fpl-15896ar and Depressive-Disorder--Treatment-Resistant

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

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

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