Tags

Type your tag names separated by a space and hit enter

Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial.
JAMA Psychiatry 2016; 73(7):675-84JP

Abstract

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.

Authors+Show Affiliations

Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Basel, Switzerland.Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York.Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York.Biostatistics, Roche Innovation Center, Basel, Switzerland.Biostatistics, Roche Innovation Center, Basel, Switzerland.Biostatistics, Roche Product Development, Roche Innovation Center, New York, New York.Pharmaceutical Research and Early Development, Clinical Development-Operations, Roche Innovation Centre, Welwyn, United Kingdom.Clinical Development Neuroscience, Roche Innovation Center, Basel, Switzerland.Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center, Basel, Switzerland.

Pub Type(s)

Clinical Trial
Clinical Trial, Phase II
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

27304433

Citation

Quiroz, Jorge A., et al. "Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: a Randomized Clinical Trial." JAMA Psychiatry, vol. 73, no. 7, 2016, pp. 675-84.
Quiroz JA, Tamburri P, Deptula D, et al. Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2016;73(7):675-84.
Quiroz, J. A., Tamburri, P., Deptula, D., Banken, L., Beyer, U., Rabbia, M., ... Santarelli, L. (2016). Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial. JAMA Psychiatry, 73(7), pp. 675-84. doi:10.1001/jamapsychiatry.2016.0838.
Quiroz JA, et al. Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: a Randomized Clinical Trial. JAMA Psychiatry. 2016 Jul 1;73(7):675-84. PubMed PMID: 27304433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial. AU - Quiroz,Jorge A, AU - Tamburri,Paul, AU - Deptula,Dennis, AU - Banken,Ludger, AU - Beyer,Ulrich, AU - Rabbia,Michael, AU - Parkar,Nikhat, AU - Fontoura,Paulo, AU - Santarelli,Luca, PY - 2016/6/16/entrez PY - 2016/6/16/pubmed PY - 2017/5/10/medline SP - 675 EP - 84 JF - JAMA psychiatry JO - JAMA Psychiatry VL - 73 IS - 7 N2 - 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. SN - 2168-6238 UR - https://www.unboundmedicine.com/medline/citation/27304433/Efficacy_and_Safety_of_Basimglurant_as_Adjunctive_Therapy_for_Major_Depression:_A_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2016.0838 DB - PRIME DP - Unbound Medicine ER -