Zuranolone, an Oral Medication for Postpartum Depression

In the year after giving birth, about one in eight new mothers experiences symptoms of postpartum depression.[1] Postpartum depression is a serious condition involving the brain, which can affect mental health and even behavior. Mental health conditions that result in suicide or death from overdose or poisoning are the leading causes of overall and preventable postpartum deaths.[2] Postpartum depression is different from the “baby blues,” which go away a few days after giving birth. Symptoms can include intense sadness, hopelessness, anxiety and feelings of detachment from the new baby; many times, this lasts for longer than two weeks.[3] Although the underlying physiological causes of the disease are unclear,[4] a personal history of depression (before or during the pregnancy) is a major risk factor.

In 2023, the Food and Drug Administration (FDA) approved zuranolone (ZURZUVAE), the first oral medication that is specifically indicated for treatment of postpartum depression. The drug is administered with fat-containing food once daily in the evening for 14 days. The Drug Enforcement Administration has classified zuranolone as a Schedule IV controlled substance, which means that the drug has the potential for abuse and dependence. Examples of other Schedule IV controlled substances are the benzodiazepines alprazolam (XANAX) and lorazepam (ATIVAN). The prescribing information for zuranolone has a boxed warning (the most prominent warning that the FDA can require). The warning states that the drug “causes driving impairment” due to its central nervous system depressant effects. Patients are advised not to drive or engage in other potentially hazardous activities for at least 12 hours after administration. Moreover, patients may be unable to assess their own ability to drive or their degree of impairment.

Background on treating postpartum depression

Treatment approaches for postpartum depression vary depending upon the severity of the illness.[5],[6] For mild to moderate cases, counseling and behavioral therapies may suffice. When drug treatment is considered for moderate to severe postpartum depression, a type of antidepressant known as selective serotonin reuptake inhibitors (SSRIs) has generally been used. Severely ill patients may report suicidal thoughts and behaviors, have obvious impairment of functioning, and because of poor judgment may place themselves and others (including children) at imminent risk of harm. SSRIs, however, take some time to yield symptom improvement.

An intravenous medication for postpartum depression

The intravenous medication brexanolone (ZULRESSO), approved by the FDA in 2019, was the first drug specifically for treatment of postpartum depression. The drug is administered with 60 hours of supervised intravenous infusions and the cost of the drug alone for a single infusion is more than $35,000. Brexanolone can cause extreme sedation and sudden loss of consciousness; the durability of its antidepressant effect and its benefits as compared with SSRIs are unclear.[7]

Brexanolone and zuranolone are both neuroactive steroid gamma-aminobutyric acid A (GABA_A) receptor positive modulators (meaning they work with other biochemicals to activate GABA_A, which inhibits brain activity).

Zuranolone, an oral alternative to brexanolone

Approved by the FDA in August 2023, zuranolone has a mechanism of action similar to brexanolone but is taken as an oral 50-mg capsule with fat-containing foods to facilitate absorption (the drug is fat-soluble).[8] For patients who respond to zuranolone, the time to symptom improvement may be more rapid than with use of SSRIs or other antidepressants. The wholesale acquisition cost for a 14-day treatment cycle is $15,900.[9]

The FDA approved zuranolone for postpartum depression based mostly on efficacy data from two randomized placebo-controlled clinical trials.[10] In both trials, the placebo effect was much larger than the added effect of the drug. The first trial included 196 adults with a major depression event that began between the third pregnancy trimester and the fourth week postpartum. Enrollment was limited to subjects with ongoing depression as confirmed with a standardized depression scale and who were less than 12 months postpartum.[11] Those with significant suicide risk or histories of psychoses, substance use disorder or sleep apnea were excluded, and subjects could not breastfeed during the trial. Treatment with another antidepressant or psychotherapy could continue.

The main outcome was the change in score from baseline to day 15 (one day after the last dose) on the Hamilton Rating Scale for Depression (HAMD-17) total score, a 17-item clinician-completed scale with scores ranging from 0 (no signs) to 53 (maximal signs),[12] where a score of at least 20 indicates moderate depression severity.[13] To enroll, subjects had to have a baseline HAMD-17 score of at least 26. By day 15, subjects receiving zuranolone had average declines from their baseline HAMD-17 score of 15.6 points, as compared with average declines of 11.6 points for subjects in the placebo group, a difference in the amount of improvement that was modest but statistically significant.

The second trial involved 149 subjects and was very similar to the first trial in both design and enrollment criteria. Key differences were that a lower dose of zuranolone was used (30 to 40 milligrams per day rather than 40 to 50 milligrams per day) and enrollment was limited to subjects who were less than six months postpartum. By day 15, subjects receiving zuranolone had average declines from baseline of 17.8 points on the HAMD-17 score, as compared with 13.6 points for subjects in the placebo group. This difference in the amount of improvement was modest but statistically significant.

Adverse effects of zuranolone include hypersomnolence, sedation, dizziness, diarrhea and fatigue, according to the drug label.[14] In the larger of the two clinical trials, 36% of the subjects in the zuranolone group experienced sedation or hypersomnia (excessive sleepiness), compared with 6% of subjects in the placebo group; 3% of subjects in the zuranolone group and none in the placebo group had memory impairment. As with other antidepressants, suicidal thoughts and behaviors may emerge. There are safety concerns about zuranolone’s use in people who are pregnant or breastfeeding,[15] as well as concerns about withdrawal effects with cessation of the drug and the potential for physicial dependence. As the drug may harm a developing fetus, those taking the drug should use effective contraception. There are limited data on the potential adverse effects of zuranolone on a child who is breastfed.

What You Can Do

If you experience symptoms of depression during or after pregnancy, seek immediate medical attention because severe major depression can be life-threatening. The decision to use zuranolone with or without other therapies for postpartum depression, including other antidepressants or counseling and behavioral therapies, should follow a full discussion with your clinician. Discuss the balance between the potential benefts of zuranolone (rapid improvement in symptoms of severe postpartum depression) and the potential risks, including the potential for suicidal thoughts and behaviors, the risk of abuse, withdrawal effects and dependence, and the inability to drive and to perform other activities of daily living that are impaired by sedation. Because many people with postpartum depression have children, there is a real concern about whether someone taking the drug can safely care for children.

Importantly, no clinical trials have directly compared zuranolone with brexanolone; other types of antidepressants, such as SSRIs; or electroconvulsive therapy, another treatment for severe depression. Moreover, data on the effectiveness of zuranolone beyond six to seven weeks are lacking. The FDA should not have approved zuranolone without requiring control groups in the clinical trials that reflected the standard of medical care for postpartum depression.[16] Until more data become available to inform discussions about the potential benefits and risks of zuranolone, Public Citizen’s Health Research Group has classified it as Do Not Use for Seven Years.
 

References

[1] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 217369Orig2s000. Integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217369Orig2s000IntegratedR.pdf. Accessed November 26, 2023.

[2] Trost S, Beauregard J, Chandra G, et al. Pregnancy-related deaths: data from maternal mortality review committees in 36 US states, 2017-2019,. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2022. https://www.cdc.gov/reproductivehealth/maternal-mortality/docs/pdf/Pregnancy-Related-Deaths-Data-MMRCs-2017-2019-H.pdf. Accessed December 11, 2023.

[3] U.S. Department of Health and Human Services. Office on Women’s Health. Postpartum depression. October 17, 2023. https://www.womenshealth.gov/mental-health/mental-health-conditions/postpartum-depression. Accessed November 26, 2023.

[4] Viguera A. Postpartum unipolar major depression: epidemiology, clinical features, assessment, and diagnosis. UpToDate. April 7, 2023.

[5] Viguera A. Mild to moderate postpartum unipolar major depression: Treatment. UpToDate. June 6, 2023.

[6] Viguera A. Severe postpartum unipolar major depression: Choosing treatment. UpToDate. August 17, 2023.

[7] Drugs for Depression. The Medical Letter. December 11, 2023.

[8] Sage Therapeutics and Biogen. Label: zuranolone (ZURZUVAE). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369Orig2s000Corrected_lbl.pdf. Accessed November 26, 2023.

[9] Safe Therapeutics announces third quarter 2023 financial results and highlights pipleline and business progress. November 7, 2023. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-third-quarter-2023-financial-results?utm_campaign=the_readout&utm_medium=email&_hsmi=281525450&_hsenc=p2ANqtz-8AuY_inv_mzKpZLA5Xi-OLW6R5OfIIRw5Va-MjVCKMagqJ3D-9zXW77XhBt66dxJjYI3T8iXguQ5Qv7479aZzaYwlqGDjYCeJlozMyQuf44tZV7yc&utm_content=281525450&utm_source=hs_email. Accessed December 21, 2023.

[10] U.S. Food and Drug Administration. Press release: FDA approves first oral treatment for postpartum depression. August 4, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression. Accessed November 26, 2023.

[11] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 217369Orig2s000. Integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217369Orig2s000IntegratedR.pdf. Accessed November 26, 2023.

[12] Chapter 42: Hamilton Rating Scale for Depression (HAM-D). in Shadid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scalesposted at: https://www.med.upenn.edu/cbti/assets/user-content/documents/Hamilton%20Rating%20Scale%20for%20Depression%20(HAM-D).pdf. Accessed November 26, 2023.

[13] NP Psych Navigator. Hamilton depression rating scale, 17 item (HAM-D-17). 2023. https://www.nppsychnavigator.com/Clinical-Tools/Psychiatric-Scales/Hamilton-Depression-Rating-Scale,-17-item-(HAM-D-1. Accessed November 26, 2023.

[14] Biogen. Label: zuranolone (ZURZUVAE). August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369Orig2s000Corrected_lbl.pdf. Accessed November 22, 2023.

[15] Prasad V, Allely D. Concerns that may limit the utility of zuranolone. JAMA .doi:10.001/jama.2023.26103. Published online December 15, 2023.

[16] Ibid.