Posted by jrbecker on February 11, 2005, at 12:21:36
In reply to Bipolar II Series - irritable-hostile depression, posted by jrbecker on February 11, 2005, at 12:20:07
Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 233-242
Bipolar Depression: Focus on Phenomenology
doi:10.1016/j.jad.2003.11.007
Copyright © 2004 Elsevier B.V. All rights reserved.
Research report
Is migraine in unipolar depressed patients a bipolar spectrum trait?
Ketil Joachim Oedegaard , and Ole Bernt FasmerDepartment of Psychiatry, Haukeland Hospital, University of Bergen, N-5021, Bergen, Norway
Received 29 September 2003; accepted 12 November 2003. Available online 22 January 2004.
Abstract
Background: It is well known that affective disorders and migraine often coexist in the same patients, and some information is available indicating that migraine is particularly prevalent in bipolar II disorder. The aims of this study were to compare the clinical features in unipolar depressed patients with and without comorbid migraine to bipolar patients. Methods: Semi-structured interview of 201 patients with major affective disorders, using DSM-IV criteria for affective disorders combined with Akiskal's criteria for affective temperaments, and IHS-criteria for migraine. Results: Compared to the group of patients having unipolar depressions without comorbid migraine (n=51) the group with unipolar depression and migraine (n=63) had a higher number of depressive episodes (4.5 vs. 2.5, P=0.017), significantly higher prevalences of affective temperaments (46% vs. 16%, P=0.001), irritability (70% vs. 45%, P=0.008), seasonal variation (22% vs. 5%, P=0.017), agoraphobia (44% vs. 26%, P=0.036), asthma (25% vs. 6%, P=0.006) and migraine in family (59% vs. 29%, P=0.002). The clinical features of unipolar depressed patients with comorbid migraine resemble the bipolar II patients (n=51) in this sample. Limitations: Non-blind, cross-sectional assessment. Conclusions: These results indicate that there may be important clinical differences between unipolar depressed patients with and without comorbid migraine, possibly indicating that migraine in depressed patients is a bipolar spectrum trait.
Author Keywords: Affective disorders; Affective temperaments; Migraine
Article Outline
1. Introduction
2. Methods
3. Results
4. Discussion
References
1. Introduction
Patients with major affective disorders often have comorbid migraine (Breslau et al., 1994 and Merikangas and Stevens, 1997). The prevalence of migraine and depression in the general population is similar, around 10%, and females are more often affected with either disease (Silberstein and Lipton, 1993 and Thase and Kupfer, 1996). Both migraine (Gardner, 1999) and bipolar affective disorders (Gelernter, 1995) have an apparent genetic background, but it has been hard to identify a single genetic locus. Moreover, there is a strong association between migraine and anxiety disorders (Breslau et al., 1994 and Swartz et al., 2000), and there seems to be a syndrome characterized by an early occurring anxiety disorder, followed by migraine and depression over the life time course (Merikangas and Stevens, 1997).
There are few studies of migraine in patients presenting primarily with psychiatric disorders. In a study from his private specialist practice in New York, Endicott (1989) found that between 20% and 50% of patients with major affective disorders also had migraine. Concerning patients with bipolar disorders a 26% prevalence of migraine has been reported (Mahmood et al., 1999). In two papers from a previous study of 102 patients we have reported that there seems to be a preferential association between migraine and bipolar II disorder, and we have suggested that the presence of migraine may be used to delineate a distinct subgroup of the major affective disorders (Fasmer, 2001 and Fasmer and Oedegaard, 2001). According to the present classification systems in psychiatry, the presence or absence of hypomania separates bipolar II from unipolar disorder. However, hypomania may be difficult to separate from mania, and depressed patients may on follow up develop mania or hypomania (Akiskal, 1996). In an extension of the previous study we have identified another 99 patients with a major affective syndrome. The purpose of this has been to collect a sufficient amount of patients to separate unipolar depressed patients with migraine from unipolar patients without comorbid migraine with regards to the type and characteristics of the clinical symptoms, looking for signs of bipolarity that might be associated with the presence of migraine.
2. Methods
The study group (n=201) comprised 177 psychiatric patients at one of the University hospitals of Bergen and 24 psychiatric patients from private praxis in the county of Fusa outside Bergen. One hundred and nineteen subjects were consecutively admitted patients to a 12 bed open psychiatric ward (62 in the first study and 57 in the second study). The remaining patients were either inpatients at other wards of the hospital (n=19), from the outpatient department or the day care unit (n=39). The mean age in the whole group was 36.9±10.2 years (range 18–64). One hundred and thirty-nine patients (69%) were female. Patients were included if they presented with a major affective syndrome (major depression or mania), which was not clearly secondary to an organic or substance abuse disorder, were between 18 and 65 years old, and gave informed consent to participate. Patients that did not speak Norwegian with sufficient fluency to be interviewed without interpreter were excluded. The patients that were psychotic at intake were not psychotic when interviewed. The local ethics committee has approved the study protocol.
We used a semi-structured interview based on DSM-IV criteria (American Psychiatric Association, 1994) for affective disorders (major depressive episode, mania, hypomania), anxiety disorders (panic disorder, agoraphobia, specific phobia, social phobia, generalized anxiety disorder, obsessive compulsive disorder) and eating disorders (anorexia nervosa and bulimia nervosa). Hyperthymic, irritable and depressive temperaments were diagnosed according to the criteria of Akiskal and Mallya (1987), and cyclothymic temperament according to Akiskal and Akiskal (1992). Criteria for the cyclothymic temperament requires at least three of five attributes of each of the following two sets, with an indeterminate early onset (<21 years). First group: (1) Hypersomnia versus decreased need for sleep. (2) Introverted self-absorption versus uninhibited people-seeking. (3) Taciturn versus talkative. (4) Unexplained tearfulness versus buoyant jocularity. (5) Psychomotor inertia versus restless pursuit of activities. Second group: (1) Lethargy and somatic discomfort versus eutonia. (2) Dulling of senses versus keen perceptions. (3) Slow-witted versus sharpened thinking. (4) Shaky self-esteem alternating between low self-confidence and overconfidence. (5) Pessimistic brooding versus optimism and carefree attitudes. The hyperthymic temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Irritable, cheerful, overoptimistic, or exuberant. (2) Naive, overconfident, self-assured, boastful, bombastic, or grandiose. (3) Vigorous, full of plans, improvident, and rushing off with restless impulse. (4) Overtalkative. (5) Warm, people-seeking, or extroverted. (6) Overinvolved and meddlesome. (7) Uninhibited, stimulus-seeking, or promiscuous. The irritable temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Habitually moody, irritable and choleric, with infrequent euthymia. (2) Tendency to brood. (3) Hypercritical and complaining. (4) Ill-humored joking. (5) Obtrusiveness. (6) Dysphoric restlessness. (7) Impulsive. The depressive temperament requires at least five of the following characteristics, with an indeterminate early onset (<21 years): (1) Gloomy, pessimistic, humorless, or incapable of fun. (2) Quiet, passive, and indecisive. (3) Sceptical, hypercritical, or complaining. (4) Brooding and given to worry. (5) Conscientious or self-disciplining. (6) Self-critical, self-reproaching, and self-derogatory. (7) Preoccupied with inadequacy, failure, and negative events to the point of morbid enjoyment of ones failures. Unipolar depressive, bipolar I disorder and bipolar II disorder were diagnosed according to DSM-IV criteria.
With regard to affective disorders the following information was recorded: age of onset of the first major affective episode and the first depressive episode, the number of depressive episodes, the presence of melancholic or atypical symptoms (DSM-IV criteria) in the present or in previous episodes, seasonal variability of depressive episodes, current or previous suicide attempt, suicidal thoughts, psychotic symptoms, and the presence of prominent irritability or suspiciousness in the current or previous major depressive episodes.
For the anxiety disorders, the age of onset was recorded for each.
Symptoms of the following psychiatric disorders were also recorded (DSM-IV criteria): attention-deficit/hyperactive disorder, dyslexia and abuse of alcohol and drugs. Use of tobacco currently or previously was noted. History of characteristic symptoms of the following somatic symptoms was asked for: allergic rhinitis or other allergic disorders, asthma, atopic eczema, Raynaud's syndrome (Miller et al., 1981) and thyroid disorders. Hand preference was assessed according to the method of Oldfield (1971).
The criteria of the Headache Classification Committee of the International Headache Society (1988) were used to establish the diagnosis of migraine. In addition to migraine with and without aura the occurrence of migraine aura without headache was specifically asked for and recorded. Age of onset of migraine and the frequency of attacks (>1 per week, >1 per month, <1 per month, no attacks last year) were recorded.
Information about serious psychiatric disorders (major depression, bipolar disorder, psychosis, suicide) or migraine in first-degree family members was obtained from interviews of patients or from hospital records.
The first 102 patients were interviewed by the second author (O.B.F.), and the last 99 patients by the first author (K.J.O.). To assure an identical diagnostic approach both authors interviewed 10 patients together.
Chi-square test, t-test (two-tailed) or Fischer's exact test were used to calculate differences between groups. SPSS version 11.0 was used for the statistical analyses.
3. Results
The mean age of the patients was 36.9±10.2 years. Sixty-nine percent were female. The index episode was depression in 90% of the patients and mania in 10%. During the index episode 69% of the patients were inpatients. One hundred and seventeen patients had migraine (57%), and among these, 57 (28%) patients had migraine with aura, 41 (20%) had migraine without aura and 18 (9%) patients had migraine aura without headache. A majority of patients had suffered from migraine within the last 12 months (86%), and most of these patients (64%) had experienced at least one attack within the last month. Characteristics of the sample, grouped according to the diagnosis unipolar, bipolar I, and bipolar II disorder are detailed in Table 1. Furthermore, the unipolar patients are subdivided into two groups, depending on the presence or not of migraine. The presentations of the bipolar groups are given as a demonstration of the sample. All significances are calculated for the comparison between the two unipolar groups with or without migraine. There were no significant differences in age, gender distribution, marital status, work activity, alcohol or substance abuse or family history of serious psychiatric illness. Concerning serious psychiatric illness in first grade relatives, a bipolar I disorder was reported by 4.8% (3/63) of the unipolar patients with migraine and in none of the unipolar patients without migraine (0/51). The frequency of depressive episodes was 52.4% (33/63) and 41.2% (21/51) in first grade relatives of unipolar patients with and without migraine, respectively. No attempt was made to discriminate possible bipolar II disorder in these relatives. As expected there were more patients in the migraine group with a family history of migraine.
Table 1. Characteristics of the whole sample (n=201), and the comparison of the of unipolar patients with and without migraine
In Table 2 the somatic characteristics of the sample are shown. The only significant difference between the unipolar groups is that the frequency of asthma is four times higher among the patients with comorbid migraine (25% vs. 6%). Concerning all the other somatic features demonstrated, the two groups are surprisingly similar, except for the higher prevalence of left- or mixed-handedness among the migraine patients, although this was not significant.
Table 2. Some somatic characteristics of the whole sample, and the comparison of unipolar disorders with and without migraine
The characteristics of depressions are demonstrated in Table 3. Several differences emerge between the unipolar patients with migraine when compared to those without migraine. The patients with migraine had a higher total number of depressive episodes (4.5 vs. 2.5, P=0.017), they had significantly more often an affective temperament (46% vs. 16%, P=0.001), irritability (70% vs. 45%, P=0.008) and seasonal variation of depressions (22% vs. 3%, P=0.017). Regarding the type of affective temperaments, the unipolar patients with migraine most often were cyclothymic (n=13), or depressive (n=12), whereas few were hyperthymic (n=3) and only one patient had an irritable temperament. In the eight unipolar patients without migraine who had an affective temperament the distribution in the groups above were, respectively 3, 4, 1 and 0. Whereas patients in both groups commonly report irritability as a symptom occurring during depressions, this must not be confused with irritable mood as an affective temperament since this was only found in one unipolar patient. Even in bipolar I and bipolar II patients the presence of an irritable temperament was rare (one and two patients, respectively), while both BP I and BP II patients most often had a cyclothymic temperament (13 vs. 18 patients) and quite seldom a hyperthymic (two vs. three patients) or depressive temperament (five vs. two patients). Notice that the characteristics of bipolar II patients resemble those found in the unipolar patients with migraine concerning both number of depressive episodes (4.9), affective temperaments (49%), irritability (77%) and seasonality (33%), whereas the bipolar I patients seem to have more depressive episodes (6.6) and affective temperaments (58%) and less irritability (56%). The presence of seasonal variation is the same in both types of bipolar disorder. On the other hand, the unipolar patients have about the same prevalences of psychotic symptoms, suspiciousness, melancholia, guilt, suicidal behavior, rejection sensitivity or other atypical features, and treatment response to SSRI's, weather they suffer from migraine or not. Concerning most of these features the bipolar I and bipolar II patients have more symptoms than the unipolar patients, although there are some obvious differences since psychotic symptoms seem to be more pronounced in bipolar I patients, and suspiciousness in bipolar II patients. It might be noteworthy that particularly bipolar I patients report to be non-responders to SSRI's during depressions. There is no significant difference between the unipolar patients with and without migraine concerning the age at onset of first depressive episode, but it might be worth mentioning that the age of onset of depressions is significantly earlier in both bipolar I (22.3 vs. 28.1; t-test, P=0.008) and bipolar II patients (23.1 vs. 28.1, t-test, P=0.007) when compared to the whole sample of unipolar patients. Moreover, the bipolar II patients appear to report an earlier onset of hypomania than of depression (age 20.9 vs. 23.1).
Table 3. Characteristics of depressions in the whole sample and the comparison of unipolar disorders with and without migraine
As shown in Table 4, unipolar patients with comorbid migraine had an overall tendency towards a higher number of anxiety disorders (2.4 vs. 1.9, NS) than the patients that did not have migraine, but this was only significant for agoraphobia (44% vs. 26%, P=0.036). Unipolar patients with migraine seem to be more akin with bipolar II patients concerning comorbid anxiety disorders than with bipolar I patients or unipolar patients without migraine, although the total burden of anxiety appears to be even higher in bipolar II patients who have a total number of anxiety disorders of 2.8. Regarding obsessive-compulsive disorder or eating disorders, however, the bipolar II patients seem to be more affected than both bipolar I patients and unipolar patients, and no significant impact related to the presence of migraine is found in the latter group.
Table 4. Anxiety and eating disorders in the whole sample and the comparison of unipolar disorders with and without migraine
4. Discussion
The present findings indicate that the unipolar depressions associated with migraine are different from unipolar depressions without comorbid migraine in several important clinical features. It is noteworthy that almost half of the patients (46%) in the migraine group had an affective temperament. In addition most of them (70%) reported increased irritability as an important symptom during depressions, and nearly one-forth (22%) stated that they had seasonal variations in their depressive symptoms. This constellation was significantly different from that seen in unipolar patients without migraine. The patients with migraine furthermore had a higher number of depressive episodes, even though they were slightly older than the non-migraine patients when the first depression started (28.7 vs. 27.4), and insignificantly older at the time of inclusion (38.5 vs. 36.4, P=0.299) in the study. Additionally, the migraine patients had a tendency towards an increased number of comorbid anxiety disorders, although this was only significant for agoraphobia. Concerning the somatic conditions recorded in this study, the only difference associated with migraine was an increased prevalence of asthma. Other characteristics such as gender distribution, age, age of onset of depressive episodes, marital status and frequency of alcohol or substance abuse were not significantly different.
Unipolar disorder in this study is defined according to DSM-IV criteria. There is substantial evidence supporting the separation of patients with cyclothymic temperament from the unipolar depressive group (Akiskal and Akiskal, 1992), and it might be argued that there are several subgroups in this realm of "soft bipolar" conditions (Akiskal and Mallya, 1987), including patients with either shorter hypomanic episodes and even hyperthymic temperament. A link between migraine and neuroticism has been reported in several epidemiological studies (Breslau and Andreski, 1995; Merikangas et al., 1993 and Merikangas et al., 1994) and Wolff introduced the notion of migraine personality more than 60 years ago, including increased mood lability and depressions characterized by anergia and particularly panic disorder and phobia (Wolff, 1937). The contemporary equivalent to these features is the atypical subtype of depression. The high prevalence of affective temperaments in the unipolar patients with migraine, which is in line with the prevalence found in the bipolar II group, may possibly reflect increased mood lability in migraine patients and represent a linkage to bipolar disorders. We did not find more atypical depressions among the unipolar migraine patients, but irritability as a prominent symptom was more common in this group. Depressive mixed states (major depressive episodes with some hypomanic symptoms) have been found to be more prevalent in atypical depressions than in non-atypical depressions (Benazzi, 2001), and both irritability, agitation, racing thoughts and increased talking are reported as common features of a mixed state (Akiskal, 1992; Akiskal and Mallya, 1987; Goodwin and Jamison, 1990; Koukopoulos et al., 1992 and Perugi et al., 1997), and repeatedly associated with bipolar II and cyclothymic or hyperthymic temperament ( (Akiskal, 1996 and Akiskal et al., 1998). It is well known that prodromal and accompanying symptoms of migraine attacks are often psychiatric in nature, such as depression, elation, racing thoughts, irritability and anxiety (Davidoff, 1995). Irritability may be both a part of the prodrome that often precedes migraine headache, and a prominent symptom during hypomanic/manic or mixed state affective episodes. The increased frequency of irritability among the unipolar migraine patients in the present study, may possibly relate them to bipolar patients.
In a study from 1984, Rosenthal found that 90% of patients who suffered from winter depressions had a bipolar disorder (Rosenthal et al., 1984). Several studies have later opposed this finding. But, in the present study seasonal variation was more common in bipolar than in unipolar disorder. However, the unipolar patients with migraine reported significantly more seasonal variation of depressions than those without migraine, and in this regard they are more in line with the bipolar patients.
Both suicidal ideation and suicide attempts have been reported to be increased in patients having migraine with aura and major depression compared to patients having major depression without migraine (Breslau, 1992). In the present study the number of patients with suicide attempts was not significantly different between the unipolar groups with and without migraine. The most probable explanation is the high baseline frequency of suicide attempts in the whole sample, obscuring any preferential association with migraine. However, we found that the rate of prior suicide attempts were 30%, 50% and 61%, respectively, in unipolar, bipolar I and bipolar II patients. This is in good agreement with recent reviews showing that bipolar II patients carry the highest suicide risk, followed by bipolar I and unipolar disorder (Rihmer and Kiss, 2002). This may be interesting, since both migraine and suicide are strongly related to serotonin disturbance, and therefore, it is not surprising that the most suicidal form of major mood disorders (bipolar II) is most strongly related to migraine.
It is well established that bipolar patients have more comorbid anxiety than found in the general population (Angst, 1998 and Kessler et al., 1997) and this comorbidity may be higher for bipolar than unipolar depression (Chen and Dilsaver, 1995). In addition, there may be more comorbid anxiety disorders found in bipolar II patients when compared to bipolar I patients (Judd et al., 2003 and Rihmer et al., 2001). In the present study the highest total number of anxiety disorders was seen in bipolar II (2.8) patients, followed by unipolar (2.2) and finally bipolar I patients (1.8). However, dividing the unipolar groups into those with and without migraine shows that the migraine patients tend to have more anxiety disorders than the non-migraineurs (2.4 vs.1.9). Although this difference was not significant, it shows a tendency towards a linkage between migraine and anxiety disorders. The migraine patients had significantly more often agoraphobia (44% vs. 26%), and the same trend was seen in panic disorder and social phobia, with differences just dropping out of significance. The association between migraine and anxiety disorders has been found in several studies (Marazziti et al., 1999a and Marazziti et al., 1999b) and patients with migraine and major depression most often have a comorbid anxiety disorder (Merikangas and Stevens, 1997). Breslau and Davis (1992) found in a community study a doubled frequency of anxiety disorders among migraine patients, and the association was especially strong for panic disorder, with a 6-fold increase. The temporal association between the onset of the different anxiety disorders, migraine and major depression is also similar to previous findings (Merikangas and Stevens, 1997). In the present study, the unipolar patients with comorbid migraine present a constellation with an early onset of an anxiety disorder, 16.5 years, followed by migraine (21.5 years) and major depression (28.7 years). In a previous study (Fasmer and Oedegaard, 2001) we found that migraine was associated with bipolar II disorder, affective temperaments and an increased number of anxiety disorders, particularly panic disorder and agoraphobia. The present study indicates that even unipolar patients with comorbid migraine share this particular symptom cluster.
We found a high frequency of asthma (25%) among the unipolar migraine patients in this study, compared to only 6% among the migraine free individuals. There may be a link between migraine and asthma since children born to mothers with migraine seem to have an increased risk for asthma (Chen and Leviton, 1990). Even in this regard unipolar patients with migraine were similar to the bipolar II patients (22% prevalence of asthma), while there was a low frequency of asthma in the bipolar I group (8%). But of course it has to be kept in mind that most bipolar II patients in this sample had migraine (78.4%), whereas this was far less common among the bipolar I patients in this sample (36.1%). Migraine has a clear genetic background (Russel et al., 1995) and this is reflected in a high prevalence of migraine in first-degree relatives both in the unipolar group with migraine (59%) and in the bipolar II group (57%).
The major limitation of the present study is a non-blind cross-sectional assessment. On the other hand two interviewers included patients separately and the distribution of diagnosis of affective disorders, affective temperaments and migraine did not vary between the investigators. The results may not be applied to the general population since the patients interviewed in this study clearly represent a selected group. Relatives were not systematically interviewed. If this had been done it could perhaps have permitted a better delineation of affective temperaments and hypomania. Regarding the statistics we have chosen to present P-values without trying to correct for multiple comparisons. The number of comparisons increased the risk of type I error. However, the main differences between the unipolar patients with and without migraine concerning affective temperaments, irritability and seasonality were highly significant, and seem robust since they point in the same direction and also are in line with previous reports on the comorbidity of migraine, affective and anxiety disorders. The present findings underscore the importance of including questions on migraine in patients with affective disorders. If the presence of migraine in unipolar patients is a bipolar spectrum trait, this finding may have treatment implications, as antidepressants may worsen the mood instability, and mood stabilizers may improve it. Besides, there is strong evidence of a prophylactic effect of valproate in the prevention of migraine headache (Klapper, 1997 and Mathew et al., 1995), and a documented effect of valproate in the treatment of panic attacks (Lum et al., 1990), additionally increasing the worth of using a drug that is effective in the treatment of bipolar disorders (Bowden et al., 1994) as well.
The serotonergic system may be involved in the pathogenesis of migraine and affective disorders (Gardner, 1999 and Gelernter, 1995). There could be a basic derangement responsible both for the short-lasting, episodic phenomena seen in these patients (migraine, panic attacks, hypomania) and for the longer-lasting disturbances (major depression, affective temperaments), possibly linked to disturbances in either the serotonergic (Chugani et al., 1999 and Wang et al., 1996) or the dopaminergic system (Peroutka, 1997). Mckinnon has in several studies established a pattern of bipolar disorder with comorbid panic disorder as a possible genetic subtype of bipolar disorders (Mckinnon et al., 1998 and Mckinnon et al., 2002) and recently even in a subphenotype with rapid mood switching (Mckinnon et al., 2003). The present classification systems group patients with affective disorders according to a clinically expressed affective dysregulation. A non-psychiatric disorder like migraine, where the underlying commonality could be the dysregulation of 5HT-metabolism, may prove useful in establishing more homogenous subgroups of the affective disorders for further neurophysiological and molecular genetic investigations.
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Journal of Affective Disorders
Volume 84, Issues 2-3 , February 2005, Pages 233-242
Bipolar Depression: Focus on Phenomenology
poster:jrbecker
thread:456267
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