A debilitating comorbidity: Migraine and depression

By Naveed Saleh, MD, MS | Medically reviewed by Amanda Zeglis, DO, MBA
Published October 21, 2022

Key Takeaways

  • Migraine and major depression often present together, with a shared molecular basis.

  • Patients with migraine and depression exhibit distinct brain pathology, including changes to the thalamus and cerebral cortex.

  • Tricyclic antidepressants, as well as serotonin and norepinephrine inhibitors, can be used to treat these comorbid conditions. In trials, botulinum toxin and monoclonal antibodies have proven to be effective.

Patients with depression are twice as likely to have migraines as those without it. In fact, there is an up to 50% chance of co-occurrence between migraine and major depressive disorder (MDD), according to a review published in Cureus.[]

Research has demonstrated that anxiety can precede migraine episodes, while depression presents concurrently with migraines.

Shared genetics

The mix of migraine and MDD presents as its own pathology. Nearly 80% of individuals with migraine also experience depression at some point during their lives, as noted in the Cureus review.

Those with chronic migraine are prone to severe anxiety and suicidal ideation.

The genetic link between headache and migraine has been demonstrated in meta-analyses of single nucleotide polymorphisms (SNPs) and genome-wide association studies (GWAS).

According to the Cureus research, three independent genome-wide SNPs in patients with both migraines and MDD include rs146377178, rs672931, and rs11858956. Two genes that are shared between these conditions are ankyrin repeat and death domain-containing 1A (ANKDD1B); and potassium channel, subfamily K, member 5 (KCNK5).

Serotonin heritability

Investigators discovered in the 1960s that higher 5-hydroxyindoleacetic acid (5-HIAA) levels mediated migraine attacks, while lower levels of serotonin induced severe depression. Both migraine and depression could be linked by low levels of 5-hydroxytryptamine (5-HT)/serotonin receptors. In serotonin transporter gene alterations, the short allele predicts depression and migraine.

"There is a robust molecular genetic background explaining the relationship between migraine and MDD. "

Jahangir, et al., Cureus

“This correlated data renders a combination of both diagnoses as a single separate entity,” the authors of the Cureus review continued.

In central and peripheral pathways, changes in serotonin levels occur in migraine patients. Experts hypothesize, in part, that SSRIs do not result in headache because extracellular levels of serotonin are increased minimally.

Brain structure

Individuals with migraine and MDD exhibit distinct cerebral cortex microarchitecture compared with those exhibiting either condition alone. Patients with these comorbidities demonstrate a discordant developmental track of the fusiform gyrus and detectable changes in the thalamus. Moderation of pain and mood are also pathologic in those with both migraine and MDD.

Patients with comorbid MDD and migraine exhibit changes at the level of the left medial prefrontal cortex, as well as a decrease in thalamic brain activity.

In addition to shared serotonin dysfunction and brain pathology, hormone dysfunction such as that of the hypothalamic-pituitary-adrenal axis or ovarian hormones could also contribute to the shared pathology of migraine and MDD.

Treatments for comorbid migraine and depression

Tricyclic antidepressants such as amitriptyline may be effective in tackling both migraine and depression due to their anti-inflammatory effects. Amitriptyline also blocks serotonin and norepinephrine reuptake. If a patient can’t tolerate amitriptyline, nortriptyline is an alternative to consider, as are serotonin and norepinephrine inhibitors.

OnabotulinumtoxinA (botulinum toxin) has also been evaluated for treatment of these conditions. Authors of a meta-analysis published in Journal of Translational Medicine found that injection of botulinum toxin resulted in improvement in depressive symptoms and quality of life, as well as migraine symptoms and frequency in patients with these comorbidities.[]

Unexpectedly, improvements in depression were greater in patients with migraine and MDD who received botulinum toxin compared with those in patients with just depression. However, improvement in migraine symptoms was greater in those with just migraine compared with those with migraine and MDD.

Although a unifying hypothesis explaining the effects of botulinum toxin in patients with migraine and MDD is needed, the Journal of Translational Medicine authors suggested that for the depression component, the agent may block the feedback of negative facial expressions such as frowning, lightening mood.

Regarding migraine, botulinum toxin injection at the level of the trigeminal dermatome blocks the release of CGRP, which is a neuropeptide that contributes to migraine.

The monoclonal antibody fremanezumab (Ajovy), which targets CGRP and is used to prevent migraine, may be effective in treating migraine in those with comorbid depression, according to research published in Headache in 2021.[]

The investigators found that this treatment was related to reduction in depression measures and improvements in migraine-related quality of life.

What this means for you

The comorbidities depression and MDD can be treated as a combined clinical entity when presenting to a specialist. Strategies to manage this combination include tricyclic antidepressants and SNRIs. Botulinum toxin or fremanezumab also have shown potential as effective therapies.

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