Antidepressants for Preventive Treatment of Migraine

  • Rebecca BurchEmail author
Headache (JR Couch, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Headache


Purpose of review

This review describes the pharmacology of each antidepressant class as it applies to migraine prevention, summarizes the evidence base for each medication, and describes relevant side effects and clinical considerations. Use of antidepressants for migraine prevention in clinical practice is also discussed.

Recent findings

Antidepressants are commonly used as migraine preventives. Amitriptyline has the best evidence for use in migraine prevention. Nortriptyline is an alternative in patients who may not tolerate amitriptyline. The sedating effect of TCAs can be beneficial for patients with comorbid insomnia. SNRIs including venlafaxine and duloxetine also have evidence for efficacy and may be the most effective treatments in patients with comorbid depression and migraine. SSRIs including fluoxetine are not effective for most patients. The side effect burden of antidepressants can be substantial. Patients should be particularly counseled about the possibility of a withdrawal effect from SNRIs.


Antidepressants are an important option for preventive treatment of migraine. Further research on the efficacy and tolerability of SNRIs as migraine preventives is needed.


Antidepressants SSRI SNRI TCA Migraine Prevention Treatment 


Compliance with Ethical Standards

Conflict of Interest

The author declares that she has no conflicts of interest.

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.
    Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018;58:496–505.CrossRefGoogle Scholar
  2. 2.
    Stewart WF, Wood GC, Manack A, Varon SF, Buse DC, Lipton RB. Employment and work impact of chronic migraine and episodic migraine. J Occup Environ Med. 2010;52:8–14.CrossRefGoogle Scholar
  3. 3.
    Dodick DW. Migraine. Lancet. 2018;391:1315–30.CrossRefGoogle Scholar
  4. 4.
    Diamond S, Bigal ME, Silberstein S, Loder E, Reed M, Lipton RB. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American migraine prevalence and prevention study. Headache. 2007;47:355–63.PubMedGoogle Scholar
  5. 5.
    • Silberstein SD. Preventive migraine treatment. Continuum. 2015;21:973–89 A comprehensive and authoritative review of the approach to preventive strategies for migraine.PubMedGoogle Scholar
  6. 6.
    Punay NC, Couch JR. Antidepressants in the treatment of migraine headache. Curr Pain Headache Rep. 2003;7:51–4.CrossRefGoogle Scholar
  7. 7.
    Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (2012) Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78:1337–1345CrossRefGoogle Scholar
  8. 8.
    Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52:930–45.CrossRefGoogle Scholar
  9. 9.
    Yaldo AZ, Wertz DA, Rupnow MFT, Quimbo RM. Persistence with migraine prophylactic treatment and acute migraine medication utilization in the managed care setting. Clin Ther. 2008;30:2452–60.CrossRefGoogle Scholar
  10. 10.
    Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.CrossRefGoogle Scholar
  11. 11.•
    Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017. A review describing why antidepressants may be effective treatments in pain conditions.CrossRefGoogle Scholar
  12. 12.
    Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573–81.CrossRefGoogle Scholar
  13. 13.
    Marks DM, Shah MJ, Patkar AA, Masand PS, Park G-Y, Pae C-U. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol. 2009;7:331–6.CrossRefGoogle Scholar
  14. 14.
    Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151:737–48.CrossRefGoogle Scholar
  15. 15.
    Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59:652–61.CrossRefGoogle Scholar
  16. 16.
    Sprenger T, Viana M, Tassorelli C. Current prophylactic medications for migraine and their potential mechanisms of action. Neurotherapeutics. 2018;15:313–23.CrossRefGoogle Scholar
  17. 17.
    •• Xu X-M, Liu Y, Dong M-X, Zou D-Z, Wei Y-D. Tricyclic antidepressants for preventing migraine in adults. Medicine. 2017;96:e6989 A comprehensive review summarizing the evidence base for TCAs as migraine preventives.CrossRefGoogle Scholar
  18. 18.
    Doyle Strauss L, Strauss LD, Weizenbaum E, Loder EW, Rizzoli PB. Amitriptyline dose and treatment outcomes in specialty headache practice: a retrospective cohort study. Headache: The Journal of Head and Face Pain. 2016;56:1626–34.CrossRefGoogle Scholar
  19. 19.
    Casucci G, Villani V, Cologno D, D’Onofrio F. Polytherapy for migraine prophylaxis. Neurol Sci. 2012;33(Suppl 1):S147–50.CrossRefGoogle Scholar
  20. 20.
    Mikulec AA, Faraji F, Kinsella LJ. Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am J Otolaryngol. 2012;33:121–7.CrossRefGoogle Scholar
  21. 21.
    Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35:478–88.CrossRefGoogle Scholar
  22. 22.
    Adelman JU, Von Seggern R. Cost considerations in headache treatment. Part 1: prophylactic migraine treatment. Headache. 1995;35:479–87.CrossRefGoogle Scholar
  23. 23.
    Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162–73.CrossRefGoogle Scholar
  24. 24.
    Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M. Serotonergic mechanisms in the migraine brain - a systematic review. Cephalalgia. 2017;37:251–64.CrossRefGoogle Scholar
  25. 25.
    Sommer C. Is serotonin hyperalgesic or analgesic? Curr Pain Headache Rep. 2006;10:101–6.CrossRefGoogle Scholar
  26. 26.
    Yücel Y, Coşkun S, Cengiz B, Özdemir HH, Uzar E, Çim A, et al. Association of Polymorphisms within the serotonin receptor genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and migraine susceptibility in a Turkish population. Clin Psychopharmacol Neurosci. 2016;14:250–5.CrossRefGoogle Scholar
  27. 27.
    Singh VP, Jain NK, Kulkarni SK. On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor. Brain Res. 2001;915:218–26.CrossRefGoogle Scholar
  28. 28.
    Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia. 1998;18:283–6.CrossRefGoogle Scholar
  29. 29.
    d’Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V, Nasta A. Fluoxetine for migraine prophylaxis: a double-blind trial. Headache. 1999;39:716–9.CrossRefGoogle Scholar
  30. 30.
    Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache. 1992;32:101–4.CrossRefGoogle Scholar
  31. 31.
    Saper JR, Silberstein SD, Lake AE 3rd, Winters ME. Fluoxetine and migraine: comparison of double-blind trials. Headache. 1995;35:233.CrossRefGoogle Scholar
  32. 32.
    Krymchantowski AV, Silva MT, Barbosa JS, Alves LA. Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache. 2002;42:510–4.CrossRefGoogle Scholar
  33. 33.
    Saper JR, Silberstein SD, Lake AE 3rd, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994;34:497–502.CrossRefGoogle Scholar
  34. 34.
    Landy S, McGinnis J, Curlin D, Laizure SC. Selective serotonin reuptake inhibitors for migraine prophylaxis. Headache. 1999;39:28–32.CrossRefGoogle Scholar
  35. 35.
    Bánk J. A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache. 1994;34:476–8.CrossRefGoogle Scholar
  36. 36.
    Tarlaci S. Escitalopram and venlafaxine for the prophylaxis of migraine headache without mood disorders. Clin Neuropharmacol. 2009;32:254–8.CrossRefGoogle Scholar
  37. 37.
    Hays P. Paroxetine prevents migraines. J Clin Psychiatry. 1997;58:30–1.CrossRefGoogle Scholar
  38. 38.
    Black KJ, Sheline YI. Paroxetine as migraine prophylaxis. J Clin Psychiatry. 1995;56:330–1.PubMedGoogle Scholar
  39. 39.
    Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry. 2001;3:22–7.CrossRefGoogle Scholar
  40. 40.
    Larson EW. Migraine with typical aura associated with fluoxetine therapy: case report. J Clin Psychiatry. 1993;54:235–6.PubMedGoogle Scholar
  41. 41.
    Bickel A, Kornhuber J, Maihöfner C, Ropohl A. Exacerbation of migraine attacks during treatment with the selective serotonin reuptake inhibitor sertraline A case report. Pharmacopsychiatry. 2005;38:327–8.CrossRefGoogle Scholar
  42. 42.
    Alemdar M, Selekler HM. Migraine with aura triggered by citalopram. Neuropsychobiology. 2007;55:121–2.CrossRefGoogle Scholar
  43. 43.
    Munera PA, Goldstein A. Migraine and sertraline. J Am Acad Child Adolesc Psychiatry. 2001;40:1125–6.CrossRefGoogle Scholar
  44. 44.
    Delva NJ, Horgan SA, Hawken ER. Valproate prophylaxis for migraine induced by selective serotonin reuptake inhibitors. Headache. 2000;40:248–51.CrossRefGoogle Scholar
  45. 45.
    Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45:144–52.CrossRefGoogle Scholar
  46. 46.
    Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg. 2004;107:44–8.CrossRefGoogle Scholar
  47. 47.
    Liu F, Ma T, Che X, Wang Q, Yu S. The efficacy of venlafaxine, flunarizine, and valproic acid in the prophylaxis of vestibular migraine. Front Neurol. 2017;8:524.CrossRefGoogle Scholar
  48. 48.
    Salviz M, Yuce T, Acar H, Karatas A, Acikalin RM. Propranolol and venlafaxine for vestibular migraine prophylaxis: a randomized controlled trial. Laryngoscope. 2016;126:169–74.CrossRefGoogle Scholar
  49. 49.
    Young WB, Bradley KC, Anjum MW, Gebeline-Myers C. Duloxetine prophylaxis for episodic migraine in persons without depression: a prospective study. Headache. 2013;53:1430–7.PubMedGoogle Scholar
  50. 50.
    Engel ER, Kudrow D, Rapoport AM. A prospective, open-label study of milnacipran in the prevention of headache in patients with episodic or chronic migraine. Neurol Sci. 2014;35:429–35.CrossRefGoogle Scholar
  51. 51.••
    Santarsieri D, Schwartz TL (2015) Antidepressant efficacy and side-effect burden: a quick guide for clinicians. Drugs Context 4:212290. An easily accessible discussion of antidepressant choices in individual patients. Focuses on depression, but the information on side effects and contraindications is relevant to migraine patients as well.CrossRefGoogle Scholar
  52. 52.
    Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87:195–203.CrossRefGoogle Scholar
  53. 53.
    Lévy E, Margolese HC. Migraine headache prophylaxis and treatment with low-dose mirtazapine. Int Clin Psychopharmacol. 2003;18:301–3.CrossRefGoogle Scholar
  54. 54.
    Brannon GE, Rolland PD, Gary JM. Use of mirtazapine as prophylactic treatment for migraine headache. Psychosomatics. 2000;41:153–4.CrossRefGoogle Scholar
  55. 55.
    Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004;62:1706–11.CrossRefGoogle Scholar
  56. 56.
    • Baskin SM, Smitherman TA. Migraine and psychiatric disorders: comorbidities, mechanisms, and clinical applications. Neurol Sci. 2009;30(Suppl 1):S61–5 Review of psychiatric comorbidities in migraine including epidemiology and treatment suggestions.CrossRefGoogle Scholar
  57. 57.
    Rampello L, Alvano A, Chiechio S, Malaguarnera M, Raffaele R, Vecchio I, et al. Evaluation of the prophylactic efficacy of amitriptyline and citalopram, alone or in combination, in patients with comorbidity of depression, migraine, and tension-type headache. Neuropsychobiology. 2004;50:322–8.CrossRefGoogle Scholar
  58. 58.
    MacGregor EA, Frith AA, Hackshaw A. Efficacy, safety, and tolerability of sertraline on depressive symptoms in women with comorbid migraine: an open-label study. J Clin Psychopharmacol. 2011;31:392–3.CrossRefGoogle Scholar
  59. 59.
    Park H-J, Lee S-T, Shim J-Y, Kim B, Hwang SH, Kim SH, et al. The effect of paroxetine on the reduction of migraine frequency is independent of its anxiolytic effect. J Clin Neurol. 2006;2:246–51.CrossRefGoogle Scholar
  60. 60.
    Volpe FM. An 8-week, open-label trial of duloxetine for comorbid major depressive disorder and chronic headache. J Clin Psychiatry. 2008;69:1449–54.CrossRefGoogle Scholar
  61. 61.
    Curone M, Tullo V, Savino M, Proietti-Cecchini A, Bussone G, D’Amico D. Outcome of patients with chronic migraine with medication overuse and depression after duloxetine: influence of coexisting obsessive compulsive disorder. Neurol Sci. 2013;34(Suppl 1):S175–7.CrossRefGoogle Scholar
  62. 62.
  63. 63.
    Evans RW. The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reports. MedGenMed. 2007;9:48.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American headache society position paper. Headache. 2010;50:1089–99.CrossRefGoogle Scholar
  65. 65.
    Orlova Y, Rizzoli P, Loder E. Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol. 2018;75:566–72.CrossRefGoogle Scholar
  66. 66.
    Kinrys G, Gold AK, Pisano VD, Freeman MP, Papakostas GI, Mischoulon D, et al. Tachyphylaxis in major depressive disorder: a review of the current state of research. J Affect Disord. 2018;245:488–97.CrossRefGoogle Scholar
  67. 67.
    Ali S, Mathew NT. Tachyphylaxis in migraine prophylaxis. Headache. 1992;32:315.CrossRefGoogle Scholar
  68. 68.
    Rizzoli P, Loder EW. Tolerance to the beneficial effects of prophylactic migraine drugs: a systematic review of causes and mechanisms. Headache. 2011;51:1323–35.CrossRefGoogle Scholar
  69. 69.
    Woolley JM, Bonafede MM, Maiese BA, Lenz RA. Migraine prophylaxis and acute treatment patterns among commercially insured patients in the United States. Headache. 2017;57:1399–408.CrossRefGoogle Scholar
  70. 70.
    Jackson JL, Mancuso JM, Nickoloff S, Bernstein R, Kay C. Tricyclic and tetracyclic antidepressants for the prevention of frequent episodic or chronic tension-type headache in adults: a systematic review and meta-analysis. J Gen Intern Med. 2017;32:1351–8.CrossRefGoogle Scholar
  71. 71.
    Taylor FR. Weight change associated with the use of migraine-preventive medications. Clin Ther. 2008;30:1069–80.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.John R. Graham Headache Center, Brigham and Women’s Hospital Department of NeurologyHarvard Medical SchoolBostonUSA

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