title: Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.
abstract: Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.
authors.affiliation: Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA. kari.nations@mail.utexas.edu
authors.forename: Kari R
authors.initials: KR
authors.lastname: Nations
authors.forename: Peter
authors.initials: P
authors.lastname: Dogterom
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.forename: Jacques
authors.initials: J
authors.lastname: Schipper
authors.forename: Scott
authors.initials: S
authors.lastname: Greenwald
authors.forename: David
authors.initials: D
authors.lastname: Zraket
authors.forename: Lev
authors.initials: L
authors.lastname: Gertsik
authors.forename: Jack
authors.initials: J
authors.lastname: Johnstone
authors.forename: Allen
authors.initials: A
authors.lastname: Lee
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Pande
authors.forename: Ge
authors.initials: G
authors.lastname: Ruigt
authors.forename: Larry
authors.initials: L
authors.lastname: Ereshefsky
mesh_terms: D000328:Adult; D000494:Allosteric Regulation; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D018091:Receptors, AMPA / Q000378:metabolism*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; C545643:Org 26576; D018091:Receptors, AMPA; D019382:Human Growth Hormone; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D006854:Hydrocortisone