Novel Agent Falls Short of Expectations for Major Depression

Nancy A. Melville

July 14, 2016

Basimglurant (F. Hoffmann-La Roche Ltd), a novel agent targeting the cortical glutamatergic system, showed mixed results in the adjunctive treatment of major depressive disorder in a phase 2b clinical trial, failing to achieve its primary endpoint but showing some signs of efficacy in secondary outcome measures.

"We could not find any effect of adjunctive basimglurant MR [modified release] on the a priori primary outcome of clinician-reported MADRS [Montgomery-Åsberg Depression Rating Scale]," write the authors, led by Jorge A. Quiroz, MD, of Translational Medicine Neuroscience at the Roche Innovation Center, Cambridge, Massachusetts.

"However, adjunctive basimglurant 1.5 mg MR daily showed an antidepressant effect across secondary end points, particularly in patient-rated measures."

The study was published in the July issue of JAMA Psychiatry.

High Placebo Effect Clouding Results?

Basimglurant, an antagonist of the postsynaptic metabotropic glutamate subtype 5 (mGlu5) receptor, has shown some efficacy in preclinical behavioral models. Interest in the drug has been boosted by a stepped-up focus in the past decade of glutamatergic-targeting drugs in general, particularly ketamine, an N-methyl-D-aspartate (NMDA) channel-blocking agent, for the treatment of depression.

The double-blind clinical trial included 333 adults diagnosed with major depressive disorder who were randomly assigned to 6 weeks of treatment with one or two doses of basimglurant MR, 0.5 or 1.5 mg, or placebo once daily as an adjunct to treatment with antidepressant therapy with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

The mean age of the patients was 47 years; 47% were women. The patients were described has having had an inadequate response to one to three adequate courses of antidepressant treatment.

The study's primary endpoint, a mean change in clinician-rated MADRS score from baseline to the end of treatment on day 42, was not achieved (-14.6 in the placebo arm, -14.1 in the 0.5-mg basimglurant MR arm, and -16.1 in the 1.5-mg basimglurant MR arm; P = .42).

There were no significant differences between groups in the proportion of patients who experienced remission (a reduction of 10 or more in the total score) or response (a 50% or more reduction in total score) on the clinician-rated MADRS.

There were some notable improvements in secondary and exploratory endpoints, however, with patients in the 1.5-mg basimglurant MR group having nominal but larger improvements compared with patients receiving placebo in patient-rated MADRS (P = .04) and patient-rated Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16; P = .009), as well as in Clinical Global Impression–Improvement and Patient Global Impression–Improvement mean scores.

In the 1.5-mg group, the patient-rated MADRS remission rate was also somewhat improved (36.0% vs 22.0%; nominal P = .03), as was the response rate, to a lesser degree (50.5% vs 40.4%; nominal P = .13). No benefits were seen with the patients receiving the 0.5-mg dose.

The most common adverse event was dizziness, which was described as mostly transient and mild.

The authors note that a relatively high placebo response may have clouded the drug's true effects, as is common factor in antidepressant trials.

"The presence of a high placebo response during the trial may have undermined the ability of this trial to detect a significant statistical difference between the placebo and active treatment arms for the primary end point of clinician-rated MADRS," they write.

As underscored in a previous meta-analysis of adjunctive therapies for depression, the inflated placebo effect in antidepressant trials is a very common problem: "Excessive placebo response is the most challenging obstacle for the development of new treatments in this patient population," the authors of this article write.

Basimglurant's mechanisms make it a potentially favorable alternative to ketamine in the pursuit of antiglutamatergic therapies, appearing to be safe and well tolerated in combination with SSRI or SNRIs.

"The postsynaptic colocalization of NMDA receptors and metabotropic glutamate subtype 5 (mGlu5) receptors in cortical and limbic regions and the downstream effects of mGlu5 receptor blockade down-regulating NMDA function provide a strong rationale for the potential antidepressant effect of mGlu5 receptor antagonism," the authors note.

"Given the concerns regarding the clinical use of ketamine, including psychogenetic effects and potential for addiction, mGlu5-negative allosteric modulators become an even more attractive target for the development of novel antidepressants."

They add that the results in the primary outcome could further reflect shortcomings in the MADRS in the assessment of antiglutamatergic therapies.

"In this context, MADRS was originally designed to detect the treatment effect of monoaminergic antidepressants, resulting in the exclusion of items that may be relevant to treatment effects emerging from therapeutics with a different mechanism of action," the authors assert.

The clinician-rated and patient-rated QIDS-SR16 measures may be more appropriate for evaluating the array of symptom domains relevant to the diagnosis of an MDD episode, they argue.

"In fact, in this study, improvements were observed on the QIDS-SR16 items of hypersomnia and general interest (P = .03 and .04, respectively) and feeling slowed down and energy levels (P = .08 and .09, respectively), suggesting that this scale covers relevant symptoms of depression not adequately addressed in the MADRS."

More Research Warranted

Commenting on the findings for Medscape Medical News, Gerard Sanacora, MD, PhD, of the Department of Psychiatry, Yale University, in New Haven, Connecticut, echoed the possibility of the need for different instruments to accurately assess antiglutamatergic drugs.

"It may not be appropriate to employ the same rating scales that were originally developed to assess the effects of classical antidepressant, mainly TCAs [tricyclic antidepressants], at the time the scales were conceived as the primary assessment tool for the potentially unique characteristics of this novel class of medications," he said.

For instance, important measures not included in the standard MADRS scores and scores on the Hamilton Rating Scale for Depression include subjective wellness, positive affect, and global quality of life.

He emphasized, however, that "this is just speculation, and it would require future studies that are specifically designed and adequately powered to address these other outcome measures."

Dr Sanacora, who also authored an accompanying editorial, noted that lackluster results from recent studies of other glutamatergic-targeting drugs, such as AZD6765 (lanicemine, an NMDA-receptor antagonist), have fueled some dissent and even a "crisis in confidence" among some in the field regarding the viability of the glutamatergic system as a target for drug development.

"Part of the problem is the fact that there is a very high 'nonspecific' response in these studies," he said, noting the exceptionally high placebo response.

"This is probably due to a number of factors, including expectation, changes in study design, and unique aspects of subject enrollment."

However, he noted, the high placebo response with basimglurant does not necessarily negate the effect seen in the 1.5-mg treatment group.

"In this study specifically, the fact that the medication did show an effect on many of the secondary measures, despite the extremely high placebo response rate, may actually suggest that there is some clinical meaningfulness.

"The data leave us unable to draw any firm conclusions regarding the efficacy of basimglurant in the adjunctive treatment of depression but clearly suggest that future studies are warranted," he said.

The study was funded by F. Hoffman-La Roche Ltd, and the authors are employees of the company. Dr Sanacoras has relationships with Allergan, Alkermes, AstraZeneca, BioHaven Pharmaceuticals, Hoffman La-Roche, Janssen, Merck, Naurex, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, and Vistagen Therapeutics. He holds shares in BioHaven Pharmaceuticals Holding Company and is a coinventor on the patent "Glutamate Agents in the Treatment of Mental Disorders" (patent 8778979).

JAMA Psychiatry. 2016;73:651-652, 675-684. Abstract, Editorial

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