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Archives of Women's Mental Health

, Volume 22, Issue 1, pp 55–63 | Cite as

GABAA dysregulation as an explanatory model for late-onset postpartum depression associated with weaning and resumption of menstruation

  • Clare S. Burke
  • Leah C. Susser
  • Alison D. HermannEmail author
Review Article

Abstract

It is well established that a subgroup of women are particularly vulnerable to affective dysregulation during times of hormonal fluctuation. One underrecognized reproductive transition may be late-onset postpartum depression (PPD) in the context of weaning from breastfeeding and the resumption of menstruation. The goal of this review is to propose a biologically plausible mechanism for affective dysregulation during these transitions. The relationship between affective symptoms and neurohormonal changes associated with weaning will be investigated through a hypothesis-driven review of relevant literature. Neurosteroids, like allopregnanolone (ALLO), are widely recognized for augmenting GABAergic inhibition and having a powerful anxiolytic effect (Belelli D and Lambert JL, Nature Reviews Neuroscience 6:565-575, 2005). However, when ALLO is administered after prolonged withdrawal, there may be a paradoxical anxiogenic effect (Smith et al., Psychopharmacology 186:323–333, 2006; Shen et al., Nat Neurosci 10:469–477, 2007). Weaning from breastfeeding is a physiologic example of fluctuating levels of ALLO after prolonged withdrawal. We propose that the complex hormonal milieu during weaning and resumption of menstruation may modify GABAA receptors such that ALLO may contribute to rather than ameliorate depressive symptoms in vulnerable individuals. The proposed model provides an initial step for understanding the mechanisms by which the changing hormonal environment during weaning and resumption of menstruation may contribute to an increased risk of depression in a subgroup of women who are hormonally sensitive. Future research investigating this model would be valuable both to identify women at increased risk for developing mood symptoms late in postpartum and to inform treatment for this and related reproductive depressive disorders.

Keywords

Postpartum depression Allopregnanolone GABA Weaning Breastfeeding Menstruation Oxytocin 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. Akwa Y, Purdy RH, Koob GF, Britton KT (1999) The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat. Behav Brain Res 106:119–125PubMedGoogle Scholar
  2. Altemus M, Neeb CC, Davis A, Occhiogrosso M, Nguyen T, Bleiberg KL (2012) Phenotypic differences between pregnancy-onset and postpartum-onset major depressive disorder. J Clin Psychiatry 73(12):1485–1491Google Scholar
  3. Backstrom T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G (2014) Allopregnanolone and mood disorders. Prog Neurobiol 113:88–94PubMedGoogle Scholar
  4. Bernardi F, Pieri M, Stomati M, Luisi S, Palumbo M, Pluchino N, Ceccarelli C, Genazzani AR (2003) Effect of different hormonal replacement therapies on circulating allopregnanolone and dehydroepiandrosterone levels in postmenopausal women. Gynecol Endocrinol 17(1):65–77PubMedGoogle Scholar
  5. Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L (2010) Inhibitory role for GABA in autoimmune inflammation. PNAS 107(6):2580–2585PubMedGoogle Scholar
  6. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR (2000) Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 157(6):924–930PubMedGoogle Scholar
  7. Bloch M, Daly RC, Rubinow DR (2003) Endocrine factors in the etiology of postpartum depression. Compr Psychiatry 44:234–246PubMedGoogle Scholar
  8. Brunton PJ, Donadio MV, Yao ST, Greenwood M, Seckl JR, Murphy D, Russell JA (2015) 5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats. J Neurosci 35(2):666–677PubMedPubMedCentralGoogle Scholar
  9. Cooper P, Murray L (1995) Course and recurrence of postnatal depression: evidence for the specificity of the diagnostic concept. Br J Psychiatry 166:191–195PubMedGoogle Scholar
  10. Cox EQ, Stuebe A, Pearson B, Grewen K, Rubinow D, Meltzer-Brody S (2015) Oxytocin and HPA stress axis reactivity in postpartum women. Psychoneuroendocrinology 55:164–172PubMedPubMedCentralGoogle Scholar
  11. Crowley SK, O’Buckley TK, Schiller CE, Stuebe A, Morrow AL, Girdler SS (2016) Blunted neuroactive steroid and HPA axis responses to stress are associated with reduced sleep quality and negative affect in pregnancy: a pilot study. Psychopharmacology 233(7):1299–1310PubMedPubMedCentralGoogle Scholar
  12. Deligiannidis KM, Sikoglu EM, Shaffer SA, Frederick B, Svenson AE, Kopoyan A, Kosma CA, Rothschild AJ, Moore CM (2013) GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: a preliminary study. J Psychistr Res 47(6):816–828Google Scholar
  13. Deligiannidis KM, Kroll-Desrosiers AR, Mo S, Nguyen HP, Svenson A, Jaitly N, Hall JE, Barton BA, Rothschild AJ, Shaffer SA (2016) Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression. Psychoneuroendocrinology 70:98–107PubMedPubMedCentralGoogle Scholar
  14. Epperson CN, Haga K, Mason GF, Sellers E, Gueorguieva R, Zhang W, Weiss E, Rothman DL, Krystal JH (2002) Cortical γ-aminobutyric acid levels across menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 59(9):851–858PubMedGoogle Scholar
  15. Eser D, Schule C, Baghai TC, Romeo E, Rupprecht R (2006) Neuroactive steroids in depression and anxiety disorders: clinical studies. Neuroendocrinology 84(4):244–254PubMedGoogle Scholar
  16. Fatemi SH, Folsom TD, Rooney RJ, Thuras PD (2013) Expression of GABAA a2-, b1- and ε-receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder. Transl Psychiatry 3:e303PubMedPubMedCentralGoogle Scholar
  17. Forty L, Jones L, Jones I, Caesar S, Cooper C, Hough A, Dean L, Dave S, Farmer A, McGuffin P, Brewster S, Craddock N, Jones I (2006) Familiality of postpartum depression in unipolar disorder: results of a family study. Am J Psychiatry 163(9):1549–1553PubMedGoogle Scholar
  18. Genazzani AD, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, Nappi RE, Luisi S, Palumbo M, Purdy RH, Luisi M (1998) Circulating levels of allopregnanolone in humans: gender, age and endocrine influences. J Clin Endocrinol Metab 83(6):2099–2103PubMedGoogle Scholar
  19. Gilbert Evans SE, Ross LE, Sellers EM, Purdy RH, Romach MK (2005) 3alpha-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol 21(5):268–279PubMedGoogle Scholar
  20. Girdler SS, Straneva PA, Light KC, Pedersen CA, Morrow AL (2001) Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder. Biol Psychiatry 49(9):788–797PubMedGoogle Scholar
  21. Gjerdingen D, Crow S, McGovern P, Miner M, Center B (2011) Changes in depressive symptoms over 0–9 months postpartum. J Women's Health 20(3):381–386Google Scholar
  22. Gordon JL, Girdler SS, Meltzer-Brody SE, Stika CS, Thurston RC, Clark CT, Prairie BA, Moses-Kolko E, Joffe H, Wisner KL (2015) Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: a novel heuristic model. Am J Psychiatry 172(3):227–236PubMedPubMedCentralGoogle Scholar
  23. Gotlib IH, Whiffen VE, Mount JH, Cordy NI (1989) Prevalence rates and demographic characteristics associated with depression in pregnancy and postpartum. J Consult Clin Psychol 57(2):269–274PubMedGoogle Scholar
  24. Gulinello M, Smith SS (2003) Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats. J Pharmacol Exp Ther 305(2):541–548PubMedGoogle Scholar
  25. Gulinello M, Gong QH, Li X, Smith SS (2001) Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat. Brain Res 910:55–66PubMedPubMedCentralGoogle Scholar
  26. Hellgren C, Akerud H, Skalkidou A, Bäckström T, Sundström-Poromaa I (2014) Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology 69(3):147–153PubMedGoogle Scholar
  27. Howie PW, McNeilly AS (1982) Breastfeeding and postpartum ovulation. IPPF Med Bull 16(2):1–3PubMedGoogle Scholar
  28. Hoyt LT, Falconi A (2015) Puberty and perimenopause: reproductive transitions and their implications for women’s health. Soc Sci Med 132:103–112PubMedPubMedCentralGoogle Scholar
  29. Jones I, Cantwell R (2010) The classification of perinatal mood disorders—suggestions for DSMV and ICD11. Arch Womens Ment Health 13:33–36PubMedGoogle Scholar
  30. Kanes S, Colquhoun H, Gunduz-Bruce H, Raines S, Arnold R, Schacterle A, Doherty J, Epperson CN, Deligiannidis KM, Riesenberg R, Hoffmann E, Rubinow D, Jonas J, Paul S, Meltzer-Brody S (2017) Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet 390:480–489PubMedGoogle Scholar
  31. Kimmel M, Clive M, Gispen F, Guintivano J, Brown T, Cox O, Beckmann MW, Kornhuber J, Fasching PA, Osborne LM, Binder E, Payne JL, Kaminsky Z (2016) Oxytocin receptor DNA methylation in postpartum depression. Psychoneuroendocrinology 69:150–160PubMedGoogle Scholar
  32. Klatzkin RR, Morrow AL, Light KC, Pedersen CA, Girdler SS (2006) Associations of histories of depression and PMDD diagnosis with allopregnanolone concentrations following the oral administration of micronized progesterone. Psychoneuroendocrinology 31(10):1208–1219PubMedGoogle Scholar
  33. Kothari C, Wiley J, Moe A, Liepman MR, Tareen RS, Curtis A (2016) Maternal depression is not just a problem early on. Public Health 137:154–161PubMedGoogle Scholar
  34. Lawrie TA, Hofmeyr GJ, De Jager M, Berk M, Paiker J, Viljoen E (1998) A double-blind randomized placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynecol 105(10):1082–1090Google Scholar
  35. Lombardi I, Luisi S, Quirici B, Monteleone P, Bernardi F, Liut M, Casarosa E, Palumbo M, Petraglia F, Genazzani AR (2004) Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome. Gynecol Endocrinol 18(2):79–87PubMedGoogle Scholar
  36. Luisi S, Petraglia F, Benedetto C, Nappi RE, Bernardi F, Fadalti M, Reis FM, Luisi M, Genazzani AR (2000) Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients. J Clin Endocrinol Metab 85(7):2429–2433PubMedGoogle Scholar
  37. MacKenzie G, Maguire J (2014) The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders. Psychopharmacology 231(17):3333–3342PubMedPubMedCentralGoogle Scholar
  38. Maguire J, Mody I (2008) GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron 59(2):207–213PubMedPubMedCentralGoogle Scholar
  39. Martinez PE, Rubinow DR, Nieman LK, Koziol DE, Morrow AL, Schiller CE, Cintron D, Thompson KD, Khine KK, Schmidt PJ (2016) 5α-Reductase inhibition prevents the luteal phase increase in plasma allopregnanolone levels and mitigates symptoms in women with premenstrual dysphoric disorder. Neuropsychopharmacology 41(4):1093–1102PubMedGoogle Scholar
  40. Melon LC, Hooper A, Yang X, Moss SJ, Maguire J (2017) Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum period engenders deficits in postpartum behaviors in mice. Psychoneuroendocrinology 12:003Google Scholar
  41. Misri S, Sinclair D, Kuan A (1997) Breast-feeding and postpartum depression: is there a relationship? Can J Psychiatr 42(10):1061–1065Google Scholar
  42. Monteleone P, Luisi S, Tonetti A, Bernardi F, Genazzani AD, Luisi M, Petraglia F, Genazzani AR (2000) Allopregnanolone concentrations and premenstrual syndrome. Eur J Endocrinol 142(3):269–273PubMedGoogle Scholar
  43. Munk-Olsen T, Munk Laursen T, Bøcker Pedersen C, Mors O, Bo Mortensen P (2006) New parents and mental disorders; a population-based register study. JAMA 296(21):2582–2589PubMedGoogle Scholar
  44. Osborne LM, Gispen F, Sanyal A, Yenokyan G, Meilman S, Payne JL (2017) Lower allopregnanolone during pregnancy predicts postpartum depression: an exploratory study. Psychoneuroendocrinology 79:116–121PubMedPubMedCentralGoogle Scholar
  45. Payne J, Palmer JT, Joffe H (2009) A reproductive subtype of depression: conceptualizing models and moving toward etiology. Harv Rev Psychiatry 17(2):72–86PubMedPubMedCentralGoogle Scholar
  46. Pearlstein T, Yonkers KA, Fayyad R, Gillespie JA (2005) Pretreatment pattern of symptom expression in premenstrual dysphoric disorder. J Affect Disord 85(3):275–282PubMedGoogle Scholar
  47. Rapkin AJ, Morgan M, Goldman L, Brann DW, Simone D, Mahesh VB (1997) Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet Gynecol 90(5):709–714PubMedGoogle Scholar
  48. Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht R (1998) Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 155(7):901–913Google Scholar
  49. Roomruangwong C, Anderson G, Berk M, Stoyanov D, Carvalho AF, Maes M (2018) A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression. Prog Neuro-Psychopharmacol Biol Psychiatry 81:262–274Google Scholar
  50. Schiller CE, Schmidt PJ, Rubinow DR (2014) Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology 231(17):3557–3567PubMedPubMedCentralGoogle Scholar
  51. Schiller CE, Meltzer-Brody S, Rubinow DR (2015) The role of reproductive hormones in postpartum depression. CNS Spectr 20(1):48–59PubMedGoogle Scholar
  52. Schmidt PJ, Purdy RH, Moore PH Jr, Paul SM, Rubinow DR (1994) Circulating levels of anxiolytic steroids in the luteal phase in women with premenstrual syndrome in control subjects. J Clin Endocrinol Metab 79(5):1256–1260PubMedGoogle Scholar
  53. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR (1998) Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 338(4):209–216PubMedGoogle Scholar
  54. Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R (2006) Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity. Mol Psychiatry 11(3):261–272PubMedGoogle Scholar
  55. Schüle C, Baghai TC, di Michele F, Eser D, Pasini A, Schwarz M, Rupprecht R, Romeo E (2007) Effects of combination treatment with mood stabilizers and mirtazapine on plasma concentrations of neuroactive steroids in depressed patients. Psychoneuroendocrinology 32(6):669–680PubMedGoogle Scholar
  56. Schüle C, Nothdurfter C, Rupprecht R (2014) The role of allopregnanolone in depression and anxiety. Prog Neurobiol 113:79–87PubMedGoogle Scholar
  57. Shaaban MM, Sayed GH, Ghaneimah SA (1987) The recovery of ovarian function during breastfeeding. J Steroid Biochem 27(4–6):1043–1052PubMedGoogle Scholar
  58. Sharma V, Corpse C (2008) Case study revisiting the association between breastfeeding and postpartum depression. J Hum Lact 24(1):77–79PubMedGoogle Scholar
  59. Shen H, Gong QH, Yuan M, Smith SS (2005) Short-term steroid treatment increases delta GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects. Neuropharmacology 49(5):573–586PubMedPubMedCentralGoogle Scholar
  60. Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, Williams K, Smith SS (2007) Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at puberty. Nat Neurosci 10(4):469–477PubMedPubMedCentralGoogle Scholar
  61. Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M (2006) Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology 186(3):323–333PubMedGoogle Scholar
  62. Smith AS, Tabbaa M, Lei K, Eastham P, Butler MJ, Linton L, Altshuler R, Liu Y, Wang Z (2016) Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrinology 63:50–58PubMedGoogle Scholar
  63. Soyka M, Preuss UW, Hesselbrock V, Zill P, Koller G, Bondy B (2008) GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res 42(3):184–191PubMedGoogle Scholar
  64. Stowe ZN, Hostetter AL, Newport DJ (2004) The onset of postpartum depression: implications for clinical screening in obstetrical and primary care. Am J Obstet Gynecol 192(2):522–526Google Scholar
  65. Strauss JF, Barbieri RL (eds) (2014) Yen & Jaffe’s reproductive endocrinology: physiology, pathophysiology, and clinical management. Elsevier/Saunders, PhiladelphiaGoogle Scholar
  66. Ströhle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F, Holsboer F, Rupprecht R (1999) Concentrations of 3α-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 45(3):274–277PubMedGoogle Scholar
  67. Ströhle A, Romeo E, diMichele F et al (2003) Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. Arch Gen Psychiatry 60:161–168PubMedGoogle Scholar
  68. Susman V, Katz J (1988) Weaning and depression: another postpartum complication. Am J Psychiatr 145(4):498–501PubMedGoogle Scholar
  69. Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A (1998) Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci 95(6):3239–3244PubMedGoogle Scholar
  70. Viktorin A, Meltzer-Brody S, Kuja-Halkola R, Sullivan PF, Landén M, Lichtenstein P, Magnusson PK (2016) Heritability of perinatal depression and genetic overlap with nonperinatal depression. Am J Psychiatr 173(2):158–165PubMedGoogle Scholar
  71. Wang M (2011) Neurosteroids and GABA-A receptor function. Front Endocrinol (Lausanne) 2:44Google Scholar
  72. Wang M, Seippel L, Purdy RH, Backstrom T (1996) Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5α-pregnane-3,20-dione and 3α-hydroxy-5α-pregnan-20-one. J Clin Endocrinol Metab 81(3):1076–1082PubMedGoogle Scholar
  73. Wieland S, Lan NC, Mirasedeghi S, Gee KW (1991) Anxiolytic activity of the progesterone metabolite 5β-pregnan-3α-ol-20-one. Brain Res 565(2):263–268PubMedGoogle Scholar
  74. Windle RJ, Wood SA, Kershaw YM, Lightman SL, Ingram CD (2013) Adaptive changes in basal and stress-induced HPA activity in lactating and post-lactating female rats. Endocrinology 154(2):749–761PubMedPubMedCentralGoogle Scholar
  75. Zhang K, Pollack S, Ghods A, Dicken C, Isaac B, Adel G, Zeitlan G, Santoro N (2008) Onset of ovulation after menarche in girls: a longitudinal study. J Clin Endocrinol Metab 93(4):1186–1194PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Clare S. Burke
    • 1
  • Leah C. Susser
    • 2
  • Alison D. Hermann
    • 3
    Email author
  1. 1.Weill Cornell Medical CollegeNew YorkUSA
  2. 2.Weill Cornell Medical CollegeWhite PlainsUSA
  3. 3.Weill Cornell Medical CollegeNew YorkUSA

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