Zuranolone for the Treatment of Adults With Major Depressive Disorder

Robak,Joshua;Lior Hilsenrath, MD;Abigail Jaeger, MD;Mullen,Mark;Tampi,Rajesh;

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Zuranolone is a positive allosteric modulator of the synaptic and extrasynaptic γ-aminobutyric acid type A (GABA_A) receptor. It is postulated to upregulate GABA_A receptor expression and enhance the inhibitory GABAergic signaling, thereby rapidly restoring network balance within the brain areas that are dysregulated in depression. This phase 3 study evaluated the efficacy, safety, and tolerability of zuranolone 50 mg/day in the treatment of major depressive disorder (MDD) among adults.

To investigate the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the GABAA receptor, for the treatment of MDD.

This study was a randomized, double-blind, placebo-controlled phase 3 clinical trial conducted from May 2020 to April 2021 at 39 sites across the United States. The study participants were otherwise healthy 18- to 64-year-old adults with MDD and a Hamilton Depression Rating Scale (HAM-D) score of greater than or equal to 24 at day 1 of treatment. The participants were randomly assigned in a 1:1 ratio to zuranolone or control groups. The participants self-administered oral zuranolone 50 mg or placebo with fat-containing food for 14 days, with a controlled follow-up period of 28 days for a total study period of 42 days. The primary outcome of this study was the least square means (LSM) change from baseline in HAM-D score at day 15.

A total of 543 individuals were enrolled in the study, with 271 assigned to zuranolone and 272 assigned to placebo. The baseline characteristics for each group were largely similar. Both groups had similar days since the start of current depressive episode (468.2 for zuranolone vs 481.0 for placebo), number of depressive episodes experienced (5.3 for both groups), and severity of depressive symptoms as assessed by HAM-D (26.8 for zuranolone vs 26.9 for placebo). Participants in both groups had similar prior psychotropic use, with one difference being that no participants in the zuranolone group had been prescribed benzodiazepine derivatives in the 6 months prior to screening vs 5 participants in the placebo group.

The primary end point of LSM change from baseline in the HAM-D scores at day 15 was significantly better in the zuranolone group compared with the placebo group (LSM change, –14.1 vs –12.3 [SE = 0.5]; P = .01; Cohen d = 0.23).

The LMS change in the Clinical Global Impressions-Severity (CGI-S) score at day 15 was numerically greater in the zuranolone group vs the placebo group, although this result did not reach statistical significance (–1.8 [SE = 0.1] vs –1.6 [SE = 0.1]; P = .12).

The LMS changes in the HAM-D scores from baseline were statistically significant in the zuranolone group at days 3 (–9.8 [SE = 0.4] vs –6.8 [SE = 0.4]; P < .001; Cohen d = 0.49), 8 (–12.0 [SE = 0.5] vs –9.5 [SE = 0.5]; P < .001; Cohen d = 0.38), and 12 (−13.7 [SE = 0.5] vs −11.2 [SE = 0.5]; P < .001; Cohen d = 0.32) when compared with the placebo group. Although the LMS changes in the HAM-D scores from baseline showed numerical superiority in the zuranolone group when compared with the placebo group at days 21 (−13.3 [SE =0.5] vs −12.1 [SE = 0.5]; P = .09), 28 (−12.6 [SE = 0.5] vs −11.6 [SE = 0.5]; P = .18), 35 (−13.0 [SE = 0.6] vs −12.3 [SE = 0.6]; P = .37), and 42 (−13.5 [SE = 0.6] vs −12.6 [SE = 0.6]; P = .23), these results did not reach statistical significance.

The investigators identified that a greater proportion of individuals in the zuranolone group achieved HAM-D response (≥ 50% reduction in score from baseline) at day 3 (29.3% vs 16.3%; odds ratio [OR] = 2.1; P < .001). Additionally, a greater proportion of individuals in the zuranolone group achieved HAM-D response at day 15 (56.0% vs 47.0%; OR = 1.4; P =.06) and at day 42 (52.9% vs 45.9%; OR = 1.4; P = .09), but these results did not reach statistical significance.

The investigators found improvements in the depressive symptoms at day 15 among the zuranolone group when compared with the placebo group, as measured by the change from baseline in the Montgomery-Åsberg Depression Rating Scale scores (LSM change, −17.5 [SE = 0.8] vs −15.1 [SE = 0.8]; P = .02).

The investigators noted that the remission rates for depression were numerically greater in the zuranolone group at days 15 (29.8% vs 27.1%; OR = 1.1; P = .55) and 42 (30.8% vs 29.6%; OR = 1.1; P = .68), but these results were not statistically significant.

A significantly greater proportion of participants in the zuranolone group had improvements in the CGI-Improvement ratings of “much improved” or “very much improved” at day 15 when compared with the placebo group (62.1% vs 51.0%).

Greater improvements in anxiety symptoms, as assessed by a change in Hamilton Anxiety Rating Scale score at day 15, were noted in the zuranolone group when compared with placebo group (LSM change, –10.4 [SE = 0.4] vs –9.1 [SE = 0.4]; P = .02).

Study Strengths

1. This was a multicenter, randomized, and placebo- controlled clinical study.

2. The participants, clinicians, and study personnel were blinded to treatment allocation for the study.

3. The subgroup analyses were performed, which allowed for further testing of the study hypothesis and provided more information for interpretation.

4. The study outcomes were measured using widely used and accepted assessment scales.

5. This study explores a medication with a novel mechanism of action and looks to improve our current treatment options for MDD.

Treatment-emergent adverse events (TEAEs) occurred in 60.1% of participants receiving zuranolone vs 44.6% of the participants receiving placebo. Most TEAEs were rated as being mild or moderate (95.0% for zuranolone vs 97.5% for placebo). The most common TEAEs were somnolence (15.3% for zuranolone vs 3.0% for placebo), dizziness (13.8% for zuranolone vs 2.2% for placebo), headache (10.8% for zuranolone vs 7.8% for placebo), sedation (7.5% for zuranolone vs 0.4% for placebo), and diarrhea (3.0% for zuranolone vs 5.2% for placebo).

Dose reduction due to TEAEs was required in 23 participants in the zuranolone group and 1 in the placebo group. The most common reasons for dose reduction were dizziness and somnolence with the zuranolone group and fatigue in the placebo group. A total of 9 participants in the zuranolone group discontinued treatment due to TEAEs vs 4 in the placebo group. The most common reasons for treatment discontinuation were dizziness and sedation in the zuranolone group and sedation and somnolence in the placebo group.

Study Limitations

1. The eligibility criteria were strict, and more than 60% of participants in both groups were women.

2. The study did not include follow-up beyond 42 days.

3. The high frequency of study visits is not reflective of normal outpatient psychiatric practice.

There were no deaths, loss of consciousness, weight gain, sexual dysfunction, or euphoria noted in the study participants. A total of 0.7% of the participants in each group experienced serious AEs.

Zuranolone 50 mg/day led to significant improvement in depressive symptoms at day 15 when compared with placebo. The observed effect was rapid, with greater improvement in the HAM-D and CGI-S being observed for zuranolone by day. Improvements in depression and anxiety symptoms were sustained through day 42 for participants taking zuranolone. Overall, zuranolone was well tolerated when compared with placebo.

Zuranolone offers a novel mechanism of action for the treatment of MDD. This study included individuals with severe depressive episodes of long duration. Zuranolone was given with other antidepressants, which suggests it could be used in combination with antidepressants to harness several psychopharmacologic mechanisms simultaneously.

This randomized, placebo-controlled, phase 3 clinical trial showed that a 14-day treatment course of oral zuranolone 50 mg/day in MDD led to significantly greater improvements in depressive symptoms when compared with placebo at day 15, with a rapid onset of effectiveness noted (day 3). The medication was generally well tolerated, with no new safety concerns when compared with previous studies of zuranolone at lower doses.

Dr Robak is a second-year psychiatry resident at Creighton University School of Medicine in Omaha, Nebraska. Dr Hilsenrath is a first-year psychiatry resident at Creighton University. Dr Jaeger and Dr Mullen are fourth-year psychiatry residents at Creighton University. Dr Tampi is professor and chairman in the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut.