Prenatal exposure to vortioxetine and vilazodone: Impact on depressive- and anxiety-like behavioral manifestations in young rat offspring.

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.

Design of vilazodone-donepezil chimeric derivatives as acetylcholinesterase inhibitors by QSAR, molecular docking and molecular dynamics simulations.

Alzheimer's disease (AD) is a disease that affects the cognitive abilities of older adults, and it is one of the biggest global medical challenges of the 21st century. Acetylcholinesterase (AChE) can increase acetylcholine concentrations and improve cognitive function in patients, and is a potential target to develop small molecule inhibitors for the treatment of Alzheimer's disease (AD). In this study, 29 vilazodone-donepezil chimeric derivatives are systematically studied using 3D-QSAR modeling, and a robust and reliable Topomer CoMFA model was obtained with: q2 = 0.720, r2 = 0.991, F = 287.234, N = 6, and SEE = 0.098. Based on the established model and combined with the ZINC20 database, 33 new compounds with ideal inhibitory activity are successfully designed. Molecular docking and ADMET property prediction also show that these newly designed compounds have a good binding ability to the target protein and can meet the medicinal conditions. Subsequently, four new compounds with good comprehensive ability are selected for molecular dynamics simulation, and the simulation results confirm that the newly designed compounds have a certain degree of reliability and stability. This study provides guidance for vilazodone-donepezil chimeric derivatives as a potential AChE inhibitor and has certain theoretical value.

Allosteric Inhibition and Pharmacochaperoning of the Serotonin Transporter by the Antidepressant Drugs Trazodone and Nefazodone.

The antidepressants trazodone and nefazodone were approved some 4 and 3 decades ago, respectively. Their action is thought to be mediated, at least in part, by inhibition of the serotonin transporter [SERT/solute carrier (SLC)-6A4]. Surprisingly, their mode of action on SERT has not been characterized. Here, we show that, similar to the chemically related drug vilazodone, trazodone and nefazodone are allosteric ligands: trazodone and nefazodone inhibit uptake by and transport-associated currents through SERT in a mixed-competitive and noncompetitive manner, respectively. Contrary to noribogaine and its congeners, all three compounds preferentially interact with the Na+-bound outward-facing state of SERT. Nevertheless, they act as pharmacochaperones and rescue the folding-deficient variant SERT-P601A/G602A. The vast majority of disease-associated point mutations of SLC6 family members impair folding of the encoded transporter proteins. Our findings indicate that their folding defect can be remedied by targeting allosteric sites on SLC6 transporters. SIGNIFICANCE STATEMENT: The serotonin transporter is a member of the solute carrier-6 family and is the target of numerous antidepressants. Trazodone and nefazodone have long been used as antidepressants. Here, this study shows that their inhibition of the serotonin transporter digressed from the competitive mode seen with other antidepressants. Trazodone and nefazodone rescued a folding-deficient variant of the serotonin transporter. This finding demonstrates that folding defects of mutated solute carrier-6 family members can also be corrected by allosteric ligands.

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.

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 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.

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.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson's Disease.

Levodopa (L-DOPA) treatment in Parkinson's disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson's disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

Identification of the Antidepressant Vilazodone as an Inhibitor of Inositol Polyphosphate Multikinase by Structure-Based Drug Repositioning.

Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.

Spinal Serotonin 1A Receptor Contributes to the Analgesia of Acupoint Catgut Embedding by Inhibiting Phosphorylation of the N-Methyl-d-Aspartate Receptor GluN1 Subunit in Complete Freund's Adjuvant-Induced Inflammatory Pain in Rats.

Acupoint catgut embedding (ACE) is a widely used traditional Chinese medicine method to manage various diseases, including chronic inflammatory pain. We sought to assess the possible analgesic effects of ACE in comparison with electroacupuncture (EA) and to study the analgesic mechanisms of ACE in a rat model of inflammatory pain induced by injection of complete Freund's adjuvant (CFA) into the hind paw of rats. The von Frey, radiant heat, and gait analysis tests were performed to evaluate the analgesic effects of ACE and EA, and Western blot and immunohistochemistry assays were carried out to determine the molecular mechanisms of ACE. ACE treatments were administered every 4 days or every week with different acupoints (ipsilateral, contralateral, or bilateral ST36 and GB30 acupoints). The most effective ACE strategy for attenuating the nocifensive response induced by CFA injection was performing ACE once a week at ipsilateral ST36 in combination with GB30. EA treatment every other day at ipsilateral ST36 and GB30 showed comparable analgesic effects. ACE inhibited the increased activation of the GluN1 subunit of the N-methyl-d-aspartate receptor and the subsequent Ca2+-dependent signals (CaMKII, ERK, and CREB) that take place in response to CFA. The effects of ACE were similar to intrathecal injection of vilazodone (a serotonin 1A receptor [5-HT1AR] agonist) and were blocked by WAY-100635 (a 5-HT1AR antagonist). In summary, we show that ACE attenuates CFA-induced inflammatory pain in rats by activating spinal 5-HT1AR and by inhibiting the phosphorylation of GluN1, thus, inhibiting the activation of Ca2+-dependent signaling cascades. PERSPECTIVE: This article presents the novel evidence concerning the spinal 5-HT1AR activation-related molecular signaling of ACE analgesia in a rat model of CFA-induced inflammatory pain. This work may help clinicians to verify the effectiveness of ACE analgesia and to better understand the underlying mechanism.

5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI.

Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [35S]-GTPγS binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation.

Revealing vilazodone's binding mechanism underlying its partial agonism to the 5-HT1A receptor in the treatment of major depressive disorder.

It has been estimated that major depressive disorder (MDD) will become the second largest global burden among all diseases by 2030. Various types of drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin receptor partial agonist/reuptake inhibitors (SPARIs), have been approved and become the primary or first-line medications prescribed for MDD. SPARI was expected to demonstrate more enhanced drug efficacy and a rapid onset of action as compared to SSRI and SNRI. As one of the most famous SPARIs, vilazodone was approved by the FDA for the treatment of MDD. Because of the great clinical importance of vilazodone, its binding mechanism underlying its partial agonism to the 5-HT1A receptor (5-HT1AR) could provide valuable information to SPARIs' drug-like properties. However, this mechanism has not been reported to date; consequently, the rational design of new efficacious SPARI-based MDD drugs is severely hampered. To explore the molecular mechanism of vilazodone, an integrated computational strategy was adopted in this study to reveal its binding mechanism and prospective structural feature at the agonist binding site of 5-HT1AR. As a result, 22 residues of this receptor were identified as hotspots, consistently favoring the binding of vilazodone and its analogues, and a common binding mechanism underlying their partial agonism to 5-HT1AR was, therefore, discovered. Moreover, three main interaction features between vilazodone and 5-HT1AR have been revealed and schematically summarized. In summary, this newly identified binding mechanism will provide valuable information for medicinal chemists working in the field of rational design of novel SPARIs for MDD treatment.

A randomized controlled pilot trial of vilazodone for adult separation anxiety disorder.

BACKGROUND: Separation anxiety disorder was recently recognized by fifth edition of the Diagnostic and Statistical Manual of Mental Disorders as a diagnosis in adults, but no publications to date have characterized a sample of patients seeking treatment for adult separation anxiety disorder (ASAD) or assessed treatment efficacy. We hypothesized that vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1a (5HT1a ) receptor partial agonist, would have efficacy in ASAD, because SSRIs have appeared efficacious in children with mixed diagnoses including separation anxiety disorder and in animal models of separation anxiety. METHODS: In this pilot study, 24 adults (ages 18-60) with a principal diagnosis of ASAD were randomized to 12 weeks of double-blind treatment with vilazodone (n = 13) or placebo (n = 11). Outcome was assessed by an independent evaluator and self-ratings, and analyzed with mixed effect models. RESULTS: This sample was predominantly female (67%), with comorbid psychiatric disorders (58%), and adult onset of separation anxiety disorder (62%). Response rates at week 12 did not differ significantly between groups. Across all time points, the vilazodone group evidenced greater improvement on the Structured Clinical Interview for Separation Anxiety Symptoms (P = .026) and the Quality of Life Enjoyment and Satisfaction Questionnaire (P = .011), and trends toward greater improvement on the Adult Separation Anxiety Questionnaire (P = .054) and the Clinical Global Impression-Change Scale (P = .086), all with large between-group effect sizes. CONCLUSIONS: Findings demonstrate feasibility of a clinical trial in ASAD, and they suggest that vilazodone may have efficacy in the treatment of ASAD and warrants further study.

Comparing the Immune-Genomic Effects of Vilazodone and Paroxetine in Late-Life Depression: A Pilot Study.

Vilazodone is a novel antidepressant agent that combines selective serotonin (5-HT) reuptake inhibitor (SSRI) activity and 5-HT(1A) receptor partial agonist activity. A pilot study was conducted to compare vilazodone (novel compound) and paroxetine (gold standard) on antidepressant effects, tolerability, and inflammation and immune modulation. A 12-week, double-blind, randomized clinical trial was conducted with 56 nondemented older adults diagnosed with major depressive disorder (MDD). Between-group differences in mood, tolerability, and safety, as well as genomic markers of inflammation and immune modulation, were examined. Both treatment groups demonstrated similar improvement in depressed mood. Leukocyte gene expression profiles demonstrated reduction of specific proinflammatory gene transcripts and bioinformatic indications of reduced nuclear factor kappa B (NF-κB), activator protein (AP)-1, and cAMP response element binding (CREB) activity in the vilazodone group compared to the paroxetine group. Transcript origin analyses implicated monocytes and dendritic cells as the primary cellular origins of transcript reductions in the vilazodone-treated group. Vilazodone's antidepressant effects may be associated with reduction of proinflammatory gene expression and immune modulation. Further research is required.

Distinct Antidepressant-Like and Cognitive Effects of Antidepressants with Different Mechanisms of Action in Middle-Aged Female Mice.

Background: Cognitive dysfunction is among the key symptoms of major depressive disorder and can be affected by antidepressants. Cognitive decline also occurs in normal aging. The effects of different antidepressants on affective and cognitive domains in older subjects are seldom assessed simultaneously. Methods: Healthy middle-aged female mice received vehicle or antidepressant (vortioxetine, vilazodone, duloxetine, or fluoxetine) at therapeutic doses. After 1 month treatment, mice were accessed for visuospatial memory and depression-like behavior. A separate cohort of mice received 3 months of treatment and was test for recognition memory and depression-like behavior. Results: After 1 month treatment, vortioxetine improved visuospatial memory and reduced depression-like behavior. Vilazodone reduced depression-like behavior. Duloxetine and fluoxetine were ineffective in both tests. After 3 months treatment, vortioxetine reduced depression-like behavior without affecting recognition memory, while fluoxetine impaired recognition memory. Duloxetine and vilazodone had no effect in both tests. Conclusion: Different antidepressants have distinct effects in middle-aged female mice.

Effects of vilazodone on sexual functioning in healthy adults: results from a randomized, double-blind, placebo-controlled, and active-controlled study.

The aim of this study is to evaluate the effects of vilazodone on sexual functioning in healthy, sexually active adults and assess the impact of medication nonadherence in this type of trial. Participants were randomized to vilazodone (20 or 40 mg/day), paroxetine (20 mg/day), or placebo for 5 weeks of double-blind treatment. The primary endpoint was change from baseline to day 35 in Change in Sexual Functioning Questionnaire (CSFQ) total score in the intent-to-treat (ITT) population. Post-hoc analyses were carried out in modified intent-to-treat (mITT) populations that excluded participants in the active-treatment groups with undetectable plasma drug concentrations at all visits (mITT-I) or at least one visit (mITT-II). In the ITT population (N=199), there were no statistically significant differences between any treatment groups for CSFQ total score change: placebo, -1.0; vilazodone 20 mg/day, -1.4; vilazodone 40 mg/day, -1.9; and paroxetine, -3.5. In mITT-I (N=197) and mITT-II (N=159), CSFQ total score change was not significantly different between vilazodone (either dose) versus placebo; the CSFQ total score decreased significantly (P<0.05) with paroxetine versus both placebo and vilazodone 20 mg/day, but not versus vilazodone 40 mg/day. Vilazodone exerted no significant effect on sexual functioning in healthy adults. Medication nonadherence can alter study results and may be an important consideration in trials with volunteer participants.

Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of vilazodone as an acute treatment for generalized anxiety disorder (GAD). Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter, flexible-dose study conducted from May 2013-March 2014. Adult patients (18-70 years, inclusive) who met DSM-IV-TR criteria for GAD were randomized (1:1) to placebo or vilazodone 20-40 mg/d for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 8 in the Hamilton Anxiety Rating Scale (HARS) total score and in the Sheehan Disability Scale (SDS) total score, respectively, analyzed using a mixed-effects model for repeated measures approach on a modified intent-to-treat population. Safety outcomes were summarized descriptively. RESULTS: Efficacy analyses were based on 400 patients (placebo = 200, vilazodone = 200); 76% completed the study (placebo = 81%, vilazodone = 71%). The least squares mean difference (95% CI) in total score change from baseline to week 8 was statistically significant for vilazodone versus placebo on the HARS (-2.20 [-3.72 to -0.68]; P = .0048) and on the SDS (-1.89 [-3.52 to -0.26]; P = .0236). Treatment-emergent adverse events reported in ≥ 5% of vilazodone patients and at least twice the rate of placebo were nausea, diarrhea, dizziness, fatigue, delayed ejaculation, and erectile dysfunction. CONCLUSION: Statistically significant differences in favor of vilazodone 20-40 mg/d versus placebo were seen on all measures of anxiety and functional impairment in patients with GAD. Vilazodone was generally well tolerated, and no new safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01844115.

Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: A role for 5-HT1A receptors?

Vilazodone (VLZ) is a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. In preclinical studies, VLZ had significantly lower sexual side effects than SSRIs and reduced serotonin transporter (SERT) levels in forebrain regions. In the current study, once-daily paroxetine (PAR, 10 mg/kg), VLZ (10 mg/kg), PAR + buspirone (BUS, 3 mg/kg; a 5-HT1A partial agonist), or vehicle (VEH) was administered to male rats for 2 weeks then switched for 7 days (eg, PAR switched to VLZ, PAR + BUS, or VEH). Sexual behavior (eg, ejaculation frequency and latency) was evaluated 1-hr postdose on days 1, 7, 14, and 21. After 2 weeks, treatment with PAR but not VLZ resulted in a significant decrease in sexual behavior. In a 30-min test, the range of ejaculation frequency was 3.08-3.5 with VLZ and 1.00-1.92 with PAR (P < 0.05 vs VEH). After switching from PAR to VEH, PAR + BUS, or VEH, sexual behaviors were normalized to control levels. In contrast, the switch from VLZ to PAR resulted in reduced sexual behaviors. This preclinical study showed that unlike PAR, an SSRI with no 5-HT1A receptor activity, initial treatment with VLZ did not result in sexual side effects at therapeutically relevant doses. Results in male rats switched from PAR to VLZ or PAR + BUS strongly suggest that activation of 5-HT1A receptors may mitigate the sexual side effects associated with conventional SSRIs.