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 (GABA
A) 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
Pu Adjustable Girl Bag Green Handbag Small Mini Blue Cute Leather Shoulder Lovely Vovotrade® TUxatZU, 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.
To read this article in full you will need to make a payment
Purchase one-time access
Or purchase The Lancet Choice
Access any 5 articles from the Lancet Family of journals
Subscribe to The Lancet
Already a print subscriber?
Claim online access
Already an online subscriber?
Sign in
Register:
Create an account
Institutional Access:
Sign in to ScienceDirect
References
Perinatal depression: a systematic review of prevalence and incidence.
Obstet Gynecol. 2005; 106:
1071-1083
Trends in postpartum depressive symptoms-27 States, 2004, 2008, and 2012.
MMWR Morb Mortal Wkly Rep. 2017; 66:
153-158
Non-psychotic mental disorders in the perinatal period.
Lancet. 2014; 384:
1775-1788
Incorporating recognition and management of perinatal and postpartum depression into pediatric practice.
Pediatrics. 2010; 126:
1032-1039
Migration and perinatal mental health in women from low- and middle-income countries: a systematic review and meta-analysis.
BJOG. 2017; 124:
742-752
Heterogeneity of postpartum depression: a latent class analysis.
Lancet Psychiatry. 2015; 2:
59-67
The costs of perinatal mental health problems.
London School of Economics,
London;
2014
https://www.nwcscnsenate.nhs.uk/files/3914/7030/1256/Costs_of_perinatal_mh.pdf
Date accessed: August 15, 2018
Risks of all-cause and suicide mortality in mental disorders: a meta-review.
World Psychiatry. 2014; 13:
153-160
All-cause mortality in women with severe postpartum psychiatric disorders.
Am J Psychiatry. 2016; 173:
635-642
Postnatal depression and its effects on child development: a review of evidence from low- and middle-income countries.
Br Med Bull. 2012; 101:
57-79
Depression during pregnancy: a risk factor for adverse neonatal outcomes? A critical review of the literature.
J Matern Fetal Neonatal Med. 2014; 27:
960-967
Prenatal depression and adverse birth outcomes: an updated systematic review.
Matern Child Health J. 2015; 19:
1306-1337
Arctic Shoulder Bag Animal 010 Fox Shoulder Arctic Arctic Bag Bag Fox Animal Animal Shoulder Fox 010 Postpartum depression effects on early interactions, parenting, and safety practices: a review.
Infant Behav Dev. 2010; 33:
1-6
Effects of postnatal depression on mother-infant interactions, and child development.
in:
Bremner JG , Wachs TD (Eds.)
Handbook of infant development. 2nd edn.
Wiley-Blackwell,
Malden;
2010:
192-220
Association of persistent and severe postnatal depression with child outcomes.
JAMA Psychiatry. 2018; 75:
247-253
Psychopathology and parenting: an examination of perceived and observed parenting in mothers with depression and PTSD.
J Affect Disord. 2017; 207:
242-250
Maternal depression during pregnancy and the postnatal period: risks and possible mechanisms for offspring depression at age 18 years.
JAMA Psychiatry. 2013; 70:
1312-1319
Effects of perinatal mental disorders on the fetus and child.
Lancet. 2014; 384:
1800-1819
Treatment of postpartum depression in mothers: Secondary benefits to the infants.
Infant Ment Health J. 2008; 29:
492-513
Antenatal and postnatal mental health: clinical management and service guidance.
Primary care screening for and treatment of depression in pregnant and postpartum women: evidence report and systematic review for the US Preventive Services Task Force.
JAMA. 2016; 315:
388-406
Screening for depression in adults: US Preventive Services Task Force Recommendation Statement.
JAMA. 2016; 315:
380-387
Patient's views on depression care in obstetric settings: how do they compare to the views of perinatal health care professionals?.
Gen Hosp Psychiatry. 2013; 35:
598-604
Treating perinatal depression: risks and stigma.
Obstet Gynecol. 2014; 124:
653-654
The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.
Psychol Med. 2017; 47:
787-799
Antidepressant treatment for postnatal depression.
Cochrane Database Syst Rev. 2014; 9 (CD002018.) (
CD002018.)
Antidepressants for preventing postnatal depression.
Backpack Unisex Adult Jansport Jansport Superbreak Bomb Black Label Unisex Dye v0ExBZ6qw
Cochrane Database Syst Rev. 2018; 4 (CD004363.) (
CD004363.)
The perinatal depression treatment cascade: baby steps toward improving outcomes.
J Clin Psychiatry. 2016; 77:
1189-1200
Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice.
Psychoneuroendocrinology. 2017; 90:
182-193
GABA(A)R plasticity during pregnancy: relevance to postpartum depression.
Neuron. 2008; 59:
207-213
The reciprocal regulation of stress hormones and GABA(A) receptors.
Front Cell Neurosci. 2011; 6:
4
Postpartum psychiatric disorders.
Nat Rev Dis Primers. 2018; 4:
18022
Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
Science. 1986; 232:
1004-1007
Lower allopregnanolone during pregnancy predicts postpartum depression: an exploratory study.
Psychoneuroendocrinology. 2017; 79:
116-121
Neuroactive steroids.
FASEB J. 1992; 6:
2311-2322
Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients.
J Clin Endocrinol Metab. 2000; 85:
2429-2433
Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.
Lancet. 2017; 390:
480-489
Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV).
American Psychiatric Press,
Washington, DC;
1996
Bag Animal Shoulder Fox Bag Animal Animal Shoulder 010 Arctic Arctic Shoulder Bag Fox Fox 010 Arctic A rating scale for depression.
J Neurol Neurosurg Psychiatry. 1960; 23:
56-62
Antenatal risk factors for postnatal depression: a large prospective study.
J Affect Disord. 2008; 108:
147-157
Perinatal major depression biomarkers: a systematic review.
J Affect Disord. 2016; 193:
391-404
Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression.
Hum Psychopharmacol. 2017; 32:
e2576
ECDEU assessment manual for psychopharmacology.
US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs,
Rockville, MD;
1976
A new depression scale designed to be sensitive to change.
Br J Psychiatry. 1979; 134:
382-389
The Hamilton depression scale. Evaluation of objectivity using logistic models.
Acta Psychiatr Scand. 1981; 63:
290-299
Exactly what does the Hamilton depression rating scale measure?.
J Psychiatr Res. 1993; 27:
259-273
Psychopathological dimensions of depression: a factor study of the 17-item Hamilton depression rating scale in unipolar depressed outpatients.
J Affect Disord. 2002; 68:
41-47
Improving the assessment of severity of depressive states: a reduction of the Hamilton Depression Scale.
Pharmacopsychiatry. 1985; 18Clutch Sequins Bag Rhinestone Purse Peacock Evening C Women's Embroidery Beaded WqpUwvTTn0:
114-115
Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale.
Br J Psychiatry. 1987; Arctic Bag Arctic Animal Animal Shoulder Arctic Bag Fox Shoulder 010 Fox Bag Shoulder Animal 010 Fox 150:
782-786
Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire.
JAMA. 1999; 282:
1737-1744
A brief measure for assessing generalized anxiety disorder: the GAD-7.
Arch Intern Med. 2006; 166:
1092-1097
The Columbia-Suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.
Am J Psychiatry. 2011; 168:
1266-1277
Quest for timely detection and treatment of women with depression.
J Manag Care Pharm. 2007; 13:
S3-S11
Relative sensitivity of the Montgomery-Asberg Depression rating scale, the Hamilton Depression rating scale and the Clinical Global Impressions rating scale in antidepressant clinical trials.
Int Clin Psychopharmacol. 2002; 17:
281-285
A randomized, placebo-controlled, double-blind trial of sertraline for postpartum depression.
Psychopharmacology. 2014; 231:
939-948
Pharmacotherapy of postpartum depression: an update.
Expert Opin Pharmacother. 2014; 15:
1223-1234
Postpartum depression: a randomized trial of sertraline versus nortriptyline.
J Clin Psychopharmacol. 2006; 26:
353-360
Diagnostic and statistical manual of mental disorders: DSM-5.
5th edn.
American Psychiatric Association,
Washington, DC;
2013
Rates of maternal depression in pediatric emergency department and relationship to child service utilization.
Gen Hosp Psychiatry. 2004; 26:
316-322
Maternal depression and filicide-case study of ten mothers.
Arch Womens Ment Health. 2008; 11:
201-206
Placebo response in studies of major depression: variable, substantial, and growing.
JAMA. 2002; 287:
1840-1847
Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987–2013.
World Psychiatry. 2017; 16:
181-192
Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review.
Neuropsychopharmacology. 2012; 37:
851-864
Article Info
Publication History
Published: August 31, 2018
IDENTIFICATION
Copyright
© 2018 Elsevier Ltd. All rights reserved.
ScienceDirect
Access this article on ScienceDirectRelated Specialty Collection
This article can be found in the following collections: