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Original Investigation |

Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression A Randomized Clinical Trial

Jorge A. Quiroz, MD, MBA1; Paul Tamburri, PharmD2; Dennis Deptula, PhD2; Ludger Banken, PhD3; Ulrich Beyer, PhD3; Michael Rabbia, MA4; Nikhat Parkar, MSc5; Paulo Fontoura, MD, PhD6; Luca Santarelli, MD7
[+] Author Affiliations
1Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Basel, Switzerland
2Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York
3Biostatistics, Roche Innovation Center, Basel, Switzerland
4Biostatistics, Roche Product Development, Roche Innovation Center, New York, New York
5Pharmaceutical Research and Early Development, Clinical Development-Operations, Roche Innovation Centre, Welwyn, United Kingdom
6Clinical Development Neuroscience, Roche Innovation Center, Basel, Switzerland
7Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center, Basel, Switzerland
JAMA Psychiatry. 2016;73(7):675-684. doi:10.1001/jamapsychiatry.2016.0838.
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Importance  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.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01437657

Figures in this Article

Figures

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Figure 1.
Flow of Patients During the Study

AE indicates adverse event.

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Figure 2.
Total Score Mean (SEM) Change From Baseline for the Clinician-Rated Montgomery-Åsberg Depression Rating Scale (MADRS), Patient-Rated MADRS, and 16-Item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) (Intent-to-Treat Sample)

MMRM indicates mixed-effects model for repeated measures. Error bars indicate SEMs.

aP < .05 (2-sided, unadjusted for multiple comparisons) for 1.5 mg vs placebo. Only showing day 42 testing.

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