Comparing the Immune-Genomic Effects of Vilazodone and Paroxetine in Late-Life Depression: A Pilot Study.
ABSTRACT: 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-?B), 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.
Project description: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.
Project description:Vilazodone is a new molecule approved for major depressive disorder (MDD). This report focuses on the efficacy and tolerability of vilazodone for MDD. MEDLINE, EMBASE, and Cochrane Library were searched. A total of 1,930 patients from four trials were included. A significant improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was seen as early as week 2 (P<0.01) in vilazodone-treated patients. The results showed a higher rate of MADRS response with vilazodone compared with placebo (P<0.001). There were also greater improvements in the Hamilton Rating Scale for Anxiety as well as the Clinical Global Impressions (severity of illness and improvement of illness) scores from baseline in vilazodone-treated patients compared to placebo patients (P<0.001). Discontinuation rates due to adverse events were higher with vilazodone than placebo (P=0.0002). The most common adverse events of vilazodone were vomiting, nausea, diarrhea, insomnia, somnolence, dizziness, and dry mouth (P<0.05). Treatment-related effects on sexual function were mild compared to placebo in men (P=0.03). In conclusion, 40 mg/day of vilazodone had a rapid onset of response and showed good improvement in anxiety symptoms as well as good tolerability during short-term treatment (8-10 weeks) for MDD. Further studies should focus on the efficacy and tolerability of vilazodone over a longer duration and should utilize active comparators.
Project description:Vilazodone, a selective and potent 5-HT1A partial agonist and 5-HT reuptake inhibitor, has been approved for treatment of major depressive disorder (MDD) in adults. The primary objective of the study was to compare the efficacy and tolerability of switching to 3 different doses of vilazodone from an equivalent dose range of generic selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in adult subjects with MDD.This was an 8-week, randomized, double-blind, parallel-group, 3-arm trial to compare vilazodone 10 mg/d, 20 mg/d, and 40 mg/d as starting doses. Data were collected from December 2012 to December 2013. There was no washout phase, prior medications were stopped at the baseline visit, and vilazodone was started the next day in adults with MDD (DSM-IV criteria). The 10-mg/d and 20-mg/d dose was increased to 40 mg/d by week 3 and week 1, respectively, and the 40-mg/d initiation dose continued unchanged. The primary efficacy measure was change in Montgomery-Asberg Depression Rating Scale (MADRS) score between the 3 dose groups. The secondary efficacy measures were changes in Clinical Global Impressions-Severity (CGI-S), CGI-Improvement (CGI-I), and Hamilton Anxiety Rating Scale (HARS) scores. Safety measures were obtained by spontaneously reported adverse events, vital signs recording, and laboratory tests. Multivariate tests were used for statistical analysis.Seventy subjects were randomized, and 60 subjects completed the study (n = 20 in each group). Overall, there was a significant reduction in MADRS score from baseline (26.08 ± 1.1) to week 8 (9.86 ± 1.2) in the entire sample (P < .001). Similarly, there was a significant improvement in CGI-S (P < .001), CGI-I (P < .001) and HDRS (P < .001) scores from baseline to the end of the trial. There were no significant differences between the 3 vilazodone dose-initiation groups in changes in MADRS scores (P = .95) or changes in CGI-S (P = .83), CGI-I (P = .51), or HARS scores (P = .61). Dry mouth (n = 55), nausea (n = 10), and diarrhea (n = 5) were the most common side effects, with diarrhea reported in 5 subjects in the 40-mg/d initiation group. No serious adverse events were reported.The present study indicates the potential benefit of switching to vilazodone in patients with MDD who are inadequate responders to SSRIs or SNRIs. There were no meaningful differences in efficacy or tolerability between the 3 different dose-initiation strategies with vilazodone; however, diarrhea appeared to be more frequently reported with the 40-mg/d dose. Given the modest sample size, larger studies are required to confirm our findings.ClinicalTrials.gov identifiers: NCT02015546 and NCT01473381.
Project description: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.
Project description:To examine the efficacy, safety, and tolerability of vilazodone for subjects (aged 18-75 years) with generalized social anxiety disorder.Forty-four subjects with generalized social anxiety disorder (DSM-IV-TR criteria) were randomized to vilazodone or placebo in a 12-week double-blind, flexible-dose trial. Change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) was the primary outcome measure. Secondary outcome measures included response and remission rates and changes in depression and anxiety. Data were collected between November 2012 and April 2014. The study was conducted at a private clinical trials facility in New York, New York.The mean baseline LSAS score was 91.9 (SD = 17.5) and the mean Clinical Global Impressions-Severity scale score was 5.3 (SD = 0.56), indicating marked to severe illness. There were no significant baseline differences in severity of social anxiety between the treatment groups. At the end of treatment, in the intent-to-treat sample (n = 39), the vilazodone group had improved significantly more than the placebo group by 14.3 points on the LSAS (t = 1.80, P = .04, one-tail test) (Cohen d = 0.58).The findings suggest that vilazodone may be a promising treatment for social anxiety disorder. Further study is needed given the limited sample size.ClinicalTrials.gov identifier: NCT01712321.
Project description:Background:Vilazodone is an FDA approved medication used to treat major depressive disorder. The authors describe two cases of accidental vilazodone exposure in toddlers who presented with symptoms similar to amphetamine exposure and also with unexplained positive amphetamine urine immunoassay drug screens. Given a lack of published data on cross-reactivity of vilazodone and its metabolites with drug of abuse screening tests, the authors investigated drug of abuse immunoassay cross-reactivity of vilazodone and metabolites using computational and empirical approaches. Methods:To ascertain the likelihood that vilazodone would cross-react with drug of abuse screening immunoassays, the authors assessed the two-dimensional (2D) similarity of the vilazodone parent molecule and known metabolites to an array of antigenic targets for urine immunoassay drug screens. To facilitate studies of the commercially unavailable M17 metabolite, it was prepared synthetically through a novel scheme. Urine and serum were spiked with vilazodone and M17 into urine (200-100,000 ng/mL) and serum (20-2000 ng/mL) samples and tested for cross-reactivity. Results:Computational analysis using 2D similarity showed that vilazodone and metabolites have generally low similarity to antigenic targets of common drug of abuse screening immunoassays, predicting weak or no cross-reactivity. The M17 metabolite had 2D similarity to amphetamines and tricyclic antidepressants in a range similar to some other compounds exhibiting weak cross-reactivity on these immunoassays. Cross-reactivity testing was therefore performed on two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. However, actual testing of cross reactivity for vilazodone and the M17 metabolite did not detect cross-reactivity for any urine amphetamines screen at concentrations up to 100,000 ng/mL and for a serum tricyclic antidepressants assays at concentrations up to 2000 ng/mL. Conclusion:While the vilazodone metabolite M17 has weak 2D structural similarity to amphetamines and tricyclic antidepressants, the current study did not demonstrate any experimental cross-reactivity with two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. Vilazodone ingestions in young children present a diagnostic challenge in their similarity to amphetamine ingestions and the lack of routine laboratory tests for vilazodone. Further work is needed to understand the metabolic profile for vilazodone in children versus adults.
Project description:Major depressive disorder (MDD) is a serious illness in children and adolescents. Vilazodone is a selective serotonin reuptake inhibitor approved for MDD in adults. This study evaluated the efficacy, safety, and tolerability of vilazodone in adolescent patients, ages 12-17 years, with MDD (NCT01878292).This double-blind, randomized, placebo-controlled, parallel-group, fixed-dose study was conducted at 56 study centers in the United States and was 10 weeks in duration (a 1-week screening period, an 8-week double-blind treatment period, and a 1-week double-blind down-taper period). Outpatients with an MDD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria were included in the study. Clinical inclusion criteria required a Children's Depression Rating Scale-Revised (CDRS-R) total score of ? 40 and Clinical Global Impressions-Severity (CGI-S) score of ? 4. Patients were randomized 1:1:1 to 8 weeks of double-blind treatment with placebo (n = 174), vilazodone 15 mg/day (n = 175), or vilazodone 30 mg/day (n = 180). The primary and secondary efficacy parameters were change from baseline to week 8 in CDRS-R total score and CGI-S score, respectively. Safety parameters included adverse events (AEs); clinical laboratory, vital sign, and electrocardiogram parameters; and the Columbia-Suicide Severity Rating Scale.Approximately 86% of patients completed double-blind treatment. There was no statistically significant difference between vilazodone 15 mg/day or 30 mg/day and placebo in change from baseline in CDRS-R score. Change in CGI-S score was not significant after adjustment for multiple comparisons. The most common treatment-emergent AEs were nausea, upper abdominal pain, vomiting, diarrhea, nasopharyngitis, headache, and dizziness. Reports of suicidal ideation (placebo, 33.3%; vilazodone 15 mg/day, 36.0%; vilazodone 30 mg/day, 31.1%) and suicidal behavior (placebo, 1.8%; vilazodone 15 mg/day, 1.1%; vilazodone 30 mg/day, 1.1%) were similar between treatment groups. There were no deaths in the study.The efficacy of vilazodone for the treatment of MDD in adolescent patients could not be confirmed in this study. Vilazodone was generally safe and well tolerated, with treatment-emergent AEs similar to those in adult patients.NCT01878292.
Project description:To investigate vilazodone, currently approved for major depressive disorder in adults, for generalized anxiety disorder (GAD).Three randomized, double-blind, placebo-controlled studies showing positive results for vilazodone (2,040 mg/d) in adult patients with GAD (DSM-IV-TR) were pooled for analyses; data were collected from June 2012 to March 2014. Post hoc outcomes in the pooled intent-to-treat population (n = 1,462) included mean change from baseline to week 8 in Hamilton Anxiety Rating Scale (HARS) total score, psychic and somatic anxiety subscale scores, and individual item scores; HARS response (? 50% total score improvement) and remission (total score ? 7) at week 8; and category shifts, defined as HARS item score ? 2 at baseline (moderate to very severe symptoms) and score of 0 at week 8 (no symptoms).The least squares mean difference was statistically significant for vilazodone versus placebo in change from baseline to week 8 in HARS total score (-1.83, P < .0001) and in psychic anxiety (-1.21, P < .0001) and somatic anxiety (-0.63, P < .01) subscale scores; differences from placebo were significant on 11 of 14 HARS items (P < .05). Response rates were higher with vilazodone than placebo (48% vs 39%, P < .001), as were remission rates (27% vs 21%, P < .01). The percentage of patients who shifted to no symptoms was significant for vilazodone on several items: anxious mood, tension, intellectual, depressed mood, somatic-muscular, somatic-sensory, cardiovascular, respiratory, and autonomic symptoms (P < .05).Treatment with vilazodone versus placebo was effective in adult GAD patients, with significant differences between treatment groups found on both psychic and somatic HARS items.ClinicalTrials.gov identifiers: NCT01629966, NCT01766401, NCT01844115.
Project description: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.
Project description:Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double-blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction.