Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder.

OBJECTIVE: To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS: This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS: Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS: Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01457677.

The effect of short-term (21-day) orlistat treatment on the physiologic balance of six selected macrominerals and microminerals in obese adolescents.

OBJECTIVES: Orlistat is a gastrointestinal lipase inhibitor used to reduce dietary fat absorption and could be used to treat overweight and obesity in adolescents. The primary objective was to assess whether orlistat has an effect on the physiologic balance of three macrominerals (calcium, phosphorus and magnesium) and three microminerals (iron, zinc and copper). METHODS: This was a 21-day, double-blind, randomized, parallel-group, placebo-controlled mineral balance study conducted in adolescent obese volunteers (BMI >or=85th percentile, adjusted for age and gender). Subjects were maintained on a hypocaloric diet with a normal daily mineral content in both treatment groups and received oral treatment with orlistat 120 mg (n = 16) or placebo (n = 16) three times daily for 21 days. Following a 14-day equilibration period, balances for calcium, phosphorus, magnesium, iron, copper and zinc were measured for days 15-21. Serum and urine electrolytes were also measured at baseline and at the end of treatment. RESULTS: On average, orlistat inhibited dietary fat absorption by approximately 27%. This degree of dietary fat inhibition caused no significant changes in mineral balance between orlistat and placebo groups. In addition, serum and urine electrolytes (sodium and potassium) as well as urinary creatinine excretion were not affected by orlistat treatment. Orlistat was well tolerated; adverse events occurred mainly in the gastrointestinal tract and were of mild or moderate intensities. CONCLUSIONS: Administration of orlistat had no significant effect on the balance of six selected minerals in adolescent obese patients.

Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers.

To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double-blind, placebo-controlled, randomized two-period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 1/3 days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0-infinity, Cmax, tmax, and t 1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one-quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t 1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.

Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects.

To investigate the influence of orlistat on the pharmacokinetics of selected concomitant medications (amitriptyline, atorvastatin, cyclosporine, losartan, metformin, phentermine, and sibutramine) at or within two-fold of therapeutic doses, open-label, multiple-dose (for 6 or 7 days), randomized, two-period (except for cyclosporine, for which a three-way crossover design was used) crossover studies were performed in healthy volunteers ages 18 to 65 years, with a body mass index between 18 and 30 kg/m2. At steady state, blood samples were taken for measuring plasma concentrations of interacting drugs and/or active metabolites. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. Treatments were compared for AUC0-24, Cmax, tmax, and t1/2 of selected concomitant medications (parent drugs and/or active metabolites). ANOVA was performed to assess the significance of the carry-over effect and provide the variance estimate for the 90% confidence intervals (CIs). With the exception of cyclosporine, whose absorption was reduced by approximately one-third, the results of the statistical analysis demonstrated equivalencefor the two primary parameters for all drugs studied: ratios of the log-transformed means for both AUC and Cmax were close to 1.00, with 90% CIs contained entirely within the bioequivalence region of 0.80 to 1.25; there were no clinically significant differences in t1/2 and tmax. There was a higher incidence of adverse events under treatment B (selective concomitant medications and orlistat) than under treatment A (selective concomitant medications alone); most of this difference was due to expected gastrointestinal adverse events known to occur with orlistat. Other adverse events were sporadic and unremarkable. All adverse events were either mild or moderate in intensity. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for cyclosporine, there was no effect of orlistat on the pharmacokinetics of selective concomitant medications when these drugs were taken concomitantly with orlistat.