Psychological and Biological Markers of Refractory Migraine

Study Overview
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Brief Summary
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The term refractory migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against Calcitonin Gene Related Peptide (CGRP). Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study on the efficacy of a CGRP-targeting monoclonal antibody in Chronic Migraine (CM) patients with at least 3 failures to previous preventive treatments, the investigators showed a higher prevalence of psychological disturbances in those who did respond to the monoclonal antibody compared with the responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological evaluations are available to explain how psychological comorbidities may contribute to treatment refractoriness. Isolated clinical evidence and growing pre-clinical evidence suggests a role for the endocannabinoid system in migraine. Hence, the present study aims to identify psychological and biological factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP.

Detailed Description
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Migraine is a common and highly disabling condition, representing the second-leading cause of disability in the global ranking of most disabling diseases . In the majority of individuals, the disease manifests as episodic (EM), with attacks recurring weekly or monthly. In a smaller (2-3% of the general population), but still significant portion of patients, migraine becomes chronic, i.e., occurring on at least 15 days per month (CM). Previous studies have shown that CM patients are characterized by the presence of multiple psychiatric comorbidities compared with subjects with episodic migraine and healthy controls. In recent years, it has also been shown that among the neurobiological systems involved in the genesis and development of mental disorders, the endocannabinoid system (ES) appears to play an active role. In particular, patients with these disorders are characterized, at the level of peripheral cells, by a gene alteration of cannabinoid receptors. Several studies reported the involvement of SE in immune responses, psychological processes, transduction of neurobiological signals and pain, including migraine pain. Recently it has been shown that the peripheral gene expression of enzymes involved in the metabolism of anandamide (AEA) and 2-aciglycerol (2-AG), the two best known endocannabinoids, is altered in migraine patients, but more markedly in the chronic subtype, suggesting a role for these lipid molecules not only in the pathophysiology of the disease, but also in its exacerbation. The role of CGRP in the pathophysiology of migraine has now been demonstrated, although the mechanism of action at both peripheral and central levels and its possible interactions with other pathways are not completely known. The term refractory migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against CGRP (Consensus document of the European Headache Federation). Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study regarding the efficacy of monoclonal antibody targeting CGRP in CM patients refractory to at least three preventive therapies,the investigators showed a higher prevalence of personality disorders (77% vs 37%) in those who were not responding to treatment at 1 year (non-responders: reduction in migraine days <50%), compared with those who were responding (responders: reduction in migraine days ≥50%). Non-responders were also characterized by a higher prevalence of anxiety spectrum disorders and more stressful events than responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological data are available to explain how psychological comorbidities may contribute to treatment refractoriness. In this frame, the present study aims to identify psychological and potential biochemical/molecular factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP. There will be a screening phase of one month in which patients will complete a daily headache diary in which they will note the occurrence, intensity and duration of attacks, as well as the use of symptomatic drugs. At baseline patients will undergo the psychological and biochemical/molecular evaluation. Subjects will then be treated with one of the three commercially available monoclonal antibodies targeting CGRP and will continue to record the characteristics of attacks and the use of symptomatic drugs in their headache diary. Follow-up visits are foreseen after 3 and 6 months of treatment. At 6 months, patients will be divided into 2 groups (responder or not responder to the treatment) depending on the reduction of monthly migraine days in the previous 3 months (>50% and <50%, respectively). The patients who failed to respond to the treatment will be considered refractory. Psychological evaluation: All patients will be evaluated by psychological interview and by adopting the DSM-V criteria for personality disturbances, anxiety and mood disorders. All patients will also be administered the Hospital Anxiety and Depression Scale (HADS) the Toronto Alexithymia Scale 20 (TAS-20), severity of dependence questionnaires (Severity Dependence Scale - SDS - and Leeds Dependence Questionnaire - LDQ), questionnaires related to Childhood trauma and Stressful life events.

Official Title
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Factors Associated With Migraine Refractoriness to Preventive Treatments: Psychological Aspects and Relationship With Components of the Endocannabinoid System

Conditions
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Migraine

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical characteristics that meet the criteria of the current International Headache Classification for Migraine or Chronic Migraine. Age >18, <65 years of both sexes At least 8 days of migraine/month and Migraine Disability Assessment Questionnaire (MIDAS) score greater than 11 at baseline*. Lack of benefit or intolerance or contraindication to at least three classes of drugs for the preventive therapy of migraine*. Drug Italian Agency (AIFA) criteria for the prescription of monoclonal antibodies directed against CGRP. Exclusion Criteria: dementia, psychosis, mental retardation women of childbearing age without contraceptive protection, pregnant and lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Personality disorders | To evaluate the association of refractory migraine with personality disorders (according to Diagnostic and Statistical Manual of mental disorders - DSM V criteria) in subjects with resistant migraine undergoing therapy with monoclonal antibodies directed against CGRP. | Change from baseline to 3-month to 6-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital Anxiety and Depression Scale (HADS) | The HADS is a fourteen item scale that generates: seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3. Higher scores are worst outcomes | Baseline, pre-receiving the treatment | 
| Toronto Alexitimia Scale 20 (TAS-20) | The TAS is a 20-item instrument that is one of the most commonly used measures of alexithymia. The TAS-20 uses cutoff scoring: equal to or less than 51 = non-alexithymia, equal to or greater than 61 = alexithymia. Scores of 52 to 60 = possible alexithymia. | Baseline, pre-receiving the treatment | 
| Childhood traumas questionnaire | The Childhood Trauma Questionnaire (CTQ) is a retrospective, self-report measure that was developed to provide a brief, reliable, and valid assessment of a broad range of traumatic experiences in childhood. It contains 70 items arranged according to four factors: physical and emotional abuse, emotional neglect, sexual abuse, and physical neglect. Responses are quantified on a 5-point Likert-type scale according to the frequency with which experiences occurred, with 1 = never true and 5 = very often true. | Baseline, pre-receiving the treatment | 
| Stressful life events questionnaire (SLESQ) | SLESQ is a 13-item self-report measure for non-treatment seeking samples that assesses lifetime exposure to traumatic events. Eleven specific and two general categories of events, such as a life-threatening accident, physical and sexual abuse, witness to another person being killed or assaulted, are examined. For each event, respondents are asked to indicate whether the event occurred (yes or no), their age at time of the event, as well as other specific items related to the event, such as the frequency, duration, whether anyone died, or was hospitalization, etc. | Baseline, pre-receiving the treatment | 
| The Leeds Dependence Questionnaire (LDQ) | The LDQ has been developed as part of a treatment evaluation package. The LDQ is a 10-item, self completion questionnaire designed to measure dependence upon a variety of substances. All items are scored 0-1-2-3. | Baseline, pre-receiving the treatment | 
| Severity of Dependence Scale (SDS) | The Severity of Dependence Scale (SDS) is a 5-item self-administered questionnaire that provides a score indicating the severity of dependence on drugs. Higher scores are worst outcomes | Baseline, pre-receiving the treatment | 
| Endocannabinoid System (ES) | Main components of the ES at the peripheral level | Baseline, pre-receiving the treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine, Refractoriness, Monoclonal antibodies directed against CGRP, Psychological disturbances, Endocannabinoid system