REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial.

Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.

A double-blind, placebo-controlled, parallel-group, flexible-dose study of venlafaxine extended release capsules in adult outpatients with panic disorder.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of venlafaxine extended release (ER) in short-term treatment of panic disorder. METHOD: In this multicenter, double-blind study, conducted from April 2001 to December 2002, 343 adult outpatients who met criteria for panic disorder (with and without agoraphobia) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were randomly assigned to flexible-dose venlafaxine ER (75-225 mg/d) or placebo for 10 weeks (N = 155 per group, intent-to-treat population). The primary outcome measure was the percentage of panic-free patients as assessed using the Sheehan Panic and Anticipatory Anxiety Scale. Key secondary measures included the Panic Disorder Severity Scale (PDSS) score and Clinical Global Impressions-Improvement (CGI-I) scale response (score = 1 or 2). Last-observation-carried-forward data were analyzed, and statistical significance was set at p

A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder.

RATIONALE: Few randomized, placebo-controlled trials have evaluated the comparative efficacy and tolerability of more than one pharmacological agent for panic disorder. OBJECTIVES: The primary objective of this study was to compare the efficacy and tolerability of venlafaxine extended release (ER) with placebo in treating panic disorder. Secondary objectives included comparing paroxetine with venlafaxine ER and placebo. METHODS: Outpatients aged > or =18 years (placebo, n = 157; venlafaxine ER 75 mg, n = 156; venlafaxine ER 225 mg, n = 160; paroxetine, n = 151), with a primary diagnosis of panic disorder (+/-agoraphobia) based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for > or =3 months were randomly assigned to receive venlafaxine ER (titrated to 75 mg/day or 225 mg/day), paroxetine (titrated to 40 mg/day), or placebo for 12 weeks. The primary efficacy measure was the percentage of patients free of full-symptom panic attacks (> or = four symptoms) at endpoint. Key secondary outcomes included the Panic Disorder Severity Scale (PDSS) mean score change and response. RESULTS: At endpoint, all active treatment groups showed a significantly (P < 0.01) greater proportion of patients free of full-symptom panic attacks, compared with placebo, and were superior (P < 0.05) on most secondary measures. The venlafaxine ER 225 mg group had significantly (P < 0.05) greater mean PDSS score improvement than the paroxetine group (-12.58 vs -11.87) and a significantly higher proportion of patients free of full symptom panic attacks (70.0 vs 58.3%). Both drugs were generally well tolerated. CONCLUSION: Venlafaxine ER 75 mg/days and 225 mg/days and paroxetine 40 mg/day were both well tolerated and effective for short-term treatment of panic disorder.

Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release.

OBJECTIVE: To compare the long-term efficacy of venlafaxine extended release (ER) with placebo in preventing panic disorder relapse in out-patient treatment responders. METHOD: Outpatients aged > or = 18 years who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for panic disorder with or without agoraphobia for at least the previous 3 months, with > or = 6 full symptom panic attacks in the 2 weeks prior to screening and > or = 3 in the 2 weeks before baseline and a Clinical Global Impressions-Severity of Illness rating > or = 4 at screen were eligible to participate. Outpatients received flexible-dose (75-225 mg/day) venla-faxine ER for 12 weeks. Treatment responders were randomly assigned to venlafaxine ER or placebo for 26 weeks. Criteria for response were < or = 1 panic attack per week during the last 2 weeks of open-label treatment and a Clinical Global Impressions-Improvement score of 1 or 2. The primary endpoint, time to relapse during double-blind treatment, defined as > or = 2 full symptom panic attacks per week for 2 consecutive weeks or discontinuation due to loss of effectiveness, was evaluated using Kaplan-Meier survival analysis. The study was conducted between December 2001 and August 2003. RESULTS: The intent-to-treat population had 291 patients in the open-label phase and 169 in the double-blind phase (placebo, N = 80; venlafaxine ER, N = 89; mean daily dose 165-171 mg). Time to relapse was significantly longer with venlafaxine ER than placebo (p < .001). All secondary measures of panic attack treatment efficacy, quality of life, and disability were significantly better with venlafaxine ER than placebo (p < or = .005). CONCLUSION: Venlafaxine ER was safe, well tolerated, and effective in preventing relapse in outpatients with panic disorder.

Sleep and residual sedation after administration of zaleplon, zolpidem, and placebo during experimental middle-of-the-night awakening.

STUDY OBJECTIVES: To assess the efficacy of zaleplon 10 mg and zolpidem 10 mg administered during experimental middle-of-the-night awakenings in patients with sleep-maintenance insomnia using objective polysomnographic measures and to assess daytime residual sedation 4 to 7 hours after dosing using sleep-latency testing. DESIGN: A randomized, double-blind, placebo-controlled, 3-period, crossover design was used to study 37 adults with insomnia who received treatment during an experimental awakening 4 hours after bedtime. Latency to persistent sleep and total sleep time before and after awakening were recorded. The primary residual sedation measure was a sleep latency test conducted hourly from 4 to 7 hours after treatment. Self-report measure of alertness and concentration and digit symbol substitution tests were examined concurrently. SETTING: Sleep disorders centers. PATIENTS: Thirty-seven adults with sleep-maintenance insomnia. INTERVENTIONS: Zaleplon 10 mg, zolpidem 10 mg, or placebo. MEASUREMENTS AND RESULTS: Thirty-one patients had efficacy-evaluable data; 37 patients received at least 1 dose of study medication and were included in the safety analysis. Compared with placebo, latency to persistent sleep after both zaleplon and zolpidem was shorter and total sleep time after administration of the drugs was longer (overall p < .001, Dunnett p < .001 for all posthoc comparisons). Significant differences from placebo were not found with zaleplon in daytime-sedation measures. At 4, 5, and 7 hours after zolpidem, sleep onset on sleep latency testing was shorter than after placebo (overall p < .001 for all, Dunnett tests for posthoc comparisons p < .001, p < .001, p < .05, respectively). Self-report measures of concentration (4, 5, and 6 hours, overall p < .05, Dunnett p < .05 for each time point) and alertness (4 hours, overall p < .05, Dunnett p < .05), and Digit Symbol Substitution Test scores (4 and 5 hours, overall p < .001, Dunnett p < .01 for both time points) after zolpidem were also lower than with placebo. CONCLUSIONS: Zaleplon 10 mg and zolpidem 10 mg effectively shorten sleep latency and lengthen sleep duration after dosing, when administered during experimental nocturnal awakening. Residual sedation was not detected as little as 4 hours after zaleplon 10 mg, whereas residual sedation was detected with zolpidem 10 mg up to 7 hours after treatment. These findings suggest that zaleplon may be an appropriate treatment for use when patients awaken during the night and have difficulty reinitiating sleep.

A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder.

BACKGROUND: Generalized social anxiety disorder is a debilitating psychiatric illness characterized by maladaptive thoughts about social situations. This double-blind study evaluated the anxiolytic efficacy, safety, and tolerability of venlafaxine extended release (ER) in adult out-patients with generalized social anxiety disorder. METHOD: Patients were randomly assigned to receive 12 weeks of treatment with a flexible dose of venlafaxine ER (75 to 225 mg/day) or placebo. The Liebowitz Social Anxiety Scale (LSAS) total score was the primary efficacy variable. Secondary efficacy variables included scores on the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, Social Phobia Inventory (SPIN), and LSAS subscales. Response was defined as a CGI-I score of 1 or 2. Two definitions of remission were used: LSAS total score < or = 30 and CGI-I score of 1. RESULTS: Data from 271 patients (intent-to-treat population) were analyzed for efficacy; 279 patients were analyzed for safety. Overall, 173 patients completed the study. Improvement on the LSAS was significantly greater with venlafaxine ER treatment than with placebo at weeks 6 through 12 (p < .05, weeks 6 and 8; p < .01, week 10; and p < .001, week 12) and at weeks 8 through 12 based on CGI-S and SPIN scores. Week 12 response and remission (LSAS score < or = 30) rates were significantly greater in the venlafaxine ER group than in the placebo group (response: 44% vs. 30%, respectively, p = .018; remission: 20% vs. 7%, respectively, p < .01). Patients experienced no unexpected or serious adverse events. CONCLUSION: Venlafaxine ER is safe, well tolerated, and efficacious in the short-term treatment of generalized social anxiety disorder.

Long-term use of sedative hypnotics in older patients with insomnia.

BACKGROUND AND PURPOSE: Insomnia is a common problem that increases with age and can last months to years. While substantial data establish the efficacy and safety of short-acting hypnotic therapy for the management of short-term insomnia using benzodiazepines receptor agonists (BzRAs), there are few studies on the continued efficacy and safety of these drugs when used for sustained periods. This paper reports the results of a 1-year open-label extension phases of two randomized, double-blind trials of zaleplon. PATIENTS AND METHODS: In the open-label phase, older patients self-administered zaleplon nightly from 6 to 12 months and were then followed through a 7-day single-blind placebo-controlled run-out period. RESULTS: The safety profile in this population of older adults was similar to that observed in a short-term trial of an equivalent population. The data also suggested that long-term therapy produced and maintained statistically significant improvement in time to persistent sleep onset, duration of sleep and number of nocturnal awakenings (P<0.001 for each variable) for treatment durations of up to 12 months. Discontinuation was not associated with rebound insomnia. CONCLUSION: The open-label trial of long-term hypnotic therapy with zaleplon 5 and 10 mg suggests that they are safe and effective for the treatment of insomnia in older patients. Placebo-controlled, double-blind trials are needed in zaleplon and other BzRAs to confirm these results.

Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial.

RATIONALE: There is a need for new pharmacological treatments for generalized social anxiety disorder (GSAD), which is a common, often disabling condition. OBJECTIVE: To compare the efficacy and safety over 6 months duration of two dose ranges of venlafaxine extended-release (ER) with placebo in patients with GSAD. METHOD: Twenty-eight-week, double-blind, multi-center study in 386 adult outpatients with DSM-IV GSAD. Patients were randomized to placebo, venlafaxine ER fixed low dose (75 mg/day), or venlafaxine ER flexible higher dose (150-225 mg/day). Primary efficacy variable was change on the Liebowitz Social Anxiety Scale (LSAS). Secondary efficacy variables included, among others, the proportion of responders on the CGI Global Improvement Item (score 1 or 2), and the proportion of remitters (defined as an LSAS score of

A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder.

Venlafaxine extended release (ER) is a dual serotonin-norepinephrine reuptake inhibitor previously shown to be effective in the treatment of major depressive disorder and generalized anxiety disorder. This placebo-controlled, multicenter, randomized, double-blind trial examined the efficacy and safety of venlafaxine ER in outpatients with generalized social anxiety disorder. Two hundred seventy-two outpatients were randomly assigned to receive either a flexible dose of venlafaxine ER (75 to 225 mg/d) or placebo for 12 weeks. Venlafaxine ER was statistically significantly more effective than placebo as demonstrated by the Liebowitz Social Anxiety Scale total scores at weeks 4 to 12. Scores of both the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales showed that venlafaxine ER was significantly more effective than placebo at weeks 4 to 12. In addition, more venlafaxine ER-treated patients achieved CGI-Improvement scores of 1 or 2 than placebo-treated patients at weeks 4 to 12, demonstrating a greater percentage of responders to venlafaxine ER treatment. Assessment using the fear/anxiety and avoidance subscales of the Liebowitz Social Anxiety Scale and the Social Phobia Inventory Scale also showed venlafaxine ER to be more effective than placebo at weeks 4 to 12 and 6 to 12, respectively. The Sheehan Disability Inventory showed that patients in the venlafaxine ER-treated group had significantly better outcomes in social life at weeks 4 and 12, and in work at week 12. Adverse events were similar to those reported in studies of venlafaxine ER in depression and generalized anxiety disorder. Venlafaxine ER was safe, well tolerated, and efficacious in the short-term treatment of generalized social anxiety disorder.

Efficacy of Venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine.

This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n = 434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p < 0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia.

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.

Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects.

BACKGROUND: Insomnia is a very common symptom, particularly in the elderly. Thus, all hypnotic medications should be carefully evaluated in the elderly population. Zaleplon, a new nonbenzodiazepine hypnotic with a short elimination half-life (approximately 1 hour), was evaluated in the current study. METHOD: This multicenter, randomized, placebo-controlled outpatient study evaluated the efficacy and safety of zaleplon, 5 and 10 mg, in elderly patients with insomnia (as defined by DSM-IV); zolpidem, 5 mg, was the active comparator. Sleep was assessed in 549 elderly patients (>/= 65 years old) by using morning questionnaires completed after each of 7 baseline nights during which placebo was given, 14 nights of double-blind treatment, and 7 nights of placebo after discontinuation of active treatment. RESULTS: Zaleplon, 10 mg, and zolpidem, 5 mg, significantly reduced sleep latency during both weeks of the study. Zaleplon, 5 mg, reduced sleep latency only during week 2. Sleep duration was increased with zolpidem, 5 mg, during weeks 1 and 2 and with zaleplon, 10 mg, during week 1. No clinically significant rebound insomnia was observed after discontinuation of treatment with zaleplon, whereas evidence of rebound effects was seen with zolpidem. There was no significant difference between either zaleplon dose and placebo in the frequency of any central nervous system adverse events. CONCLUSION: Zaleplon is effective in reducing latency to sleep without evidence of undesired effects in elderly patients with insomnia.