An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

Hospitalized cocaine detoxification patients in Paris, France: Increased patient levels and changing population characteristics since 2011.

AIM OF THE STUDY: The past twenty years have seen a rise in cocaine-related statistics in France, including cocaine use in the general population, emergency ward presentations of acute cocaine intoxication, cocaine use disorders related outpatient appointments and cocaine-related deaths. This study's objectives were to describe trends in patients' admission for specific cocaine detoxification as well as changes in patients' characteristics in the Assistance publique-Hôpitaux de Paris (AP-HP) hospitals group located in Paris region, France. METHODS: We reviewed the international classification of diseases 10th edition (ICD-10) discharge codes of the AP-HP hospitals group between 2011 and 2021. In addition, medical reports of the largest addiction medicine ward were also analysed for changes across the years 2009, 2014, 2019 and 2022. RESULTS: The regional database showed an almost 3-fold increase in cocaine-related disorders discharge codes between 2011 and 2019. This occurred due to a rise in hospital stays for cocaine dependence or cocaine acute intoxication prior to the fall in levels of inpatient stays associated with the coronavirus disease 2019 (COVID-19) pandemic. The in-depth analysis of inpatients' stays in the specialized addiction medicine ward also showed an increase in admissions for cocaine detoxification programs, with a prevalence of 1.19% in 2009 to 15.73% in 2022 (P=1.44×10-20). Inpatient characteristics showed significant changes, especially in 2022, namely: more daily users, less intravenous administration and less comorbid illicit substances use disorders, with heightened levels of cured hepatitis C patients (P<0.05). Inpatient prescriptions were primarily dopaminergic antagonists with sedatives properties (cyamemazine, loxapine and chlorpromazine), dopamine-receptors partial agonist (aripiprazole) and serotonin reuptake inhibitors. CONCLUSION: The referral to hospital care for cocaine detoxification has increased in Paris region since 2011, coupled with changes in inpatients' characteristics. This trend has significant implications for the management of inpatient hospital services.

Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability.

BACKGROUND: Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG. METHODS: We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources. RESULTS: We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia. CONCLUSION: We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG.

USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder.

The risk of developing drug addiction is strongly influenced by the epigenetic landscape and chromatin remodeling. While histone modifications such as methylation and acetylation have been studied in the ventral tegmental area and nucleus accumbens (NAc), the role of H2A monoubiquitination remains unknown. Our investigations, initially focused on the scaffold protein melanoma-associated antigen D1 (Maged1), reveal that H2A monoubiquitination in the paraventricular thalamus (PVT) significantly contributes to cocaine-adaptive behaviors and transcriptional repression induced by cocaine. Chronic cocaine use increases H2A monoubiquitination, regulated by Maged1 and its partner USP7. Accordingly, Maged1 specific inactivation in thalamic Vglut2 neurons, or USP7 inhibition, blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization. Additionally, genetic variations in MAGED1 and USP7 are linked to altered susceptibility to cocaine addiction and cocaine-associated symptoms in humans. These findings unveil an epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factors for drug addiction in humans.

Crossed clinical features between eating disorders and types of bipolar disorder: Results from the FondaMental Advanced Centers of Expertise - Bipolar Disorder cohort.

BACKGROUND: Eating disorders (EDs) are liable to alter the disease course of bipolar disorder (BD). We explored the crossed clinical features between EDs and BD, particularly as a function of BD type (BD1 vs. BD2). METHODS: 2929 outpatients attending FondaMental Advanced Centers of Expertise were assessed for BD and lifetime EDs with a semi-structured interview, and their sociodemographic, dimensional and clinical data were collected according to a standardized procedure. For each ED type, bivariate analyses were used to investigate associations between these variables and the type of BD type followed by multinomial regressions with the variables associated with EDs and BDs after Bonferroni correction. RESULTS: Comorbid EDs were diagnosed in 478 (16.4 %) cases, and were more prevalent in patients with BD2 than in those with BD1 (20.6 % vs. 12.4 %, p < 0.001). Regression models showed no difference according to the subtype of bipolar disorder on the characteristics of patients with anorexia nervosa (AN), bulimia nervosa (BN) or binge eating disorder (BED). After multiple adjustments, the factors differentiating BD patients with versus without ED were primarily age, gender, body mass index, more affective lability and comorbidity with anxiety disorders. BD patients with BED also scored higher regarding childhood trauma. BD patients with AN also showed higher risk of past suicide attempts than those with BED. CONCLUSIONS: In a large sample of patients with BD, we found a high prevalence of lifetime EDs, especially for the BD2 type. EDs were associated with several severity indicators, but not with BD type-specific characteristics. This should prompt clinicians to carefully screen patients with BD for EDs, regardless of BD and ED types.

The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study.

BACKGROUND: The relationship between psychotic disorders and cannabis use is heavily debated. Shared underlying genetic risk is one potential explanation. We investigated the genetic association between psychotic disorders (schizophrenia and bipolar disorder) and cannabis phenotypes (lifetime cannabis use and cannabis use disorder). METHODS: We used genome-wide association summary statistics from individuals with European ancestry from the Psychiatric Genomics Consortium, UK Biobank, and International Cannabis Consortium. We estimated heritability, polygenicity, and discoverability of each phenotype. We performed genome-wide and local genetic correlations. Shared loci were identified and mapped to genes, which were tested for functional enrichment. Shared genetic liabilities to psychotic disorders and cannabis phenotypes were explored using causal analyses and polygenic scores, using the Norwegian Thematically Organized Psychosis cohort. FINDINGS: Psychotic disorders were more heritable than cannabis phenotypes and more polygenic than cannabis use disorder. We observed positive genome-wide genetic correlations between psychotic disorders and cannabis phenotypes (range 0·22-0·35) with a mixture of positive and negative local genetic correlations. Three to 27 shared loci were identified for the psychotic disorder and cannabis phenotype pairs. Enrichment of mapped genes implicated neuronal and olfactory cells as well as drug-gene targets for nicotine, alcohol, and duloxetine. Psychotic disorders showed a causal effect on cannabis phenotypes, and lifetime cannabis use had a causal effect on bipolar disorder. Of 2181 European participants from the Norwegian Thematically Organized Psychosis cohort applied in polygenic risk score analyses, 1060 (48·6%) were females and 1121 (51·4%) were males (mean age 33·1 years [SD 11·8]). 400 participants had bipolar disorder, 697 had schizophrenia, and 1044 were healthy controls. Within this sample, polygenic scores for cannabis phenotypes predicted psychotic disorders independently and improved prediction beyond the polygenic score for the psychotic disorders. INTERPRETATION: A subgroup of individuals might have a high genetic risk of developing a psychotic disorder and using cannabis. This finding supports public health efforts to reduce cannabis use, particularly in individuals at high risk or patients with psychotic disorders. Identified shared loci and their functional implications could facilitate development of novel treatments. FUNDING: US National Institutes of Health, the Research Council Norway, the South-East Regional Health Authority, Stiftelsen Kristian Gerhard Jebsen, EEA-RO-NO-2018-0535, European Union's Horizon 2020 Research and Innovation Programme, the Marie Sklodowska-Curie Actions, and University of Oslo Life Science.

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression.

Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity and mortality. The causes underlying this relationship are poorly understood. Although these conditions are highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, schizophrenia (SCZ), bipolar disorder (BD) and major depression (MD) of European ancestry. Next, we characterized the identified shared loci using biological annotation resources. OUD data were obtained from the Million Veteran Program, Yale-Penn and Study of Addiction: Genetics and Environment (SAGE) (15 756 cases, 99 039 controls). SCZ (53 386 cases, 77 258 controls), BD (41 917 cases, 371 549 controls) and MD (170 756 cases, 329 443 controls) data were provided by the Psychiatric Genomics Consortium. We discovered genetic enrichment for OUD conditional on associations with SCZ, BD, MD and vice versa, indicating polygenic overlap with identification of 14 novel OUD loci at condFDR < 0.05 and 7 unique loci shared between OUD and SCZ (n = 2), BD (n = 2) and MD (n = 7) at conjFDR < 0.05 with concordant effect directions, in line with estimated positive genetic correlations. Two loci were novel for OUD, one for BD and one for MD. Three OUD risk loci were shared with more than one psychiatric disorder, at DRD2 on chromosome 11 (BD and MD), at FURIN on chromosome 15 (SCZ, BD and MD) and at the major histocompatibility complex region (SCZ and MD). Our findings provide new insights into the shared genetic architecture between OUD and SCZ, BD and MD, indicating a complex genetic relationship, suggesting overlapping neurobiological pathways.

Prevalence of benzodiazepine use disorder during hospitalization for alcohol detoxification.

Benzodiazepines (BZDs) are the first-line treatment of alcohol withdrawal. Comorbidity between benzodiazepine use disorder (BUD) and alcohol use disorders (AUD) is common. However, the risk factors are poorly characterized due to the paucity of available BUD screening tools. The present study aimed to rectify this by conducting an observational screening investigation for BUD in patients hospitalized for alcohol detoxification in a specialized unit. During a face-to-face interview, a short BUD screening tool, Echelle Cognitive d'Attachement aux benzodiazépines (ECAB), was administered to record recent patterns of BZD use, thereby allowing categorization of AUD patients as follows: non-BZD users, BZD users without BUD, and BUD (ECAB ≥6). Clinical and sociodemographic risk factors were identified and recorded during clinical assessment and were analyzed using nonparametric bivariate tests and multinomial regression for association with BUD, with p < 0.05 for significance. Of the 150 AUD patients, 23 (15%) had comorbid BUD. Several variables were associated with ECAB score, with their independence being verified using multinomial regression, with lower risk of BUD versus BZD use, when the initial prescriber was an addiction specialist compared with a psychiatrist or a general practitioner [odds ratio (OR) = 0.12, 95% confidence interval (CI) = 0.14-0.75]. A higher risk of BZD use versus no use was evident when comorbid psychiatric disorders were present (OR = 9.2, 95%CI = 1.3-65). Our findings raise clinicians' awareness that in patients hospitalized for alcohol detoxification, BUD is highly prevalent but not specifically related to psychiatric disorders. BUD can be effectively screened by utilization of the ECAB.

Physical and mental health status of former smokers and non-smokers patients with bipolar disorder.

OBJECTIVES: Up to 70% individuals with bipolar disorder (BD) are lifetime tobacco smokers, a major modifiable risk factor for morbidity. However, quitting smoking is rarely proposed to individuals with BD, mainly because of fear of unfavorable metabolic or psychiatric changes. Evaluating the physical and mental impact of tobacco cessation is primordial. The aim of this study was to characterize the psychiatric and nonpsychiatric correlates of tobacco smoking status (never- vs. current vs. former smokers) in individuals with BD. METHODS: 3860 individuals with ascertained BD recruited in the network of Fondamental expert centers for BD between 2009 and 2020 were categorized into current, former, and never tobacco smokers. We compared the sociodemographic and clinical characteristics assessed by standard instruments (e.g., BD type, current symptoms load, and non-psychiatric morbidity-including anthropometric and biological data) of the three groups using multinomial regression logistic models. Corrections for multiple testing were applied. RESULTS: Current smokers had higher depression, anxiety, and impulsivity levels than former and never-smokers, and also higher risk of comorbid substance use disorders with a gradient from never to former to current smokers-suggesting shared liability. Current smokers were at higher risk to have a metabolic syndrome than never-smokers, although this was only evidenced in cases, who were not using antipsychotics. CONCLUSIONS: Tobacco smoking was associated with high morbidity level. Strikingly, as in the general population, quitting smoking seemed associated with their return to the never-smokers' levels. Our findings strongly highlight the need to spread strategies to treat tobacco addiction in the BD population.

Identification of Novel Loci and Cross-Disorder Pleiotropy Through Multi-Ancestry Genome-Wide Analysis of Alcohol Use Disorder in Over One Million Individuals.

Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWASs across diverse ancestries focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent]. Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes enriched for brain regions relevant for AUD (striatum, hypothalamus, and prefrontal cortex) and potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically-relevant comorbidities.

A specific cognitive behavioral group therapy program for stimulant use disorder.

Introduction: Stimulant use is an important health issue. In the US in 2018, 2.8% of males and 1.5% of females older than 18 had used cocaine in the preceding 12 months. Objective: To intervene in a specific targeted group of Stimulant Use Disorder (SUD) patients according to CBT and relapse prevention theories, and to determine the program's feasibility and attendance. Method: Stimulant Use Disorder patients in addiction care were evaluated for addictive, psychological and psychiatric dimensions at baseline and conclusion in a 9-session CBT group program with several themes: define SUD, enhance motivation, involve close companions, cope with craving, decline a proposal, solve problems, invite expert patients, invest time and money, and review content. Results: In total, 41 patients attended at least one session. They were mainly poly dependent, primarily cocaine users. Sixty percent of the population also suffered from another psychiatric comorbidity. Median attendance for participants was 7/9 sessions. Conclusion: A specific targeted CBT group for stimulant dependent highly comorbid patients is feasible. These findings suggest that peers should be included in addiction care services.

The clinical course of comorbid substance use disorder and attention deficit/hyperactivity disorder: protocol and clinical characteristics of the INCAS study.

BACKGROUND: Substance use disorders (SUD) often co-occur with attention deficit hyperactivity disorder (ADHD). Although the short-term effects of some specific interventions have been investigated in randomized clinical trials, little is known about the long-term clinical course of treatment-seeking SUD patients with comorbid ADHD. AIMS: This paper presents the protocol and baseline clinical characteristics of the International Naturalistic Cohort Study of ADHD and SUD (INCAS) designed and conducted by the International Collaboration on ADHD and Substance Abuse (ICASA) foundation. The overall aim of INCAS is to investigate the treatment modalities provided to treatment-seeking SUD patients with comorbid ADHD, and to describe the clinical course and identify predictors for treatment outcomes. This ongoing study employs a multicentre observational prospective cohort design. Treatment-seeking adult SUD patients with comorbid ADHD are recruited, at 12 study sites in nine different countries. During the follow-up period of nine months, data is collected through patient files, interviews, and self-rating scales, targeting a broad range of cognitive and clinical symptom domains, at baseline, four weeks, three months and nine months. RESULTS: A clinically representative sample of 578 patients (137 females, 441 males) was enrolled during the recruitment period (June 2017-May 2021). At baseline, the sample had a mean age (SD) of 36.7 years (11.0); 47.5% were inpatients and 52.5% outpatients; The most prevalent SUDs were with alcohol 54.2%, stimulants 43.6%, cannabis 33.1%, and opioids 14.5%. Patients reported previous treatments for SUD in 71.1% and for ADHD in 56.9%. Other comorbid mental disorders were present in 61.4% of the sample: major depression 31.5%, post-traumatic stress disorder 12.1%, borderline personality disorder 10.2%. CONCLUSIONS: The first baseline results of this international cohort study speak to its feasibility. Data show that many SUD patients with comorbid ADHD had never received treatment for their ADHD prior to enrolment in the study. Future reports on this study will identify the course and potential predictors for successful pharmaceutical and psychological treatment outcomes. TRIAL REGISTRATION: ISRCTN15998989 20/12/2019.

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation.

OBJECTIVE: Mental disorders are heritable and polygenic, and genome-wide genetic correlations (rg) have indicated widespread shared genetic risk across multiple disorders and related traits, mirroring their overlapping clinical characteristics. However, rg may underestimate the shared genetic underpinnings of mental disorders and related traits because it does not differentiate mixtures of concordant and discordant genetic effects from an absence of genetic overlap. Using novel statistical genetics tools, the authors aimed to evaluate the genetic overlap between mental disorders and related traits when accounting for mixed effect directions. METHODS: The authors applied the bivariate causal mixture model (MiXeR) to summary statistics for four mental disorders, four related mental traits, and height from genome-wide association studies (Ns ranged from 53,293 to 766,345). MiXeR estimated the number of "causal" variants for a given trait ("polygenicity"), the number of variants shared between traits, and the genetic correlation of shared variants (rgs). Local rg was investigated using LAVA. RESULTS: Among mental disorders, ADHD was the least polygenic (5.6K "causal" variants), followed by bipolar disorder (8.6K), schizophrenia (9.6K), and depression (14.5K). Most variants were shared across mental disorders (4.4K-9.3K) and between mental disorders and related traits (5.2K-12.8K), but with disorder-specific variations in rg and rgs. Overlap with height was small (0.7K-1.1K). MiXeR estimates correlated with LAVA local rg (r=0.88, p<0.001). CONCLUSIONS: There is extensive genetic overlap across mental disorders and related traits, with mixed effect directions and few disorder-specific variants. This suggests that genetic risk for mental disorders is predominantly differentiated by divergent effect distributions of pleiotropic genetic variants rather than disorder-specific variants. This represents a conceptual advance in our understanding of the landscape of shared genetic architecture across mental disorders, which may inform genetic discovery, biological characterization, nosology, and genetic prediction.

What is the potential for abuse of lisdexamfetamine in adults? A preclinical and clinical literature review and expert opinion.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a prodrug approved for attention deficit/hyperactivity disorder and for moderate-to-severe binge eating disorder in adults in some countries. AREA COVERED: We aimed to specify the abuse potential of LDX in adults, using a review of pharmacokinetic/pharmacodynamic (PK/PD), animal, clinical, and pharmaco-epidemiological studies, through a PubMed search since inception until May 2021 using the following keywords: "lisdexamfetamine AND ('misuse' OR 'abuse' OR 'diversion' OR 'addiction')". EXPERT OPINION: Most of the studies highlighted a longer Tmax than dexamphetamine leading to a delayed onset of effects and a decreased Cmax. These PK parameters were often associated with a diminished feeling of euphoria, in comparison to immediate-release dexamphetamine. The potential for abuse was also limited by the prodrug property of LDX, thus reducing the risk of misuse. Nevertheless, all the data were not convergent, as some authors reported similar Cmax for LDX and dexamphetamine and reinforcing properties with a dose-dependent effect. Epidemiological studies found that abuse rates of LDX were substantially lower than those of immediate-release dexamphetamine. Overall, although LDX abuse seems possible, we did not find evidence concerning current safety signal. However, more long-term pharmaco-epidemiological studies are still needed to confirm this finding.

Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings.

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. Understanding the genetic architecture of this comorbidity could be improved by focusing on intermediate traits that show positive genetic correlation with the disorders. Thus, we aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD) -beyond genetic correlation, and boost discovery for jointly-associated loci. Summary statistics for MOOD (a binary measure of the tendency to report frequent mood swings), AC (number of standard drinks over a typical consumption week) and AUD GWASs (Ns > 200,000) were analyzed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD. To do so, we used a newly established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly associated genomic loci, which were mapped to genes and biological functions. MOOD was highly polygenic (10.4k single nucleotide polymorphisms, SNPs, SD = 2k) compared to AC (4.9k SNPs, SD = 0.6k) and AUD (4.3k SNPs, SD = 2k). The polygenic overlap of MOOD and AC was twice that of MOOD and AUD (98% vs. 49%), with opposite genetic correlation (-0.2 vs. 0.23), as confirmed in independent samples. MOOD&AUD associated SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 jointly associated loci, fifteen were novel for MOOD, AC and AUD. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated partly shared biological underpinnings, yet, clearly distinct functional patterns between MOOD&AC and MOOD&AUD, suggesting new mechanisms for the comorbidity of AUD with mood disorders.

Developing "MinDag" - an app to capture symptom variation and illness mechanisms in bipolar disorder.

Introduction: The illness course of bipolar disorder (BD) is highly heterogeneous with substantial variation between individuals with the same BD subtype and within individuals over time. This heterogeneity is not well-delineated and hampers the development of more targeted treatment. Furthermore, although lifestyle-related behaviors are believed to play a role in the illness course, such mechanisms are poorly understood. To address some of these knowledge gaps, we aimed to develop an app for collection of multi-dimensional longitudinal data on BD-relevant symptoms and lifestyle-related behaviors. Methods: An app named MinDag was developed at the Norwegian Center for Mental Disorders Research in Oslo, Norway. The app was designed to tap into selected areas: mood, sleep, functioning/activities (social, occupational, physical exercise, leisure), substance use, emotional reactivity, and psychotic experiences. Ethical, security and usability issues were highly prioritized throughout the development and for the final app solution. We conducted beta- and pilot testing to eliminate technical problems and enhance usability and acceptability. Results: The final version of MinDag comprises six modules; three which are presented for the user once daily (the Sleep module in the morning and the Mood and Functoning/Activities modules in the evening) and three which are presented once weekly (Substance Use, Emotional Reactivity, and Psychotic Experiences modules). In general, MinDag was well received in both in the beta-testing and the pilot study, and the participants provided valuable feedback that was taken into account in the final development. MinDag is now in use as part of the research protocol at the NORMENT center and in a specialized treatment unit for BD at Oslo University Hospital in Norway. Discussion: We believe that MinDag will generate unique longitudinal data well suited for capturing the heterogeneity of BD and clarifying important unresolved issues such as how life-style related behavior may influence BD symptoms. Also, the experiences and knowledge derived from the development of MinDag may contribute to improving the security, acceptability, and benefit of digital tools in mental health.

Biomarkers of Relapse in Cocaine Use Disorder: A Narrative Review.

INTRODUCTION: Cocaine use disorder is a chronic disease with severe consequences and a high relapse rate. There is a critical need to explore the factors influencing relapse in order to achieve more efficient treatment outcomes. Furthermore, there is a great need for easy-to-measure, repeatable, and valid biomarkers that can predict treatment response or relapse. METHODS: We reviewed the available literature on the Pubmed database concerning the biomarkers associated with relapse in CUD, including central nervous system-derived, genetic, immune, oxidative stress, and "other" biomarkers. RESULTS: Fifty-one articles were included in our analysis. Twenty-five imaging brain anatomic and function assessment studies, mostly using fMRI, examined the role of several structures such as the striatum activity in abstinence prediction. There were fewer studies assessing the use of neuropsychological factors, neurotrophins, or genetic/genomic factors, immune system, or oxidative stress measures to predict abstinence. CONCLUSION: Several biomarkers have been shown to have predictive value. Prospective studies using combined multimodal assessments are now warranted.

Feasibility of an Extensive Strategy for Adult Diagnosis of Attention Deficit Hyperactivity Disorder Among Patients Suffering From Substance Use Disorders.

Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is found in up to 20% adults with Substance Use Disorder (SUD). ADHD + SUD is associated with a more complex clinical presentation and poorer outcomes than each disorder alone. In the presence of SUD, adult ADHD is particularly difficult to diagnose as both disorders can mimic or hide the symptoms of each other. Our university hospital in Paris recently started an extensive outpatient diagnostic procedure for adult patients with SUD to ascertain or refute ADHD diagnosis and to provide therapeutic guidance. Here, we report the acceptability of the assessment procedure for patients and the preliminary description of the current and lifetime clinical profiles as a function of the final diagnosis "ADHD vs. no ADHD." Method: Adult SUD patients with suspected ADHD were included in the current pilot study after stating they had no objection that their de-identified data were used for research purposes, according to French ethical procedures. Patients were evaluated for ADHD, comorbid mental disorders, cognitive state and dimensional psychological variables. They were assessed by trained psychologists and psychiatrists using standardized tools over a day. ADHD diagnosis was mainly based on the Diagnostisch Interview Voor ADHD for DSM-5 (DIVA-5). Results: Out of 18 eligible patients, 17 were included in the cohort (1 excluded) and none was opposed to using their data. Thirteen (76%) participants were diagnosed with ADHD. All patients appointed for the ADHD diagnostic procedure came, respected schedules and finished the evaluation. All patients were impaired on cognitive functioning and were highly comorbid, but ADHD patients seems to suffer even more from those conditions, especially for cannabis and stimulant use disorders. Discussion: Preliminary results show high acceptability of the procedure by ADHD-SUD patients. This result could be explained by all the organization adapted to the psychopathology. Patients' baseline motivation to participate also represents an uncontrolled variable that could promote the ability to follow the procedure. Acceptance results of the protocol are promising and represent a starting point to identify the best procedures to design patient-centered pharmacological and non-pharmacological therapies.

Preventive Medication Patterns in Bipolar Disorder and Their Relationship With Comorbid Substance Use Disorders in a Cross-National Observational Study.

Objective: The potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines. Methods: Seven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication. Results: Comorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4-3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9-11, p < 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04-1.3, p = 0.038). Conclusion: SUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies.

Occurrence and severity of cocaine-induced hallucinations: Two distinct phenotypes with shared clinical factors but specific genetic risk factors.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.