WARSAW, Poland — Women with postpartum depression (PPD) can achieve rapid remission with a 60-hour infusion of brexanolone (Zulresso, Sage Therapeutics), and remission is sustained over 30 days, a pooled analysis from three randomized controlled trials shows.
Brexanolone is an intravenous formulation of allopregnanolone, an endogenous progesterone metabolite that is thought to modulate gamma-aminobutyric acid (GABA) receptors.
The US Food and Drug Administration (FDA) approved brexanolone injection on March 19 for the treatment of PPD in adult women, noting that "this is the first drug approved by the FDA specifically for PPD."
In the current analysis, Robert Lasser, MD, a psychiatrist at Sage Therapeutics, Cambridge, Massachusetts, analyzed results from three randomized trials in which 140 women with PPD were treated with one of two doses of the drug and compared the results to those of more than 100 patients given placebo.
The findings, which were described by one expert as "a revolution" in the care of PPD, were presented here at the European Psychiatric Association (EPA) 2019 Congress.
Better Efficacy Than Oral Meds
Results showed not only that 75% of patients achieved a response and that 50% were in remission by the end of the 60-hour infusion but also that the response was sustained for 30 days, with 56% still responding and 36% in remission.
Moreover, Lasser said that the results "revealed brexanolone injection to be significantly better than placebo at reducing depressive symptoms" at rates that are "notably higher" than those "commonly expected with oral medications.
"Adverse events, as expected, included dry mouth and sedation, and those cases of excessive sedation resolved with simple dose interruption," said Lasser.
Lasser began by noting that the underlying cause of PPD is unknown and is likely to involve multiple factors.
These may include a history of depression, alterations in inflammatory signaling, fluctuations in levels of gonadal hormones and neuroactive steroids, and dysregulation of stress pathways in the brain.
One potential mechanism that has been suggested for PPD, Lasser said, is the inability of the GABA system to regulate neural network activity, possibly through altered GABA receptor regulation.
To investigate the efficacy of brexanolone, the researchers conducted three randomized, double-blind trials in women with PPD.
The first trial involved patients with severe PPD, defined as the patient's having a total Hamilton Rating Scale for Depression (HAM-D) score of ≥25. Patients were randomly assigned to receive brexanolone injection at 90 µg/kg/hr (BRX90; n = 10) or placebo (n = 11).
For the second study, women with severe PPD were randomly assigned to receive BRX90 (n = 41), brexanolone injection at 60 µg/kg/hr (BRX60; n = 38), or placebo (n = 43).
In the final trial, women with moderate PPD, defined as the patient's having a total HAM-D score of 20–25, were randomly allocated to receive BRX90 (n = 51) or placebo (n = 53).
The investigators pooled the results of the three trials and conducted an efficacy analysis in 102 patients treated with BRX90 and 107 treated with placebo.
In addition, they conducted a safety analysis in 140 patients treated with BRX90 or BRX60 and 107 patients who received placebo. Both analyses were preplanned.
Patients treated with BRX90 and those given placebo both experienced substantial reductions in the least squares mean total HAM-D scores over baseline by the end of the 60-hour infusion period.
However, the mean reduction from baseline to hour 60 was significantly greater with BRX90 than placebo, with a reduction in total HAM-D scores of -17.0 vs -12.8 (P < .001).
BRX90 was also associated with significant improvements in response rates, defined as a reduction in total HAM-D scores over baseline of ≥50%, and in rates of remission, defined as a total HAM-D score of ≤7.
Specifically, the team found that 75% of patients treated with BRX90 experienced a response at hour 60, vs 56% of those given placebo (P < .0001); 50% and 26%, respectively, achieved remission (P = .0003).
The significant difference in response was sustained over the 30-day follow-up period, with 56% of BRX90 patients and 45% of those in the placebo group showing a response at the final assessment (P < .0001).
A similar pattern was seen for those who achieved remission, with 36% of BRX90 patients and 22% of those given placebo in remission at 30 days (P < .0001).
Lasser pointed out that patients who achieved a response or remission at hour 60 were likely to continue experiencing response or remission over 30 days. Of those given BRX90, 83% demonstrated a response, and 85% were in remission; of those given placebo, 81% showed a response, and 75% were in remission.
In the safety analysis, it was found that cardiac disorders, such as tachycardia; gastrointestinal disorders, including diarrhea, dry mouth, and dyspepsia; and vascular disorders, such as flushing, typically occurred in 2% to 3% of patients treated with brexanolone.
However, of greater interest were rates of sedation, particularly because this adverse event was singled out by the FDA in its approval announcement for the drug.
The FDA stated that, because "of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring."
In the current analysis, 13% of patients given BRX90 and 21% of those treated with BRX60 experienced sedation or somnolence; 3% and 5%, respectively, had loss of consciousness; and 12% and 13%, respectively, experienced dizziness, presyncope, or vertigo.
By comparison, among placebo patients, 6% experienced sedation or somnolence, and 7% experienced dizziness, presyncope, or vertigo.
Lasser said that the overall rates of sedation seen with brexanolone were "very similar to what we see with available antidepressants.
"In these cases, and with the oral medication that we're testing, it comes exactly when you need it to, which is about 10 o'clock at night, when patients are ready to go to bed," he said.
Depression Treatment Boon
Session chair Marcin Wojnar, MD, PhD, University of Michigan, Ann Arbor, told Medscape Medical News that brexanolone is "a kind of revolution in treating depression, especially postpartum depression."
He noted that this "can be a very dangerous, threatening condition, both for the mother and the child, so the faster and more effectively we could help such people, the happier we would be."
In the post-presentation discussion, Wojnar noted that in addition to the drug's "ultra-rapid action, there was also a very high level of response to placebo, which is not surprising, because most of pharmaceutical studies have such high responses, but it was really maintained afterwards."
Lasser agreed, noting that "overcoming the placebo effect is a bigger and bigger issue in trials."
He pointed out that the studies were conducted in hospital inpatients, so there was "even more potential for bias" in the placebo group.
Asked by a member of the audience whether the drug would cause any problems during breastfeeding, Lasser said that women stopped breastfeeding during the trial.
However, he added that a previous lactation study indicated that the amount of drug expressed in breast milk "is quite low; it's around 1%, and only 5% of that is available to the child. So even if you were to breastfeed for over that 60 hours [of drug infusion], we don't think it would cause an issue," Lasser said.
The study was funded by Sage Therapeutics. Lasser is an employee of and owns stock in Sage Therapeutics. Wojnar has disclosed no relevant financial relationships.
European Psychiatric Association (EPA) 2019 Congress: Abstract OC-0052. Presented April 8, 2019.
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Cite this: Newly Approved Drug a 'Revolution' for Postpartum Depression - Medscape - Apr 09, 2019.