Elsevier

The Lancet

Volume 392, Issue 10152, 22–28 September 2018, Pages 1058-1070
The Lancet

Articles
Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials

https://doi.org/10.1016/S0140-6736(18)31551-4Get rights and content

Summary

Background

Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression.

Methods

We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18–45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20–25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2).

Findings

Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference −5·5 [95% CI −8·8 to −2·2], p=0·0013 for the BRX60 group; −3·7 [95% CI −6·9 to −0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference −2·5 [95% CI −4·5 to −0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related.

Interpretation

Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder.

Funding

Sage Therapeutics, Inc.

Introduction

Post-partum depression is the most common complication of childbirth and can result in considerable suffering for mothers, children, and families.1, 2 Post-partum depression is estimated to affect 10–20% of women who give birth worldwide, and occurs in low-income, middle-income, and high-income countries.1, 2, 3, 4 Approximately 40–80% of cases of post-partum depression are considered moderate to severe.1, 3, 5, 6 In the USA, the estimated prevalence of post-partum depression in new mothers varies by state from 8–20%, with an overall mean prevalence of 11·5%.2 The public health impact of post-partum depression is substantial; in the UK, the estimated cost per case is £74 000.7 This economic burden is multifactorial, but contributing factors include maternal death from suicide,8, 9 loss of work days due to depression, maternal morbidity and child morbidity associated with impaired mother–infant attachment, and infant malnutrition during the first year of life.1, 10, 11, 12

The underlying mechanisms of impaired mother–infant attachment are likely due to multiple aspects of disrupted parenting, sometimes termed lack of sensitivity, observed in mothers with post-partum depression, including poor responsiveness, poor recognition of infant cues, disengagement and withdrawal, and intrusiveness.13, 14 The degree of parental sensitivity is associated with a child's emotional regulation during infancy, and studies15 suggest that infants of mothers with untreated post-partum depression might demonstrate an increased risk of difficulty with emotional regulation in early life and social behaviour as a consequence of disrupted parenting. This increased risk can continue through adolescence and can be associated with poorer outcomes, including decreased academic performance and increased risk of depression.16, 17, 18 Antidepressant treatment of post-partum depression with a 12 week course of therapy has been associated with improvements in the quality of mother–infant interaction and infant play.19 Increased understanding of the broad impact of post-partum depression has led to an international consensus on the importance of screening and early treatment of post-partum depression.15, 20, 21, 22

The stigma associated with maternal psychiatric illness often prevents mothers from seeking treatment for post-partum depression, and substantial disparities in education, country, race, and ethnicity might restrict access to effective treatment.23, 24, 25 Many women treated for post-partum depression with currently available therapies, such as selective serotonin-reuptake inhibitors (SSRIs), do not achieve adequate response or full remission of symptoms, and the ability of SSRIs to prevent post-partum depression is also unclear.26, 27, 28 To date, no pharmacological therapies have been developed specifically for post-partum depression. Thus, improved pharmacological treatment options are urgently needed.

The hypothalamic-pituitary-adrenal (HPA) axis, perinatal hormonal fluctuations, and γ-aminobutyric acid (GABA) signalling have been implicated in the pathophysiology of post-partum depression, and previous studies29, 30, 31, 32 have identified associations between these potential mechanisms. In mouse models of GABA dysfunction, mice were found to have post-partum depression-like maternal behaviours and defects in HPA axis regulation, indicating an association between GABA and HPA regulation.29 Additionally, plasma concentrations of allopregnanolone, a potent positive allosteric modulator of synaptic and extrasynaptic GABA type A (GABAA) receptors, which is an endogenous progesterone metabolite, decrease considerably following childbirth, indicating an association between perinatal hormonal fluctuations and GABA regulation.33, 34, 35, 36

A soluble, proprietary, β-cyclodextrin-based, intravenous formulation of allopregnanolone—brexanolone injection (formerly SAGE-547 injection)—had rapid and durable antidepressant effects during the study period in our previous double-blind, randomised, phase 2 clinical trial.37 Here, we report the results of two large phase 3, double-blind, randomised, placebo-controlled trials of brexanolone injection in women with moderate to severe post-partum depression. Additionally, integrated results from all three, placebo-controlled trials of brexanolone injection in post-partum depression are presented.

Section snippets

Study design and participants

We did two multicentre, randomised, double-blind, placebo-controlled phase 3 trials at 30 clinical research centres and specialised psychiatric units in the USA under an umbrella protocol that facilitated subsequent integrated data analyses with our previous phase 2 trial,37 which was completed before the initiation of study 1 and 2.

Patients were recruited to clinical research centres and specialised psychiatric units through self-referrals, physician referrals, and radio-based,

Results

Study 1 was done between Aug 1, 2016, and Oct, 19, 2017, and study 2 between July 25, 2016, and Oct 11, 2017. Across both studies, we screened 375 women simultaneously, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2 (figure 1). 25 (18%) of 138 patients discontinued study 1, and eight (7%) of 108 patients discontinued study 2. The most common reasons

Discussion

Women with post-partum depression have an increased risk of morbidity and mortality, and thus additional treatment options are urgently needed.53 The present phase 3, double-blind, randomised, placebo-controlled trials of brexanolone injection in women with moderate to severe post-partum depression HAM-D score ≥20), confirm and extend the findings of our smaller phase 2 study,37 which showed that brexanolone injection reduced depressive symptoms compared with placebo. The HAM-D is considered

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