benzofurans and Depressive-Disorder--Major

As a leading cause of disability, major depressive disorder (MDD) is characterized by reduced quality of life and altered functioning. Current pharmaceutical treatment options are limited in their success by modest effects and adverse events that often lead to discontinuation. One current trend in antidepressant development is to combine inhibition of the serotonin transporter with other pharmacological targets, including the norepinephrine transporter or different serotonin receptors.. In a span of < 3 years, the FDA approved three new antidepressants for the treatment of MDD: vilazodone in January 2011, levomilnacipran in July 2013 and vortioxetine in September 2013. This article reviews the efficacy, safety and tolerability of these three drugs mainly from the Phase III trial data.. All three drugs are effective in the treatment of MDD, but data comparing them to other antidepressants is currently lacking. Vilazodone was proposed to produce a more rapid onset and have fewer sexual side effects but neither effect has been conclusively shown. Levomilnacipran appears to be effective in improving functional impairment, including both social and work functioning. Vortioxetine is currently the only drug of the three with proven efficacy in elderly patients. It also appears to have cognitive enhancing properties which are largely independent of improved depressive symptoms. Overall, these drugs represent a promising step forward in antidepressant drug development.

Topics: Antidepressive Agents; Benzofurans; Clinical Trials, Phase III as Topic; Cyclopropanes; Depressive Disorder, Major; Humans; Indoles; Milnacipran; Piperazines; Sulfides; Vilazodone Hydrochloride; Vortioxetine

Vortioxetine is an antidepressant with multimodal activity which has shown efficacy in major depressive disorder (MDD) patients in six of ten short-term, randomized, placebo-controlled trials (completed end 2012).. We performed meta-regression analyses to indirectly compare vortioxetine to seven marketed antidepressants with different mechanisms of action. To ensure study comparability, only experimental drug and placebo arms from placebo-controlled registration studies were included in primary analyses. The main outcomes were efficacy (standardized mean difference in change from baseline to 2 months on primary endpoint [MADRS/HAM-D]), and tolerability (withdrawal rate due to adverse events).. For efficacy, estimates of treatment effect (negative estimates favor vortioxetine) for vortioxetine versus comparators were: agomelatine, -0.16 (p = 0.11); desvenlafaxine, 0.03 (p = 0.80); duloxetine, 0.09 (p = 0.42); escitalopram, -0.05 (p = 0.70); sertraline, -0.04 (p = 0.83); venlafaxine IR/XR, 0.12 (p = 0.33); and vilazodone, -0.25 (p = 0.11). For tolerability, all but one combination was numerically in favor of vortioxetine (odds ratio < 1), although not all differences were statistically significant: agomelatine, 1.77 (p = 0.03); desvenlafaxine, 0.58 (p = 0.04); duloxetine, 0.75 (p = 0.26); escitalopram, 0.67 (p = 0.28); sertraline, 0.30 (p = 0.01); venlafaxine, 0.47 (p = 0.01); and vilazodone, 0.64 (p = 0.18). Sensitivity analyses did not significantly alter antidepressant effect estimates or relative ranking.. These meta-regression data show that vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD. Alternative methods like mixed-treatment comparison and inclusion of all randomized studies and active reference arms may provide complementary information to this analysis (more evidence but also more heterogeneity). Key messages: Indirect comparisons based on registration studies allow a useful comparison between a recently approved antidepressant and an approved drug. Vortioxetine offers a comparable or favorable combination of efficacy (measured by MADRS/HAM-D assessments) and tolerability (measured by withdrawal rate due to adverse events) versus other antidepressants in registration studies in MDD.

Topics: Acetamides; Adult; Aged; Antidepressive Agents; Benzofurans; Citalopram; Cyclohexanols; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Humans; Hypnotics and Sedatives; Indoles; Male; Middle Aged; Piperazines; Selective Serotonin Reuptake Inhibitors; Sertraline; Sulfides; Thiophenes; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine

This review is to inform clinicians of currently available data on vilazodone for treating patients with major depressive disorder (MDD), focusing on its differential action mechanism and extended clinical utility.. A data search was conducted in June 2012 using the PubMed/ MEDLINE/relevant clinical trial databases with the key terms "vilazodone" or "Viibryd.". The efficacy, safety, and tolerability of vilazodone have been demonstrated in two pivotal 8-week, randomized, double-blinded, placebo-controlled studies. Certain pharmacological characteristics of vilazodone were observed, including early onset of action, fewer sexual side effects, the absence of known cardiac toxicity, and minimal effect on weight gain, that may provide potential clinical advantages compared with currently available antidepressants. However, such possibilities should be replicated and confirmed in more well-designed and adequately powered clinical trials. Vilazodone requires dose titration up to 2 weeks to reach a target dose of 40 mg/d due to high rate of gastrointestinal side effects. No direct comparative studies with other antidepressants are currently available to confirm the aforementioned potential clinical utility.. Vilazodone is a newer antidepressant possessing different action mechanisms compared to currently available antidepressants but whether it has superiority to other class of antidepressants in terms of efficacy and safety should still warrant further evaluation through more well-controlled and direct comparison clinical trials.

Topics: Benzofurans; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Evidence-Based Medicine; Humans; Indoles; Piperazines; Randomized Controlled Trials as Topic; Receptors, Serotonin; Treatment Outcome; Vilazodone Hydrochloride

To describe the efficacy and safety of vilazodone for the treatment of major depressive disorder (MDD).. The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.fda.gov and http://www.clinicaltrials.gov for the search term 'vilazodone'. Product labeling provided additional information..   All available clinical reports of studies were identified.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.. Vilazodone is a specific serotonin reuptake inhibitor and serotonin 5HT1A receptor partial agonist. In needs to be administered with food to ensure adequate bioavailability. Approval for the treatment of MDD was based on a clinical development programme that included two 8-week placebo-controlled randomised clinical trials in outpatients with MDD where vilazodone was titrated to a target dose of 40 mg/d over the first 2 weeks. Both trials evidenced efficacy for vilazodone as measured by the Montgomery Asberg Depression Rating Scale. NNT for response vs. placebo was 8 (95% CI 6-16) and for remission was 14 (95% CI 8-55). NNH vs. placebo for discontinuation because of an adverse event (AE) was 27 (95% CI 15-104). The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo) were diarrhoea, nausea, vomiting and insomnia, with NNH values vs. placebo of 6 (95% CI 5-8), 6 (95% CI 5-8), 30 (95% CI 18-82) and 26 (95% CI 16-78), respectively. NNH vs. placebo for any sexual AE was 12 (95% CI 9-18), but systematically collected data using rating scales of sexual function did not reveal treatment associated effects. Vilazodone was not associated with clinically relevant weight change in the short-term trials. In an open-label 1-year study of vilazodone, mean weight increased by 1.7 kg among the observed cases.. Vilazodone represents another option for the treatment of MDD. Vilazodone appears to have a favourable weight-gain profile based on short-term studies. Sexual side-effects were not consistently demonstrated when assessed using clinical rating scales but spontaneously reported AEs related to sexual functioning were observed. Additional controlled data regarding long-term efficacy and effectiveness will help characterise this new agent when used in maintenance treatment.

Topics: Antidepressive Agents; Benzofurans; Clinical Trials as Topic; Depressive Disorder, Major; Double-Blind Method; Drug Administration Schedule; Drug Labeling; Humans; Indoles; Numbers Needed To Treat; Piperazines; Randomized Controlled Trials as Topic; Treatment Outcome; Vilazodone Hydrochloride

The pharmacology and pharmacokinetics of the antidepressant vilazodone (approved for U.S. marketing in 2011) are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials.. Vilazodone (marketed as Viibryd by Forest Pharmaceuticals) is a dual-acting serotonergic agent that combines the antidepressant effects of a selective serotonin-reuptake inhibitor (SSRI) with partial serotonin (5-HT)(1A)-receptor agonist activity. In two published eight-week Phase III trials involving a total of 878 adults with major depressive disorder (MDD), vilazodone use was found to yield significant symptomatic improvements relative to placebo use, as determined by mean changes from baseline in scores on the Hamilton Depression Rating Scale and other widely used clinical assessment instruments. Vilazodone hydrochloride therapy should be initiated at a dosage of 10 mg once daily and incrementally adjusted over 14 days to the recommended target daily dose of 40 mg; for optimal bioavailability and effectiveness, it should be taken after a light or high-fat meal. The adverse effects most commonly reported in clinical trials of vilazodone were diarrhea, nausea, vomiting, and insomnia.. Vilazodone is an efficacious and safe new antidepressant for the treatment of MDD. Its relatively high cost and adverse-effect profile, as well as a lack of data demonstrating that vilazodone can produce long-term MDD remission and offer significant advantages over the current standard of care, may limit the usefulness of vilazodone in clinical practice.

Topics: Adult; Antidepressive Agents; Benzofurans; Biological Availability; Depressive Disorder, Major; Humans; Indoles; Piperazines; Psychiatric Status Rating Scales; Remission Induction; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Major depressive disorder (MDD) is characterized by dysfunction in cognition, behavior, and physical functioning, and is associated with a chronic clinical course. There are barriers to successful treatment, which often result in early discontinuation and relapse. Adverse effects (AEs) remain the most commonly cited reason for discontinuation of treatment with conventional antidepressants, particularly early on in therapy. This often translates into relapse of symptoms or recurrence of the depressive episode. The delay to therapeutic response also has a meaningful implication for treatment adherence.. This article focuses on the implications of a novel entity for the treatment of depression; the first new molecule developed for this indication in the last 10 years. Vilazodone is a novel dual-acting serotonergic antidepressant, which is a selective and potent inhibitor of serotonin reuptake, as well as a selective partial agonist of the 5-HT(1A) receptor.. The data available in the literature so far indicate clinical efficacy over placebo and a rather benign adverse event profile. Whether the early onset of clinical efficacy observed in one of the two pivotal studies represents a true or only a chance phenomenon, only future studies can tell. Adverse effects are mostly mild-moderate and most GI type AEs disappear in about one week, at a time when all patients are still on a clinically suboptimal daily dosage (10 mg/d during the first week). Sexual AEs did not differ from placebo. Vilazodone represents an interesting addition to the arsenal of available antidepressants.

Topics: Animals; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Vilazodone Hydrochloride

Vilazodone (VIIBRYD, Trovis Pharmaceuticals; New Haven, Connecticut, also known as 659746, EMD68843, SB-659746-A) is a newly introduced antidepressant that has taken approximately a decade from its discovery to approval by the Food and Drug Administration. This paper will review the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug-drug interaction potential, dosing, and administration of this agent.. Medline/PubMed/IPA/EMBASE databases were searched using the terms "vilazodone," "659746," "EMD68843," and "SB-659746-A." All English-language papers from 1985 to April 2012 were reviewed for relevance. Bibliographies of all papers were reviewed to identify further papers.. All English-language papers from 1985 to present appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any papers not identified in the searches. Data are expressed as mean or mean ± standard deviation, unless otherwise noted.. Vilazodone is the first combined selective serotonin reuptake inhibitor (SSRI)/5-HT1A receptor agonist antidepressant. Vilazodone must be administered with food to optimize bioavailability. The primary route of elimination is metabolism followed by excretion of metabolites. Advancing age and renal and hepatic impairment do not alter its disposition. Early phase II clinical trials were unable to demonstrate antidepressant efficacy. However, later phase III trials using 40 mg daily doses were able to demonstrate superior efficacy compared with placebo treatment. Adverse events, warnings, and precautions mirror those of other SSRIs.. Although there are theoretical reasons why 5-HT1A agonism may be a desirable additional property in antidepressants, there is no evidence to date that vilazodone has any advantage over existing post-tricyclic antidepressants. It has a narrow therapeutic dosing range whose upper boundary is close to that producing intolerable gastrointestinal and central nervous system adverse events. Further research will clarify and refine the role of vilazodone in the management of psychiatric disorders.

Topics: Animals; Antidepressive Agents; Benzofurans; Biological Availability; Clinical Trials as Topic; Depressive Disorder, Major; Drug Interactions; Humans; Indoles; Piperazines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

To evaluate the clinical literature on and potential clinical role of vilazodone for the treatment of major depressive disorder.. Searches were conducted on MEDLINE (1948-February 2011), Iowa Drug Information Service (1988-February 2011), EBSCO Academic Search Premier (1975-February 2011), Google Scholar (1992-February 2011), PsycINFO (1980-February 2011), and PsycARTICLES (1985-February 2011), and on general Internet search engines including Google and Bing (no lower limit-February 2011). Search terms were vilazodone, EMD 68843, depression, and major depressive disorder. Potential prior marketers of vilazodone, including Merck KGaA in Germany and Genaissance Pharmaceuticals, were contacted for any available unpublished Phase 1, Phase 2, Phase 3 studies, or preclinical information.. All applicable full-text English-language articles, abstracts, and professional poster presentations found were evaluated and included in the review, as well as marketing and Securities and Exchange Commission filings available from the patent holders.. Vilazodone is an antidepressant recently approved by the Food and Drug Administration (FDA) that is first in a new class regarding mechanism of action. It has demonstrated efficacy in the primary outcome of the Montgomery-Asberg Depression Rating Scale (MADRS) response in an 8-week pivotal Phase 3 trial. Phase 2 trials did not demonstrate efficacy for primary outcomes of the 17-item Hamilton Rating Scale for Depression but showed statistically significant improvements in select secondary outcomes such as Clinical Global Impressions severity and MADRS. Long-term efficacy data are still forthcoming. An emerging aspect to vilazodone's development has been the identification and assessment of potential genetic biomarkers associated with both therapeutic response and more serious adverse effects. Initial studies into biomarkers have been inconclusive.. Vilazodone is a new agent recently approved by the FDA for treating major depressive disorder. Response rates seen with vilazodone are similar to those of currently available antidepressants.

Topics: Adult; Animals; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Genetic Markers; Humans; Indoles; Piperazines; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSRI) activity and serotonin 5-HT(1A) receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD) in the US. It is administered orally, once daily, with food. At the recommended dosage of 40 mg/day, vilazodone was effective in the short-term treatment of MDD in adults, as evidenced by significant improvements versus placebo on multiple measures of depression, including the Montgomery-Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17), in two pivotal, 8-week, randomized, double-blind, phase III studies. Significant differences between vilazodone and placebo on the MADRS and HAM-D-17 were seen after 1 week of treatment (first efficacy timepoint) in one of the two studies. Long-term treatment with vilazodone 40 mg/day was associated with an improvement from baseline in depressive symptoms in a 52-week, noncompar-ative, phase III study. Vilazodone was generally well tolerated in the short- and long-term treatment of MDD, with diarrhoea and nausea being the most frequently occurring treatment-emergent adverse events. Vilazodone had a minimal impact on sexual functioning in the three phase III studies.

Topics: Adult; Animals; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions.. The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data.. Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug.. The FDA had access to original raw data sets for these trials.. Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates.. Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.

Topics: Benzofurans; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Depressive Disorder, Major; Drug Approval; Female; Humans; Indoles; Male; Piperazines; Selective Serotonin Reuptake Inhibitors; Sexual Dysfunction, Physiological; United States; United States Food and Drug Administration; Vilazodone Hydrochloride

On January 21, 2011, the U.S. Food and Drug Administration approved Viibryd, a new selective serotonin reuptake inhibitor (SSRI), to treat major depressive disorder in adults developed by Clinical Data, Inc.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Female; Humans; Indoles; Male; Middle Aged; Multicenter Studies as Topic; Piperazines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Vilazodone Hydrochloride; Young Adult

Major depressive disorder (MDD) affects

Topics: Animals; Antidepressive Agents; Benzofurans; Biomarkers, Pharmacological; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Humans; Indoles; Piperazines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Because of the high number of therapy-resistant depressions and the growing number of suicides, there is still a great need for the development of antidepressants with a new pharmacological spectrum. The finding that phenylethylamine and tryptamine are endogenous enhancers of the impulse propagation mediated release of catecholamines and serotonin in the brain, and the development of synthetic enhancer substances opened the possibility to stimulate catecholaminergic and serotonergic neurons in the brain stem via a previously unknown mechanism. (-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons. R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP, the recently developed tryptamine-derived selective synthetic enhancer substance, is a hundred times more potent enhancer of the catecholaminergic neuronal activity than (-)-deprenyl, and is also a highly potent stimulant of the serotonergic neurons. Evaluation of the peculiar pharmacological profile, the high potency and unusual safeness and tolerability of (-)-BPAP cherish the hope that this compound by itself and in combination with uptake inhibitors may improve the effectiveness of drug therapy in major depression and diminish the number of therapy resistant cases.

Topics: Animals; Benzofurans; Depressive Disorder, Major; Humans; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Selegiline; Tryptamines

There is still a great need for the development of antidepressants with a new pharmacological spectrum. The finding that phenylethylamine and tryptamine are endogenous enhancers of the impulse propagation mediated release of catecholamines and serotonin in the brain, and the development of synthetic mesencephalic enhancer substances opened the possibility to stimulate catecholaminergic and serotonergic neurons in the mesencephalon via a previously unknown mechanism. (-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons. R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP, the recently developed tryptamine-derived selective synthetic mesencephalic enhancer substance, a hundred times more potent compound than (-)-deprenyl, acts also on the serotonergic neurons. The evaluation of the special pharmacological profile of the synthetic mesencephalic enhancer substance, especially the high potency and the unusual safety and tolerability of (-)-BPAP provide hope that this compound may in the future significantly improve the effectiveness of drug therapy in major depression and its combination with uptake inhibitors may substantially diminish the number of therapy resistant cases.

Topics: Benzofurans; Catecholamines; Depressive Disorder, Major; Humans; Mesencephalon; Neuroprotective Agents; Selegiline; Serotonin Agents; Tryptamines

The aim of this study was to evaluate the efficacy of vilazodone using different definitions of remission. Post-hoc analyses were carried out using data from an 8-week, multicenter, randomized, double-blind, placebo-controlled trial of vilazodone 40 mg/day in adults with major depressive disorder (NCT01473394). The primary efficacy endpoint was a mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score; additional measures included the Clinical Global Impressions-Severity (CGI-S) and Hamilton Rating Scale for Anxiety (HAMA) scores. In addition to treatment response (MADRS≥50% improvement), post-hoc analyses were carried out for remission of depressive symptoms [MADRS score≤10; MADRS≤5 (complete remission)], anxiety symptoms (HAMA≤7), and combined depression and anxiety symptoms (MADRS/HAMA≤10/≤7), as well as for overall symptom severity (CGI-S=1). Odds ratios (ORs) and numbers needed to treat (NNTs) were also calculated. Significant outcomes were obtained with vilazodone versus placebo for MADRS response (50.6 vs. 33.3%, OR=2.04, P<0.001, NNT=6), remission (34.0 vs. 21.8%, OR=1.82, P=0.003, NNT=9), and complete remission (18.2 vs. 8.3%, OR=2.42, P=0.002, NNT=11). More patients receiving vilazodone rather than placebo also met remission criteria for HAMA (48.8 vs. 35.2%, OR=1.82, P=0.002, NNT=8), MADRS/HAMA (32.1 vs. 20.4%, OR=1.83, P=0.004, NNT=9), and CGI-S (24.1 vs. 11.5%, OR=2.41, P<0.001, NNT=8). Treatment with vilazodone 40 mg/day may help adult patients with major depressive disorder achieve remission of depression and/or anxiety symptoms.

Topics: Adolescent; Adult; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Models, Statistical; Piperazines; Psychiatric Status Rating Scales; Remission Induction; Symptom Assessment; Vilazodone Hydrochloride; Young Adult

Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder (MDD) treatment in adults. This was a 10-week, multicenter, double-blind, placebo-controlled and active-controlled, fixed-dose trial (NCT01473381). Adult patients with MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision criteria) were randomized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day, citalopram 40 mg/day, or placebo. Primary efficacy: Montgomery-Åsberg Depression Rating Scale (MADRS); secondary efficacy: Clinical Global Impressions-Severity and sustained response (MADRS total score≤12 for at least the last two consecutive double-blind visits). The intent-to-treat population comprised 1133 patients, (placebo=281; vilazodone 20 mg/day=288; vilazodone 40 mg/day=284; citalopram=280). MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day, vilazodone 40 mg/day, and citalopram versus placebo. Sustained response rates were numerically higher, but not significantly different, in all active treatment groups versus placebo. The most common adverse events (≥5% of vilazodone patients, twice the rate of placebo) were diarrhea, nausea, vomiting (vilazodone 40 mg/day only), and insomnia. Improved sexual function (Changes in Sexual Functioning Questionnaire scores) was seen in all groups; between-group differences were not significant. Vilazodone 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Benzofurans; Citalopram; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

To retrospectively examine the timing of depressive symptom improvement in patients treated with vilazodone, a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A partial agonist.. Post hoc analyses were conducted on pooled data from two phase III, multicenter, 8 week, double-blind, randomized, controlled trials (RCTs) of vilazodone 40 mg/day or placebo in adult patients with major depressive disorder (MDD).. Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592.. Montgomery-Åsberg Depression Rating Scale (MADRS) total score least squares (LS) mean change from baseline to Week 8; MADRS single items LS mean change from baseline; MADRS responder analyses: response = ≥50% reduction in baseline score; cumulative response = proportion of patients at each assessment who achieved response that was sustained at all subsequent weeks; sustained response = ≥50% reduction in baseline MADRS total score at last two visits; and sustained response plus MADRS score ≤12 at the last two visits of the study.. LS mean difference (LSMD) and 95% confidence interval (95% CI) for change from baseline to Week 8 was significantly greater in favor of vilazodone versus placebo (-2.8 [-4.1 to -1.4]; p < 0.0001); differences between vilazodone and placebo were statistically significant beginning at Week 1. Early improvement in depressive symptoms was suggested by statistically significant separation from placebo on seven of ten MADRS single items as early as Week 1 or Week 2. A significantly greater proportion of vilazodone patients achieved response using all responder criteria, with early and sustained improvement consistently observed.. Early and sustained improvement of depressive symptoms was retrospectively observed in patients treated with vilazodone; early findings may be related to overall treatment outcomes.

Topics: Adult; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Placebos; Retrospective Studies; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome; Vilazodone Hydrochloride

Vilazodone is a potent selective serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. To assess the efficacy of vilazodone across a range of symptoms and severities of depression, data from two phase III, 8-week, randomized, double-blind, placebo-controlled trials were pooled for analysis. Overall improvement in depressive symptoms measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale was statistically significant (P<0.05) for vilazodone treatment compared with placebo as early as Week 1 and continued throughout double-blind treatment. Vilazodone treatment compared with placebo showed significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01). Rates of response and remission were significantly greater in the vilazodone group relative to the placebo group, with numbers needed to treat ranging from eight to nine for response and 12-17 for remission. Between-group treatment differences in MADRS and the other outcome measures were similar among all depression subgroups, with no consistent pattern associated with depression severity. These findings support the efficacy of vilazodone across a broad range of depressive symptoms and severities for the treatment of major depressive disorder.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

Anxiety symptoms are prevalent in patients with major depressive disorder. A post-hoc analysis of two phase III trials was conducted to evaluate the efficacy of vilazodone on depression-related anxiety. Using the 17-item Hamilton Depression Rating Scale (HAMD17) Anxiety/Somatization subscale, patients were classified as anxious or nonanxious. Improvements in depressive symptoms were based on least squares mean changes in HAMD17 and Montgomery-Asberg Depression Rating Scale total scores. Anxiety symptoms in the anxious subgroup were evaluated using Hamilton Anxiety Rating Scale (HAMA) total and subscale (Psychic Anxiety, Somatic Anxiety) scores, HAMD17 Anxiety/Somatization subscale and item (Psychic Anxiety, Somatic Anxiety) scores, and the Montgomery-Asberg Depression Rating Scale Inner Tension item score. Most of the pooled study population [82.0% (708/863)] was classified with anxious depression. After 8 weeks of treatment, least squares mean differences between vilazodone and placebo for changes in HAMA total and HAMD17 Anxiety/Somatization subscale scores were -1.82 (95% confidence interval -2.81 to -0.83; P<0.001) and -0.75 (95% confidence interval -1.17 to -0.32; P<0.001), respectively. Statistically significant improvements with vilazodone were also found on all other anxiety-related measures, except the HAMA Somatic Anxiety subscale. Vilazodone may be effective in treating patients with major depressive disorder who exhibit somatic and/or psychic symptoms of anxiety.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Anxiety; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Piperazines; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

Vilazodone is a potent serotonin (5-HT) reuptake inhibitor and 5-HT₁A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in adults. This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD.. This 8-week, randomized (1:1), double-blind, placebo-controlled, parallel-group, fixed-dose study conducted from January 2012 to February 2013 compared vilazodone 40 mg/d with placebo in outpatients with DSM-IV-TR-diagnosed MDD. The primary efficacy measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population (placebo = 252, vilazodone = 253). Secondary efficacy outcomes were Clinical Global Impressions-Severity of Illness (CGI-S) Scale score change from baseline and MADRS sustained response rate (total score ≤ 12 for at least the last 2 consecutive double-blind visits).. Approximately 83% of patients completed the study. Least squares mean differences (95% CI) were statistically significant for vilazodone versus placebo on MADRS (-5.117 [-6.886 to -3.347], P < .00001) and CGI-S (-0.622 [-0.845 to -0.399], P < .00001) change from baseline; statistically significant improvements versus placebo occurred at week 2 and persisted for the study duration. The MADRS sustained response rate was 17% for placebo and 27% for vilazodone (P < .01). Patients taking vilazodone versus placebo had higher rates of diarrhea and nausea; most incidences were mild in severity. Weight increase and sexual dysfunction adverse events were low in both groups.. A large and significant treatment effect on the MADRS and statistically significant improvement on the CGI-S demonstrated meaningful depressive symptom improvements. Vilazodone was generally well tolerated.. ClinicalTrials.gov identifier: NCT01473394.

Topics: Adult; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Humans; Indoles; Male; Middle Aged; Piperazines; Placebos; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

  Sexual dysfunction is common in major depressive disorder (MDD), and many serotonergic antidepressants adversely affect sexual function. Vilazodone, a novel serotonin (5-HT) reuptake inhibitor and 5-HT1A partial agonist approved for MDD, exerts its effects at the 5-HT transporter and at both presynaptic and postsynaptic 5-HT1A receptors. This mechanism may limit sexual dysfunction..   To summarize effects of vilazodone (40 mg/day, with food) on sexual function in adults with MDD..   Data sources were three Phase III studies: two 8-week, placebo-controlled studies (NCT00285376 and NCT00683592) and a 52-week open-label study (NCT00644358). Sexual function was assessed by analyzing changes from baseline to end of treatment (EOT) using validated measures..   Arizona Sexual Experience Scale or Changes in Sexual Functioning Questionnaire..   Population included 869 patients (vilazodone, 436; placebo, 433) from placebo-controlled studies and 599 patients from the open-label study. Sexual dysfunction prevalence was high (50%, men; 68%, women) before treatment and declined during treatment in vilazodone and placebo groups, indicating improvement on average. At EOT, stable/improved sexual function was observed in ≥91% of patients in placebo-controlled studies; treatment group differences in sexual dysfunction at EOT were not statistically significant for either sex. Differences vs. placebo in changes from baseline of sexual function scores were small and were generally not statistically significant; effect sizes (Cohen's D) were generally of low magnitude. In the placebo-controlled studies, 8.0% of vilazodone-treated patients and 0.9% of placebo-treated patients reported ≥1 sexual-function-related treatment-emergent adverse event (P<0.001)..   Half of men and two thirds of women with MDD had sexual dysfunction at baseline; sexual function improved on average in both vilazodone and placebo groups. Results suggest that vilazodone may have a small adverse impact on sexual function in adults with MDD relative to the high prevalence of sexual dysfunction at baseline.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Piperazines; Prevalence; Serotonin 5-HT1 Receptor Agonists; Sexual Behavior; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

To evaluate the efficacy, and further establish the safety profile, of oral once-daily vilazodone, a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor, in the treatment of major depressive disorder (MDD).. This phase 3, randomized, double-blind, placebo-controlled, 8-week study (conducted March 2008-February 2009) enrolled 481 adults with DSM-IV-TR-defined MDD. Patients received vilazodone (titrated to 40 mg/d) or placebo. The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment. Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale (HDRS-17) response and change in HDRS-17, HDRS-21, Hamilton Anxiety Rating Scale (HARS), Clinical Global Impressions-Severity of Illness (CGI-S), and Clinical Global Impressions-Improvement (CGI-I) scores. The Changes in Sexual Functioning Questionnaire (CSFQ) was administered at baseline and week 8.. Vilazodone-treated patients had significantly greater improvement (P = .009) according to the MADRS than placebo patients (intent-to-treat; least-squares mean changes: -13.3, -10.8). MADRS response rates were significantly higher with vilazodone than placebo (44% vs 30%, P = .002). Remission rates for vilazodone were not significantly different based on the MADRS (vilazodone, 27.3% vs placebo, 20.3%; P = .066) or HDRS-17 (vilazodone, 24.2% vs placebo, 17.7%; P = .088). Vilazodone-treated patients had significantly greater improvements from baseline in HDRS-17 (P = .026), HDRS-21 (P = .029), HARS (P = .037), CGI-S (P = .004), and CGI-I (P = .004) scores than placebo patients. Rates of discontinuation due to adverse events were 5.1% (vilazodone) and 1.7% (placebo). The most common adverse events (vilazodone vs placebo) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%). Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo. Effects on weight were no different from placebo.. Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD.. clinicaltrials.gov Identifier: NCT00683592.

Topics: Adolescent; Adult; Aged; Antidepressive Agents, Second-Generation; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

Vilazodone, a selective serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, was efficacious in two 8-week placebo-controlled studies in adults with major depressive disorder. This open-label, multicenter study assessed the long-term safety of vilazodone. Adult patients with a 17-item Hamilton Rating Scale for Depression score of 18 or greater received vilazodone according to a fixed-titration schedule to reach a dose of 40 mg/d continued up to 1 year. Safety assessments included adverse events (AEs), physical examinations, clinical chemistry, electrocardiograms, and the Changes in Sexual Functioning Questionnaire. Effectiveness was assessed with the Montgomery-Åsberg Depression Rating Scale and Clinical Global Impressions scales. The safety population comprised 599 patients; 254 patients completed 1 year of treatment. The most frequent AEs were diarrhea (35.7%), nausea (31.6%), and headache (20.0%); greater than 90% of these AEs were mild or moderate. Adverse events resulting in discontinuation in more than 1% of patients were nausea (1.3%) and diarrhea (1.2%). There were no clinically important changes in physical examinations, electrocardiograms, or clinical chemistries. Mean weight increased by 1.7 kg (observed cases). Changes in Sexual Functioning Questionnaire mean scores (observed cases) improved throughout treatment for both males and females. Montgomery-Åsberg Depression Rating Scale mean scores were 29.9 at baseline, 11.4 at week 8, and 7.1 at week 52 (observed cases). Vilazodone 40 mg/d for 1 year was safe and well tolerated by adults with major depressive disorder.

Topics: Adult; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Female; Follow-Up Studies; Humans; Indoles; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome; Vilazodone Hydrochloride

The efficacy and tolerability of vilazodone, a combined selective serotonin reuptake inhibitor and partial 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist, were evaluated in adult patients with major depressive disorder (MDD).. This was a randomized, double-blind, placebo-controlled trial conducted from February 2006 to May 2007. Patients aged 18 through 65 years with MDD (DSM-IV criteria) and a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of >or= 22 were randomly assigned to vilazodone or placebo for 8 weeks. Vilazodone was titrated from 10 mg to 40 mg once a day over 2 weeks. Efficacy was assessed by mean change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale (MADRS), HAM-D-17, and Hamilton Rating Scale for Anxiety. Response rates were determined at week 8 for the MADRS, HAM-D-17, and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Data were analyzed using a modified last-observation-carried-forward method in the intention-to-treat (ITT) sample. The Arizona Sexual Experience Scale (ASEX) was also measured at baseline and week 8.. Of 410 randomly assigned patients, 198 receiving vilazodone and 199 receiving placebo were included in the ITT population. The mean changes in MADRS and HAM-D-17 total scores from baseline to week 8 were significantly (p = .001 and p = .022, respectively) greater with vilazodone than with placebo. Significant (p < .05) improvements in MADRS and HAM-D-17 scores were noted at week 1, the earliest time point measured. Response rates were significantly higher with vilazodone than with placebo on the MADRS (p = .007), HAM-D-17 (p = .011), and CGI-I (p = .001). Treatment-emergent adverse events with vilazodone included diarrhea, nausea, and somnolence; most adverse events were of mild or moderate intensity. There were no clinically significant differences for either gender in ASEX scores at end of treatment.. Vilazodone is effective for the treatment of MDD in adults, with symptom relief starting at 1 week, and is well tolerated at a dose of 40 mg/day.. clinicaltrials.gov Identifier: NCT00285376.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Benzofurans; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Personality Inventory; Piperazines; Psychometrics; Treatment Outcome; Vilazodone Hydrochloride

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Dl-3-n-butylphthalide (NBP) is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The aim of this study was to investigate the effect of NBP in a chronic social defeat stress model of depression and its underlying molecular mechanisms. Here, we examined depression-related behavior and performed a targeted metabolomics analysis. Real-time quantitative polymerase chain reaction and western blotting were used to examine key genes and proteins involved in energy metabolism and the AKT/cAMP response element-binding protein (CREB) signaling pathway. Our results reveal NBP attenuates stress-induced social deficits, anxiety-like behavior and despair behavior, and alters metabolite levels of glycolysis and tricarboxylic acid (TCA) cycle components. NBP affected gene expression of key enzymes of the TCA cycle, as well as protein expression of p-AKT and p-CREB. Our findings provide the first evidence showing that NBP can attenuate stress-induced behavioral deficits by modulating energy metabolism by regulating activation of the AKT/CREB signaling pathway.

Topics: Animals; Benzofurans; Cyclic AMP Response Element-Binding Protein; Depressive Disorder, Major; Energy Metabolism; Mice; Neuroprotective Agents; Proto-Oncogene Proteins c-akt; Signal Transduction; Social Defeat

Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Benzofurans; Citalopram; Depression; Depressive Disorder, Major; Eukaryotic Initiation Factor-4E; Female; Fluoxetine; Inflammation; Ketamine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Biosynthesis; Protein Serine-Threonine Kinases; Serotonin and Noradrenaline Reuptake Inhibitors; Synaptic Transmission; Tumor Necrosis Factor-alpha

Major depressive disorder (MDD) is a debilitating mental disorder associated with dysfunction of the neurotransmitter-neuroendocrine system and neuroinflammatory responses. Salvianolic acid B (SalB) has shown a variety of pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects. In this study, we examined whether SalB produced antidepressant-like actions in a chronic mild stress (CMS) mouse model, and explored the mechanisms underlying the antidepressant-like actions of SalB.. Mice were subjected to a CMS paradigm for 6 weeks. In the last 3 weeks the mice were daily administered SalB (20 mg·kg(-1)·d(-1), ip) or a positive control drug imipramine (20 mg·kg(-1)·d(-1), ip). The depressant-like behaviors were evaluated using the sucrose preference test, the forced swimming test (FST), and the tail suspension test (TST). The gene expression of cytokines in the hippocampus and cortex was analyzed with RT-PCR. Plasma corticosterone (CORT) and cerebral cytokines levels were assayed with an ELISA kit. Neural apoptosis and microglial activation in brain tissues were detected using immunofluorescence staining.. Administration of SalB or imipramine reversed the reduced sucrose preference ratio of CMS-treated mice, and significantly decreased their immobility time in the FST and TST. Administration of SalB significantly decreased the expression of pro-inflammatory cytokines IL-1β and TNF-α, and markedly increased the expression of anti-inflammatory cytokines IL-10 and TGF-β in the hippocampus and cortex of CMS-treated mice, and normalized their elevated plasma CORT levels, whereas administration of imipramine did not significantly affect the imbalance between pro- and anti-inflammatory cytokines in the hippocampus and cortex of CMS-treated mice. Finally, administration of SalB significantly decreased CMS-induced apoptosis and microglia activation in the hippocampus and cortex, whereas administration of imipramine had no significant effect on CMS-induced apoptosis and microglia activation in the hippocampus and cortex.. SalB exerts potent antidepressant-like effects in CMS-induced mouse model of depression, which is associated with the inhibiting microglia-related apoptosis in the hippocampus and the cortex.

Topics: Animals; Apoptosis; Behavior, Animal; Benzofurans; Cerebral Cortex; Corticosterone; Cytokines; Depressive Disorder, Major; Drugs, Chinese Herbal; Gene Expression; Hippocampus; Male; Mice, Inbred C57BL; Microglia; Neuroimmunomodulation; Neurons; Stress, Psychological

Topics: Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Vilazodone Hydrochloride

Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day.. The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time.. Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: -3.2 [p = 0.001], RCT-1; -2.5 [p = 0.009], RCT-2). Clinical Global Impressions-Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: -0.4 [p = 0.001], RCT-1; -0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52).. Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data.. Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592 ; open-label, long-term study: ClinicalTrials.gov identifier: NCT00644358, http://ClinicalTrials.gov/ct2/show/NCT00644358 .

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Benzofurans; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Double-Blind Method; Female; Follow-Up Studies; Humans; Indoles; Male; Middle Aged; Piperazines; Placebos; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Vilazodone Hydrochloride; Young Adult

Topics: Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Vilazodone Hydrochloride

Major depressive disorder (MDD) affects 121 million people globally and is one of the leading causes of functional disability worldwide. As a recurrent disorder, MDD is associated with significant morbidity and functional disability as well as high direct and indirect costs to the health care system. Although several drug therapies are available for treating MDD, many patients do not achieve a sustained remission. Vilazodone was approved by the United States Food and Drug Administration in 2011 and has a distinctive pharmacology profile, as the drug is a selective serotonin reuptake inhibitor and serotonin 5-HT(1A) receptor partial agonist. In two 8-week, double-blind, placebo-controlled trials, vilazodone's overall rate of response was similar to other antidepressants for the treatment of MDD. Compared with placebo, remission rates were not significantly different in one trial and were not reported in the second trial. Vilazodone was generally well tolerated, with nausea and diarrhea being the most frequent adverse events reported. Postmarketing studies and further active comparative studies will provide additional insight to the potential benefits and safety of this novel drug.

Topics: Animals; Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Vilazodone Hydrochloride

Topics: Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Drug Approval; Humans; Indoles; Piperazines; Selective Serotonin Reuptake Inhibitors; United States; United States Food and Drug Administration; Vilazodone Hydrochloride

Vilazodone hydrochloride belongs to a new class of antidepressants-the indolalkylamines-and has dual activity as a selective serotonin reuptake inhibitor (SSRI) and as a partial agonist of the serotonin 5-HT(1A) receptor. Its antidepressant activity has been demonstrated in two 8-week, double-blind, randomized, placebo-controlled trials and in a 1-year open-label study. None of these trials compared vilazodone with existing antidepressants; however, changes in depressive symptoms after vilazodone treatment were similar to those reported for SSRIs. The most common adverse events were diarrhea and nausea, although these were mild to moderate in severity and rarely a cause for discontinuation. No important clinical changes in vital signs, laboratory values, ECG morphology and sexual function were observed or reported.

Topics: Antidepressive Agents; Benzofurans; Depressive Disorder, Major; Humans; Indoles; Piperazines; Vilazodone Hydrochloride

The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D(1) receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [(11)C]NNC-112, to selectively assess D(1) receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [(11)C]NNC-112 nondisplaceable binding potential (BP(ND)) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean D(1) receptor BP(ND) was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D(1) receptor BP(ND) in this region correlated negatively with illness duration (r=-0.53; p=0.02), and the left-to-right BP(ND) ratio correlated inversely with anhedonia ratings (r=-0.65, p=0.0040). The D(1) receptor BP(ND) was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F=7.33, p=0.01). These data extended a previous finding of decreased striatal D(1) receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D(1) receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior.

Topics: Adolescent; Adult; Basal Ganglia; Benzazepines; Benzofurans; Carbon Radioisotopes; Depressive Disorder, Major; Female; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Receptors, Dopamine D1; Sex Characteristics; Young Adult