Headache Medicine, v.2, n.1, p.5-9, jan./feb./mar. 2011 5

Disease progression to chronic migraine:

onset of symptoms of headaches, anxiety and

mood disorders

Progressão da doença em enxaqueca crônica: Análise do início dos

sintomas de cefaleia, ansiedade e humor

ABSTRACTABSTRACT

ABSTRACT

Background:Background:

Background: Psychiatric conditions, mostly anxiety and mood

disorders, are common in patients with chronic migraine. There

has recently been extensive debate on migraine progression,

but little is known about the role of psychiatric disorders in this

respect.

Objective: Objective:

Objective: In order to evaluate the role of psychiatric

disorders in migraine progression, we analyzed the temporal

profile of migraine, mood and anxiety disorders, and years

since onset of symptoms in chronic migraine (CM) patients.

Methods: Methods:

Methods: Fifty CM patients diagnosed according to the

International Headache Society (2004) criteria were interviewed

and diagnosed for mental disorders using the Structured

Clinical Interview for DSM-IV (SCID-I/P).

Results:Results:

Results: Anxiety

disorders preceded the onset of episodic migraine, which was

followed by depression and daily headaches.

Conclusions:Conclusions:

Conclusions:

Psychiatric comorbidity evaluation in chronic migraine may

lead to better patient management and clinical outcomes.

Patients with a history of anxiety, episodic migraine, and

depression may be at risk of developing CM. Early treatment

of anxiety, mood disorders, and episodic migraine may prevent

disease progression to CM.

Keywords:Keywords:

Keywords: Anxiety disorders; Mood disorders; Disease

progression; Comorbidity

ORIGINAL ARTICLEORIGINAL ARTICLE

ORIGINAL ARTICLE

Juliane P. P. Mercante

1,2

; Mario F. P. Peres

; Marcio A. Bernik

; Felipe Corchs

1,2

; Vera Z. Guendler

1,3

; Eliova Zukerman

Hospital Israelita Albert Einstein, Institute of Teaching and Research, São Paulo, SP, Brazil

Institute of Psychiatry, HCFMUSP, São Paulo, SP, Brazil

Universidde Federal de São Paulo –

UNIFESP – EPM, São Paulo, SP, Brazil

Mercante JP, Peres MF, Bernik MA, Corchs F, Guendler VZ, Zukerman E

Disease progression to chronic migraine: onset of symptoms of headaches,

anxiety and mood disorders. Headache Medicine. 2011;2(1):5-9

RESUMORESUMO

RESUMO

Introdução:Introdução:

Introdução: Ansiedade e depressão são condições clínicas

comuns em pacientes com enxaqueca crônica. Um intenso

debate em relação ao processo de cronificação da enxaqueca

tem acontecido recentemente, mas pouca ênfase tem sido

dada a comorbidade psiquiátrica.

Objetivos:Objetivos:

Objetivos: Para avaliar

o papel das comorbidades psiquiátricas na progressão da

enxaqueca, analisamos o perfil temporal de início dos sintomas

de humor, ansiedade e dor nos pacientes com enxaqueca

crônica.

Métodos: Métodos:

Métodos: Cinquenta pacientes diagnosticados de

acordo com os critérios da Sociedade Internacional de Cefaleias

(2004) foram entrevistados e diagnosticados para transtornos

mentais de acordo com a entrevista estruturada para o DSM-

IV (SCID-I/P).

esultados:esultados:

esultados: Transtornos de ansiedade prece-

deram o início das enxaquecas episódicas, que foram seguidas

pelo aparecimento pelos transtornos de humor e sequen-

cialmente a evoluçãoo/transformação para enxaqueca

crônica.

Conclusões:Conclusões:

Conclusões: A avaliação das comorbidades

psiquiátricas na enxaqueca crônica podem levar a um melhor

diagnóstico e tratamento dos pacientes. Pacientes com história

de ansiedade, enxaqueca e depressão podem ter risco de

desenvolverem enxaqueca crónica. Tratamento precoce destas

condições podem previnir a ocorrência da enxaqueca crônica.

Descritores:Descritores:

Descritores: Transtornos de ansiedade; Transtornos do

humor; Progressão da doença; Comorbidade

6 Headache Medicine, v.2, n.1, p.5-9, jan./feb./mar. 2011

INTRODUÇÃO

Migraine is a chronic and sometimes progressive

disorder characterized by recurrent episodes of headache

and associated symptoms. Chronic migraine (CM) is

debilitating and has a substantial impact on a patient's

life;

(1)

it has recently been added to the second revised

International Headache Society Classification (2004),

(2)

and redefined

(3)

under a broader concept of the disorder,

accepting as migraine headaches occurring more than 8

days a month (previously 15 days), for more than three

months. The diagnosis of medication overuse headache

must be excluded.

(4)

Chronic migraine has been shown to

be an early stage of chronification of transformed

migraine.

(5)

CM is common in the general population

(6)

and accounts for up to 60% of consultations at tertiary

headache centres.

(7)

Mental disorders are common conditions among

these patients and are associated with a high degree of

disability, low level of satisfaction, and low quality of life.

)

Psychiatric comorbidities are also significant factors in the

development and maintenance of chronic headaches.

(9)

Some degree of depression is found in 85% of CM

patients, and severe depression in 25%.

(10)

Anxiety disorders

affect 75% of CM patients,

(11,12)

but anxiety and mood

disorders overlap in this condition.

(13)

CM is often difficult

to treat and its refractoriness has been attributed to

psychiatric comorbidity.

(14)

Mental disorders were also found to be more

common in migraine than in non-migraine individuals;

relative risk for major depressive disorders was 2.2%,

bipolar disorder 2.9%, generalized anxiety disorder 5.3%,

panic disorder 3.3%, simple phobia, 2.4%, and social

phobia, 2.0%.

(15)

Studies have consistently shown that

migraine with aura is more closely associated with

psychiatric comorbidity than migraine without aura.

(16)

Merikangas et al

(17)

observed that anxiety disorders

generally preceded migraine, followed by mood disorder

diagnoses, and postulated a syndromic relation between

migraine, anxiety and depression involving a range of

symptoms starting with anxiety (frequently in early

childhood), followed by migraines and depressive

episodes in adult life. CM has never been studied in this

context.

Recent evidence suggests that a subgroup of

migraine patients may have a clinically progressive

disorder,

(18-21)

but little emphasis has been given to the

putative role of psychiatric disorders in migraine

progression.

MERCANTE JP, PERES MF, BERNIK MA, CORCHS F, GUENDLER VZ, ZUKERMAN E

Our own study analyzed the years since onset of

anxiety-disorder symptoms, episodic migraine, mood

disorders, and daily headaches in chronic migraine

patients in order to evaluate the chronological relations

between these conditions. We predicted that CM would

be the next stage of disease progression after anxiety

disorders, episodic migraine and mood disorders had

set in.

METHODS

Fifty patients (forty women, ten men) were consecutively

diagnosed with chronic migraine in accordance with the

International Headache Society (2004)

(2)

criteria and

enrolled in the study. Their mean age was 41.1 ± 11.6

years (SD), range 23-65 years, most being caucasians

(45, 90%), with 4 black and 1 asian. Mean headache

frequency was 22.2 ± 2.7 days/month, mean headache

intensity (0-10 scale) was 8.1 ± 0.7. All patients had daily

headaches (more than 15 headache days/month). All

patients were enrolled at a tertiary headache centre in

Sao Paulo and interviewed using the Structured Clinical

Interview for DSM-IV SCID-I/P22;23 for psychiatric

assessment. Patients were asked about the onset of anxiety

symptoms and mood disorders using the standardized

SCID interview procedure. Questions about the onset of

symptoms of episodic and chronic migraine were asked

by the same SCID interviewer, and responses were

confirmed by the neurology team. We only included

responses with significant degree of confidence by both

patients and research team. The study protocol was

approved by the local Ethics Committee and all patients

gave written consent. We analyzed the onset of symptoms

in different groups; all patients had a history of daily

headaches and episodic migraine. We compared patients

with both anxiety and mood disorders (22 patients, 44%),

as well as patients with anxiety but not depression (16

patients, 32%), depression but not anxiety (6 patients,

12%), and no psychopathology (8 patients, 16%). A

Student t-test and Mann-Whitney rank sum test were used

to compare groups. Five percent was chosen as a

minimum level of statistical significance for two-sided tests.

Results were presented as mean ± standard deviation.

RESULTS

Forty-two patients (84%) met lifetime diagnostic criteria

for some mental disorder; 38 (76%) presented an anxiety

disorder; 25 (50%) presented a mood disorder; 22 (44%)

Headache Medicine, v.2, n.1, p.5-9, jan./feb./mar. 2011 7

DISEASE PROGRESSION TO CHRONIC MIGRAINE: ONSET OF SYMPTOMS OF HEADACHES, ANXIETY AND MOOD DISORDERS

presented both anxiety and mood disorder; 26 (52%)

presented generalized anxiety disorder; 3 (6%) presented

panic disorder, 2 (4%) obsessive-compulsive disorder, 3

(6%) posttraumatic stress disorder and 27 (54%) specific

or social phobia. Twenty-two (44%) presented major

depressive episode, 14 (28%) of them had a recent, and

17 (34%) patients had previous episodes. Two patients

met diagnostic criteria for dysthymic disorder, and 2 for

bipolar II disorder.

Patients with both anxiety and mood disorders,

episodic migraine, daily headaches onset and

comorbidities presented the following features: mean years

since onset of anxiety disorders was significantly earlier

than migraine (27.1 ± 16.9 vs. 20.5 ± 11.1 years since

onset, p=0.016), mood disorders (6.8 ± 1.9 years,

p<0.001) and daily headaches (4.6 ± 2.8 years,

p<0.001).

Migraine onset was significantly earlier than mood

disorder and daily headaches onset, p<0.001, as was

mood disorder onset compared to daily headaches onset

(p<0.01).

Anxiety disorders preceded the onset of episodic

migraine, which was followed by a mood disorder and

daily headaches (Figure 1).

In patients with anxiety but not mood disorders,

anxiety onset also preceded episodic migraine onset and

daily headaches onset (23.7 ± 17.4 vs. 21.6 ± 11.2,

p<0.01, vs. 5.5 ± 3.8, p<0.001). In patients with mood

disorders alone, episodic migraine preceded depression

symptoms (27.5 ± 8.2 vs. 4.2 ± 2.7, p<0.001). Mood

disorder onset also preceded daily headaches, but only

a trend toward significance was observed (4.2 ± 2.7 vs.

3.7 ± 2.8, p=0.054).

DISCUSSION

The findings of our study of the pattern of psychiatric

comorbidity symptoms and headaches in CM matched

those of Merikangas et al

(24)

who reported that anxiety

disorders preceded migraine, which preceded onset of

depression, but did not record daily headaches in young

adults aged 27-28 in Zurich (whereas the mean age of

our participants was 41.1 ± 11.6, range 23-65). Perhaps

the younger age of the Zurich population explains the

absence of daily headaches as a common symptom. We

also found that the last step in the symptom progression

from anxiety disorders to episodic migraine and mood

disorders may be migraine chronification and a daily

pattern. Even when anxiety patients without mood disorder

were compared with mood disorder patients without

anxiety, the same pattern was observed: anxiety preceded

episodic migraine onset in the former group, and episodic

migraine preceded mood disorders onset in the latter. The

small sample size of the latter may explain why depression

onset was not significantly different to daily headaches

onset, but a trend toward significance was found at

p=0.054.

CM may also be transformed to a wide spectrum of

symptoms, as elegantly reported by Bigal et al

(25)

who

suggested that the frequency of migraine attacks is high

in the early stages of migraine chronification, but the

frequency of nonmigraine headaches increases as the

illness progresses. Early descriptions of transformed

migraine mentioned anxiety and mood disorders as key

elements for developing daily headaches from episodic

migraines.

(26,27)

Our findings suggest that CM may be the result of a

combination of anxiety and mood disorder symptoms in

an episodic migraineur, but prospective studies are

required to draw causal inferences. In this context, CM

would be a truly neuropsychiatric condition. Another

possibility is that CM is a broader syndrome, involving

anxiety manifested frequently in early childhood,

adolescence or young adulthood, followed by episodic

migraines and then depressive disorders in adult life. There

may well be genetic predisposition for this disease

progression. Other comorbid conditions such as sleep

disorders, fibromyalgia, and other functional somatic

syndromes require further investigation to better define their

Figure 1. Mean onset age (years) of anxiety disorders, mood disorders,

episodic migraine and daily headaches. Profiling migraine and

comorbidities showed that mean ± SD onset age of anxiety disorders

was significantly lower than that of migraine (13.9 ± 13.7 (range 0-

44) vs. 20.9 ± 12.5 (range 4-54); onset of mood disorders (33.4 ±

10.1 (range 10-54); and CM (36.7 ± 11.3 (range 19-64). Mean onset

age of migraine was significantly lower than that of mood disorders

and CM, p<0.001, as it was for mood disorder onset compared to

daily headaches onset (p<0.01).

8 Headache Medicine, v.2, n.1, p.5-9, jan./feb./mar. 2011

role and level within a broader concept of disease

progression, which would hypothetically include these

syndromes.

Progression of symptoms in headache is common.

A longitudinal epidemiologic study found that 3% of

individuals with episodic headache (frequency from 2

to 104 days per year) progressed to chronic daily

headache (CDH, episode frequency >180 days per

year) in the course of a year.

(28)

The study concluded

that the incidence of CDH in subjects with episodic

headache is 3% per year. A one-year follow-up of 532

consecutive episodic migraine patients (<15 days per

month) found that 64 (14%) developed chronic daily

headache.

(29)

Despite its clinical relevance, the evidence of risk

factors for migraine progression is limited. The

prevalence of CDH has been reported to decrease

slightly with age and to be higher in women [odds ratio

(OR) = 1.65 (1.3 to 2.0)] and in divorced, separated,

or widowed individuals [OR = 1.50 (1.2 to 1.9)]. Social

risk factors have also been described: the risk of CDH in

individuals with less than high-school education was

threefold that of a college-educated sample [OR = 3.56

(2.3 to 5.6)].

(30)

CDH was also associated with a self-

reported diagnosis of arthritis [OR = 2.50 (1.9 to 3.3)],

diabetes [OR = 1.51 (1.01 to 2.3)],

(31)

previous head

trauma

(32

) and medication overuse.

(33)

Interestingly, the

highest risk factor described for development of CDH

was obesity [OR = 5.53 (1.4 to 21.8)].

(34)

A study

comparing 41 migraineurs with 41 medication overuse

headache (MOH) patients found that the latter showed

excess risk of suffering from mood and anxiety disorders

associated with use of psychoactive substances.

Psychiatric disorders occurred significantly more often

before rather than after the transformation from migraine

to medication overuse headache (MOH).

(35)

Most studies failed to explore one of the main issues

in migraine management: psychiatric comorbidity. Our

sample, although relatively small, showed a consistent

pattern of disease progression based on the onset of

symptoms described by patients. Recollection bias may

be present, but previous studies have utilized and validated

the same method.

(14)

The ideal methodology would be a

prospective study, but long term follow-up (decades) is

also very difficult.

This paper raises the possibility of early

pharmacological or non-pharmacological intervention for

adolescents or young adults with anxiety disorders in order

to prevent the future onset of migraine.

CONCLUSION

Psychiatric disorders, mostly anxiety and mood

disorders, are common in patients with CM. Anxiety

disorders may occur before the onset of episodic migraine

and be followed by depression and finally daily

headaches.

Psychiatric evaluation for CM patients may enhance

patient management and clinical outcomes. Even though

the present findings are limited by the cross-sectional

design of this study, the data suggests that anxiety disorders

may be an important risk factor for subsequent migraine

and that both anxiety and mood disorders play an

important role in migraine progression to CDH.

Therefore, early treatment of anxiety disorder and/

or episodic migraine may prevent long term

complications, such as depression and CM.

REFERENCES

1. Bigal ME, Lipton RB, Stewart WF. The epidemiology and impact of

migraine. Curr Neurol Neurosci Rep. 2004;4(2):98-104.

2. Headache Classification Subcommittee of the International

Headache Society. The International Classification of

Headache Disorders. 2nd ed. Cephalalgia. 2004; 24 Suppl

1:9-160.

3. Headache Classification Committee, Olesen J, Bousser MG,

Diener HC, Dodick D, First M, Goadsby PJ, Göbel H, Lainez MJ,

Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein

SD, Steiner TJ. New appendix criteria open for a broader concept

of chronic migraine. Cephalalgia. 2006;26(4):742-6.

4. Silberstein SD, Olesen J, Bousser MG, Diener HC, Dodick D,

First M, Goadsby PJ, Gobel H, Lainez MJ, Lance JW, Lipton RB,

Nappi G, Sakai F, Schoenen J, Steiner TJ. The International

Classification of Headache Disorders, 2nd Edition (ICHD-II) -

revision of criteria for 8.2 Medication-overuse headache.

Cephalalgia 2005;25(6):460-5. Erratum in: Cephalalgia.

2006 Mar;26 (3): 360.

5. Bigal ME, Sheftell FD, Tepper SJ, Rapoport AM, Lipton RB. Migraine

days decline with duration of illness in adolescents with

transformed migraine. Cephalalgia 2005;25(7):482-7.

6. Pascual J, Colas R, Castillo J. Epidemiology of chronic daily

headache. Curr Pain Headache Rep. 2001;5(6):529-36.

7. Mathew NT. Transformed migraine. Cephalalgia 1993;13 Suppl

12:78-83.

8. Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS,

Bryson H, de GG, Graaf R, Demyttenaere K, Gasquet I, Haro

JM, Katz SJ, Kessler RC, Kovess V, Lepine JP, Ormel J, Polidori G,

Russo LJ, Vilagut G, Almansa J, rbabzadeh-Bouchez S, Autonell

J, Bernal M, Buist-Bouwman MA, Codony M, Domingo-Salvany

A, Ferrer M, Joo SS, Martinez-Alonso M, Matschinger H, Mazzi

F, Morgan Z, Morosini P, Palacin C, Romera B, Taub N, Vollebergh

WA. Disability and quality of life impact of mental disorders in

Europe: results from the European Study of the Epidemiology of

MERCANTE JP, PERES MF, BERNIK MA, CORCHS F, GUENDLER VZ, ZUKERMAN E

Headache Medicine, v.2, n.1, p.5-9, jan./feb./mar. 2011 9

DISEASE PROGRESSION TO CHRONIC MIGRAINE: ONSET OF SYMPTOMS OF HEADACHES, ANXIETY AND MOOD DISORDERS

Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl.

2004;(420):38-46.

9. Guidetti V, Galli F, Fabrizi P, Giannantoni AS, Napoli L, Bruni O,

Trillo S. Headache and psychiatric comorbidity: clinical aspects

and outcome in an 8-year follow-up study. Cephalalgia

1998;18(7):455-62.

10. Mercante JP, Peres MF, Guendler V, Zukerman E, Bernik MA.

Depression in chronic migraine: severity and clinical features.

Arq Neuropsiquiatr. 2005;63(2A):217-20.

11. Peres MF, Zukerman E, Young WB, Silberstein SD. Fatigue in

chronic migraine patients. Cephalalgia. 2002;22(9):720-4.

12.Mercante JP, Peres MF, Bernik MA. Primary headaches in patients

with generalized anxiety disorder. J Headache Pain. 2011 (in

press).

13. Peres MF, Young WB, Kaup AO, Zukerman E, Silberstein SD.

Fibromyalgia is common in patients with transformed migraine.

Neurology 2001;57(7):1326-8.

14. Lipton RB, Silberstein SD, Saper JR, Bigal ME, Goadsby PJ. Why

headache treatment fails. Neurology 2003;60(7):1064-70.

15. Merikangas KR, Angst J, Isler H. Migraine and psychopathology.

Results of the Zurich cohort study of young adults. Arch Gen

Psychiatry 1990;47(9):849-53.

16. Peroutka SJ, Price SC, Wilhoit TL, Jones KW. Comorbid migraine

with aura, anxiety, and depression is associated with dopamine

D2 receptor (DRD2) NcoI alleles. Mol Med. 1998;4(1):14-21.

17. Merikangas KR, Merikangas JR, Angst J. Headache syndromes

and psychiatric disorders: association and familial transmission.

J Psychiatr Res. 1993;27(2):197-210.

18. Kruit MC, Launer LJ, Ferrari MD, van Buchem MA. Infarcts in the

posterior circulation territory in migraine. The population-based

MRI CAMERA study. Brain. 2005;128(Pt 9):2068-77. Comment

in: Brain. 2006 Jan;129(Pt 1):E39.

19. Dahlof CG, Linton-Dahlof P, Lainez JM, Pascual J. [Is migraine a

progressive cerebral disease?]. Neurologia. 2005;20(7):356-

65. Article in Spanish.

20. Goadsby PJ. Is migraine a progressive disorder? Considering

the clinical implications of new research data on migraine and

brain lesions. Med J Aust. 2005;182(3):103-4.

21. Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk

factors for progression. Headache 2005;45 Suppl 1:S3-S13.

22. Spitzer RL, Williams JB, Gibbon M, First MB. The Structured

Clinical Interview for DSM-III-R (SCID). I: History, rationale, and

description. Arch Gen Psychiatry 1992;49(8):624-9.

23. Ventura J, Liberman RP, Green MF, Shaner A, Mintz J. Training

and quality assurance with the Structured Clinical Interview for

DSM-IV (SCID-I/P). Psychiatry Res. 1998;79(2):163-73.

24.Merikangas KR, Swanson SA. Comorbidity in anxiety disorders.

Curr Top Behav Neurosci. 2010;2:37-59.

25. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Chronic

migraine is an earlier stage of transformed migraine in adults.

Neurology 2005;65(10):1556-61.

26. Masruha MR, Lin J, de Souza Vieira DS, Minett TS, Cipolla-Neto

J, Zukerman E, Vilanova LC, Peres MF. Urinary 6-

sulphatoxymelatonin levels are depressed in chronic migraine

and several comorbidities. Headache. 2010 ;50(3):413-9.

27. Corchs F, Mercante JP, Guendler VZ, Vieira DS, Masruha MR,

Moreira FR, Bernik M, Zukerman E, Peres MF. Phobias, other

psychiatric comorbidities and chronic migraine. Arq

Neuropsiquiatr. 2006;64(4):950-3.

28. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily

headache. Curr Pain Headache Rep. 2002;6(6):486-91.

29. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G,

Eikermann A, et al. Incidence and predictors for chronicity of

headache in patients with episodic migraine. Neurology

2004;62(5):788-90.

30. Mathew NT, Stubits E, Nigam MP. Transformation of episodic

migraine into daily headache: analysis of factors. Headache

1982;22:66-8.

31. Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine. Curr

Opin Neurol. 2005;18(3):305-10.

32. Couch JR, Bearss C. Chronic daily headache in the posttrauma

syndrome: relation to extent of head injury. Headache

2001;41(6):559-64. Comment in: Headache. 2002;42(2):

162-3.

33. Mathew NT. Transformed migraine, analgesic rebound, and other

chronic daily headaches. Neurol Clin. 1997;15(1):167-86.

34. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB.

Transformed migraine and medication overuse in a tertiary

headache centre--clinical characteristics and treatment outcomes.

Cephalalgia 2004;24(6):483-90.

35. Radat F, Creac'h C, Swendsen JD, Lafittau M, Irachabal S,

Dousset V, Henry P. Psychiatric comorbidity in the evolution

from migraine to medication overuse headache. Cephalalgia

2005;25(7):519-22.

Received: 10/8/2010

Accepted: 10/30/2010

Correspondence

DrDr

. Mario F. Mario F

. Mario F

ernando Pernando P

ernando P

rieto Prieto P

rieto P

ereseres

eres

Al. Joaquim Eugenio de Lima, 881 cj 708

01403-001 – São Paulo, SP, Brazil

Tel. 55-11-8111-6662 – Fax. 55-11-3285-5726

marioperes@yahoo.com