Investigation of the Relationship Between Migraines and Main Depressive Dysfunction

Patients with migraine headache are at greater risk of major depression (MDD), and a recent review published in Cureus suggests that the strong relationship between the disorders can be explained by a robust molecular genetic background

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

important links

In a prospective study examining the relationship between migraines and depression, Tietjen and colleagues reported that the prevalence rate of MDD was 29 percent in women with chronic headaches. The risk of MDD was 25 times higher in patients with chronic headache, very severe headache-related disabilities, and high severity of somatic symptoms compared to patients without these conditions

Amiri and colleagues conducted a literature search and meta-analysis with 16 suitable articles. They reported that migraine headaches can nearly double the risk of depression.4 On the other hand, depression was significantly associated with an increased risk of chronic migraines

Genes or environment?

Some data suggest that migraine pathophysiology includes hereditary and environmental components. A family history of migraines is very common in patients with migraines, and studies of migraines and MDD have shown moderate heritability with an estimated heritability of 30 to 50 percent between the two disorders.

Several previous studies, including double and family studies, have reported that both migraine and depression have a strong genetic basis and that both diseases share molecular pathways that control the serotonergic and glutaminergic neurotransmitter systems

Several markers of inflammation, including interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and highly sensitive C-reactive protein, have been found to be elevated in patients with depression, 1,7

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

Serotonin and other factors

In addition to genetic and inflammatory factors, many other possible mechanisms linking migraine and MDD have been suggested, including changes in serotonergic circuitry, dysfunction of the hypothalamic-pituitary-adrenal axis, and sensitization of neural networks dealing with emotion and the sensorium, including pain Processing. 9

Serotonin genes and receptors can play an important role in both conditions, as it has been found that increased levels of 5-hydroxyindole acetic acid may cause migraine attacks and decreased serotonin levels are linked to severe depression. A low level of 5-hydroxytryptamine or serotonin receptors and changes in the serotonin transporter gene can be important in both diseases

Structural changes

Morphological changes in the cerebral cortex and thalamus have been reported in patients with migraines and MDD.1 In addition, Ma and colleagues reported abnormalities in the left medial prefrontal cortex in patients with migraine and depression.

Since this region was thought to be the neural basis for self-referential mental activity, it has been suggested that abnormalities in this region may contribute to the common symptoms of migraines and MDD. In addition, this region can be used as a therapeutic target for patients with combined migraines and MDD.10

Interestingly, it has been reported that patients with a history of migraines and depression have lower brain volume compared to those with only one of the disorders, suggesting that the combination of depression and migraine may potentially accelerate the aging process

Common treatment options

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

While selective serotonin reuptake inhibitors are ineffective in most patients with MDD and migraine, serotonin-norepinephrine reuptake inhibitors, including venlafaxine and duloxetine, have evidence of effectiveness and may be the most effective treatment in patients with both diseases

Future directions

Although the data suggest “several factors associated with migraines and MDD”, they also show “the need to find the molecular and genetic overlap between these two diseases”. 1 The researchers also suggested “doing another combined analysis of the GWAS [genome wide association studies] in patients with migraines and MDD ”in the future.


1. Jahangir S., Adjepong D., Al-Shami HA, Malik BH. Is there a connection between migraines and major depression? a narrative review. Cureus. 2020; 12 (6): e8551. doi: 10.7759 / cure.8551

2. GBD 2017 Collaborators for Incidence and Prevalence of Disease and Injury. Global, regional, and national incidence, prevalence, and years of living with disability for 354 diseases and injuries in 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 chronic headaches. Neurology. 2007; 68 (2): 134-13. 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): 131-13. 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. Common genetic factors in migraines and depression: evidence of a genetic isolate. Neurology. 2010; 74 (4): 288- 294. doi: 10.1212 / WNL.0b013e3181cbcd19

7. Hasler G. Pathophysiology of Depression: Do We Have Solid Evidence of Interest for Physicians? World Psychiatry. 2010; 9 (3): 155-150; 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 migraines and major depression. Eur J Hum Genet. 2018; 26 (8): 1202-1. 1216. doi: 10.1038 / s41431-018-0150-2

9. Fugger G., Dold M., Bartova L. et al. Clinical Correlates and Outcomes of Depression and Comorbid Migraines: A Report from the European Group to Study 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. Research into intrinsic brain activity in migraines with and without comorbid depression. J headache. 2018; 19 (1): 48. doi: 10.1186 / s10194-018-0876-9

11. Gudmundsson LS, Scher AI, Sigurdsson S. et al. Migraines, 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. Migraines and their psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016; 87 (7): 741- 749. doi: 10.1136 / jnnp-2015-312233

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

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