fpl-15896ar and Depressive-Disorder--Major

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Phenethylamines; Pyridines

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).

Topics: Adolescent; Adult; Affect; Antidepressive Agents; Cross-Over Studies; Depressive Disorder, Major; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Gyrus Cinguli; Humans; Ketamine; Magnetic Resonance Imaging; Male; Middle Aged; Phenethylamines; Psychiatric Status Rating Scales; Pyridines; Treatment Outcome; Young Adult

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

Topics: Adult; Aged; Animals; Antidepressive Agents; Brain; Cross-Over Studies; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Electroencephalography; Female; Humans; Ketamine; Male; Middle Aged; Phenethylamines; Psychiatric Status Rating Scales; Pyridines; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Treatment Outcome; Young Adult

The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).. In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.. Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.. In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

Topics: Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Phenethylamines; Pyridines; Receptors, N-Methyl-D-Aspartate

Lanicemine (AZD6765) is a low-trapping N-methyl-d-aspartate receptor channel blocker that has demonstrated antidepressant efficacy in three of four clinical studies. The aim of this study was to develop a population pharmacokinetic model describing the concentration vs time profile of intravenously administered lanicemine in healthy subjects and patients with major depressive disorder (MDD) and to use the model to evaluate the impact of demographic and clinical factors and concomitant medication on the pharmacokinetics of lanicemine.. Data were derived from four studies: two Phase I trials in healthy subjects (studies 8 [NCT01069822] and 13 [NCT00785915]) and two Phase II trials in patients with MDD (studies 1 [NCT00491686] and 9 [NCT00781742]). Population pharmacokinetic analysis was performed by nonlinear mixed-effects modelling. The covariates evaluated within the model included sex, race, age and body weight parameters, clinically relevant laboratory measures, and use of concomitant medications. Goodness-of-fit plots, bootstrap and visual predictive checks were conducted to confirm concordance with observed data.. A total of 2531 plasma lanicemine concentrations were available for analysis from 191 healthy subjects and patients with MDD. The pharmacokinetics of lanicemine following intravenous infusion was best described by a two-compartment model with zero-order input and first-order elimination. Mean systemic clearance (CL) was estimated at 9.43 L/h (90% CI 9.12-9.77), central compartment volume of distribution (V1) was 106 L (90% CI 93.7-115), peripheral volume of distribution (V2) was 47.3 (95% CI 39.6-56.6), and intercompartmental clearance (Q) was 75.7 (90% CI 51.8-127). Lean body mass and body surface area had a statistically significant effect on CL and V1, respectively.. The population pharmacokinetic model developed adequately described the clinical observation of lanicemine in patients with MDD and healthy volunteers. Lean body mass and body surface area were identified as covariates that significantly influence the pharmacokinetics of lanicemine.

Topics: Antidepressive Agents; Body Composition; Body Surface Area; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Depressive Disorder, Major; Humans; Infusions, Intravenous; Models, Biological; Phenethylamines; Pyridines; Receptors, N-Methyl-D-Aspartate

Topics: Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Excitatory Amino Acid Antagonists; Female; Humans; Ketamine; Male; Phenethylamines; Pyridines; Receptors, N-Methyl-D-Aspartate