Migraine and bipolar disorder (BD) are two chronic and recurrent disorders with a major impact on patient’s quality of life. It is now well known that affective disorders and migraine are often comorbid (Leo et al. Scand J Pain. 2016; 11:136-145). Starting from these observations, we can hypothesis that BD patients with comorbid migraine might have specifical clinical and biological features.

The aim of this study was to estimate the prevalence of migraine in a cohort of French BD patients; determine sociodemographic, clinical, and biological features associated BD-migraine comorbidity.

4348 BD patients from the FACE-BD cohort were included from 2009 to 2022. Sociodemographic and clinical characteristics, lifestyle information, and data on antipsychotic treatment and comorbidities were collected, and a blood sample was drawn. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to confirm the diagnosis of BD. Migraine diagnosis was established according to a clinician-assessed questionnaire.

20.1% of individuals with BD had comorbid migraine. Half of these patients received treatment for migraine. Multivariate logistic regression model showed that risk of migraine in women was nearly twice that in men (OR = 1.758; 95% CI, 1.345-2.298). Anxiety disorder, sleep disturbances and childhood trauma were also associated with an increased risk of migraine comorbidity. Patients receiving antipsychotic treatment had less risk of developing migraine than those not receiving those treatment (OR 0.716, 95% CI, 0.554-0.925), independent of other potential confounders.

The prevalence of migraine in our cohort was lower than those previously reported in other studies. This result might suggest an overestimation of migraine diagnosis in BD patients population studies. However, BD-migraine comorbidity could constitute a subphenotype of bipolar disorder requiring specific treatments.

None Declared

Bipolar Disorder (BD) is a common psychiatric disease. It has been demonstrated a long time ago that bipolar patients are more painful than the healthy subjects. Substance use disorder is a frequent comorbidity in BD, but also in painful patients. The aim of our study was to analyze if bipolar patients with a painful expression have more substance use disorder than bipolar patients without pain.

The aim of our study was to analyze if bipolar patients with a painful expression have more substance use disorder than bipolar patients without pain

We included all bipolar patients from the FACE-BD cohort which is a prospective cohort of French outpatients with BD enrolled at the 12 advanced Centers of Expertise in Bipolar Disorder (CEBD). Pain has been evaluated by the “pain item” of the EQ-5D scale and we divided subjects in four categories: “no pain”, “slight pain”, “moderate pain”, “severe or extreme pain”. A multivariate analysis was performed to identify differences between each pain’s groups according to the kind of substance use disorder, psychiatric comorbidities and clinicals data.

The cohort enrolled 1897 bipolar patients, 970 had no pain (51.1%), 507 had slight pain (26.7%), 298 had moderate pain (15.7%) and 122 had severe or extreme pain (6.4%). We found significant differences according to age, comorbidities and clinicals data with older, more anxious, and more severe patients more represented in the more painful groups. Painful bipolar patients had also more frequently lifetime substance use disorders (alcohol, opioid, sedative, marijuana) and we were able to characterize different profiles in bipolar patients.

Bipolar patients with a painful expression had more risks to have a lifetime substance use disorder, an anxiety disorder, and a higher score on MADRS. Interestingly, subjects seemed to prefer substances with anxiolytic or antalgic effects during the acute intoxication as alcohol, marijuana, opioid and sedatives.

None Declared

Animal studies have shown that the simultaneous blockade of α1b-noradrenergic receptors and 5HT2A-serotonergic receptors strongly decreases alcohol intake. In addition, recent clinical studies have indicated that the selective α1b antagonist prazosin could be effective on alcohol use reduction in alcohol-dependent subjects.

Cocktail is a double-blind, randomised, parallel-group, three-arm, multicentre, placebo-controlled phase 2 proof-of-concept study aiming at demonstrating the superiority of a 12-week treatment with the KT110 combination of cyproheptadine (8 mg/day or 12 mg/day) and prazosin (5 mg/day or 10 mg/day) over placebo on the reduction of total alcohol consumption.

The study two main inclusion criteria are a DSM5 diagnosis of severe alcohol use disorder and a WHO high-risk drinking risk level. The primary endpoint is the change from baseline (4 weeks preceding randomization) to the end of treatment (Weeks 9-12) in the mean quantity of alcohol consumed per day in the three groups. Daily alcohol consumption is determined using the Timeline Follow Back, automatically be filled in on the basis electronic patient reported outcomes platform. The 12-week treatment period is followed by a 4-week post-treatment follow-up.

One hundred and eighty patients are planned to be randomized 1:1:1 into the two treatment groups. Enrollment of patients started in November 2019, and will end in July 2021.

In this communication, we will present the rationale for the development of the KT110 combination of cypropheptadine and prazosin for the treatment of alcohol use disorders, as well as the main features of the Coctkail study. ClinicalTrials.gov identifier: NCT04108104.

Member of advisory boards, DSMB, or steering committees, speaker honoraria or consultancy for Bioprojet, D&A Pharma Ethypharm, and Kinnov Pharmaceuticals, Lundbeck, and Pfizer D&A Pharma, Ethypharm, Kinnov Pharmaceuticals, Lundbeck, and Pfizer.

Establishing the minimum clinically important difference (MCID) in functioning and cognition is essential to the interpretation of the research and clinical work conducted in bipolar disorders (BD). The present study aimed to estimate the MCID for the Functioning Assessment Short Test (FAST) and a battery of neuropsychological tests in BD.

Anchor-based and distributive methods were used to estimate the MCID for the FAST and cognition using data from a large, multicentre, observational cohort of individuals with BD. The FAST and cognition were linked with the Clinical Global Impressions Scale-Severity (CGI-S) and Global Assessment of Functioning (GAF) using an equipercentile method. The magnitude of the standard error measurement (s.e.m.) provided another estimate of the MCID.

In total, 570 participants were followed for 2 years. Cross-sectional CGI-S and GAF scores were linked to a threshold ⩽7 on the FAST for functional remission. The MCID for the FAST equalled 8- or 9-points change from baseline using the CGI-S and GAF. One s.e.m. on the FAST corresponded to 7.6-points change from baseline. Cognitive variables insufficiently correlated with anchor variables (all ρ <0.3). One s.e.m. for cognitive variables corresponded to a range of 0.45 to 0.93-s.d. change from baseline.

These findings support the value of the estimated MCID for the FAST and cognition and may be a useful tool to evaluate cognitive and functional remediation effects and improve patient functional outcomes in BD. The CGI-S and GAF were inappropriate anchors for cognition. Further studies may use performance-based measures of functioning instead.

Brain models of drug addiction are being tackled in humans, using PET and MRI.

1. 1. Whereas tobacco and cannabis do not interact directly with dopamine sites, positron emission tomography detected lower availability in sites regulating the catecholamines homeostasis, notably in dopamine transporter sites in striatal and in extrastriatal regions. This further supports repeated and long term substance use progress towards an adaptative diminished basal dopamine level that would contribute to the switch to an addicted brain.

2. 2. Alcohol: abnormalities in brain macro- and micro- structure were searched in detoxified alcohol-dependents with preserved psychosocial functioning:

   1. - Brain function (fMRI): fronto-cerebellar overactivation detected during an auditory language task in alcohol-dependents may reflect the compensatory effort required for patients to maintain the same level of performance as controls.

   2. - Brain macrostructure (MRI). Widespread lower white matter volumes, and lower grey matter volumes in the frontal lobe, insula, hippocampus, thalami and cerebellum, were detected. Poorer neuropsychological performance correlated with smaller grey matter volumes in these regions and with lower white matter volume in the brainstem.

   3. - Brain microstructure (DTI): tractography of white matter fiber bundles revealed that brainstem bundles alteration may contribute to cognitive flexibility impairment. Regression analyses showed memory scores were related to brain microstructure in parahippocampal areas, frontal cortex, and left temporal cortex. This suggest diffusion imaging (DTI) is a useful probe to early alcohol-induced brain alterations.

While indices of dopamine down-regulation are consistency detected in several drug addictions, even “socially-adapted” alcohol dependence may induce change in brain structure.

Psychol Med. 1998 28:1039-48.

Neuropsychopharmacology. 2007 32:429-38.

IEEE Trans Med Imaging. 2007 26:553-65

J Nucl Med. 2007 48:538-46.

Neuropsychopharmacology (Chanraud S et al., 2008 Jul 9. [Epub ahead of print]).

J Clin Psychopharmacol (Leroy C et al, in press).

Le nouveau paradigme pharmacologique permet de renforcer l’idée que le choix de l’objectif du traitement (réduction ou abstinence) ne doit pas être imposé par le thérapeute, mais sera le fruit de l’interaction thérapeute-patient. Le respect du choix de l’objectif par le patient permet d’éviter le phénomène de « réactance psychologique », phénomène induit par la menace d’entraver la liberté d’action d’un individu. La réactance psychologique se manifeste par la tentative de restaurer cette liberté perdue. D’où des réactions paradoxales à la prescription de l’abstinence par le thérapeute.

Les programmes les plus classiquement proposés en France sont orientés vers l’abstinence. Les stratégies classiques de gestion du craving ou le développement d’un plan d’urgence pour faire face à un faux-pas sont typiquement adaptées à l’objectif de l’abstinence, mais pas à celui de la réduction. De nouveaux principes doivent être intégrés pour la réduction de la consommation d’alcool : définition de l’objectif de consommation (fréquence, quantité, situations), monitoring rigoureux, et stratégies de modération de la consommation (rythme, alternance avec boissons non alcoolisées,…). Finalement, alors que l’état d’esprit de la prise en charge est notablement modifié avec l’intégration du nouveau paradigme vers plus de souplesse et d’acceptation par le thérapeute, l’essentiel des composantes psychothérapiques reste similaire à l’approche classique orientée vers l’abstinence.

We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for.

To evaluate the 6 month efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol-dependent patients with high DRL from a randomised controlled trial [NCT00812461].

All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study.

The study population consisted of 317 patients: placebo N=162; nalmefene N=155 (mean age 44.8±10.3 years; 69% men; mean HDDs: 22±6.2/month; mean TAC 111±47.9g/day). Mean number of HDDs decreased to 10 days/month and mean TAC decreased to 43g/day at month 6 in the nalmefene group. There was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-2.7 [95% CI: -5.0;-0.3];p=0.0253) and TAC -10.3 [-20.2;-0.5];p=0.0404). Improvements in clinical status and alanine amino transferase were greater in the nalmefene group compared to the placebo group (p< 0.05). Adverse events were more common with nalmefene; incidence of adverse events leading to dropout was at the placebo level.

As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for treatment.

To evaluate the 6 month efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol-dependent patients with high DRL from a randomised controlled trial [NCT00811720].

All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study.

The study population consisted of 350 patients: placebo N=170; nalmefene N=180 (mean age 51.9±9.4 years; 63% men; mean HDDs: 23±5.7/month; mean TAC: 101±41.7g/day). Mean number of HDDs decreased to 11 days/month and mean TAC decreased to 44g/day at month 6 in the nalmefene group. There was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-3.7 [95% CI: -5.9;-1.5];p=0.0010) and TAC (-18.3 [-26.9;-9.7];p< 0.0001) at month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared to the placebo group (p< 0.05). Adverse events and adverse events leading to dropout were more common with nalmefene than placebo.

As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

Emergence of alternative treatment goals to abstinence in alcohol use disorder call for the development of an assessment instrument relevant to the different therapeutic objectives, especially those that meet patients' concerns. Although the measure of quality of life is now considered relevant in alcohol use disorders, reliability, content and sensitivity to change are still sensitive issues.

The purpose of this review is to clarify the concept of quality of life used in clinical trials in alcohol dependence. We described the instruments and identified the life domains explored.

After a systematic search on PubMed, clinical trials that aimed at improving the quality of life in alcohol dependent patients and used an instrument to measure the quality of life as specifically designated by the authors were included.

Of the 46 articles screened, 23 studies were included. Fourteen instruments were used as an outcome measure. Thirty-two life domains with high between-scale heterogeneity were explored. The scale used most frequently was the SF-36, a generic health status measure. The quality of life improved in more than three-quarters of the trials. However, only one-third of the comparative trials demonstrated a significant difference between groups.

The comparison of the trials on quality of life improvement is hindered by the variety of instruments. The instruments currently used may not collect information that is both relevant and accurate. The construction and validation of specific patient-reported outcomes would significantly progress the assessment of treatment efficacy.

The opioid system modulator nalmefeneis the first pharmacological therapy approved in the European Union for reduction of alcohol consumption.

To evaluate the clinical relevance of the reduction of alcohol consumption in patients with at least high drinking risk level at screening and randomisation from the two, identically designed, randomised controlled 6-month studies ESENSE1 (NCT00811720) and ESENSE2 (NCT00812461) of nalmefene versus placebo.

Study medication was taken as-needed. All patients received a motivational and adherence-enhancing intervention (BRENDA). Response criteria were based on alcohol consumption at month 6 and Clinical Global Impression – Severity of Illness/Improvement (CGI-S/I), Short Form Health Survey version 2 (SF-36) mental component summary(MCS) scores at week 24. Clinical relevance was also studied using the Drinker Inventory of Consequences (DrInC), Alcohol Dependence Scale (ADS), and liver function variables.

Pooled study population: 667 patients (placebo N=332; nalmefene N=335). The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios for response consistently significantly (p<0.05) in favour of nalmefene. The difference in the proportions of responders translated to numbers-needed-to-treat ranging from 6 to 10. Significant differences to placebo (p<0.05) in the SF-36 MCS and physical component summary score, ADS, DrInC, CGI-I/S and liver enzymes further supported the clinical relevance of the treatment effect.

In view of the immense alcohol-related burden to society, the harm to the individual and the large treatment gap partly due to a reluctance to engage in abstinence, the effect of nalmefene is clearly clinically relevant.