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Available online at

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

E-mail address: [email protected].

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

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So, after summarizing the literature dealing with migraine of migraineurs as a major, even the most important attack
and psychiatric comorbidity, we will now focus on the trigger [29–33]. A recent prospective study, measuring daily-
consequences of such an association, summarize literature perceived stress during 90 days, and recording the occurrence
dealing with the cause of this comorbidity, and then conclude of attacks in 351 migraineurs, distinguished various patterns
with the therapeutic implications. 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
2. Comorbidity between migraine and shown that stress during childhood, and more specifically
emotional disorders physical, sexual and psychological abuse during childhood, is
linked to an increase in the risk of suffering from migraine
Clinicians have long noticed the association between [35,36]. These results have been confirmed prospectively,
migraine and psychiatric comorbidity but it was in the suggesting a causal relationship [36]. The link between stress
nineties that epidemiological studies with strong methodo- and migraine attacks can be due to several neurophysiological
logy arose, mostly in the United States, followed some years pathways. Therein, orexins and hypothalamic neuropeptides
later by others in Europe. All these studies were set up in large represent a promising lead for research since they play a role
population-based samples and they used validated diagnostic in the earliest stages of migraine attacks [37] and are involved
criteria now possible with the use of the International in the stress response [38].
Classification of Headache Disorders (ICHD) criteria for It also should be noted that National Comorbidity Survey
migraine [4] and DSM criteria for psychiatric disorders [5]. Replication data show that posttraumatic stress disorder
Results of all these studies were remarkably coherent and (PTSD) and migraine are frequently associated (OR = 5.39,
showed an increased risk of suffering from major depressive 95%CI: 3.47–8.37) [27,39].
disorder, bipolar disorder, all anxiety disorders, suicide risk
and substance related disorders [6]. 2.4. Bipolar disorders

2.1. Depression Finally, a recent systematic review of the studies focusing on

comorbidity between bipolar disorders and migraine allowed
Depression is the psychiatric comorbidity that has been the some conclusions [40]. Among the 11 studies included, the
most studied and highlighted and it appears from the mean prevalence rate for migraine headache among bipolar
literature that the risk of suffering from depression is two disorder patients was 30.7% whereas the mean prevalence of
to four times higher in migraineurs than in non-migraine bipolar sufferers was 9% in clinical samples and 5% in
subjects from general population [7–22]. From a clinical point population-based samples of migraineurs. The association
of view, it is not always easy to flush out depressive symptoms was stronger in women and for bipolar II subtype illness.
in patients that sometimes prefer to hide them, fearing that Nguyen [20], in another review, states that migraine should be
their illness will be blamed on psychiatry. The practitioner can considered as a severity marker in bipolar patients as they are
use a well-validated rating scale (Hospital Depression Anxiety most often rapid cyclers, suffering from more severe depres-
Scale) [23] and must actively look at anhedonia and hope- sive episodes and comorbid anxiety, having a higher risk to
lessness. Negative cognitions are frequently related to pain, commit suicide. Migraine shares with bipolar disorder a lot of
leading to catastrophizing [24]. pathophysiological characteristics: an evolution by attacks,
the sensitization phenomenon leading to clinical worsening,
2.2. Anxiety the implication of inflammatory mediators, the prophylactic
implication of anti-comitial treatments. Although the neuro-
Concerning anxiety disorders, a recent systematic review of biology of both disorders is complex, they are thought to share
eight cross-sectional studies from primary care or tertiary care a common pathophysiology involving dysfunction of calcium
centers allowed their authors to show that there is a strong channels.
and consistent co-morbidity between migraine and anxiety, It must be highlighted that migraine with aura patients
with an average odds ratio (OR) of 2.33 (2.20–2.47) [25]. In the have a higher risk of psychiatric comorbidity than migraine
previous population-based studies, ORs showed the risk of without aura patients. Moreover, they exhibit white matter
suffering from panic disorder, phobia, generalized anxiety modifications not found in patients without comorbidity,
disorders and post-traumatic stress disorders being three to suggesting the existence of two distinct clinical phenotypes
five times higher in migraineurs than in non-migraineurs [41].
[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 3. Consequences of psychiatric comorbidity
behaviors have been called cephalalgiaphobia [28]. on migraine illness

2.3. Stress 3.1. Chronicization of migraine

Stress is not a psychiatric disorder so, to be rigorous, it should An impressive number of large population-based studies have
not be considered in this review. Nevertheless, stress has contributed to the understanding of the deleterious effect that
always been considered retrospectively by a large proportion psychiatric comorbidity has on migraine illness. Many studies

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showed that psychiatric comorbidity is associated with more it has been shown that 19% of opioid-dependent patients
frequent attacks and more medication intake [42]. This can started opioids because of headache [52]. In parallel, results of
be associated with the fact that psychiatric comorbidity has the AMPP study showed that nearly 14% of a sample of 5,796
always been found to be higher in chronic migraine, migraineurs from the general population were previous opioid
transformed migraine and medication overuse headaches users, whereas nearly 16% were current opioid users among
derived from migraine than in episodic migraine [6,22,43,44] whom 16.6% met criteria for dependence [53].
irrespective of whether studies have been located in the
United States (AMPP Study) or Europe (Eurolight Study). This 4.2. Substance-related disorders in medication overuse
raises the question of the causality of psychiatric comorbidity headache deriving from migraine
in the chronicization of migraine. This question must be
answered by prospective studies. Two large-scale North This leads to the following question: do some patients with
American prospective studies showed a chronological link medication overuse headache deriving from migraine also
between psychiatric comorbidity, specifically depression, and present addictive behavior? It has been addressed by several
chronicization of migraine. (AMPP Study, [44], CaMEO Study, authors [54,55]. All of them found that two-thirds of medica-
[45]). In a systematic review, Xu et al. identified 13 longitudinal tion overuse headache patient samples fulfilled DSMIV criteria
cohort studies in order to examine migraine progression risk for dependence. The major symptoms exhibited by these
factors [46]. The data supports increased headache day patients are: compulsive drug seeking behaviors despite the
frequency, acute medication overuse/high-frequency use knowledge of harmful consequences, headache anticipatory
and depression as major risk factors. Asthma, snoring, anxiety, obsessional drug taking and last but not least,
anxiety, obesity, also play their part, leading to a persistent unsuccessful efforts to control medication use (craving). The
activation of the trigemino-vascular system, associated with Severity Dependence Scale has been proposed in order to
central sensitization and leading to chronicization. assess behavioral dependence in migraine patients with
medication overuse. It is an easy to use five-item question-
3.2. Worsening of quality of life naire [56]. This author showed that a high dependency score
allows detection of headache subjects with medication
In 2005, the FRAMIG 3 study showed that MIDAS scores, overuse, with a maximum sensitivity and sensibility score
measuring disability, were lower in migraine subjects without above 5 for this prediction.
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 5. Explaining comorbidity
with the scores of quality of life (SF 12) [47].
The American Registry for Migraine Research study Two basic mechanisms can explain comorbidity:
showed that the severity of depression symptoms in patients
with migraine is associated with migraine-related disability,  a causal factor causing a unidirectional relationship
work interference, pain interference, and reduced career between migraine and psychiatric comorbidity;
success. Patients with more severe symptoms of depression  a common shared etiological factor explaining the co-
are more likely to have greater functional impairment [48]. The occurrence of both syndromes without a causal association
Eurolight project highlighted an interesting point, which was between them.
the interictal burden. It involves anticipatory anxiety, avoi-
dance of supposed precipitant factors, feeling of being not 5.1. Causal relationship
understood, but also being less well educated because of the
headaches, reduced earnings because of a career that had In the first case, we can consider that repeated and intense
suffered. Lost productive time was associated with high ORs pain leads to anticipatory anxiety, perceived loss of control,
(up to 5.3) of anxiety and avoidance [49]. In the same way, it and finally depression [57], in other words, that repeated pain
has been shown that psychiatric comorbidity is an aggravating is a risk factor for anxiety and depression, and that the
factor of the socio-economic deprivation effect due to association is mediated by cognitive and behavioral variables
migraine [50]. 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
4. Comorbidity between migraine and should be demonstrated, migraine preceding depression and
substance-related disorders not the reverse. On the contrary available data demonstrates
bidirectional relationship between migraine and emotional
4.1. Epidemiology disorders [10], suggesting that a common etiological factor can
be questioned [59].
While the association between migraine and substance use
disorder has been demonstrated by prior epidemiological 5.2. Common etiological factor
studies [8,51], the association between migraine and substance
abuse was no longer statistically significant in the analysis of A common etiological risk factor between migraine and
the National Comorbidity Survey Replication data when psychiatric disorders can be environmental, i.e. early stress
adjusting for depression, and PTSD confounders [27]. However, and abuse [35], biological, i.e. serotoninergic dysfunction [60],

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hypothalamic-pituitary-adrenal axis hyperactivity and 6.2. Psychological treatment

inflammation [61,62], hormonal influence [63], abnormal brain
development [38] or brain activity [64] and finally, it can be Surprisingly, in a recent Cochrane meta-analysis [75],
genetic. psychological therapies did not show long-term efficacy
Both psychiatric disorders and migraine are heritable, and for migraine prophylaxis in adults nor did they improve
both conditions have a polygenic background [65]. Twin studies medication usage, migraine-related disability or quality of
suggest that about 20% of the variability in depression and life. The authors highlight the low methodological quality
migraine headaches are due to shared genes [65,66]. Candidate of the studies. Meanwhile clinicians are used to resorting
gene association studies (CGAS) have been numerous. Candi- to psychological therapies for patients with a high stress-
date genes were selected based on their known biological exposure and an inability to cope with stress, for patients
function and their potential to integrate with current theories with psychiatric comorbidity and for patients with high
of pathophysiology, i.e. serotonin and dopamine dysfunction, frequency anti-migraine drugs intake. In these cases,
folate metabolism, GABAergic system and growth factor psychological therapies are supposed to reduce catastro-
activity [67]. But this approach increases the chance of phizing and fear of pain and to improve self-efficacy. All of
generating both false positive and false negative results. this can lead to a decrease in disability and an increase in
Genome-wide association studies (GWAS) have proven to be quality of life, and finally a lessening of the illness as a whole.
a powerful approach for detecting common variants associated This empirical clinical approach is supported by two other
with complex diseases. A large GWAS study, the Brainstorm meta-analyses [76,77] showing results conflicting with
Consortium study, indicated that migraine was correlated to the previous one. It is also worth noting that recently, the
several psychiatric disorders, including attention deficit hyper- range of psychological treatments that can be offered to
activity disorder and major depressive disorder [68]. This migraineurs is far more diversified than before: in addition
concurs with a recent Australian study specifically searching to classical relaxation therapies, biofeedback therapies and
for a shared genetic background for depression and migraine behavioral-cognitive therapies, mindfulness and other
[69]. Pathway analyses suggested several important pathways, forms of meditative practices such as yoga can now be
especially neural-related pathways of signaling and ion offered. Hypnosis, eye movement desensitization repro-
channel regulation to be involved in this shared etiology [69]. cessing (EMDR) have also been proposed, however none of
these show real evidence of efficacy in migraine prophylaxis
[78].
6. Treatment considerations for migraineurs
with psychiatric comorbidity 6.3. Integrated interventions

6.1. 5.1 Pharmacological treatment Thus, an interesting point is the notion of integrated
multidisciplinary intervention which can integrate these
Migraine patients with comorbidity, and above all severe therapies in a whole package with a pharmacological
migraine patients with comorbidity should be treated in medication creating a multidimensional treatment. Most of
association with a psychiatrist. It is hard to determine if the time these integrative interventions also include thera-
patients with comorbidity must be treated with medication peutic education [79].
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 7. Conclusion
tempting to consider this option for migraineurs with anxiety
and depression. Nevertheless, tricyclic antidepressants are To conclude, it must be highlighted that psychiatric comorbi-
the only class of antidepressants with strong efficacy evidence dity in migraine is not an ancillary topic. The epidemiological
in migraine. There is some recent and limited evidence for the data clearly shows that a vast sample of migraine patients are
efficacy of two serotonin-adrenaline reuptake inhibitors: concerned. Practitioners should systematically screen for
venlafaxine and duloxetine, whereas selective serotonin affective disorders (depression and bipolar disorders), anxiety
reuptake inhibitors are known to be ineffective in migraine disorders and substance-related disorders, all the more in
prevention [70,71]. Clinicians must be aware that tricyclic patients suffering from severe and resistant migraine. Indeed,
antidepressants present quite a lot of adverse effects (seda- one of the major consequences of psychiatric comorbidity in
tion, constipation, hypotension, weight gain). But the more migraine is the worsening of the course of the illness, with the
important pitfall, when using tricyclic antidepressant or risk of chronicization.
serotonin-adrenalin reuptake inhibitors could be to induce A lot of questions remain unanswered. What are the
mania and worsen the evolutive course of an unrecognized mechanisms explaining such comorbidity between psychia-
bipolar disorder [72]. Other migraine preventive treatments tric disorders and migraine? How should patients frequently
can potentially worsen patients’ psychiatric comorbidities, resistant to prophylactic medications be treated? Even now,
e.g. topiramate can affect mood [73]. The data about a we clearly lack the rigorous studies and algorithms for those
potential association between b-blockers and depression are patients needing integrated multidisciplinary interventions.
controversial and limited [73]. When a bipolar illness is Severe and resistant migraine patients with psychiatric
suspected, sodium valproate or lamotrigine should be pre- comorbidity must be considered for more therapeutic
ferred [74]. research.

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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