NEUROL-2485; No.

of Pages 6

revue neurologique xxx (2021) xxx–xxx

Available online at

ScienceDirect
www.sciencedirect.com

International meeting of the French society of neurology 2021

What is the link between migraine and psychiatric

disorders? From epidemiology to therapeutics

F. Radat
Cabinet medical, 107, rue Judaı̈que, 33000 Bordeaux, France

info article abstract

Article history: The association between migraine and psychiatric disorders is well documented through
Received 1st June 2021 numerous population-based studies. The results of these studies are coherent and show an
Received in revised form increased risk of suffering from depression, bipolar disorders, numerous anxiety disorders,
4 July 2021 especially post-traumatic stress disorder. This raises the question of stress as a precipitating
Accepted 6 July 2021 factor for migraine illness. Psychiatric comorbidity is even more frequent in chronic
Available online xxx migraine than in episodic migraine patients. Many prospective studies have shown that
psychiatric comorbidity could be considered as a risk factor for migraine chronicization.
Keywords: Psychiatric comorbidity is also responsible for an increase of the frequency of anti-migraine
Comorbidity drug intake, a worsening of quality of life and a worsening of functional impairment. It is
Migraine also responsible for an increase in the direct and indirect costs of migraine. The reason why
Psychiatric disorder psychiatric comorbidity is so high in migraineurs is not unambiguous. Multiple causal
Anxiety relationships and common etiological factors are linked. Recently, genome-wide association
Depression studies gave leads to a genetic common heritability between major depressive disorder and
Stress migraine. For clinicians, an important topic remains how to treat migraineurs with psy-
chiatric comorbidity. These patients suffer frequently from severe migraine or refractory
migraine. Antidepressant and anti-convulsive drugs can be useful, as well as psychological
therapies. But moreover, it is of utmost importance to propose an integrated multidisci-
plinary approach to these difficult patients.
# 2021 Elsevier Masson SAS. All rights reserved.

[2]. Psychiatric comorbidity is one of many factors contributing

1. Introduction
Migraine headache affects seven million people in France with
a prevalence of 12% in adults [1]. Women pay the heaviest
price as they are three times more impacted. Migraine can be
quite a benign affliction as well as a very burdensome one,
depending on the frequency of the attacks and on their
debilitating impact. The notion of severe migraine arose
recently with regard to patients very disabled by their illness
to this phenomenon, as it is associated with an increase in
the frequency of days with headache, with an increase of
disability, with a decrease in the quality of life. . .. It is of utmost
importance to point this out, as direct and indirect costs due to
chronic migraine patients are 4.4-fold greater than the costs
due to episodic migraine patients [3]. On their side, psychiatric
disorders are among the most debilitating afflictions and
are sometimes associated with disappointing treatment
outcomes.

E-mail address: francoise.radat@gmail.com.

https://doi.org/10.1016/j.neurol.2021.07.007
0035-3787/# 2021 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Radat F. What is the link between migraine and psychiatric disorders? From epidemiology to therapeutics.
Revue neurologique (2021), https://doi.org/10.1016/j.neurol.2021.07.007
NEUROL-2485; No. of Pages 6
2 revue neurologique xxx (2021) xxx–xxx
So, after summarizing the literature dealing with migraine
and psychiatric comorbidity, we will now focus on the
consequences of such an association, summarize literature
dealing with the cause of this comorbidity, and then conclude
with the therapeutic implications.
2. Comorbidity between migraine and
emotional disorders
Clinicians have long noticed the association between
migraine and psychiatric comorbidity but it was in the
nineties that epidemiological studies with strong methodo-
logy arose, mostly in the United States, followed some years
later by others in Europe. All these studies were set up in large
population-based samples and they used validated diagnostic
criteria now possible with the use of the International
Classification of Headache Disorders (ICHD) criteria for
migraine [4] and DSM criteria for psychiatric disorders [5].
Results of all these studies were remarkably coherent and
showed an increased risk of suffering from major depressive
disorder, bipolar disorder, all anxiety disorders, suicide risk
and substance related disorders [6].
2.1. Depression
Depression is the psychiatric comorbidity that has been the
most studied and highlighted and it appears from the
literature that the risk of suffering from depression is two
to four times higher in migraineurs than in non-migraine
subjects from general population [7–22]. From a clinical point
of view, it is not always easy to flush out depressive symptoms
in patients that sometimes prefer to hide them, fearing that
their illness will be blamed on psychiatry. The practitioner can
use a well-validated rating scale (Hospital Depression Anxiety
Scale) [23] and must actively look at anhedonia and hope-
lessness. Negative cognitions are frequently related to pain,
leading to catastrophizing [24].
2.2. Anxiety
Concerning anxiety disorders, a recent systematic review of
eight cross-sectional studies from primary care or tertiary care
centers allowed their authors to show that there is a strong
and consistent co-morbidity between migraine and anxiety,
with an average odds ratio (OR) of 2.33 (2.20–2.47) [25]. In the
previous population-based studies, ORs showed the risk of
suffering from panic disorder, phobia, generalized anxiety
disorders and post-traumatic stress disorders being three to
five times higher in migraineurs than in non-migraineurs
[7,8,11–13,15,22,26,27]. One particularity of anxiety in migrai-
neurs is the anticipatory fear of precipitating factors leading
some patients to increase avoidance behaviors. Those types of
behaviors have been called cephalalgiaphobia [28].
2.3. Stress
Stress is not a psychiatric disorder so, to be rigorous, it should
not be considered in this review. Nevertheless, stress has
always been considered retrospectively by a large proportion
Please cite this article in press as: Radat F. What is the link between migraine and psychiatric disorders? From epidemiology to therapeutics.
Revue neurologique (2021), https://doi.org/10.1016/j.neurol.2021.07.007
of migraineurs as a major, even the most important attack
trigger [29–33]. A recent prospective study, measuring daily-
perceived stress during 90 days, and recording the occurrence
of attacks in 351 migraineurs, distinguished various patterns
of relationship between stress and attack occurrence [34]. On
an aggregate level, perceived stress peaked during the pain
phase of the migraine cycle. Several retrospective studies have
shown that stress during childhood, and more specifically
physical, sexual and psychological abuse during childhood, is
linked to an increase in the risk of suffering from migraine
[35,36]. These results have been confirmed prospectively,
suggesting a causal relationship [36]. The link between stress
and migraine attacks can be due to several neurophysiological
pathways. Therein, orexins and hypothalamic neuropeptides
represent a promising lead for research since they play a role
in the earliest stages of migraine attacks [37] and are involved
in the stress response [38].
It also should be noted that National Comorbidity Survey
Replication data show that posttraumatic stress disorder
(PTSD) and migraine are frequently associated (OR = 5.39,
95%CI: 3.47–8.37) [27,39].
2.4. Bipolar disorders
Finally, a recent systematic review of the studies focusing on
comorbidity between bipolar disorders and migraine allowed
some conclusions [40]. Among the 11 studies included, the
mean prevalence rate for migraine headache among bipolar
disorder patients was 30.7% whereas the mean prevalence of
bipolar sufferers was 9% in clinical samples and 5% in
population-based samples of migraineurs. The association
was stronger in women and for bipolar II subtype illness.
Nguyen [20], in another review, states that migraine should be
considered as a severity marker in bipolar patients as they are
most often rapid cyclers, suffering from more severe depres-
sive episodes and comorbid anxiety, having a higher risk to
commit suicide. Migraine shares with bipolar disorder a lot of
pathophysiological characteristics: an evolution by attacks,
the sensitization phenomenon leading to clinical worsening,
the implication of inflammatory mediators, the prophylactic
implication of anti-comitial treatments. Although the neuro-
biology of both disorders is complex, they are thought to share
a common pathophysiology involving dysfunction of calcium
channels.
It must be highlighted that migraine with aura patients
have a higher risk of psychiatric comorbidity than migraine
without aura patients. Moreover, they exhibit white matter
modifications not found in patients without comorbidity,
suggesting the existence of two distinct clinical phenotypes
[41].
3. Consequences of psychiatric comorbidity
on migraine illness
3.1. Chronicization of migraine
An impressive number of large population-based studies have
contributed to the understanding of the deleterious effect that
psychiatric comorbidity has on migraine illness. Many studies
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showed that psychiatric comorbidity is associated with more
frequent attacks and more medication intake [42]. This can
be associated with the fact that psychiatric comorbidity has
always been found to be higher in chronic migraine,
transformed migraine and medication overuse headaches
derived from migraine than in episodic migraine [6,22,43,44]
irrespective of whether studies have been located in the
United States (AMPP Study) or Europe (Eurolight Study). This
raises the question of the causality of psychiatric comorbidity
in the chronicization of migraine. This question must be
answered by prospective studies. Two large-scale North
American prospective studies showed a chronological link
between psychiatric comorbidity, specifically depression, and
chronicization of migraine. (AMPP Study, [44], CaMEO Study,
[45]). In a systematic review, Xu et al. identified 13 longitudinal
cohort studies in order to examine migraine progression risk
factors [46]. The data supports increased headache day
frequency, acute medication overuse/high-frequency use
and depression as major risk factors. Asthma, snoring,
anxiety, obesity, also play their part, leading to a persistent
activation of the trigemino-vascular system, associated with
central sensitization and leading to chronicization.
3.2. Worsening of quality of life
In 2005, the FRAMIG 3 study showed that MIDAS scores,
measuring disability, were lower in migraine subjects without
anxiety or depression than in those with anxiety or depression
alone. Subjects with anxiety and depression had the highest
MIDAS scores. The reverse phenomenon could be observed
with the scores of quality of life (SF 12) [47].
The American Registry for Migraine Research study
showed that the severity of depression symptoms in patients
with migraine is associated with migraine-related disability,
work interference, pain interference, and reduced career
success. Patients with more severe symptoms of depression
are more likely to have greater functional impairment [48]. The
Eurolight project highlighted an interesting point, which was
the interictal burden. It involves anticipatory anxiety, avoi-
dance of supposed precipitant factors, feeling of being not
understood, but also being less well educated because of the
headaches, reduced earnings because of a career that had
suffered. Lost productive time was associated with high ORs
(up to 5.3) of anxiety and avoidance [49]. In the same way, it
has been shown that psychiatric comorbidity is an aggravating
factor of the socio-economic deprivation effect due to
migraine [50].
4. Comorbidity between migraine and
substance-related disorders
4.1. Epidemiology
While the association between migraine and substance use
disorder has been demonstrated by prior epidemiological
studies [8,51], the association between migraine and substance
abuse was no longer statistically significant in the analysis of
the National Comorbidity Survey Replication data when
adjusting for depression, and PTSD confounders [27]. However,
Please cite this article in press as: Radat F. What is the link between migraine and psychiatric disorders? From epidemiology to therapeutics.
Revue neurologique (2021), https://doi.org/10.1016/j.neurol.2021.07.007
3
it has been shown that 19% of opioid-dependent patients
started opioids because of headache [52]. In parallel, results of
the AMPP study showed that nearly 14% of a sample of 5,796
migraineurs from the general population were previous opioid
users, whereas nearly 16% were current opioid users among
whom 16.6% met criteria for dependence [53].
4.2. Substance-related disorders in medication overuse
headache deriving from migraine
This leads to the following question: do some patients with
medication overuse headache deriving from migraine also
present addictive behavior? It has been addressed by several
authors [54,55]. All of them found that two-thirds of medica-
tion overuse headache patient samples fulfilled DSMIV criteria
for dependence. The major symptoms exhibited by these
patients are: compulsive drug seeking behaviors despite the
knowledge of harmful consequences, headache anticipatory
anxiety, obsessional drug taking and last but not least,
unsuccessful efforts to control medication use (craving). The
Severity Dependence Scale has been proposed in order to
assess behavioral dependence in migraine patients with
medication overuse. It is an easy to use five-item question-
naire [56]. This author showed that a high dependency score
allows detection of headache subjects with medication
overuse, with a maximum sensitivity and sensibility score
above 5 for this prediction.
5. Explaining comorbidity
Two basic mechanisms can explain comorbidity:
 a causal factor causing a unidirectional relationship
between migraine and psychiatric comorbidity;
 a common shared etiological factor explaining the co-
occurrence of both syndromes without a causal association
between them.
5.1. Causal relationship
In the first case, we can consider that repeated and intense
pain leads to anticipatory anxiety, perceived loss of control,
and finally depression [57], in other words, that repeated pain
is a risk factor for anxiety and depression, and that the
association is mediated by cognitive and behavioral variables
such as catastrophizing and fear/avoidance [58]. In case of a
causal relationship between migraine and emotional dis-
orders, a specific order of onset between each condition
should be demonstrated, migraine preceding depression and
not the reverse. On the contrary available data demonstrates
bidirectional relationship between migraine and emotional
disorders [10], suggesting that a common etiological factor can
be questioned [59].
5.2. Common etiological factor
A common etiological risk factor between migraine and
psychiatric disorders can be environmental, i.e. early stress
and abuse [35], biological, i.e. serotoninergic dysfunction [60],
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hypothalamic-pituitary-adrenal axis hyperactivity and
inflammation [61,62], hormonal influence [63], abnormal brain
development [38] or brain activity [64] and finally, it can be
genetic.
Both psychiatric disorders and migraine are heritable, and
both conditions have a polygenic background [65]. Twin studies
suggest that about 20% of the variability in depression and
migraine headaches are due to shared genes [65,66]. Candidate
gene association studies (CGAS) have been numerous. Candi-
date genes were selected based on their known biological
function and their potential to integrate with current theories
of pathophysiology, i.e. serotonin and dopamine dysfunction,
folate metabolism, GABAergic system and growth factor
activity [67]. But this approach increases the chance of
generating both false positive and false negative results.
Genome-wide association studies (GWAS) have proven to be
a powerful approach for detecting common variants associated
with complex diseases. A large GWAS study, the Brainstorm
Consortium study, indicated that migraine was correlated to
several psychiatric disorders, including attention deficit hyper-
activity disorder and major depressive disorder [68]. This
concurs with a recent Australian study specifically searching
for a shared genetic background for depression and migraine
[69]. Pathway analyses suggested several important pathways,
especially neural-related pathways of signaling and ion
channel regulation to be involved in this shared etiology [69].
6. Treatment considerations for migraineurs
with psychiatric comorbidity
6.1. 5.1 Pharmacological treatment
Migraine patients with comorbidity, and above all severe
migraine patients with comorbidity should be treated in
association with a psychiatrist. It is hard to determine if
patients with comorbidity must be treated with medication
addressing both disorders at the same time or if each
disorder should be treated separately. As antidepressants
are commonly used for migraine prevention it might be
tempting to consider this option for migraineurs with anxiety
and depression. Nevertheless, tricyclic antidepressants are
the only class of antidepressants with strong efficacy evidence
in migraine. There is some recent and limited evidence for the
efficacy of two serotonin-adrenaline reuptake inhibitors:
venlafaxine and duloxetine, whereas selective serotonin
reuptake inhibitors are known to be ineffective in migraine
prevention [70,71]. Clinicians must be aware that tricyclic
antidepressants present quite a lot of adverse effects (seda-
tion, constipation, hypotension, weight gain). But the more
important pitfall, when using tricyclic antidepressant or
serotonin-adrenalin reuptake inhibitors could be to induce
mania and worsen the evolutive course of an unrecognized
bipolar disorder [72]. Other migraine preventive treatments
can potentially worsen patients’ psychiatric comorbidities,
e.g. topiramate can affect mood [73]. The data about a
potential association between b-blockers and depression are
controversial and limited [73]. When a bipolar illness is
suspected, sodium valproate or lamotrigine should be pre-
ferred [74].
Please cite this article in press as: Radat F. What is the link between migraine and psychiatric disorders? From epidemiology to therapeutics.
Revue neurologique (2021), https://doi.org/10.1016/j.neurol.2021.07.007
6.2. Psychological treatment
Surprisingly, in a recent Cochrane meta-analysis [75],
psychological therapies did not show long-term efficacy
for migraine prophylaxis in adults nor did they improve
medication usage, migraine-related disability or quality of
life. The authors highlight the low methodological quality
of the studies. Meanwhile clinicians are used to resorting
to psychological therapies for patients with a high stress-
exposure and an inability to cope with stress, for patients
with psychiatric comorbidity and for patients with high
frequency anti-migraine drugs intake. In these cases,
psychological therapies are supposed to reduce catastro-
phizing and fear of pain and to improve self-efficacy. All of
this can lead to a decrease in disability and an increase in
quality of life, and finally a lessening of the illness as a whole.
This empirical clinical approach is supported by two other
meta-analyses [76,77] showing results conflicting with
the previous one. It is also worth noting that recently, the
range of psychological treatments that can be offered to
migraineurs is far more diversified than before: in addition
to classical relaxation therapies, biofeedback therapies and
behavioral-cognitive therapies, mindfulness and other
forms of meditative practices such as yoga can now be
offered. Hypnosis, eye movement desensitization repro-
cessing (EMDR) have also been proposed, however none of
these show real evidence of efficacy in migraine prophylaxis
[78].
6.3. Integrated interventions
Thus, an interesting point is the notion of integrated
multidisciplinary intervention which can integrate these
therapies in a whole package with a pharmacological
medication creating a multidimensional treatment. Most of
the time these integrative interventions also include thera-
peutic education [79].
7. Conclusion
To conclude, it must be highlighted that psychiatric comorbi-
dity in migraine is not an ancillary topic. The epidemiological
data clearly shows that a vast sample of migraine patients are
concerned. Practitioners should systematically screen for
affective disorders (depression and bipolar disorders), anxiety
disorders and substance-related disorders, all the more in
patients suffering from severe and resistant migraine. Indeed,
one of the major consequences of psychiatric comorbidity in
migraine is the worsening of the course of the illness, with the
risk of chronicization.
A lot of questions remain unanswered. What are the
mechanisms explaining such comorbidity between psychia-
tric disorders and migraine? How should patients frequently
resistant to prophylactic medications be treated? Even now,
we clearly lack the rigorous studies and algorithms for those
patients needing integrated multidisciplinary interventions.
Severe and resistant migraine patients with psychiatric
comorbidity must be considered for more therapeutic
research.
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Disclosure of interest
FR participated in Novartis Scientific Committee and received
honoraria from Lilly France.
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