Association of Migraine Headache With Depression, Anxiety, and Stress in the Population of Makkah City, Saudi Arabia: A Cross-Sectional Study

Introduction Migraine is characterized by persistent headaches and a wide range of symptoms, such as nausea, vomiting, and photophobia. The chance of developing a chronic migraine might be increased by lifestyle variables like obesity, stress, and excessive medication use. According to previous studies in Saudi Arabia, migraines are more common there than they are globally. The study aimed to examine the migraine associations with depression, anxiety, and stress in the population of Makkah City, Saudi Arabia. Methods The study employed a descriptive cross-sectional design with a non-probability snowball sampling technique and an online questionnaire that included sociodemographic characteristics, the International Classification of Headache Disorders-3 (ICHD-3) criteria for migraine assessment, and the Depression, Anxiety, and Stress Scale-21 (DASS-21) measure for depression, anxiety, and stress. Results Our study included 418 participants, out of whom 73.7% were female and 26.3% were male. Regarding migraine, only 8.9% of participants met the ICHD-3 criteria for migraine headache screening, with a female predominance (78.4%). The study showed a high prevalence of depression, anxiety, and stress among the population (63.9%, 63.6%, and 55%, respectively), with females having a higher prevalence. Depression, anxiety, and stress had an equal prevalence of 78.4% among migraineurs, which was significantly higher than that of non-migraineurs. Conclusions The study found significant associations between migraine and depression, anxiety, and stress. This study provides insights into the association between these conditions. The study's findings suggest the need for screening and management of mental health conditions in patients with migraine. However, extensive efforts are needed to be applied in different cities and demographics for a more precise understanding of the association.


Introduction
Migraine is a primary headache disorder characterized by recurrent attacks of mostly unilateral headaches that are frequently accompanied by nausea, vomiting, and light sensitivity [1]. It is caused by the activation of a deep-brain mechanism that results in the production of pain-inducing inflammatory substances around the head's nerves and blood vessels [2]. Migraines are classified into two types: migraine with aura (MA) and migraine without aura (MO) [3]. Lifestyle-related factors can significantly increase the likelihood of developing migraines and the consequences on the quality of life (QoL). The most important modifiable risk factors for chronic migraine include overuse of acute migraine medication, depression, obesity, and stressful life. In addition, age, female gender, and low educational status are non-modifiable risk factors that increase the risk of chronic migraine [4]. It could be avoided if environmental, nutritional, and behavioral triggers were identified and managed [5]. 1 2 2 2 2 2 2 2 3 According to the Global Burden of Disease (GBD), headache disorders are the most prevalent and disabling diseases worldwide. The global prevalence of active headache disorders was 52.0%, of which migraine accounted for 14.0% of these cases [6]. The prevalence of migraine in Saudi Arabia is considerably higher than global averages [7]. A local study has reported the prevalence of migraine headaches to be 37.2%, with a higher prevalence among females (81.1%) and the highest prevalence observed among students (43.3%) [8]. Speaking of mortality, migraine headaches are unlikely to cause death directly. However, due to a higher risk of cardiovascular events, mortality rates were higher in women with migraine with aura [9]. A recent study conducted in Saudi Arabia reported prevalence data for depression, anxiety, and stress among the general population and found a depression prevalence of 28.9%, an anxiety prevalence of 16.4%, and a stress prevalence of 11.9% [10].
In a cross-sectional observational study conducted by Pearl et al. on 567 predominantly female (87.3%) migraine patients, they found a positive correlation between the patient's Migraine Disability Assessment Scale (MIDAS) and their Patient Health Questionnaire 2 (PHQ-2) [11]. AlQarni et al. conducted a descriptive cross-sectional survey in the Aseer region of Saudi Arabia on 1123 adults, of whom 152 (13.5%) reported no headache, 833 (74.2%) had non-migraine headaches (NMH), and 138 (12.3%) had migraine headaches, depression was reported in 26.1% of migraine patients, compared to 10.9% and 6.6% in NMH cases and adults with no headache, respectively [12].
Another study, conducted in Saudi Arabia, assessed 247 migraine patients aged between 16 and 45 years using the Depression Anxiety Stress Scale (DASS-21) questionnaire and found that 73.3% of the patients met the criteria for anxiety, while 70.9% and 72.3% of patients met the criteria for depression and stress, respectively [13]. Furthermore, a study on 1340 female students at Taif University in Saudi Arabia found that 32.5% of them have migraines and report the main triggers for migraines and stress and anxiety. The study also reported that 51.8% of migraine students were depressed [14]. Additionally, a study conducted in 2012 that aimed to assess the role of depression in migraine chronification concluded that depression is a significant predictor of migraine chronicity [15].
As per the author's knowledge, this was the first study conducted to assess the relationship between migraine headaches and anxiety, depression, and stress in Makkah City, Saudi Arabia, while only a few studies have been conducted worldwide. Therefore, the study aimed to increase understanding of the association of migraine headaches with depression, anxiety, and stress among the population of Makkah City, Saudi Arabia, and to develop more effective strategies for managing these conditions in this specific cultural and environmental context.

Study design
The study employed a descriptive cross-sectional study design with a non-probability snowball sampling technique as the sampling method. An online questionnaire (in Arabic) consisting of three parts was used for sociodemographic characteristics (Appendix). In addition, the International Classification of Headache Disorders (ICHD-3) criteria for migraine assessment and the DASS-21 measured the association between depression, anxiety, and stress in migraine patients [16,17]. The questionnaire was transferred to Google Forms and administered electronically to participants via social media platforms.
Data were extracted, reviewed, coded, and entered into BlueSky Statistics version 10.2.1 statistical software. The results were presented as frequencies and percentages. Descriptive statistics were obtained for all sociodemographic variables, including participants' age in years, gender, nationality, marital status, education level, occupation, and family monthly income in Saudi Riyal (SAR), and analysis based on frequency and percent distribution was performed for these sociodemographic variables. Migraine prevalence was estimated using ICHD-3 criteria, and the symptoms' frequencies and percentages were plotted in a graph. As for DASS-21, frequency and percentage were tabulated for depression, anxiety, and stress with the following different levels: normal, mild, moderate, severe, and extremely severe for all participants. The chi-square test was used to assess the association between demographics and migraine, demographics and depression, anxiety and stress, and lastly, depression, anxiety, and stress with migraine. A significant association was determined by a p-value of <0.05.

Ethical part and confidentiality
Consent was obtained from each participant through the questionnaire. The aims of the research were stated in the questionnaire form for all participants. Additionally, all participants' identities were kept anonymous and confidential. The responses were only accessible to the investigators. Ethical approval was obtained from the Biomedical Ethics Committee of Umm Alqura University (UQU) (#HAPO-02-K-012-2023-02-1476).

Results
A total of 567 individuals participated in the study. One participant was excluded considering he was under the age of 18 years, and 148 were excluded because they lived outside of Makkah City, leaving the included sample size at 418. The sociodemographic data in Table 1 Figure 1 shows that only 37 (8.9%) of the 418 participants met the ICHD-3 criteria for migraine headache screening. A pulsating headache was the most frequently reported symptom, as shown in Figure 2, followed by photophobia and phonophobia (83.8% and 81.1%), followed by nausea and/or vomiting at 70.3%. Moderate-to-severe headaches were reported in 64.9% of participants, and 50% of them reported that their headache was unilateral. Depression prevalence results are presented in Table 2 Table 3 shows that females had a higher prevalence of migraine than males, with 29 (9.4%) females and eight (7.3%) males. The prevalence rates for age groups 36-45 and 18-25 were eight (11.3%) and 22 (11.2%), respectively. Participants aged 46-55 years scored the lowest prevalence of migraine at 3.4%. No sociodemographic variable was significantly associated with migraine.

TABLE 3: Association between migraine headache and sociodemographic variables.
As shown in Table 4, females had a depression prevalence rate of 67.3% (207), of which the mild, moderate, severe, and extremely severe depression prevalence rates were 11.7% (36), 21.1% (65), 10.1% (31), and 24.4% (75), respectively. Depression prevalence was highest among those aged 18-25 years (71.4%), followed by adults aged 26-35 years (68.4%). Participants aged 55 years and above had the lowest prevalence of depression (36%). Single participants showed a higher prevalence of depression (72.9%), followed by divorced participants (70%) when compared to married participants (54.9%). Participants with family monthly income of 0-5,000 (SAR) scored the highest prevalence of depression at 76.2%, followed by participants with family monthly income of >20,000 (SAR) and 15,001-20,000 (SAR) at 64.7% and 64.2%, respectively, while the lowest rate of prevalence was among those with family monthly income of 10,001-15,000 (SAR) at 54.5%. The only significant variables in the association between depression and sociodemographic data were gender (p=0.003), marital status (p=0.033), and monthly family income (p=0.0049).     *P-value<0.01 is statistically highly significant. Table 7, the prevalence of mild, moderate, severe, and extremely severe depression in respondents suffering from migraines was two (5.4%), eight (21.6%), five (13.5%), and 14 (37.8%), respectively, when compared to non-migraineurs, who had a prevalence of 48 (12.6%), 74 (19.4%), 44 (11.5%), and 72 (18.9%), respectively. When it comes to anxiety, migraineurs reported no mild anxiety but a higher prevalence of moderate anxiety (5, 13.5%), severe anxiety (  The purpose of this cross-sectional study was to determine the relationship between migraine headaches and depression, anxiety, and stress in the Makkah City, Saudi Arabia, population. Our study findings revealed that only 8.9% of the study participants reported experiencing migraines. The study's migraine prevalence is lower than the global prevalence of 14% [6]. This contradicts the findings of a previous study, which concluded that migraine prevalence in Saudi Arabia is higher than the global average [7]. The most reported symptom was a pulsating headache, followed by photophobia, phonophobia, nausea, and vomiting. A higher prevalence result was reported for the female gender, which was also consistent with findings reported in a previously published study [11][12][13]. This gender difference can be explained by the fluctuations in estrogen and progesterone, which have been associated with migraine pathogenesis [18].

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The number of participants who reported normal scores regarding depression was 151 (36.1%), 152 (36.4%), and 188 (45%) for anxiety and stress. A larger proportion of participants (63.9%) reported mild, moderate, severe, or extremely severe depression, which is also found to be an alarming increase in prevalence when compared with a previous 2021 study conducted in the city of Jeddah, Saudi Arabia, studying the prevalence of migraine and its effect on QoL among the general population that concluded a depression prevalence of 37.2% [8]. In the current study, the reports of mild, moderate, severe, or extremely severe anxiety were (63.6%), and the reports of mild, moderate, severe, and extremely severe stress were (55%). The results indicate an increase in prevalence when compared to the findings of a recent 2020 study in Saudi Arabia that aimed to study the prevalence of depression, anxiety, and stress among the general population and found an anxiety prevalence of 16.4% and a stress prevalence of 11.9%. This difference could be attributed to the variation in sample demographic characteristics [10]. The findings of the current study reported that gender was significantly associated with depression, anxiety, and stress, with females being more susceptible to all of them. Additionally, depression and stress were strongly associated with marital status, with singles and divorcees being more susceptible. Despite female susceptibility to depression, anxiety, and stress, a recent 2021 study in the region demonstrated an insignificant association between gender and marital status (p>0.05) [13].
Our study found that depression, anxiety, and stress were all significantly associated with migraine, with an equally high prevalence of 78.4% among migraineurs. This is consistent with a previous study conducted among migraine patients in Saudi Arabia, which found abnormal scores for depression (70.9%), anxiety (73.3%), and stress (72.3%) [13]. Another 2020 study conducted in North America studied the impact of depression and anxiety symptoms in migraineurs and found a corresponding percentage of anxiety prevalence (75.3%), but the prevalence of depression was significantly lower (18%) [11].
The bidirectional relationship between depression and migraine has been observed in previous studies, with depression being a strong predictor of the progression of migraine [15]. However, the exact mechanism underlying this association is unclear, but one hypothesis suggests that it may be due to low levels of 5hydroxytryptamine (5-HT) or serotonin receptors [19]. As for anxiety, a study conducted in Taif City reported anxiety as one of the main triggers for migraine attacks [14]. Another study conducted in Jeddah also found that stress and anxiety accounted for 81.6% of the observed triggering factors for migraines [8]. Furthermore, stress was identified as a migraine trigger in the Taif City study [14].
The concurrent presence of depression, anxiety, and stress with migraine can significantly affect the QoL of affected individuals. We recommend screening patients with migraines for the presence or development of these mental health conditions, as well as the need to manage them effectively. It is critical to prevent the development of anxiety disorders and depression in migraine patients, which can be accomplished by reducing the number of headache episodes with effective prophylactic pharmacotherapy. We also recommend that further studies be conducted to better understand the relationship between migraine and these mental health disorders in order to develop a more coordinated and direct approach to aid in the diagnosis and management of these conditions.

Limitations
Despite making an effort to obtain accurate, precise, and representative outcomes, this study encountered certain limitations. Firstly, collecting data using an online questionnaire has inherent limitations. Second, the majority of the respondents were female (73.7%), Saudi (94.0%), and had a university-level education (76.1%). Another limitation is that the migraine prevalence in the study sample is relatively small (8.9%). These factors may have resulted in unintended biases in the findings. It is important to consider these limitations when interpreting the results of the study and to use caution when generalizing the findings to other populations or contexts. Nonetheless, this study provides insight into the current situation and confirms the outcomes of previous global and local research on the subject. The study used standardized measures to assess migraine headaches, depression, anxiety, and stress, which increases the reliability and validity of the study findings. More research in this area is required, using different methodologies, focusing on different sociodemographic characteristics, and exploring other unexplored regions of Saudi Arabia.

Conclusions
Our study provides valuable insights into the association between migraine and depression, anxiety, and stress in the population of Makkah City. The findings highlight the importance of screening and effective management of mental health conditions in patients with migraine to improve their QoL, as the results showed a significant association between migraine and depression, anxiety, and stress. Further studies with a larger sample are warranted in different cities and demographics to better understand the relationship between these conditions and develop more effective interventions.