Looking Beyond Monoamines
Most available antidepressants modulate the monoamines serotonin, norepinephrine, and dopamine, which collectively account for only a small percentage of neurotransmitters in the brain.¹ With limited monoamine expression, it is not surprising that selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs) typically provide response in only 30-50% of patients²; and even in responders, onset of efficacy typically takes 4-6 weeks.³

In contrast, gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain.¹ Abnormalities in GABA have been identified in patients with postpartum depression (PPD) and major depressive disorder (MDD), making it a promising therapeutic target.⁴

Neurosteroids targeting GABA may represent an important advancement in the treatment of depression, with the potential to shorten the interval between symptom onset and symptom control expected with current monoaminergic therapies. Given that symptoms of PPD often appear within 2 weeks postpartum,⁵ the long onset of drug effects with current therapies means that symptoms may persist for weeks, even in patients for whom treatment will eventually prove effective. As research suggests, persistent PPD is associated with maternal suicide, poor infant development, and depression in partners,⁶ particularly in adolescent mothers and those with comorbid anxiety.^7,8 Similarly, MDD not abated within 2 weeks of symptom onset is less likely to remit and remain in remission long term.⁹

Neurosteroids for Depressive Disorders – A Paradox?
The use of a neurosteroid for the management of depression may seem counterintuitive at first glance, given the fact that activation of the hypothalamic-pituitary-adrenal (HPA) axis observed in MDD increases endogenous neurosteroid levels, and that neurosteroids can act as antagonists at the GABA-A receptors.^10,11 However, neurosteroids can have positive and negative allosteric effects, and clinical trials are showing that positive allosteric modulators at the GABA-A receptors actually potentiate effects of GABA that mitigate depressive symptoms.¹⁰

GABA-A modulators can be further differentiated based on their receptor binding profiles. To date,¹¹ nineteen GABA-A receptor subunits have been identified. Neurosteroids broadly target these various subtypes but appear to show preferential effects at the δ receptor subtype, which is believed to account for its antidepressant effects. In contrast, the δ receptor subtype is not sensitive to benzodiazepines—which is why these agents do not have antidepressant effects—but instead act as anxiolytics primarily through activity at the α2 receptor.¹¹  

Formulations of the neurosteroid allopregnanolone (ALLO), a selective positive allosteric modulator targeting the GABA-A receptors,¹ have been approved in women with PPD and are being studied in patients with MDD. PPD is a natural first indication given its pathophysiology. Levels of ALLO and other steroid hormones increase dramatically during pregnancy, with corresponding increases in GABA activity. After delivery, ALLO levels may decline dramatically—along with GABA activity—creating an imbalance in neuronal excitation (glutamate) and inhibition (GABA).¹⁰ These rapid changes increase the risk of depression during pregnancy and throughout the peripartum and postpartum periods. Consideration of ALLO for the treatment of MDD is also logical because ALLO levels generally increase during acute stress, with neuroprotective effects¹²; but decrease due to chronic stress, with a corresponding increase in MDD risk.¹³

Allopregnanolone in PPD and MDD: Evidence of Efficacy
A synthetic intravenous formulation of ALLO (IV-ALLO) has been approved for the treatment of PPD. Administered in a continuous 60-hour infusion, IV-ALLO provides rapid response¹⁴ with remission rates of 40% to 60% during the 60-hour treatment, and response persisting for 30 days.¹⁵

An oral heterocyclic analogue of ALLO (O-ALLO), with improved bioavailability compared with IV-ALLO, is being studied in patients with PPD and MDD. In a phase 3 trial enrolling new mothers with PPD,¹⁶ O-ALLO met its primary endpoint, a significantly greater least squares mean (±SE) reduction from baseline in 17-item Hamilton Depression (HAM-D) total score vs placebo (O-ALLO 50 mg, 15.6 ± 0.82 vs placebo, 11.6 ± 0.82; p=0.0007). Significant improvements in symptoms were reported as early as day 3, and maintained through day 45. Significantly more patients treated with O-ALLO met criteria for response (≥50 reduction in HAM-D) and remission (HAM-D ≤7).¹²

In MDD, O-ALLO has been associated with response rates >70% and remission rates ranging from 40% to 64%^.15 In a 1-year longitudinal study, 725 patients with a Hamilton Depression (HAM-D) score ≥20 received O-ALLO 30-mg for 14 days, with treatment responders eligible for 14-day retreatments as needed. At Day 15, the response rate (≥50% reduction in HAM-D) and remission rate (HAM-D ≤7) were 71.6% and 39.8%, respectively. Among 494 patients who responded to a first O-ALLO course, 44.5% did not require a second course, 26.7% needed 2 courses, 13.4% needed 3 courses, and 10.3% and 5.5% needed 4 and 5 courses, respectively. Efficacy with repeat courses were similar to the initial course.¹⁵

The Place for Neurosteroids in PPD/MDD Therapy
Response and remission with neurosteroids—approved and in development for the treatment of PPD and MDD—occur more rapidly than with traditional monoamine-based antidepressants administered over longer periods of time. With improved efficacy, IV- and O-ALLO may represent an important advancement in the treatment of depression.

However, tolerability questions remain, particularly with the IV formulation. IV-ALLO carries black box warnings for excessive sedation and potential sudden loss of consciousness, for which patients must be continuously monitored throughout treatment. Patients must also be monitored with continuous pulse oximetry. There are also logistical hurdles with IV-ALLO; the infant is not present for the infusion, which means measures must be taken to care for the infant during treatment. Given the risk of sedation, the FDA has mandated that IV-ALLO be administered under a Risk Evaluation and Mitigation Strategy (REMS) program, which complicates and increases the cost of administration.¹⁴ Nonetheless, given the danger of PPD poses to both mother and infant, the availability of a therapeutic option that can provide rapid relief of depressive symptoms within hours of administration is a major step forward in care.

The development and eventual approval of the O-ALLO formulation, suitable for once-daily administration, would be a second major advancement for patients with PPD and MDD. Adverse events reported in clinical trials of O-ALLO typically included mild-to-moderate somnolence, dizziness, sedation, headache, and tremor,¹⁵ with no reports of loss of consciousness or other severe adverse events reported with the IV-ALLO formulation. Perhaps most importantly, if approved for PPD, O-ALLO would become the first oral medications specifically indicated for PPD.¹⁶ The ability to treat PPD in the home without professional supervision, and without a 60-hour interruption in the mother-infant routine, might greatly improve the acceptability of treatment. Hopefully, the development of O-ALLO augurs the beginning of an era of new drug discoveries that provides rapid response to patients with depressive conditions.

References
1.    Duman RS, Sanacora, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75-90. doi:10.1016/j.neuron.2019.03.013
2.    Saragoussi D, Touya M, Haro JM, et al. Factors associated with failure to achieve remission and with relapse after remission in patients with major depressive disorder in the PERFORM Study. Neuropysychiatr Dis Treat. 2017;13:2151-2165. doi:10.2147/NDT.S136343
3.    Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Ed. American Psychiatric Association;2010. Accessed August 14, 2022. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
4.    Lener MS, Niciu MJ, Ballard ED, et al. Glutamate and GABA systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry. 2017;81(10): 886–897. doi:10.1016/j.biopsych.2016.05.005.
5.    Mughal S, Azhar Y, Siddiqui W. Postpartum depression. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
6.    Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression. JAMA Psychiatry. 2021;78:1-9. doi:10.1001/jamapsychiatry.2021.1559
7.    Ladores S, Corcoran J. Investigating postpartum depression in the adolescent mother using 3 potential qualitative approaches. Clin Med Insights Pediatr. 2019;13:1179556519884042. doi:10.1177/1179556519884042
8.    Farr SL, Dietz PM, O’Hara MW, Burley K, Ko JY. Postpartum anxiety and comorbid depression in a population-based sample of women. J Womens Health (Larchmt). 2014;23(2):120-128. doi:10.1089/jwh.2013.4438
9.    Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353. doi:10.4088/jcp.07m03780
10.    Crowley SK, Girdler SS. Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans? Psychopharmacology. 2014;231(17):3619-3634. doi:10.1007/s00213-014-3572-8
11.    Zorumski CF, Paul SM, Covey DF, Mennerick S. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress. 2019;11:100196. doi:10.1016/j.ynstr.2019.100196
12.    Bali A, Jaggi AS. Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:64-78. doi:10.1016/j.pnpbp.2013.09.005
13.    Lüscher B, Möhler H. Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression ad may foster resilience. F1000Res. 2019;8:F1000 Faculty Rev-751. doi:10.12688/f1000research.18758.1.
14.    Zulresso. Prescribing Information. Sage Therapeutics, Inc; 2022.
15.    Walkery A, Leader LD, Cooke E, VandenBerg A. Review of allopregnanolone agonist therapy for the treatment of depressive disorders. Drug Design Dev Ther. 2021;15:3017-3026. doi:10.2147/DDDT.S240856
16.    Sage Therapeutics and Biogen present further analyses from phase 2 SKYLARK study of zuranolone in postpartum depression at the European College of Neuropsychopharmacology (ECNP) Congress. News release. Biogen; October 17, 2022. Accessed November 21, 2022. https://investors.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-present-further-analyses-phase-3