Journal of Affective Disorders 178 (2015) 8897

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Special review article

A meta-analysis investigating the prevalence and moderators

of migraines among people with bipolar disorder
Michele Fornaro a,b,n, Brendon Stubbs c
a

New York Psychiatric Institute, Columbia University, NYC, USA

Department of Education Sciences, University of Catania, Italy
c
Faculty of Education and Health, University of Greenwich, Southwood Site, Avery Hill Road, Eltham, London SE9 2UG, UK
b

art ic l e i nf o

a b s t r a c t

Article history:
Received 19 February 2015
Accepted 26 February 2015
Available online 9 March 2015

Background: Uncertainty exists regarding the prevalence and moderators of migraine comorbidity
among people with bipolar disorder (BD). We conducted a meta-analysis and meta-regression to
investigate the prevalence and moderators of migraine among people with BD.
Method: Two authors independently searched major electronic databases from inception till 02/2015.
Articles were included that reported the prevalence of migraine in people with BD with or without a
control group. A random effects meta-analysis and exploratory meta-regression were conducted.
Results: Fourteen studies were included encompassing 3976 individuals with BD (mean age 35.5 years,
SD 7.6, 29% male). The overall pooled prevalence of migraine was 34.8% (95% CI 25.5444.69). The
prevalence of migraine was higher among people with BD-II (54.17%, 95% CI 31.5275.95, n 742)
compared to BD-I (32.7%, 95% CI 18.1649.19, n 2138, z 3.97, p o0.0001). The prevalence of migraine
was 33.9% (95% CI 26.0242.44), 39.5% (95% CI 18.8162.39) and 47.11% (95% CI 22.2472.77) in
North America, Europe and South America respectively. The prevalence of migraine was higher when
classied according to recognized criteria at 47.91% (95% CI 32.5163.5) compared to non-recognized
criteria (20.0%, 95% CI 12.4429.06, z  8.40, po 0.0001). Meta regression suggests mean age may be a
potential moderator.
Conclusion: Migraine is common and burdensome among people with BD. People with BD-II appear to
be particularly affected. Nonetheless, future research is required to better understand these relationships,
with a special emphasis toward the course speciers of comorbid migraine cases of either BD-I vs. BD-II.
& 2015 Elsevier B.V. All rights reserved.

Keywords:
Migraine
Bipolar disorder (BD)
Comorbidity
Prevalence
Meta-analysis

Contents
1.
2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Information sources and searches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Study selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Data collection process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Risk of bias in individual studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.
Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.
Quality assessment and risk of bias across the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Study selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Included study and participant characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Quality score and quality differentiation results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Meta-analysis of the prevalence of migraine in people with bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
Sub-group analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Correspondence to: New York Psychiatric Institute, Columbia University, 1051 Riverside Drive, New York, NY 10032, unit 2712, USA. Tel.: 1 646 774 7652.
E-mail addresses: mf3000@columbia.edu (M. Fornaro), b.stubbs@greenwich.ac.uk (B. Stubbs).

http://dx.doi.org/10.1016/j.jad.2015.02.032
0165-0327/& 2015 Elsevier B.V. All rights reserved.

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3.5.1.
Prevalence of migraine according to BPD diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
3.5.2.
Prevalence of migraine according to geographical location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
3.5.3.
Prevalence of migraine according to criteria used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
3.6.
Meta-regression analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.7.
Risk of bias within and across studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.1.
Migraine associated to BD-II: specic ndings and related clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.2.
MigraineBD comorbidity and subjective pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.3.
Additional ndings and major implication of the quantitative synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.4.
Study limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Conict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

1. Introduction
Migraine is one the oldest ailments known to mankind (Mandal,
2014). Some of the earliest cases of painful headaches were recorded
by the ancient Egyptians and date back as far as 1200 B.C. (Karenberg
and Leitz, 2001). Much later, in around 400 B.C., Hippocrates referred
to the visual disturbances that can precede a migraine such as ashing
lights or blurred vision (aura) (Breitenfeld et al., 2014). However, the
credit for migraine discovery was given to Aretaeus of Cappadocia
who described in the second century the one sided or unilateral
headaches that are typical of migraines as well as the associated
vomiting and the windows of time between migraines that are
symptom free (Koehler and van de Wiel, 2001). The word migraine
itself derived from the Latin word hemicrania meaning half (hemi)
skull (crania). This term was rst used by Galenus of Pergamon to
describe the pain felt across one side of the head during a migraine
(Isler, 1992). Yet the documentation of migraine features, already
documented even in course of mood disturbances, was not unique to
Western cultures, as recorded by the Chinese surgeon Hua Tuo (late
Han Dynasty, second century A.D.) who was the rst to successfully
use acupuncture needles to relieve the recurrent migraines complained by the irritable, moody and tyrannical founder of his
kingdom (Fu, 2002). Similarly, the Islamic philospher Avicenna described migraine in his textbook on medicine El Qanoon fel teb, a
treatise which is also nowadays considered one of the earliest texts on
melancholia and mania (Omrani et al., 2012), documenting how
eating, drinking, sounds and light all worsened the pain felt during a
migraine (Abokrysha, 2009), a report that should nowadays appear
clinically intriguing also considering that hyperesthesia (sensory
over-sensitivity) has been recently linked even to anxious, irritable
and mood disturbances (Sylvia et al., 2014). Avicenna described how
these patients tended to rest alone in a dark room until the attack
passed, but it was Abu Bakr Mohamed Ibn Zakariya Rzi who pointed
to an association between migraine and hormones when he referred
to how such headaches would occur during menopause, after childbirth or during dysmenorrhea (Mandal, 2014), all conditions that
would nowadays potentially linked to the broad denition of bipolar
spectrum when leading to maternity blues, post-partum depression or menstrual disturbances (Akiskal and Mallya, 1987; Di Florio
et al., 2013; Fornaro and Perugi, 2010). Yet, it was not until the
publication of the results from large studies in carried in Zurich
(Merikangas et al., 1990) and Detroit (Breslau et al., 1994) that migraine
was systematically documented to be more frequent in mood disorder
patients, including bipolar disorder (BD) cases, than in controls.
According to the International Classication of Headache Disorders, 2nd edition (ICHD-2), migraine refers to different phenotypes
having in common a low threshold to the development of headache
among migraineurs, usually being characterized for a recurring
pattern, frequent free-interval, and usually provoked by stereotyped

triggers (Headache Classication Subcommittee of the International

Headache Society, 2004). Nonetheless, while a conclusive denition
of migraine remains elusive, especially due to the heterogeneity of
some of the frequently associated neurological and psychiatric
comorbidities, a three-fold increase in migraine prevalence in
patients with BD has been ascertained (Merikangas et al., 1993), as
outlined by a recent systematic review about the prevalence of
migraine comorbidity among people with BD (Fornaro et al., 2015).
This latter systematic review, rst of its kind at writing time, whilst
helpful, updated and informative, did not undertake a meta-analysis,
nor was there any attempt to stratify the results according to
diagnosis (BD-I vs. BD-II), setting or location. Information about
how the prevalence of migraine may be inuenced according to
the classication of BD, geographical location and the criteria used to
dene a migraine are nonetheless clinically relevant, and conducting
meta-analyses offers the potential to provide the most accurate effect
size of an actual phenomenon and enable researchers to make wider
conclusions than considering individual studies in isolation. Given
the burden of migraine among people with BD, there is a need to
better understand the prevalence and moderators of migraine.
Therefore, to the best of our knowledge, we set out to conduct the
rst meta-analysis to investigate the prevalence and moderators of
migraine comorbidity among people with BD.

2. Material and methods

The present meta-analysis adhered to the Meta-analysis Of
Observational Studies in Epidemiology (MOOSE) guidelines (Stroup
et al., 2000). The current paper followed the inclusion and exclusion
criteria already adopted for our recent Preferred Reporting Items for
Systematic reviews and Meta-Analyses (PRISMA) systematic review
(Fornaro et al., 2015), but extended the inclusion criteria to account
also for contributes indexed in PubMed since inception. In addition,
searches were updated on all databases. Please refer to PROSPERO
registration number: CRD42014009335 at http://www.crd.york.ac.
uk/PROSPERO/ for further reference and to the following lines for a
brief summary of the adopted criteria.
2.1. Eligibility criteria
We included observational studies published in the English language that fullled the following criteria: 1) Included adults with BD
(either type I or type II) diagnosed according to recognized diagnostic
criteria (e.g., DSM-IV (APA, 1994) or ICD-10 (WHO, 2010)) or through
medical record review with or without a control group without mental
illness. 2) Reported the prevalence of migraine. We accepted any
assessment of migraine including self-report physician diagnosis or
recognized criteria such as the 1988 and the 2004 editions of the

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M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

International Headache criteria (Headache Classication Subcommittee

of the International Headache Society, 2004, 1988). No publication date
of publication restrictions was placed upon the searches. Papers
covering cases of migraineBD comorbidity associated with additional
disorders (either psychiatric, neurological [including migraine due to
epilepsy, Tourette's syndrome or schizophrenia] or to other somatic
disorders/diseases) were also evaluated wherever available.
We excluded studies that reported the prevalence of BD among
people with migraine and other biased samples. We also excluded
case reports, papers not including BD migraine co-occurring cases,
those merely focusing on neurobiological, genetic or pharmacological aspects of either migraine or BD; including only children or
adolescents; or without an accurate description about the diagnostic denitions of either migraine and BD.
2.2. Information sources and searches
Two independent reviewers searched PubMed/Medline, Scopus,
PsycLit, PsycInfo, Embase, and Cochrane library from inception until
February 2015. We used the following key words or their combination
in the search strategy: migraine AND, either in the title and abstract
(or in the key words where specied). The adopted PubMed string
was: (Migraine [Title/Abstract]) AND Bipolar Disorder [Title/Abstract].
Contact with study authors was planned if ever needed. In addition,
the reference lists of all eligible articles and recent systematic reviews
(Fornaro et al., 2015; Stubbs et al., 2015) were manually screened.
2.3. Study selection
Two independent reviewers screened the titles and abstracts of
all potentially eligible articles. When a title and/or an abstract
appeared suggestive for inclusion, the full text reprint was obtained
and examined to assess its relevance according to our inclusion/
exclusion criteria. Both authors applied the eligibility criteria, and a
list of full text articles was developed through consensus. The two
reviewers then considered the full texts of these articles and the
nal list of included articles was reached through consensus.
2.4. Data collection process
A two-step literature search examined all titles and abstracts,
accessing the full texts of potentially relevant papers. Upon data
collection and extraction, the appointed authors compared their own
results with each other to reach a nal consensus based on
consensual inclusion and exclusion criteria. Data was sought for the
following characteristics: Participants, Interventions, Comparisons,
Outcomes, and Study design (PICOS), as well as funding sources.
Specically, the recorded variables for each article included in the
quantitative synthesis included the following: author(s), year publication, study design, sample size, number of patients with BD-I vs.
BD-II vs. BD Not Otherwise Specied (BD-NOS), number of patients
with- or without-comorbid migraine (stratied for type of BD and/or
type of migraine whenever the information available), and pharmacological history (including class of current medication, if ever).
Additionally, the presence of any eventual follow-up or control group,
outcome measures, conclusions, limitations, quality score, and quality differentiation were reordered wherever available.

unrepresentativeness or inhomogeneity of the sample size or lack

of control group, and selection by indication bias (nonrandom
assignment of the exposure where applicable) (McGauran et al.,
2010).
2.6. Meta-analysis
We pooled individual study data using a DerSimonianLaird
proportion method (DerSimonian and Laird, 1988) with StatsDirects. Due to anticipated heterogeneity, a random effects metaanalysis was employed. If there were 3 or more studies with
relevant data, we planned to calculate the relative risk (RR) to
investigate prevalence of migraine in those with and without BD.
In addition, we conducted numerous subgroup analyses to establish if the prevalence of migraine differed according to the
geographical region, type of bipolar disorder (BD-I vs. BD-II) and
according to the assessment of migraine criteria (International
Headache Society criteria (editions 1988 or 2004) vs. other
criteria). Finally, we conducted several meta-regression analyses
(if N Z3) to investigate potential moderators (age and percentage
males) with Comprehensive Meta-Analysiss (version 3). We
assessed publication bias with a visual inspection of funnel plots
and calculation of the Egger test and Begg test.
2.7. Quality assessment and risk of bias across the studies
The studies were rated for quality using the following eligibility
criteria: (i) representativeness of the sample (01 points); (ii) presence
of BD patients only in the sample (02 points); (iii) a priori study
design with the goal of evaluating the epidemiology of migraineBD
comorbidity (or vice versa) (02 points); (iv) extension of the followup (longitudinal studies)/clinical records (retrospective studies) 41
year (02 points); (v) validation of the clinical diagnosis and the used
treatment (if applicable) (02 points); (vi) inclusion and control of
all the available variables for potential confounders/effect modiers
that may had inuenced outcome (if applicable) (02 points); (vii)
reliability of the information gathered for the identication of BD
cases/recall bias (02 points); (viii) accuracy of the study was to
discern between manic, hypomanic, mixed, and depressive episodes
in BD (02 points); (ix) appropriateness of the number of comorbid
cases reported as results/sample size (02 points). Quality rating had
17 as the maximum score.
Studies were also differentiated in the following way: (i) good
quality: most or all criteria being fullled, and when they were not
met, the study conclusions were thought to be very unlikely to
alter (1217 points); (ii) moderate quality: some criteria being
fullled, and where they were not met, the study conclusions were
thought to be unlikely to alter (711 points); (iii) poor quality: few
criteria fullled but the conclusions of the study were thought to
be very likely to alter (06 points). Any eventual bias affecting
cumulative evidence (e.g. publication bias, selective reporting
within studies) was assessed through the study evaluation process
and accounted in the discussion of the present manuscript.

3. Results

2.5. Risk of bias in individual studies

3.1. Study selection

Potential major confounding biases in the studies were ascertained at study level focusing on the following: measurement/
diagnostic bias (e.g. lack of reliable diagnostic tools to make the
diagnosis of either migraine or BD), confounding bias (e.g. lack of
stratication and multivariate control for specic socio-demographic,
vital or clinical features), information (especially recall) bias,

The search in PubMed generated 134 papers, and 595 results in

Scopus. Thirteen additional results were obtained through search
either in Cochrane (n 7), PsycLit, PsycInfo or reference textbooks/
manual search. Refer to Fig. 1 for a synthetic ow chart of the
multi-step selection procedure which allowed to retain 14 nal
original studies accounted in our quantitative analysis.

M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

3.2. Included study and participant characteristics

With the sole exception of three retrospective studies (Holland
et al., 2011; Munoli et al., 2014; Saunders et al., 2014), crosssectional design was the only method of report we could detect
in the 14 results accounted for the present quantitative synthesis.
The mean sample size across the included studies was 283.69
(range 271461). Overall, 3976 people with bipolar disorder were
included across the meta-analysis. The sample included 2161 and
647 people identied with BD-I and BD-II respectively. The remainder of participants were mixed bipolar disorder or it was unclear
within the original studies. Overall, the mean percentage of male
participants was 29% (SD 10) and the mean age was 35.5 (SD 7.6).
3.3. Quality score and quality differentiation results
Based on the quality differentiation, original studies were ranked
as follows: poor (n 5, mean total score 4.3), moderate (n 5,
mean total score8.5) or good quality (n4, mean total score14).
No longitudinal follow-up study was found. Details about good
quality original studies have been summarized in Table 1 alongside
with their major limitations and/or biases nonetheless.
3.4. Meta-analysis of the prevalence of migraine in people with
bipolar disorder
It was possible to pool data from 14 studies accounting for 3976
unique people with bipolar disorder. Overall, the pooled prevalence of migraine was 34.8% (95% CI 25.5444.69, Q292.58

(df13); p r0.0001, Fig. 2a). The funnel plot was broadly symmetrical (Fig. 2b) and neither the BeggMazumdar (Kendall's
0.384, p 0.08) or Egger: bias (5.66, p 0.1017) were signicant indicating no evidence of publication bias.
3.5. Sub-group analyses
3.5.1. Prevalence of migraine according to BPD diagnosis
It was possible to pool data investigating the prevalence of
migraine among 2138 unique participants with bipolar disorder I to
establish a pooled prevalence of 32.7% (95% CI18.1649.19). There
was no evidence of publication bias (Egger: bias 2.744, p0.72).
The pooled prevalence of migraine among 742 people with BPD II
was 54.17% (95% CI 31.5275.95) which was signicantly higher
than the prevalence in BPD I (z3.97, po0.0001). No evidence of
publication bias was evident (Egger: bias 3.77868, p0.2831).
3.5.2. Prevalence of migraine according to geographical location
The pooled prevalence of migraine comorbidity was 33.9%
in North America (95% CI 26.029142.44, Q26.26 (df 3);
pr 0.0001, n 1215). There was no evidence of publication bias
(Egger: bias 7.614, p 0.14). The pooled prevalence of migraine
comorbidity in Europe among 2069 participants with bipolar
disorder was 39.5% (95% CI 18.8162.39, Q115.5 (df 5);
pr 0.0001) with no evidence of publication bias (Egger:
bias 3.677; p 0.514). Moreover, there was no statistically signicant difference in the prevalence of migraine comorbidity
among bipolar participants in North American and European
participants (p 40.05). Data from 530 participants with bipolar

Identification

Adaptation of the PRISMA 2009 Flow Diagram (Moher et al., 2009).

Records identified through

database searching
(n = 729)

Additional records identified

through other sources
(n = 13) (Edited books, contact with

the authors, manual search)

Eligibility

Screening

Records after duplicates removed

Included

91

(n = 632)

Records screened
(n = 116)

References assessed for

eligibility

Records excluded (e.g. not

related content) (n = 51)

Sources further excluded

(e.g. inaccurate definitions)
(n = 41)

(n = 65)

Sources included in
qualitative synthesis
(n = 14)

Included in Meta-analysis
(n = 14)
Fig. 1. Flow chart of review procedures for the quantitative synthesis (Moher et al., 2009).

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M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

Table 1
Summary of good quality studies included in the quantitative synthesis.
Author, date.
Study design

Aim/Hypothesis

Low et al., 2003.

Crosssectional
study.

Ortiz et al.,
2010. Crosssectional
study.

To explore the crossprevalence of migraine

in BD-I and BD-II
patients (study 1), then
to explore the
prevalence of
comorbid psychiatric
disorders (including
BDs) in migraine
patients (study 2).

Sample size

Main results

Conclusions

Limitations

Quality
score

A hundred and eight

To investigate the
prevalence and clinical BD patients (17 BD-II).
correlates of comorbid
migraine in BD
patients vs. noncomorbid bipolar
patients.

BD-II patients,
especially females, had
a higher prevalence of
family history of
depression and a
lower chance/
propensity to be on
lithium or other mood
stabilizers rather than
atypical
antidepressants.

BD-II patients with

migraine may be at
higher risk for MDD
misdiagnosis, family
history for psychiatric
disorder, have an
overall higher burden
and chance to receive
antidepressant alone
rather mood
stabilizers.

I 1 II 2 Good quality.
III 2
IV 0
V2
VI 2
VII 0
VIII 2
IX 1
Total12

Study N 214 subjects

(BD-I 126, BD-II 61,
BD NOS or
schizoaffective
disorder, n 27). Study
2, 102 patients, of
whom, 0 had a current
BD-I, 7 a current BD-II
and 5 had a lifetime
BD-I vs. 8 with a
lifetime BD-II).

Up to 24.5% BD
patients had comorbid
migraine; those with
BD-II had a higher
prevalence (34.8%)
compared to BD-I
(19.1%), p r 0.005).
Psychiatric
comorbidities and
suicidal behavior were
also common.

Migraine is prevalent
among BD patients,
especially BD-II cases.
Risk for suicidal
behavior and
comorbid Anxiety
disorders is also high.

Nguyen and
Low, 2013.
Retrospective
study.

N 36.984 patients
To carry between(Canadian Community
group and amonggroup comparisons of Health Survey 1.2).
migraine in BD
according to lifetime
mood episode(s)/
combination of mood
episode(s) in affective
disorder patients
(including BD) vs. rstdegree relative vs.
general population.

Migraine comorbidity
in BD was associated
with an earlier age of
onset of BD itself,
especially with
depressive polarity of
rst episode, as well as
with a higher number
of psychiatric
additional
comorbidities.

Saunders
et al., 2014.
Retrospective
study.

To explore whether the BD patients, n 412,

higher comorbidity of healthy controls,
migraine in BD women n 157.
vs. BD men
documented by most
of the previous
evidence would be
associated with
specic features of
illness and
psychosocial risk
factors that would
differ by gender and
impact outcome.

Overall, compared
with controls, the
adjusted OR of having
migraine was 2.0 (95%
CI 1.42.8) for manic
episodes alone, 1.9
(95% CI 1.62.1) for
depressive episodes
alone, and 3.0 (95%
CI 2.33.9) for
subjects with both
manic and depressive
episodes. Compared to
with those with manic
episodes alone and
depressive episodes
alone, the odds of
having migraine were
signicantly increased
in subjects with both
manic and depressive
episodes (OR 1.5 vs.
manic episodes alone;
1.8 vs. depressive
episodes alone).
Interestingly, this was
also the rst study
specically exploring
mixed symptoms,
which were found in
102 (36%) of nonmigraine cases vs. 63
(50%) of comorbid
cases. With respect to
gender distribution,
there was no
statistically signicant
difference between
rates of migraine in
the BD-II group vs. BDI one in the women
(OR 1.6; 95%, 0.83.0,
yet group differences
between women with
BD and migraine vs.
those without
comorbid migraine
included a marginally
higher rate of mixed
symptoms (OR 0.19,
95% CI, 1.03.7).

Unrepresentativeness
of the BD-II subset.
Overrepresentation of
females in the included
set. Recall bias. Use of
outdated IHS criteria
for the questionnaire
adopted for the
diagnosis of migraine.
Lack of detailed report
about different
psychiatric drugs.
The diagnosis of
migraine was made by
a self-assessment
questionnaire.
Overrepresentation of
BD-I and female cases.
The interviews were
partially conducted in
a clinic specialized in
the treatment of
migraine (chance of
Berkson's bias).
Post-hoc retrospective
chart review. Recall
bias.

Since migraine was

more common in BD
subjects (31%) vs.
controls (6%) and had
an elevated risk in BD
women compared to
men (OR 3.5; 95% CI,
2.15.8), the presence
of migraine, especially
in course of mixed
symptoms, may
prompt clinicians to
account migraine as a
common comorbidity
which may ultimately
affect the long-term
course of BD itself.

Self-reported,
physician made,
diagnoses of migraine
(recall bias). The
sample included
patients with BD
followed over time,
meaning that the most
severe end of the
bipolar spectrum may
have not been
represented; risk of
Berkson's bias. Control
group size smaller that
studied population.
Overrepresentation of
BD-I cases.

BD Bipolar Disorder; MDD Major Depressive Disorder; MDE Major Depressive Episode; NOS Not Otherwise Specied.

Quality
differentiation

I 1 II 2 Good quality.
III 3
IV 0
V1
VI 2
VII 1
VIII 2
IX 2
Total16

I 1 II 1 Good quality.
III 0
IV 2
V2
VI 2
VII 0
VIII 2
IX 2
Total12

I 1 II 2 Good quality.
III 2
IV 2
V2
VI 2
VII 1
VIII 2
IX 2
Total16

M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

93

Proportion meta analysis plot [random effects]

Oedegaard KJet al., (2005)

0.78 (0.71, 0.84)

Bapt ist a T et al., (2012)

0.61 (0.53, 0.68)

Fasmer O.B. & Oedegaard K.J. (2001)

0.56 (0.45, 0.66)

D ilsaver SC et al., (2008)

0.54 (0.43, 0.65)

Fasmer O.B. (2001)

0.44 (0.25, 0.65)

Low NC et al., (2003)

0.40 (0.31, 0.50)

Briet zke E. et al., (2012)

0.34 (0.29, 0.39)

Jet t e N et al., (2008)

0.32 (0.27, 0.37)

Saunders EF et al., (2014)

0.31 (0.26, 0.36)

Mahmood T. et al., (1999)

0.26 (0.17, 0.37)

Gordon-Smith K et al. (2015)

0.25 (0.23, 0.27)

Ort iz A et al., (2010)

0.24 (0.20, 0.30)

Holland J et al., (2011)

0.05 (0.02, 0.09)

0.02 (3.0E -3, 0.09)

Munoli RN et al., (2014)

c ombined

0.35 (0.26, 0.45)

0.0

0.3

0.6

0.9

proportion (95% confidence interval)

Fig. 2. (a) Pooled prevalence of migraine comorbidity among included participants. (b) Funnel plot for the main analysis.

disorder in South America revealed a pooled prevalence of 47.11%

(95% CI 22.2472.77, Q35, po 0.001).

3.5.3. Prevalence of migraine according to criteria used

It was possible to pool data from 7 studies representing 1094
participants with bipolar disorder to establish a pooled prevalence of migraine of 47.91% (95% CI 32.5163.5, Q 92, po 0.001)

with no evidence of publication bias (Egger: bias 4.545, p 0.29)

(see Fig. 3). The pooled prevalence of migraine according to selfreport/ nonstandardized criteria among 2882 participants with
bipolar disorder was 20.0% (95% CI 12.4429.06, Q129,
po 0.001, Egger: bias 0.369; p 0.97) which was signicantly
lower than the prevalence of migraine reported in studies using
standardized criteria (z  8.40, p o0.0001). Refer to the forest
plot depicted in Fig. 3 for further details.

94

M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

Proportion meta analysis plot [random effects]

Oedegaard KJ et al., (2005)

0.78 (0.71, 0.84)

Baptista T et al., (2012)

0.61 (0.53, 0.68)

Fasmer O.B. & Oedegaard K.J. (2001)

0.56 (0.45, 0.66)

Di lsaver SC et al., (2008)

0.54 (0.43, 0.65)

Fasmer O.B. (2001)

0.44 (0.25, 0.65)

Low NC et al., (2003)

0.40 (0.31, 0.50)

Mahmood T. et al., (1999)

0.26 (0.17, 0.37)

O rt iz A et al., (2010)

0.24 (0.20, 0.30)

c ombined

0.48 (0.33, 0.64)

0.0

0.2

0.4

0.6

0.8

1.0

proportion (95% confidence interval)

Fig. 3. Pooled prevalence of migraine comorbidity according to the International Headache Society criteria (1988 or 2004).

Regression of Logit event rate on Mean age

4.00
3.00

Logit event rate

2.00
1.00
0.00
-1.00
-2.00
-3.00
-4.00
-5.00
-6.00
10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

50.0

Mean age
Fig. 4. Meta-regression analysis of mean age.

3.6. Meta-regression analyses

In the exploratory meta regression analysis, there was a trend
for mean age to moderate the prevalence of migraine among the
entire sample (coefcient 0.0474, 95% CI  0.0972 to 0.0025,
p 0.06, R2 0.21, see Fig. 4). The percentage of males across the
samples was not associated with the prevalence of migraine
(coefcient  0.023, 95% CI  0.0689 to 0.0228, p 0.33, R2 0).
Refer to Fig. 4 for details.
3.7. Risk of bias within and across studies
Comorbidities are best studied in representative samples because
the prevalence of disease and the association among disorders may
be sometimes altered in clinic-based samples or primary care
settings (Wittchen et al., 1999). Also, a Berkson's bias leading to
under-estimation (or over-estimation) of the rate of occurrence of

migraineBD comorbidity may have occurred across the studies since

most severe cases usually tend to seek medical care instead of
participating in population-based studies instead of and this is seen
more in clinic-based ones (Berkson, 1946). Moreover, incidence rates
of a number of comorbid conditions increase with the frequency of
migraine attacks, being higher for episodic vs. chronic migraine
(Aamodt et al., 2007). An additional bias potentially often encountered in such studies and accounted for in this systematic review,
especially retrospective ones, is recall bias, due to the chance of
neglect or poor regard of some BD patients towards their own
previous (hypo-)manic episodes, which may ultimately affect even
the prevalence estimates actually documented for migraineBD
comorbidity itself. Furthermore, a gender-related publication bias
may have been occurred due to the unrepresentativeness of females
subjects (clearly) documented to be follicular phase of the menstrual
cycle (Lay and Payne, 2007); similarly a potential confounding
bias may be related to under-reported epileptic spikes eventually

M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

associated to some cases with migraineBD comorbidity (Belcastro et

al., 2013). The afore mentioned biases potentially occurring within
the studies may also affect between-studies comparisons, especially
due to the lack of clearly detectable effect sizes/z-scores in most of
the selected studies. There is also inconsistency of the diagnostic
criteria adopted for the denition of BD-II (sometimes broadened to
include affective temperaments too) or IHS editions for the diagnosis
of migraine, as well the inaccurate distinction between BD-I and BDII or specic types of migraines by some studies, especially in lowpowered and post-hoc studies.

4. Discussion
The current meta-analysis is to our knowledge a rst and
established that overall approximately one third of people with
BD are affected by comorbid migraine (34.8%, 955% CI25.54
44.69, n3976). Of particular interest, we have established that
higher prevalence of migraine exists among people with BD-II (54%)
vs. those with BD-I (32.7%, po0.0001). Interestingly, we also
established for the rst time that the prevalence of migraine
is substantially higher in studies utilizing recognized criteria
(e.g. International headache society criteria, 47.9%) compared to
non-standardized criteria such as self-report (20.0%, po0.0001).
This may mean that studies that rely on non-standardized criteria
to record migraine are underestimates and provide rationale for the
need to employ recognized criteria to investigate migraines in
people with BD with the ultimate goal to provide an early recognition and an early therapeutic management of BDmigraine comorbidity, whenever occurring. Also, the exploratory meta-regression
analyses suggest that mean age may be an important moderator of
migraine prevalence. The prevalence of migraine appears comparable in North America and Europe; yet the paucity of equivalent
evidence in non-Western societies hinders the appreciation of a
cultural-bias in the presentation and self-reported rates of migraine
across different regions, if ever existing, therefore soliciting further
comparative studies on the matter. Of particular importance, there
was insufcient data to perform a meaningful comparative metaanalysis investigating migraine among people with BD and matched
controls from the general population.
4.1. Migraine associated to BD-II: specic ndings and related
clinical implications
Based on the main ndings of the present meta-analytic
summary, the prevalence of comorbid migraine among people with
BD is remarkably high, particularly among people with BD II. This
latter nding, though in line with a narrative review (Fornaro et al.,
2015), acquires further clinical relevance nonetheless, especially
considering that type-II BD is way more common in the outpatient
setting compared to BD-I patients. Moreover, the onset of BD
involves a major depressive episode (MDE) in approximately half
of type-I (BD-I) patients, and three-quarters of those diagnosed
with BD-II (Baldessarini et al., 2013; Goodwin and Jamison, 2007;
Koukopoulos et al., 2013; Tondo et al., 2014), meaning that BD-II
patients are at increased risk to receive a delayed diagnosis of BD-II
rather MDD, despite relevant treatment implications associated to
failure to promptly recognize BD in depressed patients include
under-prescription of mood-stabilizers, an increased risk of rapid
cycling, increased cost of care due to ineffective treatment and
increased risk for suicide (Fornaro et al., 2015; Merikangas et al.,
1993). In this respect, the present meta-analytic conrmation of a
stronger association between migraine and BD-II vs. BD-I cases
should ultimately pave the ground to novel quantitative comparative studies between MDD and BD-I vs. BD-II comorbidmigraine
cases too, especially considering that most of the available reference

95

still rely on unreliable comparisons, unrepresentative samples or on

non-controlled, post-hoc reports (Fornaro et al., 2015). Furthermore,
the results coming from the present quantitative synthesis highlighted the need for further studies focusing on migraineBD-II
comorbidity including well-matched control cases with or with-out
rapid cycling features too. In fact, the only post-hoc evidence made
recently available on the matter (Gordon-Smith et al., 2015)
included a disproportionally high number of BD-I vs. BD-II cases,
despite the overall, yet still debated, wisdom of a much more
frequent occurring of rapid cycling being associated to BD-II
rather than BD-I cases (Carvalho et al., 2014). As consequence,
though acknowledged as a potential subtype of BD characterized by
a more unstable course of illness requiring a patient-tailored
therapeutic approach and potentially allowing more etiologically
oriented studies on BD itself (Gordon-Smith et al., 2015), chances
are that the actual prevalence of migraine associated to BD-II vs.
BD-I rapid cycling cases should be even higher.
4.2. MigraineBD comorbidity and subjective pain
The present meta-analysis also conrmed the close association
between subjective pain and migraine in BD patients, as we
already outlined in a recent previous meta-analytic synthesis
about the prevalence of pain in BD, pointing out high levels of
associated chronic pain in most of the cases (Stubbs et al., 2015), a
nding which also has major clinical implications considering that
an increased self-perception of pain may ultimately undermine
the adherence towards prescribed medications, particularly in
BD-II patients, especially among those cases with high levels of
somatic complaints (Fornaro et al., 2013, 2014). In our previous
meta-analysis (Stubbs et al., 2015), data pooled regarding nonmigraines (e.g. headache) found a prevalence of 14% for migraine/
headache. In addition, whilst helpful, the previous review on pain
and DB (Stubbs et al., 2015) did not set out to consider migraine
specically and its focus was on pain. Thus our results clarify the
high prevalence of migraine in BD for the rst time in a structured
manner and have for the rst time considered numerous subgroup
analyses of the prevalence and moderators of migraine in this at
risk population. Indeed, apart from clinical and epidemiological
considerations, the putative neurobiological interface between
pain (including reported migraine) and BD remains elusive. Future
research is needed to consider this including possible common
genetic polymorphisms.
4.3. Additional ndings and major implication of the quantitative
synthesis
The comorbidity between migraine and BD was conrmed to
be preferentially associated with an index episode of depression
rather than mania (Brietzke et al., 2012) and with more overall
depressive episodes vs. mania (Birgenheir et al., 2013), which may
further increase the chance of receiving improper antidepressant
monotherapies (Jette et al., 2008) rather than mood stabilizers
including valproate (Oedegaard et al., 2011) or lithium (Low et al.,
2003; Oedegaard et al., 2011).
With respect to overall medical and psychiatric comorbidities,
with the sole exception of the report by Low et al. (2003), evidence
indicated a higher number of lifetime hospitalization and lower
level of education and income (McIntyre et al., 2006; Nguyen and
Low, 2013), as well as a higher prevalence of family history for BD
in case of comorbid migraine (Dilsaver et al., 2009). Moreover,
migraine may precede BD (Ortiz et al., 2010) and the somatic
presentations may be a rst-visit hallmark for some bipolar
outpatients (Tavormina, 2011) especially in case of severe somatic
pain (Birgenheir et al., 2013), thus urging attention considering the
stigma still associated to BD worldwide, and that the evidence

96

M. Fornaro, B. Stubbs / Journal of Affective Disorders 178 (2015) 8897

covered by the present review almost entirely focused on Western

samples, thus precluding the appreciation of any pathoplastic
differential effect of migraine on BD across cultures, if ever existing
(Fornaro et al., 2009) despite the legacy of migraine spanning
across different cultures and regions worldwide (Mandal, 2014).
Finally, our results also suggest that studies relaying on selfreport and non-standardized criteria report lower prevalence of
migraine. This necessitates the need for clinicians and researchers
to endeavor to use recognized criteria to quantify migraine such as
that provided by the International Headache society, with the
ultimate goal of an earlier recognition and earlier adequate
management of the comorbid cases of migraine and BD. Also,
our quantitative synthesis conrmed the need for more methodologically rigorous studies, especially longitudinal ones, as well
as the need for additional primary research involving migraine
cases of rapid-cycling BD-II.
4.4. Study limitations
Most of the limitations of the present meta-analysis (rst of its
kind at writing time) are intrinsically related to the potential
biases of the included studies and should be taken into account in
the interpretations of the results discussed herein. First, there was
heterogeneity in the assessment of migraine and samples included
within our meta-analysis. However, in line with the MOOSE
guidelines, we attempted to negate this by conducting numerous
subgroup analyses. Second, most of the studies were cross sectional. Therefore, future prospective research is required to better
understand the relationship between BD and migraines. Third,
there was often insufcient data to conduct moderation analyses
on key variables such as medication, pain and depressive symptoms which all may inuence the prevalence of migraine. Fourth,
there was insufcient data to conduct a comparative meta-analysis
comparing the prevalence of migraine among people with BD and
matched general population controls. Future research should seek
to make direct head to head comparisons to quantify the risk of
migraine among people with BD. Nevertheless, allowing for these
caveats the current meta-analysis is the rst of its kind and offers a
unique insight into the important issue of migraine among people
with BD.

Role of funding source

The authors have no funding source to disclose in conjunction with the
present work.

Conict of interest
The authors have no conict of interest, neither nancial support to disclose in
conjunction with the present work.

Acknowledgments
None to state.

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