Migraine is a highly prevalent disease that affects an estimated 40 million adults in the United States [1,2]. People with migraine experience recurrent episodes of moderate to severe head pain that is associated with nausea and/or vomiting and sensitivity to light and sound in various combinations [3]. Migraine attacks are most common during the peak productive years (eg, ages 20‐40 years) [1,4] and commonly interfere with social and occupational functioning.

Notably, in clinic-based samples, approximately 60% of individuals with migraine report elevated depressive symptoms [5]. Because of their high prevalence and chronic nature, both migraine and depression are leading causes of disability worldwide [6,7]. When comorbid, together they account for a large portion of years lived with disability and have a bidirectional relationship [8,9], with each condition increasing the risk and severity of the other [10]. Compared to those with only migraine, individuals with migraine and depressive symptoms experience greater migraine-related disability (eg, missed work and/or social activities), greater impairment in quality of life, increased use of potentially harmful opioid therapies, twice the total annual medical costs, lower quality of life, and poorer migraine prognosis [11-15]. Despite the significant emotional, social, and economic burden of this comorbidity, few studies have evaluated the management of patients with both migraine and depression. Existing trials suggest that behavioral treatments such as cognitive behavioral therapy show promise in treating both migraine and depressive symptoms [16].

Mindfulness-based interventions have demonstrated efficacy in reducing depressive symptoms, with emerging evidence also suggesting benefits for reducing migraine disability [17], highlighting their strong potential to address this unmet clinical need. Among these approaches, mindfulness-based cognitive therapy (MBCT), which combines mindfulness and cognitive behavioral therapy approaches, has particularly strong evidence for reducing depressive symptoms [18,19] and depression relapse [20,21] and emerging evidence for reducing migraine disability [17,22]. MBCT teaches individuals to focus on present moment experiences through nonjudgmental observations of thoughts and bodily sensations [23], including migraine-related pain and other uncomfortable sensory experiences, while incorporating targeted cognitive techniques designed to address depression and its underlying mechanisms (eg, rumination).

The standard MBCT program follows a structured 8-week format that includes weekly in-person sessions lasting 2 to 2.5 hours each, a full-day meditation retreat, and 40 to 50 minutes of daily meditation practice at home. This intensive protocol is rarely feasible for full participation and engagement among patients with migraine who experience unpredictable disabling symptoms. Both the time commitment and in-person demand can be barriers and particularly burdensome for individuals with chronic health conditions such as migraine, who must balance their medical symptoms and personal and occupational responsibilities. The unpredictability of migraine attacks that involve disabling symptoms of pain, nausea, and vomiting and light or sound sensitivity further creates challenges for in-person attendance. The burden can be especially challenging for young women of reproductive age, who are disproportionately affected by migraine and often navigate multiple familial and professional roles [2]. Our prior research with patients with migraine demonstrated that MBCT delivered through individual hour-long sessions reduced headache disability compared to treatment as usual [17,24], and participants were still often unable to attend treatment appointments in person. In fact, most participants received at least one treatment session over the phone. Thus, a critical need exists for accessible, remotely delivered, and time-efficient interventions for individuals with migraine and depressive symptoms.

We created an abbreviated version of MBCT, MBCT-Brief, that reduces the weekly group session time by half or more (from 120‐150 min to 60 min) thereby reducing participant burden while maintaining alignment with reimbursement for group-based psychotherapy. MBCT-Brief has shown promising outcomes across various delivery formats (telephone and video conferencing) and populations, including reductions in depressive symptoms among individuals with depression [25,26] and decreased stress among women recovering from myocardial infarction [27]. In our prior open-arm pilot study, a remotely delivered MBCT-Brief adapted for individuals with migraine and co-occurring depressive symptoms was feasible, acceptable, and associated with improvements in both headache-related disability and depression severity [28]. While these preliminary findings are promising, they were derived from a small, single-site sample.

In this paper, we describe the protocol for a larger, multisite feasibility and acceptability trial of MBCT-Brief adapted for individuals with migraine and depressive symptoms. To increase generalizability, this study recruited from 3 geographic regions in the United States. This multisite trial will allow us to refine recruitment and retention approaches as well as compare alternative methods of intervention delivery, providing a firm foundation for future trials designed to test the efficacy of remotely delivered MBCT-Brief in individuals with co-occurring migraine and depressive symptoms.

The Treatment for Migraine and Mood (TEAM-M) 3-arm trial evaluates the feasibility and acceptability of 2 abbreviated versions of MBCT (MBCT-Brief), one delivered remotely via telephone and the other delivered remotely via videoconferencing. The third arm receives enhanced usual care (EUC), as described below. Our objectives are (1) to establish the feasibility and acceptability of both remote delivery formats and EUC across sites; (2) to demonstrate feasibility of study procedures, including recruitment and retention methods; and (3) to assess fidelity to MBCT-Brief protocols across 3 sites. A key goal is to determine which remotely delivered version of MBCT-Brief demonstrates greater feasibility and acceptability to inform phase III trial design and future clinical implementation. We are also gathering data on patient-centered outcomes including migraine-related disability and depressive symptom severity.

This 3-arm, multisite randomized controlled feasibility trial is evaluating an abbreviated MBCT protocol (MBCT-Brief) adapted for individuals with migraine and depressive symptoms and delivered remotely via telephone or videoconferencing compared to EUC.

The study was approved by the WCG Institutional Review Board (IRB; #20225608). Initial approval was granted on November 15, 2022. The IRBs at all 3 sites—Cleveland Clinic (#23‐584), Einstein College of Medicine (#2022‐13848), and Wake Forest University (#00080688)—rely on WCG IRB as the IRB of record. All participants provide informed written consent prior to participation.

We previously adapted the MBCT-Brief protocol for migraine populations and pilot-tested it in adults (N=16) with co-occurring migraine and depressive symptoms randomized to either MBCT-Brief telephone or MBCT-Brief videoconferencing conducted across 2 cohorts (n=8 per cohort) [28]. This preliminary study assessed the feasibility and acceptability of the intervention delivered via the 2 delivery formats (telephone or videoconferencing) in preparation for this trial. Results from the pilot trial demonstrated that both delivery methods were feasible and acceptable, with high usability ratings for remotely delivered components and survey procedures. We observed significant reductions in both headache disability and depressive symptoms from pretreatment to posttreatment [28]. These findings, in combination with other prior studies on MBCT-Brief, provide justification for this multisite study [25-27]. The pilot trial was registered on Clinicaltrials.gov (NCT04992494), with additional details available in the published manuscript [28].

We used three primary recruitment methods:

Interested individuals completed a Research Electronic Data Capture (REDCap; Vanderbilt University) prescreening survey with an initial e-consent. Those who preliminarily met the eligibility criteria were scheduled for a phone screening session with a member of the study team, during which the team confirmed final eligibility and obtained full study consent.

Participants randomized to the EUC condition receive educational information for migraine management and depression risk reduction, along with referrals to mental health and migraine resources. This information is delivered through 8 weekly online education modules based on content from education control groups used in previous behavioral migraine management studies (NCT03706794 and NCT03982316), adapted to include information on depressive symptoms, including vignettes depicting people with migraine and depressive symptoms to demonstrate key concepts. The modules are released weekly to mirror the MBCT-Brief schedule and cover topics including the relationship between migraines and depressive symptoms, treatment options for these co-occurring conditions, lifestyle factors for migraine and depressive symptoms, and communicating with health care providers (see Table 3). Notably, the EUC materials do not include any mindfulness-based content or practices. Participants engage with the education modules individually rather than in groups, and engagement is tracked electronically by the secure hosting website. Education modules are a pragmatic control and are not attention matched. They take approximately 15 minutes to complete weekly. When EUC participants are notified of their group assignment, they are told that they will be receiving 8 weekly self-management strategies curated by mental health and migraine specialists to help manage mood and migraine.

Among participants randomized to MBCT-Brief, we measure treatment adherence by tracking session attendance and homework compliance with the at-home daily practice logs provided in the workbook. For the EUC condition, REDCap automatically tracks the number of education modules that each participant completes. We also take steps to increase the likelihood that participants adhere to treatment. First, we use motivational interviewing strategies to assess participants’ interest in the study as well as their confidence in being able to attend most of the 8 intervention sessions on a scale of 1 to 10 (1, not interested/no confidence; 10, very interested/very confident) during screening. If a potential participant reports low interest in the study (score of ≤5), a study coordinator contacts that individual using motivational interviewing techniques to evaluate and enhance motivation for continuing through the study screening and enrollment process. If a potential participant continues to report low confidence in attending the intervention sessions (score of ≤5), they are advised to consider waiting to join the study until a more suitable time for their schedule. Second, the importance of session attendance is stated during the orientation call. Third, the study coordinator sends email reminders about the date and time of each session to every participant each week and assists with scheduling a make-up session if a participant needs to miss a live session. Lastly, during each weekly group session, the facilitator reviews the at-home practice assignments with participants to identify and overcome barriers to completion.

We manage treatment fidelity through the use of a facilitator treatment manual, session fidelity checklists that are completed by the facilitator, weekly supervision, and independent raters.

The trial is conducted in compliance with the current Good Clinical Practice guideline [37] and the principles of the Declaration of Helsinki [38]. Individuals are not eligible to enroll in the study if they are at high risk of an adverse event throughout the intervention period or require more intensive, focused treatment. This includes individuals with active suicidal ideation, psychosis, or significantly elevated trauma-related dissociative symptoms that would benefit from specialized trauma-focused interventions before participating in a mindfulness-based approach. This also includes people with medication-taking patterns that indicate potential medication overuse–induced headache. These exclusions reflect clinical considerations for participant safety and optimal treatment sequencing rather than contraindications to MBCT. Individuals meeting these criteria are referred to appropriate psychiatric or neurological services and connected with crisis or emergency services for acute needs, as needed.

The study team regularly monitors the trial for adverse events, both on weekly questionnaires and during intervention sessions. The weekly questionnaires assess new or worsening symptoms of PTSD, dissociation, pain, migraine, and any other troubling medical experiences. Each adverse event is discussed at weekly team meetings, during which the study team formulates a personalized plan for the at-risk participant to address the event and to identify any potential emerging patterns of adverse events. Considering that this trial includes individuals with elevated depressive symptoms, safety monitoring entails close observation of clinically significant increases in depressive symptoms and reports of suicidal ideation. If a participant reports suicidal ideation on the depression measure (administered at baseline and months 1, 2, 3, 6 and 9), weekly adverse event surveys, or verbally during intervention sessions, the study team implements the suicide safety protocol. As part of this protocol, the Columbia-Suicide Severity Rating Scale (C-SSRS) is either administered automatically through REDCap if suicidal ideation is endorsed on depression measures or adverse event surveys or administered verbally over the phone if suicidal ideation is reported during intervention sessions. The study team then addresses the participant’s suicidal ideation according to the corresponding risk level from the C-SSRS, with interventions including providing local mental health resources and performing warm handoffs with the 988 Suicide and Crisis Line.

All study personnel received training in suicidal ideation monitoring and safety protocol implementation, with individuals who interact directly with participants completing specialized suicide assessment and prevention training sponsored by the Suicide Prevention Resource Center [39]. This training focuses on reducing access to lethal means and working with individuals at risk for suicide and their families to minimize risk factors. Licensed clinical psychologists and neurologists at each site are available to provide oversight for psychiatric adverse events and ensure appropriate clinical response to safety concerns.

No missing data are anticipated for the primary outcomes related to treatment fidelity feasibility. Efforts are made to obtain CSQ-8 scores from all participants; however, missing CSQ-8 data will be singly imputed as the lowest possible score on the CSQ-8, indicating dissatisfaction with the treatment, and if a participant drops out of the study prior to month 2 and cannot be reached, a total score of 8 on the CSQ-8 will be imputed, reflecting dissatisfaction with all treatment domains. For secondary outcomes, missing data will be estimated using restricted maximum likelihood within mixed models procedures. The best-fitting covariance structure for each outcome will be selected using the Akaike Information Criterion. Mixed models allow for unbiased parameter estimations, even when data are not missing at random [47].

Data are collected by trained research assistants and study coordinators using electronic questionnaires administered via REDCap, a secure web-based platform for managing online surveys and databases. All surveys are deidentified and coded with unique subject identifiers to maintain participant confidentiality. Initial screening data are collected and stored on each participating site’s local REDCap platform, with only the project manager having access to data from all 3 sites for monitoring purposes. Following randomization, participants are transferred to the main REDCap database hosted at Cleveland Clinic, which serves as the central database for all intervention-related data collection and surveys. The Cleveland Clinic study team is responsible for sending and monitoring all postrandomization data collection while maintaining the site coordinators’ access to monitor and address adverse events as needed.

To ensure data quality, every 2 weeks, the study team members conduct reviews of all REDCap data collection forms to identify missing data, discrepancies, or other identified issues. Study staff follow up with participants who have not completed surveys within 1 week of administration. Any discrepancies or data-related issues are reviewed and corrected by the project manager. This comprehensive approach allows for ongoing monitoring of study progress, participant engagement, and the collection of high-quality data.

Power calculations were informed by preliminary data (means and SDs) and were adjusted for the 25% dropout rate. For treatment fidelity, all sessions met the benchmark in preliminary testing; within a 95% CI, we will achieve a power above 0.99 to detect a mean fidelity score at or above the benchmark. Similarly, the majority of participants met benchmarks for both feasibility and acceptability in preliminary testing. Thus, within a 95% CI, we will achieve a power above 0.89 to detect mean feasibility and acceptability score at or above the benchmarks [28].

The primary objective of the TEAM-M multisite trial is to evaluate the feasibility and acceptability of MBCT-Brief for co-occurring migraine and depressive symptoms. Compared to the full-length intervention, MBCT-Brief reduces the time commitment by more than half, an important modification given that time demands are a known barrier to participation in mindfulness-based interventions for this population [17] and for individuals with chronic health conditions [51,52], as well as more broadly [53-55]. Additionally, the abbreviated format allows clinicians to treat more patients within the same time frame without adding clinical workload, addressing a significant access concern given the shortage of trained MBCT instructors [56]. While this trial does not aim to address the shortage of instructors directly, this abbreviated format aligns with reimbursement policies, offering a more economically sustainable model for providers and health care systems. Our long-term goal is to evaluate the efficacy of MBCT-Brief and to improve its accessibility and scalability for depression care broadly and in the context of comorbid conditions such as migraine. Therefore, our study is an important step in addressing a critical gap in care: the lack of integrated treatments for co-occurring migraine and depressive symptoms.

Another key objective of this trial is to determine which remote delivery method (telephone or videoconferencing) demonstrates greater feasibility and acceptability, which will inform the selection of a single method in a phase III trial. Each delivery method warrants consideration. Telephone delivery offers important advantages beyond accessibility, including reduced barriers for individuals experiencing depression-related symptoms, such as appearance-related concerns or low self-esteem, which may impede participation in video-based care. Additionally, telephone delivery eliminates requirements for an internet connection or video-enabled device. However, video delivery may enhance group cohesion when members can see one another, which may in turn improve outcomes, although this requires further study. Insurance reimbursements are another point of consideration, as coverage for audio-only telehealth services varies significantly by payer, with some coverage (including Medicare) having ended in September 2025. These changes may affect long-term accessibility and scalability for telephone-delivered MBCT.

Feasibility and acceptability randomized controlled trials, like this one, are critical for laying the groundwork for larger efficacy trials by testing and refining the intervention design as well as recruitment, enrollment, and other study procedures. For example, our original protocol that included the 28-day run-in period as an inclusion criterion proved burdensome and revealed significant enrollment challenges. We experienced a higher-than-expected percentage of participants not meeting either the required diary completion threshold, the headache frequency criteria, or both, ultimately hindering study progress. As a result, we modified the protocol to decouple daily diary data collection from the inclusion criterion. We revised the assessment of headache frequency and migraine diagnosis to rely on participant self-report in the prescreening survey, an approach that has been found to be comparable to daily diary reporting for headache frequency assessment [48]. We also expanded the headache frequency inclusion criterion from 4 to 14 days per month to 4 to 20 days per month to account for day-to-day fluctuations in episodic migraine that may increase monthly headache days and to align with other behavioral migraine studies [57,58]. Daily diaries were used to assess the feasibility and acceptability of daily diary compliance to inform future trial design. These protocol modifications significantly improved enrollment rates and strengthened both the current trial and the planned phase III efficacy trial.

We acknowledge several limitations of this randomized controlled trial. While we are collecting preliminary data on headache disability, migraine-specific quality of life, and depressive symptoms to inform power analyses for a future efficacy trial, any reported efficacy data in future publications should be interpreted as exploratory. Additionally, we rely on self-report for collecting data on participants’ at-home practice, which is common in mindfulness-based trials but introduces potential bias. Future studies would benefit from the incorporation of objective tracking methods (eg, app-based monitoring of guided meditation use) to more accurately assess engagement in at-home practice.