# Clinical features and comorbidities associated with migraine in bipolar disorder: Results from the FACE-BD cohort

Ludovic Samalin, Ophelia Godin, Xavier Moisset, Ambre Chalayer, Agnes Pelletier, Antoine Lefrere, Paul Roux, Mircea Polosan, Anamaria Bogdan, Raymund Schwan, et al.

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## To cite this version:

Ludovic Samalin, Ophelia Godin, Xavier Moisset, Ambre Chalayer, Agnes Pelletier, et al. Clinical features and comorbidities associated with migraine in bipolar disorder: Results from the FACE-BD cohort. Journal of Affective Disorders, 2025, 379, pp.289-296. 10.1016/j.jad.2025.03.045. hal-04997693

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Research paper

# Clinical features and comorbidities associated with migraine in bipolar disorder: Results from the FACE-BD cohort

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Ludovic Samalin<sup>a,b,*</sup>, Ophelia Godin<sup>a,d</sup>, Xavier Moisset<sup>c</sup>, Ambre Chalayer<sup>a,b</sup>, Agnes Pelletier<sup>a,d</sup>, Antoine Lefrere<sup>a,e,f</sup>, Paul Roux<sup>a,g</sup>, Mircea Polosan<sup>a,h</sup>, Anamaria Bogdan<sup>a,i</sup>, Raymund Schwan<sup>a,j</sup>, Caroline Dubertret<sup>a,k,l</sup>, Bruno Aouizerate<sup>a,m</sup>, Raoul Belzeaux<sup>a,n</sup>, Romain Rey<sup>a,o</sup>, Dominique Januel<sup>a,p</sup>, Michel Walter<sup>a,q</sup>, Antoine Yrondi<sup>a,r,s</sup>, Emmanuel Haffen<sup>a,t</sup>, Philippe Courtet<sup>a,u</sup>, Frank Bellivier<sup>a,v</sup>, Marion Leboyer<sup>a,d</sup>, FACE-BD collaborators<sup>l</sup>, Bruno Etain<sup>a,v</sup>, Emilie Olié<sup>a,u</sup>, Pierre-Michel Llorca<sup>a,b</sup>

<footnote><sup>a</sup> Fondation Fondamental, Créteil, France</footnote>

<footnote><sup>b</sup> University of Clermont Auvergne, CHU Clermont-Ferrand, CNRS, IP, UMR 6602, Clermont-Ferrand, France</footnote>

<footnote><sup>c</sup> University of Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, Clermont-Ferrand, France</footnote>

<footnote><sup>d</sup> Univ Paris Est Créteil, INSERM, IMRB, Translational Neuro-Psychiatry, AP-HP, DMU IMPACT, FHU ADAPT, Psychiatry and addictology of Mondor University Hospital, Créteil, France.</footnote>

<footnote><sup>e</sup> Pôle de Psychiatrie, Assistance Publique Hôpitaux de Marseille, Marseille, France</footnote>

<footnote><sup>f</sup> Institut of Neurosciences de la Timone, Aix-Marseille Univ, UMR CNRS, France</footnote>

<footnote><sup>g</sup> Centre Hospitalier de Versailles, Service Hospitalo-Universitaire de Psychiatrie d'Adultes et d'Addictologie, Le Chesnay, MOODS team, INSERM UMR1018, CESP, Faculté de Médecine Paris-Saclay, Université de Versailles Saint-Quentin-En-Yvelines, Université Paris-Saclay, Villejuif, France</footnote>

<footnote><sup>h</sup> Université Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France,</footnote>

<footnote><sup>i</sup> Pôle de Psychiatrie, Centre Hospitalier Princesse Grace, Monaco</footnote>

<footnote><sup>j</sup> Université de Lorraine, Centre Psychothérapeique de Nancy, Inserm U1254, Nancy, France</footnote>

<footnote><sup>k</sup> AP-HP, Groupe Hospitalo-Universitaire AP-HP Nord, DMU ESPRIT, Service de Psychiatrie et Addictologie, Hôpital Louis Mourier, Colombes, France</footnote>

<footnote><sup>l</sup> Université de Paris, Inserm UMR1266, Sorbonne Paris Cité, Faculté de Médecine, Paris, France</footnote>

<footnote><sup>m</sup> Centre Hospitalier Charles Perrens, Laboratoire NutriNeuro (UMR INRA 1286), Université de Bordeaux, Bordeaux, France</footnote>

<footnote><sup>n</sup> Department of Psychiatry, CHU Montpellier; IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France</footnote>

<footnote><sup>o</sup> Bipolar Disorder Expert Centre, Le Vinatier Hospital, Bron; University Lyon 1, Villeurbanne; INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, Psychiatric Disorders, Neuroscience Research and Clinical Research Team, Lyon, France</footnote>

<footnote><sup>p</sup> Département de recherche clinique, pôle universitaire 93G03, EPS Ville Evrard Neuilly sur Marne, Université Sorbonne Paris-Nord, Neuilly-sur Marne, France</footnote>

<footnote><sup>q</sup> Service Hospitalo-Universitaire de Psychiatrie Générale et de Réhabilitation Psycho Sociale 29G01 et 29G02, CHRU de Brest, Hôpital de Bohars, Brest, France</footnote>

<footnote><sup>r</sup> Service de Psychiatrie et de Psychologie Médicale, Centre Expert Dépression Résistante et Bipolaire FondaMental, CHU de Toulouse, Hôpital Purpan, ToNIC Toulouse NeuroImaging Centre, Toulouse, France</footnote>

<footnote><sup>s</sup> Université de Toulouse, INSERM, UPS, Toulouse, France</footnote>

<footnote><sup>t</sup> Univ Franche-Comté, UMR INSERM 1322 LINC, Service de Psychiatrie de l'Adulte, CIC-1431 INSERM, CHU de Besançon, France</footnote>

<footnote>* Corresponding author at: Centre Hospitalier Universitaire, Service de Psychiatrie B, 58 rue Montalembert, 63000 Clermont-Ferrand, France.
E-mail address: lsamalin@chu-clermontferrand.fr (L. Samalin).</footnote>
¹ CHU Montpellier, Hôpital Lapeyronie, Psychiatric Emergency and Post Emergency Department, Pole Urgence; IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France

² AP-HP, GH Saint-Louis - Lariboisière - Fernand Widal, Pôle Neurosciences Tête et Cou, Département de Psychiatrie et de Médecine Addictologique, INSERM UMRS 1144, Université Paris Cité, Paris, France

ARTICLE INFO

**Keywords:**
Migraine
Bipolar disorder
Prevalence
Comorbidity

ABSTRACT

**Introduction:** Individuals with bipolar disorder (BD) frequently experience comorbid medical conditions, with migraine being among the most common. While research on migraine prevalence in BD is growing, the associated clinical features, comorbidities, and treatments remain underexplored and sometimes inconsistent. This study aimed to investigate the clinical features and comorbidities associated with migraine in a large cohort of adults with BD.

**Methods:** We assessed 4348 outpatients with BD attending FondaMental Advanced Centers of Expertise. Sociodemographic and clinical data were collected using a standardized procedure. Lifetime diagnoses for medical disorders, including migraine, were based on self-reports, clinician assessments, and medical history reviews. Multivariable logistic regression was used to assess associations between migraine and sociodemographic factors, clinical characteristics, comorbidities, and medications.

**Results:** The prevalence of comorbid migraine in BD was 20 %, with 29.1 % in BD type II and 19.9 % in BD type I. Multivariable analysis found that migraine was associated with younger age (OR = 0.98, CI 95 % 0.97-0.99), females (OR = 2.15, CI 95 % 1.56-2.95), sleep disturbances (OR = 1.06, CI 95 % 1.02-1.11), childhood trauma (OR = 1.01, CI 95 % 1.00-1.02), hypertension (OR = 1.88, CI 95 % 1.13-3.15), psoriasis (OR = 1.61, CI 95 % 1.01-2.56), asthma (OR = 1.65, CI 95 % 1.02-2.67) and lower use of second-generation antipsychotics (OR = 0.65, CI 95 % 0.48-0.87).

**Conclusion:** Migraine is common in BD, especially in younger individuals, females, and those with sleep disturbances or a history of trauma, who also experience a higher clinical burden. These overlapping factors highlight the need for an integrated treatment approach, addressing mood stabilization, sleep management, and trauma support to reduce migraine burden in BD patients.

# 1. Introduction

Bipolar disorder (BD) is a chronic and severe mental disorder that most often appears in young adults and affects between 2 and 4 % of the general population (Merikangas et al., 2011). BD is characterized by

recurrent mood episodes (depression, manic/hypomanic, or mixed episodes) separated by periods of clinical remission.

Individuals with BD frequently have comorbid medical conditions, with migraine being one of the most common, affecting up to 39 % of the BD population (Duan et al., 2021).

Migraine is a neurological disorder with a prevalence around 15 %, typically presenting without abnormal findings on physical or neurological examination or brain MRI (Steiner and Stovner, 2023; Stovner et al., 2018). Similar to BD, the diagnosis of migraine is clinical, relying on a patient's history and the specific characteristics of their headaches. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia (IHS, 2018). As a result, diagnosis is based on retrospective evaluation of these defining features.

A bidirectional relationship has been identified between BD and migraine (Sinha et al., 2018). Compared to the general population, the prevalence of migraine is higher in individuals with BD (Ortiz et al., 2010; Romo-Nava et al., 2021), while the prevalence of BD is also higher among those who experience migraine (Leo and Singh, 2016).

These strong connections have prompted further investigation into the association between BD and migraine, focusing the clinical characteristics linked to both conditions, other comorbidities, and potential overlapping mechanisms between the two disorders (Duan et al., 2021).

Individuals with co-occurring BD and migraine are more likely to experience conditions such as psoriasis, asthma or fibromyalgia (Ortiz et al., 2010; Romo-Nava et al., 2021). These associations suggest a potential mediating role of inflammation in the cross-sensitization between BD and migraine. Although the exact pathophysiology of both disorders remains unknown, inflammation has been implicated in their development (Brietzke et al., 2012). Specifically, disruptions in the balance between oxidative stress, the antioxidant response, and the regulation of nitrosative stress have been identified as shared mechanisms in both BD and migraine. Additionally, abnormalities in serotoninergic, dopaminergic, and glutamatergic pathways are common to both conditions (Duan et al., 2021). Genetic factors (Dilsaver et al., 2009; Sucksdorff et al., 2016) and calcium channel dysfunctions (Nanou and Catterall,

<footnote n="1">¹ List of FondaMental Advanced Center of Expertise (FACE-BD) collaborators: FACE-BD Clinical Coordinating Center (Fondation FondaMental); B. Etain, E. Olié, M. Leboyer, E. Haffen and PM Llorca; FACE-BD Data Coordinating Center (Fondation FondaMental); V. Barteau, S. Bensalem, O. Godin, H. Laouamri, and K. Souryis; FACE-BD Clinical Sites and Principal Collaborators in France; AP-HP, DHU PePSY, Pôle de Psychiatrie et d'Addictologie des Hôpitaux Universitaires H Mondor, Créteil; S. Hotier, A. Pelletier, C. Lam, V. Nicolaïdis, J. Lantier, F. Harter, C. Dominique, C. Pin; AP-HP, GH Saint-Louis-Lariboisière-Fernand Widal, Pôle Neurosciences, Paris; F. Bellivier, M. Carminati, B. Etain, V. Hennion, E. Marlinge, J. Meheust, R. Bootz and A. Richard; Hôpital C. Perrens, Centre Expert Trouble Bipolaire, Service de Psychiatrie Adulte, Pôle 3-4-7, Bordeaux; B. Antoniol, A. Desage, S. Gard, A. Jutant, K. Mbailara, I. Minois, and L. Zanouy; CHRU Montpellier, Département d'Urgence et Post Urgence Psychiatrique, Montpellier; L. Bardin, A. Cazals, P. Courtet, B. Deffinis, D. Ducasse, M. Gachet, A. Henron, F. Molière, B. Noisette, E. Olié, and G. Tarquini; Hôpital Sainte Marguerite, Pôle de Psychiatrie, Addictologie et Pédopsychiatrie, Marseille; M. Cermolacce, F. Groppi, E. Moreau, A. Lefrene, L. Lescalier, H. Polomeni. J. Baurberg, C Gonzales, A. Suray, I. Muraccioli; Centre Psychothérapique de Nancy, Pôle Hospitalo-Universitaire de Psychiatrie d'Adultes du Grand Nancy; R. Schwan, T. Schwitzer, G. Gross, R. Cohen, and O. Wajsbrot-Elgrabli; CHU de Grenoble et des Alpes, Service Universitaire de Psychiatrie, Grenoble; T. Bougerol, B. Fredembach, A. Suisse, B. Halili, A. Pouchon, and M. Polosan; Centre Hospitalier de Versailles, Service Universitaire de Psychiatrie d'adultes et d'addictologie, Le Chesnay; L. Brehon, L. Durand, P. Roux, E. Vaux; Centre Hospitalier Princesse Grace, Monaco; V. Aubin, J. Loftus, A. Bogdan, P. Martinez, I. Medecin and M.A Dupont; APHP, Groupe Hospitalo-universitaire AP-HP Nord, DMU ESPRIT Service de psychiatrie et addictologie, Hôpital Louis Mourier, Colombes, France; C. Dubertret, N. Mazer, P. Lautrent; CHU de Clermont-Ferrand, Service de Psychiatrie de l'adulte B, Centre Expert Trouble Bipolaire, Clermont-Ferrand; PM. Llorca, L. Samalin, M. Gambier, T. Bonnet, D. Lacelle, M. Vayssié, C. Beal, and O. Blanc; CHU Toulouse, Service de Psychiatrie et Psychologie Médicale, Centre Expert Trouble Bipolaire, Toulouse; A. Yrondi, R. Abidine, C. Sarramon, C. Arbus</footnote>
2018) have also been implicated in the pathophysiology of BD and
migraine.

Several studies have emphasized that the co-occurrence of BD and
migraine appears to be linked to specific clinical features of BD,
including an earlier age of onset, BD type 2, rapid cycling, comorbid
anxiety disorder and worse clinical outcomes including a higher risk of
suicide and more severe depression (Fornaro et al., 2015; Gordon-Smith
et al., 2015; Mehrhof et al., 2021; Nguyen and Low, 2013; Romo-Nava
et al., 2021).

Despite growing literature on the prevalence of migraine in in-
dividuals with BD, the associated clinical features and medical comor-
bidities, and treatment strategies for BD patients with comorbid
migraine remain underexplored and sometimes inconsistent (Brietzke
et al., 2012; Saunders et al., 2014).

The objective of this study was to investigate the clinical features and
comorbidities associated with migraine in a large sample of 4348 adults
with BD.

## 2. Material and methods

### 2.1. Study population

The study sample consisted in individuals who were clinically
assessed in the French network of FondaMental Advanced Centers of
Expertise in Bipolar Disorders (FACE-BD) from June 2009 to July 2022.
This network is supported by the French Ministry of Health and has been
developed under the aegis of the FondaMental Foundation, to provide
support to general practitioners and psychiatrists in the diagnosis and
management of individuals with BD.

All outpatients who were aged 18 years or older, diagnosed with BD
according to DSM-IV criteria (all bipolar subtypes [I, II, and not other-
wise specified: NOS]) and assessed in the network were enrolled in the
FACE-BD cohort. There were 12 expert centers in France and they all
used the same package of thorough and standardized clinical assess-
ments, described in details elsewhere (Henry et al., 2017).

The study was carried out in accordance with ethical principles for
medical research involving Humans (WMA, Declaration of Helsinki).
The assessment protocol was approved by the institutional review board
(Comité de Protection des Personnes Ile de France IX; January 18, 2010),
in accordance with the French laws for non-interventional studies and
requires only an information letter.

### 2.2. Assessments

BD diagnosis and other psychiatric diagnosis were ascertained
through a single face-to-face structured interview with a trained clini-
cian using the *Structured Clinical Interview for DSM, axis I of the Diagnostic
and Statistical Manual for Mental Disorders, fourth edition* (SCID-IV) (First
et al., 1995). Information related to the patient's age, sex (assigned at
birth), level of education and marital status, onset and course of BD and
any kind of psychiatric comorbidities were systematically recorded.
Current psychotropic treatments (lithium, anticonvulsants, second-
generation antipsychotics, antidepressants and benzodiazepines) were
recorded.

Current mood state was respectively assessed with the Montgomery
Asberg Depression Rating Scale (Montgomery and Åsberg, 1979) and
the Young Mania Rating Scale (Young et al., 1978). Other psychometric
data were assessed, as level of trait anxiety by the Y-A form of the State
Trait Inventory Anxiety (STAI-A) (Spielberger et al., 1993), the subjec-
tive sleep quality by the Pittsburgh Sleep Quality Index (PSQI) (Buysse
et al., 1989), the evening chronotype by the composite scale of morn-
ingness (Caci et al., 1999), given recent literature showing that evening
chronotype is associated with a poorer prognosis in BD and migraine
(Zou et al., 2022; Viticchi et al., 2019), the childhood traumatic events
by the Childhood Trauma Questionnaire (CTQ) (Bernstein et al., 2003),
the adherence to medication by the Medication Adherence Rating Scale

(MARS) (Fond et al., 2017). Quality of life and psychosocial functioning
were respectively assessed with the EUROQOL 5 dimensions question-
naire (EQ-5D-5L) (Feng et al., 2021; Janssen et al., 2013) and the
Functioning Assessment Short Test (FAST) (Rosa et al., 2007).

The lifetime diagnosis of migraine was established based on a pa-
tient's self-reported diagnosis, clinician assessment, and confirmation
through a review of the patient's medical history. No specific screening
instruments were used.

Other lifetime diagnoses of medical disorders, including other
neurological disorders (multiple sclerosis, epilepsy, meningitis, stroke,
head injury), cardiovascular disorders (hypertension, coronary disease,
myocardial infarction, cardiac dysrhythmia), endocrine and metabolic
disorders (diabetes, dysthyroidism, dyslipidemia), urinary tract disor-
ders (nephropathy, acute retention of urine), skin disorders (psoriasis,
eczema, toxidermia/rash, acne), liver and digestive disorders (cirrhosis,
hepatitis, peptic ulcer, inflammatory chronic intestinal diseases),
allergic and auto-immune-inflammatory disorders (asthma, allergy,
systemic lupus erythematosus, rheumatoid polyarthritis), cancer and
infectious disorders (HIV, chronic viral hepatitis) were assessed using a
systematic interview administered to all participants.

### 2.3. Statistical analysis

Categorical variables are expressed as numbers and percentages, and
continuous variables as mean ± SD (Standard Deviation). Bivariate
analyses were conducted to identify the factors associated with migraine
considered as a binary variable. We investigated the associations be-
tween migraine, and sociodemographic factors, clinical factors, psy-
chiatric and medical comorbidities, and psychotropic medications using
chi2 tests for categorical variables and t-tests or Mann-Whitney Wil-
coxon tests for continuous variables, depending of the distribution of the
variables. A multivariable logistic regression analysis was used to esti-
mate the odds ratio (OR) for factors associated with migraine. Variables
included in this model were selected based on a threshold p-value ≤0.20
in bivariate analyses, with the exception of quality of life and func-
tioning, which were considered to be consequences of BD and/or
migraine. Variable Inflation Factor (VIF) was used to assess
multicollinearity.

Statistical analyses were performed with SAS (release 9.3; SAS Sta-
tistical Institute, Cary, NC). All statistical tests were two-tailed, with α
level set at 0.05.

## 3. Results

The sample consisted of 4348 BD individuals (Table 1). There were
61.8 % of females and the mean age was 39.7 years (SD: 13.1). Most
participants had a high education level (71.3 %). BD was classified as
type I in 44.6 % of individuals, type II in 44.1 %, and type NOS in 11.3 %.

The prevalence of migraine among individuals with BD was 20.1 %.
It was higher in those with BD type II (29.1 %) than in those with BD
type I (19.9 %). The median ages of onset for BD and migraine were 20
(IQR: 17–28) and 18 years (IQR: 13–28), respectively.

The most prevalent other medical comorbidities were allergies
(other than asthma) (17 %), dyslipidaemia (14.6 %), dysthyroidism
(12.1 %), asthma (8.3 %), psoriasis (8.0 %), and hypertension (7.6 %).

### 3.1. Univariable analysis

Individuals with BD and comorbid migraine were more frequently
females ($p < 0.001$) and were more often associated with BD type II ($p <
0.001$). They had an earlier age of BD onset ($p < 0.001$), a longer illness
duration ($p = 0.002$), a higher number of lifetime mood episodes ($p =
0.040$), specifically depressive episodes ($p < 0.001$), more suicide at-
tempts ($p < 0.001$), and more rapid cycling ($p < 0.001$) compared to
individuals with BD without comorbid migraine. They also had higher
depressive and manic symptoms at inclusion ($p < 0.001$), higher level of
<table><caption>**Table 1**
Sociodemographic, clinical and treatment characteristics of BD individuals with migraine.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Total</th><th colspan="2">Migraine disorder</th><th rowspan="2">p-value</th></tr><tr><th>No<br>(n = 3476, 79.9%)</th><th>Yes<br>(n = 872, 20.1%)</th></tr></thead><tbody><tr><td colspan="5"><strong>Sociodemographic characteristics</strong></td></tr><tr><td>Age, years</td><td>39.7 (13.1)</td><td>39.9 (13.3)</td><td>39.0 (12.1)</td><td>0.184</td></tr><tr><td>Sex (women)</td><td>2689 (61.8)</td><td>2035 (58.5)</td><td>654 (75.0)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>High Education level</td><td>2601 (71.3)</td><td>2068 (71.2)</td><td>533 (71.5)</td><td>0.909</td></tr><tr><td colspan="5"><strong>Clinical characteristics</strong></td></tr><tr><td>BD type</td><td></td><td></td><td></td><td></td></tr><tr><td>Type I</td><td>1937 (44.6)</td><td>1615 (46.5)</td><td>322 (36.9)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Type II</td><td>1919 (44.1)</td><td>1486 (42.7)</td><td>433 (49.7)</td><td></td></tr><tr><td>Type NOS</td><td>492 (11.3)</td><td>375 (10.8)</td><td>117 (13.4)</td><td></td></tr><tr><td>Age of BD onset, years</td><td>23.6 (9.4)</td><td>24.0 (9.5)</td><td>22.0 (9.0)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Illness duration, years</td><td>16.2 (11.2)</td><td>16.0 (11.2)</td><td>17.0 (10.8)</td><td><strong>0.002</strong></td></tr><tr><td>Number of lifetime episode</td><td>8.9 (9.5)</td><td>8.8 (9.4)</td><td>9.5 (9.7)</td><td><strong>0.040</strong></td></tr><tr><td>Depressive episode</td><td>4.5 (3.5)</td><td>4.4 (3.5)</td><td>4.9 (3.5)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>(Hypo)manic episode</td><td>4.2 (5.6)</td><td>4.1 (5.5)</td><td>4.3 (5.7)</td><td>0.931</td></tr><tr><td>Lifetime suicide attempt (at least one)</td><td>1635 (38.2)</td><td>1239 (36.3)</td><td>396 (45.9)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Rapid cycling</td><td>653 (17.4)</td><td>486 (16.1)</td><td>167 (22.6)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>MADRS score</td><td>10.9 (9.3)</td><td>10.3 (9.1)</td><td>13.1 (9.7)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>YMRS score</td><td>2.5 (3.8)</td><td>2.3 (3.6)</td><td>3.3 (4.4)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Anxiety (STAI-A score)</td><td>43.2 (14.9)</td><td>42.5 (14.9)</td><td>46.0 (14.8)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Sleep disturbances (PSQI score)</td><td>7.3 (3.8)</td><td>7.0 (3.7)</td><td>8.4 (4.0)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Evening Chronotype (CSM)*</td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>1356 (30.3)</td><td>930 (28.6)</td><td>293 (35.6)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>No</td><td>3123 (69.7)</td><td>2326 (71.4)</td><td>531 (64.5)</td><td></td></tr><tr><td>Childhood trauma (CTQ score)</td><td>42.9 (14.6)</td><td>42.1 (13.9)</td><td>46.4 (16.6)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Medication adherence (MARS score)</td><td>6.9 (2.0)</td><td>6.9 (2.0)</td><td>6.7 (2.1)</td><td><strong>0.002</strong></td></tr><tr><td>Functioning (FAST score)</td><td>21.6 (14.8)</td><td>20.9 (14.6)</td><td>24.3 (15.4)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Quality of life (EQ-5D score)</td><td>0.17 (0.5)</td><td>0.20 (0.5)</td><td>0.11 (0.3)</td><td><strong>&lt;0.001</strong></td></tr><tr><td colspan="5"><strong>Psychiatrics comorbidities</strong></td></tr><tr><td>Substance related disorder</td><td></td><td></td><td></td><td></td></tr><tr><td>Current daily tobacco smoking</td><td>1859 (45.6)</td><td>1503 (46.0)</td><td>356 (43.5)</td><td>0.207</td></tr><tr><td>Lifetime substance use disorder</td><td>1467 (37.0)</td><td>1164 (36.7)</td><td>303 (38.0)</td><td>0.505</td></tr><tr><td>Lifetime alcohol disorder</td><td>1000 (25.0)</td><td>788 (24.9)</td><td>212 (26.6)</td><td>0.316</td></tr><tr><td>Lifetime cannabis disorder</td><td>809 (20.4)</td><td>663 (20.9)</td><td>146 (18.3)</td><td>0.102</td></tr><tr><td>Lifetime anxiety disorders</td><td>1764 (45.0)</td><td>1312 (41.9)</td><td>452 (57.2)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Eating disorders</td><td>754 (19.1)</td><td>536 (16.9)</td><td>218 (27.4)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Eating disorder subtype</td><td></td><td></td><td></td><td></td></tr><tr><td>No eating disorders</td><td>3204 (80.9)</td><td>2627 (83.1)</td><td>577 (72.6)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Anorexia nervosa</td><td>208 (5.3)</td><td>142 (4.5)</td><td>66 (8.3)</td><td></td></tr><tr><td>Bulimia nervosa</td><td>79 (2.0)</td><td>58 (1.8)</td><td>21 (2.6)</td><td></td></tr><tr><td>Binge eating disorder</td><td>349 (8.8)</td><td>254 (8.0)</td><td>95 (12.0)</td><td></td></tr><tr><td>Eating disorder not specified</td><td>118 (3.0)</td><td>82 (2.6)</td><td>36 (4.5)</td><td></td></tr><tr><td colspan="5"><strong>Physical comorbidities</strong></td></tr><tr><td>Body Mass Index, mean</td><td>25.8 (5.4)</td><td>25.7 (5.3)</td><td>26.0 (5.7)</td><td>0.308</td></tr><tr><td>Body Mass Index</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>2112 (51.3)</td><td>1686 (51.3)</td><td>426 (51.3)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>25-30</td><td>1231 (29.9)</td><td>1007 (30.7)</td><td>224 (27.0)</td><td></td></tr><tr><td>&gt;30</td><td>773 (18.8)</td><td>593 (18.0)</td><td>180 (21.7)</td><td></td></tr><tr><td>Hypertension</td><td>330 (7.6)</td><td>253 (7.4)</td><td>77 (8.9)</td><td>0.122</td></tr><tr><td>Diabetes</td><td>129 (3.0)</td><td>105 (3.1)</td><td>24 (2.8)</td><td>0.687</td></tr><tr><td>Dysthyroidism</td><td>525 (12.1)</td><td>401 (11.7)</td><td>124 (14.5)</td><td><strong>0.029</strong></td></tr><tr><td>Dyslipidaemia</td><td>634 (14.6)</td><td>512 (15.0)</td><td>122 (14.3)</td><td>0.586</td></tr><tr><td>Asthma</td><td>360 (8.3)</td><td>268 (7.7)</td><td>92 (10.6)</td><td><strong>0.006</strong></td></tr><tr><td>Other allergy</td><td>741 (17.0)</td><td>546 (15.7)</td><td>195 (22.4)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Cardiac dysrhythmia</td><td>134 (3.1)</td><td>96 (2.8)</td><td>38 (4.5)</td><td><strong>0.014</strong></td></tr><tr><td>Peptic ulcer</td><td>133 (3.1)</td><td>92 (2.7)</td><td>41 (4.8)</td><td><strong>0.001</strong></td></tr><tr><td>Psoriasis</td><td>349 (8.0)</td><td>251 (7.4)</td><td>98 (11.4)</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Neurological disorders**</td><td>175 (4.0)</td><td>132 (3.8)</td><td>43 (5.0)</td><td>0.119</td></tr><tr><td>Rheumatoid arthritis</td><td>11 (0.3)</td><td>9 (0.26)</td><td>2 (0.23)</td><td>1.000</td></tr><tr><td colspan="5"><strong>Current treatment characteristics</strong></td></tr><tr><td>Lithium</td><td>965 (33.0)</td><td>787 (33.9)</td><td>178 (29.4)</td><td><strong>0.037</strong></td></tr><tr><td>Anticonvulsants</td><td>1461 (49.9)</td><td>1155 (49.8)</td><td>306 (50.6)</td><td>0.721</td></tr><tr><td>Second generation antipsychotics</td><td>1178 (40.3)</td><td>969 (41.8)</td><td>209 (34.6)</td><td><strong>0.001</strong></td></tr><tr><td>Antidepressants</td><td>1134 (38.8)</td><td>871 (37.8)</td><td>263 (43.5)</td><td><strong>0.007</strong></td></tr><tr><td>Benzodiazepines</td><td>884 (30.2)</td><td>676 (29.1)</td><td>208 (34.4)</td><td><strong>0.012</strong></td></tr></tbody></table>

Values are given as mean (SD) or as n (%) of patients.

Bold values are *p* < 0.05.

BD, bipolar disorder; CTQ, childhood trauma questionnaire; MADRS, Montgomery Asberg Depression Rating Scale; MARS, medication adherence rating scale; NOS, unspecified; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; Young Mania Rating Scale, YMRS.

* Evening chronotype was defined by a CSM score ≤ 30 and was compared to other chronotypes (intermediate chronotype: CSM score 31–45, and morning chronotype: CSM score > 45).

** Defined by stroke or multiple sclerosis or epilepsy.
anxiety (p < 0.001), sleep disturbances (p < 0.001), and reported more frequently childhood trauma (p < 0.001). Moreover, they had a higher frequency of evening chronotype (p < 0.001), and lower adherence to medication (p = 0.002) compared to individuals with BD without comorbid migraine. Psychosocial functioning and quality of life were also significantly impaired (p < 0.001) (Table 1).

Psychiatric comorbidities, such as lifetime anxiety disorders and eating disorders (p < 0.001), were more frequently associated with individuals with BD and comorbid migraine.

Compared to BD individuals without comorbid migraine, those with comorbid migraine were more likely to suffer from certain medical comorbidities such as dysthyroidism (p = 0.029), asthma and other allergies (p < 0.001), cardiac dysrhythmia (p = 0.014), peptic ulcers (p = 0.001), and psoriasis (p < 0.001). BD individuals with comorbid migraine were less likely to receive lithium (p = 0.037) and second-generation antipsychotics (p = 0.001) but more likely to receive antidepressants (p = 0.007) and benzodiazepines (p = 0.012) (Table 1).

## 3.2. Multivariable analysis

The multivariable logistic regression analysis (Table 2) revealed that females (OR = 2.13, CI 95 % 1.54–2.97), younger age (OR = 0.98, CI 95 % 0.96–0.99), sleep disturbances (OR = 1.07, CI 95 % 1.02–1.11), childhood trauma (OR = 1.01, CI 95 % 1.00–1.02), hypertension (OR =

<caption>**Table 2**</caption>

Multivariable logistic regression analysis of variables associated with comorbid migraine in BD (including variables with *p* value <0.20 in univariable analysis).

<table><thead><tr><th></th><th>OR</th><th>95 % Wald<br>Confidence<br>limits</th><th>p-value</th></tr></thead><tbody><tr><td>Sex (woman vs man)</td><td>2.134</td><td>1.536</td><td><strong>&lt;0.001</strong></td></tr><tr><td>Age</td><td>0.979</td><td>0.962</td><td><strong>0.014</strong></td></tr><tr><td>BD type II vs BD type I</td><td>0.861</td><td>0.627</td><td>1.182</td><td>0.355</td></tr><tr><td>BD NOS vs BD I</td><td>1.136</td><td>0.704</td><td>1.832</td><td>0.601</td></tr><tr><td>Illness duration</td><td>1.006</td><td>0.987</td><td>1.026</td><td>0.538</td></tr><tr><td>Number of lifetime depressive episode</td><td>1.010</td><td>0.968</td><td>1.053</td><td>0.647</td></tr><tr><td>Lifetime suicide attempt (Yes vs No)</td><td>1.122</td><td>0.834</td><td>1.509</td><td>0.446</td></tr><tr><td>Rapid cycling (Yes vs No)</td><td>1.290</td><td>0.867</td><td>1.920</td><td>0.209</td></tr><tr><td>Depressive symptoms (MADRS score)</td><td>1.003</td><td>0.984</td><td>1.021</td><td>0.787</td></tr><tr><td>Manic symptoms (YMRS score)</td><td>1.026</td><td>0.987</td><td>1.066</td><td>0.199</td></tr><tr><td>Sleep disturbances (PSQI score)</td><td>1.065</td><td>1.021</td><td>1.111</td><td><strong>0.004</strong></td></tr><tr><td>Evening chronotype* (Yes vs No)</td><td>1.114</td><td>0.816</td><td>1.520</td><td>0.496</td></tr><tr><td>Childhood trauma (CTQ score)</td><td>1.014</td><td>1.004</td><td>1.024</td><td><strong>0.008</strong></td></tr><tr><td>Adherence to medication (MARS score)</td><td>1.015</td><td>0.938</td><td>1.097</td><td>0.716</td></tr><tr><td>Cannabis disorders (Yes vs No)</td><td>0.864</td><td>0.587</td><td>1.271</td><td>0.458</td></tr><tr><td>Lifetime anxiety disorders (Yes vs No)</td><td>1.205</td><td>0.901</td><td>1.611</td><td>0.209</td></tr><tr><td>Eating disorders (Yes vs No)</td><td>1.014</td><td>0.710</td><td>1.447</td><td>0.940</td></tr><tr><td>Body Mass Index [25–30] vs &lt;25</td><td>1.033</td><td>0.739</td><td>1.446</td><td>0.849</td></tr><tr><td>Body Mass Index &gt;30 vs &lt;25</td><td>1.112</td><td>0.763</td><td>1.620</td><td>0.581</td></tr><tr><td>Hypertension (Yes vs No)</td><td>1.884</td><td>1.126</td><td>3.153</td><td><strong>0.016</strong></td></tr><tr><td>Dysthyoidism (Yes vs No)</td><td>0.928</td><td>0.612</td><td>1.408</td><td>0.726</td></tr><tr><td>Asthma (Yes vs No)</td><td>1.651</td><td>1.021</td><td>2.670</td><td><strong>0.041</strong></td></tr><tr><td>Other allergy (Yes vs No)</td><td>1.340</td><td>0.956</td><td>1.878</td><td>0.089</td></tr><tr><td>Cardiac dysrhythmia (Yes vs No)</td><td>0.933</td><td>0.452</td><td>1.924</td><td>0.190</td></tr><tr><td>Peptic ulcer (Yes vs No)</td><td>1.631</td><td>0.785</td><td>3.387</td><td>0.850</td></tr><tr><td>Psoriasis (Yes vs No)</td><td>1.610</td><td>1.013</td><td>2.558</td><td><strong>0.044</strong></td></tr><tr><td>Neurological disorders** (Yes vs No)</td><td>1.446</td><td>0.712</td><td>2.936</td><td>0.308</td></tr><tr><td>Lithium (Yes vs No)</td><td>0.830</td><td>0.607</td><td>1.134</td><td>0.241</td></tr><tr><td>Second-generation antipsychotic (Yes vs No)</td><td>0.647</td><td>0.480</td><td>0.873</td><td><strong>0.004</strong></td></tr><tr><td>Antidepressant (Yes vs No)</td><td>0.889</td><td>0.659</td><td>1.200</td><td>0.442</td></tr><tr><td>Benzodiazepines (Yes vs No)</td><td>1.157</td><td>0.849</td><td>1.578</td><td>0.356</td></tr></tbody></table>

Bold values are *p* < 0.05.

BD, bipolar disorder; CTQ, childhood trauma questionnaire; MADRS, Montgomery Asberg Depression Rating Scale; MARS, medication adherence rating scale; NOS, unspecified; PSQI, Pittsburgh Sleep Quality Index; Young Mania Rating Scale, YMRS.

* Evening chronotype was defined by a CSM score ≤ 30 and was compared to other chronotypes (intermediate chronotype: CSM score 31–45, and morning chronotype: CSM score > 45).

** Defined by stroke or multiple sclerosis or epilepsy.

1.88, CI 95 % 1.13–3.15), psoriasis (OR = 1.61, CI 95 % 1.01–2.56), asthma (OR = 1.65, CI 95 % 1.02–2.67), and the absence of second-generation antipsychotic use (OR = 0.65, CI 95 % 0.48–0.87) were the variables associated with the migraine comorbidity in individuals with BD.

## 4. Discussion

This study evaluated the clinical features and comorbidities associated with BD and comorbid migraine, based on a large, well-characterized cohort of individuals with BD.

In our study, the prevalence of comorbid migraine among individuals with BD is 20 %, with 29.1 % in BD type II and 19.9 % in BD type I. This is slightly lower than the rates reported in other studies in BD patients but higher than in the general population, where the prevalence is estimated to be around 14–15 % (Steiner and Stovner, 2023). A systematic literature review and a meta-analysis investigated the overall pooled prevalence of comorbid migraine in BD and suggests that approximately one-third of individuals with BD experience migraine (Fornaro and Stubbs, 2015; Leo and Singh, 2016). A higher prevalence of migraine was also found among individuals with BD-II (54 %) compared to those with BD-I (32.7 %) (Fornaro and Stubbs, 2015).

As shown in our multivariable logistic regression analysis, younger age, females, sleep disorders, childhood trauma, and lower use of second-generation antipsychotics were associated with comorbid migraine in BD. Additionally, we also observed an association between comorbid migraine in BD and hypertension, psoriasis and asthma.

We did not observe any final associations with BD type II, lifetime depressive episodes, suicidality, rapid cycling, or evening chronotype. Similarly, no associations were found with comorbid psychiatric disorders (such as substance use disorder, lifetime anxiety disorder, or eating disorders). Although these findings were unexpected based on our univariate analysis, they are consistent with several previous studies that have reported similar no associations. For instance, Gordon-Smith et al. (2015) found associations with female sex, panic disorder, and rapid cycling, but none with BD type, suicidality, or lifetime depressive episodes (Gordon-Smith et al., 2015). Similarly, Romo-Nava et al. (2021) found associations with younger age, female sex, comorbid anxiety disorders, and evening chronotype, but none with BD subtypes, suicidality, or comorbid eating or substance use disorders (Romo-Nava et al., 2021). Mehrhof et al. (2021) also found associations with past depression scores and BMI, but none with BD subtypes, suicidality, or comorbid anxiety or substance use disorders (Mehrhof et al., 2021). Beyond the significant variations in sample size, patient selection procedures (e.g., tertiary clinical settings), and the number and type of variables studied in previous research, which may partially explain the differences in findings, this likely highlights the complexity of the association between BD and migraine, which is common but multifactorial.

The significant variables associated with comorbid migraine in BD in our model are also known to be associated with migraine in patients without BD. Indeed, migraine is a complex neurological condition that disproportionately affects younger individuals, particularly females, and is often associated with other stressors such as sleep disorders and childhood trauma. Previous research indicates that migraine prevalence peaks in early adulthood, with females being two to three times more likely to suffer from migraine than males, likely due to hormonal influences like estrogen fluctuations (Rossi et al., 2022; Stovner et al., 2018). Sleep disorders, including insomnia and sleep apnea, are frequently observed in individuals with migraine. These conditions may worsen both the frequency and severity of migraine attacks and are strongly associated with an increased risk of progression to chronic migraine (Buse et al., 2019; Tiseo et al., 2020). Additionally, growing evidence suggests that childhood trauma, including emotional, physical, or sexual abuse, may increase the likelihood of developing migraine later in life (Liu et al., 2024; Tietjen et al., 2010).

In patients with BD, the interplay between migraine, sleep disorders,
and trauma takes on an even more complex dimension. This comorbidity is significant because both conditions share underlying pathophysiological mechanisms, including dysregulation of serotonin and dopamine pathways, as well as inflammation. In BD patients, sleep disorders such as insomnia and disrupted circadian rhythms are particularly common (Tonon et al., 2024), frequently appear long before the onset of BD (Pancheri et al., 2019) and could contribute to both mood instability and migraine frequency. Sleep dysregulation is a key feature of BD and exacerbates migraine attacks, creating a vicious cycle that complicates treatment. Furthermore, childhood trauma, which is also prevalent in individuals with BD, has been linked to both mood dysregulation and a higher incidence of migraine. Research suggests that early trauma could exacerbate the sensitivity of the brain's stress-response systems, increasing vulnerability to both mood episodes and chronic pain conditions like migraine (Aas et al., 2016; Tietjen et al., 2016).

While the association between physical comorbidities and both BD and migraine has been well-documented, our findings—specifically the association with hypertension, psoriasis and asthma—suggest a higher clinical burden for patients exhibiting both conditions, referred to as the BD-migraine phenotype (Romo-Nava et al., 2021). Recent studies have shown that individuals with BD are more likely to suffer from conditions like psoriasis or asthma (Mo et al., 2024; Romo-Nava et al., 2023). Similarly, migraine has also been linked to psoriasis (Huang et al., 2023) or asthma (Wang et al., 2020), with this overlap suggesting that shared biological and environmental factors, such as immune system dysregulation, may increase vulnerability. Immunological mechanisms appear to play a key role in both migraine and BD, including chronic inflammation. This probably explains the association with other conditions such as psoriasis or asthma (Ha and Chu, 2024; Perry et al., 2021).

There are still no optimal alternative treatments for patients suffering from BD and comorbid migraine, but several pharmacological treatments, such as lithium, anticonvulsants (e.g., valproate, lamotrigine), or certain antidepressants (e.g., amitriptyline) in combination with a mood stabilizer are widely used to prevent both acute mood episodes (manic or depressive episodes) and migraine attacks in patients with BD (Duan et al., 2021). Our results do not confirm a higher use of these classes of medication; rather, they suggest a lower use of second-generation antipsychotics in patients with BD and comorbid migraine, as previously described (Mehrhof et al., 2021).

Consistent with previous studies, we observed that the BD-II subtype was more common than the BD-I subtype among individuals with migraine (Fornaro and Stubbs, 2015). Given that depressive polarity is more prominent in BD-II patients, this may also account for the higher number of lifetime depressive episodes observed in our sample of BD patients with migraine. This association with depression may partly explain why BD migraine patients were less likely to receive second-generation antipsychotics, which are primarily recommended for the acute and preventive treatment of mania (with the exception of que tiapine). This emphasizes the importance of personalized therapeutic approaches that take into account the specific subtype of BD when treating patients with comorbid migraine.

In summary, our results suggest that while the importance of evalu-
ating and managing sleep disturbances and trauma in BD patients has
been well recognized, there may be even greater potential benefits for
those with comorbid migraine.

More broadly, our findings highlight the importance of systemati-
cally assessing migraine in BD patients, as well as other physical
comorbidities (e.g., asthma, psoriasis, hypertension). Addressing these
physical comorbidities alongside BD, as is already recommended for
psychiatric comorbidities, could not only improve BD outcomes but also
reduce the burden of associated physical conditions. Consequently,
further research and updated recommendations are needed for man-
aging BD with comorbid physical conditions, including migraine, similar
to the approach taken by the Canadian Network for Mood and Anxiety
Treatments (CANMAT) for unipolar depressive disorders (Ramasubbu
et al., 2012).

Our findings should be interpreted in light of the study's limitations, particularly its cross-sectional design, which prevents us from establishing causal relationships. Additionally, the diagnosis of migraine was based on a patient's self-reported diagnosis, clinician assessment, and a review of the patient's medical history. The absence of use of specific screening instruments may lead to an underdiagnosis of migraine. Indeed, migraine is underdiagnosed in the general population and some migraine sufferers are unaware of this diagnosis. (Cevoli et al., 2009). Finally, although we included a well-characterized sample of BD patients, specific migraine characteristics (e.g., the presence of aura, the frequency of attacks, the type and effectiveness of preventive and acute treatments used, and the level of disability associated with migraine) that could provide greater insight into BD-migraine comorbidity were not evaluated. Further prospective studies with large samples and optimal characterization of both BD patients and comorbid migraine are needed. These prospective data would help determine whether the interactions between the characteristics of BD (e.g., severity, depressive episode, rapid cycling...) are more related to the risk of migraine attacks than to the risk of developing migraine comorbidity.

5. Conclusion

The hypothesis of a specific BD-migraine phenotype has previously been proposed, suggesting a more severe clinical course of BD, with an earlier onset of mood disturbances, more frequent depressive episodes, or higher suicide rates. While our univariate analysis did find a more severe clinical course of BD, the final multivariable analysis model does not confirm this hypothesis. However, our findings do confirm a high prevalence of migraine in BD patients, particularly in younger individuals, females, those with sleep disorders, and those with a history of childhood trauma, who also experience a higher clinical burden. These overlapping factors highlight the need for an integrated treatment approach in BD patients with comorbid migraine, addressing mood stabilization, sleep management, and psychological support for trauma to reduce the burden of migraine.

CRediT authorship contribution statement

**Ludovic Samalin:** Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Formal analysis, Conceptualization. **Ophelia Godin:** Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis. **Xavier Moisset:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Ambre Chalayer:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Agnes Pelletier:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Antoine Lefrere:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Paul Roux:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Mircea Polosan:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Anamaria Bogdan:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Raymund Schwan:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Caroline Dubertret:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Bruno Auizerate:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Raoul Belzeaux:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Romain Rey:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Dominique Januel:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Michel Walter:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Antoine Yrondi:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Emmanuel Haffen:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Philippe Courtet:**
Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Frank Bellivier:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Marion Leboyer:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Bruno Etain:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Emilie Olié:** Writing – review & editing, Visualization, Validation, Methodology, Investigation. **Pierre-Michel Llorca:** Writing – review & editing, Visualization, Validation, Methodology, Investigation, Formal analysis, Conceptualization.

## Funding sources

This work was funded by the Fondation FondaMental (RTRS Santé Mentale), by the Investissements d'Avenir program, by the ANR under reference ANR-11-IDEX-0004-02 and ANR-10-COHO-10-01. This funding source had no role in the study design, data collection, analysis, preparation of the manuscript, or decision to submit the manuscript for publication.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samalin reports a relationship with Janssen-Cilag SAS that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Samalin reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Samalin reports a relationship with Otsuka that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Samalin reports a relationship with Rovi that includes: consulting or advisory and travel reimbursement. Samalin reports a relationship with Sanofi-Aventis France SA that includes: speaking and lecture fees. Samalin reports a relationship with Teva that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Yrondi reports a relationship with Janssen-Cilag SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Yrondi reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Yrondi reports a relationship with GW Research Ltd. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Yrondi reports a relationship with Camurus that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Haffen reports a relationship with Johnson & Johnson that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Haffen reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Haffen reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Haffen reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Haffen reports a relationship with Neuraxpharm that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Eisai that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Ethypharm that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Janssen-Cilag SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Lundbeck SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with MSD France SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Neuraxpharm that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Otsuka that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Llorca reports a relationship with Rovi that includes: consulting or advisory, speaking and lecture fees, and travel

reimbursement. Llorca reports a relationship with Sanofi-Aventis France SA that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The other authors have no conflicts of interest to declare.

## Acknowledgements

We thank the Fondation Mental Foundation (www-fondation-fondament.al.org), private foundation supporting research in mental health, which developing a new model for translational research in psychiatry in France and supports the infrastructure of Bipolar Expert Centers. We express all our thanks to the nurses, and to the patients who were included in the present study.

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