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 (HDRS 17 ) score of ≥ 18, HDRS 17 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; 50 mg 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-A 6 , p = 0.51). Efficacy signals (based on prespecified 1-sided p  17 total score, 6-item subscale of HDRS 17 assessing core depressive symptoms [HAM-D 6 ], and Inventory of Depressive Symptomatology [IDS-C 30 ]) and anxiety (HDRS 17 anxiety/somatization factor, IDS-C 30 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.