Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia.

BACKGROUND: This is a placebo-controlled multi-national trial of roluperidone, a compound with antagonist properties for 5-HT2A, sigma2, and α1A-adrenergic receptors, targeting negative symptoms in patients with schizophrenia. This trial follows a previous trial that demonstrated roluperidone superiority over placebo in a similar patient population. METHODS: Roluperidone 32 mg/day, roluperidone 64 mg/day, or placebo was administered for 12 weeks to 513 patients with schizophrenia with moderate to severe negative symptoms. The primary endpoint was the PANSS-derived Negative Symptom Factor Score (NSFS) and the key secondary endpoint was Personal and Social Performance scale (PSP) total score. RESULTS: NSFS scores were lower (improved) for roluperidone 64 mg compared to placebo and marginally missing statistical significance for the intent-to-treat (ITT) analysis data set (P ≤ .064), but reached nominal significance (P ≤ .044) for the modified-ITT (m-ITT) data set. Changes in PSP total score were statistically significantly better on roluperidone 64 mg compared to placebo for both ITT and m-ITT (P ≤ .021 and P ≤ .017, respectively). CONCLUSIONS: Results of this trial confirm the potential of roluperidone as a treatment of negative symptoms and improving everyday functioning in patients with schizophrenia. Study registration: Eudra-CT: 2017-003333-29; NCT03397134.

Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms: Results From a Randomized Controlled Trial.

OBJECTIVE: Current dopamine-blocking antipsychotic drugs have little impact on the cognitive deficits associated with schizophrenia. We evaluated whether MIN-101, a molecule that combines sigma-2 antagonism and 5-HT2A antagonism, might improve cognitive deficits in individuals with moderate to severe negative symptoms in schizophrenia. METHODS: Individuals (N = 244) aged 18 to 60 years with stable symptoms of DSM-5-defined schizophrenia and moderate to severe negative symptoms were randomized to placebo (n = 83), MIN-101 32 mg (n = 78), or MIN-101 64 mg (n = 83) in a 12-week, phase 2b, prospective, double-blind, placebo-controlled, parallel-group trial between May 2015 and December 2015. In a post hoc analysis, mean z and T score changes from baseline at 12 weeks of treatment in the cognitive composite score and individual tests on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery were compared between MIN-101 and placebo. RESULTS: A total of 79 patients (95.2%) from the placebo group, 76 (97.4%) from the MIN-101 32 mg group, and 79 (95.2%) from the MIN-101 64 mg group completed the BACS at baseline. The BACS token motor (P = .04), verbal fluency (P = .01), and composite z scores (P = .05) showed significant improvements in the MIN-101 32 mg group compared to the placebo group. At week 4, the clinical improvements from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor showed a significant correlation with improvements from baseline on the BACS composite in the 64 mg group (r = -0.292, P = .020). At week 12, improvement in the PANSS negative factor showed significant correlations with improvements in the BACS composite (r = -0.408, P = .002), Trail Making Test (r = -0.394, P = .003), and verbal memory (r = -0.322, P = .017) for the 64 mg group. CONCLUSIONS: Results suggest a possible benefit of MIN-101 on cognitive performance in individuals with schizophrenia with stable positive symptoms and concurrent clinically significant negative symptoms. TRIAL REGISTRATION: EU Clinical Trials Register identifier: 2014-004878-42​.

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

OBJECTIVE: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. METHOD: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. RESULTS: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. CONCLUSIONS: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Pharmacokinetic profile of SKP-1041, a modified release formulation of zaleplon.

OBJECTIVES: Two investigations aimed to define the pharmacokinetic profile of a modified-release preparation of zaleplon (SKP-1041). METHODS: Protocol SOM001 was a 5-way crossover, double-blind, randomized trial comparing three novel modified-release formulations of zaleplon 15 mg (SKP-1041A, SKP-1041B, SKP-1041C) to placebo and immediate-release zaleplon 10 mg. Protocol SOM002 was a randomized, crossover, open-label trial to compare the pharmacokinetics of SKP-1041B after day and night administration. In SOM001, study drug was administered at 9:00 a.m. (fasted); blood samples were obtained beginning 1 h predose through 12 h postdose. In study SOM002, study drug was administered at 9:00 a.m. or 10:30 p.m.; blood samples were obtained beginning 1 h predose through 12 h postdose. Subjects were 19 (SOM001) and 23 (SOM002) healthy adults between ages 20-46. RESULTS: Dose-normalized total AUCs for modified-release preparations A, B, C and immediate-release zaleplon were not significantly different; peak plasma concentrations were similar for A and B, and both were significantly higher than C. Time to peak plasma concentration for A, B, and C were 4-5 h compared to 1.5 h for immediate-release zaleplon; mean terminal phase half-life was in the range 1-2 h for A, B and immediate-release zaleplon. No significant differences were noted between day and night administration in the SOM002 study. CONCLUSIONS: Zaleplon, 15 mg, in a novel, modified-release formulation (SKP-1041) had a time to peak plasma concentrations at 4-5 h postdose compared to 1.5 h for immediate-release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle-of-the-night awakening.

Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia.

OBJECTIVE: To compare the hypnotic effects of a single dose of a sublingual formulation of zolpidem (Edluar*) 10 mg vs oral formulation (Ambien dagger ) 10 mg by polysomnography (PSG) in DSM-IV primary insomnia patients. Primary objective was to compare the two formulations on sleep induction, measured by latency to persistent sleep (LPS), sleep onset latency (SOL) and latency to stage 1 (ST1L). RESEARCH AND METHODS: This was a randomized, double-blind, two-period, cross-over multi-centre study in which each period comprised two successive PSG recording nights. Treatment was administered when PSG recordings started. Subjective sleep and residual effects were assessed the next morning. RESULTS: Seventy female and male patients aged 19-64 were analysed. Sublingual zolpidem significantly shortened LPS by 34% or 10.3 minutes as compared to oral zolpidem (95% CI: -4.3 min to -16.2 min, p = 0.001). SOL and ST1L were also significantly shortened (p < 0.01). Furthermore the two formulations were comparable in terms of sleep maintenance properties based on total sleep time (TST). The improvement in subjective sleep and next-day residual effects did not differ between the two treatments. Both routes of administration were well tolerated. CONCLUSIONS: The results demonstrate that sublingual zolpidem is superior to an equivalent dose of oral zolpidem in terms of sleep inducing properties in a carefully selected sample of primary insomnia patients.

Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia.

STUDY OBJECTIVES: Long-duration (> or = 6 months) polysomnographic studies of insomnia medications are lacking. This study evaluated the long-term efficacy of ramelteon, a selective MT1/MT2 melatonin-receptor agonist used for insomnia treatment. DESIGN: Six-month, randomized, double-blind, placebo-controlled study. SETTING: Forty-six investigative sites in the United States, Europe, Russia, and Australia. PARTICIPANTS: Four hundred fifty-one adults (age > or = 18 years) with chronic primary insomnia. INTERVENTIONS: Ramelteon, 8 mg, or placebo 30 minutes before bedtime nightly for 6 months. MEASUREMENTS: Sleep was evaluated by polysomnography and morning questionnaires on the first 2 nights of Week 1; the last 2 nights of Months 1, 3, 5, and 6; and Nights 1 and 2 of the placebo run-out. Next-morning residual effects as well as adverse effects and vital signs were recorded at each visit. Rebound insomnia and withdrawal effects were evaluated during placebo run-out. RESULTS: Over the 6 months of treatment, ramelteon consistently reduced latency to persistent sleep compared with baseline and with placebo; significant decreases were observed at Week 1 and Months 1, 3, 5, and 6 (P < 0.05). Ramelteon significantly reduced subjective sleep latency relative to placebo at Week 1, Month 1, and Month 5 (P < 0.05), with reductions nearing statistical significance at Months 3 and 6 (P < or = 0.08). No significant next-morning residual effects were detected during ramelteon treatment. No withdrawal symptoms or rebound insomnia were detected after ramelteon discontinuation. Most adverse events were mild or moderate in severity. CONCLUSIONS: In adults with chronic insomnia, long-term ramelteon treatment consistently reduced sleep onset, with no next-morning residual effects or rebound insomnia or withdrawal symptoms upon discontinuation.

Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia.

STUDY OBJECTIVE: To perform an early evaluation of the efficacy and safety of gaboxadol in the treatment of primary insomnia. METHODS: 26 adults (18-65 years) with DSM-IV criteria for primary insomnia were randomly assigned gaboxadol (5 mg, 15 mg) or placebo in a double-blind, crossover study. After a 3-night polysomnographic (PSG) screen, treatment was administered 30 min before bedtime on 2 consecutive nights during 3 separate sessions including PSG. Efficacy analyses (n = 23) were based on the average of Nights 1 and 2, and compared gaboxadol versus placebo. Baseline was the average of Nights 2 and 3 of the screening session. Both gaboxadol doses significantly (P < 0.05) improved mean total sleep time (mean +/- SD: baseline = 368.0 +/- 51.1 min, 15 mg = 420.3 +/- 24.5 min, 5 mg = 419.8 +/- 20.4 min, placebo = 408.7 +/- 30.4 min). Both gaboxadol doses reduced mean wake after sleep onset, although statistical significance was only achieved with 5 mg (baseline = 61.6 +/- 35.4 min, 15 mg = 38.0 +/- 21.1 min, 5 mg = 34.6 +/- 14.3 min, placebo = 43.4 +/- 22.9 min). Gaboxadol 15 mg also significantly reduced mean latency to persistent sleep (baseline = 55.6 +/- 27.0 min, 15 mg = 23.6 +/- 15.1 min, placebo = 30.0 +/- 19.1 min) and enhanced slow wave duration (baseline = 72.4 +/- 20.8 min, 15 mg = 114.0 +/- 37.5 min, placebo = 93.9 +/- 31.3 min) with no significant effects on REM sleep duration. Patient reports (Leeds Sleep Evaluation Questionnaire) of reduced time to sleep and increased sleep quality showed significant improvement with gaboxadol 15 mg. No next-day residual effects were observed with either dose of gaboxadol (assessed 2 h and 9 h after lights on). All adverse events were mild or moderate. CONCLUSION: Gaboxadol 15 mg was effective and generally well tolerated in the short-term treatment of patients with primary insomnia. Gaboxadol also enhanced slow wave sleep duration and had no significant effects on REM sleep duration. These findings suggest that gaboxadol may be a useful treatment for insomnia.

Sleep microstructure around sleep onset differentiates major depressive insomnia from primary insomnia.

In the present study we investigate whether alterations of sleep propensity or of wake propensity are implicated in sleep initiation disturbances encountered in major depressive insomnia and in primary insomnia. For this purpose, the time course of electroencephalogram (EEG) power density during the period preceding sleep onset and during the first non-rapid eye movement (REM) period was examined in three age and gender matched groups of 10 women and 11 men (healthy controls, primary insomniacs and depressive insomniacs). In contrast to healthy controls and depressive insomniacs, patients with primary insomnia did not experience a gradual decrease of their alpha and beta1 power during the sleep onset period and had a lower delta activity in the 5 min preceding sleep onset. Compared with the two other groups, depressive patients exhibit less dynamic changes in slow wave activity during the first non-REM period. The present results suggest that hyperarousal (high 'Process W') may mainly be implicated in the sleep initiation difficulties of primary insomniacs whereas the homeostatic sleep regulation process seems to be partially maintained. In our major depressed patients, the sleep initiation disturbances appeared to relate to a lower sleep pressure (low 'Process S') rather than to hyperarousal. This study supports the idea that different mechanisms are implicated in sleep disturbances experienced by primary insomniacs and major depressive insomniacs.