Discussion

Without considering common causes or other explanations, these results align with earlier findings supporting a bidirectionality to a migraine–depression association: in crude analyses, migraine status predicted incident depression, and depression status predicted incident migraine. However, both directions of this relationship are largely explained by stressors that likely increase risk for both migraine and depression: adjusting for all measured forms of stress in these surveys attenuated each estimate considerably (estimates decreased from 1.62 to 1.30 and 1.55 to 1.19) and the associations were no longer significant after adjustment. Implications for research as well as clinical and public-health practices are discussed.

Importantly, all stressors studied here did attenuate the results, suggesting that any form of stress may be an important common cause to consider when studying migraine and depression. This finding follows from prior research that supports both acute and chronic forms of stress as being confounders, since these have been shown to predict depression and migraine.10 ,17–21 The present study suggests that these stressors collectively explain much of the perceived migraine–depression association; research that does not account for these common causes when studying depression and migraine may be presenting misleading estimates. The perceived migraine–depression associations presented in many prior studies may be largely explained by unmeasured confounding by such types of stressors. The magnitude of confounding due to each specific stressor is dependent on several factors, including the strength of the covariate–exposure association, the strength of the covariate–outcome association and the prevalence of the covariate. Our measure of chronic stress was strongly predictive of both migraine and depression onsets, as well as associated with these disorders at baseline, and thus was the strongest risk factor considered in the present analyses. On the other hand, recent changes in employment and marital status were relatively rare life events, and were not strongly predictive of these disorders, so the magnitude of attenuation when considering each of these variables was minor. Optimally, future studies of migraine and depression would assess all potential confounders; as this is not always feasible, investigators may consider prioritising assessing chronic stress over some of these other stressors, and accompany results with sensitivity or bias analyses for any stressors that remained unmeasured.

Our finding that chronic stress was the strongest stress-related risk factor fits into the broader context of research, suggesting that chronic stress may be causative of various types of chronic pain and major depression. In disentangling the relationship between depression, chronic stress and chronic pain such as fibromyalgia, it has been proposed that chronic stress may lead to dysfunction in the hypothalamic–pituitary–adrenal axis, which in turn could lead to both depression and some forms of chronic pain.25 Research specific to stress and migraine supports this biological theory.26 Notably, childhood trauma was a strong risk factor in migraine predicting depression; as many of the types of trauma assessed were chronic in nature, this aligns with the finding that perhaps chronic forms of stress are especially potent common causes of migraine and depression.

Although certainly some of the crude association between depression and migraine may still be explained by genetics, other common causes and/or biological pathways between the two disorders, the current findings suggest interesting considerations when developing future intervention strategies. Given the possibility of a biological mechanism between these two disorders, much research attention has been focused on the efficacy of antidepressant medications on preventing and managing migraine, with mixed success.27–29 However, the current study suggests that perhaps a primary strategy could target reducing stress, particularly chronic stress, as this may both reduce the burden of the index disorder as well as potentially prevent the second condition from occurring. Indeed, there have been studies showing that various behavioural or stress management therapies (eg, Cognitive-Behavioral Therapy) are effective treatments for migraine, supporting one aspect of this hypothesis.30–32 Given how much chronic stress and other stressors seem to explain the comorbidity, such a strategy may have the potential for reducing this comorbidity burden on a larger scale than some of these other postulated pharmacological strategies, although further research actually comparing such treatment strategies would be needed. Utilising a stress-reducing strategy to address this comorbidity assumes that stress is (directly or indirectly) causative of both disorders, while it is possible that stress is a risk factor through associations with a common cause.

The study has numerous strengths. This is one of only a few studies to prospectively assess the migraine–depression comorbidity bidirectionally,1 ,2 ,10 and extends these previous findings by examining whether a rich assortment of widely used stress measures explained the associations found. The nationally representative nature of the study aids the generalisability of these findings, and the sample size and length of follow-up are exceptional.

However, certain limitations warrant consideration. Migraine was assessed as only a single, self-reported question at each cycle. Self-reported symptom-based assessments do generally report a higher prevalence than doctor diagnoses;33 the assessment in the NPHS inquires about diagnosis by a health professional which may offset some of this over-reporting, but certainly misclassification may still be an issue. Specifically, self-report may be further inflated in depressed individuals, which may actually contribute to some overestimation in our associations. While the measure of major depression (CIDI-SFMD) has demonstrated psychometric properties,22 ,34 ,35 the 12-month diagnosis (which thus does not cover the 2 years between each study assessment) hinders inference about the history of major depression, possible episodes unmeasured in the gap years of the study and actual timing of onset of the disorder; subjects who have less frequent depressive episodes or episodes that are shorter in duration would be less likely to be measured accurately. However, by using an interim cycle as ‘baseline’, we were able to construct over a half-decade profile of subjects’ ‘history’ of major depression to diminish the issue regarding assessing history. Finally, we did not have complete follow-up for all subjects. Weighting was used to correct for attrition between Cycles 1 and 4. From Cycle 4 through 8 the majority of subjects were assessed 8 years later (see figure 1), and follow-up duration was not associated with migraine or depression status at baseline. Follow-up duration, however, was associated with age and a few stressors (greater chronic stress, recent unemployment and recent divorce were associated with shorter follow-up; p's<0.05); however, as stress likely predicts higher levels of the outcome disorders, it is likely this implies that some subjects were censored prior to the onset of the outcome, meaning that stress would explain even more of the association measured had complete follow-up occurred.

These analyses highlight considerations for future research. These analyses represent a rich assortment of stressors, but several other stressors may also merit examination, for example, childhood sexual abuse, acute recent traumas such as injury or illness, etc. Further, as some of the stressors were only assessed in one or two cycles, we were not able to fully address the time-varying nature of the relationships between stress and these episodic conditions. Given that we found recent and prior stress to be relevant in this comorbidity, future research may wish to more closely examine the time-varying relationship between stress and these two conditions individually and comorbidly. Specifically, while stress is a risk factor for both disorders, it may also be caused by each disorder, and thus assessing temporal relationships using models that account for time-varying confounding appropriately (eg, marginal structural models) may highlight the relationship between these variables further.

Understanding the causal mechanisms underlying the migraine–depression comorbidity may have a major public health impact. Major depression is a chief cause of disability worldwide,36 estimated by the WHO to become the second leading cause of disease burden by the year 2020.37 Meanwhile, migraine affects 11% of the adult population, and when combined with other headache disorders also makes it into the top 10 causes of disability by WHO estimates.38 Moreover, studies suggest that the disability and burden of these disorders may be compounded when present together;5 disease severity appears greater when these disorders are comorbid, for example, frequency and duration of migraine attacks have a significant association with psychiatric comorbidity.39 Migraine patients with a psychiatric disorder report generally a lower quality of life than other migraine patients;8 in parallel, depression patients who report migraine also report poorer quality of life compared with other depression patients.40 As such, implementation of effective stress-management strategies for migraineurs and those suffering from depression (as well as similar strategies to prevent the index disorder onset) may have major implications for prevention and intervention strategies that may lower the societal costs and burdens of both disorders.