There is a need for rapid treatment in postpartum depression, as each month of this potentially severe condition can take a toll on infant development. That is why brexanolone (Zulresso), which was recently fast-tracked for approval by the FDA, is causing such a splash.

Brexanolone is a neurosteroid that activates GABAA receptors. It was originally developed as an anticonvulsant before its antidepressant properties were discovered. The pending approval is based on three randomized, double-blind, placebo-controlled trials involving 267 women with moderate or severe postpartum depression (Meltzer-Brody S et al, Lancet 2018;392:1058–1070). Most were not taking antidepressants. Patients randomized to brexanolone surpassed those on placebo by 2–5 points on the Hamilton Depression Rating Scale. Furthermore, most of the responders (94%) maintained their improvement for 30 days after administration of the medication, which is given as an injection. Women with severe depression saw the greatest improvements. Longer follow-up data are not available, but an oral version of the drug is being developed that could play a role in prevention. The treatment was well-tolerated, with mild increases in headache, dizziness, and somnolence.

Is it just for postpartum depression?
Brexanolone’s mechanism is particularly relevant to the postpartum period, but it plays a role in other psychiatric disorders as well. It is actually a prescription form of allopregnanolone, a neuroactive steroid with known effects in anxiety, depression, aggression, and negative symptoms of schizophrenia in both women and men (Schüle C et al, Prog Neurobio 2014;113:79–87). Basically, brexanolone is to allopregnanolone as levothyroxine is to thyroxine (T4).

Allopregnanolone activates GABAA receptors, the same ones responsible for the anxiolytic effects of benzodiazepines. Its levels rise during pregnancy and then fall abruptly after childbirth. Some women are particularly sensitive to that fall, and the state of GABAergic withdrawal it creates is thought to be one of the pathways to postpartum depression. Allopregnanolone levels also rise and fall during the menstrual cycle, though to a lesser degree, and those fluctuations are thought to contribute to premenstrual dysphoric disorder (PMDD).

In other psychiatric disorders, it is low levels of allopregnanolone rather than fluctuations that appear to play a role. Allopregnanolone is persistently low in major depression, post-traumatic stress disorder, and chronic stress. Several antidepressants raise allopregnanolone levels (SSRIs, tricyclics, and mirtazapine). However, as with most hormones, balance is the issue. Too much allopregnanolone can cause anxiety, depression, and irritability (Bäckström T et al, Prog Neurobiol 2014;113:88–94).

What’s next?
The FDA is expected to make a final decision on brexanolone in early 2019. If approved, there will still be hurdles to overcome because brexanolone must be delivered as an IV infusion over 60 hours. Unless overnight clinics step in to supervise the treatment, hospitalization will be required.

An oral version is expected in the future, and that may broaden its indications. Oral brexanolone (SAGE-217) has a positive randomized controlled trial in major depression and is currently undergoing phase III clinical trials for that condition.