This study demonstrates that in persons with EM, depression for 1 year is associated with the new onset of CM in the next year. Depression, as measured by the PHQ-9, remained a significant predictor of transformation after adjusting for sociodemographic variables, headache features including monthly headache day frequency, other comorbidities and medication use. In addition, analyses probing the dose–response effect of depression demonstrated that the risk of CM onset increased with the severity of depression. Though there is a large literature demonstrating that migraine and depression are comorbid and bidirectionally linked [10
], the influence of depression on the clinical course of migraine has rarely been investigated. We are not aware of comparable longitudinal population-based studies that assess the role of depression as a risk factor for the transformation of EM to CM. In evaluating this association, we endeavored to identify a parsimonious set of potential confounders and effect modifiers. We assessed candidate covariates based on previous population-based reports [4
] and univariate analyses in this sample.
In addition to depression, BMI, anxiety, several headache features (including headache frequency, average pain intensity, migraine symptom severity score, and allodynia) and medication overuse all had univariate associations with CM onset (Table ). We also examined sociodemographic variables including age, marital status and race as well as medical covariates (SRPD-diabetes, SRPD-hypertension and smoking), previously associated with migraine prognosis [4
]; these sociodemographic and medical covariates were not predictors of CM onset in the current study. Though alcohol consumption and smoking are associated with depression [25
], they were not associated with CM onset and were not included in our final models. In a longitudinal model adjusting for sociodemographic covariates only (Model 1), depression was associated with a threefold increased risk of CM onset. In the fully adjusted model (Model 2), the effect of depression on CM onset, though highly significant, was substantially attenuated. Along with depression, headache frequency, migraine symptom severity and medication overuse remained significant predictors of CM onset. Because the relationships among covariates are complex, we ran a series of nested models presented in the Webtable. The effects of allodynia and BMI vary in these models, depending upon the other covariates.
We also assessed the influence of treatment on progression to CM from EM. Medication overuse was a significant risk factor for development of CM, a finding compatible with earlier studies [4
]. Use of antidepressants was not significantly associated with risk of CM onset in our data; however, confounding by indication may contribute to this result. That is, persons selected for antidepressants may be at higher risk for progression prior to treatment by virtue of the association between depression (or factors associated with depression) and CM onset. Antidepressant pharmacotherapy, employed in both depression treatment and migraine prophylaxis, may reduce the risk of progression through an effect on both headache frequency and depression.
Though our findings indicate that persons with EM and depression develop CM at increased rates, the causal nature of this association remains uncertain. The process of CM onset is likely heterogeneous. We propose three hypotheses to account for the linkage between depression and the onset of CM based on the approach suggested by Lipton and Silberstein [28
]: (1) depression may directly contribute to the onset of CM, (2) depression may arise as a consequence of escalating migraine frequency, and (3) CM and depression may share genetic or environmental risk factors that contribute to this association. These hypotheses should not be considered mutually exclusive as more than one of them may be at least partially correct.
Under the first hypothesis, depression is involved in an as yet to be determined causal path which increases the probability that persons with EM will progress to CM. This possibility is supported by the development of depression prior to the onset of CM, the depression-dose effect and the robustness of the findings despite adjustment for many potential confounders. In addition, the association has a biologically plausible foundation based on central sensitization, as discussed below [29
The relationship between cutaneous allodynia, a marker of central sensitization, and depression has been addressed in experimental animal and human pain studies [30
]. Animal studies [31
] have also shown that depression may induce hyperalgesia, another marker of central sensitization. Patients with migraine and chronic tension-type headaches have previously been reported to have muscular and cutaneous hyperalgesia [32
]. Given the strong association between depression and allodynia [33
], depression and CM [10
] and the higher prevalence of allodynia in CM [33
], it is possible that depression facilitates the development of allodynia in EM which in turn lowers the threshold for headache onset, increasing the number of headache days [18
]. In further support of this mechanism, functional neuroimaging studies in clinical chronic and experimental pain have demonstrated neuroplastic changes in the anterior cingulate cortex and the amygdala [34
]. Depression and anxiety are also associated with increased activity in the amygdala which may contribute to the activation of pain-facilitating pathways [35
]. In combination, these findings support the hypothesis that depression could cause CM onset through effects on central sensitization.
Appropriate randomized trials to support this model have not been conducted. In such a trial, one could treat patients with EM and depression with an antidepressant that did not influence headache (e.g., a selective serotonin reuptake inhibitor or bupropion), predicting that treating depression should prevent CM onset. The credibility of inferences under such a design depends upon convincing evidence that the treatment influences depression but not migraine.
Under the second mechanism, depression may arise as a consequence of more severe or escalating disease. The assumption here is that escalating attack frequency, below the level needed to meet a CM definition, may contribute to the development of depression. Escalating headache frequency could reduce self-efficacy creating depression through the mechanism of learned helplessness [36
]. For inferential tests of this hypothesis to be valid, treatments employed in an experimental design would be required to effectively treat CM but not directly influence depression. In a small, open label study, researchers demonstrated that treating CM with onabotulinumtoxinA resulted not only in reductions of headache frequency, but also improvements in depression and anxiety, thus demonstrating that reducing headache frequency, without treating depression directly, leads to improvement in psychological outcomes [37
]. Larger scale, randomized trial data could provide much stronger support for this hypothesis.
Under our third hypothesis, CM and depression are linked by shared genetic or environmental risk factors. For example, variants in catecholamine genes could predispose people to both CM and depression and account for the linkage between them [38
]. Alternatively, a persistently stressful environment could contribute to both the development of CM and depression [39
]. Chronic stress is a well-recognized risk factor for both depression and CM [39
]. Specifically, Rivat et al. [40
] found that chronic stress, a common precursor to depression as outlined above, increases the expression of genes governing the iNOS and COX-2 inflammatory molecules and induces neuroinflammatory conditions suppressing the mechanical nociceptive threshold thereby increasing hypersensitivity and hyperalgesia. Given accurate measures of any of these possible mechanisms, mediation models could be examined in which the association between depression and CM onset could be tested for robustness to the intervening effect of potential shared genetic or environmental variables.
These hypotheses seem to be reasonable explanations for the association between depression and CM onset observed in this study. The experimental designs and analyses described, if undertaken, would serve to elucidate the relative strength of each possible mechanism discussed.
This study has a number of strengths. We evaluated a large population-based sample, followed participants longitudinally and systematically assessed both migraine and depression using well-validated instruments. The AMPP study diagnostic module is validated for the diagnosis of migraine in the population [14
]. In addition, our measure of depression was based on the validated PHQ-9 assessment.
There are a number of limitations in our study. Assessments of migraine and depression status were based on self-reported validated questionnaires and not in-person interviews or review of medical data. Moreover, anxiety was assessed by self-report of having received a diagnosis from a healthcare professional. Misclassification of exposures and outcomes is possible. For example, we included respondents meeting criteria for chronic tension-type headache in the control group. While a legitimate transition state for those with EM in a preceding year, the inclusion of chronic tension-type headache in the reference group could attenuate the degree of association between depression and transformation. However, our findings were robust, and this effect is likely very small due to the modest number of chronic tension-type headache respondents observed in the reference groups for the two transformation events (N = 14 and N = 28, respectively). Therefore, the impact of the inclusion of chronic tension-type headache in the reference is likely small.
This longitudinal population-based study demonstrates the association between depression and the onset of CM. Given that this is an observational study, we cannot determine what role depression plays linking EM to CM. However, given the strong association between depression and CM onset observed here, for the sake of patients routine screening for depression should be considered, if for no other reason than that it is a strong comorbidity with CM onset and a complicating factor for treatment. In addition, because we do not, as yet, have a biomarker useful for identifying patients at risk for CM onset, given the predictive strength of the covariates as risk factors for CM onset, clinicians can routinely screen for depression, allodynia, headache frequency, migraine symptom severity, and medication overuse, as markers to improve detection of and modify treatment for at-risk patients. Future work will focus on appropriately designed trials to elucidate the operating mechanism linking EM, depression, and CM onset.