Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3α-reduced pregnane steroids are potent positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor. During major depression, there is a disequilibrium of 3α-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3α-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3α,5α-tetrahydrodeoxycorticosterone. The modulation of GABAA receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Keywords:
Neurosteroids, γ-Aminobutyric acid type A receptor, Ligand-gated ion channel, Antidepressants, Partial sleep deprivation, Transcranial magnetic stimulation, Electroconvulsive therapy, Cholecystokinine-tetrapeptide, Panic disorder
1.
Evans RM: The steroid and thyroid hormone receptor superfamily. Science 1988;240:889–895.
2.
Lambert JJ, Belelli D, Hill-Venning C, Peters JA: Neurosteroids and GABAA receptor function. Trends Pharmacol Sci 1995;16:295–303.
3.
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM: Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232:1004–1007.
4.
Paul SM, Purdy RH: Neuroactive steroids. FASEB J 1992;6:2311–2322.
5.
Rupprecht R, Holsboer F: Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999;22:410–416.
6.
Akwa Y, Morfin RF, Robel P, Baulieu EE: Neurosteroid metabolism. 7α-Hydroxylation of dehydroepiandrosterone and pregnenolone by rat brain microsomes. Biochem J 1992;288:959–964.
7.
Baulieu EE: Neurosteroids: a new function in the brain. Biol Cell 1991;71:3–10.
8.
Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H: Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 1999;51:63–81.
9.
Majewska MD, Mienville JM, Vicini S: Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons. Neurosci Lett 1988;90:279–284.
10.
Majewska MD, Demigören S, Spivak CE, London ED: The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor. Brain Res 1990;526:143–146.
11.
Wu FS, Gibbs TT, Farb DH: Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol 1991;40:333–336.
12.
Monnet FP, Mahé V, Robel P, Baulieu EE: Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus. Proc Natl Acad Sci USA 1995;92:3774–3778.
13.
Rupprecht R: The neuropsychopharmacological potential of neuroactive steroids. J Psychiatr Res 1997;31:297–314.
14.
Reddy DS, Kaur G, Kulkarni SK: Sigma (σ1) receptor mediated antidepressant-like effects of neurosteroids in the Porsolt forced swim test. Neuroreport 1998;9:3069–3073.
15.
Melchior CL, Ritzmann RF: Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on plus-maze. Pharmacol Biochem Behav 1994;48:893–897.
16.
Majewska MD, Bluet-Pajot MT, Robel P, Baulieu EE: Pregnenolone sulfate antagonizes barbiturate-induced hypnosis. Pharmacol Biochem Behav 1989;33:701–703.
17.
Majewska MD: Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992;38:379–395.
18.
Mienville JM, Vicini S: Pregnenolone sulfate antagonizes GABAA receptor-mediated currents via a reduction of channel opening frequency. Brain Res 1989;489:190–194.
19.
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;35:775–780.
20.
Semeniuk T, Jhangri GS, Le Melledo JM: Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci 2001;13:396–398.
21.
Heydary B, Le Melledo JM: Low pregnenolone sulfate plasma levels in patients with social anxiety disorder. Psychol Med 2001;32:929–933.
22.
Bicikova M, Tallová J, Hill M, Krausova Z, Hampl R: Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. Neurochem Res 2000;25:1623–1627.
23.
Wang M, Seippel L, Purdy RH, Bäckström 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;81:1076–1082.
24.
Urani A, Roman FJ, Phan VL, Su TP, Maurice T: The antidepressant-like effect induced by σ1-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J Pharmacol Exp Ther 2001;298:1269–1279.
25.
Melchior CL, Ritzmann RF: Dehydroepiandrosterone is an anxiolytic in mice on the plus maze. Pharmacol Biochem Behav 1994;47:437–441.
26.
Barrett-Connor E, von Muhlen 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;47:685–691.
27.
Goodyer IM, Herbert J, Altham PM: Adrenal steroid secretion and major depression in 8- to 16-year-olds. 3. Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major depression. Psychol Med 1998;28:265–273.
28.
Fabian TJ, Dew MA, Pollock BG, Reynolds CF, Mulsant BH, Butters MA, Zmuda MD, Linares AM, Trottini M, Kroboth PD: Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults. Biol Psychiatry 2001;50:767–774.
29.
Tollefson GD, Haus E, Garvey MJ, Evans M, Tuason VB: 24-hour urinary dehydroepiandrosterone sulfate in unipolar depression treated with cognitive and/or pharmacotherapy. Ann Clin Psychiatry 1990;2:39–45.
30.
Heuser I, Deuschle M, Luppa P, Schweiger U, Standhardt H, Weber B: Increased diurnal plasma concentrations of dehydroepiandrosterone in depressed patients. J Clin Endocrinol Metab 1998;83:3130–3133.
31.
Takebayashi M, Kagaya A, Uchitomi Y, Kugaya A, Muraoka M, Yokota N, Horiguchi J, Yamawaki S: Plasma dehydroepiandrosterone sulfate in unipolar major depression. Short communication. J Neural Transm 1998;105:537–542.
32.
Maayan R, Yagorowski Y, Grupper D, Weiss M, Shtaif B, Kaoud MA, Weizman A: Basal plasma dehydroepiandrosterone sulfate level: a possible predictor for response to electroconvulsive therapy in depressed psychotic inpatients. Biol Psychiatry 2000;48:693–701.
33.
Bitran D, Purdy RH, Kellogg CK: Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav 1993;45:423–428.
34.
Reddy DS, O’Malley BW, Rogawski MA: Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology 2005;48:14–24.
35.
Brambilla F, Biggio G, Pisu MG, Bellodi L, Perna G, Bogdanovich-Djukic V, Purdy RH, Serra M: Neurosteroid secretion in panic disorder. Psychiatry Res 2003;118:107–116.
36.
Brambilla F, Mellado C, Alciati A, Pisu MG, Purdy RH, Zanone S, Perini G, Serra M, Biggio G: Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder. Psychiatry Res 2005;135:185–190.
37.
Brambilla F, Biggio G, Pisu MG, Purdy RH, Gerra G, Zaimovich A, Serra M: Plasma concentrations of anxiolytic neurosteroids in men with normal anxiety scores: a correlation analysis. Neuropsychobiology 2004;50:6–9.
38.
Akwa Y, Purdy RH, Koob GF, Britton KT: The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat. Behav Brain Res 1999;106:119–125.
39.
Bitran D, Hilvers RJ, Kellogg CK: Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 1991;561:157–161.
40.
Reddy DS, Kulkarni SK: Differential anxiolytic effects of neurosteroids in the mirrored chamber behavior test in mice. Brain Res 1997;752:61–71.
41.
Rodgers RJ, Johnson NJ: Behaviorally selective effects of neuroactive steroids on plus-maze anxiety in mice. Pharmacol Biochem Behav 1998;59:221–232.
42.
Wieland S, Lan NC, Mirasedeghi S, Gee KW: Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Brain Res 1991;565:263–268.
43.
Wieland S, Belluzi JD, Stein L, Lan NC: Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents. Psychopharmcol 1995;118:65–71.
44.
Crawley JN, Glowa JR, Majewska MD, Paul SM: Anxiolytic activity of an endogenous adrenal steroid. Brain Res 1986;398:382–385.
45.
Heydari B, Le Melledo JM: Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med 2002;32:929–933.
46.
Ströhle A, Romeo E, di Michele F, Pasini A, Yassouridis A, Holsboer F, Rupprecht R: GABAA receptor modulatory neuroactive steroid composition in panic disorder and during paroxetine treatment. Am J Psychiatry 2002;159:145–147.
47.
Rupprecht R: Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003;28:139–168.
48.
Strohle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht R: Induced panic attacks shift γ-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. Arch Gen Psychiatry 2003;60:161–168.
49.
Zwanzger P, Eser D, Padberg F, Baghai TC, Schule C, Rupprecht R, di Michele F, Romeo E, Pasini A, Strohle A: Neuroactive steroids are not affected by panic induction with 50 microg cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. J Psychiatr Res 2004;38:215–217.
50.
Koszycki D, Zacharko RM, Le Mellédo JM, Bradwejn J: Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a comparison of panickers and nonpanickers. Depress Anxiety 1998;8:1–7.
51.
Eser D, di Michele F, Zwanzger P, PasiniA, Baghai TC, Schule C, Rupprecht R, Romeo E: Panic induction with cholecystokinin-tetrapeptide (CCK-4) increases plasma concentrations of the neuroactive steroid 3α,5α tetrahydrodeoxycorticosterone (3α,5αTHDOC) in healthy volunteers. Neuropsychopharmacology 2005;30:192–195.
52.
Purdy RH, Morrow AL, Moore PH, Paul SM: Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991;8:4553–4557.
53.
Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A: Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci USA 2001;98:2849–2854.
54.
Matsumoto K, Uzunova V, Pinna G, Taki K, Uzunov DP, Watanabe H, Mienville JM, Guidotti A, Costa E: Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss. Neuropharmacology 1999;38:955–963.
55.
Guidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E: The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders. Brain Res Brain Res Rev 2001;37:110–115.
56.
Uzunova V, Ceci M, Kohler C, Uzunov DP, Wrynn AS: Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression. Brain Res 2003;976:1–8.
57.
Romeo E, Ströhle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht R: Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 1998;155:910–913.
58.
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A: Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 1998;95:3239–3244.
59.
Ströhle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F, Holsboer F, Rupprecht R: Fluoxetine decreases concentrations of 3α,5α-tetrahydrodeoxycorticosterone (THDOC) in major depression. J Psychiatr Res 2000;34:183–186.
60.
Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM: Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology 2003;29:486–500.
61.
Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Raum WJ, Ormiston S, Johnson R, Canick J, Brizendine L, Weingartner H: Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry 1997;41:311–318.
62.
Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR: Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry 1999;45:1533–1541.
63.
Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E: Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999;156:646–649.
64.
Schmidt PJ, Daly RC, Bloch M, Smith MJ, Danaceau MA, St Clair LS, Murphy JH, Haq N, Rubinow DR: Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry 2005;62:154–162.
65.
Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M, Weizman A: Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003;60:133–141.
66.
Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R: Progesterone-induced changes in sleep in male subjects. Am J Physiol 1997;272:E885–E891.
67.
Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD: Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J 1980;290:1617–1621.
68.
Baker ER, Best RG, Manfredi RL, Demers LM, Wolf GC: Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome. J Assist Reprod Genet 1995;12:205–209.
69.
Magill PJ: Investigation of the efficacy of progesterone pessaries in the relief of symptoms of premenstrual syndrome. Progesterone Study Group. Br J Gen Pract 1995;45:589–593.
70.
Freeman E, Rickels K, Sondheimer SJ, Polansky M: Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 1990;264:349–353.
71.
Vanselow W, Dennerstein L, Greenwood KM, de Lignieres B: Effect of progesterone and its 5α and 5β metabolites on symptoms of premenstrual syndrome according to route of administration. J Psychosom Obstet Gynaecol 1996;17:29–38.
72.
Freeman EW, Rickels K, Sondheimer SJ, Polansky M: A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995;274:51–57.
73.
Dalton K: Successful prophylactic progesterone for idiopathic postnatal depression. Int J Prenatal Perinatal Stud 1989;1:323–327.
74.
Lawrie TA, Hofmeyr GJ, De Jager M, Berk M, Paiker J, Viljoen E: A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynaecol 1998;105:1082–1090.
75.
Lawrie TA, Herxheimer A, Dalton K: Oestrogens and progestogens for preventing and treating postnatal depression. Cochrane Database Syst Rev 2000;CD001690.
76.
Uzunova V, Wrynn AS, Kinnunen A, Ceci M, Kohler C, Uzunov DP: Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat. Eur J Pharmacol 2004;486:31–34.
77.
Uzunov DP, Cooper TB, Costa E, Guidotti A: Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996;93:12599–12604.
78.
Serra M, Pisu MG, Muggironi M, Parodo V, Papi G, Sari R, Dazzi L, Spiga F, Purdy RH, Biggio G: Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain. Psychopharmacology 2001;158:48–54.
79.
Griffin LD, Mellon SH: Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA 1999;96:13512–13517.
80.
Trauger JW, Jiang A, Stearns BA, LoGrasso PV: Kinetics of allopregnanolone formation catalyzed by human 3α-hydroxysteroid dehydrogenase type III (AKR1C2). Biochemistry 2002;41:13451–13459.
81.
Serra M, Pisul MG, Dazzi L, Purdy RH, Biggio G: Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine. J Psychopharmacol 2002;16:133–138.
82.
Schule C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R: Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity. Mol Psychiatry 2006;11:261–272.
83.
Schule C, di Michele F, Baghai T, Romeo E, Bernardi G, Zwanzger P, Padberg F, Pasini A, Rupprecht R: Influence of sleep deprivation on neuroactive steroids in major depression. Neuropsychopharmacology 2003;28:577–581.
84.
Padberg F, di Michele F, Zwanzger P, Romeo E, Bernardi G, Schule C, Baghai TC, Ella R, Pasini A, Rupprecht R: Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression. Neuropsychopharmacology 2002;27:874–878.
85.
Baghai TC, di Michele F, Schule C, Eser D, Zwanzger P, Pasini A, Romeo E, Rupprecht R: Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology 2005;30:1181–1186.
86.
Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZX: Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience 2005;138:749–756.
87.
Kita A, Kohayakawa H, Kinoshita T, Ochi Y, Nakamichi K, Kurumiya S, Furukawa K, Oka M: Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. Br J Pharmacol 2004;142:1059–1072.
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