benzofurans and Sexual-Dysfunction--Physiological

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

  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 of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies.. We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats.. The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 μM for norepinephrine, and 136.9 μM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats.. The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.

Topics: Animals; Benzofurans; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Ejaculation; Male; Neurotransmitter Uptake Inhibitors; Norepinephrine Plasma Membrane Transport Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Adrenergic; Receptors, Dopamine; Receptors, Muscarinic; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Sexual Dysfunction, Physiological; Symporters