This narrative review used manufacturer-sponsored vortioxetine clinical trial database (doses of 5-20 mg) to evaluate the effect of vortioxetine treatment on short- and long- term functional outcomes in major depressive disorder (MDD), in both the clinical trial setting and in routine practice. The Sheehan Disability Scale (SDS) was the most used functional scale and, based on this measure, short-term, placebo-controlled studies demonstrated significant improvements with vortioxetine 10 mg (reductions ranged from -0.92 to -2.10 points vs placebo after 6-8 weeks treatment) and 20 mg (reductions ranged from -0.88 to -3.92 vs placebo). Of note, the acute beneficial effects of vortioxetine on functionality were seen in patients with severe baseline depressive symptoms as well as those with significant anxiety. Long-term open-label extension studies further showed that maintenance treatment was associated with continued functional improvements over one year (reaching an average reduction of -6.2 SDS points from baseline) that were correlated with continued improvements in residual symptoms. Evidence from real-world studies, using multiple functional outcomes, further demonstrated generalizability to routine practice where patients are living with multiple comorbidities previously excluded from the randomized controlled trials. Taken overall, the findings from several head-to-head studies indicated a functional advantage of vortioxetine compared with other classes of antidepressants and demonstrated the effectiveness of vortioxetine as first-line treatment while also confirming its effectiveness in improving functional outcomes when given later in the treatment journey. In summary, vortioxetine is an effective treatment option for improving functional outcomes in people living with MDD.

BackgroundDepressive symptoms are common in Alzheimer's disease (AD), leading to an increasing use of antidepressants.ObjectiveTo compare the effects of vortioxetine with other conventional antidepressants on cognition in AD patients with depressive symptoms.MethodsThis analysis is a subgroup of a 12-month, prospective, randomized, open-label, parallel-group study involving 108 outpatients receiving either vortioxetine or escitalopram, paroxetine, or bupropion as part of routine care. Data were collected at baseline, 6 and 12 months. Cognitive symptoms were assessed using the Mini-Mental State Examination (MMSE), Attentive Matrices (AM), Coloured Progressive Matrices (CPR), and Digit Span; depressive symptoms using the Hamilton Depression Scale (HAM-D) and the Cornell Scale for Depression in Dementia (CSDD). Results for patients on vortioxetine were compared to those on other antidepressants.ResultsTotal scores on cognitive measures improved in all groups. Improvements versus baseline in MMSE, AM, and CPM were statistically significant in the vortioxetine group (p < 0.001), but not in the other antidepressant groups. Digit Span scores did not differ significantly from baseline. The between-group differences in MMSE, AM, and CPM changes were statistically significant in favor of vortioxetine (p < 0.05), while the Digit Span change showed a trend towards superiority with vortioxetine, but did not reach statistical significance. The between-group differences in HAM-D and CSDD changes were also statistically significant for vortioxetine (p < 0.05).ConclusionsVortioxetine was superior in improving both cognitive and depressive symptoms compared to other antidepressants. Larger studies which may also help to understand whether the beneficial effect observed with vortioxetine was a direct effect or mediated by its specific antidepressant efficacy are required.

Vortioxetine is a multimodal antidepressant with a high tolerability profile. Recent evidence suggests a role for vortioxetine in improving cognitive function and reducing functional disability linked to depression. We conducted a systematic review on the use of vortioxetine in different neurological disorders.

PubMed was searched for articles published from inception until June 2024. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials focused on the use of vortioxetine in cerebrovascular diseases, movement disorders and cognitive impairments were included. The systematic review protocol was developed using guidance from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Our search identified 236 citations, 8 of which ultimately met the criteria for inclusion in the synthesis. The included studies consisted of 3 randomized controlled trials, 1 nonrandomized clinical trial and 4 single-arm observational studies. Subsequently, we grouped these articles into three sections of neurological interest (cerebrovascular diseases, movement disorders and cognitive dysfunction).

Through its multimodal mechanism of action, the antidepressant vortioxetine shows potential benefit in improving depressive symptoms in patients with depression and different, comorbid neurological condition. In addition, the pro-cognitive effect of this agent may represent a possible indication for its use in the treatment of adults with depression and/or neurological cognitive impairment. Future research is needed to explore and clarify other possible implications for a rational administration of this molecule in other neurological fields.

Elevated neutrophil-to-lymphocyte ratio, a marker of inflammation, has been reported in adult and late-life depression. Vortioxetine has shown efficacy in treatment of late-life depression, yet little is known regarding its immunomodulatory role in clinical trials.

This is a post-hoc analysis of an eight-week randomized controlled trial. Depressed patients aged 65 or above were treated by vortioxetine, duloxetine or placebo. 321 patients that have taken blood tests at baseline and endpoint were included in the analysis. Neutrophil-to-lymphocyte ratio (NLR) was calculated using the absolute counts of each cell type. Cognitive performance was assessed by composite score of Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT) tasks, while depressive symptoms were assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) and Geriatric Depression Scale (GDS).

NLR levels decreased significantly in the entire analysis set (t(320) = 2.64, p = 0.008) and in the vortioxetine group (M = -0.186, t(105) = 2.070, p = 0.041, Cohen's d = 0.20), but not in the two other groups. This decrease was not significantly different compared to placebo (F(1, 213) = 0.420, p = 0.517). Furthermore, larger NLR changes in vortioxetine arm predicted significant cognitive improvement (β = -4.03, p = 0.03), specifically regarding the DSST correct symbols (β = -1.97, p = 0.04) and RAVLT delayed recall (β = -1.87, p = 0.02) tasks. Additionally, decreased NLR significantly predicted reduced GDS score (β = 1.82, p = 0.02), yet not MADRS score.

Vortioxetine treatment was associated with decreased NLR levels in late-life depression, and reductions in NLR predicted improvements in cognitive function and depressive symptoms, suggesting a potential link between inflammation and clinical outcomes.

The activation and functionalization of C─F bonds, the strongest bonds between carbon and any other element, via C─N bond formation to generate complex molecules has remained a compelling challenge. Herein, we present a ligand-centered redox-controlled effective strategy employing a zinc amide catalyst (C) to achieve facile defluoroamination of fluoroarenes with several N-nucleophiles (>90 substrates) under mild conditions. Notably, this adaptable protocol works readily with most types of fluoroarenes and a diverse range of N─H moieties that include secondary and primary amines, indoles, azoles, and amides under the same reaction conditions and encouragingly offers excellent functional group compatibility. Intriguingly, we also demonstrated its application in one-pot synthesis of (un)symmetrical triaryl amines from primary amine itself and the selective activation of C─F bonds to access F-containing amines, relevant to drug synthesis. Finally, detailed mechanistic probes via active-intermediate-capture, EPR analysis, and various control experiments indicate that the reaction proceeds through a radical-mediated C─N coupling pathway. Importantly, use of Zn(II) center as a template to hold the two amide moieties together in C enables facile intramolecular electron transfer to generate the radical intermediates for the present protocol. Finally, the practical utility of this methodology was showcased by synthesizing various drug derivatives.

Given their great importance, as one of the most prescribed types of therapeutic drugs worldwide, we have analyzed the role of serendipity in the discovery of new antidepressants, ranging from selective serotonin reuptake inhibitors to more contemporary developments.

We carried out a historical analysis of the discovery of new antidepressants, resorting to the original articles published on their development (initial pharmacological and clinical information) and applied an operational criterion of serendipity developed by our group.

Selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine, citalopram, paroxetine, sertraline, and escitalopram), selective dopamine and noradrenaline reuptake inhibitors (bupropion), noradrenaline and serotonin reuptake inhibitors (venlafaxine, milnacipram, duloxetine, and desvenlafaxine), selective noradrenaline reuptake inhibitors (reboxetine), noradrenergic and specific serotonergic antidepressants (mirtazapine), melatonergic agonists (agomelatine), and serotonin modulators and stimulators (vortioxetine, vilazodone, tianeptine) correspond to the type IV pattern. Moclobemide, a reversible monoamine oxidase inhibitor, corresponds to the type II pattern, for which the initial serendipitous findings (i.e., the chance discovery of the inhibitory effects of monoamine oxidase (MAO) whilst being studied for their antihyperlipidemic properties) led to subsequent non-serendipitous discoveries (clinical antidepressant efficacy). Ketamine, a glutamatergic modulator, corresponds to the type III pattern, characterized by a non-serendipitous origin (initial development as an anesthetic agent) leading to a serendipitous observation (the discovery of antidepressant efficacy in individuals illicitly using).

The majority of new antidepressants adhere to a type IV pattern, characterized by a rational and targeted design process where serendipity played no part, except moclobemide (type II pattern) and ketamine (type III pattern).

Activity-regulated cytoskeleton-associated protein (aka activity-regulated gene Arg3.1) belongs to the effector gene family of the immediate early genes. This family encodes effector proteins, which act directly on cellular homeostasis and function. Arc/Arg3.1 is localized at dendritic processes, allowing the protein local synthesis on demand, and it is considered a reliable index of activity- dependent synaptic changes. Evidence also exists showing the critical role of Arc/Arg3.1 in memory processes. The high sensitivity to changes in neuronal activity, its specific localization as well as its involvement in long-term synaptic plasticity indeed make this effector gene a potential, critical target of the action of psychotropic drugs. In this review, we focus on antipsychotic and antidepressant drugs as well as on psychostimulants, which belong to the category of drugs of abuse but can also be used as drugs for specific disorders of the central nervous system (i.e., Attention Deficit Hyperactivity Disorder). It is demonstrated that psychotropic drugs with different mechanisms of action converge on Arc/Arg3.1, providing a means whereby Arc/Arg3.1 synaptic modulation may contribute to their therapeutic activity. The potential translational implications for different neuropsychiatric conditions are also discussed, recognizing that the treatment of these disorders is indeed complex and involves the simultaneous regulation of several dysfunctional mechanisms.

The frequent co-occurrence of major depressive disorder (MDD) and substance use disorders (SUDs) entails significant clinical challenges. Compared to patients with MDD alone, patients with MDD and SUD often show increased anhedonia, emotional blunting, and impaired cognitive function. These symptoms lead to an inability to control cravings, more substance use, increased relapse rates, and poor adherence to the treatment. This fosters a detrimental cycle leading to more severe depressive symptoms, functional impairment, and chronicity, culminating in heightened morbidity, mortality, and healthcare resource utilization. Data on antidepressant treatment of MDD-SUD patients are inconclusive and often conflicting because of a number of confounding factors in clinical trials or difficulty in dissecting the specific contributions of pharmacological versus psychological interventions in real-world studies. The patient's unique clinical features and specific SUD and MDD subtypes must be considered when choosing treatments. Ideally, drug treatment for MDD-SUD should act on both conditions and address core symptoms such as anhedonia, craving, and cognitive dysfunction while ensuring minimal emotional blunting, absence of drug interactions, and no addictive potential. This approach aims to address unmet needs and optimize the outcomes in a clinical population often underrepresented in treatment paradigms.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotoninnoradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants.

To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS.

We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2).

The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events.

The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings.

Pharmacotherapy for depression includes drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors (NaSSAs), and atypical antidepressants; these drugs exert differentially beneficial effects on symptoms of depression after acute and chronic treatment in animal models. Said effects are established through neuroplastic mechanisms involving changes in neurogenesis and synaptogenesis as result of the activation of intracellular signaling pathways associated with neurochemical and behavioral changes. Antidepressants increase the synaptic availability of monoamines (monoaminergic hypothesis) such as 5-HT, NA, and gamma-aminobutyric acid (GABA) by inhibiting their reuptake or degradation and activating intracellular signaling pathways such as the responsive element binding protein (cAMP-CREB) cascade, which regulates the expression of genes related to neuroplasticity and neurogenesis, such as brain-derived neurotrophic factor (BDNF), in various brain structures implicated in depression. The aim of this review is to analyze the mechanisms of action of different antidepressants and to compare the effects of acute and chronic treatment on neuroplasticity in animal models of depression. A thorough search was conducted in PubMed, Scopus, and Web of Science, focusing on studies since 1996 with keywords like antidepressants, acute and chronic treatment, neuroplasticity, and experimental depression. Studies included had to investigate antidepressant effects experimentally, with full-text access, while excluding those that did not. Data extraction focused on study design, findings, and relevance to understanding treatment differences. Only high-quality, peer-reviewed studies were considered to ensure a comprehensive synthesis of current knowledge.

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound 11b demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H3 receptor (H3R), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound 11b when it forms a complex with SERT, NET, and the histamine H3 receptor. In vivo behavioral studies, compound 11b dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound 11b had a favorable pharmacokinetic profile in rats. Thus, compound 11b has the potential to develop a novel class of drugs for the treatment of depression.

Age at first onset of depression as a clinical factor affecting cognitive improvement in late life depression was investigated.

This is a secondary analysis of an eight-week randomized controlled trial involving 452 elderly patients treated by vortioxetine, duloxetine or placebo (1:1:1). Patients were subcategorized into early-onset (LLD-EO) and late-onset (LLD-LO) groups divided by onset age of 50. Cognitive performance was assessed by composite score of Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT) tasks, while depressive symptoms were assessed by Montgomery-Åsberg Depression Rating Scale (MADRS).

Vortioxetine and duloxetine exhibited advantages versus placebo in improving cognitive performance in the LLD-LO group, yet not in the LLD-EO group after eight weeks. Patients in the LLD-EO group showed overall advantage to placebo in depressive symptoms before endpoint (week 8) of treatment, while patients in the LLO-LO group showed no advantage until endpoint. Path analysis suggested a direct effect of vortioxetine (B = 0.656, p = .036) and duloxetine (B = 0.726, p = .028) on improving cognition in the LLD-LO group, yet in all-patients treated set both medications improved cognition indirectly through changes of depressive symptoms.

Reliability of clinical history could raise caution as it was collected by subjective recall of patients.

Age at first onset might affect cognitive improvement as well as change in depressive symptoms and its mediation towards cognitive improvement in late life depression treated with vortioxetine and duloxetine.

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression. Molecular docking was employed to elucidate the differences in activity and selectivity of the corresponding compounds on SERT, NET, and DAT. In vitro experiments demonstrated that compound A3 has a relatively balanced multi-target activity profile with SERT reuptake inhibition (IC50 = 12 nM), NET reuptake inhibition (IC50 = 78 nM), DAT reuptake inhibition (IC50 = 135 nM), and 5-HT1AR agonism (EC50 = 34 nM). Pharmacokinetic experiments revealed that A3 exhibited excellent bioavailability and low clearance in mice. Subsequent behavioral experiments further confirmed its significant antidepressant effects. These results further highlight the rationality of our design strategy.

This study aimed to assess the effectiveness of vortioxetine for improving depressive symptoms, cognitive performance, daily and global functioning in patients with Alzheimer's disease (AD) and major depressive disorder (MDD) in real-world clinical practice. We retrospectively identified 46 AD patients who had received treatment for 12 months with vortioxetine. Drug effects were evaluated at baseline, 4, 8, and 12 months. The primary endpoint was change from baseline in the Hamilton Depression Rating Scale (HDRS) and in the Cornell Scale for Depression in Dementia (CSDD) to month 12. Cognitive and daily and global functioning changes were also evaluated. Significant baseline-to-endpoint improvement in depressive symptom severity was observed (p < 0.0001). At month 12, the least-square mean (standard error) change score from baseline was -10.48 (±0.42) on the HDRS and -9.04 (±0.62) on the CSDD. Significant improvements in cognitive performance were observed for the Rey Auditory Verbal Learning Test, the Symbol Digit Modalities Test, the Letter Fluency Test, the Category Fluency Test, and the Trail Making Test-A. Patients also experienced significant improvements in daily and global functioning. Vortioxetine was safe and well tolerated. Patients with AD and MDD receiving vortioxetine showed meaningful improvements in depressive symptoms, cognitive performance, and daily and global functioning over the 12-month treatment period.

Major depressive disorder (MDD) affects millions of people worldwide, with women at a higher risk during the childbearing age. Vortioxetine (VOX) and Vilazodone (VLZ) are newer antidepressants with improved therapeutic profile commonly used, but their safety during pregnancy and long-term effects on offspring are poorly understood due to paucity of literature in preclinical and clinical studies. This study aimed to investigate whether prenatal exposure to VOX and VLZ impacts depressive- and anxiety-like neurobehavioral alterations in offspring, focusing on neurotransmitter-mediated mechanisms. Pregnant Wistar dams received either VOX or VLZ, 1 mg/day and 2 mg/day of the drug orally from gestation day (GD) 6-21. The dams naturally delivered their offspring and reared until they reached postnatal day (PND) 21. Offspring of both sexes were tested for display of depressive-and anxiety-like behaviors from PND 56-70. After PND 70, offspring were sacrificed, and their brains were collected to estimate neurotransmitter levels. As per protocol, controls were maintained simultaneously for each experimental design. Prenatal exposure to VOX or VLZ induced an increased state of depressive- and anxiety-like behaviors in both male and female offspring. Additionally, neurotransmitter (serotonin, dopamine, and nor-epinephrine) levels in the prefrontal cortex region of the brain were substantially reduced in exposed offspring. No sex specific neurobehavioral and neurochemical implications were observed in the present study. Our findings suggest that prenatal exposure to VOX and VLZ disrupts neurochemical balance in the fetal brain, leading to long-lasting neurobehavioral impairments in offspring of both sexes.

Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

The multinational, open-label COMPLETE study (NCT03835715) investigated the effectiveness of vortioxetine in alleviating emotional blunting in patients with major depressive disorder (MDD) experiencing inadequate response and emotional blunting while being treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI). This paper presents results for the subgroup of patients enrolled in Spain.

Patients with MDD (n = 67) experiencing partial response and emotional blunting during monotherapy with an SSRI or SNRI were switched to vortioxetine (10-20 mg/day) for 8 weeks. The primary study outcome was emotional blunting, assessed by the Oxford Depression Questionnaire (ODQ).

After 8 weeks of vortioxetine, the mean (SE) change in ODQ total score from baseline was -26.0 (2.9) (P < 0.001). Respective changes in Montgomery-Åsberg Depression Rating Scale (MADRS), Motivation and Energy Inventory, Digit Symbol Substitution Test, and Sheehan Disability Scale (SDS) total scores were -14.9 (0.8), +34.2 (4.5), +6.3 (1.6), and ‒9.0 (1.3) (all P < 0.001 vs baseline). At week 8, 70.4% of patients no longer reported emotional blunting and 53.7% had achieved remission from their depressive symptoms (defined as a MADRS total score ≤10). Mediation analysis showed 77.1% of the change in SDS total score to be a direct effect of the improvement in ODQ total score after switching to vortioxetine. Adverse events were reported by 35 patients (52.2%), most commonly nausea (14 patients, 20.9%). At week 8, 33/54 patients (61.1%) were receiving vortioxetine 20 mg/day.

In this study investigating the effectiveness of vortioxetine in Spanish patients with MDD who experienced inadequate response and emotional blunting on SSRI/SNRI monotherapy, significant improvements in emotional blunting, core depressive symptoms (including anhedonia), sleep duration, motivation and energy, cognitive performance, and overall patient functioning were observed during the 8 weeks of treatment. Two-thirds of patients no longer reported emotional blunting and over half were in remission from their depressive symptoms at week 8.

Several 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).

The 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.

The 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.

The 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.

An air-stable, robust, and well-defined copper(II)-7-azaindole-N-oxide-based catalyst [Cu2II(7-AINO)4] (abbreviated as Cu(II)-7-AINO) has been demonstrated as an efficient catalyst for various Ullmann-type coupling reactions. This easily prepared and cost-effective catalyst facilitates the arylation and heteroarylation of diverse N-, S-, and O-nucleophiles, including azoles, aminoazoles, (hetero)arylthiols, and phenols. Notably, they also exhibit substantial compatibility with a wide range of functional groups. Furthermore, the catalyst demonstrates significant selectivity for -NH sites of aminoazoles and -SH sites of aminothiophenols over -NH2 sites in both cases, enhancing its versatility. Exploiting the catalyst's chemo- and regioselective properties, we have successfully demonstrated the applicability of our methodology in synthesizing various drug molecules. Specifically, Epirizole analogue, Nilotinib, and Vortioxetine were successfully synthesized using our protocol.

Hyperactivity of serotonin 3 receptors (5-HT3R) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity competitive antagonists, are used in the treatment of these conditions. Although generally effective for chemotherapy-induced nausea and vomiting, the use of setrons for treating irritable bowel syndrome has been impaired by adverse side effects. Partial agonists are now being considered as an alternative strategy, with potentially less severe side effects than full antagonists. However, a structural understanding of how these ligands work is lacking. Here, we present high-resolution cryogenic electron microscopy structures of the mouse 5-HT3AR in complex with partial agonists (SMP-100 and ALB-148471) captured in pre-activated and open-like conformational states. Molecular dynamics simulations were used to assess the stability of drug-binding poses and interactions with the receptor over time. Together, these studies reveal mechanisms for the functional differences between orthosteric partial agonists, full agonists and antagonists of the 5-HT3AR.

Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases. These disorders are characterized by lack of social interaction, by repetitive behavior, and often anxiety and learning disabilities. The brain serotonin (5-HT) system is known to be crucially implicated in a wide range of physiological functions and in the control of different kinds of normal and pathological behavior. A growing number of studies indicate the involvement of the brain 5-HT system in the mechanisms underlying both ASD development and ASD-related behavioral disorders. There are some review papers describing the role of separate key players of the 5-HT system in an ASD and/or autistic-like behavior. In this review, we summarize existing data on the participation of all members of the brain 5-HT system, namely, 5-HT transporter, tryptophan hydroxylase 2, MAOA, and 5-HT receptors, in autism in human and various animal models. Additionally, we describe the most recent studies involving modern techniques for in vivo regulation of gene expression that are aimed at identifying exact roles of 5-HT receptors, MAOA, and 5-HT transporter in the mechanisms underlying autistic-like behavior. Altogether, results of multiple research articles show that the brain 5-HT system intimately partakes in the control of some types of ASD-related behavior, and that specific changes in a function of a certain 5-HT receptor, transporter, and/or enzyme may normalize this aberrant behavior. These data give hope that some of clinically used 5-HT-related drugs have potential for ASD treatment.

We report a catalyst-free electrophilic amination, which enables the synthesis of aromatic and heterocyclic amines. By subjecting diarylzinc or diheteroarylzinc compounds to readily accessible O-2,6-dichlorobenzoyl hydroxylamines in the presence of MgCl2 in dioxane at a temperature of 60 °C (8-16 h). This new electrophilic amination allowed an expedited synthesis of two pharmaceutically significant compounds: vortioxetine is a key intermediate of delamanid. This approach offers opportunities for the streamlined synthesis of amine-based molecules in the pharmaceutical industry.

A large number of drugs are introduced each year to treat different diseases. Most of the time, patients suffer from more than one health problem which makes it necessary to take multiple drugs. When drugs are combined, the problem of drug-drug interaction becomes relevant. In this work, we studied the drug-drug interaction between escitalopram and ibuprofen or paracetamol using density functional theory and quantum theory of atoms in molecules. The results suggest that following the interactions, the activity of drugs changes according to site of interaction. Most reactive and most stable interactions would be preferable for the purpose of use. The in silico drug-likeness studies show that escitalopram and paracetamol couple is more bioavailable than escitalopram and ibuprofen couple. Moreover, in order to gain additional insights into the mentioned drugs' interactions, the drugs were docked separately and jointly against the potential targets for antidepressants and NSAIDs, namely 6HIS and 2PXX. The molecular docking results showed a potential improvement of the effectiveness of the drugs after combining by forming hydrogen bonds, hydrophobic contacts and π…π stacking.Communicated by Ramaswamy H. Sarma.

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.

Vortioxetine has demonstrated dose-dependent efficacy in patients with major depressive disorder (MDD), with the greatest effect observed with vortioxetine 20 mg/day. This analysis further explored the clinical relevance of the more rapid and greater improvement in depressive symptoms observed with vortioxetine 20 mg/day vs 10 mg/day.

Analysis of pooled data from six short-term (8-week), randomized, placebo-controlled, fixed-dose studies of vortioxetine 20 mg/day in patients with MDD (N = 2620). Symptomatic response (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] total score), sustained symptomatic response, and remission (MADRS total score ≤10) were assessed by vortioxetine dosage (20 or 10 mg/day).

After 8 weeks, 51.4% of patients receiving vortioxetine 20 mg/day had achieved symptomatic response vs 46.0% of those receiving vortioxetine 10 mg/day (P < .05). Significantly more patients achieved symptomatic response vs placebo from week 2 onwards for vortioxetine 20 mg/day and from week 6 onwards for vortioxetine 10 mg/day (both P ≤ .05). Sustained response was achieved from week 4 for 26.0% of patients receiving vortioxetine 20 mg/day vs 19.1% of those receiving vortioxetine 10 mg/day (P < .01), increasing to 36.0% and 29.8%, respectively, over the 8-week treatment period (P < .05). At week 8, 32.0% of patients receiving vortioxetine 20 mg/day were in remission vs 28.2% of those receiving vortioxetine 10 mg/day (P = .09). Rates of adverse events and treatment withdrawal were not increased during the week following vortioxetine dose up-titration to 20 mg/day.

Vortioxetine 20 mg/day provides more rapid and more sustained symptomatic response than vortioxetine 10 mg/day in patients with MDD, without compromising tolerability.

Pharmacological treatment of major depressive disorder (MDD) still relies on the use of serotonergic drugs, despite their limited efficacy. A few mechanistically new drugs have been developed in recent years, but many fail in clinical trials. Several hypotheses have been proposed to explain MDD pathophysiology, indicating that physiological processes such as neuroplasticity, circadian rhythms, and metabolism are potential targets. Here, we review the current state of pharmacological treatments for MDD, as well as the preclinical and clinical evidence for an antidepressant effect of molecules that target non-serotonergic systems. We offer some insights into the challenges facing the development of new antidepressant drugs, and the prospect of finding more effectiveness for each target discussed.

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.

Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost-effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling with metal-complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom- and step-economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook.

Adolescent major depressive disorder (MDD) is a prevalent mental health problem with low treatment success rates. Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is the more effective initial treatment for adolescent MDD remains controversial, and few studies have investigated whether treatment switching or augmentation is preferred when the initial treatment is not working well.

We developed a multicentre open-label Sequential Multiple Assignment Randomized Trial (SMART) design, consisting of two phases lasting 8 weeks each. In phase 1 (at baseline), patients will be recruited and grouped in fluoxetine group or fluoxetine combined with CBT group by patient self-selection. In phase 2 (after 8 weeks of treatment), the nonresponders will be randomly assigned to six groups, in which participants will switch to sertraline, vortioxetine, or duloxetine or added aripiprazole, olanzapine, or lithium carbonate to fluoxetine. After the full 16 weeks of treatment, we will assess the long-term sustainability of the treatment effects by evaluating participants during their subsequent naturalistic treatment. The primary outcome will be the response rate, determined by the Children's Depression Rating Scale-Revised (CDRS-R). Secondary outcomes include the change in scores on the Beck Depression Inventory (BDI), the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Safe Assessment.

The results from this study will aid clinicians in making informed treatment selection decisions for adolescents with MDD.

This protocol was registered at ClinicalTrials.gov with Identifier: NCT05814640.

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.

The present study examined the relations between clinical characteristics and cognitive deficits in adult patients with major depressive disorder (MDD) from a local outpatient psychiatric clinic in Malaysia.

The present sample included 110 participants aged 20-60 years old. Participants were invited to provide their information on sociodemographic variables (age, gender, and educational level) and clinical characteristics (age at onset of depression and duration of illness) and to complete a series of cognitive performance measures including the Trail Making Tests A (psychomotor speed) and B (executive function), the Digit Symbol Substitution Test (attention), and the Auditory Verbal Learning Test (immediate free recall, acquisition phase, and delayed recall). The Mini International Neuropsychiatric Interview Version 6.0 was used to confirm the diagnosis of MDD and the Montgomery-Åsberg Depression Rating Scale was used to assess illness severity.

At the bivariate level, relations of age and educational level to all cognitive deficit domains were significant. At the multivariate level, only educational level and illness severity consistently and significantly predicted all cognitive deficits domains.

Therapeutic modalities should be individualised whilst considering the impacts of cognitive deficits in an attempt to prevent further deterioration in psychosocial functioning of MDD patients.KEY POINTSCognitive deficits are an elemental component of Major Depressive Disorder (MDD) persisting during a current major depressive episode or during remission, altering individuals' ability to process information and changes the way they perceive and interact with the environment.Cognitive deficits in MDD are evident among the upper-middle income groups in South-Eastern Asian countries warranting more local research as such deficits could lead to functional decline and work performance such as absenteeism and presenteeism.Therapeutic modalities should be individualised by taking the impacts of cognitive deficits into consideration to promote psychosocial functioning of MDD patients.

Aryl sulfides are common and ubiquitous motifs in natural products and pharmaceuticals. Presented herein is the first example of the synthesis of diaryl sulfide derivatives via dehydroaromatization under simple basic conditions. Dehydroaromatization reactions between indolines or cyclohexanones with aryl thiols are performed in an environmentally benign manner by the use of air (molecular oxygen) as the oxidant, with producing water as the only byproduct. The methodology provides a simple and practical route to diaryl sulfides with wide functional groups in good to excellent yields. Preliminary mechanistic studies suggest that a radical process is involved in the transformation.

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists.

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.

Patients with major depressive disorder (MDD) often experience comorbid anxiety symptoms. Vortioxetine has demonstrated efficacy in treating anxiety symptoms in patients with MDD; however, efficacy and tolerability have not been assessed across the entire approved dosage range.

The efficacy and tolerability of vortioxetine 5-20 mg/day were assessed in patients with MDD and high levels of anxiety symptoms (Hamilton Anxiety Rating Scale [HAM-A] total score ≥ 20) using pooled data from four randomized, fixed-dose, placebo-controlled studies (n = 842). Data from a randomized, double-blind study of vortioxetine 10-20 mg/day versus agomelatine 25-50 mg/day in patients with an inadequate response to prior therapy (n = 299) were analyzed separately. Mean changes from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A, and Sheehan Disability Scale (SDS) total scores were analyzed by vortioxetine dosage.

The pooled analysis of fixed-dose studies demonstrated a clear dose-response relationship for vortioxetine 5-20 mg/day for improvements in MADRS, HAM-A, and SDS total scores. Vortioxetine 20 mg/day demonstrated significant effects versus placebo from week 4 onwards. In the post-hoc analysis of the active-controlled study in patients with an inadequate response to prior therapy, vortioxetine 10-20 mg/day was superior to agomelatine across all outcome measures from week 4 onwards. Up-titration of vortioxetine to 20 mg/day was not associated with an increase in adverse events.

Short-term trials.

Vortioxetine is efficacious and well tolerated in patients with MDD and high levels of anxiety symptoms, including those with an inadequate response to prior therapy. The greatest therapeutic benefits were observed with vortioxetine 20 mg/day.

NCT01140906, NCT01153009, NCT01163266, NCT01255787, NCT01488071.

Depression is one of the most common mental illnesses, affecting almost 300 million people. According to the WHO, depression is one of the world's leading causes of disability and morbidity. People with this illness require both psychological and pharmaceutical treatment because severe depressive episodes often result in suicide. Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants that target the human serotonin transporter (hSERT). The crystallization of hSERT and the experimental data available allows cost and time-efficient computational tools like virtual screening (VS) to be utilized in the development of therapeutic agents. Here, we synthesized, characterized, and evaluated the biological activity of a novel SSRI analog of paroxetine, rationally designed by applying an artificial neural network-based QSAR model and a molecular docking analysis on hSERT. The analog N-substituted 18a showed higher affinity for the transporter (-10.2 kcal/mol), lower Ki value (1.19 nM) and a safer toxicological profile than paroxetine and was synthesized with a 71% yield. The in vitro cytotoxicity of the analog was evaluated using human glioblastoma (U87 MG), human neuroblastoma (SH SY5Y) and murine fibroblast (L929) cell lines. Also, the hemolytic ability of the compound was assessed on human erythrocytes. Results showed that analog 18a did not exhibit cytotoxic activity on the cell lines used and has no hemolytic activity at any of the concentrations tested, whereas with paroxetine, hemolysis was observed at 2.3, 1.29 y 0.67 mM. Based on these results, it is possible to suggest that analog 18a could be a promising new SSRI candidate for the treatment of this illness.

A novel hydroiodic acid-promoted metal-free C(sp²)-H sulfenylation of electron-rich arenes was developed using stable and easy-to-handle sodium sulfinates as sulfur sources. Diverse kinds of asymmetric aryl sulfides were afforded in good yields from various commercially available aromatic substrates under mild conditions. Comprehensive mechanistic experiments demonstrate that RSO₂SR and RSSR are the key intermediates responsible for the redox process.

Vortioxetine is an antidepressant recently licensed in USA and EU for the treatment of major depressive disorder. Neither fatal case due to overdose nor data about postmortem concentrations on blood or other specimens have been reported. The aims of this study were the development and validation of a method for vortioxetine analysis by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) in postmortem samples and its application in an authentic case. The method was validated and applied on blood, vitreous humor, bile, brain, liver, kidney, and gastric content. After protein precipitation, the supernatant was directly injected into LC-MS/MS. Analysis was carried out by Multiple Reaction Monitoring (MRM) mode. The authentic case concerned a 38 years-old woman, affected by depression, who was found hanged at home. The method determined an acceptable sensitivity, selectivity, linearity, precision, and accuracy for all matrices. No interference was shown for all matrices. The matrices do not significantly reduce the peak intensity of vortioxetine. No carryover was shown. Toxicological analysis of the authentic case showed vortioxetine in blood (234 ng/ml), vitreous humor (10.5 ng/ml), brain (490 ng/g), lung (479 ng/g), liver (3751 ng/g), kidney (798 ng/g), bile (2267 ng/ml) and gastric content (253 ng/ml). Our case suggests that even at blood concentrations of vortioxetine equal to 234 ng/ml, the subject was able to stage and carry out the hanging. Vortioxetine concentrations found in the other cadaveric samples (biological fluids, organs, and gastric content) may be helpful to evaluate further similar comparable cases.

Depression and anxiety are highly prevalent in most neurological disorders and can have a major impact on the patient's disability and quality of life. However, mostly due to the heterogeneity of symptoms and the complexity of the underlying comorbidities, depression can be difficult to diagnose, resulting in limited recognition and in undertreatment. The early detection and treatment of depression simultaneously with the neurological disorder is key to avoiding deterioration and further disability. Although the neurologist should be able to identify and treat depression initially, a neuropsychiatry team should be available for severe cases and those who are unresponsive to treatment. Neurologists should be also aware that in neurodegenerative diseases, such as Alzheimer's or Parkinson's, different depression symptoms could develop at different stages of the disease. The treatment options for depression in neurological diseases include drugs, cognitive-behavioral therapy, and somatic interventions, among others, but often, the evidence-based efficacy is limited and the results are highly variable. Here, we review recent research on the diagnosis and treatment of depression in the context of Alzheimer's disease, Parkinson's disease, and strokes, with the aim of identifying common approaches and solutions for its initial management by the neurologist.

Analysis of efficacy and tolerability of vortioxetine 20 mg/day, and optimal timing of dose adjustment, in patients with major depressive disorder (MDD).

Pooled analysis of six randomized, fixed-dose studies of vortioxetine 5 to 20 mg/day. Mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was analyzed by vortioxetine dose using a mixed model for repeated measures. Tolerability was assessed over the 8-week treatment period and from day 8 (ie, following dose increase to 20 mg/day). Data from three randomized, flexible-dose studies were examined for frequency and timing of dose adjustment.

A clear dose-response relationship for vortioxetine was confirmed in terms of improvement in MADRS total score. Significant differences vs placebo were seen for vortioxetine 20 mg/day from week 2 onwards; vortioxetine 10 mg did not separate from placebo until week 4. At week 8, mean change in MADRS total score from baseline was significantly greater for vortioxetine 20 mg/day vs 10 mg/day (difference, -1.03 points; P < .05). Incidence of adverse events was not increased in patients who received vortioxetine 20 mg/day vs 10 mg/day. In flexible-dose studies, dosage was increased to 20 mg/day after 1 week in 48.0% of patients; final dosage was 20 mg/day in 64.3% of patients.

Vortioxetine 20 mg is significantly more effective than vortioxetine 10 mg in patients with MDD, with a similar tolerability profile. In flexible-dose studies, almost half of all patients received 20 mg/day after 1 week and two-thirds received 20 mg/day as their final dosage.

Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects-in comparison with conventional antidepressants or mood-stabilising antipsychotics-due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network-which could be unaffected by conventional therapeutic agents-via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings.

Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT_1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT_1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes.

The [³⁵S]GTPγS binding assay for G_i/o proteins coupled with 5-HT_1A receptors was performed in rat brain membranes and postmortem human brain membranes.

The specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT_1A receptor agonism, involvement of other components, e.g., 5-HT_1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT_1A receptor neutral antagonist. Negligible stimulatory effects were obtained as to lurasidone and asenapine.

Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT_1A receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group.

Vortioxetine has demonstrated procognitive effects in patients with major depressive disorder (MDD). We assessed the effectiveness and safety of vortioxetine in a cohort of patients with MDD and comorbid Alzheimer's disease participating in a large post-marketing surveillance study in South Korea.

Subgroup analysis of a 6-month, prospective, multicenter, non-interventional cohort study in outpatients with MDD with a pre-baseline diagnosis of Alzheimer's disease receiving vortioxetine in routine care settings (n = 207). Patients were assessed at baseline and after 8 weeks; a subset of patients was also assessed after 24 weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) scale, cognitive symptoms using the Perceived Deficits Questionnaire-Depression, Korean version (PDQ-K), and cognitive performance using the Digit Symbol Substitution Test (DSST).

Most patients were receiving a mean daily vortioxetine dose of 5 mg/day (174/190 patients; 91.6%). After 24 weeks of vortioxetine treatment, 71.4% of patients (40/56) had experienced overall clinical improvement (i.e., CGI-Improvement score ≤3) and 51.9% (28/54) had achieved remission from depressive symptoms (i.e., MADRS total score ≤10 points). Respective mean changes in MADRS, PDQ-K, and DSST total scores from baseline to week 24 were -11.5 (p < 0.0001), -5.1 (p = 0.03), and +3.8 points (p = 0.0524). Adverse events were reported by 27 patients (13.0%) and were mostly mild (89.2%).

Patients with MDD and comorbid Alzheimer's disease receiving vortioxetine in routine care settings in South Korea demonstrated clinically meaningful improvements in depressive symptoms, cognitive symptoms, and objective cognitive performance over the 6-month treatment period. Treatment with vortioxetine was well tolerated in this patient cohort, with reported adverse events consistent with the established tolerability profile of vortioxetine.