Vilazodone in the treatment of major depressive disorder: efficacy across symptoms and severity of depression.

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.

A 1-year, open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder.

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.

A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder.

OBJECTIVE: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00683592.

Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00285376.

The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are highly efficacious antidepressants, but safety concerns have limited their broad use. METHODS: We reviewed key safety and tolerability data from all clinical trials of patients with major depressive disorder (MDD) accrued during the clinical development of the selegiline transdermal system (STS), as reported to the Food and Drug Administration. This review includes data from both controlled and uncontrolled clinical trials involving STS-treated (n=2036) and placebo-treated (n=668) patients. RESULTS: Except for the initial trial, subsequent trials, which involved STS doses ranging from 3 mg/24 h to 12 mg/24 h, lacked tyramine restrictions, and no acute hypertensive reactions occurred during study treatment. Safety experience with STS 6 mg/24 h supports this therapeutic dose without tyramine dietary modifications, but until more data are available for STS doses 9 mg/24 h and 12 mg/24 h, foods that are rich sources of tyramine should be avoided. The principal side effects of STS therapy were local dermal reactions and insomnia, both of which were dose-related. Side effects associated with MAOI treatment, such as sexual dysfunction and excessive weight gain, were uncommon. CONCLUSIONS: A comprehensive review of safety from the clinical development program suggests that the STS is safe and well tolerated, with an improved safety margin compared with orally administered MAOIs.

Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials.

OBJECTIVE: Given the concern that mortality rates may be increased in geriatric patients exposed to atypical antipsychotic agents, we assessed mortality rates for adult patients with schizophrenia assigned to an investigational antipsychotic (olanzapine, quetiapine, risperidone, or ziprasidone), a control antipsychotic (haloperidol or chlorpromazine), or placebo in preapproval clinical development programs to assess relative risk with atypical antipsychotics as compared to typical antipsychotics or placebo. METHOD: We reviewed safety data (from clinical trials conducted from approximately 1982 to 2002) for 16,791 adult patients with schizophrenia (DSM-III or DSM-IV criteria) in U.S. Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports for 6 antipsychotic drugs. Mortality rates were calculated for each treatment group (investigational agent, active control, or placebo) on the basis of patient exposure years (PEY) and gross mortality. We compared the differences in mortality rates between placebo and investigational agents, active controls, and all antipsychotic drugs combined using odds ratios. RESULTS: By PEY analysis, the mortality rate for patients assigned to placebo treatment was significantly higher (p < .05) than for either the investigational antipsychotic (OR = 0.23, 95% CI = 0.13 to 0.45) or the active control group (OR = 0.19, 95% CI = 0.08 to 0.45). Although rates based on gross mortality were also higher with placebo treatment, statistical significance was only seen when comparing patients assigned to placebo with those assigned to the active control antipsychotic group (OR = 0.35, 95% CI = 0.15 to 0.82). CONCLUSIONS: Despite reported excess mortality with antipsychotic use in elderly patients with dementia, SBA data did not reveal a similar increased risk of antipsychotics in adult patients with schizophrenia. However, methodological limitations of the FDA SBA reports may affect the generalizability of these findings.

Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.

OBJECTIVE: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). METHODS: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. RESULTS: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. CONCLUSIONS: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.

Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial.

OBJECTIVE: This study investigated the efficacy, safety, and tolerability of the selegiline transdermal system (STS) administered in a dose range of 6 mg/24 hours to 12 mg/24 hours for treating major depressive disorder (MDD). METHOD: Patients meeting DSM-IV criteria for MDD (N = 265) were randomly assigned to blinded treatment with STS or a matching placebo patch for 8 weeks. Patients failing to meet or maintain protocol-defined therapeutic response criteria at predetermined time points had their STS (or placebo) dose increased. Assessments were conducted at weeks 1, 2, 3, 5, 6, and 8. Patients were not required to follow a tyramine-restricted diet. The study ran from September 2001 through August 2002. RESULTS: Selegiline transdermal system treatment resulted in significantly greater improvement (p < or = .05) compared with placebo treatment on the 3 depression rating scales: the 28-item Hamilton Rating Scale for Depression (HAM-D28) (primary outcome measure), the Montgomery-Asberg Depression Rating Scale, and the Inventory for Depressive Symptomatology-Self Rated. The treatment effect measured by the HAM-D28 was modest, primarily due to insomnia side effects. The antidepressant efficacy of STS was substantiated further by the significantly greater improvement in core depression symptoms (HAM-D Bech-6 subscale). The side effects of highest incidence were application site reactions and insomnia. There were no safety concerns based on routine clinical laboratory and electrocardiogram monitoring, and there were no occurrences of hypertensive crisis. CONCLUSION: Results of this double-blind, placebo-controlled, dose titration trial provide evidence of short-term efficacy, safety, and tolerability of STS in the dose range of 6 mg/24 hours to 12 mg/24 hours for treatment of MDD. Selegiline transdermal system has an improved margin of safety compared with oral monoamine oxidase inhibitors and represents a useful addition to the existing array of antidepressants.

A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone.

BACKGROUND: Gepirone, a 5-HT(1A) receptor agonist, has been assessed for use in the treatment of anxiety and depressive disorders. Azapirones, including gepirone, act to maintain neurotransmission at 5-HT(1A) receptors. OBJECTIVE: The aim of this article was to review the pharmacology and clinical data for gepirone extended-release (ER) and immediate-release (IR) formulations for the treatment of major depressive disorder (MDD). METHODS: Articles were identified by searching MEDLINE (1966 to present) using the search term gepirone. The reference list retrieved was reviewed for relevant clinical articles. RESULTS: Initial placebo-controlled clinical trials demonstrated that gepirone IR improved symptoms of depression; however, the short half-life of gepirone necessitated frequent administration, and high peak plasma concentrations at higher doses were associated with an increased incidence of adverse events. An ER formulation of gepirone reduced peak-to-trough fluctuations in plasma concentration while maintaining total drug exposure similar to that seen with the IR formulation; the evidence further suggested that lower peak plasma concentrations resulted in fewer adverse events. In clinical trials, both formulations significantly improved symptoms of depression. However, by permitting the use of higher doses of gepirone, the ER formulation had better efficacy and was less likely to produce adverse events (eg, lightheadedness, nausea, dizziness). CONCLUSION: Several clinical trials have suggested that gepirone ER formulations have significant antidepressant effects and better tolerability than gepirone IR formulations when used to treat MDD.

Monoamine oxidase inhibitors: a new generation.

Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of psychopharmacology in the 1950s, have remained useful in the treatment of depression despite important safety concerns, such as acute hypertensive episodes brought on by ingestion of foods with high-tyramine content. Experience has shown that MAOIs are broadly effective in the treatment of depressive disorders, including atypical, chronic, and double depressions. Newer selective and reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO) enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been shown to be effective in the treatment of depression at higher oral doses where selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first-pass metabolism and avoids impairment of the gastrointestinal barrier provided by MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline transdermal system (STS) does not significantly affect sensitivity to ingested tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has been found to be efficacious in the treatment of patients with major depression in placebo-controlled trials, without the need for dietary precautions. The favorable safety profile of STS should allow this MAOI to be a broadly used antidepressant drug.