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Adjunctive basimglurant may improve depressive symptoms in MDD

Adjunctive basimglurant modified-release was not superior to placebo regarding clinician-rated changes in depressive symptoms; however, it did show an antidepressant effect in patient-rated measures.

“Basimglurant is a potent, selective, and safe mGlu5-negative allosteric modulator with good oral bioavailability and long half-life supportive of once-daily administration in humans. It also possesses robust antidepressant and anxiolytic-like properties in preclinical models,” Jorge A. Quiroz, MD, MBA, of the Roche Innovation Center, Basel, Switzerland, and colleagues wrote. “Unpublished data (clinicaltrials.gov, NCT00809562) from a placebo-controlled study in inpatients with treatment-resistant depression treated for 10 days revealed that 0.1-mg to 1.5-mg basimglurant was well-tolerated, with trends of clinical effects warranting further evaluation in a larger, well-powered clinical trial.”

Jorge A. Quiroz

To assess safety and efficacy of basimglurant modified-release as adjunctive therapy to ongoing antidepressant therapy in major depressive disorder (MDD), researchers conducted a phase 2b, double blind, randomized clinical trial among 333 adults with a DSM-IV-TR diagnosis of MDD. Study participants received 0.5 mg or 1.5 mg of basimglurant modified-release or placebo once daily as an adjunct to ongoing selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor treatment. The primary outcome was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline, as rated by a clinician at week 6. Study participants had a mean age of 47 years.

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

Mean change in clinician-rated MADRS scores from baseline to end of treatment was lower in each treatment arm; by –14.6 in the placebo arm, –14.1 in the 0.5 mg basimglurant modified-release arm and –16.1 in the 1.5 mg basimglurant modified-release arm.

Neither active treatment was significantly different from placebo, with an adjusted effect size of –0.05 (P = .74) in the 0.5 mg basimglurant modified-release arm and 0.16 (P = .42) in the 1.5 mg basimglurant modified-release arm.

Post-hoc analysis indicated larger differences between participants who received 1.5 mg of basimglurant modified-release and placebo regarding patient-rated MADRS scores (–16.2 vs. –13.3; P = .04), Quick Inventory of Depressive Symptomatology-Self-Report scores (7.5 vs. 5.8; P = .009), Clinical Global Impression-Improvement mean scores and Patient Global Impression–Improvement mean scores.

Participants who received 1.5 mg of basimglurant modified-release also had improved patient-rated MADRS remission rate (36% vs. 22%; P = .03) and response rate (50.5% vs. 40.4%; P = .13).

The 0.5-mg dose of basimglurant modified-release was not superior to placebo in any of the measures.

The most common adverse event was dizziness, according to researchers.

“The study by Quiroz et al provides intriguing data suggesting that a negative allosteric modulator of the mGlu5 receptor may possess adjunctive antidepressant properties,” Gerard Sanacora, MD, PhD, of Yale University, New Haven, Connecticut, wrote in an accompanying editorial. “This finding adds to the rapidly accumulating studies examining the clinical efficacy of drugs that target the glutamatergic neurotransmitter system in the treatment of depression. However, like several other recent clinical trials, the high rates of placebo response make it difficult to draw any firm conclusions regarding basimglurant’s true clinical efficacy or the future value of developing novel glutamate modulating drugs.” – by Amanda Oldt

Disclosure: Quiroz reports he was an employee of F. Hoffmann-La Roche Ltd during the conduct of the study and may own equity in F. Hoffmann-La Roche Ltd. Sanacora reports receiving consulting fees form Allergan, Alkermes, AstraZeneca, BioHaven Pharmaceuticals, Hoffman La-Roche, Janssen, Merck, Naurex, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, and Vistagen Therapeutics during the last 24 months. He also reports receiving additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co, Johnson & Johnson, Hoffman La-Roche, Merck & Co, Naurex, and Servier during the last 24 months. Free medication was provided to Sanacora for a NIH–sponsored study by Sanofi-Aventis. In addition, he reports holding shares in BioHaven Pharmaceuticals Holding Company and is a coinventor on the patent “Glutamate Agents in the Treatment of Mental Disorders” (patent 8778979). Please see the full study for a list of all authors’ relevant financial disclosures.