By Nicole Cirino, MD, CST, IF
Reproductive Psychiatrist, Associate Professor, Department of Obstetrics and Gynecology and Department of Psychiatry, Oregon & Health Science University, Portland
Dr. Cirino reports no financial relationships relevant to this field of study.
In two double-blind, randomized, placebo-controlled, Phase III trials of brexanolone, a new medicine for postpartum depression, researchers found a significant reduction in symptoms at 60 hours of infusion compared to placebo.
Meltzer-Brody S, et al. Brexanolone injection in post-partum depression: Two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018;392:1058-1070.
Brexanolone (Zulresso), a proprietary agent developed by Sage Pharmaceuticals, is chemically identical to the endogenous neuroactive steroid allopregnanolone. It is slated to be the first FDA-approved compound for the treatment of postpartum depression (PPD).
Meltzer-Brody and colleagues conducted two large, multicenter, randomized, controlled trials (RCTs) at 30 clinical sites. Previously, they published results of an open-label trial and a prior RCT on this agent.1,2 They included the results from the first RCT of brexanolone (BRX) in the analysis in this current article. The three RCTs were conducted using a similar protocol but varied in dose and severity of depression. Inclusion criteria were ambulatory female patients 18-45 years of age with moderate to severe depression as measured by the Hamilton Rating Scale for Depression (HAM-D). Patients had qualifying HAM-D total scores of ≥ 26 for study 1 (severe depression) and 20-25 for study 2 (moderate depression). Women had to be less than six months postpartum and had to agree to cease breastfeeding at the start of the infusion and for four days after the infusion ended. Onset of depression had to occur between the third trimester of pregnancy and four weeks after delivery. Women taking prescribed psychiatric medication had to be at a stable dose 14 days prior to screening until completion of the 72-hour assessment post-infusion.
Exclusion criteria were active psychosis, alcohol or drug abuse in the prior year, attempted suicide in the current episode, and medical history of schizophrenia, bipolar disorder, renal failure, or anemia.
The researchers screened 375 women with moderate to severe PPD, 246 of whom were assigned. Patients in study 1 were randomized 1:1:1 to BRX 90 mcg/kg per hour, BRX 60 mcg/kg per hour (BRX90 and BRX60), or placebo, respectively, for 60 continuous hours in a medically supervised setting. The entire medically supervised period was 72 hours. Patients in study 2 were randomized 1:1 to either BRX90 or placebo. The patients, study team, site staff (with the exception of pharmacists), and the principal investigator were masked to treatment allocations, and all infusion bags were identical in appearance.
The primary endpoint was change in baseline HAM-D scores at 60 hours after the start of the infusion. Blinded onsite raters were trained to administer HAM-D to enable consistent scoring. A blinded onsite rater scored all participants, and a separate independent, blinded central reviewer recorded and scored the HAM-D assessment in 50% of the patients. Scores were assessed at hours 0, 2, 4, 8, 12, 24, 48, 60, and 72 and at days 7 and 30. Other secondary outcome measures were Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9, Generalized Anxiety Disorder 7-item scale, and Clinical Global Impression scale-improvement subscale.
Demographics and baseline characteristics were well balanced across treatment groups. Twenty-two percent of patients were taking antidepressants at baseline. When analyzed using a mixed effects model, there were no statistically significant differences in response between the women who had been taking an antidepressant vs. those who had not. Women receiving BRX had a greater reduction in HAM-D scores compared to placebo at the primary endpoint of 60 hours and at many, but not all, endpoints between two hours and 30 days. Notably, however, the placebo arm also showed a rapid and robust response. At no point did the drug perform worse than placebo. In study 1, at 60 hours, the mean reduction in HAM-D total score from baseline was -19.5 points in the BRX60 group and -17.7 points in the BRX90 group compared with -14.0 points in the placebo group (difference, -5.5; 95% confidence interval [CI], -8.8 to -2.2; P = 0.0013 for the BRX60 group; and -3.7; 95% CI, -6.9 to -0.5; P = 0.0252 for the BRX90 group). In study 2, at 60 hours, the mean reduction in HAM-D total score from baseline was -14.6 points in the BRX90 group compared with -12.1 points for the placebo group (difference -2.5; 95% CI, -4.5 to -0.5; P = 0.0160).
A more familiar and clinically relevant tool, the EPDS also was administered and analyzed. These data were included in the supplementary appendix of the article. The EPDS revealed statistical and clinically significant results at 30 days for BRX60 only. The mean change at 30 days in EPDS score from baseline was -9.2 points in the placebo group. The BRX60 group demonstrated a -12.8 point change in EPDS scores from baseline to day 30, or 3.7 points greater reduction than placebo, which was found to be a significant difference (P = 0.0290). In contrast, the BRX90 group demonstrated a -11.0 point change in EPDS scores (baseline to day 30), representing a non-statistically significant difference from placebo (-1.8 points difference; P = 0.2701).
The most common adverse events in both studies were headache (15-18% BRX vs. 11-16% placebo), dizziness (10-16% BRX vs. 2-8% placebo), and somnolence (5-18% BRX vs. 4-7% placebo). One BRX60 subject in study 1 had two serious adverse events (suicidal ideation and intentional overdose) following infusion, and one BRX90 subject in study 2 had two serious adverse events (altered state of consciousness and syncope). Although total adverse effects were similar in BRX and placebo arms, dizziness and somnolence were particularly evident in patients receiving BRX injections. Sedation effects reversed within 15 minutes of cessation of infusion and resolved within 90 minutes.
COMMENTARY
I have been following the emergence of this drug since its inception, as it has generated significant interest in the reproductive psychiatry community. It is perplexing that it has taken this long to find an effective “hormonal treatment” for PPD given the robust evidence showing that hormonal factors play a key role in etiology. Our patients routinely request hormonal treatment for perinatal mood and anxiety disorders, but none are available. BRX is novel in its approach, yet quite simple in its mechanism of action, as it is chemically equivalent to allopregnanolone. We know plasma concentrations of allopregnanolone increase during pregnancy and decrease substantially after childbirth in both rodents and humans, and fluctuations in allopregnanolone affect anxiety and depression in animal models.3 Dosing of this agent was developed to mimic allopregnanolone levels in the third trimester.
The neuroactive properties of allopregnanolone are due to its effect as a positive allosteric modulator of GABA type A (GABAA) receptors, which are the major inhibitory transmitter receptors in the brain and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants.4 It is no surprise that the most common adverse effects were dizziness and somnolence, which resolved when the infusion was discontinued. The antianxiety effect of the GABAA mechanism of action also likely plays a role in response rates.
The trial was well-designed and well-executed. The placebo response rate was high, as the authors noted, but this is not unusual in neurobehavioral interventions. I suspect that the intensity of treatment, as well as the removal of the patient from the role of primary caregiver and cessation of breastfeeding, may play a role in response in both the placebo and treatment groups.
The other novel characteristic of this new compound is the rapidity of response for depression symptoms. In this study and in most depression literature, depressive symptom response is defined as a 50% reduction in HAM-D score. Typically, antidepressants take two weeks or longer for response. In this study by Meltzer-Brody et al, response rates separated from placebo within 24 hours. For the BRX60 group, the depressive symptom response rate separated from placebo at 24, 36, 60, and 72 hours and at day 30. In the integrated BRX90 data from all three RCTs, the response rate was significant compared to placebo at hours 24, 48, 60, and 72 and at days 7 and 30.
Remission rates are another important feature to consider in antidepressants trials and are worth paying attention to in this trial. Typically in depression literature, remission is defined as HAM-D score < 7 for a prolonged period, often up to four to six months.5 There is inconsistency in the depression literature regarding the length of time required for a patient to be asymptomatic before the participant is “in remission.” Meltzer-Brody et al defined remission as a HAM-D score ≤ 7 at any given time. This would signify that the patient is symptom-free from depression for that point in time only. Fifty-one percent of BRX60 patients achieved “remission” of symptoms at 60 hours vs. 16% in the placebo arm in study 1; and 61% vs. 38% placebo achieved remission at 60 hours in study 2. The integrated data from all three RCTs of BRX90 showed remission rates of 50% vs. 28% placebo at 60 hours. Of the patients who had a response at 60 hours, 94% did not relapse at day 30. We do not know if this effect can be sustained for more than 30 days or will require maintenance infusions for full remission of PPD. Since PPD has a different etiology than typical unipolar depression and the mechanism of action and delivery are novel for BRX, it may be that response rates for PPD are more rapid than response rates for depression in other periods of the female reproductive life cycle.
The most significant limitation with this treatment option is the 60-hour infusion, which likely will require overnight hospitalization until the issues around safety have been explored fully. Most psychiatric inpatient units are not equipped to administer any intravenous infusions, and psychiatric inpatient bed shortages are already at crisis levels nationally. The cost of a 60-hour infusion with 72-hour medical monitoring will be prohibitive, particularly in the field of mental health, where basic services often are denied or underinsured for many patients. Sage Pharmaceuticals has announced it is working on injectable and oral forms of a similar agent. Thus, the very real barrier to the successful launch of this product is not in the science behind it, but the ability to navigate the healthcare delivery system to be able to provide it. The FDA initially announced a priority review of this product for Dec. 19, 2018, but postponed the review for three months to March 19, 2019, to allow time to develop a Risk Evaluation and Mitigation Strategy with Elements to Assure Safe Use.6
Clinically, the first-line treatment for moderate to severe PPD will remain selective-serotonin reuptake inhibitors (SSRIs) combined with psychosocial interventions. Pending FDA approval and accessibility in the healthcare system, BRX will present a strong alternative to SSRIs for first-line treatment of PPD because of its rapid onset of action, robust response rate, and low side effect profile. I hope further research will explore its efficacy in perinatal bipolar depression and perinatal anxiety disorders.
REFERENCES
- Kanes S, et al. Brexanolone (SAGE-547 injection) in post-partum depression: A randomised controlled trial. Lancet 2017;390:480-489.
- Kanes SJ, et al. Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol 2017;32:e2576. doi: 10.1002/hup.2576.
- Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum depression. Neuron 2008;59:207-213.
- Sieghart W, Savic MM. International Union of Basic and Clinical Pharmacology. CVI: GABAA receptor subtype- and function-selective ligands: Key issues in translation to humans. Pharmacol Rev 2018;70:836-878.
- Kennedy S. Full remission: A return to normal functioning. J Psychiatry Neurosci 2002;27:233-234.
- Sage Therapeutics. Sage Therapeutics Receives Notification of PDUFA Extension for ZULRESSO (brexanolone) Injection. [Press Release] Nov. 20, 2018. Available at: https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-receives-notification-pdufa-extension. Accessed Dec. 18, 2018.
