Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial.
OBJECTIVE
Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression.


OBJECTIVE
To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode.


METHODS
In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.5 or 1.5 mg) or placebo once daily, adjunctive to ongoing antidepressant medication therapy (selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor). Patients were enrolled from October 5, 2011, through July 26, 2013.


METHODS
Six-week treatment with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo once daily, adjunctive to ongoing antidepressant medication therapy.


METHODS
The primary end point was the mean change from baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS), as rated by the clinician at week 6. Other measures included patient-rated MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, Clinical Global Impression-Improvement, Patient Global Impression-Improvement, and Clinical Global Impression-Severity Scales and adverse events.


RESULTS
A total of 596 patients were screened, and 333 were randomized into the study (mean [SD] age, 47 [11.2] years; 216 female [65.1%]). The primary end point (mean change in clinician-rated MADRS score from baseline to end of treatment) was not met (effect size [ES] = 0.16, P = .42; intent-to-treat [ITT] mixed-effects model for repeated measures [MMRM] analysis for comparing 1.5-mg basimglurant MR and placebo). Across secondary and exploratory end points, 1.5-mg basimglurant MR revealed larger improvements vs placebo on the patient-rated MADRS (-16.2 vs -13.3, ES = 0.28, nominal P = .04), Quick Inventory of Depressive Symptomatology-Self-Report (-7.5 vs -5.8; ES = 0.37, nominal P = .009), Clinical Global Impression-Improvement mean score, and Patient Global Impression-Improvement mean score. Improvements were also seen in the patient-rated MADRS remission rate (36.0% vs 22.0%; nominal P = .03) and response rate (50.5% vs 40.4%; nominal P = .13), A 0.5-mg dose of basimglurant MR had no benefit over placebo in any of these measures. The most common adverse event was dizziness, which was mostly transient and of mild intensity.


CONCLUSIONS
No difference was observed on the study's primary outcome measure, the clinician-rated MADRS change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Adjunctive 1.5-mg basimglurant MR daily revealed, however, an antidepressant effect across secondary end points, particularly in patient-rated measures. These findings combined with good tolerability warrant further investigation with this compound in depressive disorders.


BACKGROUND
clinicaltrials.gov Identifier: NCT01437657.
Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Basel, Switzerland.
Jorge A
JA
Quiroz
Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York.
Paul
P
Tamburri
Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York.
Dennis
D
Deptula
Biostatistics, Roche Innovation Center, Basel, Switzerland.
Ludger
L
Banken
Biostatistics, Roche Innovation Center, Basel, Switzerland.
Ulrich
U
Beyer
Biostatistics, Roche Product Development, Roche Innovation Center, New York, New York.
Michael
M
Rabbia
Pharmaceutical Research and Early Development, Clinical Development-Operations, Roche Innovation Centre, Welwyn, United Kingdom.
Nikhat
N
Parkar
Clinical Development Neuroscience, Roche Innovation Center, Basel, Switzerland.
Paulo
P
Fontoura
Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center, Basel, Switzerland.
Luca
L
Santarelli
D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010552:Personality Assessment; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; D000928:Antidepressive Agents; D003692:Delayed-Action Preparations; D007093:Imidazoles; D011725:Pyridines