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. 2022 Oct 31;176(12):1176–1187. doi: 10.1001/jamapediatrics.2022.3940

Anxiety and Depressive Symptoms and Disorders in Children and Adolescents With Migraine

A Systematic Review and Meta-analysis

Katherine Falla 1, Jonathan Kuziek 1, Syeda Rubbia Mahnaz 2, Melanie Noel 3, Paul E Ronksley 4, Serena L Orr 4,5,✉
PMCID: PMC9623478  PMID: 36315158

This study attempts to determine if there is an association between internalizing symptoms and disorders and migraine in children and adolescents.

Key Points

Question

Is there an association between anxiety and depressive symptoms and disorders and migraine in children and adolescents, and if so, what is its magnitude?

Findings

In this systematic review and meta-analysis of 80 observational studies, we found a significant association between anxiety and depressive symptoms and disorders, mixed internalizing symptoms and disorders, and migraine in children and adolescents (with moderate to large effect sizes for each association).

Meaning

In this study, children and adolescents with migraine were more likely to experience internalizing symptoms and disorders compared with their peers without migraine; screening for these symptoms and disorders in clinical practice may be beneficial.

Abstract

Importance

Though it is presumed that children and adolescents with migraine are at risk of internalizing symptoms and disorders, high-level summative evidence to support this clinical belief is lacking.

Objective

To determine if there is an association between internalizing symptoms and disorders and migraine in children and adolescents.

Data Sources

A librarian-led, peer-reviewed search was performed using MEDLINE, Embase, PsycINFO, and CINAHL databases (inception to March 28, 2022).

Study Selection

Case-control, cohort, and cross-sectional studies on the association between internalizing symptoms and disorders and migraine in children and adolescents 18 years or younger were eligible.

Data Extraction and Synthesis

Two investigators independently completed abstract and full-text screening, data extraction, and quality appraisal using the Newcastle-Ottawa scales. Studies were pooled with random-effects meta-analyses using standardized mean differences (SMD) or odds ratios (OR) with 95% CIs. Where sufficient data for pooling were unavailable, studies were described qualitatively.

Main Outcomes and Measures

The primary outcome was migraine diagnosis; additional outcomes included migraine outcomes and incidence. Associations between these outcomes and internalizing symptoms and disorders were evaluated.

Results

The study team screened 4946 studies and included 80 studies in the systematic review. Seventy-four studies reported on the association between internalizing symptoms and disorders and migraine, and 51 studies were amenable to pooling. Meta-analyses comparing children and adolescents with migraine with healthy controls showed: (1) an association between migraine and anxiety symptoms (SMD, 1.13; 95% CI, 0.64-1.63); (2) an association between migraine and depressive symptoms (SMD, 0.67; 95% CI, 0.46-0.87); and (3) significantly higher odds of anxiety disorders (OR, 1.93, 95% CI, 1.49-2.50) and depressive disorders (OR, 2.01, 95% CI, 1.46-2.78) in those with, vs without, migraine. Stratification of results did not reveal differences between clinical vs community/population-based samples and there was no evidence of publication bias. Twenty studies assessing the association between internalizing symptoms or disorders and migraine outcomes (n = 18) or incident migraine (n = 2) were summarized descriptively given significant heterogeneity, with minimal conclusions drawn.

Conclusions and Relevance

In this study, children and adolescents with migraine were at higher risk of anxiety and depression symptoms and disorders compared with healthy controls. It may be beneficial to routinely screen children and adolescents with migraine for anxiety and depression in clinical practice. It is unclear whether having anxiety and depressive symptoms or disorders has an affect on migraine outcomes or incidence.

Introduction

One in 10 children and adolescents experience migraine1,2 and, across the life span, it is the second most prevalent and disabling disease worldwide.3 The optimal management of migraine in children and adolescents comprises a multimodal approach that combines evidence-based acute treatment, preventive treatment where indicated, education, identification, and treatment of comorbid disorders.4,5

Internalizing symptoms, defined as an individual’s tendency to react to stress with internal processes (eg, anxiety and depressive symptoms),6 are thought to be elevated in children and adolescents with migraine,7,8 though high-level summative evidence for this clinical belief is lacking. Also, it is unclear whether children and adolescents with migraine are at higher risk of having internalizing disorders, whereby the level of internalizing symptoms meet criteria for a clinical psychiatric disorder (eg, anxiety or depressive disorder) compared with their peers.7,9 Although a few published systematic reviews and meta-analyses have aimed to address these questions,10,11,12,13,14 they have either been too limited (eg, including studies using a particular measurement instrument or clinical population)10,12 or too broad in their scope (eg, including studies with heterogeneous populations, such as children and adolescents with a variety of headache disorders) to draw definite conclusions in children and adolescents with migraine.13,14

To address this gap in the literature, we completed a systematic review and meta-analysis that aimed to estimate the association between internalizing symptoms and disorders and the outcome of migraine in children and adolescents. We hypothesized that: (1) migraine would be strongly associated with internalizing symptoms or migraine would be modestly associated with internalizing disorders; (2) internalizing symptoms would be associated with poorer outcomes in children and adolescents with migraine; and (3) internalizing symptoms would be a risk factor for incident migraine.

Methods

A detailed protocol for this study has been previously published15 and registered on the International Prospective Register of Systematic Reviews (PROSPERO 161788). This article adheres to the reporting guidelines from the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines16 and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.17

Objectives

We aimed to determine if there is an association between internalizing symptoms and disorders and migraine in children and adolescents. We also aimed to: (1) determine if internalizing symptoms are associated with outcomes in children and adolescents with migraine (eg, higher attack frequency) and (2) determine if there is an association between internalizing symptoms and incident migraine in children and adolescents.

Eligibility Criteria

We included case-control, cohort, and cross-sectional studies assessing the association between internalizing symptoms and/or disorders and migraine in children and adolescents 18 years or younger. Eligible studies assessed symptoms and disorders on the spectrum of anxiety disorders, depressive disorders, and trauma- and stressor-related disorders, as defined in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Abstracts of otherwise eligible studies were included. We excluded studies that had participants older than 18 years if the data for the younger participants were not reported separately, and we excluded studies with other headache disorders if the data for the migraine group was not reported separately. Studies were not restricted by language.

Information Sources and Search Strategy

MEDLINE, Embase, PsycINFO, and CINAHL were searched from inception to March 28, 2022. Reference lists of included studies and review articles were searched for additional information sources. A research librarian with experience in systematic reviews drafted the search strategy, which was peer reviewed by a second research librarian using the Peer Review of Electronic Search Strategies standard.18,19 The search strategies used for each database are in the published protocol.15

Study Selection

During the first screening phase, 2 independent screeners reviewed each abstract using the Abstrackr software.20 Disagreements were initially present for 1296 of the abstracts (26.2%). An expert screener (S.L.O.) then screened all conflicts and made final inclusion decisions. For the second eligibility screens, the full-text manuscripts were downloaded into Mendeley. Two independent screeners reviewed the full texts and made inclusion decisions. Where discrepancies arose, an expert screener (S.L.O.) made the final decision.

Data Collection

Data extraction was carried out as per a priori plans15 by 2 researchers using standardized forms. Where raw data were available, data for the most adjusted associations were extracted and entered into a master Excel file, which was reviewed by 2 researchers.

Risk of Bias Assessment

For case-control and cohort studies, the validated Newcastle-Ottawa scale was used to rate risk of bias. For cross-sectional studies, an adapted version of the Newcastle-Ottawa scale was used, as per Loney et al.21 For each study, 2 researchers independently rated risk of bias using standardized data collection tables published in the study protocol.15

Synthesis of Results

For our primary objective, studies reporting raw data on the association between internalizing symptoms or disorders and migraine were pooled together in stratified meta-analyses. In cases where the raw data were unpublished, the authors were contacted on 2 occasions, 2 weeks apart, with a request to share the raw data. Where not available after contact, data were summarized descriptively. Data were stratified based on whether internalizing symptoms or internalizing disorders were assessed. Data were also stratified based on the control group (ie, children and adolescents with no headache vs children and adolescents with other headache disorders).

For the meta-analyses, in the case of continuous outcomes, group means and standard deviations from the studies were used to generate standardized mean difference (SMD) estimates with 95% CIs, with SMD estimates 0.5 or less considered small, more than 0.5 to 0.8 considered moderate, and more than 0.8 considered large in magnitude. For dichotomous outcomes, the most adjusted data available were used to generate odds ratios (OR) and 95% CIs (ie, we selected adjusted ORs and their 95% CIs, if unavailable, we used unadjusted ORs and their 95% CIs and where only raw proportion data were available, we hand calculated unadjusted ORs and 95% CIs). Estimates of the association between internalizing symptoms or disorders and migraine were generated using random effects meta-analyses (DerSimonian and Laird method). Statistical heterogeneity was measured using the I2 statistic.

Publication Bias Assessment

For the studies in the meta-analysis, the Begg test was used to assess publication bias (P < .05 considered significant). P values were 2-tailed.

Results

Study Selection

We screened 4946 studies, of which 4866 were excluded, for a final of 80 included studies (Figure 1). Of note, the included studies assessed anxiety and depressive symptoms and/or disorders, or combined internalizing symptoms and/or disorders; none assessed the association between trauma- and stressor-related symptoms and/or disorders and migraine.

Figure 1. PRISMA Diagram.

Figure 1.

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Study Characteristics

Characteristics of included studies are summarized in Table 1 and the Supplement includes more detailed summary of studies’ tables (eTables 1, 2, and 3 in the Supplement). Seventy-four studies reported on the association between internalizing symptoms, internalizing disorders, and migraine,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95 and 51 of these studies22,23,25,26,27,28,29,30,31,32,33,36,38,40,42,45,46,48,51,53,54,55,56,60,61,63,64,65,67,69,71,72,73,74,75,76,77,78,79,82,83,84,86,87,88,89,90,92,95 were amenable to pooling of at least some of their data in meta-analyses, while the remaining study results were summarized descriptively (Table 1 and Figure 2). Eighteen studies assessed the association between internalizing symptoms or disorders and a migraine outcome.27,29,31,36,46,47,64,68,69,83,85,95,96,97,98,99,100 Only 2 studies reported on the association between internalizing symptoms or disorders and incident migraine.40,101 Given significant outcome heterogeneity for the migraine outcomes and incidence studies, meta-analysis was not appropriate and these studies were summarized descriptively.

Table 1. Characteristics of Included Studies.

Characteristic No. (%)
Association studies Migraine outcomes studies Incidence studies
In meta-analysis Not in meta-analysis
No. of total studies 51 29 18 2
Study design
Cross-sectional 21 (41.2) 10 (34.5) 8 (44.4) 0
Case-control 28 (54.9) 17 (58.6) 8 (44.4) 0
Cohort 2 (3.9) 2 (6.9) 2 (11.2) 2 (100.0)
Setting
Clinical 34 (66.7) 19 (65.5) 15 (83.3) 0
Community 5 (10.0) 1 (3.5) 1 (5.6) 2 (100.0)
Population-based 8 (15.7) 3 (10.3) 0 0
Not reported 4 (7.8) 6 (20.7) 2 (11.1) 0
Sample size
<50 4 (7.8) 5 (17.2) 0 0
50-100 16 (31.4) 8 (27.6) 11 (61.1) 0
>100-1000 20 (39.2) 10 (34.5) 4 (22.2) 0
>1000 11 (21.6) 6 (20.7) 3 (16.7) 2 (100.0)
Ages
<12 y 4 (7.8) 0 0 0
≥12-18 y 11 (21.6) 7 (24.1) 2 (11.2) 2 (100.0)
Mixed ages 36 (70.6) 22 (75.9) 16 (88.8) 0
Sex distribution
<50% Female 11 (21.6) 5 (17.2) 4 (22.2) 1 (50.0)
50%-60% Female 21 (41.2) 8 (27.7) 7 (38.9) 1 (50)
>60%-70% Female 8 (15.7) 0 3 (16.7) 0
>70% Female 8 (15.7) 5 (17.2) 3 (16.7) 0
Not reported 3 (5.9) 11 (37.9) 1 (5.5) 0
Outcome type
Episodic migraine only 5 (10.0) 5 (17.2) 1 (5.6) 0
Chronic migraine only 4 (7.8) 1 (3.5) 1 (5.6) 1 (50.0)
Mixed episodic and chronic migraine 17 (33.3) 6 (20.7) 9 (50) 1 (50.0)
Not reported 25 (49.0) 17 (58.6) 7 (38.8) 0
Outcome ascertainment
ICHD criteria 43 (84.3) 14 (48.3) 15 (83.3) 1 (50.0)
Not ICHD criteria 6 (11.8) 7 (24.1) 2 (11.2) 1 (50.0)
Not reported 2 (3.9) 8 (27.6) 1 (5.5) 0
Results adjusted for important covariates (eg, age, sex)
Yes 13 (25.5) 5 (17.2) 7 (38.9) 2 (100.0)
No 38 (74.5) 24 (82.8) 11 (61.1) 0
Study quality rating
High (>80%) 12 (23.5) 1 (3.4) 2 (11.2) 1 (50.0)
Moderate (50%-80%) 31 (60.8) 14 (48.3) 12 (66.6) 1 (50.0)
Low (<50%) 8 (15.7) 14 (48.3) 4 (22.2) 0
Exposure type(s) measureda
Anxiety symptoms 21 10 9 0
Anxiety disorders 19 6 3 0
Depressive symptoms 21 15 9 0
Depressive disorders 20 8 2 1
Mixed-internalizing symptoms 13 5 2 1
Mixed-internalizing disorders 10 3 2 0
Exposure assessment toolb
Symptom level
Validated questionnaire
Anxiety symptoms 20 (95.2) 10 (100.0) 8 (88.9) NA
Depressive symptoms 21 (100.0) 14 (93.3) 8 (88.9) NA
Mixed-internalizing symptoms 13 (100.0) 5 (100.0) 2 (100.0) 1 (100.0)
Unvalidated tool
Anxiety symptoms 1 (4.8) 0 1 (11.1) NA
Depressive symptoms 0 1 (6.7) 1 (11.1) NA
Mixed-internalizing symptoms 0 0 0 0
Disorder level
Validated diagnostic interview
Anxiety disorders 12 (63.1) 3 (50.0) 1 (33.3) NA
Depressive disorders 12 (60.0) 3 (37.5) 1 (50.0) 0
Mixed-internalizing disorders 0 1 (33.3) 1 (50.0) NA
Validated questionnaire cutoff score
Anxiety disorders 6 (31.6) 1 (16.7) 0 NA
Depressive disorders 7 (35.0) 2 (25.0) 0 1 (100.0)
Mixed-internalizing disorders 10 (100.0) 2 (66.7) 1 (50.0) NA
Other
Anxiety disorders 1 (5.3) 2 (33.3) 2 (66.7) NA
Depressive disorders 1 (5.0) 2 (25.0) 1 (50.0) 0
Mixed-internalizing disorders 0 0 0 NA
Exposure-outcome association (most adjusted results) c
Positive association
Anxiety symptoms 13 (61.9) 4 (40.0) 3 (33.3) NA
Anxiety disorders 8 (42.1) 2 (33.3) 2 (66.7) NA
Depressive symptoms 12 (57.1) 11 (73.3) 7 (87.5) NA
Depressive disorders 4 (20.0) 3 (37.5) 0 1 (100.0)
Mixed-internalizing symptoms 12 (92.3) 5 (100.0) 2 (100.0) 0
Mixed-internalizing disorders 8 (80.0) 0 1 (50.0) NA
No association
Anxiety symptoms 5 (23.9) 6 (60.0) 4 (44.4) NA
Anxiety disorders 2 (10.5) 1 (16.7) 0 NA
Depressive symptoms 6 (28.6) 3 (20.0) 1 (12.5) NA
Depressive disorders 4 (20.0) 1 (12.5) 1 (50.0) 0
Mixed-internalizing symptoms 0 0 0 1 (100.0)
Mixed-internalizing disorders 0 1 (33.3) 1 (50.0) NA
Negative association
Anxiety symptoms 0 0 1 (11.1) NA
Anxiety disorders 0 0 0 NA
Depressive symptoms 0 0 0 NA
Depressive disorders 0 0 0 0
Mixed-internalizing symptoms 0 0 0 0
Mixed-internalizing disorders 0 0 0 NA
Measured, association not reported
Anxiety symptoms 3 (14.2) 0 1 (22.2) NA
Anxiety disorders 9 (47.4) 3 (50.0) 1 (33.3) NA
Depressive symptoms 3 (14.3) 1 (6.7) 0 NA
Depressive disorders 12 (60.0) 4 (50.0) 1 (50.0) 0
Mixed-internalizing symptoms 1 (7.7) 0 0 0
Mixed-internalizing disorders 2 (20.0) 2 (66.7) 0 NA
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Abbreviations: ICHD, International Classification of Headache Disorders; NA, not applicable.

a

Because many studies reported on multiple exposure types, percentage not given.

b

Percentage reflects proportion of studies measuring a given exposure type using a given type of exposure assessment tool over the total number of studies measuring that exposure type.

c

Percentage reflects proportion of studies reporting a given association direction for a given type of exposure over the total number of studies measuring that exposure type. Here, a positive association denotes: (1) for association studies, that higher exposure to internalizing symptoms/disorders was associated with migraine diagnosis; (2) for migraine outcomes studies, that higher exposure to internalizing symptoms/disorders was associated with worse outcomes; and (3) for incidence studies, that higher exposure to internalizing symptoms/disorders was associated with higher incidence of migraine. Associations that are marked as not reported were either not reported because hypothesis testing was not done, or the migraine group was not compared with a healthy control group (eg, compared with other headache control), or to any control group.

Figure 2. Direction of Exposure-Outcome Associations for Studies.

Figure 2.

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Illustration of the direction of the exposure-outcome association observed in the association studies and includes studies in both in the meta-analysis and not in the meta-analysis.

Risk of Bias Within Studies

The quality ratings of the studies are summarized in Table 1, and detailed quality ratings are available in eTables 4, 5, and 6 in the Supplement. Overall, 13 of 80 studies (16.3%) were rated as high quality (more than 80% score on the quality scales), 46 of 80 studies (57.5%) were rated as moderate quality (50% to 80% range score on the scales), and 21 of 80 studies (26.2%) were rated as low quality (less than 50% score on the scales). The quality of the studies not in the meta-analysis was poorer as compared with the studies in the meta-analysis (48.3% of the studies not in the meta-analysis vs 15.7% of the studies in the meta-analysis had low quality ratings).

Association Studies in the Meta-analysis

As illustrated in Figure 3, anxiety symptoms were significantly higher in children and adolescents with migraine as compared with controls, with a large effect size observed (n = 16 studies; SMD, 1.13; 95% CI, 0.64-1.63; I2 = 96%). The odds of having an anxiety disorder were higher among children and adolescents with migraine as compared with controls (n = 15 studies; OR, 1.93; 95% CI, 1.49-2.50; I2 = 61.3%).

Figure 3. Results of Meta-analyses Comparing Migraine With Healthy Controls.

Figure 3.

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Forest plots illustrating pooled results of studies comparing migraine vs healthy control samples. Weights are from random effects.

Depressive symptoms were also significantly higher in children and adolescents with migraine compared with controls, with a moderate effect size (n = 17 studies; SMD, 0.67; 95% CI, 0.46-0.87; I2 = 89.7%). Moreover, the odds of having a depressive disorder were higher among children and adolescents with migraine as compared with controls (n = 18 studies; OR, 2.01, 95% CI, 1.46-2.78; I2 = 57.8%). Similar results were seen in studies that pooled internalizing symptoms or disorders together: children and adolescents with migraine had significantly higher internalizing symptoms than controls, with a large effect size observed (n = 10 studies; SMD, 0.88; 95% CI, 0.66-1.09; I2 = 63.9%) and also had higher odds of experiencing mixed internalizing disorders than controls (n = 9 studies that reported on pooled prevalence of anxiety and/or depressive disorders; OR, 4.69; 95% CI, 3.08-7.14; I2 = 82.2%; eFigure 1 in the Supplement).

When children and adolescents with migraine were compared with children and adolescents with other headache disorders (eg, tension-type headache, new daily persistent headache),22,23,28,29,30,32,33,36,40,42,45,46,51,53,54,55,61,67,71,72,74,75,78,83,84 no significant differences emerged for internalizing symptoms nor disorders between the 2 groups (eFigure 2 in the Supplement).

When studies were stratified by setting, whereby clinical samples were compared with community or population-based samples, no differences were seen in the effect sizes for anxiety or depressive symptoms or disorders, though studies with recruitment from other settings (mostly unreported settings) had different effect-size magnitudes, and in some cases the cell sizes were small, which complicates interpretation of the stratified results (Table 2). For mixed internalizing symptoms, there was a large vs moderate effect size (SMD, 1.05; 95% CI, 0.77-1.33 vs SMD, 0.61; 95% CI, 0.22-0.99) and a higher odds of mixed internalizing disorders (OR, 8.02; 95% CI, 4.77-13.49 vs. OR, 3.76; 95% CI, 2.37-5.97) when comparing clinical with community or population-based samples. In sensitivity analyses where studies with outlying values were excluded, the results did not change significantly (eTable 7 in the Supplement). There was no evidence of publication bias (Begg tests all P > .05).

Table 2. Stratification of Meta-analysis Results by Setting.
Studies Stratification by setting
Exposure type Control group Measure Studies, No. Clinical Community/population-based Unknown setting
Anxiety symptoms Healthy controls SMD (95% CI) 16 0.88 (0.50-1.27) 0.63 (0.45-0.81) 3.39 (3.06-3.73)
No. NA NA NA 14 1a 1a
Anxiety disorders Healthy controls OR (95% CI) 15 2.02 (1.25-3.24) 2.04 (1.33-3.13) 1.16 (0.47-2.85)
No. NA NA NA 10 3 2a
Depressive symptoms Healthy controls SMD (95% CI) 17 0.71 (0.36-1.05) 0.68 (0.39-0.98) NA
No. NA NA NA 13 4 NA
Depressive disorders Healthy controls OR (95% CI) 18 2.19 (1.17-4.09) 2.36 (2.03-2.74) 0.95 (0.33-2.78)
No. NA NA NA 11 5 2a
Internalizing symptoms Healthy controls SMD (95% CI) 10 1.05 (0.77-1.33) 0.61 (0.22-0.99) NA
No. NA NA NA 7 3 NA
Internalizing disorders Healthy controls OR (95% CI) 9 8.02 (4.77-13.49) 3.76 (2.37-5.97) NA
No. NA NA NA 4 5 NA
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Abbreviations: OR, odds ratio; NA, not applicable; SMD, standardized mean difference.

a

Small number of studies in cell make interpretation of stratified results more challenging.

Association Studies Not in the Meta-analysis

Results of the 29 studies that included data that were not amenable to pooling are summarized in Table 1 and Figure 3. Comparing studies in the meta-analysis vs those not in the meta-analysis, there were similar proportions of studies that found positive associations between internalizing symptoms and disorders and migraine as compared with no significant associations. For studies assessing the association between migraine and anxiety symptoms, there was a discrepancy between the studies in the meta-analysis vs not in the meta-analysis, with a higher proportion of the studies not in the meta-analysis finding no association between anxiety symptoms and migraine as compared to the studies in the meta-analysis (60% vs 23.9%). A significant proportion of the studies assessing internalizing disorders that were not in the meta-analysis had no hypothesis testing (50% to 66.7%), and only reported disorder proportions among a migraine sample; minimal conclusions can be drawn about these results. Most of these studies were small and did not report sample size calculations; thus, it is unclear if they were powered to detect clinically meaningful effect sizes.

Studies Assessing Migraine Outcomes

Internalizing Symptoms and Outcomes in Children and Adolescents With Migraine

Of the 13 studies reporting on the association between migraine outcomes and internalizing symptoms in children and/or adolescents,27,29,46,68,83,85,95,96,97,98,99,100 10 were cross-sectional (Table 1).27,28,29,46,68,83,96,98,99,100 One of these studies assessed school functioning,46 4 measured migraine-specific disability scores,27,29,68,83 and the remaining 5 studies examined headache frequency and/or severity cross-sectionally.28,96,98,100 It is difficult to draw conclusions about the association between anxiety and depressive symptoms and migraine outcomes from these cross-sectional studies, as they were limited in number, had heterogeneous outcomes, and were minimally comparable.

Only 3 of the studies measuring the association between internalizing symptoms and migraine outcomes were longitudinal (length of follow-up ranging from 1 to 4 months; eTable 2 in the Supplement).85,95,97 All of these assessed the association between internalizing symptoms and the outcome of headache frequency, and each found a positive association, whereby higher anxiety,95 depressive,85,97 and mixed internalizing symptoms85 were associated with higher headache frequencies at follow-up in children and adolescents with migraine.

Internalizing Disorders and Outcomes in Children and Adolescents With Migraine

Five heterogeneous studies reported on the association between internalizing disorders and outcomes in children and adolescents with migraine.31,36,47,64,69 Mixed internalizing disorders were associated with lower quality of life,31 as well as higher headache frequencies,31 and anxiety disorders were associated with higher headaches frequencies64 and a higher risk of headache persistence at 8-year follow up36 in single studies. In contrast, 1 study found no association between baseline depressive disorders and headache persistence at 8-year follow up,36 and another study found no association between having any psychiatric comorbidity and treatment response at 3-month follow up.69 Additionally, 1 study found that, among children and adolescents hospitalized for migraine, those with any psychiatric comorbidity were more likely to receive medication, have longer lengths of stay, and have higher hospitalization costs compared with those without any psychiatric comorbidity.47

Incidence Studies

Two population-based or community-based studies reported on the outcome of incident migraine40,101 and found a positive association between baseline internalizing symptoms and incident migraine at follow-up in adolescence (length of follow-up ranging from 2 to 7 years; eTable 3 in the Supplement).

Discussion

The results of our systematic review and meta-analyses demonstrate that children and adolescents with migraine are more likely to have anxiety and depressive symptoms and anxiety and depressive disorders (approximately double the odds), as compared with healthy controls. With regards to whether the presence of internalizing symptoms or disorders influences migraine outcomes, few studies (n = 18) were identified and heterogeneity in their design and measured outcomes precluded both statistical pooling and drawing meaningful conclusions. One observation of note was that of the 8 studies that assessed the association between depressive symptoms and migraine outcomes, 87.5% (n = 7 of 8) reported that higher depressive symptoms were associated with worse migraine outcomes, indicative of high homogeneity with regards to the presence and directionality of the association. This observation suggests that depressive symptoms may be associated with worse migraine-related outcomes, though without the ability to pool the data and with heterogeneous outcomes across studies, more work is required prior to drawing this conclusion definitively. It is also unclear whether treatment of depressive symptoms (or any comorbid internalizing symptoms or disorders) can influence migraine-specific outcomes. Next, only 2 studies assessed the association between baseline internalizing symptoms and risk of incident migraine, and both studies showed that baseline internalizing symptoms were associated with a higher risk of incident migraine in community/population-based samples of adolescents. The small number of incidence studies and their heterogeneous designs precludes any strong conclusions from being drawn from these studies. Additionally, no studies were identified that assessed the association between trauma- and stressor-related symptoms or disorders and migraine, despite inclusion of these in our aims and search strategy. This represents a substantial gap in the pediatric migraine literature, especially given that work in the broader pediatric pain literature has identified that trauma- and stressor-related symptoms and disorders are associated with chronic pain and worse outcomes in children and adolescents.102,103,104

The association between migraine and anxiety and depressive symptoms and disorders is likely bidirectional and multifactorial.8 First, environmental risk factors are an important link to consider. The experience of pain and internalizing symptoms may result in mutually reinforcing behaviors, such as reduced sleep and withdrawal from activities, and mutually reinforcing cognitive patterns, such as negativity bias and attention bias.102 Additionally, exposure to environmental adversity (eg, family-level stressors and adverse childhood experiences) during critical periods of brain development may increase the risk of developing both anxiety and depressive symptoms and disorders, as well as migraine.40,105,106 There is also genetic overlap between migraine, anxiety, and depression, with shared genetic factors having been identified in prior work.107,108,109,110 Though it is clear that the association between internalizing symptoms, disorders, and migraine is complex, bidirectional, and driven by both environmental and genetic factors, there is work to be done in this area. Untangling the reasons for why these comorbidities exist and how they influence each other presents an opportunity to better understand disease etiology from a biopsychosocial perspective and has the potential to add to the treatment landscape.

Considering the associations identified between depressive and anxiety symptoms and disorders and migraine, clinicians should screen for these in clinical practice. Formal, validated screening tools can be used to supplement the clinical assessment. As an example, the Patient-Reported Outcomes Measurement Information System111 is a validated system of measurement tools that are freely available and that have been translated in several languages.

Limitations

There are several strengths and limitations to this work. To our knowledge, this is the first comprehensive systematic review with meta-analyses that included all studies on the association between depressive and anxiety symptoms and disorders and migraine in children and adolescents. We included studies in all languages, and studies that had, and did not have, adequate data for meta-analysis, to provide an unbiased overview of the available literature. We followed PRISMA and MOOSE reporting guidelines and the process described in our a priori published protocol. We used random-effects meta-analyses to pool the association data that was amenable to pooling and stratification and sensitivity analyses to ensure that the results were robust, which improves confidence in the effect size estimates. Limitations include our inability to further stratify results based on important covariates, such as headache frequency (eg, episodic vs chronic migraine) and sex; this is a reflection of inadequate stratified reporting in the original studies. Although we used the most adjusted estimates available for our meta-analyses and descriptive synthesis of the data, most included studies (66 of 80 [82.5%]) reported only unadjusted associations, thereby increasing the risk of bias due to unmeasured confounders. Additionally, over a quarter (21 of 80 [26.3%]) of the studies had low quality ratings, and there are certainly various types of bias present in the pooled review on our risk of bias assessment.

Conclusions

In this systematic review and meta-analysis, children and adolescents with migraine had more depressive and anxiety symptoms, and higher odds of depressive and anxiety disorders, as compared with their peers without migraine. These results have critical implications for clinical practice, underscoring the need to screen all children and adolescents with migraine for anxiety and depression. It remains unclear if the presence of anxiety and depressive symptoms or disorders has any effect on migraine-specific outcomes or risk of incident migraine. Future work should address these questions and aim to determine whether trauma- and stressor-related symptoms and disorders are associated with migraine in children and adolescents, as no studies on this topic were identified in our searches.

Supplement.

eTable 1. Summary of studies examining the association between migraine and anxiety and depressive symptoms/disorders (n=74)

eTable 2. Summary of studies examining migraine outcomes (n=18)

eTable 3. Summary of studies examining migraine incidence (n=2)

eTable 4. Risk of bias ratings for case-control studies

eTable 5. Risk of bias ratings for cross-sectional studies

eTable 6. Risk of bias ratings for cohort studies

eFigure 1. Results of meta-analyses comparing migraine to healthy controls for internalizing symptoms and disorders (presented in forest plots)

eFigure 2. Results of meta-analyses comparing migraine to other headache controls (presented in forest plots)

eTable 7. Sensitivity analyses with removal of outlying studies

Click here for additional data file. (1.8MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Summary of studies examining the association between migraine and anxiety and depressive symptoms/disorders (n=74)

eTable 2. Summary of studies examining migraine outcomes (n=18)

eTable 3. Summary of studies examining migraine incidence (n=2)

eTable 4. Risk of bias ratings for case-control studies

eTable 5. Risk of bias ratings for cross-sectional studies

eTable 6. Risk of bias ratings for cohort studies

eFigure 1. Results of meta-analyses comparing migraine to healthy controls for internalizing symptoms and disorders (presented in forest plots)

eFigure 2. Results of meta-analyses comparing migraine to other headache controls (presented in forest plots)

eTable 7. Sensitivity analyses with removal of outlying studies

Click here for additional data file. (1.8MB, pdf)

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