The Role of Neuroactive Steroids in Anxiety Disorders

  • Erin M. MacKenzie
  • Glen B. Baker
  • Jean-Michel Le Mellédo

Given that neuroactive steroids modulate the activity of a number of neurotransmitter receptors in the brain thought to be involved in the pathophysiology of mood and anxiety disorders (including GABAA and NMDA receptors), it is not surprising that increasing evidence suggests that levels of some neuroactive steroids may be altered in individuals suffering from these disorders. This chapter will provide an in-depth summary of the findings regarding neuroactive steroid abnormalities in panic disorder, generalized anxiety disorder, generalized social phobia and post-traumatic stress disorder. How these abnormalities may be related to illness symptoms or whether they may reflect compensatory mechanisms for maintaining homeostasis will be explored. Furthermore, the regulation of steroidal abnormalities by drugs used to treat the above-mentioned disorders will be discussed.

Keywords

Neuroactive steroids neurosteroids anxiety post-traumatic stress disorder panic disorder social phobia hypothalamic-pituitary-adrenal axis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Baulieu EE, Robel P. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci USA 1998; 95:4089–4091.PubMedCrossRefGoogle Scholar
  2. 2.
    Rupprecht R. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003; 28:139–168.PubMedCrossRefGoogle Scholar
  3. 3.
    Bitran D, Hilvers RJ, Kellogg CK. Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 1991; 561:157–161.PubMedCrossRefGoogle Scholar
  4. 4.
    Mayo W, Vallee M, Darnaudry M, et al. Neurosteroids. Behavioral studies. In: Baulieu EE, Robel P, Schumacher M (eds). Contemporary endocrinology: neurosteroids. A new regulatory function in the nervous system. Totowa, NJ: Humana, 1999, pp. 317–335.Google Scholar
  5. 5.
    Crawley JN, Glowa JR, Majewska MD, et al. Anxiolytic activity of an endogenous adrenal steroid. Brain Res 1986; 398:382–385.PubMedCrossRefGoogle Scholar
  6. 6.
    Wieland S, Lan NC, Mirasedeghi S, et al. Anxiolytic activity of the progesterone metabolite 5 alpha-pregnan-3 alpha-o1–20-one. Brain Res 1991; 565:263–268.PubMedCrossRefGoogle Scholar
  7. 7.
    Frye CA, Walf AA. Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats. Horm Behav 2002; 41:306–315.PubMedCrossRefGoogle Scholar
  8. 8.
    de Brito Faturi C, Teixeira-Silva F, Leite JR. The anxiolytic effect of pregnancy in rats is reversed by finasteride. Pharmacol Biochem Behav 2006; 85:569–574.PubMedCrossRefGoogle Scholar
  9. 9.
    Jain NS, Hirani K, Chopde CT. Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats. Neuropharmacology 2005; 48:627–638.PubMedCrossRefGoogle Scholar
  10. 10.
    Kavaliers M, Wiebe JP, Galea LA. Reduction of predator odor-induced anxiety in mice by the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP). Brain Res 1994; 645:325–329.PubMedCrossRefGoogle Scholar
  11. 11.
    Hirani K, Sharma AN, Jain NS, et al. Evaluation of GABAergic neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats. Psychopharmacology (Berl) 2005; 180:267–278.CrossRefGoogle Scholar
  12. 12.
    Rasmusson AM, Pinna G, Paliwal P, et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry 2006; 60:704–713.PubMedCrossRefGoogle Scholar
  13. 13.
    Purdy RH, Morrow AL, Moore PH, Jr., et al. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991; 88:4553–4557.PubMedCrossRefGoogle Scholar
  14. 14.
    Barbaccia ML, Roscetti G, Bolacchi F, et al. Stress-induced increase in brain neuroactive steroids: antagonism by abecarnil. Pharmacol Biochem Behav 1996; 54:205–210.PubMedCrossRefGoogle Scholar
  15. 15.
    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; 120:1582–1588.PubMedCrossRefGoogle Scholar
  16. 16.
    Patchev VK, Shoaib M, Holsboer F, et al. 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; 62:265–271.PubMedCrossRefGoogle Scholar
  17. 17.
    Patchev VK, Hassan AH, Holsboer DF, et al. The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 1996; 15:533–540.PubMedCrossRefGoogle Scholar
  18. 18.
    Guo AL, Petraglia F, Criscuolo M, et al. Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats. Gynecol Endocrinol 1995; 9:1–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Owens MJ, Ritchie JC, Nemeroff CB. 5 alpha-pregnane-3 alpha, 21-diol-20-one (THDOC) attenuates mild stress-induced increases in plasma corticosterone via a non-glucocorticoid mechanism: comparison with alprazolam. Brain Res 1992; 573:353–355.PubMedCrossRefGoogle Scholar
  20. 20.
    Aguilera G, Rabadan-Diehl C. Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications for stress adaptation. Regul Pept 2000; 96:23–29.PubMedCrossRefGoogle Scholar
  21. 21.
    Bartanusz V, Jezova D, Bertini LT, et al. Stress-induced increase in vasopressin and corticotropin-releasing factor expression in hypophysiotrophic paraventricular neurons. Endocrinology 1993; 132:895–902.PubMedCrossRefGoogle Scholar
  22. 22.
    Herman JP, Adams D, Prewitt C. Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 1995; 61:180–190.PubMedCrossRefGoogle Scholar
  23. 23.
    Kalimi M, Shafagoj Y, Loria R, et al. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 1994; 131:99–104.PubMedCrossRefGoogle Scholar
  24. 24.
    Kudielka BM, Hellhammer J, Hellhammer DH, et al. Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment. J Clin Endocrinol Metab 1998; 83:1756–1761.PubMedCrossRefGoogle Scholar
  25. 25.
    Silva MT, Alves CR, Santarem EM. Anxiogenic-like effect of acute and chronic fluoxetine on rats tested on the elevated plus-maze. Braz J Med Biol Res 1999; 32:333–339.PubMedGoogle Scholar
  26. 26.
    Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004; 65:1696–1707.PubMedCrossRefGoogle Scholar
  27. 27.
    Hedges DW, Brown BL, Shwalb DA, et al. The efficacy of selective serotonin reuptake inhibitors in adult social anxiety disorder: a meta-analysis of double-blind, placebo-controlled trials. J Psychopharmacol 2007; 21:102–111.PubMedCrossRefGoogle Scholar
  28. 28.
    Bhagwagar Z, Wylezinska M, Taylor M, et al. Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 2004; 161:368–370.PubMedCrossRefGoogle Scholar
  29. 29.
    Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA 1999; 96:13512–13517.PubMedCrossRefGoogle Scholar
  30. 30.
    Uzunov DP, Cooper TB, Costa E, et al. Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996; 93:12599–12604.PubMedCrossRefGoogle Scholar
  31. 31.
    Serra M, Pisu MG, Muggironi M, et al. Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain. Psychopharmacology (Berl) 2001; 158:48–54.CrossRefGoogle Scholar
  32. 32.
    Pinna G, Costa E, Guidotti A. Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids. Proc Natl Acad Sci USA 2004; 101:6222–6225.PubMedCrossRefGoogle Scholar
  33. 33.
    Matsumoto K, Puia G, Dong E, et al. 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; 10:3–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Nechmad A, Maayan R, Spivak B, et al. Brain neurosteroid changes after paroxetine administration in mice. Eur Neuropsychopharmacol 2003; 13:327–332.PubMedCrossRefGoogle Scholar
  35. 35.
    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 (Berl) 2006; 186:362–372.CrossRefGoogle Scholar
  36. 36.
    Vaiva G, Thomas P, Ducrocq F, et al. Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder. Biol Psychiatry 2004; 55:250–254.PubMedCrossRefGoogle Scholar
  37. 37.
    Vaiva G, Boss V, Ducrocq F, et al. Relationship between posttrauma GABA plasma levels and PTSD at 1-year follow-up. Am J Psychiatry 2006; 163:1446–1448.PubMedCrossRefGoogle Scholar
  38. 38.
    Bremner JD, Innis RB, Southwick SM, et al. Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157:1120–1126.PubMedCrossRefGoogle Scholar
  39. 39.
    Fujita M, Southwick SM, Denucci CC, et al. Central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder. Biol Psychiatry 2004; 56:95–100.PubMedCrossRefGoogle Scholar
  40. 40.
    Olff M, Guzelcan Y, de Vries GJ, et al. HPA- and HPT-axis alterations in chronic posttraumatic stress disorder. Psychoneuroendocrino 2006; 31:1220–1230.CrossRefGoogle Scholar
  41. 41.
    Yehuda R, Teicher MH, Trestman RL, et al. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry 1996; 40:79–88.PubMedCrossRefGoogle Scholar
  42. 42.
    Yehuda R, Kahana B, Binder-Brynes K, et al. Low urinary cortisol excretion in Holocaust survivors with posttraumatic stress disorder. Am J Psychiatry 1995; 152:982–986.PubMedGoogle Scholar
  43. 43.
    Spivak B, Maayan R, Kotler M, et al. Elevated circulatory level of GABA(A)-antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol Med 2000; 30:1227–1231.PubMedCrossRefGoogle Scholar
  44. 44.
    Yehuda R, Brand SR, Golier JA, et al. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr Scand 2006; 114:187–193.PubMedCrossRefGoogle Scholar
  45. 45.
    Sondergaard HP, Hansson LO, Theorell T. Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: findings from a longitudinal study of refugees in Sweden. Psychother Psychosom 2002; 71:298–303.PubMedCrossRefGoogle Scholar
  46. 46.
    Rasmusson AM, Vasek J, Lipschitz DS, et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacol 2004; 29:1546–1557.CrossRefGoogle Scholar
  47. 47.
    Butterfield MI, Stechuchak KM, Connor KM, et al. Neuroactive steroids and suicidality in posttraumatic stress disorder. Am J Psychiatry 2005; 162:380–382.PubMedCrossRefGoogle Scholar
  48. 48.
    Bertagna X, Escourolle H, Pinquier JL, et al. Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation. J Clin Endocrinol Metab 1994; 78:375–380.PubMedCrossRefGoogle Scholar
  49. 49.
    van Haarst AD, Oitzl MS, Workel JO, et al. Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. Endocrinology 1996; 137:4935–4943.PubMedCrossRefGoogle Scholar
  50. 50.
    Sageman S, Brown RP. 3-Acetyl-7-oxo-dehydroepiandrosterone for healing treatment-resistant posttraumatic stress disorder in women: 5 case reports. J Clin Psychiatry 2006; 67:493–496.PubMedCrossRefGoogle Scholar
  51. 51.
    Berigan T. Treatment of posttraumatic stress disorder with tiagabine. Can J Psychiatry 2002; 47:788.PubMedGoogle Scholar
  52. 52.
    van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttraumatic stress disorder. J Clin Psychiatry 1994; 55:517–522.PubMedGoogle Scholar
  53. 53.
    Vermetten E, Vythilingam M, Schmahl C, et al. Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder. Ann NY Acad Sci 2006; 1071:184–202.PubMedCrossRefGoogle Scholar
  54. 54.
    Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 2004; 65(Suppl 5):29–33.PubMedGoogle Scholar
  55. 55.
    Goddard AW, Narayan M, Woods SW, et al. Plasma levels of gamma-aminobutyric acid and panic disorder. Psychiatry Res 1996; 63:223–225.PubMedCrossRefGoogle Scholar
  56. 56.
    Rimon R, Lepola U, Jolkkonen J, et al. Cerebrospinal fluid gamma-aminobutyric acid in patients with panic disorder. Biol Psychiatry 1995; 38:737–741.PubMedCrossRefGoogle Scholar
  57. 57.
    Goddard AW, Mason GF, Almai A, et al. Reductions in occipital cortex GABA levels in panic disorder detected with 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry 2001; 58:556–561.PubMedCrossRefGoogle Scholar
  58. 58.
    Ham BJ, Sung Y, Kim N, et al. Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:403–411.PubMedCrossRefGoogle Scholar
  59. 59.
    Bremner JD, Innis RB, White T, et al. SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000; 47:96–106.PubMedCrossRefGoogle Scholar
  60. 60.
    Malizia AL, Cunningham VJ, Bell CJ, et al. Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998; 55:715–720.PubMedCrossRefGoogle Scholar
  61. 61.
    Goddard AW, Mason GF, Appel M, et al. Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder. Am J Psychiatry 2004; 161:2186–2193.PubMedCrossRefGoogle Scholar
  62. 62.
    Erhardt A, Ising M, Unschuld PG, et al. Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder. Neuropsychopharmacol 2006; 31:2515–2522.CrossRefGoogle Scholar
  63. 63.
    Abelson JL, Khan S, Liberzon I, et al. HPA axis activity in patients with panic disorder: review and synthesis of four studies. Depress Anxiety 2007; 24:66–76.PubMedCrossRefGoogle Scholar
  64. 64.
    Brambilla F, Mellado C, Alciati A, et al. Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder. Psychiatry Res 2005; 135:185–190.PubMedCrossRefGoogle Scholar
  65. 65.
    Brambilla F, Biggio G, Pisu MG, et al. Neurosteroid secretion in panic disorder. Psychiatry Res 2003; 118:107–116.PubMedCrossRefGoogle Scholar
  66. 66.
    Strohle A, Romeo E, di Michele F, et al. GABAA receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment. Am J Psychiatry 2002; 159:145–147.PubMedCrossRefGoogle Scholar
  67. 67.
    Maayan R, Touati-Werner D, Ram E, et al. The protective effect of frontal cortex dehydroepiandrosterone in anxiety and depressive models in mice. Pharmacol Biochem Behav 2006; 85:415–421.PubMedCrossRefGoogle Scholar
  68. 68.
    Zwanzger P, Eser D, Padberg F, et al. 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.PubMedCrossRefGoogle Scholar
  69. 69.
    Strohle A, Romeo E, di Michele F, 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; 60:161–168.PubMedCrossRefGoogle Scholar
  70. 70.
    Eser D, di Michele F, Zwanzger P, et al. Panic induction with cholecystokinin-tetrapeptide (CCK-4) Increases plasma concentrations of the neuroactive steroid 3alpha, 5alpha-tetrahydrodeoxycorticosterone (3alpha, 5alpha-THDOC) in healthy volunteers. Neuropsychopharmacol 2005; 30:192–195.CrossRefGoogle Scholar
  71. 71.
    Martel FL, Hayward C, Lyons DM, et al. Salivary cortisol levels in socially phobic adolescent girls. Depress Anxiety 1999; 10:25–27.PubMedCrossRefGoogle Scholar
  72. 72.
    Furlan PM, DeMartinis N, Schweizer E, et al. Abnormal salivary cortisol levels in social phobic patients in response to acute psychological but not physical stress. Biol Psychiatry 2001; 50:254–259.PubMedCrossRefGoogle Scholar
  73. 73.
    Potts NL, Davidson JR, Krishnan KR, et al. Levels of urinary free cortisol in social phobia. J Clin Psychiatry 1991; 52(Suppl):41–42.PubMedGoogle Scholar
  74. 74.
    Uhde TW, Tancer ME, Gelernter CS, et al. Normal urinary free cortisol and postdexamethasone cortisol in social phobia: comparison to normal volunteers. J Affect Disord 1994; 30:155–161.PubMedCrossRefGoogle Scholar
  75. 75.
    Condren RM, O’Neill A, Ryan MC, et al. HPA axis response to a psychological stressor in generalised social phobia. Psychoneuroendocrino 2002; 27:693–703.CrossRefGoogle Scholar
  76. 76.
    Levin AP, Saoud JB, Strauman T, et al. Responses of “generalized” and “discrete” social phobics during public speaking. J Anxiety Disord 1993; 7:207–221.CrossRefGoogle Scholar
  77. 77.
    Heydari B, Le Melledo JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med 2002; 32:929–933.PubMedCrossRefGoogle Scholar
  78. 78.
    Laufer N, Maayan R, Hermesh H, et al. Involvement of GABAA receptor modulating neuroactive steroids in patients with social phobia. Psychiatry Res 2005; 137:131–136.PubMedCrossRefGoogle Scholar
  79. 79.
    Heimberg RG, Liebowitz MR, Hope DA, et al. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry 1998; 55:1133–1141.PubMedCrossRefGoogle Scholar
  80. 80.
    Baker GB, Wong JT, Yeung JM, et al. Effects of the antidepressant phenelzine on brain levels of gamma-aminobutyric acid (GABA). J Affect Disord 1991; 21:207–211.PubMedCrossRefGoogle Scholar
  81. 81.
    Davidson JR, Potts N, Richichi E, et al. Treatment of social phobia with clonazepam and placebo. J Clin Psychopharmacol 1993; 13:423–428.PubMedCrossRefGoogle Scholar
  82. 82.
    van Vliet IM, den Boer JA, Westenberg HG. Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine. Psychopharmacology (Berl) 1994; 115:128–134.CrossRefGoogle Scholar
  83. 83.
    Lepola U, Bergtholdt B, St Lambert J, et al. Controlled-release paroxetine in the treatment of patients with social anxiety disorder. J Clin Psychiatry 2004; 65:222–229.PubMedCrossRefGoogle Scholar
  84. 84.
    Van Ameringen M, Mancini C, Pipe B, et al. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65:1674–1678.PubMedCrossRefGoogle Scholar
  85. 85.
    Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 1999; 19:341–348.PubMedCrossRefGoogle Scholar
  86. 86.
    Pande AC, Feltner DE, Jefferson JW, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol 2004; 24:141–149.PubMedCrossRefGoogle Scholar
  87. 87.
    Lyrica (Pregabalin)–New gabapentinoid with wide clinical application. Pfizer. Available at: http://www.drugdevelopment-technology.com/projects/pregabalin. Accessed on June 2, 2007.

Copyright information

© Springer Science + Business Media, B.V 2008

Authors and Affiliations

  • Erin M. MacKenzie
    • 1
  • Glen B. Baker
    • 1
  • Jean-Michel Le Mellédo
    • 1
  1. 1.Department of PsychiatryUniversity of AlbertaCanada

Personalised recommendations