Next-day residual effects of flibanserin on simulated driving performance in premenopausal women.

OBJECTIVE: The objective of this study was to determine the next-day residual effects of acute and steady-state nighttime dosing of flibanserin on simulated driving performance and cognitive function in healthy premenopausal women. METHODS: In this randomized, double-blind, placebo-controlled, four-way crossover study, 72 subjects were treated with either acute oral doses of placebo, zopiclone 7.5 mg (positive control) or flibanserin 100 mg at bedtime (indicated therapeutic dose), or after chronic nightly oral doses of flibanserin 100 mg for 1 week followed by a single bedtime dose of flibanserin 200 mg (supratherapeutic dose). Simulated driving assessments were conducted 9 hr after dosing and cognitive function tests were administered immediately before or during the driving assessment. RESULTS: Zopiclone increased standard deviation of lateral position (≥3.1 cm; p < .0001) relative to placebo and impaired other parameters previously shown to be sensitive to sedation. No impairment was detected for flibanserin at either dose relative to placebo. Flibanserin 200 mg was similar to the 100-mg dose on cognitive testing and driving performance even though commonly reported adverse events for flibanserin were predictably increased at the higher dose. CONCLUSIONS: At both therapeutic and supratherapeutic doses, flibanserin did not impair next-day driving performance and cognitive function compared to placebo.

A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance.

N-methyl-D-aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment-resistant major depressive disorder. This phase I, randomized, multicenter, placebo-controlled, five-period, crossover, single-dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60-min 100-km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10-min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p < 0.02). Rapastinel 900 and 1800 mg did not significantly affect simulated driving performance compared to placebo (both p > 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p < 0.002); ketamine significantly impaired driving compared to placebo (p = 0.0001). Results for the additional measures were similar to the primary end point. No new safety signals were observed for any study interventions. This first study of rapastinel effects on simulated driving found that rapastinel 900 and 1800 mg did not impair driving performance, but ketamine 0.5 mg/kg resulted in significantly impaired driving performance. Ketamine's effects on driving were maintained for at least 105 min, indicating that clinicians should be vigilant to prevent or postpone driving in patients after ketamine treatment.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

A double-blind, placebo-controlled study of selegiline transdermal system in depressed adolescents.

OBJECTIVE: A randomized, double-blind, placebo-controlled flexible-dose, parallel group trial was conducted at 26 clinical investigational sites in the United States to examine the safety and efficacy of the selegiline transdermal system (STS) (EMSAM®) in adolescents (ages 12-17 years) meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for moderate to severe major depressive disorder (MDD) without psychotic features. METHODS: Adolescents (n=308) with moderate to severe MDD were randomized to either STS (n=152) or placebo (n=156). Two hundred and fifteen (69.8%) subjects completed the study and 17 (5.5%) reported discontinuation because of adverse events (AEs). The primary efficacy outcome measure was the mean change from baseline to end of study (week 12 last observation carried forward [LOCF]) in the Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary outcome measures included end-point Clinical Global Impressions - Severity (CGI-S) and Clinical Global Impressions - Improvement (CGI-I). RESULTS: Patients on STS or placebo had a significant decline from baseline (p<0.001) on their CDRS-R total score with mean reductions±SD as follows: STS 21.4±16.6; placebo 21.5±16.5. Both groups had similar response rates (58.6% vs. 59.3%) defined as CGI-I of 1 or 2 at study end. However, these between-group efficacy findings were without statistical significance. The overall incidence of reported AEs was 62.5% for STS-treated patients and 57.7% for placebo-treated patients. Most commonly reported AEs in STS or placebo groups were application site reactions (STS=24.3%; placebo=21.8%), headache (STS=17.1%; placebo=16.7%), and nausea (STS=7.2%; placebo=7.7%). Treatment groups did not differ on any laboratory parameters, vital signs, or electrocardiogram (ECG) findings. No suspected hypertensive crises were reported in the trial. CONCLUSIONS: These data demonstrated that the STS was safe and well tolerated in this adolescent sample. However, both STS-treated and placebo-treated subjects demonstrated a decline from baseline in depressive symptoms (CDRS-R total score) over the length of the study, without statistical superiority by either group.