Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression

Stephen J Kanes, Helen Colquhoun, James Doherty, Shane Raines, Ethan Hoffmann, David R Rubinow, Samantha Meltzer-Brody, Stephen J Kanes, Helen Colquhoun, James Doherty, Shane Raines, Ethan Hoffmann, David R Rubinow, Samantha Meltzer-Brody

Abstract

Objective: Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study.

Methods: Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD.

Results: All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements.

Conclusions: Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.

Keywords: GABAA receptor; brexanolone; neuroactive steroid; positive allosteric modulation; postpartum depression; psychiatric disorder.

© 2017 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

Figures

Figure 1
Figure 1
Overview of trial design and dosing. Dosing began in the morning of Day 1 with a 12‐hour titration period in which brexanolone was infused at 25%, 50%, then 75% of the maintenance dose for 4 hours at each level. Maintenance dosing began at Hour 12 and continued for 36 hours to achieve a target steady‐state plasma concentration of ~150 nM. At Hour 48, the dose was then tapered over the next 12 hours to 75%, 50%, and then 25% of the maintenance dose to allow physiologic adjustment to decreasing allopregnanolone levels. AE = adverse event; SAE = serious adverse event
Figure 2
Figure 2
Mean total scores for efficacy assessments (N = 4). Mean change from baseline values for HAMD, EPDS, GAD‐7, and PHQ‐9 total scores at each time point assessed. For HAMD, total score ≤ 7 was considered a measure of symptom remission. Planned assessment at end of infusion (Hour 60) revealed a significant decrease versus baseline (p = .001). HAMD = Hamilton Rating Scale for Depression; EPDS = Edinburgh Postnatal Depression Scale; GAD‐7 = Generalized Anxiety Disorder 7‐item Scale; PHQ‐9 = Patient Health Questionnaire

References

    1. Abramowitz, J. S. , Meltzer‐Brody, S. , Leserman, J. , Killenberg, S. , Rinaldi, K. , Mahaffey, B. L. , & Pedersen, C. (2010). Obsessional thoughts and compulsive behaviors in a sample of women with postpartum mood symptoms. Archives of Women's Mental Health, 13, 523–530.
    1. Amin, Z. , Mason, G. F. , Cavus, I. , Krystal, J. H. , Rothman, D. L. , & Epperson, C. N. (2006). The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in women. Pharmacology Biochemistry and Behavior, 84, 635–643.
    1. Andréen, L. , Nyberg, S. , Turkmen, S. , Van Wingen, G. , Fernández, G. , & Bäckström, T. (2009). Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators. Psychoneuroendocrinology, 34, 1121–1132.
    1. Austin, M. P. V. , Middleton, P. , Reilly, N. M. , & Highet, N. J. (2013). Detection and management of mood disorders in the maternity setting: The Australian clinical practice guidelines. Women and Birth. Australian College of Midwives, 26, 2–9.
    1. Beck, C. T. (1995). The effects of postpartum depression on maternal–infant interaction: A meta‐analysis. Nursing Research, 44, 298–304.
    1. Belelli, D. , Harrison, N. L. , Maguire, J. , Macdonald, R. L. , Walker, M. C. , & Cope, D. W. (2009). Extrasynaptic GABAA receptors: Form, pharmacology, and function. The Journal of Neuroscience, 29, 12757–12763.
    1. Bernstein, I. H. , Rush, A. J. , Yonkers, K. , Carmody, T. J. , Woo, A. , Mcconnell, K. , & Trivedi, M. H. (2008). Symptom features of postpartum depression: Are they distinct? Depression and Anxiety, 25, 20–26.
    1. Bloch, M. , Schmidt, P. J. , Danaceau, M. , Murphy, J. , Nieman, L. , & Rubinow, D. R. (2000). Effects of gonadal steroids in women with a history of postpartum depression. American Journal of Psychiatry, 157, 924–930.
    1. Cox, J. L. , Holden, J. M. , & Sagovsky, R. (1987). Detection of postnatal depression: Development of the 10‐item Edinburgh Postnatal Depression scale. British Journal of Psychiatry, 150, 782–786.
    1. De Crescenzo, F. , Perelli, F. , Armando, A. , & Vicari, S. (2014). Selective serotonin reuptake inhibitors (SSRIs) for post‐partum depression (PPD): A systematic review of randomized clinical trials. Journal of Affective Disorders, 152‐154, 39–44.
    1. Earls, M. F. (2010). Incorporating recognition and management of perinatal and postpartum depression into pediatric practice. Pediatrics, 126, 1032–1039.
    1. Fihrer, I. , Mcmahon, C. A. , & Taylor, A. J. (2009). The impact of postnatal and concurrent maternal depression on child behaviour during the early school years. Journal of Affective Disorders, 119, 116–123.
    1. Gavin, N. I. , Gaynes, B. N. , Lohr, K. N. , Meltzer‐Brody, S. , Gartlehner, G. , & Swinson, T. (2005). Perinatal depression: A systematic review of prevalence and incidence. Obstetrics and Gynecology, 106, 1071–1083.
    1. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56–62.
    1. Hellgren, C. , Åkerud, H. , Skalkidou, A. , Bäckström, T. , & Sundström‐Poromaa, I. (2014). Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology, 69, 147–153.
    1. Hendrick, V. , Altshuler, L. , Strouse, T. , & Grosser, S. (2000). Postpartum and nonpostpartum depression: Differences in presentation and response to pharmacologic treatment. Depression and Anxiety, 11, 66–72.
    1. Hoddes, E. , Zarcone, V. , Smythe, H. , Phillips, R. , & Dement, W. C. (1973). Quantification of sleepiness: A new approach. Psychophysiology, 10, 431–436.
    1. Howard, L. M. , Flach, C. , Mehay, A. , Sharp, D. , & Tylee, A. (2011). The prevalence of suicidal ideation identified by the Edinburgh Postnatal Depression Scale in postpartum women in primary care: Findings from the RESPOND trial. BMC Pregnancy and Childbirth, 11, 57.
    1. Kim, D. R. , Epperson, C. N. , Weiss, A. R. , & Wisner, K. L. (2014). Pharmacotherapy of postpartum depression: An update. Expert Opinion on Pharmacotherapy, 15, 1223–1234.
    1. Kimmel, M. C. , Lara‐Cinisomo, S. , Melvin, K. , Di Florio, A. , Brandon, A. , & Meltzer‐Brody, S. (2016). Treatment of severe perinatal mood disorders on a specialized perinatal psychiatry inpatient unit. Archives of Women's Mental Health, 19, 645–653.
    1. Kroenke, K. , Spitzer, R. L. , & Williams, J. B. (2001). The PHQ‐9: Validity of a brief depression severity measure. Journal of General Internal Medicine, 16, 606–613.
    1. Lambert, J. J. , Belelli, D. , Harney, S. C. , Peters, J. A. , & Frenguelli, B. G. (2001). Modulation of native and recombinant GABA(A) receptors by endogenous and synthetic neuroactive steroids. Brain Research. Brain Research Reviews, 37, 68–80.
    1. Luisi, S. , Petraglia, F. , Benedetto, C. , Nappi, R. E. , Bernardi, F. , Fadalti, M. , … Genazzani, A. R. (2000). Serum allopregnanolone levels in pregnant women: Changes during pregnancy, at delivery, and in hypertensive patients. Journal of Clinical Endocrinology and Metabolism, 85, 2429–2433.
    1. Maguire, J. , & Mody, I. (2008). GABAAR plasticity during pregnancy: Relevance to postpartum depression. Neuron, 59, 207–213.
    1. Meltzer‐Brody, S. , Brandon, A. R. , Pearson, B. , Burns, L. , Raines, C. , Bullard, E. , & Rubinow, D. (2014). Evaluating the clinical effectiveness of a specialized perinatal psychiatry inpatient unit. Archives of Women's Mental Health, 17, 107–113.
    1. Misri, S. , Swift, E. , Abizadeh, J. , & Shankar, R. (2016). Overcoming functional impairment in postpartum depressed or anxious women: A pilot trial of desvenlafaxine with flexible dosing. Ther Adv Psychopharmacol, 6, 269–276.
    1. Molyneaux, E. , Howard, L. M. , Mcgeown, H. R. , Karia, A. M. , & Trevillion, K. (2014). Antidepressant treatment for postnatal depression. Cochrane Database of Systematic Reviews, CD002018.
    1. Nappi, R. E. , Petraglia, F. , Luisi, S. , Polatti, F. , Farina, C. , & Genazzani, A. R. (2001). Serum allopregnanolone in women with postpartum “blues”. Obstetrics and Gynecology, 97, 77–80.
    1. O'connor, T. G. , Monk, C. , & Burke, A. S. (2016). Maternal affective illness in the perinatal period and child development: Findings on developmental timing, mechanisms, and intervention. Current Psychiatry Reports, 18, 24.
    1. Paoletti, A. M. , Romagnino, S. , Contu, R. , Orrù, M. M. , Marotto, M. F. , Zedda, P. , … Melis, G. B. (2006). Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA‐A receptor agonist activity. Psychoneuroendocrinology, 31, 485–492.
    1. Posner, K. , Brown, G. K. , Stanley, B. , Brent, D. A. , Yershova, K. V. , Oquendo, M. A. , … Mann, J. J. (2011). The Columbia‐Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults. American Journal of Psychiatry, 168, 1266–1277.
    1. Schiller, C. E. , Meltzer‐Brody, S. , & Rubinow, D. R. (2014a). The role of reproductive hormones in postpartum depression ( pp. 1–12). September: CNS Spectr.
    1. Schiller, C. E. , Schmidt, P. J. , & Rubinow, D. R. (2014b). Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology (Berlin), 5, 3557–3567.
    1. Schiller, C. E. , Meltzer‐Brody, S. , & Rubinow, D. R. (2015). The role of reproductive hormones in postpartum depression. CNS Spectrums, 20, 48–59.
    1. Schule, C. , Nothdurfter, C. , & Rupprecht, R. (2014). The role of allopregnanolone in depression and anxiety. Progress in Neurobiology, 113, 79–87.
    1. Spitzer, R. L. , Kroenke, K. , Williams, J. B. W. , & Löwe, B. (2006). A brief measure for assessing generalized anxiety disorder: The GAD‐7. Archives of Internal Medicine (Chicago, Ill.: 1908), 166, 1092–1097.
    1. Zimmerman, M. , Martinez, J. H. , Young, D. , Chelminski, I. , & Dalrymple, K. (2013). Severity classification on the Hamilton Depression Rating Scale. Journal of Affective Disorders, 150, 384–388.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit