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#51 Antidepressants for preventing headaches: Which work and how well?

In the prevention or prophylaxis of headaches (including migraines), which antidepressants work and how effective are they?

Daily tricyclic antidepressants, particularly amitriptyline, effectively reduce headache severity and frequency (for 1 in 8 over placebo). They are effective regardless of headache type and the benefit improves with time.  

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Two systematic reviews and meta-analyses provide the best evidence: 
  • Tricyclic antidepressants (TCA):1 37 trials (17 tension, 13 migraine, rest mixed); 3,176 patients, mean age 40, 73% female.  
    • Versus Placebo, daily TCA resulted in statistically significant: 
      • Reduced “burden of headache” (standard mean difference -0.96, -1.39 to -0.53). 
      • More patients experienced 50% reduction in headaches: 38.4% versus 24.9%, Number Needed to Treat (NNT)=8. 
      • Both migraine and tension type benefited. 
      • Benefit improved with time.   
      • Higher adverse events with TCA (NNT to harm=5) but no difference in withdrawal. 
    • Versus Selective Serotonin Re-uptake Inhibitor (SSRI): TCA’s were superior. 
    • Versus other agents: Limited data but direct comparisons suggest no efficacy difference between TCA and topiramate (two trials) or beta-blockers (three trials).
  • No evidence to support the use of SSRI or SNRI antidepressants for migraine prophylaxis:2 11 trials, 585 patients.   
  • A review of all medications for migraine prophylaxis places amitriptyline (with propranolol and nadolol) as first line agents.3   
    • Dual benefits with amitriptyline can be achieved when patients have co-morbid depression and/or early insomnia.3 
    • Blood pressure medicines for headache prophylaxis are covered in the next Tools for Practice (#52). 
  • Majority of TCA trials used amitriptyline (30 of 37 trials) at doses of 10-150 mg, mean 80 mg)1 
    • Slow titration can maximize benefit while limiting adverse events. 
  • Beta-Blockers, some anticonvulsants and some blood pressure medications (other than just beta-blockers) have also been shown to be effective for migraine prevention.4-6
    • For example, NNT is 4-7 for topiramate producing 50% reduction in migraine frequency.4  
updated apr 30, 2015 by Emelie

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  • G. Michael Allan MD CCFP
  • Michelle Levy MD CCFP

1. Jackson JL, Shimeall W, Sesums L, et al. BMJ. 2010; 341:c5222.

2. Banzi R, Cusi C, Randazzo C, et al. Cochrane Database Syst Rev. 2015:CD002919.

3. Pringsheime T, Davenport WJ, Becker WJ. CMAJ. 2010 Apr 20; 182(7):E269-76.

4. Chronicle E, Mulleneres W. Cochrane Database Syst Rev. 2004; (3):CD003226.

5. Shamliyan TA, Choi JY, Ramakrishnan MPH, et al. J Gen Intern Med. 2013; 28:1225-37.

6. Kapusta MJ, Allan GM. Tools for Practice, Alberta College of Family Physicians. 2011 September 19. Available for download from:

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.

Most recent review: 30/04/2015

By: Emélie Braschi MD PhD


Evidence Updated: Meta-analysis; Bottom Line: No change.

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