Article

GABA Receptor Modulators Offer Rapid Relief and New Hope for Mothers with Postpartum Depression

As a primary care physician, you might feel frustrated when traditional antidepressants take too long to work or are ineffective for postpartum unipolar depression. You may have heard of GABA receptor modulators but are uncertain how they would benefit your patients. Learning about this class of medication will reveal their ability to overcome numerous treatment-related challenges.

Traditional Antidepressants Work Too Slowly

Traditional antidepressants like serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), previously the postpartum depression (PPD) treatment standard, act slowly.¹'² Maximal treatment effect may take up to 12 weeks, placing an undue burden on you, your patients, their families, and the health care system.¹'² Although patients may attain remission with these agents, they require aggressive and persistent treatment, often necessitating multiple therapeutic trials, each lasting months.³

 

Many Patients Don’t Want to Take SSRIs and SNRIs

In many cases, your patients don’t have the chance to obtain relief anyway because they don’t take antidepressants for the recommended duration.⁴ The relationship between treatment adherence and efficacy in postpartum depression is bidirectional: low adherence reduces efficacy, while decreased efficacy often leads patients to stop using SSRIs or SNRIs prematurely.⁴⁻⁶ This issue is compounded by the lack of immediate response from treatment, resulting in only about half of patients achieving remission.⁴⁻⁶

Moreover, antidepressants’ side effects—including nausea, sleep disturbances, and sexual dysfunction—represent a common reason patients discontinue or refuse treatment.⁵ In fact, a quarter of patients who stop taking their antidepressants within the first 6 months of treatment do so due to side effects.⁷ Breastfeeding mothers might also show reluctance to take antidepressant medications, stemming from concerns about potential adverse effects.⁸ Due to the intensive caution instilled in mothers about medication intake during pregnancy, this vigilance often persists postpartum, leading to wariness about antidepressant use.⁸

Convincing patients to take traditional antidepressants can also be challenging due to the stigma that they are facing.⁹'¹⁰ You may have encountered mothers for whom discussing PPD treatment feels overwhelming and like a judgment of character.⁸ Some women are concerned that revealing symptoms of depression could lead to the loss of parental rights.⁸ Others hesitate to seek help because they perceive “baby blues” as a normal part of adapting to motherhood.⁸

You Need Additional Options for Patients With PPD

Although you may be comfortable with prescribing traditional antidepressants, they may not be the best available option.⁴ The quality of evidence for traditional antidepressants’ effectiveness remains very low, especially for women with severe symptoms or suicidal ideation, as they were excluded from most clinical trials.⁴ The lack of high-quality studies on antidepressant treatment for PPD also limits conclusions about the effectiveness and possible negative effects on mother and child.⁴ Moreover, because the acceptability of these pharmacological treatments is low, you may need to consider other options that patients are more open to.⁴

GABA Receptor Modulators Can Benefit You and Your Patients

Although learning about a new class of medication may seem challenging, it can potentially improve patient outcomes, especially for your most vulnerable patients. For mothers who are unable to get out of bed or care for their child, or who feel suicidal, it would help to have an option that provides timely relief—these patients can’t afford to wait 12 weeks for treatment effects.¹¹ GABA receptor modulators are a new class of medication specifically approved for PPD treatment that offer advantages for you and your patients, overcoming issues related to inefficacy, slow response times, and the challenges linked to stigma and adherence.¹² Currently approved GABA receptor modulators include brexanolone and zuranolone.¹³'¹⁴

GABA receptors are structures found on cells in the brain that play a key role in mood regulation.¹⁰'¹⁵'¹⁶ Allopregnanolone, a substance naturally found in the body that rises during pregnancy and drops after childbirth, modulates GABA receptors’ actions.¹⁰'¹⁵'¹⁶ After childbirth, there's typically a massive decrease in allopregnanolone as well as GABA levels and function, contributing to PPD in susceptible women.¹⁰'¹⁷ Brexanolone and zuranolone work by mimicking the action of allopregnanolone, helping to stabilize mood.¹³'¹⁷'¹⁸

GABA Receptor Modulators Work Quickly and Offer Long-Lasting Relief

Because GABA receptor modulators quickly restore allopregnanolone’s actions, they work much faster than traditional antidepressants and are a good option for patients who need a rapid onset of action.¹'¹³'¹⁴'¹⁹ In clinical studies, brexanolone significantly reduced depressive symptoms, when compared to placebo, within 60 hours of treatment.¹⁴ While no direct studies compare SSRIs with brexanolone, indirect methods analyzing different studies suggest that brexanolone offers superior efficacy in PPD treatment.²⁰'²¹ Zuranolone also showed rapid results, with noticeable improvements in depressive symptoms by the third day of treatment.¹³ Overall, GABA receptor modulators, showing quicker results in PPD treatment, can outperform SSRIs and SNRIs in some patients.¹'¹³'¹⁴

Even though they have a rapid onset, GABA receptor modulators are prescribed short-term and have long-lasting results.¹⁰'¹³'¹⁴'²² Brexanolone offered lasting relief for the 30-day study period in trials leading to its approval.²³ Among patients who showed improvement at 60 hours, 94% maintained their progress without relapsing by day 30.²³ In a smaller post-commercialization study, 73% of patients remained in remission 90 days after treatment.²⁴ Zuranolone also offers long-lasting effects, with sustained improvement measured 45 days after treatment.²² In one trial, only 7.9% of patients needed to start a new antidepressant within the 45-day follow-up period.²⁵ These findings highlight the idea that GABA receptor modulators provide enduring benefits and maintain therapeutic effects well beyond the completion of the treatment course.²²⁻²⁴

Patients Are Likely to Tolerate and Accept Treatment with GABA Receptor Modulators

During the short treatment period, side effects are generally well-tolerated and unlikely to lead to treatment discontinuation, in contrast with traditional antidepressants. ¹'⁴ The most frequently reported side effects are presented in Table 1.¹³'¹⁴

With brexanolone, events like sedation, somnolence, and altered consciousness are typically mild, brief, and resolve on their own.²³ However, zuranolone can cause driving impairment because it depresses the central nervous system; patients need to wait at least 12 hours after each dose before driving.¹³

Your patients may ask questions about this medication class’s impact on breastfeeding. Side effects are unlikely in breastfed infants of mothers who receive GABA receptor modulators due to their low presence in breast milk.¹³'¹⁴ However, patients should be informed of the paucity of data in breastfed infants to aid them in making an informed decision about breastfeeding during treatment.¹³'¹⁴

Even when patients’ concerns about side effects and breastfeeding are alleviated, the stigma of antidepressant use can still hinder new mothers from initiating treatment.⁸⁻¹⁰ Addressing this issue, some specialists suggest the favorable side effect profile and short treatment period of GABA receptor modulators might improve adherence by diminishing the stigma related to using antidepressants.²⁶ This could be one less concern for your patients.²⁶

Once your patients agree to treatment with these agents, knowing how to prescribe them correctly is crucial. Table 2 summarizes their characteristics. Brexanolone is a 60-hour intravenous infusion that must be administered in a supervised clinical setting.¹ Zuranolone is a 14-day oral treatment that patients can self-administer at home.¹³ Because of sedation-related side effects with both medications, you should be cautious of use with other central nervous system-depressing agents, such as benzodiazepines, opioids, and tricyclic antidepressants.¹³⁻¹⁴ 

Offer GABA Receptor Modulators to Patients Who Need Quick Relief

Ultimately, GABA receptor modulators are another potentially beneficial intervention for PPD patients, particularly those requiring rapid onset of action or those who are not candidates for treatment with antidepressants.¹¹'¹³'¹⁴ This includes mothers with severe depression who are having difficulty bonding with their baby or who are suicidal.¹¹ Keep in mind that both treatments can be used as monotherapy or as adjuncts to other antidepressant treatments; you may propose it as an add-on treatment for patients who still require a traditional antidepressant.¹'²⁷

Consider prescribing GABA receptor modulators to patients who need rapid efficacy or those who refuse long-term treatment. Visit www.zulresso.com and www.zurzuvae.com for more information on how to prescribe GABA receptor modulators.

References

1.            Patatanian E, Nguyen DR. Brexanolone: A Novel Drug for the Treatment of Postpartum Depression. Journal of Pharmacy Practice. 2022;35(3):431-436. doi:10.1177/0897190020979627

2.            Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol Psychiatry. 2002;7(1):S23-S28. doi:10.1038/sj.mp.4001015

3.            Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Spencer D, Fava M. The STAR*D study: treating depression in the real world. Cleveland Clinic Journal of Medicine. 2008;75(1):57-66. doi:10.3949/ccjm.75.1.57

4.            Molyneaux E, Howard LM, McGeown HR, Karia AM, Trevillion K. Antidepressant treatment for postnatal depression. Cochrane Database Syst Rev. 2014;2014(9):CD002018. doi:10.1002/14651858.CD002018.pub2

5.            Keller MB, Hirschfeld RMA, Demyttenaere K, Baldwin DS. Optimizing outcomes in depression: focus on antidepressant compliance. International Clinical Psychopharmacology. 2002;17(6):265.

6.            Cox EQ, Sowa NA, Meltzer-Brody SE, Gaynes BN. The Perinatal Depression Treatment Cascade: Baby Steps Toward Improving Outcomes. J Clin Psychiatry. 2016;77(9):20901. doi:10.4088/JCP.15r10174

7.            Demyttenaere K, Enzlin P, Dewe W, Boulanger B, Bie JD, Mesters P. Compliance With Antidepressants in a Primary Care Setting, 1: Beyond Lack of Efficacy and Adverse Events. J Clin Psychiatry. 2001;62(suppl 22):3551.

8.            Byatt N, Moore Simas T, Lundquist R, Johnson J, Ziedonis D. Strategies for improving perinatal depression treatment in North American outpatient obstetric settings. Journal of psychosomatic obstetrics and gynaecology. 2012;33:143-161. doi:10.3109/0167482X.2012.728649

9.            Byatt N, Biebel K, Friedman L, Debordes-Jackson G, Ziedonis D, Pbert L. Patient’s views on depression care in obstetric settings: how do they compare to the views of perinatal health care professionals? Gen Hosp Psychiatry. 2013;35(6):598-604. doi:10.1016/j.genhosppsych.2013.07.011

10.         Meltzer-Brody S. Treating perinatal depression: risks and stigma. Obstet Gynecol. 2014;124(4):653-654. doi:10.1097/AOG.0000000000000498

11.         Sullivan K. Clinicians May Not Prescribe New Postpartum Depression Drug. Medscape. Published November 22, 2023. Accessed December 8, 2023. https://www.medscape.com/viewarticle/998731

12.         Gerbasi ME, Meltzer-Brody S, Acaster S, et al. Brexanolone in Postpartum Depression: Post Hoc Analyses to Help Inform Clinical Decision-Making. Journal of Women’s Health. 2021;30(3):385-392. doi:10.1089/jwh.2020.8483

13.         Zurzuvae Prescribing Information. Published online November 2023. Accessed January 12, 2024. https://www.zurzuvae.com

14.         Healthcare Providers | ZULRESSO® (brexanolone) Prescribing Information. Published online June 2022. Accessed December 19, 2023. https://www.zulressohcp.com/

15.         Schiller CE, Schmidt PJ, Rubinow DR. Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology. 2014;231(17):3557-3567. doi:10.1007/s00213-014-3599-x

16.         Lüscher B, Möhler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience. F1000Res. 2019;8:F1000 Faculty Rev-751. doi:10.12688/f1000research.18758.1

17.         Reddy DS, Mbilinyi RH, Estes E. Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy. Psychopharmacology. 2023;240(9):1841-1863. doi:10.1007/s00213-023-06427-2

18.         Reddy DS. Neuroendocrine insights into neurosteroid therapy for postpartum depression. Trends in Molecular Medicine. 2023;29(12):979-982. doi:10.1016/j.molmed.2023.07.006

19.         Babaev O, Piletti Chatain C, Krueger-Burg D. Inhibition in the amygdala anxiety circuitry. Exp Mol Med. 2018;50(4):1-16. doi:10.1038/s12276-018-0063-8

20.         Signorovitch JE, Sikirica V, Erder MH, et al. Matching-Adjusted Indirect Comparisons: A New Tool for Timely Comparative Effectiveness Research. Value in Health. 2012;15(6):940-947. doi:10.1016/j.jval.2012.05.004

21.         Cooper MC, Kilvert HS, Hodgkins P, Roskell NS, Eldar-Lissai A. Using Matching-Adjusted Indirect Comparisons and Network Meta-analyses to Compare Efficacy of Brexanolone Injection with Selective Serotonin Reuptake Inhibitors for Treating Postpartum Depression. CNS Drugs. 2019;33(10):1039-1052. doi:10.1007/s40263-019-00672-w

22.         Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression. AJP. 2023;180(9):668-675. doi:10.1176/appi.ajp.20220785

23.         Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet. 2018;392(10152):1058-1070. doi:10.1016/S0140-6736(18)31551-4

24.         Patterson R, Krohn H, Richardson E, Kimmel M, Meltzer-Brody S. A Brexanolone Treatment Program at an Academic Medical Center: Patient Selection, 90-Day Posttreatment Outcomes, and Lessons Learned. Journal of the Academy of Consultation-Liaison Psychiatry. 2022;63(1):14-22. doi:10.1016/j.jaclp.2021.08.001

25.         Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(9):951. doi:10.1001/jamapsychiatry.2021.1559

26.         Presse AAF. US Approves Pill For Postpartum Depression. Accessed January 13, 2024. https://www.barrons.com/news/us-approves-pill-for-postpartum-depression-389d70bc

27.         Parikh SV, Aaronson ST, Mathew SJ, et al. Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study. Neuropsychopharmacol. Published online October 24, 2023:1-9. doi:10.1038/s41386-023-01751-9