.69 and 0.82. ODQ scores had strong positive correlations with symptom severity assessed using the Montgomery and Åsberg Depression Rating Scale and were moderately correlated with work productivity, overall functioning, and quality of life scales.Conclusion: Data from this prospective analysis confirm that the Japanese version of the ODQ retains the good validity and reliability of the original English scale and is suitable for use in prospective studies wanting to capture treatment effects on emotional blunting in MDD.Keywords: emotional blunting, major depressive disorder, Oxford depression questionnaire, MADRS-emotional blunting, validation, vortioxetine

The relationship between depression and insomnia is bidirectional and both conditions need to be treated adequately, especially in a vulnerable neurodevelopmental stage of adolescence. This study aimed to evaluate the effects of antidepressant treatment using vortioxetine (VOR) on the sleep architecture of depressed adolescents by using video-polysomnography (v-PSG), which has not been researched before. The v-PSG was performed on 30 adolescent in-patients (mean age of 15.0 years ± 1.5 SD, 21 girls) treated with VOR (dosage of 10/15/20 mg/day) administered orally once a day, before and after VOR treatment. The evaluated parameters were conventional sleep parameters, sleep fragmentation parameters, and selected spectral power indices. Symptoms of depression and insomnia before and after the treatment period were evaluated using valid and reliable questionnaires (the Children´s Depression Inventory and the Athens Insomnia Scale). Depressed adolescents showed higher REM latency and decreased REM sleep percentage after treatment than before the treatment period (p = 0.005, p = 0.009, respectively). Our study revealed REM suppression (increased REM latency and reduced REM sleep percentage), indicating altered sleep architecture as a potential result of VOR treatment, which seems to be dose-dependent.

Wanjun Bai,1 Haojing Song,1 Yiting Hu,1 Xueyuan Zhang,2 Xiaoru Wang,3 Caihui Guo,1 Bo Qiu,1 Zhanjun Dong1 1Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China; 2Shanghai Innovstone Therapeutics Limited, Shanghai, People’s Republic of China; 3CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang, People’s Republic of ChinaCorrespondence: Zhanjun Dong, Department of Pharmacy, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang City, Hebei Province, 050051, People’s Republic of China, Tel +86 311 85988604, Email 13313213656@126.comObjective: This study compared the pharmacokinetic and safety profiles of generic and original vortioxetine hydrobromide tablets under fasting and fed conditions, and evaluated the bioequivalence of two vortioxetine formulations to obtain sufficient evidence for abbreviated new drug application.Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions (n = 32 per study). Eligible healthy Chinese subjects received a single 10-mg dose of the test or reference vortioxetine hydrobromide tablet, followed by a 28-day washout interval between periods. Serial blood samples were collected up to 72 h after administration in each period, and the plasma concentrations of vortioxetine were detected using a validated method. The primary pharmacokinetic (PK) parameters were calculated using the non-compartmental method. The geometric mean ratios for the PK parameters of the test drug to the reference drug and the corresponding 90% confidence intervals were acquired for bioequivalence analysis. A safety evaluation was performed throughout the study.Results: Under fasting and fed conditions, the PK parameters of the test drug were similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 96.44– 105.81% for peak concentration (Cmax), 97.94– 105.05% for the area under the curve truncated at 72 hours (AUC0-72 h) under fasting conditions, 93.92– 104.15% for Cmax, and 96.67– 102.55% for AUC0-72 h under fed conditions, all of which were within the accepted bioequivalence range of 80.00– 125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study.Conclusion: The PK bioequivalence of the test and reference vortioxetine hydrobromide tablets in healthy Chinese subjects was established under fasting and fed conditions, which met the predetermined regulatory criteria. Both formulations were safe and well tolerated.Keywords: vortioxetine, bioequivalence, pharmacokinetics, safety

Cenesthopathy is a rare syndrome characterized by strange bodily and oral sensations and is classified as a delusional disorder, somatic type, according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Cenesthopathy has been considered difficult to treat. However, to improve cenesthopathy, many pharmacotherapeutic options are reported, including antidepressants and antipsychotics. In this case report, vortioxetine significantly alleviated the distress of oral cenesthopathy in a patient with cerebral ischemia and depression without any adverse effects. To the best of our knowledge, this is the first report on the efficacy of vortioxetine in treating cenesthopathy. Though it is unclear why vortioxetine was effective for cenesthopathy in our case, we stated two possibilities for improving his oral cenesthopathy. When treating oral cenesthopathy in elderly patients, clinicians consider to be one of the options to prescribe vortioxetine. In this case report, vortioxetine significantly alleviated the distress of oral cenesthopathy in a patient with cerebral ischemia and depression without any adverse effects. [ABSTRACT FROM AUTHOR]

Importance of the problem. Diseases of the cardiovascular system are in the first place among the causes of death and disability in most industrialized countries, which is undoubtedly an urgent medical and social problem and causes significant economic damage. The prevalence of depressive disorders in modern society, according to WHO estimates, is quite high, and the causes of depressive disorders and methods for their correction in patients with various somatic diseases have been the subject of study by specialists around the world for many decades. The comorbidity of depressive disorders with cardiac pathology is beyond doubt, and the bidirectional relationship of these disorders significantly aggravates the condition of patients, worsens their quality of life and reduces adherence to treatment. The most important conditions for the use of antidepressants in cardiology practice are good tolerability, absence of toxic effect, minimal interaction with other drugs, and relative safety in case of overdose. Vortioxetine, being a modern multimodal antidepressant, demonstrates not only a sufficiently high antidepressant and anti-anxiety activity, but also has a procognitive effect, as well as minimal side effects and undesirable cross-interactions with other drugs, which is confirmed by international randomized placebo-controlled trials. The aim of this work was to evaluate the efficacy and safety of Vortioxetine in the treatment of concomitant depressive disorders in patients with coronary heart disease (CHD), angina pectoris 2-3 functional class (FC) (I 20.8 according to ICD-10), receiving complex therapy for the main (cardiological) diseases at the inpatient and outpatient stages of therapy. Materials and methods. The study included patients with a diagnosis of coronary artery disease, angina pectoris FC 2-3, hypertension 2-3, aged 45 to 66 years (mean age 57.1±1.1 years), receiving complex therapy for the underlying cardiac disease and Vortioxetine at a dose of 10-15 mg/day. within 8 weeks. Anxiety and depressive manifestations were assessed on the HADS scale, the level of cognitive impairment on the PDQ questionnaire, social functioning on the SF-36 questionnaire, the general clinical impression on the CGI-C scale, and the main indicators of the functioning of the cardiovascular system upon admission to the hospital, after 4 weeks of hospitalization. treatment and another 4 weeks after discharge during the period of outpatient observation.The result of the combined therapy of patients with cardiac pathology and concomitant depressive disorder (basic therapy for CVD and Vortioxetine) was not only an improvement in the cardiovascular system (decrease in heart rate, blood pressure, the frequency of anginal pain, an increase in exercise tolerance), but also the relief of depressive manifestations, which contributed to an increase in the adherence of cardiological patients to the implementation of medical recommendations, and, in turn, led to a decrease in the level of end points—mortality, hospitalization rates, progression of chronic heart failure and disability. Conclusions. Appointment of Vortioxetine to cardiac patients with concomitant depressive disorder of moderate severity is quite effective not only in terms of relief of painful manifestations of the CVS, but also leads to a reduction in anxiety-depressive disorders and an improvement in cognitive and social functioning. The good tolerability of the drug makes it possible to recommend it for the treatment of depressive disorders in cardiological patients in a hospital setting and in outpatient practice.

Abstract Background Major depressive disorder (MDD) is a recurrent psychiatric condition that presents challenges in responding to treatment and achieving long-term remission. To improve outcomes, a shared decision-making treatment approach with patient and healthcare practitioner (HCP) engagement is vital. PatientsLikeMe (PLM), a peer community of patients, provides information on MDD, symptoms, and treatment through forums and resources, helping patients stay engaged in their treatment journey. Data on PLM can be harnessed to gain insights into patient perspectives on MDD symptom management, medication switches, and treatment goals and measures. Methods This ongoing, decentralized, longitudinal, observational, prospective study is being conducted using the PLM platform in two parts, enrolling up to 500 patients with MDD in the United States aged ≥ 18 years to compare vortioxetine with other monotherapy antidepressants. The first qualitative component consists of a webinar and discussion forum with PLM community members with MDD, followed by a pilot for functionality testing to improve the study flow and questions in the quantitative survey. The quantitative component follows on the PLM platform, utilizing patient-reported assessments, over a 24-week period. Three surveys will be conducted at baseline and weeks 12 and 24 to collect data on patient global impression of improvement, depression severity, cognitive function, quality of life (QoL) and well-being, medication satisfaction, emotional blunting, symptoms of anhedonia and resilience, as well as goal attainment. Quantitative results will be compared between groups. The qualitative component is complete; patient recruitment is underway for the quantitative component, with results expected in late 2023. Discussion These results will help HCPs understand patient perspectives on the effectiveness of vortioxetine versus other monotherapy antidepressants in alleviating symptoms of MDD and improvements in QoL. Data from the PLM platform will support a patient goal-based treatment approach, as results can be shared by patients with their HCPs, providing them with insights on patient-centric goals, treatment management and adherence, as well as allowing them to observe changes in patient-related outcomes scores. Findings from the study will also help to optimize the PLM platform to build scalable solutions and connectivity within the community to better serve patients with MDD.

Abstract Background Jitteriness/anxiety syndrome is a recognized adverse effect observed during the initiation or change of dose in antidepressant treatment. Managing patients who develop this syndrome remains a challenge. While escitalopram is a widely used antidepressant known to cause these symptoms, this report explores vortioxetine as a therapeutic alternative. Case Presentation Three distinct clinical scenarios were observed in patients who manifested jitteriness/anxiety syndrome while on escitalopram treatment for depression. Patient A was initiated on escitalopram and experienced an initial alleviation in depressive symptoms, but 3 months later displayed mood elevation, talkativeness, and increased activity, which disturbed his daily life. A transition to vortioxetine subsequently resolved the mood elevation. Patient B exhibited elevated mood, hyperactivity, irritability, and talkativeness just 6 days post‐initiation of treatment with escitalopram. After the discontinuation of escitalopram and unsuccessful trials with aripiprazole, lurasidone, and lamotrigine, her depressive mood intensified, culminating in suicidal ideation. Starting vortioxetine led to a consistent improvement of her symptoms, and she resumed work and was emotionally stable. Patient C was initially diagnosed with bipolar disorder and faced a relapse into depression despite undergoing various treatments. After 2 weeks on escitalopram, she exhibited irritability and self‐harm urges. Three months later, after being re‐diagnosed with depressive disorders with anxious distress, vortioxetine was administered, which significantly reduced her depressive symptoms and allowed her to continue her education. Conclusion Vortioxetine presents as a promising therapeutic alternative that is worth considering for patients with escitalopram‐induced jitteriness/anxiety syndrome.

Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations. These instructions are variable and rarely based on dedicated studies in people with obesity. This review briefly discusses the current clinical use of body measurements to guide chronic dosing instructions and highlights the need for obesity‐specific dosing instructions when the half‐life of a drug is prolonged (typically through increased volume of distribution) in people with obesity. Examples of drugs with apparent opportunities for either ramp‐up, loading, or washout instructions for patients based on body mass index are identified, specifically for vortioxetine, posaconazole, and brexpiprazole. We call for inclusion of people with obesity in clinical studies as a special subpopulation during drug development and propose the use of body mass index to guide dosing decisions among these patients. [ABSTRACT FROM AUTHOR]

Vortioxetine is a novel drug for the treatment of major depressive disorder (MDD). It has been reported that vortioxetine exhibits positive effect on the acute stage of MDD, while it can effectively prevent the recurrence of MDD during the maintenance period. Currently, the results of systematic reviews on vortioxetine are insufficient since several efficacy measures, such as the 24-Items Hamilton Rating Scale for Depression (HADRS-24) total score and other safety factors have not been evaluated. Therefore, the present study aimed to evaluate the efficacy and safety of different doses of vortioxetine on the treatment of adult patients with MDD via assessing more efficacy and safety indicators. The clinical, double-blind, parallel and randomized controlled trials (RCTs) on the effect of vortioxetine on MDD were retrieved from PubMed\Medline, EBSCO, Embase, Cochrane Library, OVID, Web of Science and clinical trial registration websites from database inception to November 2022. A total of two investigators independently screened the included references and independently evaluated their quality. The meta-analysis was performed using Revman 5.0 software. The present systematic review was registered in PROSPERO (registration no. CRD42018106343). In the present study 11 RCTs were included, with a total of 4,908 adult patients with MDD. More specifically, 1,158 patients were included in the 5-mg vortioxetine group, 736 in the 10-mg group, 298 in the 15-mg group, 864 in the 20-mg group and 1,852 in the placebo group. All 11 studies were randomized, double-blinded and parallel control trials, and all publications were evaluated as high quality. The meta-analysis results showed that patients in the 5-, 10- and 20-mg vortioxetine groups exhibited significantly higher Montgomery-Asberg Depression Rating Scale (MADRS) response (≥50%) and remission (≤10%) rates compared with the placebo group (P<0.05). The pooled analysis also revealed a statistically significant change in the total score of HADRS-24, MADRS, Sheehan Disability Scale (SDS), Clinical Global Impression Scale-Improvement (CGI-I) and HADRS-24 response rate in the 10- and 20-mg vortioxetine groups compared with the placebo group (P<0.05). However, no statistically significant changes in the total score of HADRS-24, MADRS, SDS, CGI-I and HADRS-24 response rate were obtained in the 5-mg group compared with the placebo group (P>0.05). Furthermore, the most common adverse events were nausea, hyperhidrosis, insomnia and vomiting, the incidence of which was increased with higher doses of vortioxetine. Overall, the results suggested that vortioxetine administration at doses of 5-20 mg was significantly effective and safe compared with placebo in the treatment of MDD. However, 5 mg vortioxetine displayed no difference in the HADRS-24, MADRS, SDS and CGI-I total scores, and HADRS-24 response rate. Furthermore, patient treatment with increasing vortioxetine doses was associated with good tolerance and high safety. Nevertheless, more multi-center, high-quality and long-term RCTs are still needed to support the aforementioned findings. [ABSTRACT FROM AUTHOR]

Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not only serotoninergic but also noradrenergic and dopaminergic transmission. At the same time, its pharmacokinetic properties determine good tolerance and safety, which are also observed in elderly patients and those burdened with somatic comorbidity. This work aims to sum up the knowledge coming from the most recent studies assessing the efficacy of vortioxetine. The efficacy of vortioxetine in the treatment of depression was confirmed in a large number of open studies, randomized controlled studies with placebo control, and meta-analyses thereof. What is more, the latest research shows that this drug allows depressed patients to achieve not only symptomatic remission but also an improvement of anhedonia and recovery in cognitive and occupational function. Furthermore, there are studies showing that vortioxetine is efficacious in the treatment of elderly patients, as well as subjects who have experienced trauma or suffer from bipolar depression. Vortioxetine is characterized by a good tolerance profile and safety; rarely does it cause severe adverse effects. [ABSTRACT FROM AUTHOR]

Depression and dementia are highly prevalent in older adults and often co-occur. This Phase IV study investigated the effectiveness and tolerability of vortioxetine in improving depressive symptoms, cognitive performance, daily and global functioning and health-related quality of life (HRQoL) in patients with major depressive disorder (MDD) and comorbid early-stage dementia. Patients (n = 82) aged 55–85 years with a primary diagnosis of MDD (onset before age 55 years) and comorbid early-stage dementia (diagnosed ≥6 months before screening and after onset of MDD; Mini-Mental State Examination-2 total score, 20–24) received vortioxetine for 12 weeks (initiated at 5 mg/day and up-titrated to 10 mg/day at day 8, with flexible dosing thereafter [5–20 mg/day]). The primary endpoint was change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 12. Significant improvement in depressive symptom severity was seen from week 1 onwards (P < 0.0001). At week 12, the least-square mean (standard error) change in MADRS total score from baseline was −12.4 (0.78). Significant improvements in cognitive performance were observed (from week 1 for the Digit Symbol Substitution Test and week 4 for the Rey Auditory Verbal Learning Test). Patients also experienced significant improvements in daily and global functioning, and HRQoL. Vortioxetine was well tolerated. From week 4 onwards, more than 50 % of patients were receiving 20 mg/day. Open-label study. Vortioxetine demonstrated effectiveness in clinically significantly improving depressive symptoms, cognitive performance, daily and global functioning, and HRQoL in patients with MDD and comorbid early-stage dementia treated for 12 weeks. ClinicalTrials.gov/ct2/show/NCT04294654. • Depression and dementia are highly prevalent in older adults and often co-occur. • Effectiveness of vortioxetine was assessed in patients with MDD and early-stage dementia. • Significant improvement in depressive symptom severity after vortioxetine initiation. • Cognitive performance significantly improved as assessed by the DSST and RAVLT. • Daily and global functioning and quality of life also improved with vortioxetine. [ABSTRACT FROM AUTHOR]

The placental barrier regulates the passage of nutrients, waste, drugs, and chemicals between maternal and fetal tissues. Mono and co-culture systems were constituted with human placental choriocarcinoma cells (BeWo) and human umbilical cord vein cells (HUVEC) on biocompatible poly (2-hydroxyethyl methacrylate) (PHEMA)-based cryogels. PHEMA cryogels were supported with extracellular matrix (ECM) elements. According to the Fourier transform infrared spectrometry-Attenuated Total Reflectance (FTIR-ATR) results, it was confirmed that gelatin, folic acid (FA), fibronectin (FN), and collagen type IV (COL Type IV) were successfully incorporated into the structure of cryogels. The mean pore size of the cryogels confirmed by micro-computed tomography analysis was in the range of 15–195 µm. The antidepressant active ingredient Vortioxetine was investigated by 3-(4,5-dimethylthiazol2-yl)− 2,5-diphenyltetrazolium-bromide (MTT) viability analysis in the constituted cryogel co-culture system. The cryogels did not cause any toxic effect on the cells. High doses of Vortioxetine showed reduced cell viability in monocultures, but not the expected reduction in cell viability at the same doses of co-culture. The highest amount of human chorionic gonadotropin hormone was in the PHEMA+COL Type IV+FA group. There were no significant changes in matrix metalloproteinase (MMP) 2 and 9 protein levels due to Vortioxetine dose administration. [Display omitted] • A cryogel system was established by co-culture of placental and endothelial cells. • Gelatin, fibronectin and collagen type IV were used in cryogels. • In 3D cryogel systems, the cells were observed to be more resistant to toxicity. • Collagen type IV and Folic acid cryogel has the highest cell viability. • Chorionic gonadotropin hormone level was highest in Collagen type IV and Folic acid cryogel. [ABSTRACT FROM AUTHOR]

To find out how common cognitive impairment is in people with major depressive disorder (MDD) and assess how well vortioxetine works for treating both cognitive dysfunction and depressive symptoms. Study Design Multicenter, cross-sectional, prospective follow up design Place & Duration of Study The research took place over the course of 12 weeks at 16 different psychiatric outpatient clinics throughout Pakistan. Method The study included 498 individuals with serious depressive disorder diagnoses. The degree of depression symptoms and cognitive impairment was assessed. Psychiatrists gave trial participants vortioxetine after completing the Clinical Global Impression-Severity scale (CGI-S), the Patient Health Questionnaire-9 (PHQ-9), and the Perceived Deficits Questionnaire (PDQ). The variables were reassessed one week (+/- 3 days), one month (+/- 7 days), and three months (+/- 14 days) after the treatment began. Results After completing a 12-week course of therapy with vortioxetine, mean PHQ 9 and PDQ scores of MDD individuals showed significant improvements. This indicates that vortioxetine is effective in reducing depression symptoms as well as cognitive impairments in MDD patients. A strong connection was seen between PHQ 9 and PDQ scores, indicating a direct relationship between cognitive impairment and depressed symptoms. Conclusions The results of the research demonstrate how well vortioxetine works to treat cognitive impairments in MDD patients while also reducing depressed symptoms. These findings demonstrate the possibility of vortioxetine as a beneficial therapeutic option for those with MDD diagnoses who also have cognitive impairment. Additional investigation is required to validate these findings and assess their suitability for other demographics. [ABSTRACT FROM AUTHOR]

Background Although thought of as a multimodal-acting antidepressant targeting the serotonin system, more molecules are being shown to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1. Methods Two mouse models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress–induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mouse models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, lentiviral-mTORC1-short hairpin RNA-enhanced green fluorescence protein (LV-mTORC1-shRNA-EGFP) was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice. Results Vortioxetine administration produced significant reversal effects against the chronic stress–induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and mPFC. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice. Conclusions Activation of the mTORC1 system in the hippocampus and mPFC is required for the antidepressant actions of vortioxetine in mice. [ABSTRACT FROM AUTHOR]

Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an in vitro incubation system of 200 µL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC50) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (Ki) values of 2.17 µM and 9.37 µM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its Ki values were 7.26 µM and 6.96 µM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with Ki values were 8.55 µM and 4.17 µM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (Ki = 4.41 and 100.9 µM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (Ki = 2.87 and 0.12 µM). The inhibition types of CYP2C-1 and CYP2C-3 (Ki = 39.91 and 4.23 µM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided. [ABSTRACT FROM AUTHOR]