Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.

Attrition in randomized controlled clinical trials: methodological issues in psychopharmacology.

Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.

Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia.

STUDY OBJECTIVES: Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled 28-day parallel-group study. SETTING: Eleven sleep centers in Germany. PATIENTS: One hundred sixty-one patients with primary insomnia. INTERVENTIONS: Patients received vestipitant (15 mg) or placebo for 28 days; 2-night polysomnographic assessment occurred on nights 1/2 and 27/28. MEASUREMENTS AND RESULTS: Wake after sleep onset (WASO) was improved on nights 1/2 and 27/28 (ratio, vestipitant versus placebo [95% confidence interval]: 0.76 [0.65, 0.90], P = 0.001 and 0.79 [0.65, 0.96], P = 0.02, respectively), demonstrating maintenance of the effect following repeated dosing. Latency to persistent sleep was shorter with vestipitant on nights 1/2 (P = 0.0006 versus placebo), but not on nights 27/28. Total sleep time (TST) improved with vestipitant (nights 1/2: P < 0.0001, nights 27/28: P = 0.02 versus placebo). Next-day cognitive function tests demonstrated no residual effects of vestipitant (P > 0.05 versus placebo). Adverse events (AEs) occurred in 25% of vestipitant patients versus 22% for placebo. Headache was the most common AE (8% of vestipitant patients versus 9% for placebo). CONCLUSIONS: Vestipitant improved sleep maintenance in patients with primary insomnia, with no associated next-day cognitive impairment. The effects on wake after sleep onset and total sleep time were maintained following repeated dosing.

Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.

Anthropometry of the human scaphoid.

PURPOSE: Internal fixation has become a well-established alternative to casting for acute scaphoid fractures. Screw design has evolved, and several different types of screws of varying sizes are now available. The purpose of this study was to establish morphometric data for the human scaphoid, document variation in scaphoid dimensions between genders, and to evaluate symmetry in scaphoid measurements between the two sides. METHODS: We measured length, width, and morphology of the scaphoid in 30 paired cadaveric specimens with reference to the long axis of the scaphoid from the proximal pole to the distal articular surface. The width of the bone was compared with diameters of commercially available screws. RESULTS: When measured along an axis from proximal pole to the distal articular surface, male scaphoids (31.3 mm +/- 2.1) were significantly longer than female specimens (27.3 mm +/- 1.7). The male scaphoid was also significantly wider than the female specimen when measured perpendicular to the long axis 2 mm from the proximal pole (4.5 mm +/- 1.4 vs 3.7 mm +/- 0.5) and at the waist (13.6 mm +/- 2.6 vs 11.1 mm +/- 1.2). There was no significant difference in the distal pole diameter measured 2 mm from the tip between genders (7.2 mm +/- 1.0 vs 7.2 mm +/- 1.2). The diameters of most commercially available standard screws were larger than the proximal pole of the female scaphoid. CONCLUSIONS: Allowing for countersinking of the screw 2 mm beneath either pole, our data suggest the usual screw length will be 27 mm and 23 mm for male and female scaphoids, respectively. The small width of the proximal pole of the female scaphoid will not accommodate standard-sized screws from most manufacturers, and consideration must be given to distal to proximal screw placement or use of "mini" screws if the implant is to be inserted in a proximal to distal direction.