Managing Comorbid Migraine and Mood Disorders: A Synergistic Approach

Migraine is “a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder.”¹ It affects 12% of US adults,² predominantly female — in fact, it affects 3 times as many women as men.³

The varying symptoms that accompany migraine, beginning with the prodromal stage and continuing through the headache phase, “suggest that multiple neuronal systems function abnormally,” structurally and functionally altering the brain.¹

Patients with migraine are significantly more likely to suffer from a psychiatric comorbidity than patients with other types of headaches.⁴ Individuals with migraine are 2 to 5 times more likely to be diagnosed with a depressive or anxiety disorder, even after controlling for variables such as age and gender.⁴ Migraineurs have a more than 3-fold risk for developing depression compared with patients who do not have migraines; on the other hand, patients with depression who had previously not had migraines have a more than 3-fold risk for developing migraine compared with non-depressed patients.⁵

“Depression and migraine are highly comorbid, with a longstanding literature base across multiple countries, multiple languages, diagnostic interviews, and screening tools all suggesting the high level of comorbidity,” Elizabeth Seng, PhD, assistant professor at Ferkauf Graduate School of Psychology, Yeshiva University, and research assistant professor, Department of Neurology, Albert Einstein College of Medicine, Bronx, New York.

Bidirectional Process

“There is an interesting literature base^6,7 suggesting that migraines and depression are bidirectional,” Dr Seng observed. “People who experience migraine earlier in life are more likely to develop depression, and vice versa, over the course of [the] their lifetime.”

She noted that there are “likely shared mechanisms involved, but we don’t understand fully what they are.”

Common genetic and/or environmental risk factors may underlie both migraine and psychiatric disorders.⁸ Other mechanisms include a possible association between a dopamine D2 receptor genotype common to migraine with aura, major depressive disorder (MDD), and generalized anxiety disorder (GAD).⁸ Also implicated in both migraine and psychiatric disorders are serotonin receptors and transporters and catecholamines. Several antidepressants (including selective serotonin reuptake inhibitors [SSRIs] and selective norepinephrine reuptake inhibitors [SNRIs]) have shown efficacy in migraine prevention, suggesting shared dysfunction in these neurotransmitters.⁸

Migraine and depression are both associated with fluctuations in female hormones — eg, during times of falling estrogen levels, such as menses, and in the postpartum and perimenopausal periods.⁸ Ovarian hormones, which modulate many neurotransmitters, therefore appear to play an important role in migraine as well as depression.⁸

Imaging studies have suggested that depression and migraine are associated with atypical function and structure of brain regions important for determining affective-motivational responses to sensory stimuli and also for affecting mood.⁹ These regions are “key components” of the brain regions involved with emotion: the limbic system, salience network, and default mode network.⁹ So the emotional aspects of migraine symptoms and the relationship between migraine and comorbid psychiatric disorders may be partially explained by stronger functional activation and connectivity in those particular regions.⁹

“We know that people with migraine seem to be especially sensitive to changes in their neurological environment,” Dr Seng said.

“For example, women may be more sensitive to hormonal changes over the course of the month, and people may be more sensitive to skipping meals [and] changes in sleep or stress patterns, as are people with depression, pointing to shared mechanisms with psychiatric illnesses in general and depression in particular,” she noted.

There is also a psychological component. “Migraine is very disabling, which takes a toll on mood — [resulting in] both depression and anxiety. People who have generalized anxiety disorder (GAD) have heightened arousal and sensitivity and worry about things in their environment more than those without GAD,” she said.

In a disease like migraine, in which a potentially disabling neurologic event can strike unpredictably, “the person may start to worry about the cause of the attacks and how to prevent them, and identify all sorts of triggers,” she said. When patients do that, “they restrict their lives more and more, leading to poor quality of life in the long run.”

Pharmacologic Treatments for Migraine and Depression

Ideally, migraines and depression should be treated simultaneously. “It is a mistake to think that migraine should not be addressed until the depressive symptoms have resolved, or vice versa. The 2 conditions can be treated at the same time,” Dr Seng emphasized. “Patients with these conditions should be receiving aggressive treatments on all fronts to help reduce both migraine and depressive symptomatology.”

Choosing migraine-preventive medication in patients with psychiatric comorbidities should be based on a number of factors, including the severity of the psychiatric comorbidity, patients’ preferences, patients’ risk for adverse events, and prior treatment history.⁹

If the psychiatric comorbidity is mild, it may be possible to use monotherapy for migraine prevention as well as the psychiatric condition. However, with severe conditions, or the absence of overlap, separate treatments are needed.⁹ In addition, using separate treatments for migraine and psychiatric comorbidity rather than monotherapy appears to improve outcomes and minimize side effects.⁹

Treatment should proceed in a “sequential stepwise manner with close monitoring of potential side effects and treatment interactions.”⁹ Some migraine preventives like topiramate can affect mood, while it is possible (albeit controversial) that β-blockers may be associated with depression.⁹ Table 1 lists pharmacotherapies for migraine prevention and psychiatric comorbidities.

Table 1: Pharmacotherapies For Migraine and Psychiatric Comorbidities

Class/Agent	Psychiatric Use	Migraine Prevention Use
TCAs (eg, amitriptyline)	Effective for depression at high doses with more side effects	Effective for migraine prevention at low doses with minimal side effects
SNRIs (eg, venlafaxine)	Effective for depression and anxiety	Only venlafaxine has grade B evidence of efficacy for migraine prevention
SNRIs (eg, venlafaxine)	Effective for depression and anxiety	Only venlafaxine has grade B evidence of efficacy for migraine prevention
SNRIs (eg, venlafaxine)	Effective for depression and anxiety	Only venlafaxine has grade B evidence of efficacy for migraine prevention
SNRIs (eg, venlafaxine)	Effective for depression and anxiety	Only venlafaxine has grade B evidence of efficacy for migraine prevention
SNRIs (eg, venlafaxine)	Effective for depression and anxiety	Only venlafaxine has grade B evidence of efficacy for migraine prevention

SNRIs = selective norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants Source: Minen MT, et al. J Neurol Neurosurg Psychiatry. 2016 Jul;87(7):741-749.

Non-pharmacologic Treatments for Migraine and Depression

A growing body of research supports the use of an approach integrating cognitive behavioral therapy (CBT) with pharmacotherapy for comorbid migraine and depression, as the combination can have a “synergistic effect.”⁹

For example, a 12-week study compared routine care, consisting of standard medications, with routine care plus CBT in 66 patients with comorbid migraine and MDD. The researchers found that participants in the treatment group improved significantly more than participants in the control group from pre- to post-treatment on measures of headache, depression, anxiety, and quality of life. In addition, improvements were sustained at 4-month follow-up.¹⁰

In another 16-month study, 232 adults with a diagnosis of migraine with or without aura were divided into 1 of 4 preventive treatments: β-blocker, matched placebo, behavioral migraine management plus placebo, or behavioral migraine management plus β-blocker.¹¹

The researchers found that the addition of combined medication plus behavioral migraine management improved migraine outcomes by reducing the number of migraines and improving quality of life.¹¹

A secondary study conducted by Seng and Holroyd analyzing the same data found that participants with comorbid mood or anxiety disorder diagnoses recorded a greater reduction in migraine days, quality of life, and headache disability than participants with neither diagnosis.¹²

“The take-home message of that study was that people with depression and anxiety can experience at least as large a change in headache and migraine days and migraine-related disability as people without the psychiatric comorbidity — in fact, under certain circumstances, the improvement might be larger,” Dr Seng commented.

Tips for Psychiatrists

Attend to the patient’s lifestyle

“We know that lifestyle and behavior matter both in migraine and in mood disorders, such as depression and anxiety,” Dr Seng said. “Stress reduction is an important component, as stress is the most prominently cited migraine trigger, so patients experiencing stress should ideally be referred to some type of stress reduction program.”

Poor sleep is also associated with migraine onset,⁹ she noted. “Many psychiatric diagnoses include poor sleep or insomnia in their diagnostic criteria, and sleep disturbances should be addressed in these patients.”

She recommended CBT for insomnia as the “gold standard,” noting that emerging evidence in migraine suggests that CBT for insomnia seems to affect both sleep and headache outcome.¹³

“Consistency is very important in patients with migraine; for example, going to sleep and getting up at the same time each day and not skipping meals,” she added.

Additional evidence-based behavioral treatments include progressive muscle relaxation, biofeedback, meditation, yoga, Qigong, and other mind-body approaches.^9,14-16

Screen patients with mood disorders for migraine

Since migraine is such a common comorbidity in depression and anxiety, Dr Seng recommended screening these patients for migraine. She added that emerging literature points to a strong comorbidity with bipolar disorder as well.¹⁷ The Migraine Disability Assessment Scale (MIDAS) is a global validated scale for measuring migraine disability outcomes.¹⁸

Engage in multidisciplinary collaboration

People with migraines and comorbid mood disorders often need treatments that address both conditions, as well as management of sleep, stress, and lifestyle issues. The treatment plan should be coordinated between all the physicians involved in a patient’s care⁹ and might also include psychologists, social workers, and other healthcare professionals.^19,20

References

1. Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015;35(17):6619-6629.
2. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
3. Weitzel KW, Strickland JM, Smith KM, Goode JR. Gender-specific issues in the treatment of migraine. J Gend Specif Med. 2001;4:64-74.
4. Smitherman TA. Psychiatric comorbidity and migraine. Headache. www.headachejournal.org/view/0/PsychiatricComorbidityandMigraine.html. Published January 26, 2011. Accessed May 30, 2018.
5. Torelli P, Lambru G, Manzoni GC. Psychiatric comorbidity and headache: clinical and therapeutical aspects. Neurol Sci. 2006;27(2):S73-S76.
6. Breslau N, Davis GC, Schultz LR, Peterson EL. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache. 1994;34(7):387-393.
7. Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology. 2003;60(8):1308-1312.
8. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi P, Costa A. Migraine and psychiatric comorbidity: a review of clinical findings. J Headache Pain. 2011;12(2):115-125.
9. Minen MT, Begasse De Dhaem O, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87(7):741-749.
10. Martin PR, Aiello R, Gilson K, Meadows G, Milgrom J, Reece J. Cognitive behavior therapy for comorbid migraine and/or tension-type headache and major depressive disorder: An exploratory randomized controlled trial. Behav Res Ther. 2015;73:8-18.
11. Holroyd KA, Cottrell CK, O’Donnell FJ, et al. Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ. 2010;341:c4871.
12. Seng EK, Holroyd KA. Psychiatric comorbidity and response to preventative therapy in the treatment of severe migraine trial. Cephalalgia. 2012;32(5):390-400.
13. Smitherman TA, Kuka AJ, Calhoun AH, et al. Cognitive-behavioral therapy for insomnia to reduce chronic migraine: a sequential bayesian analysis [published online May 6, 2018]. Headache. doi:10.1111/head.13313
14. Wells RE, Burch R, Paulsen RH, Wayne PM, Houle TT, Loder E. Meditation for migraines: a pilot randomized controlled trial. Headache. 2014;54(9):1484-1495.
15. Kisan R, Sujan M, Adoor M, et al. Effect of Yoga on migraine: a comprehensive study using clinical profile and cardiac autonomic functions. Int J Yoga. 2014;7(2):126-132.
16. Wahbeh H, Elsas S-M, Oken BS. Mind–body interventions: applications in neurology. Neurology. 2008;70(24):2321-2328.
17. Holder SD. Psychotic and bipolar disorders: bipolar disorder. FP Essent. 2017;455:30-35.
18. Edmeads J, Lainez JM, Brandes JL, et al. Potential of the migraine disability assessment (MIDAS) questionnaire as a public health initiative and in clinical practice. Neurology. 2001;56(6 Suppl 1):S29-S34.
19. Wallasch T-M, Kropp P. Multidisciplinary integrated headache care: a prospective 12-month follow-up observational study. J Headache Pain. 2012;13(7):521-529.
20. Martins V, Temótio J, Murta I. Psychiatric comorbidities associated with headaches: the experience of the liaison consultation. Acta Med Port. 2015;28(1):44-50.

This article originally appeared on Psychiatry Advisor