In many ways, migraine and Major Depressive Disorder look very different. Migraine is a disorder with repeated attacks that usually have acute triggers and unfold over a relatively short timespan (hours to days). Triggers can include foods, sounds, smells, atmospheric pressure, lighting (too bright, too much contrast, or blinking), irregular sleep, hormones and more. Migraine attacks unfold in characteristic phases including a prodrome phase (characterized by mood changes, cognitive impairments, yawning, and other symptoms), in some patients aura (visual hallucinations and/or partial paralysis), headache (including extreme sensory hypersensitivity), and a post-drome phase (lingering symptoms, fatigue, depressive mood).
By contrast, depression tends to last much longer (weeks, months, or even years) and is much less time-specific in how symptoms may present. Patients display at least five symptoms that include depressed mood, diminished interest or pleasure, changes in weight or sleep, psychomotor agitation or slowed thinking, fatigue, feelings of worthlessness or excessive guilt, diminished concentration, or recurrent thoughts of death or suicide).
We (as authors) have known people personally who have suffered from both migraine and depression and have thought a lot about what might be the relationship, if any, between these seemingly very different conditions. Does one disorder predispose a person to the other? Are there shared underlying relationships in brain or nervous system physiology that might provide a causal link?
We surveyed what is currently known about the mechanistic contributors to each disorder and examined what they have in common across treatment and physiological mechanisms from genetics through brain-wide communication.
Common Threads:
Our literature search found several emergent themes of mechanistic overlap between migraine and MDD spanning multiple levels of analysis, including:
- Key genetic risk variants and genes common to both disorders
- Overlap in the mechanisms of therapeutics used to treat each disorder, including the effects of these treatments on neurotransmitters and peptides
- Shared disruptions in the regulation of sensory sensation and mood
- Key brain regions and circuits
- Common physiological responses to environmental factors
- The critical role of sex differences and clues from hormones
Why Now?
With emerging therapies for each of these disorders, there are new opportunities to consider for patients. Having a better understanding of where mechanisms between these two disorders overlap and differ can shed light on 1) therapeutics that may not have been thought of for the opposite disorder, or that may work for both conditions, 2) unexplored mechanisms that are worth further probing for each disorder and 3) for creating therapeutics with the least likelihood of unwanted side-effects. Focusing on the mechanisms that these disorders have in common provides a strategy for scientists to consider for developing therapeutics to best target the comorbid condition.
An example of an emerging therapy in migraine with relevance to depression includes anti-CGRP therapies. Calcitonin gene-related peptide (CGRP) is a peptide involved in inflammation, blood vessel dilation, and many other physiological functions and provides one of the most exciting recent examples of a therapeutic derived from neuroscience research. A promising new development is that a recent clinical trial showed success for one such anti-CGRP therapy in the treatment of migraine with comorbid depression (https://jamanetwork.com/journals/jamaneurology/fullarticle/2833452). Given that historically, patients living with migraine and comorbid depression have been excluded from many such studies, this finding represents an important step forward .
By contrast, an example of an emerging therapy in depression with relevance to migraine is ketamine. Ketamine impacts a wide range of biology but is best characterized for its role as a glutamate receptor antagonist, thus impacting excitatory/inhibitory balance, a mechanism important in migraine. Several small studies have found success with ketamine for treating migraine, opening the door to larger studies that can ask whether there are specific patients that may especially be good candidates for ketamine.
Overall, such findings may pave the way for development of novel therapeutics designed to target both disorders instead of treating them as separate problems. Our review provides a roadmap for future studies to truly understand these two disorders and the comorbid condition. We hope it will ignite conversation and provide fresh insight into patients with a dual diagnosis.
Have further thoughts or questions on this topic? Leave us a comment below!
For more information about the Laboratory for Brain-Network Based Molecular Medicine, please visit our lab website here: https://hultman.lab.uiowa.edu/
Artwork credit: Jeff MacInnes https://www.decimalpoint.studio/