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