The associations between migraine, unipolar psychiatric comorbidities, and stress-related disorders and the role of estrogen


Migraine is a common and often disabling neurovascular disorder. It has been linked with several psychiatric disorders, such as depression and anxiety, and to stress-related disorders, such as abuse and posttraumatic stress disorder (PTSD). Epidemiological data have consistently shown a higher prevalence of migraine, depression, anxiety, abuse, and PTSD in women as compared with men. The increased vulnerability of women to migraine and psychiatric disorders often occurs during periods of marked hormonal fluctuations of ovarian hormones. One consequence of these associations is the hypothesis that estrogens have a role in the pathophysiology of both disorders. This article offers an in-depth review of several studies linking psychiatric disorders and stress-related disorders with migraine. We also discuss the role of estrogen in the pathophysiologic overlap between these disorders. Finally, we briefly touch on where future research may be headed, in light of these data.

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References and Recommended Reading

  1. 1.

    Bigal M, Liberman JN, Lipton R: Age-dependent prevalence and clinical features of migraine. Neurology 2006, 67:246–251.

    PubMed  Article  Google Scholar 

  2. 2.

    Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003, 106:81–89.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Peterlin BL, Rosso AL, Rapoport AM, Scher AI: Obesity and migraine: the effect of age, gender and adipose tissue distribution. Headache 2009(in press).

  4. 4.

    Peterlin BL, Ward TN: Neuropsychiatric aspects of migraine. Curr Psychiatry Rep 2005, 7:371–375.

    PubMed  Article  Google Scholar 

  5. 5.

    Peterlin BL, Ward T, Lidicker J, et al.: A retrospective, comparative study on the frequency of abuse in migraine and chronic daily headache. Headache 2007, 47:397–401.

    PubMed  Google Scholar 

  6. 6.

    Tietjen GE, Herial NA, Hardgrove J, et al.: Migraine comorbidity constellations. Headache 2007, 47:857–865.

    PubMed  Article  Google Scholar 

  7. 7.

    De Leeuw R, Schmidt JE, Carlson CR: Traumatic stressor and post-traumatic stress disorder symptoms in headache patient. Headache 2005, 45:1365–1374.

    PubMed  Google Scholar 

  8. 8.

    Peterlin BL, Tietjen GE, Brandes JL, et al.: Posttraumatic stress disorder in migraine. Headache 2009, 49:541–551.

    PubMed  Article  Google Scholar 

  9. 9.

    Radat F, Swendsen J: Psychiatric comorbidity in migraine: a review. Cephalalgia 2004, 25:165–178.

    Article  Google Scholar 

  10. 10.

    Soares CN, Poitras JR, Prouty J: Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Drugs Aging 2003, 20:85–100.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Riolo SA, Nguyen TA, Greden JF, et al.: Prevalence of depression by race/ethnicity: findings from the National Health and Nutrition Examination Survey III. Am J Public Health 2005, 95:998–1000.

    PubMed  Article  Google Scholar 

  12. 12.

    Breslau N, Schultz LR, Stewart WF, et al.: Headache and major depression: is the association specific to migraine? Neurology 2000, 54:308–314.

    PubMed  CAS  Google Scholar 

  13. 13.

    Merikangas KR, Angst J, Isler H: Migraine and psychopathology: results of the Zurich Cohort Study of Young Adults. Arch Gen Psychiatry 1990, 47:849–853.

    PubMed  CAS  Google Scholar 

  14. 14.

    Breslau N, Lipton RB, Stewart WF, et al.: Comorbidity of migraine and depression. Neurology 2003, 60:1308–1312.

    PubMed  CAS  Google Scholar 

  15. 15.

    McWilliams LA, Goodwin RD, Cox BJ: Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain 2004, 111:77–83.

    PubMed  Article  Google Scholar 

  16. 16.

    Tietjen GE, Brandes JL, Digre KB, et al.: High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology 2007, 68:134–140.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Lanteri-Minet M, Radat F, Chatuard M, Lucas C: Anxiety and depression associated with migraine: influence on migraine subjects’ disability and quality of life and acute migraine management. Pain 2005, 319–326.

  18. 18.

    Molgat CV, Patten SB: Comorbidity of major depression and migraine: a Canadian population-based study. Can J Psychiatry 2005, 50:832–837.

    PubMed  Google Scholar 

  19. 19.

    Jette N, Patten S, William J, et al.: Comorbidity of migraine and psychiatric disorders: a national population-based study. Headache 2008, 48:501–516.

    PubMed  Article  Google Scholar 

  20. 20.

    Patel NV, Bigal ME, Kolodner KB, et al.: Prevalence and impact of migraine and probable migraine in a health plan. Neurology 2004, 63:1432–1438.

    PubMed  CAS  Google Scholar 

  21. 21.

    Oedegaard KJ, Neckelmann D, Mykletun A, et al.: Migraine with and without aura: association with depression and anxiety disorder in a population-based study. The HUNT Study. Cephalalgia 2006, 26:1–6.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Samaan Z, Farmer AE, Craddock N, et al.: A case-control study of migraine in recurrent depression. Br J Psychiatry 2009 (in press).

  23. 23.

    Camarda C, Pipia C, Taglialavori A, et al.: Comorbidity between depressive symptoms and migraine: preliminary data from the Zabut Aging Project. Neuro Sci 2008, 29:S149–S1451.

    Article  Google Scholar 

  24. 24.

    Breslau N, Davis GC, Schultz LR, et al.: Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache 1994, 34:387–393.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Kessler RC, Berglund P, Demler O, et al.: Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005, 62:593–602.

    PubMed  Article  Google Scholar 

  26. 26.

    Kessler RC, Chiu WT, Demler O, Walters EE: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005, 62:617–627.

    PubMed  Article  Google Scholar 

  27. 27.

    Vesga-López O, Schneier FR, Wang S, et al.: Gender differences in generalized anxiety disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry 2008, 69:1606–1616.

    PubMed  Article  Google Scholar 

  28. 28.

    Breslau N, Davis GC: Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiat Res 1993, 27:211–221.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Zwart JA, Dyb G, Hagen K, et al.: Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag Study. Eur J Neurol 2003, 10:147–152.

    PubMed  Article  Google Scholar 

  30. 30.

    Tan HJ, Suganthi C, Dhachayani S, et al.: The coexistence of anxiety and depressive personality traits in migraine. Singapore Med J 2007, 48:307–310.

    PubMed  CAS  Google Scholar 

  31. 31.

    Pesa J, Lage MJ: The medical costs of migraine and comorbid anxiety and depression. Headache 2004, 44:562–570.

    PubMed  Article  Google Scholar 

  32. 32.

    Butterfield MI, Becker M, Marx CE: Post-traumatic stress disorder in women: current concepts and treatments. Curr Psychiatry Rep 2002, 4:474–486.

    PubMed  Article  Google Scholar 

  33. 33.

    Goodwin RD, Hoven CW, Murison R, Hotopf M: Association between childhood physical abuse and gastrointestinal disorders and migraine in adulthood. Am J Public Health 2003, 93:1065–1067.

    PubMed  Article  Google Scholar 

  34. 34.

    Tietjen GE, Brandes JL, Digre KB, et al.: History of childhood maltreatment is associated with comorbid depression in women with migraine. Neurology 2007, 69:959–968.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Saunders K, Merikangas K, Low NCP, et al.: Impact of comorbidity on headache-related disability. Neurology 2008, 70:538–547.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    de Leeuw R, Schmidt JE, Carlson CR: Traumatic stressors and post-traumatic stress disorder symptoms in headache patients. Headache 2005, 45:1365–1374.

    PubMed  Google Scholar 

  37. 37.

    Grigoriadis S, Kennedy SH: Role of estrogen in the treatment of depression. Am J Therapeutics 2002, 9:503–509.

    Article  Google Scholar 

  38. 38.

    MacGregor EA: Headache and hormone replacement therapy in the postmenopausal woman. Curr Treat Options Neurol 2009, 11:10–17.

    PubMed  Article  Google Scholar 

  39. 39.

    Dalton K: Menstruation and acute psychiatric illnesses. BMJ 1959, 34:148–149.

    Article  Google Scholar 

  40. 40.

    Somerville BJ: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 1972, 22:3655–3665.

    Google Scholar 

  41. 41.

    Weissman MM, Bland RC, Canino GJ, et al.: Cross-national epidemiology of depression and bipolar disorder. JAMA 1996, 276:293–299.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Thorpe L, Whitney DK, Kutcher SP, et al.: Clinical guidelines for the treatment of depressive disorders VI. Special populations. Can J Psychiatry 2001, 46:S63–S67.

    Google Scholar 

  43. 43.

    Easterbrook CC: Organo-therapeutics in mental disease. BMJ 1900, 2:813–823.

    Google Scholar 

  44. 44.

    Soares CN, Almeida OP, Joffe H, et al.: Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001, 58:529–534.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Schmidt PJ, Nieman L, Danaceau MA, et al.: Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000, 183:414–420.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Klaiber EL, Broverman DM, Vogel W, et al.: Estrogen therapy for severe persistent depression in women. Arch Gen Psychiatry 1979, 36:550–554.

    PubMed  CAS  Google Scholar 

  47. 47.

    Campbell S, Whitehead M: Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977, 4:31–47.

    PubMed  CAS  Google Scholar 

  48. 48.

    Coope J: Is oestrogen therapy effective in the treatment of menopausal depression? J R Coll Gen Pract 1981, 31:134–140.

    PubMed  CAS  Google Scholar 

  49. 49.

    Schmidt PJ, Roca CA, Bloch M, et al.: The perimenopause and affective disorders. Semin Reprod Endocrinol 1997, 15:91–100.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Cohen LS, Soares CN, Poitras JR, et al.: Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 2003, 160:1519–1522.

    PubMed  Article  Google Scholar 

  51. 51.

    Shapira B, Oppenheim G, Zohar J, et al.: Lack of efficacy of estrogen supplementation to imipramine in resistant depressives. Biol Psychiatry 1985, 20:570–583.

    Article  Google Scholar 

  52. 52.

    Schneider LS, Small GW, Hamilton SH, et al.: Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry 1997, 5:97–106.

    PubMed  CAS  Google Scholar 

  53. 53.

    Amsterdam J, Garcia-Espana F, Fawcett J, et al.: Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord 1999, 55:11–17.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Schneider LS, Small GW, Clary CM: Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am j Geriatr Psychiatry 2001, 9:393–399.

    PubMed  CAS  Google Scholar 

  55. 55.

    Saper JR, Silberstein SD, Lake AE 3rd, Winters ME: Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994, 34:497–502.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Ziegler DK, Hurwitz A, Preskorn S, et al.: Propranolol and amitriptyline in prophylaxis of migraine: pharmacokinetic and therapeutic effects. Arch Neurol 1993, 50:825–830.

    PubMed  CAS  Google Scholar 

  57. 57.

    Martin VT, Behbehani M: Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis: part I. Headache 2006, 46:3–23.

    PubMed  Article  Google Scholar 

  58. 58.

    Denuelle M, Fabre N, Payoux P, et al.: Hypothalamic activation in spontaneous migraine attacks. Headache 2007, 47:1418–1426.

    PubMed  Google Scholar 

  59. 59.

    Solomon MB, Herman JP: Sex differences in psychopathology: of gonads, adrenals and mental illness. Physiol Behav 2009, 97:250–258.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Walf AA, Frye CA: A review and update of mechanisms of estrogen in the hippocampus and amygdale for anxiety and depression behavior. Neuropsychopharmacology 2006, 31:1097–1111.

    PubMed  CAS  Google Scholar 

  61. 61.

    Dieudonné MN, Leneveu MC, Giudicelli Y, et al.: Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol 2004, 286:C655–C661.

    PubMed  Article  Google Scholar 

  62. 62.

    Pedersen SB, Bruun JM, Hube F, et al.: Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: influences of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 2001, 182:27–37.

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Mather AA, Cox BJ, Enns MW, Sareen J: Associations of obesity with psychiatric disorder and suicidal behaviours in a nationally representative sample. J Psychosom Res 2009, 66:277–285.

    PubMed  Article  Google Scholar 

  64. 64.

    Rivenes AC, Harvey SB, Mykletun A: The relationship between abdominal fat, obesity, and common mental disorders: results from the HUNT study. J Psychosom Res 2009, 66:269–275.

    PubMed  Article  Google Scholar 

  65. 65.

    Pulkki-Råback L, Elovainio M, Kivimäki M, et al.: Depressive symptoms and the metabolic syndrome in childhood and adulthood: a prospective cohort study. Health Psychol 2009, 28:108–116

    PubMed  Article  Google Scholar 

  66. 66.

    Noll JG, Zeller MH, Trickett PK, Putnam FW: Obesity risk for female victims of childhood sexual abuse: a prospective study. Pediatrics 2007, 120:e61–e67.

    PubMed  Article  Google Scholar 

  67. 67.

    King TK, Clark MM, Pera V: History of sexual abuse and obesity treatment outcome. Addict Behav 1996, 21:283–290.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Tietjen GE, Peterlin BL, Brandes JL, et al.: Depression and anxiety: effect on the migraine-obesity relationship. Headache 2007, 47:866–875.

    PubMed  Article  Google Scholar 

  69. 69.

    Nomura M, Akama KT, Alves SE, et al.: Differential distribution of estrogen receptor (ER)-alpha and ER-beta in the midbrain raphe nuclei and periaqueductal gray in male mouse: predominant role of ER-beta in midbrain serotonergic systems. Neuroscience 2005, 130:445–456.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to B. Lee Peterlin.

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Peterlin, B.L., Katsnelson, M.J. & Calhoun, A.H. The associations between migraine, unipolar psychiatric comorbidities, and stress-related disorders and the role of estrogen. Current Science Inc 13, 404–412 (2009).

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  • Migraine
  • Sexual Abuse
  • Mood Disorder
  • Migraine With Aura
  • Chronic Daily Headache