Current Treatment Options in Psychiatry

, Volume 5, Issue 4, pp 377–400 | Cite as

Neurosteroids in the Pathophysiology and Treatment of Mood and Anxiety Disorders

  • Elizabeth C. Perkins
  • D. Jeffrey NewportEmail author
Mood Disorders (C Nemeroff and J Newport, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Mood Disorders


Purpose of review

Neurosteroids have been implicated in the pathophysiology of mood, anxiety, and trauma-related disorders, as well as syndromes specific to women such as premenstrual syndrome, premenstrual dysphoric disorder, postpartum depression, peri- and post-menopausal depression. This review summarizes the role of neurosteroids in the neurobiology of stress and that of pharmaceuticals that modulate neurosteroids in the treatment of these disorders.

Recent findings

Neurosteroids may provide novel treatments of mood and anxiety disorders. While endogenous neurosteroids have poor bioavailability, there are other means by which neurosteroid activity may be pharmacologically modulated. Various synthetic neurosteroids are under investigation. In addition, naturally produced exogenous molecules that positively modulate neurosteroid action at GABAA, as well as agents targeting enzymes that degrade or promote synthesis of neurosteroids, are being used to manipulate neurosteroid systems.


Neurosteroids act on a wide variety of neuroreceptors, particularly GABAA, playing roles in both homeostasis and the pathophysiology of stress. There is evidence that many pharmaceuticals used for mood and anxiety disorders including antidepressants, antipsychotics, and mood stabilizers may be effective secondary to their ability to modulate neurosteroids. Synthetic versions of neurosteroids, as well as pharmaceuticals that act indirectly to increase synthesis of neurosteroids, are being studied as possible treatments for a variety of mood and anxiety disorders.


Neurosteroid GABAA Allopregnanolone DHEA Progesterone Estrogen Depression Anxiety Early life adversity 


Compliance with Ethical Standards

Conflict of Interest

Dr. Perkins has nothing to disclose. Dr. Newport has received research support from Eli Lilly & Company (Lilly), Glaxo SmithKline (GSK), Janssen, National Alliance for Research on Schizophrenia and Depression (NARSAD), National Institutes of Health (NIH), SAGE, Takeda Pharmaceuticals, and Wyeth. He has served on speakers’ bureaus for Astra-Zeneca (AZ), Lilly, GSK, Pfizer and Wyeth, and advisory boards for GSK and Janssen. Neither he nor family members have ever held equity positions in biomedical or pharmaceutical corporations.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pisu MG, Serra M. Neurosteroids and neuroactive drugs in mental disorders. Life Sci. 2004;74:3181–97.PubMedGoogle Scholar
  2. 2.
    Dubrovsky BO. Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(2):169–92.PubMedGoogle Scholar
  3. 3.
    Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006;84:644–55.PubMedGoogle Scholar
  4. 4.
    Wojtal K, Trojnar MK, Czuczwar SJ. Endogenous neuroprotective factors: neurosteroids. Pharmacol Rep. 2006;58:335–40.PubMedGoogle Scholar
  5. 5.
    Aszalós Z. Neurological and psychiatric aspects of some endocrine diseases. The role of neurosteroids and neuroactive steroids. Orvosi Hetilap. 2007;148(41):1929–37.PubMedGoogle Scholar
  6. 6.
    Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci. 1999;22:410–6.PubMedGoogle Scholar
  7. 7.
    Espallergues J, Givalois L, Temsamani J, Laruelle C, Maurice T. The 3β-hydroxysteriod dehydrogenase inhibitor trilostane shows antidepressant properties in mice. Psychoneuroendocrinology. 2009;34:644–59.PubMedGoogle Scholar
  8. 8.
    •• Tuem KB, Atey TM. Neuroactive steroids: receptor interactions and responses. Front Neurol. 2017;8:442 This is an excellent review of the physiology of neurosteroids, addressing their mechanisms of action, biosynthesis and metabolism, and biological effects at a wide assortment of receptor types.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Stoffel-Wagner B. Neurosteroid biosynthesis in the human brain and its clinical implications. Ann N Y Acad Sci. 2003;1007:64–78.PubMedGoogle Scholar
  10. 10.
    Borowicz KK, Piskorska B, Banach M, Czuczwar SJ. Neuroprotective actions of neurosteroids. Front Endocrinol. 2011;2:50.Google Scholar
  11. 11.
    Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311–22.PubMedGoogle Scholar
  12. 12.
    Maurice T, Phan VL, Urani A, Kamei H, Noda Y, Nabeshima T. Neuroactive neurosteroids as endogenous effectors for the sigma1 receptor: Pharmacological evidence and therapeutic opportunities. Jpn J Pharmacol. 1999;81(2):125–55.PubMedGoogle Scholar
  13. 13.
    Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, et al. Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci U S A. 2001;98:2849–54.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct. 2012;8:61.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Eser D, Romeo E, Baghai TC, di Michele F, Schule C, Pasini A, et al. Neuroactive steroids as modulators of depression and anxiety. Neuroscience. 2006;138:1041–8.PubMedGoogle Scholar
  16. 16.
    Sabeti J, Nelson TE, Purdy RH, Gruol DL. Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors. Hippocampus. 2007;17(5):349–69.PubMedGoogle Scholar
  17. 17.
    Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, et al. Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of post-finasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med. 2013;10(10):2598–603.PubMedGoogle Scholar
  18. 18.
    Wang Q. The roles of estrogen and progestin in epileptogenesis and their mechanisms of action. Sheng Li Ke Xue Jin Zhan. 2000;31(3):231–3.PubMedGoogle Scholar
  19. 19.
    Prossnitz ER, Maggiolini M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol. 2009;308(1–2):32–8.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Stárka L, Dušková M, Hill M. Dehydroepiandrosterone: a neuroactive steroid. J Steroid Biochem Mol Biol. 2015;145:254–60.PubMedGoogle Scholar
  21. 21.
    Moura PJ, Petersen SL. Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy. Rev Neurosci. 2010;21:363–80.PubMedGoogle Scholar
  22. 22.
    Groves NJ, McGrath JJ, Burne THJ. Vitamin D as a neurosteroid affecting the developing and adult brain. Ann Rev Nutr. 2014;34:117–41.Google Scholar
  23. 23.
    Rasmusson AM, Marx CE, Pineles SL, Locci A, Scioli-Salter ER, Nillni YI, et al. Neuroactive steroids and PTSD treatment. Neurosci Lett. 2017;649:156–63.PubMedGoogle Scholar
  24. 24.
    Nagai T, Noda Y, Nozaki A, Nabeshima T. Neuroactive steroid and stress response. Nihon Shinkei Seishin Yakurigaku Zasshi. 2001;21(5):157–62.PubMedGoogle Scholar
  25. 25.
    Strous RD, Maayan R, Weizman A. The relevance of neurosteroids to clinical psychiatry: from the laboratory to the bedside. Eur Neuropsychopharmacol. 2006;16:155–69.PubMedGoogle Scholar
  26. 26.
    Rupprecht R, di Michele F, Hermann B, Strohle A, Lancel M, Romeo E, et al. Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. Brain Res Brain Res Rev. 2001;37(1–3):59–67.PubMedGoogle Scholar
  27. 27.
    Girdler SS, Klatzkin R. Neurosteroids in the context of stress: implications for depressive disorders. Pharmacol Ther. 2007;116:125–39.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci U S A. 2003;100(24):14439–44.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA. 1999;96:12905–10.PubMedGoogle Scholar
  30. 30.
    Akk G, Covey DF, Evers AS, Steinbach JH, Zorumski CF, Mennerick S. Mechanisms of neurosteroid interactions with GABAA receptors. Pharmacol Ther. 2007;116:35–57.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Dine J, Kühne C, Deussing JM, Eder M. Optogenetic evocation of field inhibitory postsynaptic potentials in hippocampal slices: a simple and reliable approach for studying pharmacological effects on GABAA and GABAB receptor-mediated neurotransmission. Front Cell Neurosci. 2014;8:2.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986;232(4753):1004–7.PubMedGoogle Scholar
  33. 33.
    Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol. 1992;38:379–95.PubMedGoogle Scholar
  34. 34.
    Lambert JJ, Belelli D, Hill-Venning C, Peters JA. Neurosteroids and GABAA receptor function. Trend Pharmacol Sci. 1995;16:295–303.Google Scholar
  35. 35.
    Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol. 1995;7(3):171–7.PubMedGoogle Scholar
  36. 36.
    Poisbeau P, Feltz P, Schlichter R. Modulation of GABAA receptor-mediated IPSCs by neuroactive steroids in a rat hypothalamo-hypophyseal coculture model. J Physiol. 1997;500(Pt. 2):475–85.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Calza A, Sogliano C, Santoru F, Marra C, Angioni MM, Mostallino MC, et al. Neonatal exposure to estradiol in rats influences neuroactive steroid concentrations, GABAA receptor expression, and behavioral sensitivity to anxiolytic drugs. J Neurochem. 2010;113(5):1285–95.PubMedGoogle Scholar
  38. 38.
    Sundstrom Poromoaa I, Smith S, Gulinello M. GABA receptors, progesterone and premenstrual dysphoric disorder. Arch Womens Ment Health. 2003;6:23–41.Google Scholar
  39. 39.
    Brot MD, Akwa Y, Purdy RH, Koob GF, Britton KT. The anxiolytic-like effects of the neurosteroid allopregnanolone: interactions with GABAA receptors. Eur J Pharmacol. 1997;325(1):1–7.PubMedGoogle Scholar
  40. 40.
    Reddy DS, Kulkarni SK. Role of GABAA and mitochondrial diazepam binding inhibitor receptors in the anti-stress activity of neurosteroids in mice. Psychopharmacology (Berl). 1996;128:280–92.Google Scholar
  41. 41.
    Pick CG, Peter Y, Terkel J, Gavish M, Weizman R. Effect of the neuroactive steroid α-THDOC on staircase test behavior in mice. Psychopharmacology (Berl). 1996;128(1):61–6.Google Scholar
  42. 42.
    Gerak LR, France CP. Quantitative analyses of antagonism: combinations of midazolam and either flunitrazepam or pregnanolone in rhesus monkeys discriminating midazolam. J Pharmacol Exp Ther. 2012;340:742–9.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Biggio F, Gorini G, Caria S, Murru L, Mostallino MC, Sanna E, et al. Plastic neuronal changes in GABAA receptor gene expression induced by progesterone metabolites: in vitro molecular and functional studies. Pharmacol Biochem Behav. 2006;84(4):545–54.PubMedGoogle Scholar
  44. 44.
    Hauser CA, Wetzel CH, Rupprecht R, Holsboer F. Allopregnanolone acts as an inhibitory modulator on α1- and α6-containing GABAA receptors. Biochem Biophys Res Commun. 1996;219:531–6.PubMedGoogle Scholar
  45. 45.
    Follesa P, Concas A, Porcu P, Sanna E, Serra M, Mostallino MC, et al. Role of allopregnanolone in regulation of GABAA receptor plasticity during long-term exposure to and withdrawal from progesterone. Brain Res Rev. 2001;37(1–3):81–90.PubMedGoogle Scholar
  46. 46.
    Gerak LR. Selective changes in sensitivity to benzodiazepines, and not other positive GABAA modulators, in rats receiving flunitrazepam chronically. Psychopharmacology. 2009;204:667–77.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Kaura V, Ingram CD, Gartside SE, Young AH, Judge SJ. The progesterone metabolite allopregnanolone potentiates GABAA receptor-mediated inhibition of 5-HT neuronal activity. Eur Neuropsychopharm. 2007;17:108–15.Google Scholar
  48. 48.
    Robichaud M, Debonnel G. Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats. Int J Neuropsychopharmacol. 2006;9(2):191–200.PubMedGoogle Scholar
  49. 49.
    Klink R, Robichaud M, Debonnel G. Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part I: effects of gender and pregnancy. Neuropharmacology. 2002;43:1119–28.PubMedGoogle Scholar
  50. 50.
    Robichaud M, Debonnel G. Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids. J Endocrinol. 2004;182:11–21.PubMedGoogle Scholar
  51. 51.
    Frokjaer VG, Erritzoe D, Juul A, Nielsen FA, Holst K, Svarer C, et al. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding. Psychoneuroendocrinology. 2010;35:1311–20.PubMedGoogle Scholar
  52. 52.
    Maurice T. Neurosteroids and sigma1 receptors, biochemical and behavioral relevance. Pharmacopsychiatry. 2004;37(Suppl 3):S171–82.PubMedGoogle Scholar
  53. 53.
    Noda Y, Kamei H, Kamei Y, Nagai T, Nishida M, Nabeshima T. Neurosteroids ameliorate conditioned fear stress: an association with sigma receptors. Neuropsychopharmacology. 2000;23:276–84.PubMedGoogle Scholar
  54. 54.
    Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma-1 receptor function: behavioral consequences and therapeutic opportunities. Brain. 2001;37:116–32.Google Scholar
  55. 55.
    Bergeron R, de Montigny C, Debonnel G. Pregnancy reduces brain sigma receptor function. Br J Pharmacol. 1999;127:1769–76.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Reddy DS, Kaur G, Kulkarni SK. Sigma1 receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test. Neuroreport. 1998;9:3069–73.PubMedGoogle Scholar
  57. 57.
    Wang Y, Tang L, Yin W, Chen J, Leng T, Zheng X, et al. Simultaneous determination of seven neuroactive steroids associated with depression in rat plasma and brain by high performance liquid chromatography-tandem mass spectrometry. Anal Sci. 2016;32(9):981–8.PubMedGoogle Scholar
  58. 58.
    Starkey NJ, Bridges NJ. The effects of acute, chronic and withdrawn progesterone in male and female Mongolian gerbils (Meriones unguiculatus) in two tests of anxiety. Behav Brain Res. 2010;207(2):490–9.PubMedGoogle Scholar
  59. 59.
    Childs E, Van Dam NT, de Wit H. Effects of acute progesterone administration upon responses to acute psychosocial stress in men. Exp Clin Psychopharmacol. 2010;18(1):78–86.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Reddy DS, O’Malley BW, Rogawski MA. Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology. 2005;48(1):14–24.PubMedGoogle Scholar
  61. 61.
    Murray HE, Gillies GE. Investigation of the ontogenetic patterns of rat hypothalamic dopaminergic neurone morphology and function in vitro. J Endocrinol. 1993;139(3):403–14.PubMedGoogle Scholar
  62. 62.
    Zimmerberg B, Brown RC. Prenatal experience and postnatal stress modulate the adult neurosteroid and catecholaminergic stress responses. Int J Dev Neurosci. 1998;16(3–4):217–28.PubMedGoogle Scholar
  63. 63.
    Grobin AC, Roth RH, Deutch AY. Regulation of the prefrontal cortical dopamine system by the neuroactive steroid 3α,21-dihydroxy-5α-pregnane-20-one. Brain Res. 1992;578(1–2):351–6.PubMedGoogle Scholar
  64. 64.
    Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A. 1991;88(10):4553–7.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Barbaccia ML, Roscetti G, Bolacchi F, Concas A, Mostallino MC, Purdy RH, et al. Stress-induced increase in brain neuroactive steroids: antagonism by abecarnil. Pharmacol Biochem Behav. 1996;54(1):205–10.PubMedGoogle Scholar
  66. 66.
    Genazzani AR, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, et al. Circulating levels of allopregnanolone in humans: gender, age, and endocrine influences. J Clin Endocrinol Metab. 1998;83(6):2099–103.PubMedGoogle Scholar
  67. 67.
    Patchev VK, Hassan AH, Holsboer DF, Almeida OF. The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology. 1996;15(6):533–40.PubMedGoogle Scholar
  68. 68.
    Naert G, Maurice T, Tapia-Arancibia L, Givalois L. Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats. Psychoneuroendocrinology. 2007;32(8–10):1062–78.PubMedGoogle Scholar
  69. 69.
    Calogero AE, Bernardini R, Gold PW, Chrousos GP. Regulation of rat hypothalamic corticotropin-releasing hormone secretion in vitro: potential clinical implications. Adv Exp Med Biol. 1988;245:167–81.PubMedGoogle Scholar
  70. 70.
    Patchev VK, Shoaib M, Holsboer F, Almeida OF. The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus. Neuroscience. 1994;62(1):265–71.PubMedGoogle Scholar
  71. 71.
    Girdler SS, Lindgren M, Porcu P, Rubinow DR, Johnson JL, Morrow AL. A history of depression in women is associated with an altered GABAergic neuroactive steroid profile. Psychoneuroendocrinology. 2012;37(4):543–53.PubMedGoogle Scholar
  72. 72.
    Talani G, Biggio F, Licheri V, Locci V, Biggio G, Sanna E. Isolation rearing reduces neuronal excitability in dentate gyrus granule cells of adolescent C57BL/6 J mice: role of GABAergic tonic currents and neurosteroids. Front Cell Neurosci. 2016;10:158.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, et al. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABAA receptor function in rat brain. J Neurochem. 2000;75(2):732–40.PubMedGoogle Scholar
  74. 74.
    Turkmen S, Backstrom T, Wahlstrom G, Andreen L, Johansson IM. Tolerance to allopregnanolone with focus on the GABAA receptor. Br J Pharmacol. 2011;162(2):311–27.PubMedPubMedCentralGoogle Scholar
  75. 75.
    MacKenzie EM, Odontiadis J, Le Mellédo JM, Prior TI, Baker GB. The relevance of neuroactive steroids in schizophrenia, depression, and anxiety disorders. Cell Mol Neurobiol. 2007;27(5):541–74.PubMedGoogle Scholar
  76. 76.
    Bali A, Jaggi AS. Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:64–78.PubMedGoogle Scholar
  77. 77.
    Reddy DS. Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions. Neuroscience. 2006;138(3):911–20.PubMedGoogle Scholar
  78. 78.
    Llidó A, Mòdol L, Darbra S, Pallarès M. Interaction between neonatal allopregnanolone administration and early maternal separation: effects on adolescent and adult behaviors in male rat. Horm Behav. 2013;63(4):577–85.PubMedGoogle Scholar
  79. 79.
    Zimmerberg B, Kajunski EW. Sexually dimorphic effects of postnatal allopregnanolone on the development of anxiety behavior after early deprivation. Pharmacol Biochem Behav. 2004;78(3):465–71.PubMedGoogle Scholar
  80. 80.
    Mitev YA, Darwish M, Wolf SS, Holsboer F, Almeida OF, Patchev VK. Gender differences in the regulation of 3α-hydroxysteroid dehydrogenase in rat brain and sensitivity to neurosteroid-mediated stress protection. Neuroscience. 2003;120(2):541–9.PubMedGoogle Scholar
  81. 81.
    Evans J, Sun Y, McGregor A, Connor B. Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress. Neuropharmacology. 2012;63(8):1315–26.PubMedGoogle Scholar
  82. 82.
    Patchev VK, Montkowski A, Rouskova D, Koranyi L, Holsboer F, Almeida OF. Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events. J Clin Invest. 1997;99(5):962–6.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Pisu MG, Garau A, Olla P, Biggio F, Utzeri C, Dore R, et al. Altered stress responsiveness and hypothalamic-pituitary-adrenal axis function in male rat offspring of socially isolated parents. J Neurochem. 2013;126(4):493–502.PubMedGoogle Scholar
  84. 84.
    Youssef NA, Lockwood L, Su S, Hao G, Rutten BPF. The effects of trauma, with or without PTSD, on the transgenerational DNA methylation alterations in human offsprings. Brain Sci. 2018;8(5):83.PubMedCentralGoogle Scholar
  85. 85.
    Yeshurun S, Hannan AJ. Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. Mol Psychiatry. 2018.
  86. 86.
    Heydari B, Le Mellédo JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med. 2002;32(5):929–33.PubMedGoogle Scholar
  87. 87.
    Semeniuk T, Jhangri GS, Le Mellédo JM. Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci. 2001;13(3):396–8.PubMedGoogle Scholar
  88. 88.
    Laufer N, Maayan R, Hermesh H, Marom S, Gilad R, Strous R, et al. Involvement of GABAA receptor modulating neuroactive steroids in patients with social phobia. Psychiatry Res. 2005;137(1–2):131–6.PubMedGoogle Scholar
  89. 89.
    Le Mellédo JM, Baker GB. Neuroactive steroids and anxiety disorders. J Psychiatry Neurosci. 2002;27(3):161–5.PubMedPubMedCentralGoogle Scholar
  90. 90.
    George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry. 1994;35(10):775–80.PubMedGoogle Scholar
  91. 91.
    Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A. 1998;95(6):3239–44.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Romeo E, Ströhle A, Spalletta G, di Michele F, Hermann B, Holsboer F, et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry. 1998;155(7):910–3.PubMedGoogle Scholar
  93. 93.
    Ströhle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F, et al. Fluoxetine decreases concentrations of 3α,5α-tetrahydrodeoxycorticosterone (THDOC) in major depression. J Psychiatr Res. 2000;34(3):183–6.PubMedGoogle Scholar
  94. 94.
    Barrett-Connor E, von Mühlen D, Laughlin GA, Kripke A. Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study. J Am Geriatr Soc. 1999;47(6):685–91.PubMedGoogle Scholar
  95. 95.
    • Dichtel LE, Lawson EA, Schorr M, Meenaghan E, Paskal ML, Eddy KT, et al. Neuroactive steroids and affective symptoms in women across the weight spectrum. Neuropsychopharmacology. 2018;43(6):1436–44 This study reported that serum allopregnanolone levels were lower among obese women and those with anorexia nervosa and that low allopregnanolone levels were associated with more severe anxiety and depressive symptoms.PubMedGoogle Scholar
  96. 96.
    Eser D, Schüle C, Romeo E, Baghai TC, di Michele F, Pasini A, et al. Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders. Psychopharmacology (Berl). 2006;186(3):373–87.Google Scholar
  97. 97.
    Tait GR, McManus K, Bellavance F, Lara N, Chrapko W, Le Mellédo JM. Neuroactive steroid changes in response to challenge with the panicogenic agent pentagastrin. Psychoneuroendocrinology. 2002;27(4):417–29.PubMedGoogle Scholar
  98. 98.
    Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73(9):1220–3.PubMedGoogle Scholar
  99. 99.
    Melcangi RC, Santi D, Spezzano R, Grimoldi M, Tabacchi T, Fusco ML, et al. Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. J Steroid Biochem Mol Biol. 2017;171:229–35.PubMedGoogle Scholar
  100. 100.
    Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, et al. Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma. J Steroid Biochem Mol Biol. 2015;146:74–9.PubMedGoogle Scholar
  101. 101.
    Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol. 2011;347(1–2):121–7.PubMedGoogle Scholar
  102. 102.
    Milman A, Zohar O, Maayan R, Weizman R, Pick CG. DHEAS repeated treatment improves cognitive and behavioral deficits after mild traumatic brain injury. Eur Neuropsychopharmacol. 2008;18(3):181–7.PubMedGoogle Scholar
  103. 103.
    Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999;156(4):646–9.PubMedGoogle Scholar
  104. 104.
    • Šrámková M, Dušková M, Hill M, Bičíková M, Řípová D, Mohr P, et al. The role of steroids in the prediction of affective disorders in adult men. Steroids. 2017;121:47–53 This study suggests that low levels of sulfated neurosteroids, e.g., DHEA sulfate, pregNENolone sulfate, etc., may play a role in the pathophysiology of depression in men.PubMedGoogle Scholar
  105. 105.
    Schüle C, Eser D, Baghai TC, Nothdurfter C, Kessler JS, Rupprecht R. Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs? Neuroscience. 2011;191:55–77.PubMedGoogle Scholar
  106. 106.
    Verleye M, Akwa Y, Liere P, Ladurelle N, Pianos A, Eychenne B, et al. The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol Biochem Behav. 2005;82(4):712–20.PubMedGoogle Scholar
  107. 107.
    Liere P, Pianos A, Oudinet JP. Schumacher M1, Akwa Y. Differential effects of the 18-kDa translocator protein (TSPO) ligand etifoxine on steroidogenesis in rat brain, plasma and steroidogenic glands: pharmacodynamic studies. Psychoneuroendocrinology. 2017;83:122–34.PubMedGoogle Scholar
  108. 108.
    Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, et al. Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity. Mol Psychiatry. 2006;11(3):261–72.PubMedGoogle Scholar
  109. 109.
    Schüle C, Baghai TC, Eser D, Schwarz M, Bondy B, Rupprecht R. Effects of mirtazapine on dehydroepiandrosterone-sulfate and cortisol plasma concentrations in depressed patients. J Psychiatr Res. 2009;43(5):538–45.PubMedGoogle Scholar
  110. 110.
    Schüle C, Baghai TC, di Michele F, Eser D, Pasini A, Romeo E, et al. Mirtazapine does not influence tetrahydrodeoxycorticosterone levels in depressed patients. World J Biol Psychiatry. 2010;11(2 Pt 2):308–13.PubMedGoogle Scholar
  111. 111.
    Pinna G, Costa E. Guidotti A. SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. Curr Opin Pharmacol. 2009;9(1):24–30.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Khisti RT, Chopde CT, Jain SP. Antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav. 2000;67(1):137–43.PubMedGoogle Scholar
  113. 113.
    Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A. 1999;96(23):13512–7.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Trauger JW, Jiang A, Stearns BA, LoGrasso PV. Kinetics of allopregnanolone formation catalyzed by human 3α-hydroxysteroid dehydrogenase type III (AKR1C2). Biochemistry. 2002;41(45):13451–9.PubMedGoogle Scholar
  115. 115.
    Fry JP, Li KY, Devall AJ, Cockcroft S, Honour JW, Lovick TA. Fluoxetine elevates allopregnanolone in female rat brain but inhibits a steroid microsomal dehydrogenase rather than activating an aldo-keto reductase. Br J Pharmacol. 2014;171(24):5870–80.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Niwa T, Hiroi T, Tsuzuki D, Yamamoto S, Narimatsu S, Fukuda T, et al. Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine. catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004;129(1–2):117–23.PubMedGoogle Scholar
  117. 117.
    Turan Ş, Yıldırım A, Aksoy-Poyraz C, Bolayırlı M, Savrun M. Effects of electroconvulsive therapy on plasma levels of neuroactive steroids in inpatients with major depression. Int J Psychiatry Clin Pract. 2014;18(4):261–4.PubMedGoogle Scholar
  118. 118.
    Schüle C, di Michele F, Baghai T, Romeo E, Bernardi G, Zwanzger P, et al. Influence of sleep deprivation on neuroactive steroids in major depression. Neuropsychopharmacology. 2003;28(3):577–81.PubMedGoogle Scholar
  119. 119.
    Baghai TC, di Michele F, Schüle C, Eser D, Zwanzger P, Pasini A, et al. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology. 2005;30(6):1181–6.PubMedGoogle Scholar
  120. 120.
    Padberg F, di Michele F, Zwanzger P, Romeo E, Bernardi G, Schüle C, et al. Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression. Neuropsychopharmacology. 2002;27(5):874–8.PubMedGoogle Scholar
  121. 121.
    Eser D, Schüle C, Baghai TC, Romeo E, Uzunov DP, Rupprecht R. Neuroactive steroids and affective disorders. Pharmacol Biochem Behav. 2006;84(4):656–66.PubMedGoogle Scholar
  122. 122.
    Le Mellédo JM, Baker G. Role of progesterone and other neuroactive steroids in anxiety disorders. Expert Rev Neurother. 2004;4(5):851–60.PubMedGoogle Scholar
  123. 123.
    Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ. Decreased brain GABAA-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55(8):715–20.PubMedGoogle Scholar
  124. 124.
    Ströhle A, Romeo E, di Michele F, Pasini A, Yassouridis A, Holsboer F, et al. GABAA receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment. Am J Psychiatry. 2002;159(1):145–7.PubMedGoogle Scholar
  125. 125.
    Ströhle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, et al. Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. Arch Gen Psychiatry. 2003;60(2):161–8.PubMedGoogle Scholar
  126. 126.
    Reddy DS. Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions? Trends Pharmacol Sci. 2003;24(3):103–6.PubMedGoogle Scholar
  127. 127.
    Eser D, di Michele F, Zwanzger P, Pasini A, Baghai TC, Schüle C, et al. Panic induction with cholecystokinin-tetrapeptide (CCK-4) Increases plasma concentrations of the neuroactive steroid 3α,5α tetrahydrodeoxycorticosterone (3α,5α-THDOC) in healthy volunteers. Neuropsychopharmacology. 2005;30(1):192–5.PubMedGoogle Scholar
  128. 128.
    Zwanzger P, Eser D, Romeo E, di Michele F, Baghai TC, Pasini A, et al. Changes in CCK-4 induced panic after treatment with the GABA-reuptake inhibitor tiagabine are associated with an increase in 3α,5α-tetrahydrodeoxycorticosterone concentrations. Psychoneuroendocrinology. 2009;34(10):1586–9.PubMedGoogle Scholar
  129. 129.
    Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 2014;113:79–87.PubMedGoogle Scholar
  130. 130.
    Brambilla F, Mellado C, Alciati A, Pisu MG, Purdy RH, Zanone S, et al. Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder. Psychiatry Res. 2005;135(3):185–90.PubMedGoogle Scholar
  131. 131.
    Lovick TA. Sex determinants of experimental panic attacks. Neurosci Biobehav Rev. 2014;46(Pt 3):465–71.PubMedGoogle Scholar
  132. 132.
    Brambilla F, Biggio G, Pisu MG, Bellodi L, Perna G, Bogdanovich-Djukic V, et al. Neurosteroid secretion in panic disorder. Psychiatry Res. 2003;118(2):107–16.PubMedGoogle Scholar
  133. 133.
    Ströhle A, Holsboer F. Stress responsive neurohormones in depression and anxiety. Pharmacopsychiatry. 2003;36(Suppl 3):S207–14.PubMedGoogle Scholar
  134. 134.
    Yehuda R, Brand SR, Golier JA, Yang RK. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr Scand. 2006;114(3):187–93.PubMedGoogle Scholar
  135. 135.
    Spivak B, Maayan R, Kotler M, Mester R, Gil-Ad I, Shtaif B, et al. Elevated circulatory level of GABAA--antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol Med. 2000;30(5):1227–31.PubMedGoogle Scholar
  136. 136.
    Rasmusson AM, Pinna G, Paliwal P, Weisman D, Gottschalk C, Charney D, et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry. 2006;60(7):704–13.PubMedGoogle Scholar
  137. 137.
    Scioli-Salter ER, Forman DE, Otis JD, Gregor K, Valovski I, Rasmusson AM. The shared neuroanatomy and neurobiology of comorbid chronic pain and PTSD: therapeutic implications. Clin J Pain. 2015;31(4):363–74.PubMedGoogle Scholar
  138. 138.
    Butterfield MI, Stechuchak KM, Connor KM, Davidson JR, Wang C, MacKuen CL, et al. Neuroactive steroids and suicidality in posttraumatic stress disorder. Am J Psychiatry. 2005;162(2):380–2.PubMedGoogle Scholar
  139. 139.
    Nagaya N, Acca GM, Maren S. Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats. Front Behav Neurosci. 2015;9:205.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Pineles SL, Nillni YI, King MW, Patton SC, Bauer MR, Mostoufi SM, et al. Extinction retention and the menstrual cycle: different associations for women with posttraumatic stress disorder. J Abnorm Psychol. 2016;125(3):349–55.PubMedGoogle Scholar
  141. 141.
    Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470(7335):492–7.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Pinna G, Rasmusson AM. Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci. 2014;8:256.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Rasmusson AM, Marx CE, Jain S, Farfel GM, Tsai J, Sun X, et al. Stein MB. A randomized controlled trial of ganaxolone in posttraumatic stress disorder. Psychopharmacology (Berl). 2017;234(15):2245–57.Google Scholar
  144. 144.
    Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G. Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder. J Clin Psychopharmacol. 2006;26(4):379–84.PubMedGoogle Scholar
  145. 145.
    Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI, et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology. 2006;31(6):1249–63.PubMedGoogle Scholar
  146. 146.
    Marx CE, Yuan P, Kilts JD, Madison RD, Shampine LJ, Manji HK. Neuroactive steroids, mood stabilizers, and neuroplasticity: alterations following lithium and changes in Bcl-2 knockout mice. Int J Neuropsychopharmacol. 2008;11(4):547–52.PubMedGoogle Scholar
  147. 147.
    Marx CE, VanDoren MJ, Duncan GE, Lieberman JA, Morrow AL. Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology. 2003;28(1):1–13.PubMedGoogle Scholar
  148. 148.
    Marx CE, Shampine LJ, Khisti RT, Trost WT, Bradford DW, Grobin AC, et al. Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions. Pharmacol Biochem Behav. 2006;84(4):609–17.PubMedGoogle Scholar
  149. 149.
    Barbaccia ML, Affricano D, Purdy RH, Maciocco E, Spiga F, Biggio G. Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat. Neuropsychopharmacology. 2001;25(4):489–97.PubMedGoogle Scholar
  150. 150.
    Locchi F, Dall’olio R, Gandolfi O, Rimondini R. Olanzapine counteracts stress-induced anxiety-like behavior in rats. Neurosci Lett. 2008;438(2):146–9.PubMedGoogle Scholar
  151. 151.
    Brown ES, Park J, Marx CE, Hynan LS, Gardner C, Davila D, et al. Holmes T. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867–73.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Lovick TSSRI. the female brain--potential for utilizing steroid-stimulating properties to treat menstrual cycle-linked dysphorias. J Psychopharmacol. 2013;27(12):1180–5.PubMedGoogle Scholar
  153. 153.
    Guille C, Spencer S, Cavus I, Epperson CN. The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment. Epilepsy Behav. 2008;13(1):12–24.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Kask K, Bäckström T, Lundgren P, Sundström Poromaa I. Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls. Pharmacol Biochem Behav. 2009;92(4):608–13.PubMedGoogle Scholar
  155. 155.
    Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338(4):209–16.PubMedGoogle Scholar
  156. 156.
    Wang M, Seippel L, Purdy RH, Bãckström T. 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. 1996;81(3):1076–82.PubMedGoogle Scholar
  157. 157.
    Freeman EW, Frye CA, Rickels K, Martin PA, Smith SS. Allopregnanolone levels and symptom improvement in severe premenstrual syndrome. J Clin Psychopharmacol. 2002;22(5):516–20.PubMedGoogle Scholar
  158. 158.
    Devall AJ, Santos JM, Fry JP, Honour JW, Brandão ML, Lovick TA. Elevation of brain allopregnanolone rather than 5-HT release by short term, low dose fluoxetine treatment prevents the estrous cycle-linked increase in stress sensitivity in female rats. Eur Neuropsychopharmacol. 2015;25(1):113–23.PubMedGoogle Scholar
  159. 159.
    Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, et al. Paradoxical effects of GABAA modulators may explain sex steroid induced negative mood symptoms in some persons. Neuroscience. 2011;191:46–54.PubMedGoogle Scholar
  160. 160.
    Melcangi RC, Panzica GC. Allopregnanolone: state of the art. Prog Neurobiol. 2014;113:1–5.PubMedGoogle Scholar
  161. 161.
    Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, et al. Allopregnanolone and mood disorders. Prog Neurobiol. 2014;113:88–94.PubMedGoogle Scholar
  162. 162.
    Licheri V, Talani G, Gorule AA, Mostallino MC, Biggio G, Sanna E. Plasticity of GABAA receptors during pregnancy and postpartum period: From Gene to Function. Neural Plast. 2015;2015:170435.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Smith SS. Withdrawal properties of a neuroactive steroid: implications for GABAA receptor gene regulation in the brain and anxiety behavior. Steroids. 2002;67(6):519–28.PubMedGoogle Scholar
  164. 164.
    Segebladh B, Bannbers E, Moby L, Nyberg S, Bixo M, Bäckström T, et al. Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder. Arch Womens Ment Health. 2013;16(2):131–7.PubMedGoogle Scholar
  165. 165.
    Epperson CN, Haga K, Mason GF, Sellers E, Gueorguieva R, Zhang W, et al. Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry. 2002;59(9):851–8.PubMedGoogle Scholar
  166. 166.
    Sundström I, Andersson A, Nyberg S, Ashbrook D, Purdy RH, Bäckström T. Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocrinology. 1998;67(2):126–38.PubMedGoogle Scholar
  167. 167.
    Sundström I, Ashbrook D, Bäckström T. Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study. Psychoneuroendocrinology. 1997;22(1):25–38.PubMedGoogle Scholar
  168. 168.
    Sundström I, Bäckström T. Citalopram increases pregnanolone sensitivity in patients with premenstrual syndrome: an open trial. Psychoneuroendocrinology. 1998;23(1):73–88.PubMedGoogle Scholar
  169. 169.
    Gulinello M, Gong QH, Li X, Smith SS. Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 2001;910(1–2):55–66.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Bicíková M, Tallová J, Hill M, Krausová Z, Hampl R. Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. Neurochem Res. 2000;25(12):1623–7.PubMedGoogle Scholar
  171. 171.
    •• Bixo M, Johansson M, Timby E, Michalski L, Bäckström T. Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder. J Neuroendocrinol. 2018;30(2):e12553 This review summarizes the paradoxical findings for allopregnanolone in premenstrual dysphoric disorder and the potential utility of an allopregnanolone antagonist in its treatment.Google Scholar
  172. 172.
    Concas A, Follesa P, Barbaccia ML, Purdy RH, Biggio G. Physiological modulation of GABAA receptor plasticity by progesterone metabolites. Eur J Pharmacol. 1999;375(1–3):225–35.PubMedGoogle Scholar
  173. 173.
    Ferando I, Mody I. Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons. Front Neural Circuits. 2013;7:144.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Maayan R, Strous RD, Abou-Kaoud M, Weizman A. The effect of 17β estradiol withdrawal on the level of brain and peripheral neurosteroids in ovarectomized rats. Neurosci Lett. 2005;384(1–2):156–61.PubMedGoogle Scholar
  175. 175.
    Bitran D, Smith SS. Termination of pseudopregnancy in the rat produces an anxiogenic-like response that is associated with an increase in benzodiazepine receptor binding density and a decrease in GABA-stimulated chloride influx in the hippocampus. Brain Res Bull. 2005;64(6):511–8.PubMedGoogle Scholar
  176. 176.
    Hellgren C, Comasco E, Skalkidou A, Sundström-Poromaa I. Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. Horm Behav. 2017;94:106–13.PubMedGoogle Scholar
  177. 177.
    Hellgren C, Åkerud H, Skalkidou A, Bäckström T, Sundström-Poromaa I. Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology. 2014;69(3):147–53.PubMedGoogle Scholar
  178. 178.
    Deligiannidis KM, Kroll-Desrosiers AR, Mo S, Nguyen HP, Svenson A, Jaitly N, et al. Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression. Psychoneuroendocrinology. 2016;70:98–107.PubMedPubMedCentralGoogle Scholar
  179. 179.
    Nappi RE, Petraglia F, Luisi S, Polatti F, Farina C, Genazzani AR. Serum allopregnanolone in women with postpartum “blues”. Obstet Gynecol. 2001;97(1):77–80.PubMedGoogle Scholar
  180. 180.
    Kanes S, Colquhoun H, Gunduz-Bruce H, Raines S, Arnold R, Schacterle A, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480–9.PubMedGoogle Scholar
  181. 181.
    •• Meltzer-Brody S, Colquhoun H, Riesenberg R, Epperson CN, Deligiannidis KM, Rubinow D, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058–70 This article reports results of two successful randomized trials of an allopregnanolone analog, braxanolone, producing significantly greater reductions in symptoms of postpartum depression than placebo.PubMedGoogle Scholar
  182. 182.
    Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996;347(9006):930–3.PubMedGoogle Scholar
  183. 183.
    Sichel DA, Cohen LS, Robertson LM, Ruttenberg A, Rosenbaum JF. Prophylactic estrogen in recurrent postpartum affective disorder. Biol Psychiatry. 1995;38(12):814–8.PubMedGoogle Scholar
  184. 184.
    Schmidt PJ, Murphy JH, Haq N, Danaceau MA, St Clair L. Basal plasma hormone levels in depressed perimenopausal women. Psychoneuroendocrinology. 2002;27(8):907–20.PubMedGoogle Scholar
  185. 185.
    Morgan ML, Rapkin AJ, Biggio G, Serra M, Pisu MG, Rasgon N. Neuroactive steroids after estrogen exposure in depressed postmenopausal women treated with sertraline and asymptomatic postmenopausal women. Arch Womens Ment Health. 2010;13(1):91–8.PubMedGoogle Scholar
  186. 186.
    Barbaccia ML, Lello S, Sidiropoulou T, Cocco T, Sorge RP, Cocchiarale A, et al. Plasma 5α-androstane-3α,17βdiol, an endogenous steroid that positively modulates GABAA receptor function, and anxiety: a study in menopausal women. Psychoneuroendocrinology. 2000;25(7):659–75.PubMedGoogle Scholar
  187. 187.
    •• Rubinow DR, Johnson SL, Schmidt PJ, Girdler S, Gaynes B. Efficacy of estradiol in perimenopausal depression: so much promise and so few answers. Depress Anxiety. 2015;32(8):539–49 This review delivers a compelling argument that estrogen replacement therapy is often efficacious for perimenopausal depression but not postmenopausal depression.PubMedGoogle Scholar
  188. 188.
    Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):149–57.PubMedGoogle Scholar
  189. 189.
    Gunter BW, Jones SA, Paul IA, Platt DM, Rowlett JK. Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects. Psychopharmacology (Berl). 2016;233(17):3237–47.Google Scholar
  190. 190.
    Fischer BD, Rowlett JK. Anticonflict and reinforcing effects of triazolam + pregnanolone combinations in rhesus monkeys. J Pharmacol Exp Ther. 2011;337(3):805–11.PubMedPubMedCentralGoogle Scholar
  191. 191.
    Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004;29(4):486–500.PubMedGoogle Scholar
  192. 192.
    Latapy C, Rioux V, Guitton MJ, Beaulieu JM. Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2460–74.PubMedPubMedCentralGoogle Scholar
  193. 193.
    Gunosewoyo H, Midzak A, Gaisina IN, Sabath EV, Fedolak A, Hanania T, et al. Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis. J Med Chem. 2013;56(12):5115–29.PubMedPubMedCentralGoogle Scholar
  194. 194.
    Kling MA, Coleman VH, Schulkin J. Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus? Depress Anxiety. 2009;26(7):641–9.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Espallergues J, Temsamani J, Laruelle C, Urani A, Maurice T. The antidepressant-like effect of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane involves a regulation of β-type estrogen receptors. Psychopharmacology (Berl). 2011;214(2):455–63.Google Scholar
  196. 196.
    Espallergues J, Mamiya T, Vallée M, Koseki T, Nabeshima T, Temsamani J, et al. The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels. Neuropharmacology. 2012;62(1):492–502.PubMedGoogle Scholar
  197. 197.
    Zhang LM, Qiu ZK, Zhao N, Chen HX, Liu YQ, Xu JP, et al. Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2014;17(10):1659–69.PubMedGoogle Scholar
  198. 198.
    Li P, Reichert DE, Rodríguez AD, Manion BD, Evers AS, Eterović VA, et al. Mechanisms of potentiation of the mammalian GABAA receptor by the marine cembranoid eupalmerin acetate. Br J Pharmacol. 2008;153(3):598–608.PubMedGoogle Scholar
  199. 199.
    Holubova K, Nekovarova T, Pistovcakova J, Sulcova A, Stuchlík A, Vales K. Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models. Front Behav Neurosci. 2014;8:130.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Vales K, Rambousek L, Holubova K, Svoboda J, Bubenikova-Valesova V, Chodounska H, et al. 3α5β-pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia. Behav Brain Res. 2012;235(1):82–8.PubMedGoogle Scholar
  201. 201.
    Serra M, Madau P, Chessa MF, Caddeo M, Sanna E, Trapani G, et al. 2-Phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats. Br J Pharmacol. 1999;127(1):177–87.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Vanover KE, Rosenzweig-Lipson S, Hawkinson JE, Lan NC, Belluzzi JD, Stein L, et al. Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3α, 21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), a selective modulator of GABAA receptors. J Pharmacol Exp Ther. 2000;295(1):337–45.PubMedGoogle Scholar
  203. 203.
    Wieland S, Belluzzi J, Hawkinson JE, Hogenkamp D, Upasani R, Stein L, et al. Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593. Psychopharmacology (Berl). 1997;134(1):46–54.Google Scholar
  204. 204.
    Scaglione JB, Jastrzebska I, Krishnan K, Li P, Akk G, Manion BD, et al. Neurosteroid analogues. 14. Alternative ring system scaffolds: GABA modulatory and anesthetic actions of cyclopenta[b]phenanthrenes and cyclopenta[b]anthracenes. J Med Chem. 2008;51(5):1309–18.PubMedGoogle Scholar
  205. 205.
    Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, et al. Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the GABAA receptor. J Med Chem. 2017;60(18):7810–9.PubMedGoogle Scholar
  206. 206.
    Hogenkamp DJ, Tran MB, Yoshimura RF, Johnstone TB, Kanner R, Gee KW. Pharmacological profile of a 17β-heteroaryl-substituted neuroactive steroid. Psychopharmacology (Berl). 2014;231(17):3517–24.Google Scholar
  207. 207.
    Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T. Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone. Psychopharmacology (Berl). 2006;187(2):209–21.Google Scholar
  208. 208.
    Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T. Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators. Psychoneuroendocrinology. 2009;34(8):1121–32.PubMedGoogle Scholar
  209. 209.
    Melchior CL, Ritzmann RF. Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze. Pharmacol Biochem Behav. 1994;48(4):893–7.PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Psychiatry & Behavioral SciencesUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Department of Obstetrics & GynecologyUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Don Soffer Clinical Research CenterUniversity of Miami Miller School of MedicineMiamiUSA

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