Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia.

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology.

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Drug Repurposing to Inhibit Histamine N-Methyl Transferase.

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 µM and 45.01 µM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.

Attenuation of the levels of pro-inflammatory cytokines prevents depressive-like behavior during ethanol withdrawal in mice.

Clinical studies indicate that alcohol-dependent patients may develop depressive symptoms during abstinence, which may increase the likelihood of relapse. It is known that both in alcohol exposure and depression, there is an increase in the levels of pro-inflammatory cytokines in the brain. However, the putative contribution of increased levels of pro-inflammatory cytokines in the development of depressive-like behavior during ethanol withdrawal has not been evaluated. In the present study, we aimed to investigate if ethanol withdrawal-induced depressive-like behavior is related to increased levels of pro-inflammatory cytokines in the brain. Male mice were treated with vehicle (saline 0.9%, v.o.) or ethanol (2 g/kg, v.o.) for 14 days. After 5 days of cessation of the ethanol treatment, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT) and then sacrificed. Their brains were analyzed for the levels of pro-inflammatory cytokines. Ethanol withdrawal mice showed increased immobility time in the FST and TST than by the control group, indicating increased depressive-like behavior. No alterations in OFT were observed. Ethanol withdrawal increased the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus and striatum, interleukin-1 beta (IL-1ß) in the hippocampus, and IL-6 in the prefrontal cortex and hippocampus. Treatment of mice with nimesulide (5 or 10 mg/kg/day), a cyclooxygenase-2 inhibitor, during ethanol withdrawal prevented the increase in immobility time in the TST. Similar results were observed in the FST upon nimesulide treatment, although with a higher dose. Nimesulide treatment (10 mg/kg) prevented the ethanol withdrawal-induced alterations in the levels of TNF-α, IL-1ß, and IL-6 in the hippocampus, prefrontal cortex, and striatum. Treatment of mice with an atypical antidepressant drug, vilazodone (0.3 or 1 mg/kg) prevented the increase in depressive-like behavior induced by ethanol withdrawal in the TST. In the FST, the increase in immobility time was prevented only by 1 mg/kg vilazodone treatment. Vilazodone prevented the increase in the levels of TNF-α, IL-1ß, and IL-6 in the hippocampus, IL-6 in the prefrontal cortex, and TNF-α in the striatum. In conclusion, these data indicate that increased levels of pro-inflammatory cytokines may play a role in the development of depressive-like behavior during ethanol withdrawal in mice.

Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates.

Conformational changes are fundamental events in the transport mechanism. The serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin after its release by serotonergic neurons and is the molecular target for antidepressant drugs and psychostimulants. Despite significant progress in characterizing the structure-function relationship of SERT, its conformational mechanism has not been fully understood. We present here a cell-based method for determining conformational changes in SERT with its fluorescent substrates by fluorescence imaging analysis. This method fluorometrically measures accessibility of strategically positioned cysteine residues in the substrate permeation pathway to calculate the rate constants of reactivity with MTS reagents in live or permeabilized cells. We validated this method by investigating ligand and ion-induced conformational changes in both the extracellular and cytoplasmic pathways of SERT. Furthermore, we applied this method for examining the influence of Cl- binding and vilazodone inhibition on SERT conformation. Our results showed that Cl- ion, in the presence of Na+, facilitates the conformational conversion from outward to inward open states, and that vilazodone binding stabilizes SERT in an outward open and inward-closed conformation. The present work provided insights into the conformational mechanism of SERT and also indicated that the cell-based fluorometric method is robust, straightforward to perform, and potentially applicable to any monoamine transporters in exploring the transport mechanism and mechanism of action of therapeutic agents for the treatment of several psychiatric disorders.

Vilazodone-phospholipid mixed micelles for enhancing oral bioavailability and reducing pharmacokinetic variability between fed and fasted states.

Despite the effectiveness and high tolerability of vilazodone (VLZ) as an antidepressant, its use is still limited due to its poor solubility and food dependent absorption. This study aims to load VLZ-phospholipid complex into self-assembled micelles forming VLZ-PL mixed micelles (VLZ-PL-MM), that can enhance VLZ solubility, improve its bioavailability and reduce the pharmacokinetic variability between the fed and fasting conditions. The effect of surfactant type and concentration was assessed using four different non-ionic surfactants (Brij 58, Tween 80, Labrasol and Pluronic F127) in four different weight ratios between the drug-complex and surfactant (1:0.5, 1:1, 1:2 and 1:3 w/w). Two VLZ-PL-MM formulae prepared using Brij 58 and Labrasol in 1:3 w/w ratio were selected as optimised ones since they have the highest encapsulation efficiency (100.83 and 93.87%, respectively), a particle size below 250 nm (206.73 and 221.33 nm, respectively) and negative zeta potential values (-29.63, -17.20 mV, respectively). Lyophilisation of these formulations using 3% sucrose was successful with no statistical changes in particle size and zeta potential upon rehydration. Both formulations elicited faster and higher in-vitro drug release profiles compared to the pure drug and the marketed tablet. In addition, both selected formulae improved ex-vivo permeation across rabbit intestinal membrane compared to the pure drug and the marketed tablet, with marked superiority of the one prepared using Brij 58. The results of the in-vivo study in male albino rabbits revealed similar AUC0-24 values after the oral administration of the best achieved VLZ-PL-MM system under fed and fasted conditions (769.89 and 741.55 ng.h mL-1, respectively). On the other hand, the marketed product showed significantly lower values of the AUC0-24 relative to the VLZ-PL-MM system and there was a marked enhancement of absorption of drug from the marketed product in presence of food (244.24 and 174.96 ng.h mL-1 under fed and fasted conditions, respectively). In addition, VLZ concentrations in the brain after 24 h obtained from the selected VLZ-PL-MM were significantly higher than those obtained from marketed tablet under fed and fasted conditions. Thus, the phospholipid mixed micelles formulation enhances the oral bioavailability of the poorly soluble drug and reduces the pharmacokinetic variability between fasting and fed conditions.

Involvement of kynurenine pathway and N-methyl-d-aspartate receptors in the antidepressant-like effect of vilazodone in the tail suspension test in mice.

The present study evaluated the antidepressant-like effects of vilazodone using the tail suspension test in mice. We also investigated the contribution of kynurenine pathway and N-methyl-d-aspartate receptors to this effect. For this purpose, we pretreated animals with sub-effective doses of L-kynurenine, 3-hydroxykynurenine, or quinolinic acid. We then assessed the immobility time, an indicative measure of depressive-like behavior, in the tail suspension test. We also evaluated the possible effects of sub-effective doses of vilazodone combined with sub-effective doses of ketamine (N-methyl-d-aspartate receptor antagonist) in a separate group. Vilazodone (3mg/kg, intraperitoneal) significantly reduced immobility time in the tail suspension test. L-kynurenine (1.7 mg/kg, intraperitoneal), 3-hydroxykynurenine (10 mg/kg, intraperitoneal), and quinolinic acid (3 nmol/site, intracerebroventricular) significantly increased the immobility time in the tail suspension test. The antidepressant-like effects of vilazodone (3mg/kg, intraperitoneal) were inhibited by pre-treatment with non-effective doses of L-kynurenine (0.83 mg/kg, intraperitoneal), 3-hydroxykynurenine (3.33 mg/kg, intraperitoneal), or quinolinic acid (1 nmol/site, intracerebroventricular). Pretreatment of mice with sub-effective doses of ketamine (1 mg/kg, intraperitoneal) optimized the action of a sub-effective dose of vilazodone (0.3mg/kg, intraperitoneal) and reduced the immobility time in the tail suspension test. None of the drugs used in this study induced any changes in locomotor activity in the open field test. The results showed that vilazodone induced an antidepressant-like effect in the tail suspension test, which may be mediated through an interaction with the kynurenine pathway and N-methyl-d-aspartate receptors.

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats.

Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1A agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients.

The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats.

Parkinson's disease is a neurodegenerative disease often characterized by motor deficits and most commonly treated with dopamine replacement therapy. Despite its benefits, chronic use of L-DOPA results in abnormal involuntary movements known as L-DOPA-induced dyskinesia. Growing evidence shows that with burgeoning dopamine cell loss, neuroplasticity in the serotonin system leads to the development of L-DOPA-induced dyskinesia through the unregulated uptake, conversion, and release of L-DOPA-derived dopamine into the striatum. Previous studies have shown that coincident 5-HT1A agonism and serotonin transporter inhibition may have anti-dyskinetic potential. Despite this, few studies have explicitly focused on targeting both 5-HT1A and the serotonin transporter. The present study compares the 5-HT compounds Vilazodone, YL-0919, and Vortioxetine which purportedly work as simultaneous 5-HT1A receptor agonists and SERT blockers. To do so, adult female Sprague Dawley rats were rendered hemiparkinsonian and treated daily for two weeks with L-DOPA to produce stable dyskinesia. The abnormal involuntary movements and forehand adjusting step tests were utilized as measurements for L-DOPA-induced dyskinesia and motor performance in a within-subjects design. Lesion efficacy was determined by analysis of striatal monoamines via high-performance liquid chromatography. Compounds selective for 5-HT1A/SERT target sites including Vilazodone and Vortioxetine significantly reduced L-DOPA-induced dyskinesia without compromising L-DOPA pro-motor efficacy. In contrast, YL-0919 failed to reduce L-DOPA-induced dyskinesia, with no effects on L-DOPA-related improvements. Collectively, this work supports pharmacological targeting of 5-HT1A/SERT to reduce L-DOPA-induced dyskinesia. Additionally, this further provides evidence for Vilazodone and Vortioxetine, FDA-approved compounds, as potential adjunct therapeutics for L-DOPA-induced dyskinesia management in Parkinson's patients.

The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression.

Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT1A receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT1A receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression.

Hippocampal BMP signaling as a common pathway for antidepressant action.

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.

Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson's Disease.

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.

The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter.

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

New generation antidepressants for depression in children and adolescents: a network meta-analysis.

BACKGROUND: Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications. OBJECTIVES: To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020. SELECTION CRITERIA: Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs). DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results. MAIN RESULTS: Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants. AUTHORS' CONCLUSIONS: Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.

Spectrofluorimetric determination of tianeptine using its quenching effect on Vilazodone.

A rapid, cost effective, simple and reliable method was developed for the determination of Tianeptine (TIA) drug in bulk and in pharmaceutical formulation. The fluorescence of Vilazodone was measured in isopropanol at room temperature. The method was optimized by measuring the factors that may affect the fluorescence intensity such as: pH, diluting solvent, temperature and mixing time. The developed method was validated according to ICH guidelines in terms of accuracy, precision, linearity, range, LOD and LOQ. The concentration range was found to be linear in the range of 10-100 ng/ml. The LOD and LOQ values were found to be very small (1.86, 5.62 ng/mL. The % RSD and the % R were found within the acceptable range. Unlike the HPLC procedures, the proposed method for TIA determination has many advantages over the reported analytical methods represented in its rapidity, lower cost and environmental safety as the instrument is simple with low operating cost.

Cost-effectiveness of vortioxetine compared with levomilnacipran and vilazodone in patients with major depressive disorder switching from an initial antidepressant.

Introduction: Many patients with major depressive disorder (MDD) do not achieve remission with their first antidepressant (AD), resulting in a high burden due to treatment failure. Vortioxetine is a valid treatment option for patients with MDD only partially responding to their first AD. Characterization of vortioxetine's potential benefits versus other approved treatments is important. Areas covered: The cost-effectiveness of vortioxetine, including cognitive outcomes, was modeled in comparison with levomilnacipran and vilazodone for patients switched to these medications after inadequate responses to a first AD. Expert opinion: Vortioxetine was associated with incremental quality-adjusted life-year (QALY) gains versus levomilnacipran (0.008) or vilazodone (0.009). Vortioxetine was dominant versus levomilnacipran and cost-effective versus vilazodone (incremental cost-effectiveness ratio [ICER],33,829 USD/QALY). In sensitivity analyses using residual cognitive dysfunction rates (vortioxetine, 49%; levomilnacipran, 58%, and vilazodone, 64%), incremental QALY gains for vortioxetine versus levomilnacipran (0.0085) or vilazodone (0.0109) were found. Vortioxetine remained dominant versus levomilnacipran and cost-effective versus vilazodone (ICER, 27,633 USD/QALY). ICER reduction was found with cognition outcomes inclusion. This model provides additional support for considering vortioxetine for patients requiring a switch of MDD treatments, although its conclusions are limited by the data available for inclusion. Additional research and real-world trials are needed to confirm the findings.

Serotonin Syndrome Associated With Vilazodone Overdose in a 22-Month-Old Treated With Dexmedetomidine.

BACKGROUND: Vilazodone was approved by the U.S. Food and Drug Administration in 2011 as a treatment for major depression disorder. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A agonist used in the treatment of depression in adults. Vilazodone increases the availability and activity of serotonin and its neural pathways. Vilazodone blocks the serotonin reuptake pump and desensitizes serotonin receptors (especially 5HT1A autoreceptors), therefore increasing serotonergic neurotransmission. Its partial agonist actions at presynaptic somatodendritic 5HT1A autoreceptors theoretically enhance serotonergic activity, contributing to antidepressant actions. There are limited reports exploring its effects in children after unintentional ingestion. Typical adult dosing is titrated from an initial dose of 10 mg up to a maximum dose of 40 mg daily. Serotonin syndrome classically manifests with restlessness, hyperthermia, tachycardia, mydriasis, and increased tone, and is typically treated with benzodiazepines, cyproheptadine, and supportive care. Dexmedetomidine has also been used in case reports to treat serotonin syndrome. CASE REPORT: We report the case of a toddler with a laboratory-confirmed vilazodone overdose exhibiting symptoms of serotonin syndrome, including restlessness, hyperthermia, mydriasis, dystonia, agitation, seizure-like activity, roving eye movement, tachycardia, and elevated creatine kinase. The patient was admitted and initially treated with supportive care and lorazepam per recommendations of the poison center, which did not recommend cyproheptadine use. On decompensation with suspected serotonin syndrome, the patient was treated with dexmedetomidine. In addition, urine toxicology screening (Amphetamines II assay; Roche, Indianapolis, IN) was positive for amphetamines; however, confirmatory testing (gas chromatography-mass spectrometry) was negative. The patient improved and was discharged after returning to her baseline status at 74 h post ingestion. Importantly, this patient did not require intubation and mechanical intubation, in spite of the large amount of vilazodone ingested. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: With increasing prescription of vilazodone, emergency physicians should have a high level of suspicion so as not to miss this toxidrome. The possibility of false-positive amphetamine screenings when an overdose of vilazodone is suspected should be investigated. Finally, systematic evaluation of the use of dexmedetomidine as treatment for serotonin syndrome or vilazodone ingestion should be done to confirm efficacy.