Migraine is a highly prevalent disabling complex neurological disorder and a major cause of global population ill health with adverse effects on multiple domains (personal, psychosocial and economic) besides the neurobiological symptoms (1–3). Migraine remains inadequately treated despite its association with considerable disability, impaired functioning, and decreased quality of life (QoL) in patients and a substantial socioeconomic burden (2–5).

Many sleep disorders (i.e., insomnia, restless legs syndrome, sleep apnea, and daytime sleepiness) and psychiatric comorbidities (anxiety and depression in particular) are more prevalent among migraine patients than in the general population, as associated with increased headache frequency and migraine disability, poor treatment response and an increased risk for migraine progression to chronic form over time in these patients (4, 6–8).

The relationship between sleep and migraine is intricate (9). While their bidirectional comorbidity is well-established, the nature of this relationship is still not fully understood (4, 8). Patients with chronic migraine (CM) tend to experience more symptoms of insomnia compared to patients with episodic migraine (EM), suggesting a potential link between sleep disturbances and the progression of migraine (8, 10). Migraineurs are significantly more likely to suffer from poor sleep quality, insomnia and night-time fatigue (4). The frequency of headaches in CM patients decreased following insomnia treatment, highlighting the impact of sleep on migraine patterns (11). In addition, another study identified a correlation between high monthly headache frequency and diminished sleep quality within a broader population of migraine patients (12). This correlation emphasizes the complex connection between the frequency of headaches and the overall quality of sleep in individuals with migraine. Understanding and addressing these links could potentially lead to more effective strategies for managing and treating migraine in affected populations. A meta-analysis revealed that patients with migraine generally scored higher on the Pittsburgh Sleep Quality Index (PSQI) compared to healthy controls (13). Elevated PSQI scores, indicate poor sleep quality, and are associated with increased migraine-related burden (14).

Galcanezumab, a humanized monoclonal antibody (mAb) targeting calcitonin gene-related peptide (CGRP)-mediated signaling cascade, is specifically developed for migraine prophylaxis in adults with EM and CM (15, 16). Several studies have consistently shown the efficacy of galcanezumab in enhancing migraine outcomes, including improvements in functional and disability scores, all while maintaining a favorable safety and tolerability profile (15–17).

Indeed, most comorbidities are considered among the exclusion criteria in the clinical trial settings. Therefore, real-world galcanezumab studies in migraineurs with comorbidities such as sleep disorders and anxiety and/or depression are of critical importance to investigate the effectiveness of this treatment on different migraine facets beyond the reduction of both monthly headache days (MHDs) and monthly migraine days (MMDs) (16, 18). Studies on how galcanezumab treatment affects sleep in migraine patients are lacking. Our real-world study in EM and CM patients aimed to investigate the impact of the galcanezumab injection series on sleep quality and migraine outcome in addition to several multidimensional patient-reported outcome measures (PROMs) such as negative emotional states, Health-related Quality of Life (HRQoL), headache impact and migraine-related disability.

This real-world study, conducted in patients with EM and CM who had prevalent comorbidities such as sleep disorders and psychiatric problems, demonstrated that galcanezumab treatment was associated with a rapid onset and significant improvement in migraine outcomes. This amelioration included a reduction in MHDs, MMDs, and headache severity. Beyond addressing pain-related parameters, galcanezumab also proved to be effective in enhancing sleep quality in the overall study population, with the decrease in the percentage of patients reporting poor sleep quality (total PSQI scores ≥ 5) by nearly 20% from baseline to the 1st and 2nd months. Besides the overall improvement in sleep quality, galcanezumab specifically improved the total PSQI scores along with the subjective sleep quality and daytime dysfunction domains within a 3-month treatment period in the subgroup of patients with sleep disorder at baseline, and the sleep disturbances domain particularly in patients without baseline depression or anxiety. Moreover, various PROMs, such as HIT-6, MIDAS, and SF-36 HRQoL, as well as BDI and BAI, were rapidly improved following the series of galcanezumab injections. These findings collectively highlight the multifaceted positive impact of galcanezumab on both migraine-related and psychological aspects, emphasizing its potential as an effective therapeutic option in individuals with comorbidities in a real-world clinical setting.

The effect of galcanezumab on sleep parameters in our migraineurs appeared to be a comorbidity-based and domain-specific effect, which involved sleep disturbances domain in patients without depression or anxiety at baseline but the total PSQI scores, subjective sleep quality and daytime dysfunction in those with sleep disorder at baseline.

It is worth noting that, in another real-world study involving galcanezumab in patients with EM and CM, no change in sleep quality, as assessed by the Medical Outcomes Study sleep scale, was observed from baseline after the third and sixth administrations (18). These findings underscore the potential variability in treatment responses and outcomes across different populations and measurement scales in real-world settings.

In a study involving patients with EM and CM receiving erenumab, fremanezumab, or galcanezumab, the PSQI showed a significant reduction from baseline to the 3^rd month. However, it did not reach the cut-off of <5 for good sleep quality (32). The study suggests that a more prolonged treatment duration of 6–12 months with erenumab, fremanezumab, or galcanezumab may be required for substantial improvement in sleep quality, especially in CM patients. Additionally, the use of objective measures of sleep quality, such as polysomnography, may reveal positive outcomes even after 3 months of treatment (33, 34). These findings imply the potential for galcanezumab to improve sleep abnormalities over longer treatment periods. The suggestion for further investigation based on objective measures of sleep quality, such as polysomnography, indicates the need for more comprehensive and precise data on sleep parameters in patients undergoing preventive migraine treatments (18).

Although the precise mechanisms are still unclear, CGRP seems to have a role in regulating sleep and arousal. Glutamatergic neurons in the external lateral parabrachial nucleus of the mice, particularly those expressing CGRP, may play a vital role in the arousal response to elevated CO2 or hypoxia. Selective inhibition of these neurons stops waking up in response to CO2 (35). In mouse models with neuropathic pain, preventing sleep fragmentation was achieved by genetically silencing peripheral sensory neurons or ablating CGRP-positive neurons in the parabrachial nucleus (36). CGRP impacts pathways to thalamic trigeminovascular neurons, possibly affecting pain sensitivity in primary headaches during conditions like sleep deprivation (37).

The improvements in sleep parameters (total scores, subjective sleep quality and daytime dysfunction) in the subgroup of patients with baseline sleep disorder is notable given that this group accounts for 40% of the overall study population. The improvement in daytime dysfunction seems to be particularly important since the excessive daytime sleepiness was considered to have a stronger association with the migraine-related disability, compared to other sleep disturbances (i.e., deteriorated sleep quality or increased sleep apnea risk) in patients with CM (38).

Another important finding of the present study seems to be the marked improvement in sleep disturbances domain from baseline to the 3rd month in subgroups of patients with low anxiety and none/minimal depression at baseline. These findings seem notable given the complex association of sleep disturbance with depression, which may precede or follow the onset and recurrence of depression, and the likelihood of individuals with depressive symptoms to suffer from a greater burden of comorbid anxiety symptoms in case of comorbid sleep disturbance (39). Indeed, the sleep disturbance is considered an acute headache trigger for migraine and an independent risk factor for progression from episodic to chronic headache (40). Hence, our findings emphasize that migraine patients without anxiety and/or depression may effectively benefit from galcanezumab, particularly in terms of improving sleep problems through the amelioration of migraine outcomes. However, in those with comorbid anxiety and depression, the improved migraine outcome alone, without addressing the management of psychiatric disorders, may not be sufficient to effectively improve sleep problems.

Some studies reported the association of CM, compared to EM, with higher PSQI scores (worse subjective sleep quality) and higher prevalence of excessive daytime sleepiness and depressive and anxiety symptoms (13, 41, 42). Notably, while our CM and EM patients had similar change from baseline to 3rd month for PSQI total and domain scores, the sleep disturbances domain was particularly improved after galcanezumab treatment in subgroups of patients with low anxiety and none/minimal depression at baseline. Hence, while galcanezumab was effective in ameliorating depressive and anxiety symptoms, its potential to improve sleep disturbances seems to be more prominent in patients without depression or anxiety at baseline. These findings seem to support that in some migraineurs, there is no reciprocal association between negative emotional states and poor sleep quality (43–45).

The observed amelioration in MHDs and MMDs in our current study aligns with other real-world studies on galcanezumab, indicating a more extensive improvement in MHDs and MMDs than reported in randomized controlled trials RCTs (18, 46–48). Notably, in both CM and EM patients, the correlation between MMDs and scores on the MIDAS and the HIT-6 was reported to be stronger during galcanezumab treatment than their correlation recorded at baseline. This emphasizes the presence of treatment benefits extending beyond headache frequency to encompass more subtle aspects of the disease (46, 49, 50).

In our patient population, significant improvements were not only observed in migraine outcome parameters but also in several PROMs linked to migraine-related impairment in functioning. These include substantial improvements in HIT-6 and MIDAS scores, in addition to critical enhancements in SF-36 HRQoL scores. Furthermore, there was a noteworthy enhancement in all domains of HRQoL measured by the SF-36 in galcanezumab-treated patients with both EM and CM. These findings suggest the potential of galcanezumab to alleviate the existing disease burden and improve HRQoL in migraine patients, with implications for increased capabilities in work and daily activities, heightened productivity, and enhanced emotional well-being (51, 52).

Other real-world studies also indicated that monthly prophylactic treatment with galcanezumab was effective in both CM and EM, especially in reducing migraine burden and disability with significant improvements in several PROMs, including HIT-6, MIDAS, and MSQ (18, 46). In this study, the median MIDAS scores started at 50.0 at baseline, then decreased to 9.0 by the 3rd month, indicating a shift from “severe disability” to “little or no/mild” disability. Also, median HIT-6 scores were 67.0 at baseline and ranged from 56 to 58 after galcanezumab treatment, suggesting amelioration from “severe impact” to “substantial impact.” Nonetheless, while the three-month follow-up provides initial insights, extending this to 6–12 months could offer a better understanding of the long-term effects and sustainability of treatment benefits.

PROMs, reflecting the patient’s perspective and experience, are increasingly used in clinical practice to improve patient-centered care, patient engagement, and shared decision-making (53). Nonetheless, while the disability assessment tools widely used in headache research such as MIDAS and HIT-6 are useful as outcome measures, individually they cannot capture the entire experience of headache disability (54). Also, PROMs measures differ with respect to their ability to capture treatment efficacy from a patient’s perspective and to reliably indicate a patient’s real clinical improvement (54, 55). In this regard, the use of multimodal PROMs that assess migraine as well as comorbidities and QoL in our study seems to strengthen our findings, enabling a concomitant evaluation of several individual variables and a more comprehensive picture of treatment outcomes related to improvement in several domains besides the headache (54, 55).

Disability in migraine patients is a multifaceted phenomenon influenced by personal functioning and the psychological burden of the disease, in addition to the number of headache days (46). In our patient cohort, BDI and BAI scores showed significant improvement following the galcanezumab loading dose, and this effect was sustained throughout the subsequent injection series. Similarly, in another real-world study involving a cohort of 43 patients with HFEM and CM, galcanezumab treatment was associated with improved Migraine-Specific Quality of Life scores and a reduction in depressive symptoms and anxiety (18). The ability of galcanezumab to rapidly alleviate depressive and anxious symptoms is particularly notable, considering that both depression and anxiety are recognized as risk factors for migraine chronification, associated with decreased treatment response, impaired quality of life, and increased overall disease burden (18, 43, 56).

It’s worth noting that almost ~80% of our patients had comorbid sleep disorders or psychiatric diseases before galcanezumab treatment. This suggests that galcanezumab may be a favorable therapeutic option in migraine patients with a considerable burden of comorbidities. In a real-world study with CM patients, the response rate to galcanezumab was 64.3%, with daily headache, the presence of depression, and absence of accompanying symptoms of migraine identified as significant predictors of a poor response to galcanezumab treatment (57). In a post hoc analysis of the REGAIN and pooled EVOLVE-1 and EVOLVE-2 studies, a medical history of anxiety and/or depression was reported to interfere with the response to galcanezumab in patients with CM, decreasing the likelihood of a reduction in overall MHD and functional improvement in those with comorbid anxiety and/or depression (58).

The majority of our patients and physicians considered galcanezumab to be effective or very effective at each visit, and the reported TEAEs in our cohort were consistent with the well-known high safety and tolerability profile of galcanezumab (16, 18). In this context, our findings support the notion that the high tolerability of galcanezumab, facilitated by its monthly administration and sustained effectiveness, establishes a significant foundation for improved adherence and, ultimately, enhanced outcomes in patients with both EM and CM (52, 59).

This study has several limitations that should be acknowledged. Firstly, the single-center design with a limited number of participants may raise concerns about the generalizability of the findings, potentially limiting the external validity. Secondly, the analysis of data on negative emotional states and sleep quality relied on self-reported measures using PROMs rather than face-to-face psychiatric evaluations. This method may not fully capture the complexity of emotional and sleep-related conditions. Thirdly, the relatively short 3-month follow-up period might have limitations in capturing the long-term response to galcanezumab and monitoring potential risks associated with the treatment. An extended follow-up duration could provide a more comprehensive understanding of the treatment’s efficacy and safety profile over time. The association of continued treatment beyond 3 months with a likely delayed response in non-responders is recognized in the literature (43). Fourthly, absence of a control group in this real-life data is another limitation, given that inclusion of a control group for comparison would strengthen the conclusions drawn about galcanezumab’s effectiveness against standard care or placebo.

In conclusion, this real-world study indicates the likelihood of galcanezumab to be a promising and effective emerging agent for migraine prophylaxis, offering not only reduced headache days but also reduced migraine disability and improved functionality and negative emotional states. Galcanezumab demonstrates notable benefits in improving sleep quality, along with a comorbidity-based and domain-specific effect on sleep parameters, which involved sleep disturbances domain in patients without depression or anxiety at baseline but the total PSQI scores, subjective sleep quality and daytime dysfunction in those with sleep disorder at baseline. Given the improved sleep parameters in galcanezumab-treated CM and EM patients within 3-months treatment, the real potential of galcanezumab on improved sleep problems may appear in the longer term. Nonetheless, its effectiveness in population of migraineurs suffering from either comorbid sleep disorder or psychiatric disease seem to indicate the likelihood of galcanezumab to be a favorable therapeutic option in migraine patients with comorbidities. There is a need for real-world studies with longer follow-up periods assessing galcanezumab’s effectiveness against standard care or placebo to better understand effectiveness and safety profile of galcanezumab and to optimize the positioning of this new drug within the current migraine prophylaxis practice.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

This study was conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” and approved by Acibadem University School of Medicine Medical Research Ethics Committee (Approval number: 2023-20/671). The participants provided their written informed consent to participate in this study.

EI: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. TE: Data curation, Formal analysis, Investigation, Writing – review & editing. PY: Data curation, Formal analysis, Investigation, Supervision, Writing – review & editing.