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Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications

The Journal of Headache and Pain volume 20, Article number: 51 (2019) Cite this article

Abstract

Background

Migraine is a highly prevalent and disabling neurological disorder which is commonly linked with a broad range of psychiatric comorbidities, especially among subjects with migraine with aura or chronic migraine. Defining the exact nature of the association between migraine and psychiatric disorders and bringing out the pathophysiological mechanisms underlying the comorbidity with psychiatric conditions are relevant issues in the clinical practice.

Methods

A systematic review of the most relevant studies about migraine and psychiatric comorbidity was performed using “PubMed”, “Scopus”, and “ScienceDirect” electronic databases from 1 January 1998 to 15 July 2018. Overall, 178 studies met our inclusion criteria and were included in the current review.

Results

According to the most relevant findings of our overview, the associations with psychiatric comorbidities are complex, with a bidirectional association of major depression and panic disorder with migraine. Importantly, optimizing the pharmacological and non-pharmacological treatment of either migraine or its psychiatric comorbidities might help clinicians to attenuate the burden of both these conditions.

Conclusions

The available data highlight the need for a comprehensive evaluation of psychiatric disorders in migraine in order to promote an integrated model of care and carefully address the burden and psychosocial impairment related to psychiatric comorbidities in migraine.

Background

Both migraine and psychiatric disorders are prevalent and burdensome conditions challenging the health care systems worldwide [1,2,3,4,5]. These conditions show a large overlap [6, 7] and epidemiological studies suggest that patients with migraine – especially those with chronic migraine (CM) and migraine with aura – are at increased risk for major depression, anxiety, or suicidal behavior when compared to subjects without migraine (e.g., [8,9,10]). Besides, according to a recent large genome-wide association study, when compared to other neurological disorders, migraine showed a higher genetic correlation with psychiatric disorders suggesting common genetic bases or pathways [11]. The comorbidity between migraine and psychiatric disorders is highly relevant in the clinical practice, as it might influence both the response to treatment and likelihood to achieve remission [6]. Therefore, an interdisciplinary approach using pharmacological and non-pharmacological treatment strategies aimed to manage both migraine and comorbid psychiatric disorder is essential.

The comorbidity between migraine and psychiatric disorders presumably implies multiple causes, including either unidirectional causal explanations, but even shared environmental and/or genetic risk factors, and their interaction at multiple levels [12]. All the mentioned aspects need to be carefully considered regarding the diagnostic and therapeutic implications related to migraine comorbidity.

This systematic review will provide an updated and comprehensive overview of the current literature focusing on the comorbidity of migraine with depression, bipolar disorder (BD), anxiety disorders, post-traumatic stress disorder (PTSD), and other psychiatric disorders, including personality, substance use, and somatoform disorders, outlining the general findings, potential mechanisms of association, and implications for migraine treatment.

Materials and methods

To achieve a high standard of reporting, we selected the most relevant studies in accordance with the PRISMA guidelines [13]. We included observational studies that explicitly and clearly report the adopted definitions of migraine and its psychiatric comorbidities; we also included clinical trials, open label studies, systematic reviews, guidelines, commentaries, editorials, and letters to editors focusing on the review topic. When a title/abstract appeared to describe a study eligible for inclusion, the full-text article was carefully analyzed to evaluate its relevance for our systematic review. Eligible papers had to be written in English and published from 1 January 1998 to 15 July 2018 on the following 3 major electronic databases: PubMed, Scopus, or ScienceDirect. The following search string was used in all databases: (“Headache” OR “migraine”) AND “comorbidity” AND (“psychiatric disorders” OR “substance abuse” OR “personality disorders” OR “major affective disorders” OR “bipolar disorder” OR “unipolar disorders” OR “psychotic disorders” OR “psychoses” OR “suicid*” OR “anxiety” OR “schizophrenia” OR “depression”). The reference lists of the retrieved articles were also screened to find eligible studies not covered by the above-mentioned search string. Two Reviewers (MP and GSf) conducted the literature search and independently screened titles and abstracts; later, they retrieved and selected full-text articles. Disagreements among these two Reviewers were solved by consensus. The relevant steps and main results of the literature search are shown in Fig. 1.

Fig. 1
figure 1

Flowchart of study selection. Figure 1 includes all the relevant steps and main results of the literature search upon the main topic. The most relevant studies have been selected in accordance with the PRISMA guidelines. Specifically, observational studies, clinical trials, open label studies, systematic reviews, guidelines, commentaries, editorials, and letters to editors focusing on the review topic were included

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Major depression

Major depressive episodes are characterized by periods of at least two weeks with symptoms including depressed or irritable mood, decreased interest or pleasure in most activities, significant weight change, change in sleep (insomnia or hypersomnia), change in activity (psychomotor agitation or retardation), fatigue or loss of energy, guilt/worthlessness, diminished ability to think or concentrate or more indecisiveness, and suicidality [14].

Depression is almost twice as frequent in patients with migraine when compared to the general population. The prevalence estimates in migraine vary across countries, from 6.1% to 73.7% (e.g., [15,16,17]) while the prevalence odds ratios vary from 0.8 to 5.8 (see Table 1). Such differences may be mainly due to different sex, age, and ethnic composition of study samples, as well as from different psychometric instruments aimed to assess migraine and depression [18]. Comorbid major depression is linked to more frequent and disabling headache [19]. Notably, the risk of suicide attempts is particularly higher in migraine patients with comorbid anxiety and depressive symptoms [20].

Table 1 Quantitative association between migraine and psychiatric comorbidities in observational studies. Studies reporting the proportions of comorbidities (first column) may not coincide with those reporting the effect sizes of associations (fourth column)
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Mechanisms potentially involved in the comorbidity

Given the potential explanations of the comorbidity between migraine and major depression [12], studies indicate the existence of a bidirectional relation [21]. For instance, a cohort study found that the presence of each disorder (both migraine or depression) enhanced the risk for a first onset of the other [22], whereas in an older sample the presence of depression did not predict the onset of migraine [23]. Both migraine and depression show a specific heritability of about 40–50% having a polygenic background [24]. Twin studies suggest that about 20% of the variability in both migraine and depression can be attributed to shared genes with a bidirectional pattern [25, 26].

The serotonin (5-HT) system plays a crucial role in the association between migraine and depression. Indeed, patients with migraine have increased ictal 5-HT concentrations and decreased interictal 5-HT plasma levels, suggesting that a chronically reduced interictal 5-HT availability may predispose to cortical spreading depression and increased sensitivity of trigemino-vascular pathways [27]. Besides, a polymorphism in the 5-HT transporter gene has been linked to migraine as well as depression [28]. In addition, the migraine abortive drugs triptans usually act as 5-HT agonists and even selective serotonin reuptake inhibitors (SSRIs) may be used in preventing migraine, even if they are not a first-line preventive treatment and not recommended by existing guidelines.

A second possible key player in the association between migraine and depression is the dopaminergic system, as a dopamine D2 receptor genotype is significantly associated with comorbid migraine with aura, depression, and anxiety [29].

A study found significantly lower GABA cerebrospinal fluid (CSF) levels in CM patients with depression when compared to those without, suggesting that GABA is a possible mediator of the association between CM and depression [30]. A further possible link between depression and CM may be represented by the shared involvement of the hypothalamic-pituitary adrenal (HPA) axis [31]. Specifically, an imbalance between pro-inflammatory and anti-inflammatory cytokines resulting in abnormal increased pro-inflammatory cytokines levels has been hypothesized as a possible link between depression, migraine, obesity, and the progression from episodic migraine (EM) to CM, with underlying dysfunctions in tryptophan metabolism and serotonergic activation of the HPA axis [32]. This further points towards the potential role of the 5-HT system in the association between migraine and depression, suggesting multiple neural mechanisms interacting in that association.

Recent neuroimaging studies showed that specific pain-modulating brain areas, including the amygdala, anterior cingulate cortex, and periaqueductal gray show functional and structural alterations in both migraine and affective disorders, suggesting a common matrix underlying these conditions [33]. This would imply a dysfunction of a “neuro-limbic” pain network underlying migraine, in line with the findings from the current literature showing that the presence of anxiety-depressive symptoms influence the clinical presentation of migraine [34].

Finally, according to a psychological point of view, specific shared vulnerabilities between migraine and depression exist. Stress is a migraine trigger [35] and a risk factor of migraine chronification [36], but it also has a pivotal role in inducing major depression [33]. In addition, broad and unspecific personality traits, mostly neuroticism, have been implicated in the comorbidity between depression and migraine [37].

Implications for treatment

The assumed bidirectional influence and the shared mechanisms underlying migraine and major depression could be used in a beneficial synergistic way when treating patients.

For instance, there is evidence that in patients with CM and comorbid depression, the prophylactic use of onabotulinumtoxin A significantly reduces headache as well as depressive and anxiety symptoms [38, 39]. Similarly, cognitive-behavioral therapy (CBT) improved headache symptoms, depression, anxiety, and quality of life of patients with migraine and/or tension-type headache and comorbid depression – with improvements that were maintained for at least 4 months [40]. Migraine guidelines recommend the use of amitriptyline, a tricyclic antidepressant, for migraine prophylaxis, which should be preferred when a comorbid depression has been diagnosed [41, 42]; however, it should be noted that the amitriptyline doses required for the treatment of migraine are lower than those used to treat depression [42]. Conversely, caution is needed regarding the use of flunarizine and beta-blockers to prevent migraine as they may be contraindicated in the presence of depression. Comorbid major depression is a complex and more difficult to treat clinical condition; yet, these patients do respond well to headache treatment, also resulting in an improved quality of life [19]. Hence, treating both disorders adequately may result in symbiotic treatment outcomes, preventing the development of chronification [42].

Bipolar disorder

BD is characterized by a periodic course of depressive episodes and episodes with exceptionally increased mood (mania or hypomania). It is commonly divided into BD type I (at least one manic or mixed episodes) and BD type II (at least one hypomanic, but no full manic phase), with BD I usually impairing more severely the individual functioning [14].

Patients with BD display an increased prevalence of migraine that can reach up to 55.3% (Table 1), although – as stated above in the case of major depression – rates may considerably vary across countries due to several factors. Migraine prevalence seems to be higher in BD II than BD I [43, 44], and mostly migraine precedes the onset of BD [45]. In a population-based study, the prevalence of migraine was higher in subjects with both manic and depressive episodes than in those with depressive episodes only [46]. The available data suggest that BD has a more severe course when it is comorbid with migraine [47].

Mechanisms potentially involved in the comorbidity

BD shows the highest heritability in the group of affective disorders, with a consistent overlap with migraine. The available literature data show that a positive family history of BD is a consistent risk factor for migraine [43, 47, 48], pointing at towards a possibly shared hereditary basis. Furthermore, based on a genome-wide linkage study [49] and association study [50], some shared genetic vulnerabilities may be supposed. Overall, multifactorial polygenetic mechanisms seem to confirm the existence of the comorbidity between migraine and BD.

As already stated above for comorbid depression, several neurotransmitter systems have been hypothesized to be involved in BD and comorbid migraine, with studies suggesting a dysfunction in serotonergic [27, 51, 52], dopaminergic [53, 54], and glutamatergic pathways [55, 56]. Furthermore, rather at the cellular level, alterations in specific sodium and calcium ion channels have been found in both migraine [57,58,59] and BD [60,61,62], a finding which might explain the common action of anti-epileptic drugs such as valproate in both disorders [63,64,65]. Finally, as in the case of major depression, even for BDy pro-inflammatory cytokines might play a role in determining the migraine-BD comorbidity [66].

Implications for treatment

Among the available treatments with documented stabilizing properties in BD, valproate and topiramate have also been proven effective in the management of migraine [65] and there is some evidence suggesting the effectiveness of lamotrigine (which is only approved for the management of depressive recurrences in bipolar depression) for migraine prevention ([63], but also see [67]); the shared action of those drugs might point to a similar pathophysiology underlying BD and migraine. In addition to specific psychoactive medications, CBT [68] and particularly social rhythm therapy – a variant of interpersonal psychotherapy aimed at stabilizing endogenous circardian rhythms – were effective for the treatment of both BD and migraine [69, 70].

Conversely, the use of SSRIs and even more serotonin–norepinephrine reuptake inhibitors (SNRIs) is associated with the risk of exacerbating mania or initiating a more rapid cycling course in BD [71]. As migraine usually precedes the BD diagnosis [44], a switch into manic episodes might be precipitated by antidepressants aimed to treat migraine or first symptoms of depression. This underlines a considerable risk for misdiagnosis and mistreatment in comorbid patients.

Anxiety disorders

Table 1 shows the quantitative data regarding the association between migraine and anxiety. Notably, the prevalence of anxiety increases with migraine frequency [72, 73], suggesting a ‘dose-response’ effect; the comorbidity between migraine and anxiety disorders is also enhanced by the presence of medication overuse [74] and concurrent depression [75]. As for major depression, the risk of suicide attempts is increased in patients with migraine and anxiety disorders [20].

Panic disorder

Panic disorder (PD) is characterized by unexpected recurrent panic attacks, accompanied by physical symptoms such as sweating, trembling, palpitations, dizziness, chest pain, the fear of going crazy or dying, often co-occurring with agoraphobia [14]. When compared to individuals without migraine, patients with migraine are 1.2 to 9.6 times more likely to be diagnosed with PD (e.g., [76]) (see Table 1). According to the current literature, PD occurs earlier in patients with migraine as compared to those without [77]. However, the association between the two conditions is likely to be bidirectional, with the influence being primarily from headaches to PD although a weaker, yet significant influence was observed in the opposite direction [76]. The prevalence of PD is about 2–3 times higher in CM than in EM [78].

Phobic disorders

Phobic disorders include specific phobia (fear of objects or situations) and social phobia (fear of socially relevant interactions) [14]. Evidence regarding the comorbidity between phobias and migraine is scarce [16, 79]. There seems to be an overlap regarding specific avoidance behaviors in migraine and phobias, which led some researchers to introduce the term ‘cephalalgiaphobia’, which may be linked to the risk of transformation to CM and medication-overuse headache (MOH) [80, 81]. A core feature of phobic-avoidant disorders is anticipatory anxiety, which may be the reason why some patients take hold of analgesics in the least warning of pain, eventually leading to a vicious circle of headache and medication overuse.

Generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by the presence of pervasive anxiety and repetitive worries about specific events [14]. The prevalence of GAD is higher in subjects with migraine than in those without migraine (see Table 1) [82]. If migraine is comorbid with depression and anxiety, patients tend to suffer from more severe migraine attacks, respond poorly to commonly available treatments, and are at increased risk of developing MOH [82,83,84,85,86]. Besides, the presence of GAD seems to precede migraine diagnosis which may have important treatment implications [87].

Mechanisms potentially involved in the comorbidity

The bidirectional association between migraine and PD suggests that shared genetic or environmental factors might be involved in the comorbidity of PD with migraine and other severe headaches [76, 85]. Migraine and PD are likely to share an altered autonomic regulation. A further possible mechanism of association is somatization, which is typically found in patients with PD and might increase the prevalence of somatic symptoms, including migraine headaches [84].

In a rat model of CM, researchers found a high prevalence of anxiety- and depression-like symptoms, which could be reduced by a low-dose amitriptyline administration. Moreover, CM was associated with lower prefrontal 5-HT and dopamine levels. Translating these findings to humans, alterations in these neurotransmitter systems seem to contribute to both CM and anxiety [88].

Anxiety-depression symptoms in migraine may be linked to higher migraine trigger susceptibility. Here, central sensitization in migraine patients might be modulated and enhanced by comorbid anxiety-depression symptoms, increasing the risk of transformation to CM [89]. Such mechanism could be able to explain the prevalence of more severe headache or CM in anxiety.

On the neural level, anxiety might directly influence migraine symptoms acting on relay trigeminovascular thalamic neurons transmitting headache-related nociceptive signals, which are modulated by several excitatory and inhibiting input fibers. Surprisingly, the absence of calcitonin gene-related peptide (CGRP)-containing fibers around the thalamus indicates that CGRP is presumably not acting here, but more on a neurohormone level [90]. Finally, a small Chinese study in MOH patients indicates that headache and anxiety may be linked to changes in hippocampal volume [91].

Evidence regarding the comorbidity between migraine and anxiety disorders is mainly focused on shared neurotransmitter systems, primarily serotonergic dysfunction, which anxiety disorders share with depression. Other potential mechanisms involve ovarian hormone fluctuations, HPA axis dysregulation, and shared genetic influences [92]. Migraine and anxiety have been associated with the serotonin transporter gene 5-HTTLPR polymorphism and the C/C NcoI polymorphism within the dopamine receptor D2 gene [29, 93, 94]. However, there are association studies that did not find an association between the migraine-PD comorbidity and dopamine receptor genes [95]. This again points towards a multifactorial pattern of association.

A Dutch twin study found that anxious depression shared the heritability pattern of migraine, suggesting a bidirectional causal relation [25], while another Dutch study stressed the importance of anxiety and depression in pain disorders and suggested that anxiety and depression explain a substantial amount of the migraine comorbidity with other pain conditions [92].

Interoceptive conditioning, fear of pain, anxiety sensitivity, and avoidance behaviors have been considered as vulnerability factors for migraine and PD in their development and maintenance. Interactions between these variables warrant further longitudinal studies to elucidate etiological trajectories and pathophysiological mechanisms [94].

Implications for treatment

A retrospective study found that the treatment of PD with antidepressant medications (SSRIs, tricyclic antidepressants [TCAs]) may may not only act beneficially on PD but also on comorbid migraine [77]. This finding hints towards a prophylactic effect, which could result in a win-win-solution for the patients.

Options for treating comorbid migraine and anxiety disorders include anticonvulsants [67, 96]: pregabalin, which is used for GAD, has been suggested as a useful alternative prophylaxis in CM according to one open-label study [97], while topiramate, which is used for social phobia, has been suggested as a useful treatment alternative for those who do not respond to or cannot tolerate SSRIs [98]. The antiglutamatergic effect of lamotrigine on migraine with aura and GABAergic effect of topiramate and valproate on migraine without aura might act on the neural alterations implied in both depression and anxiety [99].

Teaching about dysfunctional avoidance patterns in migraine, including excessive painkiller intake, may help patients to get insights into their avoidance of migraine triggers [100]. Henceforth, psychological interventions may be important to prevent medication overuse. In addition, treatment of phobias in CM may lead to lower anxiety and depression levels as well as better quality of life [79].

Considering that anxiety increases the likelihood to develop migraine, it is therapeutically important to notice subthreshold symptoms. Associations between subthreshold anxiety and primary headache have been described and subthreshold anxiety showed significantly higher ORs for all headaches, migraine, and CM [101, 102].

The careful screening of children, adolescents, and young adults who suffer from migraine for both anxiety and depression, and vice versa, might result in better treatment options and improved long-term outcomes for the patient [103, 104]. Besides, the adequate screenings may reveal underlying or subclinical psychiatric disorders [89].

An integration of behavioral strategies for managing comorbid conditions into existing treatment protocols pursues to modify dysfunctional behaviors and cognitions [36].

Recognition of comorbid psychiatric disorders is also advisable to prevent unwanted drug effects in comorbid patients and to permit drugs effective for both disorders [105], aiming to prevent headache worsening, chronification, or medication overuse.

CBT strategies are usually aimed at modifying dysfunctional behaviors, thoughts, and feelings that incidentally maintain both depression and anxiety. This may enhance adherence to pharmacotherapy, helping to minimize the potential for headache chronification. Some behaviors associated with anxiety include dysfunctional avoidance patterns for which CBT may be really helpful in the clinical practice [36, 106, 107].

A multidisciplinary treatment approach in migraine (i.e., combining both pharmacological and psychological approaches with other strategies such as physiotherapy) (see e.g., [108]) should be aimed at excluding conflicts, aggression as well as factors that contribute to anxiety. The multidisciplinary treatment approach should be personalized and take into account both the patients’ usual behavior and environment, thus helping patients to recover their stability and avoid the anxious anticipation of the next attack [109].

Stress and post-traumatic stress disorder

The relation between stress and migraine is bidirectional and may be direct or indirect. Patients with migraine report higher stress levels when compared to healthy controls (e.g., [109]), and stressors are usually reported as migraine triggers [84, 110,111,112,113,114,115]. Conversely, migraine itself acts as a stressor resulting in a vicious circle with a strong impact on important individual domains such as work and social functioning [116]. Stress exposure might also mediate the association between migraine and other psychiatric comorbidities, including major depression [112], and is implied in the transformation of headache into chronic headache [117, 118].

The development of PTSD mandatorily depends on the direct or indirect exposure to traumatic life events and is characterized by intrusive symptoms, avoidance, and negative alterations in both cognitions and mood [14]. PTSD is related to the development of pain disorders [119], with a higher prevalence in patients with migraine, and mostly CM, compared to healthy controls [120]. Notably, the available studies found a higher incidence of childhood abuse in migraine patients with BD or depression as compared to those with migraine only [110, 121]. There is also evidence suggesting that PTSD, but not the mere exposure to a traumatic event, is correlated with migraine [122], while in the absence of definite PTSD, only repetitive (≥3) traumatic events enhance the risk for migraine [123,124,125,126]. Besides, CM is associated with a higher susceptibility for PTSD compared to EM; indeed, patients with CM were more influenced by traumatic events, as evident in more avoidant and re-experiencing symptoms when compared to patients with EM [127].

PTSD is more frequent among patients with CM when compared to those with chronic tension-type headache [128], suggesting that the association is specific to migraine. Moreover, PTSD with comorbid depression was associated with a higher risk of migraine chronification when compared to depression alone [120]. In line with those findings, an Italian study found that major traumatic events were associated with CM and MOH [129]. Not surprisingly, patients with migraine and comorbid PTSD report greater headache-related disability and quality of life impairment than those with migraine only [120, 122, 130].

Mechanisms potentially involved in the association

The higher prevalence of stress and stress-related disorders in patients with migraine compared to non-migraineurs might be explained by the central sensitization theory, which postulates a stress-induced abnormal activation of the trigeminal nucleus caudalis, hypothesized to be involved in pain processing [131]. Stress-induced mechanisms acting on underlying genetic and epigenetic vulnerability are able to modify neural circuits, neurotransmitter balance, and autonomic and endocrine responses [132]. The stress response seems to be dysfunctional even in children with migraine [111, 133]. The load of stress and repeated migraine attacks may impair the allostasis of the brain, resulting in a dysregulated neural and endocrine response, i.e., the “allostatic load” [134].

Serotonin is likely a mediator of the relation between migraine and stress [27, 90], even if the available data did not show a specific mediation of serotonin in the association between PTSD and migraine. Stress plays a major role even in the trigemino-vascular system, whose activation is provoked from prolonged stress through the action of the HPA axis [135].

A theory explaining the higher prevalence of migraine in PTSD is the so-called “limbically augmented pain syndrome” [136]. According to that theory, if the normal arousal induced by pain becomes chronic, the brain fails to adjust adequately, causing an abnormal endocrine response as well as permanent changes in the limbic system. This phenomenon is shared by both migraine and PTSD, in which the exposure to major traumatic events impairs the normal limbic response. Another possible explanation of the comorbidity between stress and migraine is that chronic stress provokes a state of prolonged inflammation leading to a damage and substantial modifications on some sensitive specific brain areas, even implied in pain perception [132, 136,137,138,139].

Implications for treatment

Individuating the presence of PTSD in patients with migraine is crucial for the management of migraine, considering that treating PTSD alone could improve the sense of well-being, and significantly reduce pain and disability in patients with migraine [120].

Controlling the amount of stress may be crucial for headache management [112] as migraine may also be associated with a dysfunctional coping style [140]. Adolescents with CM are more prone to adopt passive coping strategies to face stress, especially when migraine is associated with depression [141]. In this context, CBT is increasingly gaining consensus as a fundamental part of migraine management. CBT may be really focused on attack prevention [106]. The aim of this treatment approach is to change dysfunctional behaviors which are significantly involved in maintaining depression and anxiety [36] and comprises stress management and coping [106]. The highest benefits of CBT are observed when combined with pharmacological treatment [117, 142].

Other psychiatric comorbidities

Personality traits/disorders

Current evidence suggests that there are not dominant personality profiles among migraine patients; however, personality disorders seem to complicate headache treatment [117, 143].

A meta-analysis of ten observational studies showed that children with migraine tend to show more internalizing (“anxious, inhibited”) and externalizing (“aggressive and antisocial”) behaviors, as measured by the Child Behavior Checklist (CBCL), than healthy children, even if the difference was more evident for internalizing behavior [144]. According to a systematic review, children with migraine tend to show more somatic complaints and internalizing behaviors than healthy controls, which might be attributed to chronic pain rather than to psychological dysfunctioning [145].

Compared to healthy controls, females aged 18–65 years with a migraine had higher scores in the Harm Avoidance (HA) and Persistence (P) sections and lower scores in the Self-Directness sections of the Temperament and Character Inventory [146]. A population-based study performed among females aged 40–74 years found no association between lifetime migraine and personality traits or psychiatric disorders; however, in elderly females (60–74 years), the risk for active migraine was significantly and consistently associated with a history of major depression, higher levels of stress susceptibility and somatic trait anxiety [147].

An Italian multi-center study performed in tertiary headache clinics applied the Minnesota Multiphasic Personality Inventory (MMPI-2) and found – as compared to healthy controls – that patients with MOH and episodic headache, respectively, scored higher in the so-called ‘neurotic scales’ (i.e., Hypochondriasis, Depression, Hysteria) and lower in the Ego Strength and Dominance scales; besides, patients with MOH had higher scores in the Hypochondriasis and Health Concerns scales when compared to those with episodic headache [140]. Moreover, patients with CM and MOH did not only report more stress, emotional and physical traumatic experiences than those with EM, but also show more problems in identifying feelings according to an alexithymia subscale [129]. These findings indicate that CM, rather than EM, is associated with specific personality traits. This does not mean that chronicity triggers personality disorders; however, it is important that clinicians pay attention to personality traits in CM as they may significantly interfere with the treatment.

Substance use behavior/disorders

Migraine and specific substance use may commonly co-occur. For instance, early epidemiological research found that nicotine dependence and illicit drug use was more frequent among patients with migraine compared to those without; however, a review pointed out, that the association may be more complex [117, 148]. More recent data indicate that the association between migraine and substance use was present only in patients with comorbid depression or PTSD [17, 149]. Thus, substance use may be considered a consequence of other comorbid psychiatric conditions [8].

Higher caffeine consumption could be a risk factor for migraine transformation [150]; indeed, a population-based study found that patients with chronic daily headache were significantly more likely to have been higher caffeine users compared to healthy control subjects [151]. Interestingly, the HEAD-Hunt study found that higher caffeine consumption was positively correlated with infrequent headache and negatively correlated with frequent headache [152], suggesting that either patients with frequent headache avoid caffeine or high-caffeine consumption acts exerting analgesic properties. So far, there is no unequivocal conclusion.

Studies suggest that alcohol consumption is equally or less prevalent in patients with migraine as compared to the general population; possibly, patients self-restrict alcohol consumption because of its actual or assumed action as a trigger of migraine attacks [23, 35, 153,154,155]. Yet, there is still uncertainty about the mechanisms by which alcohol triggers migraine attacks [156].

Somatoform disorders/somatic symptoms disorder

Whether somatoform disorders are associated with migraine is generally a matter of debate. According to a literature review, patients with EM without other psychiatric comorbidities display a comparable prevalence of somatoform disorders when compared to non-headache patients [117].

A cross-sectional study performed in a primary headache center found that, among patients with CM, somatic symptoms were significantly more frequent than in patients with EM, while during the follow-up a decrease in somatic symptoms was highly associated with a decrease in headache frequency [157]. In line with these results, the Primary Care Evaluation of Mental Disorders (PRIME-MD) study found that, when compared to patients with episodic headaches, patients with CM had a higher rate of somatic symptoms which increased, together with headache frequency, the likelihood to develop a psychiatric comorbidity [158]. Finally, children with migraine equivalents tend to have more somatic complaints (see above, [145]) and feel more fearful and shy when compared to those without migraine equivalents [159]. However, all those findings are related to somatic symptoms rather than to definite somatoform disorders.

Eating disorders

Whether eating disorders are linked to migraine is quite controversial. A Finnish study found that, in women with anorexia nervosa or bulimia nervosa, the prevalence of migraine was almost 2-fold higher compared to women without eating disorders (22% vs. 11%); however, a further analysis revealed that the association between eating disorders and migraine was mediated by depression [160].

Thus, eating disorders may enhance the likelihood to develop migraine in specific subgroups of subjects, possibly through the influence of other factors such as anxiety or depression. If migraine patients present themselves with low weight or rapid weight changes, therapists should pay attention to depressive symptoms, given the association between eating disorders and depression. Moreover, specific manifestations of eating disorders, such as dieting, fasting or skipping meals, are often reported as migraine triggers [35, 155].

Discussion

Overall, our review underlines the consistent association between migraine and psychiatric disorders (e.g., major depression, bipolar disorder, anxiety disorders, PTSD, and other mental disorders including substance-related behavior and personality disorders) that might be attributed to common etiological (both environmental or genetic) factors or to the existence of bidirectional relations between the disorders, as for major depression and panic disorder. Although the actual nature of this complex association between neurological and mental disorders is difficult to determine given the available studies, for therapists it is important to recognize it and to include it into the diagnostic and therapeutic process [161] (see Table 2). This also requires a more intense collaboration between the disciplines of neurology and psychiatry, which are mostly taught separately in medical schools.

Table 2 Summary of mechanisms and implications for therapy
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The present systematic review should be considered in the light of the following limitations/shortcomings. For instance, most studies included in the present review used cross-sectional designs, limiting the assessment of causal relations between phenomena (e.g., [161]). Besides, the distribution of sex, age, and migraine subtype, as well as methods to diagnose migraine and psychiatric disorders were largely heterogeneous among the different studies, limiting the possibility of quantifying the real impact of comorbidities in the general population (for more details, see Table 1). Moreover, there are few and mostly indirect data examining the neural mechanisms underlying the comorbidity between migraine and psychiatric comorbidities. Having more than only one psychiatric comorbidity (e.g., concurrent anxiety disorder and major depression) poses another caveat which is often not sufficiently considered in existing studies, but may have further consequences on the course and treatment of migraine [25, 120, 160]. All the mentioned criticisms once again enhance the complexity of migraine and psychiatric comorbidities regarding etiology, pathophysiology or interactions over time. However, the more consistent implications from the reviewed studies have been summarized in Table 2.

Major affective and anxiety disorders have been shown to be the most frequent and disabling psychiatric comorbidities associated with migraine, influencing its clinical course, treatment response, and clinical outcome. Here, the comorbidity has important clinical and therapeutic implications, demanding specific attention by practitioners. For instance, having a comorbid major depression or anxiety disorder can increase the likelihood of suicide attempts in patients with migraine [20]. The comorbidity with psychiatric disorders is not uniformly increased in the different migraine subtypes, but generally more elevated in patients with CM or migraine with aura, suggesting the need for more specific care in those patients.

Genetic variants, dysfunction in neurotransmitters (especially 5-HT), and HPA axis dysregulation are among the most supported pathophysiological mechanisms underlying the comorbidity between migraine and depression. Specific neural network patterns overlap between both entities, which may be the result of the above hypothesized mechanisms. Unfortunately, no specific and valid biomarkers have been documented for the risk of comorbid migraine and depression. Still, it is not sufficiently clear, if the observed biological or chemical parameters are indicators of specific underlying etiological and pathogenic pathways or if they represent epiphenomena.

The relation between migraine and major depression is likely to be bidirectional. Regarding the bipolar spectrum, clinicians need to suspect and identify the possible comorbidity between migraine and BD, especially among female patients and subjects with BD II. Here, the possible misidentification of unipolar depressive subtypes should be avoided, as pharmacological indications for the two conditions widely differ or may be counterproductive.

Whether the comorbidity between migraine and anxiety is uni- or bidirectional is a matter of debate. Excess worry, fear, and other anxiety symptoms such as avoidance behavior are usually part of the clinical migraine presentation, while, conversely, headache symptoms may also be part of a clinical anxiety disorder. This implies the need to correctly identify the clinical characteristics of both these conditions, to derive a working hypothesis regarding which of the disorders may be primary or secondary, as the adequate treatment of the primary condition may be beneficial for the outcome of the secondary condition. PD appears to be more consistently associated with migraine than most other anxiety disorders. Comorbid PD is associated with greater health care costs, higher disability, and functional impairment as well as risk for chronification, medication overuse, and henceforth MOH. As with migraine and depression, the relation between PD and migraine appears to be bidirectional. The link between PTSD and migraine seems to be more evident in chronic forms, as the repeated exposure to stressful situations/factors causes cortical response modification with modulation of the vascular trigeminal system leading to a lower pain threshold.

There are few and sometimes conflicting studies in the current literature concerning the comorbidity between migraine and psychiatric disorders associated with minor incidence in the general population, including personality disorders, substance use disorders, somatoform disorders, and eating disorders. Here, the association may be also due to or mediated by concurrent major depression. Specific heed should be paid to MOH, which is more common in patients with comorbid psychiatric disorders [162]. In this condition, pain-relieving drugs for the acute treatment of headache symptoms may themselves lead to headache when taken frequently for long periods. Here, therapists should explain this phenomenon in detail to the patients in order to assure a proper use of prescribed or over-the-counter medication. In some cases of MOH, comorbid psychiatric symptoms might be considered an epiphenomenon of medication overuse – at least animal data imply such a mechanism [163].

Reviewing the current literature, we are still far from comprehensively understanding the biological origin/axis underlying the migraine and psychiatric disorder comorbidity. For most of the comorbid disorders, the commonly mentioned pathogenic players such as heritability, specific genes or neurotransmitter systems may play a significant role (Fig. 2). As influences seem to be generally complex and dynamic in their nature over time, simple therapeutic solutions are not available and combined approaches are required. Instead, the involvement of different disciplines is needed in order to carefully account for each patient’s disorder and treatment history in a multimodal treatment approach perspective.

Fig. 2
figure 2

Scheme of the association mechanisms between migraine and psychiatric disorders. The Figure summarizes the mechanisms potentially involved in the comorbidity of migraine and psychiatric disorders on different levels. Shared genetic susceptibility and traumatic life events can be considered important influencing factors. On the neural level, cellular changes (channels), neurohormonal changes (HPA axis), neurotransmitter changes (serotonergic, dopaminergic, and glutamatergic neural pathways) and neural network changes are discussed. On the clinical level, migraine co-occurs with different manifestations of psychiatric disorders (for abbreviations see below)

Full size image

Clarifying the comorbidity between psychiatric disorders and migraine is essential not only at the clinical diagnostic level but above all for the complex therapeutic implications of such comorbidity [164]. CBT has been shown in several population studies to be a valid alternative in addition to pharmacological treatments in patients with migraine and psychiatric comorbidity. Importantly, the pharmacological prophylaxis of migraine might be influenced by psychiatric comorbidities. Many biological and neural aspects related to the comorbidity still need to be clearly elucidated to better approach the real complexity of this issue.

Conclusion

Our intention is to conclude this review emphasizing three most relevant key points for clinicians:

  1. 1)

    Psychiatric comorbidity in migraine is common and invalidating.

  2. 2)

    The careful history taking and diagnostic procedures related to migraine should carefully take into account the existence of comorbidities.

  3. 3)

    Migraine management and treatment should be tailored to consider the presence of psychiatric comorbidities, taking into account the potential beneficial or synergistic effects as well as treatment complications.

Abbreviations

5-HT:

Serotonin

5-HTTLPR:

Serotonin-transporter-linked polymorphic region

BD:

Bipolar disorder

CBCL:

Child Behavior Checklist

CBT:

Cognitive-behavioral therapy

CGRP:

Calcitonin gene-related peptide

CM:

Chronic migraine

D2 receptor:

Dopamine D2 receptor

EM:

Episodic migraine

GABA:

Gamma-Aminobutyric acid

GAD:

Generalized anxiety disorder

HPA axis:

Hypothalamic-pituitary adrenal axis

HR:

Hazard ratio

MMPI-2:

Minnesota Multiphasic Personality Inventory

MOH:

Medication-overuse headache

OCD:

Obsessive-compulsive disorder

OR:

Odds ratio

PD:

Panic disorder

PR:

Prevalence ratio

PRIME-MD:

Primary Care Evaluation of Mental Disorders

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PTSD:

Post-traumatic stress disorder

RR:

Relative risk

SNRIs:

Serotonin–norepinephrine reuptake inhibitors

SSRIs:

Selective serotonin reuptake inhibitors

SUD:

Substance use disorder

References

  1. Group GBDNDC (2017) Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet Neurol 16(11):877–897

    Article  Google Scholar 

  2. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z (2018) Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain. 19(1):17

    Article  PubMed  PubMed Central  Google Scholar 

  3. Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V et al (2014) The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol 43(2):476–493

    Article  PubMed  PubMed Central  Google Scholar 

  4. Patel V, Chisholm D, Parikh R, Charlson FJ, Degenhardt L, Dua T et al (2016) Addressing the burden of mental, neurological, and substance use disorders: key messages from disease control priorities, 3rd edition. Lancet. 387(10028):1672–1685

    Article  PubMed  Google Scholar 

  5. Walker ER, McGee RE, Druss BG (2015) Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72(4):334–341

    Article  PubMed  PubMed Central  Google Scholar 

  6. Seng EK, Seng CD (2016) Understanding migraine and psychiatric comorbidity. Curr Opin Neurol 29(3):309–313

    Article  PubMed  Google Scholar 

  7. Zarcone D, Corbetta S (2017) Shared mechanisms of epilepsy, migraine and affective disorders. Neurol Sci 38(Suppl 1):73–76

    Article  PubMed  Google Scholar 

  8. Radat F, Swendsen J (2005) Psychiatric comorbidity in migraine: a review. Cephalalgia. 25(3):165–178

    Article  CAS  PubMed  Google Scholar 

  9. McLean G, Mercer SW (2017) Chronic migraine, comorbidity, and socioeconomic deprivation: cross-sectional analysis of a large nationally representative primary care database. J Comorb 7(1):89–95

    Article  PubMed  PubMed Central  Google Scholar 

  10. Trejo-Gabriel-Galan JM, Aicua-Rapun I, Cubo-Delgado E, Velasco-Bernal C (2018) Suicide in primary headaches in 48 countries: a physician-survey based study. Cephalalgia. 38(4):798–803

    Article  PubMed  Google Scholar 

  11. Brainstorm Consortium, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J et al (2018) Analysis of shared heritability in common disorders of the brain. Science 360(6395):eaap8757

  12. Lipton RB, Silberstein SD (1994) Why study the comorbidity of migraine? Neurology. 44(10 Suppl 7):S4–S5

    CAS  PubMed  Google Scholar 

  13. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  PubMed  PubMed Central  Google Scholar 

  14. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing

  15. Chen YC, Tang CH, Ng K, Wang SJ (2012) Comorbidity profiles of chronic migraine sufferers in a national database in Taiwan. J Headache Pain. 13(4):311–319

    Article  PubMed  PubMed Central  Google Scholar 

  16. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi P, Costa A (2011) Migraine and psychiatric comorbidity: a review of clinical findings. J Headache Pain. 12(2):115–125

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jette N, Patten S, Williams J, Becker W, Wiebe S (2008) Comorbidity of migraine and psychiatric disorders--a national population-based study. Headache. 48(4):501–516

    Article  PubMed  Google Scholar 

  18. Yong N, Hu H, Fan X, Li X, Ran L, Qu Y et al (2012) Prevalence and risk factors for depression and anxiety among outpatient migraineurs in mainland China. J Headache Pain. 13(4):303–310

    Article  PubMed  PubMed Central  Google Scholar 

  19. Heckman BD, Holroyd KA, Himawan L, O'Donnell FJ, Tietjen G, Utley C et al (2009) Do psychiatric comorbidities influence headache treatment outcomes? Results of a naturalistic longitudinal treatment study. Pain. 146(1–2):56–64

    Article  PubMed  PubMed Central  Google Scholar 

  20. Breslau N, Schultz L, Lipton R, Peterson E, Welch KM (2012) Migraine headaches and suicide attempt. Headache. 52(5):723–731

    Article  PubMed  Google Scholar 

  21. Moschiano F, D'Amico D, Canavero I, Pan I, Micieli G, Bussone G (2011) Migraine and depression: common pathogenetic and therapeutic ground? Neurol Sci 32(Suppl 1):S85–S88

    Article  PubMed  Google Scholar 

  22. Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM (2003) Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology. 60(8):1308–1312

    Article  CAS  PubMed  Google Scholar 

  23. Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW (2000) Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore epidemiologic catchment area follow-up study. Arch Gen Psychiatry 57(10):945–950

    Article  CAS  PubMed  Google Scholar 

  24. Ligthart L, Hottenga JJ, Lewis CM, Farmer AE, Craig IW, Breen G et al (2014) Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Hum Genet 133(2):173–186

    Article  PubMed  Google Scholar 

  25. Ligthart L, Nyholt DR, Penninx BW, Boomsma DI (2010) The shared genetics of migraine and anxious depression. Headache. 50(10):1549–1560

    Article  PubMed  Google Scholar 

  26. Schur EA, Noonan C, Buchwald D, Goldberg J, Afari N (2009) A twin study of depression and migraine: evidence for a shared genetic vulnerability. Headache. 49(10):1493–1502

    Article  PubMed  Google Scholar 

  27. Hamel E (2007) Serotonin and migraine: biology and clinical implications. Cephalalgia. 27(11):1293–1300

    Article  CAS  PubMed  Google Scholar 

  28. Marino E, Fanny B, Lorenzi C, Pirovano A, Franchini L, Colombo C et al (2010) Genetic bases of comorbidity between mood disorders and migraine: possible role of serotonin transporter gene. Neurol Sci 31(3):387–391

    Article  PubMed  Google Scholar 

  29. Peroutka SJ, Price SC, Wilhoit TL, Jones KW (1998) Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Mol Med 4(1):14–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vieira DS, Naffah-Mazacoratti MG, Zukerman E, Senne Soares CA, Alonso EO, Faulhaber MH et al (2006) Cerebrospinal fluid GABA levels in chronic migraine with and without depression. Brain Res 1090(1):197–201

    Article  CAS  PubMed  Google Scholar 

  31. Peres MF, Sanchez del Rio M, Seabra ML, Tufik S, Abucham J, Cipolla-Neto J et al (2001) Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry 71(6):747–751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bigal ME, Lipton RB, Holland PR, Goadsby PJ (2007) Obesity, migraine, and chronic migraine: possible mechanisms of interaction. Neurology. 68(21):1851–1861

    Article  PubMed  Google Scholar 

  33. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, Powers S, Schwedt TJ, Lipton R et al (2016) Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry 87(7):741–749

    Article  PubMed  Google Scholar 

  34. Maizels M, Aurora S, Heinricher M (2012) Beyond neurovascular: migraine as a dysfunctional neurolimbic pain network. Headache. 52(10):1553–1565

    Article  PubMed  Google Scholar 

  35. Pellegrino ABW, Davis-Martin RE, Houle TT, Turner DP, Smitherman TA (2018) Perceived triggers of primary headache disorders: a meta-analysis. Cephalalgia. 38(6):1188–1198

    Article  PubMed  Google Scholar 

  36. Smitherman TA, Maizels M, Penzien DB (2008) Headache chronification: screening and behavioral management of comorbid depressive and anxiety disorders. Headache. 48(1):45–50

    Article  PubMed  Google Scholar 

  37. Ligthart L, Boomsma DI (2012) Causes of comorbidity: pleiotropy or causality? Shared genetic and environmental influences on migraine and neuroticism. Twin Res Hum Genet 15(2):158–165

    Article  PubMed  Google Scholar 

  38. Boudreau GP, Grosberg BM, McAllister PJ, Lipton RB, Buse DC (2015) Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: an open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety. Int J Gen Med 8:79–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang H, Zhang H, Wei Y, Lian Y, Chen Y, Zheng Y (2017) Treatment of chronic daily headache with comorbid anxiety and depression using botulinum toxin a: a prospective pilot study. Int J Neurosci 127(4):285–290

    Article  CAS  PubMed  Google Scholar 

  40. Martin PR, Aiello R, Gilson K, Meadows G, Milgrom J, Reece J (2015) Cognitive behavior therapy for comorbid migraine and/or tension-type headache and major depressive disorder: an exploratory randomized controlled trial. Behav Res Ther 73:8–18

    Article  PubMed  Google Scholar 

  41. Diener HC, Gaul C. Kropp P, Dresler T, Förderreuther S, Gantenbein A et al (2018). Therapie der Migräneattacke und Prophylaxe der Migräne, S1-Leitlinie, 2018 [Therapy of migraine attacks and migraine prophylaxis]. In Deutsche Gesellschaft für Neurologie (Eds.), Leitlinien für Diagnostik und Therapie in der Neurologie. Online: www.dgn.org/leitlinien

  42. Finocchi C, Villani V, Casucci G (2010) Therapeutic strategies in migraine patients with mood and anxiety disorders: clinical evidence. Neurol Sci 31(Suppl 1):S95–S98

    Article  PubMed  Google Scholar 

  43. Fasmer OB (2001) The prevalence of migraine in patients with bipolar and unipolar affective disorders. Cephalalgia. 21(9):894–899

    Article  CAS  PubMed  Google Scholar 

  44. Low NC, Du Fort GG, Cervantes P (2003) Prevalence, clinical correlates, and treatment of migraine in bipolar disorder. Headache. 43(9):940–949

    Article  PubMed  Google Scholar 

  45. Ortiz A, Cervantes P, Zlotnik G, van de Velde C, Slaney C, Garnham J et al (2010) Cross-prevalence of migraine and bipolar disorder. Bipolar Disord 12(4):397–403

    Article  PubMed  Google Scholar 

  46. Nguyen TV, Low NC (2013) Comorbidity of migraine and mood episodes in a nationally representative population-based sample. Headache. 53(3):498–506

    Article  PubMed  Google Scholar 

  47. Saunders EF, Nazir R, Kamali M, Ryan KA, Evans S, Langenecker S et al (2014) Gender differences, clinical correlates, and longitudinal outcome of bipolar disorder with comorbid migraine. J Clin Psychiatry. 75(5):512–519

    Article  PubMed  PubMed Central  Google Scholar 

  48. Dilsaver SC, Benazzi F, Oedegaard KJ, Fasmer OB, Akiskal HS (2009) Is a family history of bipolar disorder a risk factor for migraine among affectively ill patients? Psychopathology. 42(2):119–123

    Article  PubMed  Google Scholar 

  49. Oedegaard KJ, Greenwood TA, Lunde A, Fasmer OB, Akiskal HS, Kelsoe JR et al (2010) A genome-wide linkage study of bipolar disorder and co-morbid migraine: replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11. J Affect Disord 122(1–2):14–26

    Article  CAS  PubMed  Google Scholar 

  50. Oedegaard KJ, Greenwood TA, Johansson S, Jacobsen KK, Halmoy A, Fasmer OB et al (2010) A genome-wide association study of bipolar disorder and comorbid migraine. Genes Brain Behav 9(7):673–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bigal ME, Krymchantowski AV, Ho T (2009) Migraine in the triptan era: progresses achieved, lessons learned and future developments. Arq Neuropsiquiatr 67(2B):559–569

    Article  PubMed  Google Scholar 

  52. Mahmood T, Silverstone T (2001) Serotonin and bipolar disorder. J Affect Disord 66(1):1–11

    Article  CAS  PubMed  Google Scholar 

  53. Akerman S, Goadsby PJ (2007) Dopamine and migraine: biology and clinical implications. Cephalalgia. 27(11):1308–1314

    Article  CAS  PubMed  Google Scholar 

  54. Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH et al (2017) The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry 22(5):666–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen G, Henter ID, Manji HK (2010) Presynaptic glutamatergic dysfunction in bipolar disorder. Biol Psychiatry 67(11):1007–1009

    Article  PubMed  PubMed Central  Google Scholar 

  56. Vaccaro M, Riva C, Tremolizzo L, Longoni M, Aliprandi A, Agostoni E et al (2007) Platelet glutamate uptake and release in migraine with and without aura. Cephalalgia. 27(1):35–40

    Article  CAS  PubMed  Google Scholar 

  57. Pietrobon D (2007) Familial hemiplegic migraine. Neurotherapeutics. 4(2):274–284

    Article  CAS  PubMed  Google Scholar 

  58. van de Ven RC, Kaja S, Plomp JJ, Frants RR, van den Maagdenberg AM, Ferrari MD (2007) Genetic models of migraine. Arch Neurol 64(5):643–646

    Article  PubMed  Google Scholar 

  59. Wessman M, Kaunisto MA, Kallela M, Palotie A (2004) The molecular genetics of migraine. Ann Med 36(6):462–473

    Article  CAS  PubMed  Google Scholar 

  60. Askland K, Read C, Moore J (2009) Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission. Hum Genet 125(1):63–79

    Article  CAS  PubMed  Google Scholar 

  61. el-Mallakh RS, Wyatt RJ (1995) The Na,K-ATPase hypothesis for bipolar illness. Biol Psychiatry 37(4):235–244

    Article  CAS  PubMed  Google Scholar 

  62. Kato T (2008) Molecular neurobiology of bipolar disorder: a disease of 'mood-stabilizing neurons'? Trends Neurosci 31(10):495–503

    Article  CAS  PubMed  Google Scholar 

  63. Lampl C, Katsarava Z, Diener HC, Limmroth V (2005) Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry 76(12):1730–1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sidor MM, Macqueen GM (2011) Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 72(2):156–167

    Article  CAS  PubMed  Google Scholar 

  65. Vikelis M, Rapoport AM (2010) Role of antiepileptic drugs as preventive agents for migraine. CNS Drugs 24(1):21–33

    Article  CAS  PubMed  Google Scholar 

  66. Brietzke E, Mansur RB, Grassi-Oliveira R, Soczynska JK, McIntyre RS (2012) Inflammatory cytokines as an underlying mechanism of the comorbidity between bipolar disorder and migraine. Med Hypotheses 78(5):601–605

    Article  CAS  PubMed  Google Scholar 

  67. Mulleners WM, Chronicle EP (2008) Anticonvulsants in migraine prophylaxis: a Cochrane review. Cephalalgia. 28(6):585–597

    Article  CAS  PubMed  Google Scholar 

  68. da Costa RT, Range BP, Malagris LE, Sardinha A, de Carvalho MR, Nardi AE (2010) Cognitive-behavioral therapy for bipolar disorder. Expert Rev Neurother 10(7):1089–1099

    Article  PubMed  Google Scholar 

  69. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM et al (2005) Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry 62(9):996–1004

    Article  PubMed  Google Scholar 

  70. Miklowitz DJ, Otto MW (2007) Psychosocial interventions for bipolar disorder: a review of literature and introduction of the systematic treatment enhancement program. Psychopharmacol Bull 40(4):116–131

    PubMed  Google Scholar 

  71. Frye MA (2011) Clinical practice. Bipolar disorder--a focus on depression. N Engl J Med 364(1):51–59

    Article  CAS  PubMed  Google Scholar 

  72. Goulart AC, Santos IS, Brunoni AR, Nunes MA, Passos VM, Griep RH et al (2014) Migraine headaches and mood/anxiety disorders in the ELSA Brazil. Headache. 54(8):1310–1319

    Article  PubMed  Google Scholar 

  73. Zwart JA, Dyb G, Hagen K, Odegard KJ, Dahl AA, Bovim G et al (2003) Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag health study. Eur J Neurol 10(2):147–152

    Article  PubMed  Google Scholar 

  74. Lampl C, Thomas H, Tassorelli C, Katsarava Z, Lainez JM, Lanteri-Minet M et al (2016) Headache, depression and anxiety: associations in the Eurolight project. J Headache Pain. 17:59

    Article  PubMed  PubMed Central  Google Scholar 

  75. Oedegaard KJ, Neckelmann D, Mykletun A, Dahl AA, Zwart JA, Hagen K et al (2006) Migraine with and without aura: association with depression and anxiety disorder in a population-based study. The HUNT Study. Cephalalgia 26(1):1–6

    Article  CAS  PubMed  Google Scholar 

  76. Breslau N, Schultz LR, Stewart WF, Lipton R, Welch KM (2001) Headache types and panic disorder: directionality and specificity. Neurology. 56(3):350–354

    Article  CAS  PubMed  Google Scholar 

  77. Yamada K, Moriwaki K, Oiso H, Ishigooka J (2011) High prevalence of comorbidity of migraine in outpatients with panic disorder and effectiveness of psychopharmacotherapy for both disorders: a retrospective open label study. Psychiatry Res 185(1–2):145–148

    Article  PubMed  Google Scholar 

  78. Juang KD, Wang SJ, Fuh JL, Lu SR, Su TP (2000) Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache. 40(10):818–823

    Article  CAS  PubMed  Google Scholar 

  79. Corchs F, Mercante JP, Guendler VZ, Vieira DS, Masruha MR, Moreira FR et al (2006) Phobias, other psychiatric comorbidities and chronic migraine. Arq Neuropsiquiatr 64(4):950–953

    Article  PubMed  Google Scholar 

  80. Peres MF, Mercante JP, Guendler VZ, Corchs F, Bernik MA, Zukerman E et al (2007) Cephalalgiaphobia: a possible specific phobia of illness. J Headache Pain. 8(1):56–59

    Article  PubMed  PubMed Central  Google Scholar 

  81. Giannini G, Zanigni S, Grimaldi D, Melotti R, Pierangeli G, Cortelli P et al (2013) Cephalalgiaphobia as a feature of high-frequency migraine: a pilot study. J Headache Pain. 14:49

    Article  PubMed  PubMed Central  Google Scholar 

  82. Bhatia MS, Gupta R (2012) Migraine: clinical pattern and psychiatric comorbidity. Ind Psychiatry J 21(1):18–21

    Article  PubMed  PubMed Central  Google Scholar 

  83. Carolei A, Ciancarelli I, Cerone D, Sacco S (2003) Comorbidities of migraine: a user-friendly overview. J Headache Pain 4(1):s23–ss5

    Article  PubMed Central  Google Scholar 

  84. Green MW (2011) Headaches: psychiatric aspects. Neurol Clin 29(1):65–80 vii

    Article  PubMed  Google Scholar 

  85. Guidetti V, Galli F (2002) Psychiatric comorbidity in chronic daily headache: pathophysiology, etiology, and diagnosis. Curr Pain Headache Rep 6(6):492–497

    Article  PubMed  Google Scholar 

  86. Smitherman TA, Rains JC, Penzien DB (2009) Psychiatric comorbidities and migraine chronification. Curr Pain Headache Rep 13(4):326–331

    Article  PubMed  Google Scholar 

  87. Mercante JP, Peres MF, Bernik MA (2011) Primary headaches in patients with generalized anxiety disorder. J Headache Pain. 12(3):331–338

    Article  PubMed  PubMed Central  Google Scholar 

  88. Zhang M, Liu Y, Zhao M, Tang W, Wang X, Dong Z et al (2017) Depression and anxiety behaviour in a rat model of chronic migraine. J Headache Pain. 18(1):27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Baldacci F, Lucchesi C, Cafalli M, Poletti M, Ulivi M, Vedovello M et al (2015) Migraine features in migraineurs with and without anxiety-depression symptoms: a hospital-based study. Clin Neurol Neurosurg 132:74–78

    Article  PubMed  Google Scholar 

  90. Noseda R, Kainz V, Borsook D, Burstein R (2014) Neurochemical pathways that converge on thalamic trigeminovascular neurons: potential substrate for modulation of migraine by sleep, food intake, stress and anxiety. PLoS One 9(8):e103929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Chen Z, Chen X, Liu M, Ma L, Yu S (2018) Lower hippocampal subfields volume in relation to anxiety in medication-overuse headache. Mol Pain 14:1744806918761257

    PubMed  PubMed Central  Google Scholar 

  92. Ligthart L, Gerrits MM, Boomsma DI, Penninx BW (2013) Anxiety and depression are associated with migraine and pain in general: an investigation of the interrelationships. J Pain 14(4):363–370

    Article  PubMed  Google Scholar 

  93. Gonda X, Rihmer Z, Juhasz G, Zsombok T, Bagdy G (2007) High anxiety and migraine are associated with the s allele of the 5HTTLPR gene polymorphism. Psychiatry Res 149(1–3):261–266

    Article  CAS  PubMed  Google Scholar 

  94. Smitherman TA, Kolivas ED, Bailey JR (2013) Panic disorder and migraine: comorbidity, mechanisms, and clinical implications. Headache. 53(1):23–45

    Article  PubMed  Google Scholar 

  95. Stochino ME, Asuni C, Congiu D, Del Zompo M, Severino G (2003) Association study between the phenotype migraine without aura-panic disorder and dopaminergic receptor genes. Pharmacol Res 48(5):531–534

    Article  CAS  PubMed  Google Scholar 

  96. Senaratne R, Van Ameringen M, Mancini C, Patterson B, Bennett M (2010) The prevalence of migraine headaches in an anxiety disorders clinic sample. CNS Neurosci Ther 16(2):76–82

    Article  PubMed  PubMed Central  Google Scholar 

  97. Calandre EP, Garcia-Leiva JM, Rico-Villademoros F, Vilchez JS, Rodriguez-Lopez CM (2010) Pregabalin in the treatment of chronic migraine: an open-label study. Clin Neuropharmacol 33(1):35–39

    Article  CAS  PubMed  Google Scholar 

  98. Van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M (2004) An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 65(12):1674–1678

    Article  PubMed  Google Scholar 

  99. Casucci G, Villani V, Finocchi C (2010) Therapeutic strategies in migraine patients with mood and anxiety disorders: physiopathological basis. Neurol Sci 31(Suppl 1):S99–S101

    Article  PubMed  Google Scholar 

  100. Martin PR, MacLeod C (2009) Behavioral management of headache triggers: avoidance of triggers is an inadequate strategy. Clin Psychol Rev 29(6):483–495

    Article  PubMed  Google Scholar 

  101. Lucchetti G, Peres MF, Lucchetti AL, Mercante JP, Guendler VZ, Zukerman E (2013) Generalized anxiety disorder, subthreshold anxiety and anxiety symptoms in primary headache. Psychiatry Clin Neurosci 67(1):41–49

    Article  PubMed  Google Scholar 

  102. Peres MFP, Mercante JPP, Tobo PR, Kamei H, Bigal ME (2017) Anxiety and depression symptoms and migraine: a symptom-based approach research. J Headache Pain. 18(1):37

    Article  PubMed  PubMed Central  Google Scholar 

  103. Dindo LN, Recober A, Haddad R, Calarge CA (2017) Comorbidity of migraine, major depressive disorder, and generalized anxiety disorder in adolescents and Young adults. Int J Behav Med 24(4):528–534

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fielding J, Young S, Martin PR, Waters AM (2016) Headache symptoms consistent with migraine and tension-type headaches in children with anxiety disorders. J Anxiety Disord 40:67–74

    Article  PubMed  Google Scholar 

  105. Savarese M, Guazzelli M, Prudenzano MP, Carnicelli M, Rossi M, Cardinali V et al (2005) Tertiary treatment for psychiatric comorbidity in headache patients. J Headache Pain. 6(4):231–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lipchik GL, Smitherman TA, Penzien DB, Holroyd KA (2006) Basic principles and techniques of cognitive-behavioral therapies for comorbid psychiatric symptoms among headache patients. Headache. 46(Suppl 3):S119–S132

    Article  PubMed  Google Scholar 

  107. Torelli P, Lambru G, Manzoni GC (2006) Psychiatric comorbidity and headache: clinical and therapeutical aspects. Neurol Sci 27(Suppl 2):S73–S76

    Article  PubMed  Google Scholar 

  108. Gaul C, Liesering-Latta E, Schafer B, Fritsche G, Holle D (2016) Integrated multidisciplinary care of headache disorders: a narrative review. Cephalalgia. 36(12):1181–1191

    Article  PubMed  Google Scholar 

  109. Wacogne C, Lacoste JP, Guillibert E, Hugues FC, Le Jeunne C (2003) Stress, anxiety, depression and migraine. Cephalalgia. 23(6):451–455

    Article  CAS  PubMed  Google Scholar 

  110. Kivilcim Y, Altintas M, Domac FM, Erzincan E, Gulec H (2017) Screening for bipolar disorder among migraineurs: the impact of migraine-bipolar disorder comorbidity on disease characteristics. Neuropsychiatr Dis Treat 13:631–641

    Article  PubMed  PubMed Central  Google Scholar 

  111. Rains JC (2009) Epidemiology and neurobiology of stress and migraine. Headache. 49(9):1391–1394

    Article  PubMed  Google Scholar 

  112. Swanson SA, Zeng Y, Weeks M, Colman I (2013) The contribution of stress to the comorbidity of migraine and major depression: results from a prospective cohort study. BMJ Open 3(3):e002057

    Article  PubMed  PubMed Central  Google Scholar 

  113. Wober C, Brannath W, Schmidt K, Kapitan M, Rudel E, Wessely P et al (2007) Prospective analysis of factors related to migraine attacks: the PAMINA study. Cephalalgia. 27(4):304–314

    Article  CAS  PubMed  Google Scholar 

  114. Calati R, Courtet P, Norton J, Ritchie K, Artero S (2017) Association between lifetime headache and history of suicide attempts in the elderly. Eur Psychiatry 41:132–139

    Article  CAS  PubMed  Google Scholar 

  115. Haque B, Rahman KM, Hoque A, Hasan AT, Chowdhury RN, Khan SU et al (2012) Precipitating and relieving factors of migraine versus tension type headache. BMC Neurol 12:82

    Article  PubMed  PubMed Central  Google Scholar 

  116. Malone CD, Bhowmick A, Wachholtz AB (2015) Migraine: treatments, comorbidities, and quality of life, in the USA. J Pain Res 8:537–547

    Article  PubMed  PubMed Central  Google Scholar 

  117. Lake AE 3rd, Rains JC, Penzien DB, Lipchik GL (2005) Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance. Headache. 45(5):493–506

    Article  PubMed  Google Scholar 

  118. Siniatchkin M, Riabus M, Hasenbring M (1999) Coping styles of headache sufferers. Cephalalgia. 19(3):165–173

    Article  CAS  PubMed  Google Scholar 

  119. Sachs-Ericsson NJ, Sheffler JL, Stanley IH, Piazza JR, Preacher KJ (2017) When emotional pain becomes physical: adverse childhood experiences, pain, and the role of mood and anxiety disorders. J Clin Psychol 73(10):1403–1428

    Article  PubMed  PubMed Central  Google Scholar 

  120. Peterlin BL, Tietjen GE, Brandes JL, Rubin SM, Drexler E, Lidicker JR et al (2009) Posttraumatic stress disorder in migraine. Headache. 49(4):541–551

    Article  PubMed  Google Scholar 

  121. Tietjen GE, Brandes JL, Digre KB, Baggaley S, Martin VT, Recober A et al (2007) History of childhood maltreatment is associated with comorbid depression in women with migraine. Neurology. 69(10):959–968

    Article  CAS  PubMed  Google Scholar 

  122. McDermott MJ, Fulwiler JC, Smitherman TA, Gratz KL, Connolly KM, Tull MT (2016) The relation of PTSD symptoms to migraine and headache-related disability among substance dependent inpatients. J Behav Med 39(2):300–309

    Article  PubMed  Google Scholar 

  123. Fuh JL, Wang SJ, Juang KD, Lu SR, Liao YC, Chen SP (2010) Relationship between childhood physical maltreatment and migraine in adolescents. Headache. 50(5):761–768

    Article  PubMed  Google Scholar 

  124. Brennenstuhl S, Fuller-Thomson E (2015) The painful legacy of childhood violence: migraine headaches among adult survivors of adverse childhood experiences. Headache. 55(7):973–983

    Article  PubMed  Google Scholar 

  125. Lee S, Tsang A, Von Korff M, de Graaf R, Benjet C, Haro JM et al (2009) Association of headache with childhood adversity and mental disorder: cross-national study. Br J Psychiatry 194(2):111–116

    Article  PubMed  PubMed Central  Google Scholar 

  126. Peterlin BL, Katsnelson MJ, Calhoun AH (2009) The associations between migraine, unipolar psychiatric comorbidities, and stress-related disorders and the role of estrogen. Curr Pain Headache Rep 13(5):404–412

    Article  PubMed  PubMed Central  Google Scholar 

  127. Corchs F, Mercante JP, Guendler VZ, Masruha MR, Vieira DS, Bernik MA et al (2011) Sensitivity to aversive stimulation, posttraumatic symptoms and migraines: what do they have in common? Med Hypotheses 77(4):534–535

    Article  PubMed  Google Scholar 

  128. Zarei MR, Shabani M, Chamani G, Abareghi F, Razavinasab M, Nazeri M (2016) Migraine patients have a higher prevalence of PTSD symptoms in comparison to chronic tension-type headache and healthy subjects: a case-control study. Acta Odontol Scand 74(8):633–635

    Article  PubMed  Google Scholar 

  129. Bottiroli S, Galli F, Viana M, Sances G, Tassorelli C (2018) Traumatic experiences, stressful events, and alexithymia in chronic migraine with medication overuse. Front Psychol 9:704

    Article  PubMed  PubMed Central  Google Scholar 

  130. Rao AS, Scher AI, Vieira RV, Merikangas KR, Metti AL, Peterlin BL (2015) The impact of post-traumatic stress disorder on the burden of migraine: results from the National Comorbidity Survey-Replication. Headache. 55(10):1323–1341

    Article  PubMed  PubMed Central  Google Scholar 

  131. Grassini S, Nordin S (2017) Comorbidity in migraine with functional somatic syndromes, psychiatric disorders and inflammatory diseases: a matter of central sensitization? Behav Med 43(2):91–99

    Article  PubMed  Google Scholar 

  132. Shulman RB (2015) Chapter 18 - the psychiatric approach to headache. In: Diamond S (ed) Headache and migraine biology and management. Academic Press, San Diego, pp 223–238

    Chapter  Google Scholar 

  133. Huss D, Derefinko K, Milich R, Farzam F, Baumann R (2009) Examining the stress response and recovery among children with migraine. J Pediatr Psychol 34(7):707–715

    Article  PubMed  Google Scholar 

  134. Borsook D, Maleki N, Becerra L, McEwen B (2012) Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Neuron. 73(2):219–234

    Article  CAS  PubMed  Google Scholar 

  135. Burstein R, Jakubowski M (2009) Neural substrate of depression during migraine. Neurol Sci 30(Suppl 1):S27–S31

    Article  PubMed  Google Scholar 

  136. Rome HP Jr, Rome JD (2000) Limbically augmented pain syndrome (LAPS): kindling, corticolimbic sensitization, and the convergence of affective and sensory symptoms in chronic pain disorders. Pain Med 1(1):7–23

    Article  PubMed  Google Scholar 

  137. Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65(9):732–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR et al (1996) A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry 53(5):380–387

    Article  CAS  PubMed  Google Scholar 

  139. Cady R, Farmer K, Dexter JK, Schreiber C (2005) Cosensitization of pain and psychiatric comorbidity in chronic daily headache. Curr Pain Headache Rep 9(1):47–52

    Article  PubMed  Google Scholar 

  140. Sances G, Galli F, Anastasi S, Ghiotto N, De Giorgio G, Guidetti V et al (2010) Medication-overuse headache and personality: a controlled study by means of the MMPI-2. Headache. 50(2):198–209

    Article  PubMed  Google Scholar 

  141. Kaczynski KJ, Claar RL, Lebel AA (2013) Relations between pain characteristics, child and parent variables, and school functioning in adolescents with chronic headache: a comparison of tension-type headache and migraine. J Pediatr Psychol 38(4):351–364

    Article  PubMed  Google Scholar 

  142. Holroyd KA, O'Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW (2001) Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA. 285(17):2208–2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Guidetti V, Galli F, Sheftell F (2010) Headache attributed to psychiatric disorders. Handb Clin Neurol 97:657–662

    Article  PubMed  Google Scholar 

  144. Balottin U, Fusar Poli P, Termine C, Molteni S, Galli F (2013) Psychopathological symptoms in child and adolescent migraine and tension-type headache: a meta-analysis. Cephalalgia. 33(2):112–122

    Article  PubMed  Google Scholar 

  145. Bruijn J, Locher H, Passchier J, Dijkstra N, Arts WF (2010) Psychopathology in children and adolescents with migraine in clinical studies: a systematic review. Pediatrics. 126(2):323–332

    Article  PubMed  Google Scholar 

  146. Mongini F, Fassino S, Rota E, Deregibus A, Levi M, Monticone D et al (2005) The temperament and character inventory in women with migraine. J Headache Pain 6(4):247–249

    Article  PubMed  PubMed Central  Google Scholar 

  147. Mattsson P, Ekselius L (2002) Migraine, major depression, panic disorder, and personality traits in women aged 40-74 years: a population-based study. Cephalalgia. 22(7):543–551

    Article  CAS  PubMed  Google Scholar 

  148. Breslau N, Davis GC (1993) Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiatr Res 27(2):211–221

    Article  CAS  PubMed  Google Scholar 

  149. Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB (2013) Psychiatric comorbidities of episodic and chronic migraine. J Neurol 260(8):1960–1969

    Article  PubMed  Google Scholar 

  150. Dodick DW (2009) Review of comorbidities and risk factors for the development of migraine complications (infarct and chronic migraine). Cephalalgia. 29(Suppl 3):7–14

    PubMed  Google Scholar 

  151. Scher AI, Stewart WF, Lipton RB (2004) Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology. 63(11):2022–2027

    Article  CAS  PubMed  Google Scholar 

  152. Hagen K, Thoresen K, Stovner LJ, Zwart JA (2009) High dietary caffeine consumption is associated with a modest increase in headache prevalence: results from the Head-HUNT study. J Headache Pain. 10(3):153–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Panconesi A (2008) Alcohol and migraine: trigger factor, consumption, mechanisms. A review. J Headache Pain 9(1):19–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Zlotnik Y, Plakht Y, Aven A, Engel Y, Am NB, Ifergane G (2014) Alcohol consumption and hangover patterns among migraine sufferers. J Neurosci Rural Pract 5(2):128–134

    Article  PubMed  PubMed Central  Google Scholar 

  155. Peroutka SJ (2014) What turns on a migraine? A systematic review of migraine precipitating factors. Curr Pain Headache Rep 18(10):454

    Article  PubMed  Google Scholar 

  156. Zaeem Z, Zhou L, Dilli E (2016) Headaches: a review of the role of dietary factors. Curr Neurol Neurosci Rep 16(11):101

    Article  PubMed  CAS  Google Scholar 

  157. Maizels M, Burchette R (2004) Somatic symptoms in headache patients: the influence of headache diagnosis, frequency, and comorbidity. Headache. 44(10):983–993

    Article  PubMed  Google Scholar 

  158. Maizels M, Smitherman TA, Penzien DB (2006) A review of screening tools for psychiatric comorbidity in headache patients. Headache. 46(Suppl 3):S98–S109

    Article  PubMed  Google Scholar 

  159. Tarantino S, De Ranieri C, Dionisi C, Gagliardi V, Capuano A, Vigevano F et al (2015) Migraine equivalents and related symptoms, psychological profile and headache features: which relationship? J Headache Pain. 16:536

    Article  PubMed  Google Scholar 

  160. Mustelin L, Raevuori A, Kaprio J, Keski-Rahkonen A (2014) Association between eating disorders and migraine may be explained by major depression. Int J Eat Disord 47(8):884–887

    Article  PubMed  Google Scholar 

  161. Ratcliffe GE, Enns MW, Jacobi F, Belik SL, Sareen J (2009) The relationship between migraine and mental disorders in a population-based sample. Gen Hosp Psychiatry 31(1):14–19

    Article  PubMed  Google Scholar 

  162. Diener HC, Holle D, Dresler T, Gaul C (2018) Chronic headache due to overuse of analgesics and anti-migraine agents. Dtsch Arztebl Int 115(22):365–370

    PubMed  PubMed Central  Google Scholar 

  163. Wanasuntronwong A, Jansri U, Srikiatkhachorn A (2017) Neural hyperactivity in the amygdala induced by chronic treatment of rats with analgesics may elucidate the mechanisms underlying psychiatric comorbidities associated with medication-overuse headache. BMC Neurosci 18(1):1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Serafini G, Pompili M, Innamorati M, Gentile G, Borro M, Lamis DA et al (2012) Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. Eur Rev Med Pharmacol Sci 16(10):1389-1398

  165. Beghi E, Bussone G, D'Amico D, Cortelli P, Cevoli S, Manzoni GC, et al. Headache, anxiety and depressive disorders: the HADAS study. J Headache Pain. 2010;11(2):141-50.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Bera SC, Khandelwal SK, Sood M, Goyal V. A comparative study of psychiatric comorbidity, quality of life and disability in patients with migraine and tension type headache. Neurol India. 2014;62(5):516-20.

    Article  PubMed  Google Scholar 

  167. Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KM. Headache and major depression: is the association specific to migraine? Neurology. 2000;54(2):308-13.

    Article  CAS  PubMed  Google Scholar 

  168. Dilsaver SC, Benazzi F, Oedegaard KJ, Fasmer OB, Akiskal KK, Akiskal HS. Migraine headache in affectively ill latino adults of mexican american origin is associated with bipolarity. Prim Care Companion J Clin Psychiatry. 2009;11(6):302-6.

    Article  PubMed  Google Scholar 

  169. Fernandez-de-Las-Penas C, Hernandez-Barrera V, Carrasco-Garrido P, Alonso-Blanco C, Palacios-Cena D, Jimenez-Sanchez S, et al. Population-based study of migraine in Spanish adults: relation to socio-demographic factors, lifestyle and co-morbidity with other conditions. J Headache Pain. 2010;11(2):97-104.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Kalaydjian A, Merikangas K. Physical and mental comorbidity of headache in a nationally representative sample of US adults. Psychosom Med. 2008;70(7):773-80.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Kececi H, Dener S, Analan E. Co-morbidity of migraine and major depression in the Turkish population. Cephalalgia. 2003;23(4):271-5.

    Article  CAS  PubMed  Google Scholar 

  172. Ligthart L, Penninx BW, Nyholt DR, Distel MA, de Geus EJ, Willemsen G, et al. Migraine symptomatology and major depressive disorder. Cephalalgia. 2010;30(9):1073-81.

    Article  PubMed  Google Scholar 

  173. McWilliams LA, Goodwin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain. 2004;111(1-2):77-83.

    Article  PubMed  Google Scholar 

  174. Molgat CV, Patten SB. Comorbidity of major depression and migraine--a Canadian population-based study. Can J Psychiatry. 2005;50(13):832-7.

    Article  PubMed  Google Scholar 

  175. Oh K, Cho SJ, Chung YK, Kim JM, Chu MK. Combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study. BMC Neurol. 2014;14:238.

  176. Peterlin BL, Rosso AL, Sheftell FD, Libon DJ, Mossey JM, Merikangas KR. Post-traumatic stress disorder, drug abuse and migraine: new findings from the National Comorbidity Survey Replication (NCS-R). Cephalalgia. 2011;31(2):235-44.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, et al. Migraine in recurrent depression: case-control study. Br J Psychiatry. 2009;194(4):350-4.

    Article  Google Scholar 

  178. Tietjen GE, Brandes JL, Digre KB, Baggaley S, Martin V, Recober A, et al. High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology. 2007;68(2):134-40.

    Article  CAS  PubMed  Google Scholar 

  179. Oh K, Cho SJ, Chung YK, Kim JM, Chu MK. Erratum to: Combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study. BMC Neurol. 2016;16:51.

  180. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life, and depression: a population-based case-control study. Neurology. 2000;55(5):629-35.

    Article  CAS  PubMed  Google Scholar 

  181. Baptista T, Uzcategui E, Arape Y, Serrano A, Mazzarella X, Quiroz S, et al. Migraine life-time prevalence in mental disorders: concurrent comparisons with first-degree relatives and the general population. Invest Clin. 2012;53(1):38-51.

  182. Brietzke E, Moreira CL, Duarte SV, Nery FG, Kapczinski F, Miranda Scippa A, et al. Impact of comorbid migraine on the clinical course of bipolar disorder. Compr Psychiatry. 2012;53(6):809-12

    Article  PubMed  Google Scholar 

  183. McIntyre RS, Konarski JZ, Wilkins K, Bouffard B, Soczynska JK, Kennedy SH. The prevalence and impact of migraine headache in bipolar disorder: results from the Canadian Community Health Survey. Headache. 2006;46(6):973-82.

    Article  Google Scholar 

  184. Oedegaard KJ, Fasmer OB. Is migraine in unipolar depressed patients a bipolar spectrum trait? J Affect Disord. 2005;84(2-3):233-42.

    Article  PubMed  Google Scholar 

  185. Smitherman TA, Kolivas ED. Trauma exposure versus posttraumatic stress disorder: relative associations with migraine. Headache. 2013;53(5):775-86.

    Article  Google Scholar 

  186. Sarchielli P, Corbelli I, Messina P, Cupini LM, Bernardi G, Bono G, et al. Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study. Eur J Neurol. 2016;23(1):85-91.

    Article  PubMed  Google Scholar 

  187. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2010;81(4):428-32.

    Article  CAS  Google Scholar 

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Acknowledgements

The European Headache Federation and the Department of Clinical and Molecular Medicine, Sapienza University of Rome, are gratefully acknowledged for supporting this work. Figure 2 was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License, https://smart.servier.com/.

Funding

This work was supported by the European Headache Federation.

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Author notes

  1. Thomas Dresler, Salvatore Caratozzolo, Raffaele Ornello and Gianluca Serafini these authors contributed equally.

Authors and Affiliations

  1. Department of Psychiatry & Psychotherapy, University Hospital Tuebingen, Tuebingen, Germany

    Thomas Dresler

  2. LEAD Graduate School & Research Network, University of Tuebingen, Tuebingen, Germany

    Thomas Dresler

  3. Neurology Unit - Neurological and Vision Sciences Department, ASST Spedali Civili of Brescia, Brescia, Italy

    Salvatore Caratozzolo

  4. Department of Neurology, University Hospital Brussels, Jette, Belgium

    Kaat Guldolf

  5. Praxis Gendolla, Specialized care for Psychiatry, Neurology, Psychotherapy and Pain Therapy, Essen, Germany

    Jana-Isabel Huhn

  6. Child Neuropsychiatry school, University of Palermo, Palermo, Italy

    Carmela Loiacono

  7. Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia

    Triinu Niiberg-Pikksööt

  8. Headache Centre & Neurocritical Care Unit, Department of Human Neurosciences, Sapienza - University of Rome, Viale dell’Università 30, 00185, Rome, Italy

    Marta Puma

  9. Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Headache Center, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Giorgia Sforza

  10. Child Neuropsychiatry Unit, ASL 3, Turin, Italy

    Anna Tobia

  11. Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy

    Raffaele Ornello

  12. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy

    Gianluca Serafini

  13. IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, Italy

    Gianluca Serafini

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  1. Thomas Dresler
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on behalf of the European Headache Federation School of Advanced Studies (EHF-SAS)

Contributions

TD, SC, GS, and RO conceived and designed the review. All authors drafted the manuscript and revised it for intellectual content. All authors read and approved the final manuscript.

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Correspondence to Gianluca Serafini.

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TD has received an honorarium for serving on an expert panel from Novartis. JIH has received travel grants and consultant fees from Allergan. All other Authors declare no competing interests.

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Dresler, T., Caratozzolo, S., Guldolf, K. et al. Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications. J Headache Pain 20, 51 (2019). https://doi.org/10.1186/s10194-019-0988-x

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Keywords

  • Migraine
  • Psychiatric disorders
  • Comorbidity
  • Biological pathways

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