Introduction

A strong relationship between migraine and psychiatric disorders has been demonstrated [1–5], the most important comorbidities being mood, anxiety, and panic disorders [2, 4, 6]. The coexistence of psychiatric disorders may have relevant clinical implications influencing quality of life and disability levels as well as the course of migraine and its final prognosis [3, 6, 7].

Migraine and depression are comorbid: in population studies individuals with migraine are from 2.2 to 4.0 times more likely to have depression [4]. Understanding the inner nature of these relationships could have practical implications for diagnosis and specific treatments. Currently, the nature of the relationship is largely unclear, because most of the literature on the topic is of an epidemiologic nature [6], while pathogenetic mechanisms and therapeutic implications have been partially explored.

The aim of this work is to briefly review the literature about the comorbidity of depression and migraine, hypothesizing a common pathogenetic and therapeutic ground.

Comorbidity of depression and migraine

The association between migraine and depression has been previously evaluated in young adults by a number of population-based, cross-sectional studies.

In a population of patients aged over 65 years, Wang et al. [8] found that the risk of current depression was greater in elderly migraine patients than in non-migraine. Lipton [9] confirmed a higher risk of current depression among migraineurs, in a population-based case–control study conducted in a community setting.

Merikangas et al. [10] investigated 457 younger subjects and found a strong association between migraine and major depression (OR 2.22, 95% CI 1.1–4.8) in migraineurs compared to controls. In a population-based study, Breslau et al. [11] found that migraine was strongly associated with major depression (sex-adjusted OR 3.5, 95% CI 2.6–4.6).

In a prospective population-based study, Swartz et al. [12] confirmed a strong association between migraine and major depression (OR 3.1, 95% CI 2.0–4.8).

Prevalence of major depression in migraineurs accounts for about 28% of subjects [13, 14]. Increased rates of depression were found in migraine sufferers, with a higher prevalence in those with migraine with aura than in those with migraine without aura; this difference being present also as far as suicide attempt rates [15–17].

Some longitudinal studies have shown that the relationship between migraine and depression is bidirectional: one disorder may increase the risk for the other and vice versa [5, 11, 18, 19]. In these studies, the risk of first-onset migraine in people with pre-existing depression ranged from 2.8 to 3.5 and, conversely, the risk of first-onset depression in people with preexisting migraine ranged from 2.4 to 5.8 [8].

Findings of a bidirectional relationship between migraine and depression suggest a common neurobiology.

Possible mechanisms underlying this relationship

Common pathogenetic mechanisms between migraine and depression have been hypothesized, including drug overuse, serotoninergic and dopaminergic dysfunction, ovarian hormone fluctuation and central sensitization [6, 20].

A serotoninergic dysfunction may be a possible common pathogenetic mechanism. Polymorphisms in the serotonin (5-HT) transporter have been associated with susceptibility to migraine [21–23] and frequency of attacks [24]. In migraineurs, increased concentrations of 5-HT during migraine attacks and decreased plasma levels of 5-HT between the attacks have been demonstrated [25]. A chronic low serotoninergic availability may predispose to cortical spreading depression and increases sensitivity of trigeminovascular pathways involved in migraine [25]. The 5-HTTLPR polymorphism in the promoter region of the 5-HTT gene is associated with depression and may influence sensitivity to stress and anxiety [26–30]. In addition, the efficacy of medications that increase central serotonin levels—such as selective serotonin agonists (triptans) or selective serotonin reuptake inhibitors (SSRI)—offers an indirect evidence for a shared serotoninergic dysfunction.

There is an evidence about the role of dopamine in migraine and in depression. An association between a particular dopamine D2 receptor genotype and comorbid migraine with aura, major depression and generalized anxiety disorders [31] has been reported. In addition, migraine prodromes are often characterized by dopaminergic symptoms and antidopaminergic compounds can often be helpful to treat them [32].

Migraine and depression are 2–3 times more common in women than in men [33, 34]. Ovarian hormones appear to play an important role in migraine as well as in depression through modulation of many neurotransmitters [35]. In fact, female migraineurs often experience migraine attacks associated with the fall of estrogen levels due to menses, and many women may suffer from mood disturbance during menses as well as during postpartum and perimenopausal period. In the late luteal phase of the menstrual cycle, women are at particular risk for migraine attacks and depression: during menses as the estrogen levels precipitously decline in association with an up-regulation of the sympathetic system and a down-regulation of the serotoninergic and GABAergic systems [36].

Both in migraine and depression, everyday experience indicates that the frequency of attacks can increase with time, and progress to chronic status, with poor recovery between episodes and development of drug resistance. This suggests that sensitization phenomena may underlie both disorders [37]. Some studies have hypothesized the implication of numerous sensory and emotional neural network [38–40].

There are many clinical evidences supporting the fact that depression plays a role in processing and perception of pain, and that depressed patients are more vulnerable to pain. Cutaneous allodynia is a clinical marker of central sensitization: it is common in both frequent and chronic migraine and in anxiety and depression [7, 41, 42].

Welch et al. [43] have shown the dysfunction of periaqueductal gray area in very frequent migraine; Videbech et al. [44] have reported evidence that repeated episodes of unipolar depression are able to reduce hippocampal volume.

The dysregulation of the hypothalamic-pituitary adrenal (HPA) axis seems to be involved in migraine and affective disorders [45, 46]. A proinflammatory mechanism has been hypothesized as a possible link between affective disorders, migraine and obesity [47], and the progression from episodic migraine to chronic migraine, with dysfunctions in tryptophan metabolism, serotoninergic transmission activation of HPA axis activation [47, 48].

Clinical and therapeutic implications

The first clinical implication of the previous considerations is that all patients presenting with frequent episodic or chronic migraine should be screened for psychiatric disorders and particularly for depression [49]. Secondly, the most appropriate treatment strategies for patients with comorbid migraine headaches and depression should be defined. It is known that psychiatric comorbidity contributes to poor prognosis and poor quality of life; on the other hand, there is a little evidence about treatment outcomes in patients with migraine and depression comorbidity. Heckman et al. prospectively examined the relationship between psychiatric disorders and treatment outcomes in a group of patients with primary headaches. Migraineurs with psychiatric comorbidity are certainly difficult patients, but their expectations to improve are enhanced if psychiatric comorbidity is treated [50].

Literature data supporting a common pathogenetic ground for migraine and depression have not been adequately supported by scientific evidence on therapeutic efficacy of antidepressants. Although different antidepressants generally share a comparable efficacy in the treatment of depressive disorders, available data on their efficacy in headache prophylaxis are not definitive, and vary for the different classes/compounds. Specific therapeutic guidelines for the treatment of depression in migraineurs are lacking [6, 7]. Drugs which could negatively influence mood, such as flunarizine and beta-blockers, should be avoided [7]. Amitriptyline could be considered, but clinicians should know that the dose required for treating migraine may be insufficient to treat depression, and its adverse event profile should always be taken into account [51]. Nortriptyline, an active metabolite of amitriptyline commonly used for depression, has not been proven as a headache preventive agent [51]. Poor evidence supports the use of SSRI and serotonin norepinephrine reuptake inhibitors (SNRI) as migraine preventive agents, and their efficacy in treating both comorbid depression or anxiety and migraine symptoms has not been clearly demonstrated [7, 52, 53]. A number of studies reported an appreciable benefit in migraine prevention for sertraline, fluoxetine and venlafaxine [7, 53]. We note that only venlafaxine has been included among the compounds suggested for migraine prophylaxis by the recently published European Guidelines, the only other antidepressant being amitriptyline [54].

We note that future studies are needed to explore also possible surgical options. Chronic vagal nerve stimulation may be one of these, as it seems effective in depressive disorders [55], and preliminary data suggested its efficacy in patients with refractory chronic migraine and comorbid depression [56].

Conclusive remarks

The relationship between migraine and depression is still incompletely understood. Findings indicating a bidirectional influence between migraine and depression suggest common neurobiological mechanisms. There is a lack of studies concerning therapeutic strategies in patients with migraine and depression. Further studies are needed both to improve our understanding of this comorbidity and to address adequate treatment strategies in this clinically relevant subgroup of patients.