Neurosteroids and Affective Disorders in Women

Author(s): Rodrigo Guiza-Zayas*, Mónica Flores-Ramos, Norma Bernal-Santamaría, María Fernanda Del-Pino Mijares, Marián Serna-García.

Journal Name: Current Psychopharmacology

Volume 8 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Neurosteroids (NS) are steroid derived molecules synthesized in the central nervous system (CNS) involved in modulating brain transmission by its activity on gamma-aminobutyric acid (GABA) receptors; this interaction has been identified as an important factor in the pathophysiology of affective disorders.

Objective: The aim of the present paper is to describe the relation of neurosteroids with affective disorders in women and novel treatments in this regard in an understandable and synthesized review of the subject.

Methods: A thoroughly made research has been performed in order to find the latest information in this regard using scientific databases such as PubMed and Google Scholar using the keywords Neurosteroids, affective disorders, depression, postpartum depression and dysphoric premenstrual disorder.

Results: It has been seen that NS levels during physiological fluctuation such as during menstrual cycle or postpartum may modify the response to GABA by GABA-A receptors in susceptible women. Recent pharmacological assays have been developed in order to treat affective disorders in women focusing on NS fluctuations.

Conclusion: Within this paper, we review recent findings in NS modulating mechanisms, its pathophysiological implications in affective disorders and recent clinical assays in this regard.

Keywords: Affective disorders, allopregnanolone, dehydroepiandrosterone, GABA, GABA-A receptor, neurosteroid, women.

Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 2010; 186: 113-37.
Giatti S, Garcia-Segura LM, Barreto GE, Melcangi RC. Neuroactive steroids, neurosteroidogenesis and sex. Prog Neurobiol 2018; 176: 1-7.
Herbert J. Neurosteroids: a new regulatory function in the nervous system. J Psychiatry Neurosci 2001; 26(5): 421-2.
Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG. Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci 2008; 65(5): 777-97.
Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct 2012; 8: 61.
Giatti S, Romano S, Pesaresi M, et al. Neuroactive steroids and the peripheral nervous system: An update. Steroids 2015; 103: 23-30.
Vega-Vela NE, Osorio D, Avila-Rodriguez M, et al. L-type calcium channels modulation by estradiol. Mol Neurobiol 2017; 54(7): 4996-5007.
Le Mellédo J-M, Baker GB. Neuroactive steroids and anxiety disorders. J Psychiatry Neurosci 2002; 27(3): 161-5.
Rupprecht R, Reul JM, Trapp T, et al. Progesterone receptor-mediated effects of neuroactive steroids. Neuron 1993; 11(3): 523-30.
Calixto González E, Brailowsky S. Neuroesteroides. Neuromoduladores de la excitabilidad cerebral. Gac Med Mex 1998; 134(1): 69-84.
Chen Z-W, Bracamontes JR, Budelier MM, et al. Multiple functional neurosteroid binding sites on GABAA receptors. PLoS Biol 2019; 17(3)e3000157
Hosie AM, Wilkins ME, da Silva HM, Smart TG. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 2006; 444(7118): 486-9.
Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the δ subunit. J Neurosci 2002; 22(5): 1541-9.
Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992; 38(4): 379-95.
Seljeset S, Laverty D, Smart TG. Inhibitory neurosteroids and the GABAA receptor. Adv Pharmacol 2015; 72: 165-87.
Barbaccia ML. Neurosteroidogenesis: relevance to neurosteroid actions in brain and modulation by psychotropic drugs. Critic Rev Neurobiol 2004; 16(1&2): 67-74.
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.
Bäckström T, Andersson A, Andreé L, et al. Pathogenesis in menstrual cycle-linked CNS disorders. Ann N Y Acad Sci 2003; 1007(1): 42-53.
Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 2005; 8(6): 797-804.
Uzunova V, Sampson L, Uzunov DP. Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action. Psychopharmacology 2006; 186(3): 351-61.
Eser D, Romeo E, Baghai TC, Schüle C, Zwanzger P, Rupprecht R. Neuroactive steroids as modulators of depression and anxiety. Expert Rev Endocrinol Metab 2006; 1(4): 517-26.
Brambilla F, Biggio G, Pisu MG, et al. Neurosteroid secretion in panic disorder. Psychiatry Res 2003; 118(2): 107-16.
Marx CE, Trost WT, Shampine LJ, et al. The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry 2006; 60(12): 1287-94.
Ladurelle N, Eychenne B, Denton D, et al. Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse. Brain Res 2000; 858(2): 371-9.
Brown RC, Han Z, Cascio C, Papadopoulos V. Oxidative stress-mediated DHEA formation in Alzheimer’s disease pathology. Neurobiol Aging 2003; 24(1): 57-65.
Maguire J, Mody I. Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci 2007; 27(9): 2155-62.
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.
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.
Barbaccia ML, Roscetti G, Trabucchi M, et al. The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations. Br J Pharmacol 1997; 120(8): 1582-8.
Kehoe P, Mallinson K, McCormick CM, Frye CA. Central allopregnanolone is increased in rat pups in response to repeated, short episodes of neonatal isolation. Brain Res Dev Brain Res 2000; 124(1-2): 133-6.
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.
Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005; 22(1): 106-18.
Sayeed I, Parvez S, Wali B, Siemen D, Stein DG. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone. Brain Res 2009; 1263: 165-73.
Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M. Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology 2006; 186(3): 323-33.
Shen H, Gong QH, Aoki C, et al. Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at puberty. Nat Neurosci 2007; 10(4): 469-77.
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron 2008; 59(2): 207-13.
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci 2009; 29(30): 9592-601.
Tuem KB, Atey TM. Neuroactive steroids: receptor interactions and responses. Front Neurol 2017; 8: 442.
Berry A, Bellisario V, Capoccia S, et al. Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice. Psychoneuroendocrinology 2012; 37(6): 762-72.
Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol 2014; 113: 79-87.
Longone P, Rupprecht R, Manieri GA, Bernardi G, Romeo E, Pasini A. The complex roles of neurosteroids in depression and anxiety disorders. Neurochem Int 2008; 52(4-5): 596-601.
Shirayama Y, Muneoka K, Fukumoto M, et al. Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats. Hippocampus 2011; 21(10): 1105-13.
Pinna G, Costa E, Guidotti A. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology 2006; 186(3): 362-72.
Matsumoto K, Puia G, Dong E, Pinna G. GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress 2007; 10(1): 3-12.
Pinna G. In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis. Behav Pharmacol 2010; 21(5-6): 438-50.
Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30(1): 65-91.
Kamin HS, Kertes DA. Cortisol and DHEA in development and psychopathology. Horm Behav 2017; 89: 69-85.
Rigaud AS, Pellerin J. Neuropsychic effects of dehydroepiandrosterone. Ann Med Interne 2001; 152(Suppl. 3): IS43-9.
Kaminska M, Harris J, Gijsbers K, Dubrovsky B. Dehydroepiandrosterone sulfate (DHEAS) counteracts decremental effects of corticosterone on dentate gyrus LTP. Implications for depression. Brain Res Bull 2000; 52(3): 229-34.
Hu Q, Zhang SY, Liu F, Zhang YL, Zhu DM, Zang YY. Clinical significance of decreased protein expression of dehydroepiandrosterone sulfate in the development of depression: a meta-analysis. J Affect Disord 2015; 174: 416-23.
Goodyer IM, Park RJ, Netherton CM, Herbert J. Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology. Br J Psychiatry 2001; 179: 243-9.
Uh D, Jeong HG, Choi KY, Oh SY, Lee S, Kim SH, et al. Dehydroepiandrosterone sulfate level variesnonlinearly with symptom severity in major depressive disorder. Clin Psychopharmacol Neurosci 2017; 15(2): 163-9.
Morita T, Senzaki K, Ishihara R, et al. Plasma dehydroepiandrosterone sulfate levels in patients with major depressive disorder correlate with remission during treatment with antidepressants. Hum Psychopharmacol 2014; 29(3): 280-6.
Hough CM, Lindqvist D, Epel ES, et al. Higher serum DHEA concentrations before and after SSRI treatment are associated with remission of major depression. Psychoneuroendocrinology 2017; 77: 122-30.
Levchuk LA, Vyalova NM, Ivanova SA, Simutkin GG, Lebedeva EV, Bokhan NA. Serum levels of neurosteroids in patients with affective disorders. Bull Exp Biol Med 2015; 158(5): 638-40.
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.
Paslakis G, Luppa P, Gilles M, et al. Venlafaxine and mirtazapine treatment lowers serum concentrations of dehydroepiandrosterone-sulfate in depressed patients remitting during the course of treatment. J Psychiatr Res 2010; 44(8): 556-60.
Herrera-Pérez JJ, Martínez-Mota L, Jiménez-Rubio G, et al. Dehydroepiandrosterone increases the number and dendrite maturation of doublecortin cells in the dentate gyrus of middle age male Wistar rats exposed to chronic mild stress. Behav Brain Res 2017; 321: 137-47.
Samardzic J, Hencic B, Jancic J, et al. Neurosteroid dehydroepiandrosterone improves active avoidance retrieval and induces antidepressant-like behavior in rats. Neurosci Lett 2017; 660: 17-21.
Fedotova J, Sapronov N. Behavioral effects of dehydroepiandrosterone in adult male rats. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28(6): 1023-7.
Genud R, Merenlender A, Gispan-Herman I, Maayan R, Weizman A, Yadid G. DHEA lessens depressive-like behavior via GABA-ergic modulation of the mesolimbic system. Neuropsychopharmacology 2009; 34(3): 577-84.
Wolkowitz OM, Reus VI, Roberts E, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry 1997; 41(3): 311-8.
Schmidt PJ, Daly RC, Bloch M, et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry 2005; 62(2): 154-62.
Cameron DR, Braunstein GD. The use of dehydroepiandrosterone therapy in clinical practice. Treat Endocrinol 2005; 4(2): 95-114.
Paoletti AM, Romagnino S, Contu R, et al. 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 2006; 31(4): 485-92.
Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet 2017; 390(10093): 480-9.
Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018; 392(10152): 1058-70.
Scott LJ. Brexanolone: First Global Approval. Drugs 2019; 79(7): 779-83.
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
Hammarbäck S, Bäckström T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand 1988; 67(2): 159-66.
Hammarbäck S, Ekholm U-B, Bäckström T. Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome. Acta Endocrinol 1991; 125(2): 132-7.
Muse KN, Cetel NS, Futterman LA, Yen SC. The premenstrual syndrome. Effects of “medical ovariectomy”. N Engl J Med 1984; 311(21): 1345-9.
Björn I, Bixo M, Nöjd KS, Nyberg S, Bäckström T. Negative mood changes during hormone replacement therapy: a comparison between two progestogens. Am J Obstet Gynecol 2000; 183(6): 1419-26.
Andréen L, Bixo M, Nyberg S, Sundström-Poromaa I, Bäckström T. Progesterone effects during sequential hormone replacement therapy. Eur J Endocrinol 2003; 148(5): 571-7.
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 2006; 187(2): 209-21.
Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives containing drospirenone for premenstrual syndrome. Cochrane Database Syst Rev 2012; (2): CD006586
Marjoribanks J, Brown J, O’Brien PMS, Wyatt K. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database of Systematic Reviews 2013; (6): CD001396
Bixo M, Ekberg K, Poromaa IS, et al. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial. Psychoneuroendocrinology 2017; 80: 46-55.
Martinez PE, Rubinow DR, Nieman LK, et al. 5α-reductase inhibition prevents the luteal phase increase in plasma allopregnanolone levels and mitigates symptoms in women with premenstrual dysphoric disorder. Neuropsychopharmacology 2016; 41(4): 1093-102.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [89 - 98]
Pages: 10
DOI: 10.2174/2211556008666190724113554

Article Metrics

PDF: 30
PRC: 1