Key messages
• Compared to placebo (an inactive or 'dummy' medication), zuranolone probably helps more women by reducing their depression symptoms, but also increases the number of harmful, unwanted events they experience.
• Brexanolone may make little or no difference to women's depression symptoms compared to placebo, and probably makes little or no difference to the number of unwanted, harmful events they experience.
• We need studies that compare these medications to traditional antidepressants and talking therapies, and look at longer-term outcomes, to better understand their benefits and harms.
What is postnatal depression?
Postnatal depression (also known as postpartum depression) is depression that starts within a year of a woman having a baby. Many women are affected. It can involve a persistent low mood, loss of interest or pleasure in things once enjoyed, changes in appetite and energy levels, disturbed sleep and low self-confidence. Postnatal depression can have serious short- and long-term effects on the mother, the baby and the whole family.
How is it treated?
There are several ways to treat postnatal depression. These include medication (such as antidepressants), talking therapies or structured support (for example, peer support). The type of treatment offered depends on the woman's choice, how severe the depression is and the presence of other illnesses. In general, women who are pregnant or breastfeeding often worry about the potential unwanted effects of medications on their baby.
Pharmaceutical companies have developed new treatments for postnatal depression that work on specific brain receptors. Brexanolone and zuranolone are two examples. As a group, they are called 'neurosteroid GABAA receptor positive allosteric modulators'. Zuranolone is given as a tablet by mouth ('oral' administration); brexanolone is infused into a vein over 60 hours ('intravenous' administration). These new treatments work faster than traditional antidepressants. However, their benefits and harms are uncertain.
What did we want to find out?
We wanted to understand the benefits and harms of the neurosteroid GABAA positive allosteric modulators, such as brexanolone and zuranolone, for treating women with postnatal depression.
What did we do?
In January 2024, we searched for studies of neurosteroid GABAA positive allosteric modulators for women with postnatal depression. We looked for studies in which women were randomly assigned to take either the medication or a placebo. These studies give the most reliable evidence.
The outcome we focused on was how well the medication worked. This was measured by the number of women who responded well to the treatment ('response') or who no longer met criteria for depression after treatment ('remission'). We also examined whether women and/or their babies experienced unwanted, harmful (also known as 'adverse') effects from the treatment.
What did we find?
We found six studies involving 674 women. Three studies compared (intravenous) brexanolone with a placebo. Another study compared a different intravenous drug from the same family, called ganaxolone, with placebo. Two studies compared (oral) zuranolone with placebo. No study compared these treatments with other medications, treatment as usual (also called 'watch and wait'), talking therapies or other forms of support.
Main results
Intravenous neurosteroid GABAA positive allosteric modulators
• The intravenous medications (brexanolone and ganaxolone) may produce little or no improvements in depression remission, response or severity, compared to placebo.
• There is probably little or no difference in adverse events for the mothers between the intravenous medications and placebo.
• They are probably less acceptable (leading to more women leaving the studies) than placebo.
• The studies did not measure some other outcomes that we were interested in, including quality of life, parenting abilities and effect on the infant.
Oral neurosteroid GABAA positive allosteric modulators
• The oral medication, zuranolone, probably helps more women by reducing their depression symptoms (response and remission) than placebo.
• Zuranolone probably increases the number of maternal adverse events compared to placebo.
• The women may have found zuranolone and placebo to be equally acceptable (roughly the same number of women in each group left the studies early).
• Compared to placebo, zuranolone probably reduces depression severity at 5 to 12 weeks after starting the treatment.
• Zuranolone may improve the mother's parenting abilities compared to placebo.
What are the limitations of the evidence?
Our findings are based on only a few studies conducted up to 45 days after treatment started. Our conclusions may change if more studies are conducted. We need to better understand how these medications compare to other treatments for postnatal depression, including antidepressant medication, in the longer term and also their safety during breastfeeding.
How current is this evidence?
This evidence is current to January 2024.
Read the full abstract
Postnatal depression – depression that occurs up to one year after a woman has given birth – is an important and common disorder that can have short- and long-term adverse impacts on the mother, her child and the family as a whole. Recommended treatment for postnatal depression is psychological therapy, and for more severe depression, antidepressants. However, many antidepressants are associated with limited response. Neurosteroid gamma-aminobutyric acid (GABAA) receptor positive allosteric modulators have been developed for the treatment of depression, including postnatal depression, and have a different mechanism of action than traditional antidepressants.
Objectives
To assess the benefits and harms of brexanolone, zuranolone and related neurosteroid GABAA receptor positive allosteric modulators compared to another active treatment (pharmacological, psychological or psychosocial), placebo or treatment as usual for postnatal depression.
Search strategy
We searched Cochrane Common Mental Disorders' Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO in January 2024. We also searched two international trials registries and contacted experts in the field to identify the studies that are included in the review.
Selection criteria
We included randomised controlled trials (RCTs) of women with depression during the first 12 months following childbirth that compared neurosteroid GABAA receptor positive allosteric modulators with any other treatment (pharmacological, psychological or psychosocial), placebo or treatment as usual.
Data collection and analysis
We used standard Cochrane methodological procedures. The primary outcomes were depression response, depression remission and adverse events experienced by the mother, nursing baby, or both. The secondary outcomes were depression severity, treatment acceptability, quality of life and parenting- and child-related outcomes. We grouped analyses according to whether the neurosteroid GABAA receptor positive allosteric modulator was intravenous or oral. We assessed the certainty of the evidence using GRADE criteria.
Main results
We identified six RCTs (674 women); all were placebo-controlled trials. Three studies tested intravenous brexanolone; one, intravenous ganaxolone; and two studies, oral zuranolone. Sample sizes ranged from 21 to 196. All were conducted in the USA. We judged the risks of selection, performance, detection, attrition and reporting biases to mostly be low, although the risk of selection and attrition bias was unclear in two studies. The biopharmaceutical companies which made the drugs sponsored all six included studies. They appear to have had a considerable role in the design and conduct of the studies.
Intravenous neurosteroid GABAA receptor positive allosteric modulators versus placebo
Low-certainty evidence suggests there may be little or no difference in depression response (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.74 to 2.06; I2 = 78%; 3 studies, 267 women) or remission (RR 1.18, 95% CI 0.59 to 2.38; I2 = 73%; 3 studies, 267 women) at 30 days (classified in this review as the 'early phase' of treatment: between 0 and 5 weeks from commencement of treatment). There is also probably little or no difference in the number of adverse events affecting the mother (RR 1.02, 95% CI 0.71 to 1.48; I2 = 46%; 4 studies, 325 women; moderate-certainty evidence).
There is low-certainty evidence that there may be little or no difference in depression severity (mean difference (MD) -4.22, 95% CI -8.46 to 0.02; I2 = 78%; 3 studies, 267 women) in the early phase (at 30 days following commencement of treatment); Hamilton Rating Scale for Depression (HAMD-17) score range 0 to 52. Moderate-certainty evidence suggests lower acceptability than placebo, leading to study dropout (RR 2.77, 95% CI 1.22 to 6.26; I2 = 0%; 3 studies, 267 women).
No studies measured quality of life or parenting- and child-related outcomes.
Oral zuranolone versus placebo
Moderate-certainty evidence suggests that zuranolone is probably associated with an improvement in depression response (RR 1.26, 95% CI 1.03 to 1.55; I2 = 13%; 2 studies, 349 women) and remission (RR 1.65, 95% CI 1.22 to 2.22; I2 = 0%; 2 studies, 349 women) at 45 days from commencement of treatment. Moderate-certainty evidence also suggests that zuranolone probably increases the rate of maternal adverse events (RR 1.24, 95% CI 1.03 to 1.48; I2 = 0%; 2 studies, 349 women), when all adverse events are considered; the most frequent adverse event was somnolence.
Zuranolone is also probably effective in reducing depression severity at day 45 (MD -3.79, 95% CI -5.60 to -1.97; I2 = 0%; 2 studies, 349 women; moderate-certainty evidence); HAMD-17 score range 0 to 52. Low-certainty evidence suggests little or no difference in terms of treatment acceptability between zuranolone and placebo (RR 0.95, 95% CI 0.50 to 1.81; I2 = 5%; 2 studies, 349 women).
No studies measured quality of life. One study reported the Barkin Index of Maternal Functioning (a validated measure of patient-reported maternal functioning within the first year of childbirth), and found that zuranolone improved maternal functioning at day 45 (MD 7.20, 95% CI 1.42 to 12.98; 153 women), but the certainty of this evidence was low.
Authors' conclusions
This review provides moderate-certainty evidence that zuranolone probably improves depression response and remission but also increases maternal adverse events compared to placebo. There may be little or no difference in depression response and remission and probably little or no difference in maternal adverse events with intravenous neurosteroid GABAA positive allosteric modulators such as brexanolone, compared to placebo. Evidence from this review, alongside current clinical guidelines and reference to evidence from the general adult population, could be used to inform an individualised risk‐benefit discussion with women seeking treatment for postnatal depression. However, it is difficult to make recommendations about the use of neurosteroid GABAA receptor positive allosteric modulators for the treatment of postnatal depression as no studies have compared them to active treatment.
