title: Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression.
abstract: This phase 2a, randomized, multicenter, double-blind, proof-of-concept study was designed to evaluate, efficacy, safety and tolerability of JNJ-40411813/ADX71149, a novel metabotropic glutamate 2 receptor positive allosteric modulator as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. Eligible patients (18-64 years) had a DSM-IV diagnosis of MDD, Hamilton Depression Rating Scale-17 (HDRS17) score of ≥ 18, HDRS17 anxiety/somatization factor score of ≥ 7, and an insufficient response to current treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. The doubly-randomized, 8-week double-blind treatment phase was comprised of two 4-week periods, from which a combined test statistic was generated, with pre-determined weights assigned to each of the 2 treatment periods. Period 1: patients (n=121) were randomly assigned (1:1) to JNJ-40411813 (n=62; 50mg to 150 mg b.i.d, flexibly dosed) or placebo (n=59); Period 2: placebo-treated patients (n=22) who continued to meet entry severity criteria were re-randomized (1:1) to JNJ-40411813 or placebo, while other patients underwent sham re-randomization and continued on their same treatment. Of 121 randomized patients, 100 patients (82.6%) were completers. No efficacy signal was detected on the primary endpoint, the 6-item Hamilton Anxiety Subscale (HAM-A6, p=0.51). Efficacy signals (based on prespecified 1-sided p<0.20) were evident on several secondary outcome measures of both depression (HDRS17 total score, 6-item subscale of HDRS17 assessing core depressive symptoms [HAM-D6], and Inventory of Depressive Symptomatology [IDS-C30]) and anxiety (HDRS17 anxiety/somatization factor, IDS-C30 anxiety subscale). Although well-tolerated, the results do not suggest efficacy for JNJ-40411813 as an adjunctive treatment for patients with MDD with significant anxious symptoms in the dose range studied.
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA. Electronic address: jkent@its.jnj.com.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Kent
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Ella
authors.initials: E
authors.lastname: Daly
authors.affiliation: ID Statsol, Antwerp, Belgium.
authors.forename: Iva
authors.initials: I
authors.lastname: Kezic
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Lane
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Lim
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Heidi
authors.initials: H
authors.lastname: De Smedt
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Boer
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Nueten
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Ceusters
mesh_terms: D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D011728:Pyridones / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D010880:Piperidines; D011728:Pyridones; D017367:Selective Serotonin Reuptake Inhibitors; C000594993:1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone
keywords: Anxiety; JNJ-40411813; Major depressive disorder; Metabotropic glutamate receptor-2; Positive allosteric modulator