Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018 61
Management of psychiatric comorbidities in migraine
Manejo das comorbidades psiquiátricas na migrânea
Mario Fernando Prieto Peres
1,2
, Marcelo Moraes Valença
3
, Raimundo Pereira Silva-Neto
4
1
Hospital Israelita Albert Einstein, São Paulo, Brazil
2
Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
3
Federal University of Pernambuco, Recife, Brazil
4
Federal University of Piauí, Teresina, Brazil
Peres MFP, Valença MM, Silva-Neto RP. Management of psychiatric comorbidities in migraine.
Headache Medicine. 2018;9(2):61-67
VIEW AND REVIEW
ABSTRACT
Psychiatric commorbidities are one of the main issues in
migraine management. Diagnosis and treatment strategies are
deeply affected by mental health diagnosis and symptoms.
Depression and anxiety has been the most studied topics, anxiety
aspects such as excessive worry, inability to control worries,
inability to relax are highligheted. It is also reviewed in this
paper data on the relation of psychiatric symptoms and
migraine; the rationale for using a symptom-based approach;
how migraine overlaps with anxiety, ADHD, and bipolar
symptoms. Screening tools addressing specific mental health
topics are discussed, as a comprehensive approach for frequent
acute medication intake considering psychiatric comorbidity.
An algorythm is proposed for the general management of
psychiatric comorbidity in migraine.
Keywords:
Migraine; Psychiatric comorbidities; Anxiety;
Depression; Bipolar; ADHD
RESUMO
As comorbidades psiquiátricas são um dos principais pro-
blemas no manejo da migrânea. As estratégias de diagnós-
tico e tratamento são profundamente afetadas pelos diag-
nósticos e sintomas na esfera da saúde mental. Depressão e
ansiedade têm sido os tópicos mais estudados, aspectos de
ansiedade como preocupação excessiva, incapacidade de
controlar preocupações e incapacidade de relaxar são ele-
vados. Também é revisado neste artigo os dados sobre a
relação entre sintomas psiquiátricos e migrânea; a justifica-
tiva para usar uma abordagem baseada em sintomas; como
a enxaqueca se sobrepõe a ansiedade, TDAH e sintomas
bipolares. Ferramentas de triagem abordando tópicos espe-
cíficos de saúde mental são discutidas, como uma aborda-
gem abrangente para ingestão freqüente de medicação agu-
da onsiderando comorbidade psiquiátrica. Um algoritmo é
proposto para o tratamento geral da comorbidade psiquiá-
trica na migrânea.
Palavras-chave:
Enxaqueca; Comorbidades psiquiátricas;
Ansiedade; Depressão; Bipolar; TDAH
INTRODUCTION
Migraine is a neurological condition affecting near 12%
of the population worldwide,
(1)
considered to be the third
most disabling disorder in adults less than 50 years-old age.
(2)
Psychiatric comorbidities have been linked to migraine,
interfering substantially with its diagnosis and treatment.
Anxiety and mood disorders have been the most studied
conditions, shown to be 2-10 times more common in migraine
when compared to healthy controls in general population.
(3)
In clinical settings, psychiatric comorbidities lead to
poorer quality of life
(4)
more health care expenditures,
(5)
increase risk for progression from episodic to chronic
migraine,
(6)
being a more difficult to treat patient.
(7)
In this paper we review the relevant data on psychiatric
commorbidity in migraine, propose algorythms for its
management and how the field have to move in the next
five years.
Psychiatric disorders in the population
Psychiatric disorders are common and debilitating
conditions. Although overlap between mental health diseases
62 Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018
PERES MFP, VALENÇA MM, SILVA-NETO RP.
is the rule, the field divides in several areas, the following
are the ones considered to be the most prevalente and
relevant: mood disorders (major depression, bipolar
depression), substance abuse disorders (nicotine, alcohol,
cannabis, cocaine), anxiety disorders (generalized anxiety
disorder, panic disorder, phobias), psychotic disorders
(schizophrenia, psychosis).
(8)
The prevalence of having any mental health disorder
have been found to be 15.4% worldwide, ranging from
12.1% in low/lower-middle income countries to 15.4% for
upper-middle and to 17.0% in high-income.
(9)
The global burden of disease study calculated disability-
adjusted life years (DALYs) by the sum of years of life lost
due to premature mortality (YLL) and years lived with disability
(YLD), showing major depression the 11th cause of DALYs.
Considering YLDs, seven out of the 19 highest where men-
tal health disorders (Major depression, #2, anxiety disorders,
#7; drug use disorders, #12; alcohol use disorders, #15;
bipolar disorder, #17; schizophrenia, #18; dysthymia,
#19; while pain disorders ranked also very high, including
migraine being #8.
(2)
Psychiatric comorbidities in migraine
Psychiatric comorbidities are common in migraine
patients, affecting its management considerably. Studies in
general population, clinical settings, tertiary headache
specialty centers have all shown high rates of psychiatric
diagnosis in migraine, particularly more in women, in
patients with aura, and in chronic versus episodic migraine
subjects.
(10)
Depression and anxiety disorders have been
the most studied topics, as shown in the Graph 1.
Epidemiological studies suggest a bidirectional
relationship between depression and migraine,
(11)
high
prevalence of bipolar disorders and a significant impact
have been described, particularly in bipolar II women,
migraine with aura or cyclothymic temperament.
(12)
In ge-
neral, psychiatric symptoms are associated with severe
migraine-related disability.
(11)
Diagnostic approach of psychiatric disorders in
headache patients
The diagnosis of psychiatric disorders are challenging
for all specialties dealing with headache patients, from
family practice physicians to headache specialists. Training
in psychiatry is limited among neurologists and other
clinical specialties. Diagnosis in psychiatry, like in
headache disorders, is based in clinical, subjective
information given by patients, analyzed and defined by
physicians throughout a non-biological, arbitrary criteria.
As important as taking headache related clinical history
for diagnosis according to the International Classification
of Hedache Disorders
(13)
is a mental health history for
defining not only psychiatric disorders associated with
headaches but physical and mental symptoms that could
interfere with patients quality of life.
The approach to the psychiatric diagnosis in headache
patients has the difficult task of stablishing what is cause
what is consequence, or even if a third factor could be
causing both conditions, such as hormonal, metabolic, re-
nal, hepatic, or cardiovascular disorders, trauma, substances
(medications, alcohol, caffeine, other drugs). A detailed
clinical history plays pivotal role in determining the time of
occurrence and causality between one or another condition,
however, a memory recall bias limits aperfect definition.
Like in headache disorders, the concepts of spectrum
and/or continuum in psychiatric disorders are critical. The
current understanding of bipolar disorders consider a wide
variety of clinical presentations.
(14)
Overlap between
psychiatric disorders, in diagnostic criteria and symptoms
occurs. As the migraine/tension-type headache continuum
is familiar for the headache care physician, continuums
between depression and anxiety, anxiety and ADHD,
bipolar spectrum and ADHD are part of daily clinical di-
lemas for the psychiatrist,
(15)
and naturally should also
happen in the management of psychiatric comorbidity in
migraine patients. More complexity adds to the issue when
migraine is considered, as a possible spectrum/continuum
between migraine and anxiety, as migraine and mood
disorders exist.
When looking at anxiety and mood related symptoms
one may understand how much of migraine features are
actually part of psychiatric symptoms or exacerbate them.
Graph 1. Number of studies published with migraine and psychiatric
comorbidity keywords appearing in title (PubMed)
Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018 63
In generalized anxiety disorder (GAD) diagnosis, criteria
C symptoms are very influenced by chronic headaches and
headache attacks, including sleep complaints, irritability,
muscle tension, concentration, and fatigue, all occurring
prior, during or after the headache phase (Table 1).
In depression, the two main symptoms, loss of pleasure
and mood are directly affected by pain experience. Other
symptoms such as decrease or excessive sleep, fatigue, poor
concentration, psychomotor retardation, can also be part
of the migraine attack. Weight loss or gain, guilt, and death
thoughts are not part of migraine.
In addition, when further analyzing mood swings in
bipolar depression, the clear depressive mood of being in
a headache attack, and the swing to a pain-free state is
Figure 1. Venn diagram showing the overlap in symptoms between migraine and ADHD, anxiety and bipolar disorders.
MANAGEMENT OF PSYCHIATRIC COMORBIDITIES IN MIGRAINE
already a mood fluctuation, confounding diagnosis.
Migraine itself maybe a factor for a specific modulation,
possibly interfering in how comorbidities develop over time.
In the Venn diagram we exemplify how migraine
interacts with ADHD, anxiety and the bipolar spectrum
symptoms, where irritability lies in the middle, being part
of four clinical syndromes.
The diagnostic based approach can be performed
through a referral to a psychiatrist or psychologist, or
performed by the headache care provider, using screening
and diagnostic tools such as CIDI (Composite International
Diagnostic Interview) or SCID (Standardized Clinical
Evaluation),
(16)
based on DSM-V, or individually, using
specific self-report measures by asking patients to com-
plete paper-and-pencil, tablet or smartphone-based tools.
Another way of assessing psychiatric comorbidities in
migraine is by a symptom-based approach.
Rationale for the symptom-based approach in
migraine psychiatric comorbidity
Symptom-based approach is a new paradigm in men-
tal health research.
(17)
Diagnosis in headache as in mental
health is based in clinical criteria, where classification systems
try to find cluster of symptoms and define specific diagnosis,
separating one disease to another. Defining disorders as
separate entities is important for the advance of medicine,
but this has brought an artificial concept, lacking the fact
that most of disorders overlap. In addition, mental health
64 Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018
PERES MFP, VALENÇA MM, SILVA-NETO RP.
symptoms may occurr and afffect substantially the migraine
clinical picture and response to treatment, therefore mental
health diagnosis should consider subsyndromic diagnosis,
and even further, looking at main symptoms, such as
excessive worry, irritability, lack of control anxiety or inability
to relax.
We studied recently anxiety and mood symptoms in a
symptom-based approach.
(18)
We found anxiety symptoms
were more relevant in migraine than depression, where
physical symptoms were more commonly related than
psychological, such as felling down and deaths thoughts.
Figure 2. Odds ratios for migraine risk according to anxiety (left) and depression symptons (right)
Moreover, the most significant aspects found in migraine
sufferers versus controls where not being able to control
worrying, if occurring on a daily basis showed OR of 49.
Trouble relaxing, excessive worry, and being anxious, all
on a daily basis range OR near 25, as shown in Figure 2,
much higher than the 2 to 10 range found in all previous
epidemiological studies.
When choosing the strategy of self-administered
screening and get more information on specific aspects of
psychiatric comorbidities in migraine one may consider the
following tools as shown in Table 2.
Other relevant mental health related aspects
Other mental health aspects are important, not only in
general population and across several cultures but also in
headache patients. Optimism, pessimism, catastrophization,
religiosity/spirituality, traumatic life events need further studies
on how they are related to symptoms, psychiatric diagnosis
and their influence in migraine management.
Treatment challenges
After choosing the ideal approach according to the
setting of headache provider, and getting a correct diagnosis,
treatment challenges arise.
Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018 65
One of the main issues in migraine management is
medication overuse. Its approach has to be tailored and
therapy choosen according to how medication overuse is
classified. For management purposes is important to stratify
acute medication/analgesic use in headache patients in
five different categories.
First is when daily intake is excessive because headaches
are frequent, analgesic use then is just the consequence of
having frequent headaches, no cause relationship exist.
Second is when acute medication is causing side effects,
such as tachycardia, insomnia, sleepiness, concentration
problems, gastritis, tremor. Third when psychiatric comorbidity
lead migraineurs to be more prone to excessive use, because
of lack of control in anxiety or ADHD(18), or fear of having
a headache(19); fourth when analgesic intake is causing a
headache through rebound; and fifth is when a substance
abuse disorder is present. All topics may occurr together but
has different management approaches (Figure 3).
Psychiatric commorbidity algorithm management
in migraine patients
In Figure 4 we find a symptom-based and diagnostic
approach to psychiatric comorbidity in migraine. As observed
in Figure 1, irritability is part of anxiety, ADHD and bipolar
diagnosis. If it is present in the migraineur one may have to
explore the correct diagnosis, also considering the possibility
of all occurring altogether. Sometimes the definition would
be done in a therapeutic trial. All patients should be given
a nonpharmachological customized prescription, whereas
according to what is present, the pharmachological
regimem should be choosen. Associations of different drug
classes may be needed. Sleep problems could shift toward
a different approach, but this is not being further considered
in this paper.
Many of the medication may cause weight gain, what
can decrease patient stisfaction, reducing adherence, as
well as lead to clinical complications, such as obesity, dia-
betes, hypertension and other. In this case, a specific strategy
should be inserted, with dietary and physical exercise advise
and medications such as topiramate, melatonin or
stimulants.
Expert commentary
I (MFPP) find in my clinical practice the symptom-
based approach a lot more suitable for the management of
psychiatric comorbidity in migraine than the full-blown, DSM
diagnosis approach. When the disorder is severe, diagnosis
MANAGEMENT OF PSYCHIATRIC COMORBIDITIES IN MIGRAINE
Figure 3. Frequent acute medication decision tree.
* Limit analgesic intake may exacerbate anxiety in daily headache patients.
Figure 4. Psychiatric commorbidity algorithm management in migraine patients
* Complete decision tree for anxiety disorders in Figure 5.
** Olanzapine and quetiapine have antidepressant effect and anedoctal efficacy in migraine; *** Lamotrigine is a good choice for bipolar disorder but limited
evidence in migraine prevention; # Amytriptilin needs doses 75 mg or higher for antidepressant efficacy; ## SSRIs such as fluoxetine and sertraline failed
migraine prevention trials, citalopran, escitalopran, paroxetine are better options.
66 Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018
PERES MFP, VALENÇA MM, SILVA-NETO RP.
become easier, but many patients bring only the main
symptom and will not fill out complete diagnostic criteria.
Referring to a psychologist or psychiatrist for a diagnosis
is often difficult, due to availability, timing, and clinical
severity, therefore, the symptom-based approach and the
use of diagnostic self-administered tools speed up patients
management.
The more severe cases are definitely more complex in
psychiatric comorbidity, with more severity and more features
involved, refractory patients are in general not diagnosed
or not well managed in their mental health needs.
Although an evidence-based guideline is ideal, some
caveats from our clinical experience we would like to share,
as this topic allows. Olanzapine is very effective and fast,
may be difficult to manage in long term, because of weight
gain and metabolic consequences, but for initial therapy is
equally effective for severe headaches, severe depression,
refractory insomnia, and anxiety. When patients are stabilized
one may shift to a more long term strategy.
If depression and sleep are the most important aspects,
mirtazapine is one of the most effective antidepressives, being
weight gain limits its use in long term. Escitalopram is in
our experience the most effective of the SSRIs, not only for
depression and anxiety, but also effective for migraine control,
although fluoxetine and sertraline failed migraine prophylaxis
trials, and limited evidence for others SSRIs, escitalopram
has been one of the main options in my clinical practice in
the past 15 years.
For patients with anxiety, sleep problems and migraine,
and some depression (not severe) agomelatine appears to
be a safe option. It is not clear to me yet whether melatonin
could have the same effect.
If ADHD is suspected, don't be affraid of a stimulant
trial, the experience is favorable not only for ADHD symptoms
but also for migraine control.
It gets more complicated when you think the overlap
with depression/bipolar spectrum, anxiety and ADHD
themselves, without considering other pain disorders, other
headache disorders, and migraine headaches.
Five-year view
In this topic, we bring a speculative viewpoint on how
the field will evolve in 5 years time. One view is derived
from what is desireable but other is what actually may
happen if nonpharmaceutical stake holders don't move in
the right direction.
Pharmaceutical companies invest annually 60 billion
US$ in drug discovery, whereas the NIH budget for
medicine is 30 billion. Notwhistandly, 90 billions are spent
in marketing by pharmaceutical companies. Only for
comparison, 600 billion is spent annually in defense.
(20)
Therefore, one may not expect any extreme change in
medical discoveries when 20 times more is spent in war
than in health.
Nowadays innovation in health sciences is not patient
centered. Many effective therapies could be discovered if
investment in psychological, physical, dietary-based
treatments were studied. In addition, pharmachological
options deserving more studies, such as non patent protected
medication (old medications, vitamins, minerals, herbs). But
the reality is that only new drugs with financial return on
investment have the chance to be studied.
The new era of CGRP monoclonal antibody compounds
may bring some insights for the treatment of psychiatric
comorbidity itself or even opening windows in psychiatric
therapy. CGRP is realeased in the bed nucleus of the stria
terminalis, and has been related to reward and anxiety
mechanisms.
(21)
Key issues
1. Psychiatric comorbidity is an important topic in
migraine management
2. Depression has been the most studied topic but
anxiety symptoms have the strongest connection in migraine
patients.
3. The symptom-based approach is usefull approaching
mental health aspects in migraine patients.
4. Generalized anxiety disorder symptoms such as fa-
tigue, irritability, muscle tension, concentration, and sleep
complaints are common issues in migraine patients.
5. Migraine overlaps with anxiety, ADHD, and bipolar
symptoms, irritability connects all.
6. Screening tools addressing specific topics maybe
usefull in psychiatric comorbidity assessment.
Figure 5. Decision tree for the diagnosis of anxiety disorders.
PTSD: Postraumatic stress disorder
OCD: Obsessive-compulsive disorder
GAD: Generalized anxiety disorder
Headache Medicine, v.9, n.2, p.61-67, Apr./May/Jun. 2018 67
7. Frequent acute medication intake may occur in five
different situations: a) increase in intake is just because
headaches are frequente (non-causality), b) acute
medication is causing side effects, c) rebound, d) psychiatric
is predisposing acute medication intake, and e) there is a
substance abuse disorder.
8. Consider also other anxiety diagnosis in migraineus
including PTSD, OCD, panic, and phobias.
9. An algorythm (proposed in this paper) may be followed
in psychiatric comorbidity management in migraine.
REFERENCES
1. Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people
worldwide featuring recent rise: A systematic review and meta-
analysis of community-based studies involving 6 million
participants. J Neurol Sci. 2017 Jan 15;372:307-15.
2. Global Burden of Disease Study C. Global, regional, and
national incidence, prevalence, and years lived with disability
for 301 acute and chronic diseases and injuries in 188
countries, 1990-2013: a systematic analysis for the Global
Burden of Disease Study 2013. Lancet. 2015 Aug 22;386
(9995):743-800.
3. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, Powers S,
Schwedt TJ, Lipton R, et al. Migraine and its psychiatric
comorbidities. J Neurol Neurosurg Psychiatry. 2016 Jul;87(7):
741-9.
4. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart
WF. Migraine, quality of life, and depression: a population-
based case-control study. Neurology. 2000 Sep 12;55(5):
629-35.
5. Pesa J, Lage MJ. The medical costs of migraine and comorbid
anxiety and depression. Headache. 2004 Jun;44(6):562-70.
6. Bigal ME, Lipton RB. Modifiable risk factors for migraine
progression. Headache. 2006 Oct;46(9):1334-43.
7. Smitherman TA, Penzien DB, Maizels M. Anxiety disorders and
migraine intractability and progression. Curr Pain Headache
Rep. 2008 Jun;12(3):224-9.
8. Stinchfield R, McCready J, Turner NE, Jimenez-Murcia S, Petry
NM, Grant J, et al. Reliability, Validity, and Classification
Accuracy of the DSM-5 Diagnostic Criteria for Gambling
Disorder and Comparison to DSM-IV. J Gambl Stud. 2016
Sep;32(3):905-22.
9. Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Ustun
TB, et al. Days out of role due to common physical and mental
conditions: results from the WHO World Mental Health surveys.
Mol Psychiatry. 2011 Dec;16(12):1234-46.
10. Baskin SM, Smitherman TA. Migraine and psychiatric disorders:
comorbidities, mechanisms, and clinical applications. Neurol
Sci. 2009 May;30 Suppl 1:S61-5.
11. Seng EK, Buse DC, Klepper JE, S JM, Grinberg AS, Grosberg
BM, et al. Psychological Factors Associated With Chronic
Migraine and Severe Migraine-Related Disability: An
Observational Study in a Tertiary Headache Center. Headache.
2017 Apr;57(4):593-604.
12. Fornaro M, De Berardis D, De Pasquale C, Indelicato L, Pollice
R, Valchera A, et al. Prevalence and clinical features associated
to bipolar disorder-migraine comorbidity: a systematic review.
Compr Psychiatry. 2015 Jan;56:1-16.
13. Headache Classification Committee of the International
Headache S. The International Classification of Headache
Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;
33(9):629-808.
14. Perugi G, Akiskal HS, Micheli C, Musetti L, Paiano A, Quilici C,
et al. Clinical subtypes of bipolar mixed states: validating a
broader European definition in 143 cases. J Affect Disord. 1997
May;43(3):169-80.
15. Wang HR, Jung YE, Chung SK, Hong J, Ri Kang N, Kim MD, et
al. Prevalence and correlates of bipolar spectrum disorder
comorbid with ADHD features in nonclinical young adults. J
Affect Disord. 2017 Jan 01;207:175-80.
16. Drill R, Nakash O, DeFife JA, Westen D. Assessment of clinical
information: Comparison of the validity of a Structured Clinical
Interview (the SCID) and the Clinical Diagnostic Interview. J Nerv
Ment Dis. 2015 Jun;203(6):459-62.
17. Schmidt U. A plea for symptom-based research in psychiatry.
Eur J Psychotraumatol. 2015;6:27660.
18. Peres MFP, Mercante JPP, Tobo PR, Kamei H, Bigal ME. Anxiety
and depression symptoms and migraine: a symptom-based
approach research. J Headache Pain. 2017 Dec;18(1):37.
19. Peres MF, Mercante JP, Guendler VZ, Corchs F, Bernik MA,
Zukerman E, et al. Cephalalgiaphobia: a possible specific phobia
of illness. J Headache Pain. 2007 Feb;8(1):56-9.
20. Hernandez SE, Conrad DA, Marcus-Smith MS, Reed P, Watts
C. Patient-centered innovation in health care organizations: a
conceptual framework and case study application. Health Care
Manage Rev. 2013 Apr-Jun;38(2):166-75.
21. Gungor NZ, Pare D. CGRP inhibits neurons of the bed nucleus
of the stria terminalis: implications for the regulation of fear
and anxiety. J Neurosci. 2014 Jan 01;34(1):60-5.
Correspondence
Mario Fernando Prieto Peres, MD, PhD
R Joaquim Eugenio de Lima, 881 cj 709
01403-001, São Paulo, Brazil
+55 11 3285-5726
mariop3r3s@gmail.com
Received: June 22, 2018
Accepted: June 24, 2018
MANAGEMENT OF PSYCHIATRIC COMORBIDITIES IN MIGRAINE
