Text version
With new treatments for postpartum depression emerging, wouldn’t it be great to have a head-to-head comparison with the previously first-line treatments? Are we ready to abandon the old for the new?
Hi! Jim Phelps here for the Psychopharmacology Institute. The new medications are steroid modulators, including the injectable brexanolone and now, the oral zuranolone. However, not all treatments for postpartum depression are pharmaceutical. According to a 2016 review in the New England Journal of Medicine, treatment options for postpartum depression should depend on the severity of symptoms and the level of functional impairment. That makes sense. Mild depression can be addressed with peer support and nondirective counseling and moderate depression with more formal psychotherapy. Indeed, interpersonal therapy has also been specifically adapted for postpartum depression.
In the 2016 update of the Canadian Network for Mood and Anxiety Treatment—that’s the CANMAT—conventional CBT is also considered as a first-line option, whereas medications, meaning, until recently, standard antidepressants, are generally recommended for severe depression or lack of response to nondrug therapy. Which antidepressants? A 2021 pharmacist review recommends sertraline, whereas the CANMAT guidelines are broader, including not only sertraline but also citalopram and escitalopram. Now, a new class of medications has become available for the treatment of postpartum depression, namely the steroid modulators.
One of the key neurosteroids in the story of mood disorders is allopregnanolone, a steroid compound expressed in glutamatergic and GABA-ergic neurons in several regions of the brain. In animal models, acute stress increases its synthesis whereas chronic stress lowers it. During pregnancy, progesterone triggers upregulation of allopregnanolone and the levels reach their highest during the third trimester. After delivery, allopregnanolone levels decrease more quickly and to even lower levels in women who develop postpartum depression. Very suggestive, isn’t it?
However, the mechanisms of the new steroid-modulating medications, brexanolone and now zuranolone, are much more complicated than just raising allopregnanolone levels. It’s still being worked out. Those mechanisms clearly involve changes in synaptic and extra-synaptic GABA receptors, the density and function of which are associated with mood symptoms and suicide. So, there’s a lot more to learn here. It’s not simply that your allopregnanolone levels are too low.
Nevertheless, we come now to a new trial of zuranolone funded by the manufacturer, as one would expect for the large trials that are needed to gain FDA approval. Given its publication in a major journal, in this case JAMA Psychiatry, and given that some of the authors work for the company, you’d probably expect that the results were good. The question is, how good, how fast, and for how long? Sure enough, by Day 3, there was a statistically significant difference in response for zuranolone vs placebo. This difference is maintained and increases slightly through the 8-week trial, where the reduction in HAM-D scores at 2 weeks was 18 points vs 13.5 points on placebo. That’s a 4.5 difference in the HAM-D scores, where 2 or 3 points on that scale would generally be regarded as clinically significant in this context.
What about side effects? The most frequent was somnolence in 15% of the zuranolone group, but this was present in 11% of the placebo group as well. All of the rest of the reported side effects were about the same in each group, often higher on placebo, which might be explained by a drop in anxiety scores for patients receiving zuranolone more than placebo. In fact, the anxiety decrease paralleled the reduction in depression scores.
This is just the beginning of learning about zuranolone. We don’t know anything about its long-term effects yet. We also need a head-to-head trial against standard antidepressants, although, interestingly, 20% of patients in this study were on an antidepressant, something which was allowed and continued during the trial.
Finally, here is one more interesting finding that I stumbled upon reviewing this article. In 2019, zuranolone didn’t outperform placebo in major depression trials, and the share value of the company that makes it fell by 50%. Nearly half the corporate workforce was cut in restructuring. But now they’ve obtained an FDA indication—not for major depression but postpartum depression. Rejoice if you still have your job.
To conclude, remember that the first-line treatment for postpartum depression is psychotherapy for mild-to-moderate cases. Only for severe cases would these new agents be considered and only in contrast to the antidepressants that we’ve been using for several decades.
For more on this, I’ve included in the references an understandable history of neurosteroids, including their complex chemistry, in a 2020 review entitled “Allopregnanolone, the Neuromodulator Turned Therapeutic Agent.” The link to this review can be found here at the Psychopharmacology Institute.
Abstract
Importance: Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.
Objective: To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD.
Design, setting, and participants: This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.
Interventions: Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks.
Main outcomes and measures: Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments.
Results: Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo.
Conclusions and relevance: In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.
Download PDF and other files
Reference
Deligiannidis, K. M., Meltzer-Brody, S., Gunduz-Bruce, H., Doherty, J., Jonas, J., Li, S., … & Lasser, R. (2021). Effect of zuranolone vs placebo in postpartum depression: A randomized clinical trial. JAMA Psychiatry, 78(9), 951-959.
Related References
Pinna, G. (2020). Allopregnanolone, the neuromodulator turned therapeutic agent: Thank you, next?. Frontiers in Endocrinology, 11, 236.
