Understanding the Link Between Bipolar Disorder, Migraine

In a review published in Frontiers in Psychiatry, researchers outlined potential mechanisms accounting for comorbid bipolar disorder and migraine and examined therapeutic targets for treatment to improve prognosis in these patients.

In a review published in Frontiers in Psychiatry, researchers outlined potential mechanisms accounting for comorbid bipolar disorder (BD) and migraine and examined therapeutic targets for treatment to improve prognosis in these patients.

BD is a severe psychiatric disorder characterized by recurrent episodes of manic/hypomanic (BD-I and BD-II, respectively) or depressive symptoms and euthymic periods, the authors explained. Some patients with BD experience a gradual deterioration of illness and subsequent cognitive deficits.

Although BD-II is not severe enough to cause social or occupational functional impairment, those with BD-I often experience manic and psychotic symptoms requiring hospitalization.

Approximately 2.1% of the global population suffers from BD, while a diagnosis is associated with an average decrease of 9 years in life expectancy. Suicide rates are also high for men and women with BD (7.8% and 4.9%, respectively), and complications related to the condition include metabolic and cardiovascular diseases.

To better understand the relationship between migraine and BD, investigators conducted a systematic search of PubMed and Embase and compiled all studies on the 2 conditions published from January 1991 through July 2020.

In migraineurs, psychiatric disorders are common and a heritable link between BD and migraine has been established. Parental migraine was associated with increased likelihood for BD and was a risk factor for offspring with BD, even in the absence of parental BD, the researchers wrote. Prevalence of migraine in individuals with BD may reach as high as 39%, and the 2 conditions share multiple risk factors, including genetic and environmental risk factors, oxidative stress, and disturbances of inflammatory cytokines.

When it comes to underlying mechanisms, “Patients with BD always exhibit a disturbed balance between pro-inflammatory factors and anti-inflammatory factors.” Specifically, “The peripheral levels of inflammatory factors, including the interleukin (IL) family, IFN-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), are upregulated in the manic episode of BD patients compared to those in healthy controls, while the level of IL-4 is downregulated in BD patients compared to that in healthy controls,” the authors found.

Although the exact underlying mechanism of migraine remains unknown, studies have shown levels of pro-inflammatory cytokines, including IL-10, TNF-α, and IL-1β, “were significantly upregulated during acute migraine attacks compared to those outside of acute attacks, while the levels of IL-10 and TNF-α were increased in migraine patients soon after headache onset but decreased over time.”

Because BD is more closely related to comorbid migraine than parental migraine, the comorbidity may also be attributed to nongenetic factors. Chronic inflammation, defined as a disturbance of the balance between oxidative stress and the antioxidative stress response, in addition to the regulation of nitrosative stress, may both play a role in pathogenesis.

Currently, no optimal treatments for patients suffering from comorbid BD and migraine exist. However, “several pharmacological treatments such as valproate, lithium, lamotrigine, quetiapine, and topiramate are widely used to prevent onset of both migraine attacks and acute manic or depressive episodes in patients with BD,” the researchers wrote.

Cognitive behavioral therapy and social rhythm therapy have also been affectatious in both conditions, while neuromodulatory approaches may also offer therapeutic effects. Additional clinical experimental studies ought to be conducted to expand the investigation of new therapies for treating concurrent BD and migraine, the researchers wrote.

As the underlying mechanisms for both conditions are complex and migraine symptoms may exacerbate BD symptoms and interfere with BD management, it is difficult to determine a specific strategy that can improve the comorbidity based on results of current studies, marking a limitation to the review.

“To improve the prognosis of patients with comorbid BD and migraine, the identification of more effective and less toxic drugs and the improvement of poor compliance are essential,” the authors concluded.


Duan J, Yang R, Lu W, Zhao L, Hu S, Hu C. Comorbid bipolar disorder and migraine: from mechanisms to treatment. Front Psychiatry. Published online January 11, 2020. doi:10.3389/fpsyt.2020.560138

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