The present study demonstrated a strong association between migraine and stress-related disorders. Female predominance observed in this study is consistent with previous Indian and international studies, likely due to hormonal and psychosocial factors. Young adults were more commonly affected because of occupational stress, academic pressure, family responsibilities, and lifestyle changes. Anxiety and depression emerged as the most common psychiatric comorbidities. Stress acts as both a triggering and aggravating factor for migraine attacks. Chronic activation of stress pathways results in neurochemical alterations involving serotonin, norepinephrine, and cortisol, thereby contributing to migraine pathophysiology. Sleep disturbances observed in migraine patients may further worsen headache frequency and emotional instability. Similar findings have been reported in previous studies conducted in India and abroad. The retrospective nature of the study limits causal interpretation; however, the findings emphasize the importance of psychological assessment in migraine management. Migraine is one of the most prevalent disorders in the world. Mood disorders, such as depression and anxiety, similarly, have a high prevalence rate across various geographic locations and populations. Comorbidity means the coexistence of any additional ailment in a person with an index disease [1]. It has been definitely established by numerous population and clinical research studies that mood disorders are comorbid with migraine with a frequency more than would be expected by chance [2] For example, major depression was present in 8.6%–47.9% of individuals with migraine in a meta-analytic study [3] while one study found migraineurs to be 4 or 5 times more likely to suffer from generalized anxiety disorder [4]. These issues are of more than academic interest for the following reasons. One, in diagnosis, as the presence of one disorder, migraine, should prompt the clinician proactively to search for mood disorders and vice versa. Secondly it helps in the management, as management of both migraine and mood disorders are necessary for optimum and quick recovery. For example, the presence of untreated depression has been found to be a risk factor for conversion of low-frequency episodic migraine to chronic migraine [5] Third, comorbid depression and anxiety also are associated with poorer long-term headache outcomes, higher medical costs, healthcare utilization, and increased headache-related disability [6]. Hence, from a public health perspective, measures to reduce the disability of migraine should include both disorders. Finally, a detailed study of the common epidemiological as well as anatomical and neurochemical associations between the two disorders may well give valuable clues regarding their etiology and pathogenesis. We hypothesized that comorbid mood disorders are more common in migraineurs and that the disability in such patients would be more. The present study was conducted to study the prevalence of mood disorders in migraineurs uncomplicated by other types of headaches, to identify any migraine-related clinical features which may be associated with co-morbid mood disorders, and to compare migraine-related disability in patients with and without comorbid mood disorders.

The cases were identified to have migraine by International Classification of Headache Disorder 3 beta criteria. Each patient was evaluated in detail with a questionnaire with details regarding the duration of headache, frequency and duration of each episode, site, quality and severity of pain, auras, migraine accompaniments such as photo or phonophobia, nausea, vomiting as well as triggers. To assess disability, Migraine Disability Assessment Questionnaire (MIDAS) was applied to all patients. The MIDAS is a well-validated method [7] and consists of five questions to be answered by the patient about the impact of migraine headaches in the past 3 months on their personal, professional and social lives as well another section regarding severity and frequency of these headaches. A score of 6 or more is taken as positive with cut offs for mild, moderate, and severe disability. The presence of concurrent anxiety and mood disorders was assessed by the Hospital Anxiety and Depression Scale (HADS) [8]. This consists of 14 items in two subscales, HADS-Anxiety and HADS-Depression, each with 7 items. Each item expresses the subjective experience of the respondent in the preceding week and is rated 0–3, with zero indicating the maximum symptom severity. The sum of each subscale has a potential range from 0 to 21. A score of 11 or more was taken as positive for either anxiety or depression depending on the subscale. Neuro-imaging studies (magnetic resonance imaging) were done in all patients to rule out structural lesions, in addition to blood counts, erythrocyte sedimentation rate, and routine blood biochemistry.

A total of 200 patients were studied during the study. The sample consisted mostly of (n = 160, 80%) of middle age (20-50 years) Individuals with mean (standard deviation [SD]) of age of 35.12 (8.58) years. It was a female predominant sample (n = 138, 69%). As per HADS score, among the 22 patients (11%) suffering from depressive symptoms, 50% had borderline abnormal score and 16% (n = 32) had abnormal score whereas among the 27 persons (54%) suffering from anxiety 18% had borderline score and 50% had abnormal score. Mean HADS score (SD) of depression was 11.24 (3.04) while that of anxiety was 13.81 (2.71). Median of duration of headache was 6 years with SD of 6.5 years. Here, duration of disease was not normally distributed, so nonparametric statistics were applied. Though female individuals had more duration of illness (mean rank: 69.87), it was not significantly different (P = 0.04) from males (mean rank: 58.47). Middle-aged individuals suffered more duration of illness than other age groups (P < 0.04). Mean rank of the frequency of headache attacks in case of females was 71.4 (P < 0.04). Thus, females had more frequency of illness. No correlation between gender/age group and frequency of headache attacks was found. 75% (n = 150) of individuals had nausea and vomiting. No association with gender or age group with nausea or vomiting was found. 62% (n = 124) had photophobia and photophobia. The clinical correlates between migraine and mood disorders are summarized in the appended No association was found between mood symptoms and age or gender group with mood changes. 25% (n = 50) of patients suffered from mood changes. No association was found between mood changes and gender or age group. In addition, no association was found between photo and phonophobia symptoms and mood changes. The correlation was found between mood changes and frequency of headache attacks (P = 0.03) which signifies that the more the frequency of migraine headaches the more the chance of having mood symptoms and vice versa. There was no correlation between occurrence/severity of mood changes and total duration of illness. 16% (n= 32) individuals had aura with the migraine episodes. There was no association between aura and mood changes. Median (SD) of the duration of attack (h) was 8 (9.5). The more the attack duration, the more severe were the mood changes (mean rank 80.11), and this was significantly correlated (P = 0.01). Only 15% (n = 30) had menstrual headache and 2% (n = 4) had menstrual mood changes. There was no significant correlation with mood changes and menstrual headaches. Regarding disability, as per MIDAS, 40% (n = 80) had no disability, 3% (n = 6) had mild disability, 32% (n = 64) had moderate disability, and 26% (n = 52) had severe disability. A significant association was present between MIDAS score severity with mood changes (P < 0.001) and between severity of the mood changes with severity of disability. Table 1: Clinical and demographic profile Parameter Gender (M/F) 62 (31%)/138 (69%) Age group (Mean±SD) 35.12±8.58 years HADS score Depression (Mean±SD) 11.24±3.04 Anxiety ((Mean±SD) 13.82±2.72 Table 2: Relation between migraine associated features and mood changes Parameter P value Gender 0.31 Age group 0.24 Photophobia and phonophobia 0.57 Frequency 0.01 Total duration of migraine 0.5 Aura 0.51 Attack duration of each episode 0.01 Disability 0.001

Migraineurs are 2.5 times more likely to be depressed than those without migraine [9,10] and 2–5 times more likely to have anxiety disorders [11]. However, various studies have demonstrated highly variable prevalence rates of mood disorders in migraine. For example, the meta-analytic study [12] alluded to above, reported the existence of comorbid major depressive disorder in 8.6%–47.9% of migraineurs. Indeed, a few studies have not found an association between migraine and depression [13]. This is likely due to differences in the inclusion criteria (for example the presence of other type of concurrent headaches), clinic epidemiological variations between different geographic populations as well as differences between the different scales used to demonstrate psychopathology. Similarly, many studies have confirmed the comorbidity of migraine and anxiety disorders [11,14,16]. In fact, the association between migraine and anxiety disorders is even stronger than affective disorders [17]. The majority of migraineurs (51%–58%) will meet criteria for at least one anxiety disorder during their lifetimes [18]. Generalized anxiety disorders and social phobia were the commonest anxiety disorders associated with migraine. Many epidemiological studies indicate that anxiety disorders are nearly twice as common among migraineurs as is depression [18,20]. Several authors have proposed that the onset of anxiety disorders precedes migraine which in turn precedes depression onset [12]. Analysis of data obtained from our study confirms our hypothesis. 16% of the study population had anxiety, and 11% had depressive symptoms. Mood disorders observed more commonly in migraine than would be expected by chance and the disability in these patients is significantly more than in individuals without mood disorders. We have carefully excluded cases with other types of headaches especially tension-type headaches and analgesic overuse headaches. This is of vital importance as tension-type headaches are independently strongly associated with depression [20,21] while analgesic dependent headaches can significantly worsen disability in migraineurs. Hence, we have also carefully excluded individuals on prophylactic migraine medicines. This is to nullify the effect of commonly used prophylactic medicines such as beta-blockers, flunarizine, and topiramate which can cause adverse mood reactions such as depression and cognitive slowing. The HADS score was selected as it is a well-validated, convenient and suitable to application in an outpatient department setting as well as the fact that it emphasizes the subjective manifestations of anxiety and depression and does not include any questions regarding somatic or pain symptoms which may paradoxically include headache as well.

Migraine is strongly associated with stress-related disorders such as anxiety, depression, and sleep disturbances. Psychological stress significantly increases the frequency and severity of migraine attacks. Early diagnosis and integrated management involving neurologists, psychiatrists, and psychologists can improve treatment outcomes and quality of life among migraine patients. Stress management techniques, counseling, lifestyle modification, yoga, meditation, and psychiatric intervention should be considered essential components of migraine treatment in the Indian healthcare setting. We concluded that the mood disorders are comorbid with migraine at a rate comparable to or less than that described in many studies in international literature and the occurrence of mood disorders significantly contributes to migraine associated disability.

1. Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis. 1970; 23:455–68. 2. Baskin SM, Lipchik GL, Smitherman TA. Mood and anxiety disorders in chronic headache. Headache. 2006;46(Suppl 3): S76–87. 3. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi P, Costa A, et al. Migraine and psychiatric comorbidity: A review of clinical findings. J Headache Pain. 2011; 12:115–25. 4. Breslau N. Psychiatric comorbidity in migraine. Cephalalgia. 1998;18(Suppl 22):56–8. 5. May A, Schulte LH. Chronic migraine: Risk factors, mechanisms and treatment. Nat Rev Neurol. 2016; 12:455–64. 6. Smitherman TA, Maizels M, Penzien DB. Headache chronification: Screening and behavioral management of comorbid depressive and anxiety disorders. Headache. 2008; 48:45–50. 7. 7.Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the migraine disability assessment (MIDAS) questionnaire to assess headache-related disability. Neurology. 2001;56: S20–8. 8. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67:361–70. 9. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life, and depression: A population-based case-control study. Neurology. 2000; 55:629–35. 10. 10. Zwart JA, Dyb G, Hagen K, Ødegård KJ, Dahl AA, Bovim G, et al. Depression and anxiety disorders associated with headache frequency. The Nord-Trøndelag health study. Eur J Neurol. 2003; 10:147–52. 11. Breslau N. Psychiatric comorbidity in migraine. Cephalalgia. 1998;18(Suppl 22):56–8. 12. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi P, Costa A, et al. Migraine and psychiatric comorbidity: A review of clinical findings. J Headache Pain.2011;12:115–25. 13. Wacogne C, Lacoste JP, Guillibert E, Hugues FC, Le Jeunne C. Stress, anxiety, depression and migraine. Cephalalgia. 2003; 23:451–5. 14. Breslau N, Davis GC. Migraine, physical health and psychiatric disorder: A prospective epidemiologic study in young adults. J Psychiatr Res. 1993; 27:211–21. 15. Oedegaard KJ, Neckelmann D, Mykletun A, Dahl AA, Zwart JA, Hagen K, et al. Migraine with and without aura: Association with depression and anxiety disorder in a population-based study. The HUNT studies. Cephalalgia. 2006; 26:1–6. 16. Devlen J. Anxiety and depression in migraine. J R Soc Med. 1994; 87:338–41. 17. Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Results of the Zurich cohort study of young adults. Arch Gen Psychiatry. 1990; 47:849–53. 18. Baldacci F, Lucchesi C, Cafalli M, Poletti M, Ulivi M, Vedovello M, et al. Migraine features in migraineurs with and without anxiety-depression symptoms: A hospital-based study. Clin NeurolNeurosurg. 2015; 132:74–8. 19. Smitherman TA, Kolivas ED, Bailey JR. Panic disorder and migraine: Comorbidity, mechanisms, and clinical implications. Headache. 2013; 53:23–45. 20. Saunders K, Merikangas K, Low NC, Von Korff M, Kessler RC. Impact of comorbidity on headache-related disability. Neurology. 2008; 70:538–47. 21. De Benedittis G, Lorenzetti A. The role of stressful life events in the persistence of primary headache: Major events vs.daily hassles. Pain. 1992; 51:35–42. 22. Stronks DL, Tulen JH, Pepplinkhuizen L, Verheij R, Mantel GW, Spinhoven P, et al. Personality traits and psychological reactions to mental stress of female migraine patients. Cephalalgia. 1999; 19:566–74.