New GABA Modulator Promising in Depression

Batya Swift Yasgur, MA, LSW

September 06, 2019

SAGE-217, a novel modulator of γ-aminobutyric acid–A (GABAA), reduced depressive symptoms in patients with major depression in a new study.

Investigator compared patients who had major depression and were treated with SAGE-217 to patients who received lacebo for a 2-week period.

They found that a larger percentage of patients in the SAGE-217 group demonstrated a response to the treatment or remission, compared to those in the placebo group. There were no serious or severe adverse events.

"In this trial of SAGE-217, patients who received SAGE-217 reported significantly greater reduction in depression symptoms from baseline at day 15, compared to patients who received placebo," lead author Handan Gunduz-Bruce, MD, senior medical director, Medical Science, Sage Therapeutics, Cambridge, Massachusetts, told Medscape Medical News.

The study was published online September 5 in the New England Journal of Medicine.

Different Mechanism

"Despite availability of a number of antidepressants for many decades, depression continues to be one of the major causes of disability worldwide," Gunduz-Bruce said.

"GABA is a major inhibitory neurotransmitter in the brain and has been implicated in the pathophysiology of depression," she continued.

She explained that the mechanism of action of SAGE-217 differs from those of available antidepressants that target the monoaminergic system (ie, serotonin, noradrenalin, and dopamine).

"SAGE-217 is a neuroactive steroid and an allosteric modulator of GABAA-type receptors, and it increases the function of the GABAA receptor without directly stimulating the receptor," she explained.

SAGE-217, which is synthetically produced and is taken orally, was previously studied in an open-label, uncontrolled, 14-day pilot trial in which patients with major depressive disorder (MDD) received treatment for a 14-day period.

"The results suggested that SAGE-217...may be associated with a rapid onset of action," the authors note.

In the current trial, patients aged 18 to 65 years who had moderate to severe MDD were assigned to receive either 30 mg of SAGE-217 or placebo for a 14-day period (n = 45 and n = 44, respectively).

Demographics for participants in the treatment and the placebo groups were similar, although there was a larger number of men in the treatment group (44% vs 32%), the patients in the treatment group were older than those in the placebo group (mean age, 49.1 ± 13.6 vs 38.3 ± 12.2), and there was a larger percentage of black individuals in the treatment group (80% vs 28%).

Most patients in both the treatment group and the placebo group (96% and 91%, respectively) reported having had previous depressive episodes. In addition, 27% of patients in the treatment group were receiving antidepressants at baseline, as compared with 23% in the placebo group.

The primary endpoint was the change in the 17-item Hamilton Depression Rating Scale (HAM-D) from baseline to day 15. Secondary endpoints included the change from baseline in HAM-D score on days 2 to 8 and on days 15, 21, 28, 35, as well as reduction from baseline of >50% on the HAM-D score.

Significant Improvement

The baseline mean score on the HAM-D was 25.2 for SAGE-217 group, compared to 25.7 for the placebo group.

There was a significant difference in the least-squares mean change from baseline in the HAM-D between the treatment group and the placebo group on day 15 (for the SAGE-17 group, −17.4 ± 1.3 points; for the placebo group, −10.3 ± 1.3 points; least-squares mean difference in change, −7.0; 95% confidence interval, −10.2 to −3.9; P < .001).

Sensitivity analyses that accounted for missing data yielded similar findings.

The percentage of patients who demonstrated a reduction of <50% from baseline in the HAM-D score at day 15 was 79% for the treatment group, vs 41% for the placebo group.

The percentage of patients whose HAM-D score of ≤7 at day 15 was 64% in the treatment group, vs 26% in the placebo group.

SAGE-217 continued to show superior results to placebo at day 28: the percentage of patients with a reduction of > 50% from baseline in the HAM-D was 62% vs 46%, respectively, and the percentage of patients with a HAM-D score of ≤7 was 52% and 28%, respectively.

Patients in the SAGE-217 group were given fewer antidepressants during the follow-up period, compared to those in the placebo group (three vs 11 patients, respectively).

No serious adverse events or deaths occurred during the trial, although the percentage of patients who had ≥1 adverse event during the treatment period was higher in the treatment group than in the placebo group (53% vs 45%, respectively).

Headache, dizziness, nausea, and somnolence were the most common adverse events reported by patients in the treatment group.

"Among patients with moderate-to-severe major depressive disorder, treatment with SAGE-217 for 14 days resulted in a reduction in depressive symptoms, as assessed on the basis of the change in the HAM-D score from baseline to day 15, and of changes in secondary endpoint assessments that also were generally in the same direction as those of the primary outcome," the authors summarize.

They note that limitations of the trial "include the small sample size, lack of adjustment of multiplicity in the testing of secondary endpoint results, limited diversity in racial representation among participants, and power to detect changes in depression severity only at day 15, and not through the entire follow-up period."

"Promising Pharmacologic Strategy"

Commenting on the study for Medscape Medical News, Mónica Flores-Ramos, PhD, of the Instituto Nacional de Psiquiatria Ramón de la Fuente Muñiz, Mexico, who was not involved with the study, said that the "authors show the efficacy and safety of using the new drug in patients who were or were not taking antidepressants in the baseline" and that the findings "provide hope for a promising pharmacologic strategy for symptoms remission."

Including patients with "this characteristic implies that the new drug could be used for patients who have not had an adequate response to treatment but also could be used as monotherapy for depression," she said.

She considers the potential use of this agent "especially useful" in women, "in whom it has been observed that neurosteroids have a crucial role on depression symptoms, particularly in some periods related to hormonal fluctuation."

Moreover, she noted, "Depression is more frequent in women than in men."

The effect of SAGE-217 "should be explored on women with dysphoric premenstrual disorder and perimenopausal depression," she suggested.

In an accompanying editorial, Emil Coccaro, MD, of the Department of Psychiatry and Behavioral Neuroscience, Pritzker School of Medicine, University of Chicago, noted that the trial "did not include patients with treatment-resistant depression, and whether SAGE-217 is efficacious in a large proportion of patients with major depressive disorder in a population that includes this group is not known."

Moreover, although SAGE-217 "represents an exciting conceptual development in new agents for major depressive disorder, only time will tell whether positive allosteric modulators of GABAA receptors will enter the pharmacopeia of agents that are effective for major depressive disorder," he writes.

Gunduz-Bruce added, "We are conducting several clinical trials in MDD, including a larger clinical trial that also examines the efficacy of a lower-dose SAGE-217 and 12-month-long clinical trials that include repeated 2-week treatment periods with SAGE-217."

The study was supported by Sage Therapeutics. Gunduz-Bruce reports receiving personal fees and other fees from Sage Therapeutics outside the submitted work. In addition, she has a pending patent application, Neuroactive Steroids and Their Methods of Use. The other authors' disclosures are listed on the original article. Coccaro has received grants from the National National Institute of Mental Health and the National Institute on Alcohol Abuse and Alcoholism; personal fees from the journal UptoDate, personal fees from Brackett, Inc, personal fees and other fees from Azevan Pharma, Inc, and personal fees from Avanir Pharma, Inc, outside the submitted work. Flores-Ramos has disclosed no relevant financial relationships.

New Engl J Med. Published online September 5, 2019. Abstract, Editorial

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