Examining the Links Between Migraine and Major Depressive Disorder

Photo taken in Chiang Mai, Thailand
Dr Amit Akirov examines the evidence suggesting associations between migraine and major depressive disorder (MDD).

Patients with migraine headaches are at greater risk for major depressive disorder (MDD), and a recent review published in Cureus suggests that the strong relationship between the conditions may be explained by a robust molecular genetic background.1

Migraine headache and MDD are common debilitating disorders that may have a significant impact on patients’ quality of life.2 Studies have shown that MDD is associated with poor academic performance, decreased productivity, and poor appetite and sleep.1

Significant Links

In a prospective study to examine the association between migraine and depression, Tietjen and colleagues reported that among women with chronic headache, the prevalence rate of MDD was 29 percent. The risk for MDD was 25 times greater among patients with chronic headache, very severe headache-related disability, and high somatic symptom severity, compared with patients without any of these conditions.3

Amiri and colleagues completed a literature search and a meta-analysis that included 16 eligible articles. They reported that migraine headaches can nearly double the risk for depression.4 On the other hand, depression was significantly associated with an increased risk for chronic migraine.5

Genes or Environment?

Some data suggest that migraine pathophysiology involves heritable and environmental components. Family history of migraine is very common in patients with migraine, and studies conducted for migraine and MDD showed a moderate heritability with an estimated heritability of 30 to 50 percent between both conditions.

Several previous studies, including twin- and family-based studies, reported that both migraine and depression have a strong genetic basis and both diseases share molecular pathways controlling serotonergic and glutaminergic neurotransmitter system.6

Several inflammatory markers, including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and high sensitivity C-reactive protein, were found to be increased in patients with depression.1,7

A comprehensive analysis to determine the genetic overlap between MDD and migraine and to identify shared genetic factors between the 2 conditions at the molecular level has shown a significant overlap at both the single nucleotide polymorphism and gene level. Genome-wide association studies identified 3 single nucleotide polymorphisms (rs146377178, rs672931, and rs11858956) associated with migraine and MDD; gene-based association analyses revealed 2 genome-wide significant genes, including ankyrin repeat and death domain containing 1A (ANKDD1B) and potassium channel, subfamily K, member 5 (KCNK5).8

Serotonin and Other Factors

In addition to genetic and inflammatory factors, many other potential mechanisms linking migraine and MDD have been suggested, including alterations of serotonergic circuits, dysfunction of the hypothalamic-pituitary-adrenal axis, and sensitization of neuronal networks dealing with emotions and the sensorium, including pain processing.9

Serotonin genes and receptors can play a major role in both conditions because increased levels of 5-hydroxy indole acetic acid were found to potentially cause migraine attacks, and diminished serotonin levels were associated with severe depression. In both diseases, a low level of 5-hydroxytryptamine or serotonin receptors, as well as alterations in serotonin transporter gene, may be important.1

Structural Changes

Morphological changes in cerebral cortex and thalamus were reported in patients with migraines and MDD.1 Furthermore, Ma and colleagues reported abnormalities in the left medial prefrontal cortex in the patients with both migraine and depression.

Because this region was thought to be the neural basis of self-referential mental activity, it was suggested that abnormalities in this region may contribute to the common symptoms of migraine and MDD. Furthermore, this region may be used as a therapeutic target for patients with combined migraine and MDD.10

Interestingly, patients with a history of migraines and depression were reported to have smaller brain volumes when compared with patients with only one of the conditions, suggesting that the combination of depression and migraine can potentially accelerate the aging process.11

Shared Treatment Options

Amitriptyline, a tricyclic antidepressant that inhibits serotonin and norepinephrine uptake, is an effective treatment option for both migraine and MDD. However, the antidepressant efficacy of amitriptyline usually requires high doses, associated with more side effects and less tolerability for most patients.12 Nortriptyline may be used as an alternative treatment option for patients who cannot tolerate amitriptyline.1

While selective serotonin reuptake inhibitors are not effective for most patients with MDD and migraine, serotonin-norepinephrine reuptake inhibitors, including venlafaxine and duloxetine, have evidence for efficacy and may be the most effective treatments in patients with both diseases.13

Future Directions

Although data indicates “multiple factors associated with migraine and MDD,” they also depict “the need to find the molecular and genetic overlap between these two diseases.”1 Researchers additionally suggested “performing further combined analysis of the GWAS [genome wide association studies] on patients with migraine and MDD” in the future.  


1. Jahangir S, Adjepong D, Al-Shami HA, Malik BH. Is there an association between migraine and major depressive disorder? a narrative review. Cureus. 2020;12(6):e8551. doi:10.7759/cureus.8551

2. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi:10.1016/S0140-6736(18)32279-7

3. Tietjen GE, Brandes JL, Digre KB, et al. High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology. 2007;68(2):134-140. doi:10.1212/01.wnl.0000251195.55563.02

4. Amiri S, Behnezhad S, Azad E. Migraine headache and depression in adults: a systematic review and meta-analysis. Neuropsychiatr. 2019;33(3):131-140. doi:10.1007/s40211-018-0299-5

5. Xu J, Kong F, Buse DC. Predictors of episodic migraine transformation to chronic migraine: a systematic review and meta-analysis of observational cohort studies. Cephalalgia. 2020;40(5):503-516. doi:10.1177/0333102419883355

6. Stam AH, de Vries B, Janssens AC, et al. Shared genetic factors in migraine and depression: evidence from a genetic isolate. Neurology. 2010;74(4):288-294. doi:10.1212/WNL.0b013e3181cbcd19

7. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry. 2010;9(3):155-161. doi:10.1002/j.2051-5545.2010.tb00298.x

8. Yang Y, Zhao H, Boomsma DI, et al; International Headache Genetics Consortium. Molecular genetic overlap between migraine and major depressive disorder. Eur J Hum Genet. 2018;26(8):1202-1216. doi:10.1038/s41431-018-0150-2

9. Fugger G, Dold M, Bartova L, et al. Clinical correlates and outcome of major depressive disorder and comorbid migraine: a report of the European Group for the Study of Resistant Depression. Int J Neuropsychopharmacol. 2020;23(9):571-577. doi:10.1093/ijnp/pyaa035

10. Ma M, Zhang J, Chen N, Guo J, Zhang Y, He L. Exploration of intrinsic brain activity in migraine with and without comorbid depression. J Headache Pain. 2018;19(1):48. doi:10.1186/s10194-018-0876-9

11. Gudmundsson LS, Scher AI, Sigurdsson S, et al. Migraine, depression, and brain volume: the AGES-Reykjavik Study. Neurology. 2013;80(23):2138-2144. doi:10.1212/WNL.0b013e318295d69e

12. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87(7):741-749. doi:10.1136/jnnp-2015-312233

13. Burch R. Antidepressants for preventive treatment of migraine. Curr Treat Options Neurol. 2019;21(4):18. doi:10.1007/s11940-019-0557-2