Migraine and Psychiatric Comorbidities

CATEGORY 1 CME

Premiere Date: August 20, 2026 

Expiration Date: February 20, 2028

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To enhance understanding of the complex relationship between migraine and psychiatric disorders by reviewing their shared clinical features, epidemiology, neurobiological mechanisms, and treatment considerations, thereby improving the identification, assessment, and integrated management of patients with co-occurring neuropsychiatric conditions.

LEARNING OBJECTIVES

1. Identify the diagnostic features of migraine and recognize common psychiatric comorbidities that may complicate assessment, prognosis, and treatment.

2. Evaluate current evidence regarding shared neurobiological pathways and therapeutic strategies in migraine and psychiatric disorders to optimize patient-centered care while minimizing unnecessary polypharmacy.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource^®, LLC, and Psychiatric Times. Physicians’ Education Resource, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received.

OFF-LABEL DISCLOSURE/DISCLAIMER

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST MITIGATION

None of the staff of Physicians’ Education Resource, LLC orPsychiatric Timesor theplanners or the authors of this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

For content-related questions, email us at [email protected]; for questions concerning the accreditation of this CME activity or how to claim credit, please contact [email protected] and include “Migraine and Psychiatric Comorbidities” in the subject line.

HOW TO CLAIM CREDIT

PER® is an ACCME Innovation Partner. As an ACCME Innovation Partner, PER® offers physician learners the option, upon completion of the activity evaluation, to request that their CME credit be reported on their behalf to the ACCME and made available in CME Passport™, ACCME's free, centralized CME data system.

CME Passport™ is a free, centralized service from the ACCME that enables physicians to find, track, and share CME credit reported on their behalf by accredited providers. Learn more at www.cmepassport.org.

Once you have read the article, please use the following URL to evaluate and request credit: https://education.gotoper.com/activity/ptcme26aug. If you do not already have an account with PER^®, you will be prompted to create one. You must have an account to evaluate and request credit for this activity.

The landscape of neuropsychiatric phenomenology is of keen interest to the clinician and the neuroscientist alike. The level of comorbidity observed is striking. Sometimes, who treats what is more a matter of convention and medical cultural history, particularly when it comes to conditions such as migraine.

Migraine is a prevalent and disabling neurobiological disorder that frequently co-occurs with a range of psychiatric conditions, most notably major depressive disorder, anxiety disorders, bipolar disorder, and posttraumatic stress disorder (PTSD).¹ The high rates of comorbidity observed between migraine and psychiatric disorders have attracted considerable research interest, as these conditions share overlapping clinical features, biological mechanisms, and adverse effects on quality of life. The bidirectional relationship between migraine and psychiatric illness complicates assessment, diagnosis, and treatment, often contributing to greater symptom burden and poorer clinical outcomes. Both migraine and psychiatric disorders are characterized by complex subjective experiences that can involve affective, cognitive, sensory, and somatic symptoms, suggesting the presence of interconnected neurobiological pathways. Understanding the nature of this comorbidity is essential for developing integrated models of pathophysiology and improving patient-centered care.

Diagnosis

Not all headaches are created equal. In fact, a migraine is not just a bad headache; it is a complex neurological condition. It involves headache pain of moderate to severe intensity that is usually throbbing or pulsating and can last up to 72 hours. The headache is often unilateral, accompanied by nausea, photophobia, phonophobia, and sensitivity to odors. Routine physical activity can often aggravate the pain. It can be associated with auras, also known as visual, sensory, or speech disturbances. It tends to fluctuate with the atmospheric pressure and hormonal changes.

The differential diagnosis includes tension headaches, cluster headaches, sinusitis, subarachnoid hemorrhage, brain tumor, and meningitis. Red flag symptoms requiring further evaluation beyond the neurological examination are characterized by the mnemonic SNOOP: Systemic symptoms such as fever or weight loss; Neurological signs or symptoms; Onset, which is sudden (thunderclap headache); Older age of onset (50 years or older); and a Progressive pattern or change in headache characteristics.

Demographics

Migraines can occur at any age. Prevalence increases during adolescence and early adulthood. The highest prevalence is typically between the ages of 25 and 55 years (the prime working years). Frequency often declines after age 60. Before puberty, migraines occur at similar rates for both boys and girls, though slightly higher in boys. After puberty, migraines become much more common in women. Women experience migraines 2 to 3 times more often than men. This is thought to be largely the result of hormonal influences such as fluctuations in estrogen.

Worldwide, migraine affects patients of all backgrounds. Population rates vary somewhat due to a variety of factors, including underdiagnosis in areas of limited health care access. Although migraines occur across all socioeconomic groups, higher disability burden is often observed among people of lower income, lower educational attainment, and limited access to health care. Migraine can significantly affect work productivity, school performance, and quality of life. According to the World Health Organization, migraine is among the leading causes of years lived with disability worldwide.

A typical person with migraine is a younger to middle-aged woman with a family history of migraine who experiences recurrent episodes beginning in adolescence or early adulthood. Lifetime prevalence is approximately 12% to 15% of the population. The female to male ratio is approximately 3:1 in adults. The age of onset is between 25 and 55 years. A family history is present in 50% to 75% of cases.

Comorbidity Landscape

The most common psychiatric comorbidities in people with migraine are major depressive disorder, anxiety disorders, bipolar disorder, PTSD, and substance use disorder.² To be sure, one condition can even exacerbate the other; however, it would be a mistake to think that addressing one issue will result in fixing the other. After all, you would not think of treating cellulitis with insulin or diabetes with antibiotics.

Pathophysiology

Empirically, similarities in treatments and their mechanisms of action have given rise to thoughts about underlying etiologies and pathophysiology. There is cumulative evidence involving the serotonergic system, neuropeptides (such as calcitonin gene-related peptide), pituitary adenylate cyclase-activating polypeptide, substance P, neuropeptide Y, and orexins.³ Dysregulation of both hypothalamic and thalamic pathways has been implicated.⁴ Neuronal hyperexcitability is an important overlapping mechanism that plays out in different ways. For instance, patients often complain of “stimulus overload” and instinctively make changes in their environment, such as lowering the brightness of lights and soundproofing. Sensory hypersensitivity is not unusual. Many patients also report having hyperacusis.

Single-cell RNA sequencing in patients with migraine has found as many as 45 shared genes with expression in the dopaminergic, serotonergic, glutamatergic, and endocannabinoid systems.⁵ Genome-wide association studies (GWASs) have also been instructive. Findings from a recent GWAS elucidated substantial genetic overlap and asymmetric causal relationships when assessing Mendelian randomization.⁶ Pleiotropic-associated loci provided significant genetic evidence.⁷ The findings also highlighted that postpartum depression is genetically related to migraine but is a potentially distinct entity.⁶ Intriguingly, there appears to be an inverse protective relationship with schizophrenia.⁸ Findings from epidemiological studies had previously described an inverse relationship between migraines and schizophrenia clinically. Van der Auwera and colleagues posit that this is mediated by glutamatergic N-methyl-D-aspartate (NMDA) receptor dysfunction. Utilizing findings from a recent GWAS focused on schizophrenia, they found that polygenic risk scores for schizophrenia were inversely associated with migraine. They concluded that this association was exclusively based on the genome-wide hits and on single-nucleotide polymorphisms near or within genes encoding proteins involved in glutamatergic neurotransmission.

Whether we are describing repeated migraine episodes or recurrent bouts of depression, we can say that metabolically, this is a troubled brain. A tightly interwoven profile of metabolic collapse, chronic inflammation, and oxidative stress is present. Elevated energy requirements result in mitochondrial dysfunction, which leads to hypometabolism (energy deficits). This often presents as localized brain insulin resistance, impairing the neuron’s ability to utilize glucose. Immune cells in the brain (microglia) shift into an aggressive, hyperactive state. They produce proinflammatory cytokines—such as tumor necrosis factorα (TNF-α), IL-6, and C-reactive protein (CRP)—which can break down the blood-brain barrier. Systemic inflammation from the body (often originating from the gut or adipose tissue) is now allowed to cross directly into the brain. Damaged mitochondria release excessive reactive oxygen species and reactive nitrogen species.⁹ The brain is highly vulnerable to this because of its high concentration of polyunsaturated fats, which undergo lipid peroxidation, ultimately destroying the cell. This destructive feedforward loop is sometimes described as a vicious cycle.

Treatment

It comes as no surprise that good migraine treatment starts with education and patient understanding. The patient must understand that they have a chronic condition with a potential for relapse that must be managed over time. As such, episodic, “as-needed” treatment is unlikely to be significantly helpful. The key is long-term management and prevention of episodes.

Lifestyle management becomes critical, especially when it comes to insulin resistance. Exercise, the Mediterranean diet, and addressing obesity are as important to the treatment plan as any medication. Findings from studies show that insulin resistance and metabolic syndrome are much more prevalent in patients with migraines than in healthy controls.¹⁰ The severity and frequency of migraine attacks are often much higher in those with metabolic dysfunction.¹⁰ The Mediterranean diet, which is high in antioxidants, is recommended. Maintaining stable blood sugar through hydration and regular, balanced meals is also critical. Food and beverage avoidance may also play a part. Common migraine triggers include caffeine, alcohol, aged cheeses, processed meats, and artificial sweeteners. Foods containing tyramine and histamine may overstimulate the nervous system and/or cause blood vessel changes in sensitive individuals.¹¹

Pharmacological prophylaxis is another important mainstay. The neuronal hyperexcitability previously described makes the category of anticonvulsants a very reasonable choice. Although several anticonvulsants are commonly utilized, only topiramate and valproate have formal US Food and Drug Administration (FDA) indications for migraine and have Level A evidence for clinical efficacy.¹² In cases of status migrainosus (migraine persisting for longer than 72 hours), intravenous valproate has been quite useful.¹³ It is noteworthy that intravenous valproate has also been used in the treatment of acute manic episodes, suggesting overlapping pathophysiology.¹⁴

Serotonin receptor agonists have also been used in the acute (abortive) treatment of migraines as well as preventive treatments. These include triptans and ditans. The latter do not cause vasoconstriction, which may be better for some patients with cardiovascular risk factors. Some familiar agents are commonly used in prevention: tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), as well as serotonin-norepinephrine reuptake inhibitors (SNRIs).¹⁵ At times, the comorbidity gives rise to concerns about serotonin syndrome, given the shared mechanism of action of multiple conditions. The triptans act as selective agonists for serotonin (5-HT1B and 5-HT1D) receptors and, when taken together with an SSRI or SNRI, may increase the risk of serotonin syndrome. At the same time, parsimonious prescribing may allow for addressing multiple conditions with one agent.

Glutamate, the brain’s principal excitatory neurotransmitter, would understandably be a target in a condition noted for neuronal hyperexcitability. This includes topiramate (which blocks α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate glutamate receptors), memantine (a moderate noncompetitive antagonist at NMDA receptors), magnesium (which modulates NMDA receptors), and ketamine (a noncompetitive NMDA receptor antagonist). There is emerging research on kynurenic acid analogues to block glutamate activation. The low-glutamate diet has also been suggested.¹⁶

OnabotulinumtoxinA is an FDA-approved preventive treatment for chronic migraines. It blocks the release of nociceptive chemicals and reduces neuronal hyperexcitability.¹⁷ In treatment-resistant depressive disorders, findings from randomized controlled trials and meta-analyses have shown significant improvements, with findings from some studies reporting remission rates comparable to those of SSRIs.¹⁸ The theorized mechanism of action involves emotional proprioception—relaxing “frown muscles” blocks the facial-feedback loop in the brain. Positive findings from phase 2 trials have shown that injecting onabotulinumtoxinA into the procerus and corrugator muscles has a statistically significant effect on mood, even when the aesthetic effect is not achieved. It is proposed that this involves reduced amygdala hyperactivity, increased brain-derived neurotrophic factor expression, and enhanced monoaminergic transmission. Findings from preclinical studies confirm that botulinum neurotoxin type A modulates limbic and brainstem circuits, possibly implicated in affective regulation.¹⁹

Migraines, mood disorders, and anxiety disorders are both individually and together quite difficult to treat. Thus, it is not unusual to see patients prescribed multiple medications for each condition. There is certainly a role for judicious deprescribing. Maximizing lifestyle management may also give rise to the opportunity for more simplified pharmacotherapy.

Concluding Thoughts

Though not an exhaustive review, this article is an exercise in elucidating the commonalities between migraines and other neuropsychiatric conditions. One can foresee a day when genotyping may allow us to cut through the trial-and-error method inherent in genetic heterogeneity and utilize treatments tailored for the individual. We currently use genotyping to tell us what medications will not work. It may also be that some genotypes respond best to certain treatments. If this were to be the case, genotyping could even be used in prevention. Ultimately, by better understanding the factors at play, we hope to better understand our patients, reduce their suffering, and help them achieve a better quality of life.

Dr Capote is medical director of the Division of Neuropsychiatry at DENT Neurologic Institute in Amherst, New York, and medical director of addiction services at BryLin Hospital in Buffalo, New York. He is also the neuropsychiatry section editor for Psychiatric Times.

References

1. Minen MT, Begasse De Dhaem O, Kroot Van Diest A, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87(7):741-749.

2. George A, Minen MT. Episodic migraine and psychiatric comorbidity: a narrative review of the literature. Curr Pain Headache Rep. 2023;27(9):461-469.

3. Viudez-Martínez A, Torregrosa AB, Navarrete F, García-Gutiérrez MS. Understanding the biological relationship between migraine and depression. Biomolecules. 2024;14(2):163.

4. Pelzer N, de Boer I, van den Maagdenberg AMJM, Terwindt GM. Neurological and psychiatric comorbidities of migraine: concepts and future perspectives. Cephalalgia. 2023;43(6):3331024231180564.

5. Androulakis XM, Yu X, Zhu X, et al. Migraine and major depression: localizing shared genetic susceptibility in different cell types of the nervous systems. Front Neurol. 2023;14:1254290.

6. Zhang M, Li Q, Zhao Y, et al. Shared genetic architecture between depression and migraine: a large-scale genome-wide cross-trait analysis. J Headache Pain. Published online May 25, 2026.

7. Li WW, Zhang JX, Wang J, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between migraine and five psychiatric disorders. Front Neurol. 2024;15:1432966.

8. Van der Auwera S, Teumer A, Hertel J, et al. The inverse link between genetic risk for schizophrenia and migraine through NMDA (N-methyl-D-aspartate) receptor activation via D-serine. Eur Neuropsychopharmacol. 2016;26(9):1507-1515.

9. Akhtar A. Editorial: bridging inflammation, oxidative stress, and metabolic dysfunction in brain disorders. Brain Sci. 2025;15(11):1211.

10. Ali M, Hussein M, Magdy R, et al. The potential impact of insulin resistance and metabolic syndrome on migraine headache characteristics. BMC Neurol. 2022;22(1):422.

11. Hindiyeh NA, Zhang N, Farrar M, et al. The role of diet and nutrition in migraine triggers and treatment: a systematic literature review. Headache. 2020;60(7):1300-1316.

12. Rollo E, Romozzi M, Vollono C, et al. Antiseizure medications for the prophylaxis of migraine during the anti-CGRP drugs era. Curr Neuropharmacol. 2023;21(8):1767-1785.

13. Norton J. Use of intravenous valproate sodium in status migraine. Headache. 2000;40(9):755-757.

14. Fontana E, Mandolini GM, Delvecchio G, et al. Intravenous valproate in the treatment of acute manic episode in bipolar disorder: a review. J Affect Disord. 2020;260:738-743.

15. Negro A, Koverech A, Martelletti P. Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res. 2018;11:515-526.

16. Hoffmann J, Charles A. Glutamate and its receptors as therapeutic targets for migraine. Neurotherapeutics. 2018;15(2):361-370.

17. Escher CM, Paracka L, Dressler D, Kollewe K. Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(2):127-135.

18. Wollmer MA, Magid M, Kruger THC, Finzi E. Treatment of depression with botulinum toxin. Toxins (Basel). 2022;14(6):383.

19. Gambini M, Gurrieri R, Russomanno G, et al. Botulinum toxin: an unconventional tool for the treatment of depression? Brain Sci. 2025;15(9):971.