Migraine, particularly chronic migraine, as well as other chronic headaches, have high rates of comorbidity with mood and anxiety disorders.
Migraine is not a psychiatric disorder, although behavioral factors can critically influence the onset and course of headache episodes. Beginning in the 1950s, the conceptualization of migraine as a psychophysiological disorder by Wolff1 and others ultimately supplanted the earlier and purely psychogenic or psychopathological view of migraine based on psychoanalytic principles of psychosomatic medicine. Just the same, migraine disproportionately presents comorbidly with a variety of psychiatric illnesses. Identifying and managing comorbid illness is essential and can prove challenging in the treatment of migraineurs.
Migraine affects approximately 12% of Americans each year. It is 3 times more common among women than men (17.1% vs 5.6%, respectively) and peaks in prevalence between ages 25 and 55.2 Whereas migraine often manifests as an episodic disorder, migraine is now recognized as a chronic disease that persists or progresses over time as a function of biological and psychosocial risk factors.3 Depressive and anxiety disorders are recognized as modifiable risk factors for transformation of episodic (fewer than 15 d/mo) into chronic (at least 15 d/mo) migraine and for development of frequent and refractory headache resulting from overuse of acute medications (medication overuse headache [MOH]).
Individuals with migraine are 2 to 4 times more likely to suffer from MDD than are those without migraine. Lifetime rates of MDD range from 22% to 32% among those with episodic migraine and are as high as 57% among those with chronic migraine.4,5 Migraineurs also have a 3- to 4-fold increase in risk for bipolar disorder and for suicide attempts, even after controlling for psychiatric history.6
Among migraine sufferers, anxiety disorders are twice as common as depression, and migraineurs have a 3- to 5-fold increase in risk for various anxiety disorders compared with controls.4,7 Panic disorder, phobias, and generalized anxiety disorder (GAD) are most common among migraineurs, although there is growing interest among researchers and clinicians in comorbidity with PTSD.7 Rates of depression, sui-cide attempts, and anxiety are most common among those who have greater headache frequency, those with aura symptoms, and those who seek treatment.
The temporal relationship between migraine and depression is bidirectional—either disorder increases the subsequent risk of developing the other. This bidirectional relationship appears unique to migraine, because depression typically occurs subsequent to onset of other severe headache diagnoses.8 Some evidence suggests that panic disorder and migraine also occur bidirectionally.9 However, depression is rarely present without anxiety among migraineurs, and among those with both diagnoses, the anxiety disorder typically predates depression.10 The patterning of these relationships indicates that depression and anxiety observed among migraineurs are not merely reactions to living with this chronic pain condition.
What new information does this article provide?
This article presents recent research highlighting increased rates of comorbid psychiatric disorders among migraine patients and reviews the impact of these comorbidities on migraine management and mechanistic hypotheses.
What are the implications for psychiatric practice?
All migraine patients should be screened for depression and anxiety at a minimum. Management of both migraine and the psychiatric condition often requires separate agents to target each individually or supplementation with behavioral therapies.
Impact of psychiatric comorbidities
Psychiatric comorbidities are relevant clinically because they negatively impact the patient and complicate clinical decision making. Com-pared with migraineurs without a comorbid disorder, those with psychiatric comorbidity incur $5000 to $7800 more in yearly medical expenses, experience greater headache-related disability pertaining to daily role functioning, and have poorer quality-of-life and coping skills.11-13 In many cases, the comorbid disorder perpetuates a preoccupation with somatic sensations and fear of pain, in turn fostering avoidance of situations and behaviors that are actually unrelated to migraine.
Clinicians often expect the presence of psychiatric comorbidity to portend a poorer migraine prognosis. Clinical studies that have examined psychiatric comorbidities as prognostic factors are few and their findings are somewhat mixed. Nevertheless, most researchers and clinicians continue to maintain that psychiatric comorbidities likely will interfere with headache treatment outcomes under a variety of circumstances.
Particularly compelling evidence is provided by a longitudinal study that found the presence of psychiatric disorders (particularly multiple diagnoses) to be predictive of poor headache outcomes.14 Results demonstrated that 86% of headache sufferers who had 2 or more comorbid psychiatric disorders either had no improvement or had deterioration in their headache condition. Similarly, 62% with a single comorbid condition remained unchanged or worsened. In contrast, the absence of psychiatric disorders was associated with remission of headaches after 8 years.
Comorbid depression or anxiety is a negative prognostic indicator for patient compliance across a wide variety of medical conditions, including headache.15 Patients with MOH syndromes are particularly at risk for mood, anxiety, and psychoactive substance use disorders, and certain psychological states may play a key role in headache medication overuse (eg, fear of headache, anticipatory anxiety, obsessional drug-taking behaviors, psychological drug dependence).16 Headache patients with personality disorders (particularly cluster B disorders-antisocial, borderline, histrionic, narcissistic) are especially likely to be nonadherent.17 This negative prognosis associated with psychiatric comorbidity emphasizes the importance of psychological assessment and identification of psychopathology among headache sufferers.
Potential mechanisms of comorbidity
Several mechanistic hypotheses might account for the comorbidity of migraine and psychiatric disorders, including serotonergic dysfunction, ovarian hormone influences (for women), and processes perpetuating central sensitization.18 None of these is likely to be the sole contributor. Central serotonergic dysfunction is the explanation most commonly proffered, because the pharmacological agents of choice for depression/anxiety (ie, SSRIs and SNRIs) and for acute migraine (ie, triptans) are those that increase central serotonergic availability. A lowered serotonergic disposition predisposes migraineurs to cortical spreading depression (the source of migraine aura) and subsequent sensitization of trigeminovascular pathways.19
The female preponderance of migraine and affective comorbidities argues also for a strong role of hormonal influences. Precipitous drops in estrogen levels, such as those that occur during menstruation and perimenopause, are linked both to migraine attacks and affective disturbance. Obviously, large declines in estrogen are not relevant for male migraineurs. Among persons with chronic migraine, central sensitization and dysregulation of the hypothalamic-pituitary-adrenal axis also have been implicated. These 3 hypotheses await further research.
Assessment and diagnostic implications
All patients with headache should be evaluated for depression and anxiety. The recommended self-report screening measure for depression is the 9-item depression module of the Patient Health Questionnaire (PHQ-9) and for anxiety, it is the Generalized Anxiety Disorder 7-item scale (GAD-7).20,21 The GAD-7 has adequate sensitivity and specificity for detecting not only GAD but also PTSD, panic disorder, and social phobia.22 A score of 10 or higher on either measure indicates significant symptoms that merit further assessment. Because symptoms such as sleep disturbance, nausea, irritability, muscle tension, and difficulty in concentrating are common to both migraine and affective disorders, differential diagnosis is facilitated by focusing primarily on the core cognitive and emotional symptoms of the suspected psychiatric condition.
In rare cases, headache may be a symptom of a psychiatric disorder.23 “Headaches secondary to psychiatric disorders” are usually distinguished from migraine by headache occurrence only during active phases of the psychiatric condition. Most commonly, headache occurs as one of many unexplained symptoms in a somatization disorder or as a delusion during psychosis, such as that occurring as part of a severe major depressive episode, schizophrenia, or delusional disorder (somatic type). In the case of headache as delusion content, the delusion typically centers on the origin of the head pain (eg, alien insertion, undiagnosed brain tumor despite clear evidence to the contrary). Sufferers are usually women in whom numerous standard therapies have failed and who obtain headache relief only after direct and successful treatment of the psychiatric disorder.
If migrainous headache occurs at times other than during the active phase of the psychiatric illness or fails to remit when the psychiatric symptoms abate, then migraine is the appropriate diagnosis. Assessing the temporal patterning of headache in relation to psychiatric symptoms is most valuable diagnostically. Migraine is also the appropriate differential diagnosis if a psychiatric illness worsens a preexisting headache.
Treatment and management
Pharmacological management of comorbid psychiatric disorders may involve administering a single agent for both migraine and the comorbid disorder or using separate agents for each condition. In clinical practice, monotherapy usually is unrealistic because of differing efficacy and dosing profiles by condition. Preventive migraine medications (eg, propranolol, amitriptyline, sodium valproate) are indicated for patients with 4 or more headache days per month or significant functional impairment.
Regarding antidepressants, SSRIs are not efficacious for migraine prevention and SNRIs have not been sufficiently evaluated in large controlled trials.24 The TCA amitriptyline is the only antidepressant or anxiolytic with strong evidence of effectiveness for migraine prevention, but the dosage required to treat affective disturbance is much higher than that used for migraine and often causes sedation and weight gain.25 As such, pharmacological management of migraine and psychiatric disorders typically requires separate agents by condition, in which case, the prescribing physician should be attentive to potential drug interactions and consider using a “staggered” initiation.
Acute and abortive medications are indicated for patients with infrequent migraines. Triptans are the abortive agents of choice, and generic sumatriptan remains the most cost-effective option for patients. Other triptans that include additional agents or use alternative delivery systems (ie, sublingual, intranasal, transdermal) may benefit patients who have difficulty with oral or needle-based formulations or experience nausea or stomach upset. Despite the FDA’s black box warning, empirical data indicate that risk of serotonin syndrome among patients receiving a triptan and other serotonergic agent (for depression/anxiety) is incredibly low, with most affected patients experiencing mild symptoms that remit on discontinuation of one of the medications.26
Other commonly used acute and abortive medications include ergotamine derivatives, opioids, and other analgesics. Continuous opioid therapy for headache should be avoided except as a last resort, particularly for those with severe psychopathology or a history of substance abuse, because opioid use at a frequency of even 2 or 3 days per week can increase headache frequency, render migraine refractory to other treatments, and beget MOH.
Any effective acute or abortive medication (even over-the-counter analgesics) can lead to MOH, but the risk of MOH is highest with opioid analgesics. The most common cause of chronic migraine is opiate overuse, and migraineurs who take opiates 10 or more times per week should be assumed to have MOH until proved otherwise. Patients with MOH often prove highly refractory to headache treatment until they undergo withdrawal from the overused medication. These patients should be referred to a neurologist, preferably a headache specialist, for management of their headache. Because they are also the patients most likely to have psychiatric comorbidity, close collaboration between psychiatrist/mental health practitioner and neurologist is essential for treatment success.
A final treatment option is to supplement pharmacotherapy with behavioral management of migraine or the psychiatric disorder. Over the past 4 decades, behavioral headache treatments (including relaxation training, biofeedback, cognitive-behavioral therapy/stress-management training) have amassed a sizable evidence base that shows improvement rates that are competitive with prophylactic pharmacotherapies for migraine.27
The strength of this evidence has led numerous professional practice organizations to recommend use of behavioral headache treatments alongside pharmacological treatments for primary headache. Mild to moderate depression responds equally well to behavioral therapy as to medication. Patients with panic disorder, obsessive-compulsive disorder, and PTSD are best treated with exposure therapy because it is more effective than medication and because benzodiazepine use can function as an avoidance mechanism and lead to addiction.
Mild depression or anxiety among migraineurs often is sufficiently managed nonpharmacologically and improves as headache decreases. Migraineurs with more severe affective distress are likely to require pharmacological management of the psychiatric comorbidity and/or intensive psychotherapy from a mental health provider with expertise in behavioral medicine.
Migraine, particularly chronic migraine, as well as other chronic headaches, have high rates of comorbidity with mood and anxiety disorders. Migraine and psychiatric disorders share underlying pathophysiological mechanisms, with bidirectional, interdependent effects. Psychiatric comorbidity complicates headache and may portend a poorer prognosis for treatment. Emerging evidence suggests that the psychiatric disorder itself may contribute to transformation of episodic migraine to chronic and daily headaches.
Effective treatment for comorbid mood and anxiety disorders requires screening headache patients and accurately diagnosing specific psychiatric disorders when present. Many well-validated and relatively simple screening tools exist to facilitate recognition of psychiatric comorbidity and quantification of psychiatric symptoms. Pharmacological interventions that target both headaches and comorbid depressive or anxiety disorders, which often require separate agents by condition, can lead to improved headache treatment outcomes.
1. Wolff HG. Stress and Disease. Springfield, IL: Charles C. Thomas; 1953.
2. Lipton RB, Bigal ME, Diamond M, et al; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
3. Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache. 2008;48:7-15.
4. Breslau N. Psychiatric comorbidity in migraine. Cephalalgia. 1998;18(suppl 22):56-61.
5. Juang KD, Wang SJ, Fuh JL, et al. Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache. 2000;40:818-823.
6. Breslau N, Schultz L, Lipton R, et al. Migraine headaches and suicide attempt. Headache. 2012; 52:723-731.
7. Radat F, Swendsen J. Psychiatric comorbidity in migraine: a review. Cephalalgia. 2005;25:165-178.
8. Breslau N, Schultz LR, Stewart WF, et al. Headache and major depression: is the association specific to migraine? Neurology. 2000;54:308-313.
9. Breslau N, Schultz LR, Stewart WF, et al. Headache types and panic disorder: directionality and specificity [published correction appears in Neurology. 2001;56:1124]. Neurology. 2001;56:350-354.
10. Breslau N, Davis GC, Andreski P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. Psychiatry Res. 1991;37:11-23.
11. Saunders K, Merikangas K, Low NC, et al. Impact of comorbidity on headache-related disability. Neurology. 2008;70:538-547.
12. Pesa J, Lage MJ. The medical costs of migraine and comorbid anxiety and depression. Headache. 2004;44:562-570.
13. Radat F, Mekies C, GÃ©raud G, et al. Anxiety, stress and coping behaviours in primary care migraine patients: results of the SMILE study. Cephalalgia. 2008;28:1115-1125.
14. Guidetti V, Galli F, Fabrizi P, et al. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia. 1998;18:455-462.
15 Rains JC, Lipchik GL, Penzien DB. Behavioral facilitation of medical treatment for headache-part I: review of headache treatment compliance. Headache. 2006;46:1387-1394.
16 Radat F, Creac’h C, Swendsen JD, et al. Psychiatric comorbidity in the evolution from migraine to medication overuse headache. Cephalalgia. 2005;25:519-522.
17 Saper JR, Lake AE 3rd. Borderline personality disorder and the chronic headache patient: review and management recommendations. Headache. 2002;42:663-674.
18 Baskin SM, Smitherman TA. Migraine and psychiatric disorders: comorbidities, mechanisms, and clinical applications. Neurol Sci. 2009;30 (suppl 1):S61-S65.
19 Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27:1293-1300.
20 Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613.
21 Spitzer, RL, Kroenke K, Williams JB, LÃ¶we B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092-1097.
22 Kroenke K, Spitzer RL, Williams JB, et al. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146:317-325.
23 Smitherman TA, Baskin SM. Headache secondary to psychiatric disorders. Curr Pain Headache Rep. 2008;12:305-310.
24 Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev. 2005;3:CD002919.
25 Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
26 Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012;52:198-203.
27 Campbell JK, Penzien DB, Wall EM. Evidence-based guidelines for migraine headache: behavioral and physical treatments. 2000. http://www.aan.com/professionals/practice/pdfs/gl0089.pdf. Accessed December 5, 2012.