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The Bipolar Spectrum in Migraine Patients
Lawrence Robbins, MD
Posted December 1999

Abstract
1000 consecutive migraine patients, both with and without aura, were evaluated for bipolar illness. Bipolar I, bipolar II, and cyclothymia were defined according to DSM-IV guidelines. However, bipolar disorder not otherwise specified was modified and expanded. The lifetime prevalence of bipolar illness in the 1000 migraineurs is as follows: Bipolar I: 2.1%.  Bipolar II: 2.4%.  Cyclothymic Disorder: 1.3%. Bipolar disorder not otherwise specified: 2.8%.  Total for the Bipolar Spectrum: 8.6%. Bipolar illness is relatively common in the migraine population (8.6% in the current study). The mood stabilizers (such as sodium valproate) are beneficial for many of the bipolar patients, both for moods and for headache. The recognition of bipolar illness, particularly the milder forms, is crucial in leading to an improved quality of life for these patients.

Descriptors: bipolar, migraine, headache, depression, Depakote

Introduction
Clinicians and researchers have consistently noted an increase in mood disorders in migraine patients ^1,2. Anxiety disorders are the most common comorbidity ³. Depression, both recurrent major depression and dysthymia, also are seen with increased frequency in this population ^4,5,6.

The bipolar spectrum has been shown to exist with increased frequency in migraineurs 2. Previous studies have primarily focused on bipolar I and II. The current study also includes the 'softer, milder' end of the bipolar spectrum. Identifying and recognizing bipolar illness is not simply an academic exercise; the clinical stakes for missing bipolar are enormous. Because of the vailability of the mood stabilizers, particularly sodium valproate (Depakote), the quality of life of the bipolar patient and the family can be greatly enhanced.

Materials and Methods
A thousand consecutive migraine patients between the ages 30 to 81 were evaluated. They were patients at the Robbins Headache Clinic. Inclusion criteria were: age 30 or older; and a history of migraine (with or without aura), as defined by the International Headache Society criteria. Chart review and interview with the patients were done by the attending physician. Lifetime prevalence of bipolar was assessed in these patients.

Bipolar illness was defined according to the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). In addition, the modifications to DSM-IV by Akiskal ^7,8,9 were utilized in defining bipolar disorders.

Bipolar I disorder was defined according to the DSM-IV criteria; there had to be at least one episode, currently or in the past, of true mania.

Bipolar II was assessed according to DSM-IV. There had to have been one or more major depressive episodes, at least one hypomanic episode; no mania or mixed episodes, and these episodes caused significant distress or impairment in functioning.

Cyclothymic disorder was defined according to DSM-IV criteria: at least two years of numerous periods of hypomania and numerous episodes of depressive symptoms that do not meet criteria for major depressive episode. During the two year period, the person was not without the symptoms for more than two months at a time, and no major depressive episode, manic episode, or mixed episode had been present during the first two years of the disturbance. These symptoms had to cause clinically significant distress or impairment in functioning, and were not due to substance abuse or a medical condition.

Bipolar disorder not otherwise specified was defined according to DSM-IV, with additions according to Akiskal ^10,11,12. Examples of patients included in this category were: 1. Rapid alterations between manic and depressive symptoms that do not meet minimal criteria for a full manic episode or for a major depressive episode. 2. Recurrent hypomanic episodes without intercurrent depressive symptoms 3. Presence of a hyperthymic temperament as the habitual, long-term functioning of the person. In these patients, a strong family history of bipolar illness also aided in the diagnosis of bipolarity. Also, a hypomanic reaction to an antidepressant was considered an additional bipolar trait in these hyperthymic individuals. Hyperthymic temperament is defined, according to Akiskal ⁷, as habitual long-term functioning of the individual, with the following attributes: cheerful and exuberant; articulate and jocular; overoptimistic and carefree; overconfident, boastful, and grandiose; extroverted and people seeking; high energy level; full of plans and improvident activities; versatile with broad interests; overinvolved and meddlesome;uninhibited and stimulus seeking; and a habitual short sleeper (less than 6 hours per night). 4. Presence of a persistently agitated, angry, moody personality("temperamental instability"), particularly with a strong family history for bipolar disorder and/or a hypomanic reaction to an antidepressant. 5. The temperamental triad of mood lability, daydreaming, and energy activity also was used as additional indicators of bipolarity ⁷.

Results
Table 1. Lifetime prevalence of bipolar illness in 1000 consecutive migraineurs ages 30 to 81.

Conclusion
Bipolar illness was seen with increased frequency in the migraine population. In this study, 8.6% of the patients were classified as being somewhere along the bipolar spectrum. Because the clinical stakes for missing bipolar illness are enormous, recognition of the common comorbidity of bipolar with migraine is essential.

Discussion
The comorbidity of migraine with anxiety and depression is well established, both in clinically based studies and in epidemiologic samples from community populations ^1,3. The physiologic overlap between migraine and depression is considerable, and antidepressants or mood stabilizers often help both conditions ^13,14. In the vast majority of migraine patients who suffer from depression, anxiety is a complicating factor. The anxiety disorder often precedes the age of onset of migraine, with depression following afterward ¹⁵.

It is possible that poorly controlled migraine headaches may fuel the onset of depression or depression may, at times, increase headache. However, it is more likely that shared environmental and genetic factors link migraine and depression.

The relationship between bipolar illness and migraine has not been as well studied as depression and migraine. However, in several studies bipolar I and bipolar II were found to be increased in migraineurs ^2,15. One study indicated that the one-year prevalence for bipolar spectrum among migraineurs was 8.8%, and 3.3% among those without migraine ⁴. Another similar population based study indicated a lifetime prevalence for a manic episode of 4.7% (controls=0.9%), and for bipolar II of 3.9% (controls=0.8%) ⁵. The usual prevalence in the general population of bipolar disorder is listed as ranging from 0.4% to 1.7% ^16,17.

The clinical spectrum of bipolar disorders is an evolving concept. The DSM has historically inherent biases against independently diagnosing bipolarity, and bipolar II is defined very conservatively in DSM-IV ⁷. For example, in DSM-IV, the important hypomanic reaction to an antidepressant is not included in helping to determine bipolarity. Some authors feel DSM IV has an inherent bias towards diagnosing personality disorders, rather than bipolar disorders⁷. These biases lead to bipolar disorders being missed and underdiagnosed.

In our current study, we expanded the definition of bipolar disorder, not otherwise specified, to include those with hyperthymic temperaments. In addition, we included migraineurs with persistently agitated, angry personalities, who had a strong family history of bipolar, and/or a hypomanic reaction to an antidepressant. These patients, along with those who have "persistent temperamental instability", with a strong bipolar family history, constitute part of the milder end of the bipolar spectrum. It is these milder bipolar patients who tend to be missed and underdiagnosed ⁷.

The therapeutic implications for recognizing bipolarity are enormous. These patients, when not diagnosed, often are given a number of antidepressants, with predictable hypomanic results. The tricyclic antidepressants appear to have the highest propensity towards triggering mania, followed by the selective serotonin reuptake inhibitors (ssri's) ^7,18. Bupropion (Wellbutrin) has, in the small studies available, exhibited little tendency toward triggering mania, as has trazodone(Desyrel).

Once the bipolar diagnosis is established or suspected, mood stabilizers often are very helpful for the moods and headaches. Divalproex sodium (Depakote) is effective for mania, hypomania, depression associated with bipolar disorder, and for headache prevention ¹⁹. Divalproex sodium has been extremely well studied for these conditions, and has become one of the primary migraine and chronic daily headache preventives. Lithium carbonate is not utilized as readily in the headache population, due to increased side effects, as well as lack of efficacy for migraine. One or more of the newer antiepileptics may prove to be helpful for bipolar disorders and /or migraine. Carbamazepine (Tegretol) has some utility as a mood stabilizer, but not for migraine prophylaxis. When a mood stabilizer is given to a bipolar patient, we often see the underlying agitation/anger/anxiety/depression improve greatly. In addition, once bipolar patients are on an effective mood stabilizer, they often are able to tolerate antidepressants, particularly ssri’s. The mood stabilizer adds significant protection against a manic reaction.

The recognition of an increased comorbidity between migraine and bipolar illness has important clinical implications. By broadening our concept of the bipolar realm, we can improve outcome in these patients.

Funding Disclosure: This study was supported by a grant from Abbott Laboratories.

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