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Zusammenfassung. Hintergrund: Eine Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindesalter stellt einen Risikofaktor für Substanzmissbrauch und Störungen durch Substanzgebrauch (Substance Use Disorder, SUD) in der Pubertät und dem (frühen) Erwachsenenalter dar. ADHS und SUD treten auch häufig bei therapiesuchenden Jugendlichen auf, was die Diagnosestellung und Therapie erschwert sowie mit schlechten Behandlungsergebnissen verbunden ist. Forschungsergebnisse über die Wirkung der Behandlung von ADHS im Kindesalter auf die Prävention von SUD im Jugendalter sind nicht eindeutig und Studien über die Diagnose und Behandlung von Jugendlichen mit ADHS und SUD sind selten. Daher reicht die verfügbare Evidenz allgemein nicht aus, um starke Behandlungsempfehlungen zu rechtfertigen. Fragestellung: Ziel dieser Arbeit war es, eine Konsenserklärung auf der Grundlage von wissenschaftlichen Daten und klinischen Erfahrungen zu erhalten. Methodik: Es wurde eine modifizierte Delphi-Studie durchgeführt, um basierend auf der Kombination von wissenschaftlichen Daten und klinischer Erfahrung mit einer multidisziplinären Gruppe von 55 Expert_innen aus 17 Ländern einen Konsens zu erzielen. Die Expert_innen wurden gebeten, eine Reihe von Aussagen über die Wirkung der Behandlung von ADHS im Kindesalter auf die SUD bei Jugendlichen sowie über das Screening, die Diagnostik und die Behandlung von Jugendlichen mit komorbidem ADHS und SUD zu bewerten. Ergebnisse: Nach drei iterativen Bewertungsrunden und der Anpassung von 37 Aussagen wurde ein Konsens über 36 dieser Aussagen erzielt, die sechs Bereiche repräsentieren: allgemein ( n = 4), Risiko der Entwicklung einer SUD ( n = 3), Screening und Diagnostik ( n = 7), psychosoziale Behandlung ( n = 5), pharmakologische Behandlung ( n = 11) und komplementäre Behandlungen ( n = 7). Der Einsatz von Routinescreenings auf ADHS wird bei adoleszenten Patient_innen in einer Suchtbehandlung ebenso wie Routinescreenings auf SUD bei jugendlichen Patient_innen mit ADHS in allgemeinpsychiatrischen Therapiesettings empfohlen. Langwirksame Stimulanzien werden als Behandlung der ersten Wahl von ADHS bei Jugendlichen mit gleichzeitiger ADHS und SUD empfohlen. Die Pharmakotherapie sollte vorzugsweise in psychosoziale Behandlung eingebettet werden. Die einzige nichtkonsentierte Aussage betraf die Notwendigkeit von Abstinenz vor Beginn einer pharmakologischen Behandlung bei Jugendlichen mit ADHS und gleichzeitigem SUD. Im Gegensatz zur Mehrheit verlangten einige Expert_innen eine vollständige Abstinenz vor Beginn einer pharmakologischen Behandlung, einige waren gegen die Verwendung von Stimulanzien bei der Behandlung dieser Patient_innen (unabhängig von Abstinenz), während einige sich gegen die alternative Anwendung von Bupropion aussprachen. Schlussfolgerungen: Diese internationale Konsenserklärung kann von Kliniker_innen und Patient_innen zusammen in einem gemeinsamen Entscheidungsprozess genutzt werden, um die besten Interventionen auszuwählen und die bestmöglichen Ergebnisse bei adoleszenten Patient_innen mit gleichzeitiger ADHS und SUD zu erzielen.

The individual risk of developing drug addiction is highly determined by the epigenetic landscape1,2. Chromatin remodeling regulates drug-induced transcriptional and behavioral effects and the consequent development of addictive behaviors2,3. Several chromatin modifications in the ventral tegmental area and nucleus accumbens, including histone H3 methylation, H3 and H4 acetylation, have been implicated in drug addiction. Still, the contribution of other histones and their post-translational modifications (PTMs), such as monoubiquitination is unknown4–8. Here we found that H2A monoubiquitination in the paraventricular thalamus (PVT) plays a major role in cocaine-adaptive behaviors and local cocaine-evoked transcriptional repression. Mice undergoing chronic cocaine administration showed a specific increased monoubiquitination of H2A. Furthermore, we showed that this histone PTM is controlled, in the PVT, by an interaction between melanoma-associated antigen D1 (Maged1), a scaffold protein involved in drug addiction9, and USP7, a deubiquitinase10. Accordingly, Maged1 specific inactivation in thalamic vGluT2 neurons, or USP7 inhibition, blocked cocaine-evoked H2A monoubiquitination and abolished cocaine locomotor sensitization. Finally, we identified genetic variations ofMAGED1andUSP7associated with modified transition to cocaine addiction and cocaine-induced aggressive behavior in human subjects. These findings identified a new epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factor for drug addiction in human.

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, SCZ, BD and MD. Next, we characterized the identified shared loci using biological annotation resources. OUD data was obtained from the Million Veteran Program (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 was 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 condFDRDRD2 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.

Objectives Bipolar Disorder (BD) is frequently comorbid with other psychiatric disorders. However, few studies systematically examine which disorders are more likely to occur pre- or post-BD onset. We examine the prevalence and Age At Onset (AAO) of psychiatric conditions in adults with BD. Methods A structured clinical interview was used to assess lifetime history and AAO of alcohol and cannabis misuse, suicide attempts, anxiety and eating disorders in a French sample of euthymic patients with BD (n = 739). Regression analyses were used to test for statistically significant associations between rates and AAO of comorbidities in BD groups stratified by sex or subtype. Results Prevalence of alcohol and cannabis misuse was associated with male sex and BD-I subtype; whilst most anxiety and eating disorders were associated with female sex. The AAO of most comorbid conditions preceded that of BD, except for panic disorder, agoraphobia and alcohol misuse. Few variations were observed in AAO of comorbidities according to groups. Limitations All assessments were retrospective, so estimates of prevalence rates and especially exact AAO of some comorbidities are at risk of recall bias. Conclusions Sex and BD subtype are associated with different rates of comorbid disorders. However, there were minimal between group differences in median AAO of comorbidities. By describing the chronological sequence of comorbidities in BD we were able to demonstrate that a minority of comorbidities typically occurred post-onset of BD. This is noteworthy as these disorders might be amenable to interventions aimed at early secondary prevention.

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. We aimed to characterize the sharedvs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD), a relevant transdiagnostic factor, using large genome-wide association studies (GWASs) data. We hypothesize that cross-analyzing these phenotypes would shed light on their unique and shared polygenicity, increase our knowledge regarding the genetic basis of the comorbidity between AUD and mood disorders, and boost discovery for jointly-associated loci. Summary statistics for MOOD, AC and AUD GWASs (Ns =363,705; 200,680 and 200,004; respectively) were analysed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD, respectively. To do so, we used a newly-established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify the cross-phenotype polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly-associated genomic loci. These loci were functionally characterized and mapped to genes and biological functions. We also performed validation in independent samples and phenotypic analyses. MOOD was highly polygenic (10,400 single nucleotide polymorphisms, SNPs) compared to AC and AUD (4,900 SNPs, SD =600 and 4,300 SNPs, SD =2,000; respectively). The polygenic overlap of MOOD and AC was much larger than that of MOOD and AUD (98%vs. 49%) and genetic correlation was opposite (−0.2vs. 0.23), which was confirmed in independent samples. MOOD&AUD causal SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 loci identified in the joint analysis, sixteen were novel for MOOD, AC and AUD. Similarly distinct patterns were evidenced for SNP localization, function and previous GWAS associations outside of the phenotypes that were currently studied. 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 shared biological underpinnings but clearly distinct functional patterns between MOOD&AC and MOOD&AUD. Using the MOOD endophenotype, the current study suggests new mechanisms for the comorbidity of AUD with mood disorders.

Introduction Le trouble du déficit de l’attention/hyperactivité chez l’enfant (TDAH) est un facteur de risque de mésusage et de troubles de l’usage de substances (TUS) chez l’adolescent et le jeune adulte. Le TDAH et le TUS coexistent également fréquemment chez les adolescents en demande de soins, compliquant le diagnostic et le traitement et étant associé à de mauvais résultats thérapeutiques. Les recherches concernant l’effet du traitement du TDAH chez l’enfant sur la prévention du TUS à l’adolescence sont peu concluantes et les études sur le diagnostic et le traitement des adolescents atteints de TDAH et de TUS comorbides sont rares. Ainsi, les preuves disponibles ne sont pas suffisantes pour justifier des recommandations de traitement solides. Objectif Le but de cette étude était d’aboutir à une déclaration de consensus basée sur une combinaison de données scientifiques et d’expérience clinique. Méthode La méthode Delphi modifiée a été utilisée pour parvenir à un consensus basé sur la combinaison de données scientifiques et d’expérience clinique, avec un groupe multidisciplinaire de 55 experts provenant de 17 pays. Les experts ont été invités à évaluer un ensemble d’énoncés portant sur l’effet du traitement du TDAH de l’enfant sur le TUS à l’adolescence ainsi que sur le dépistage, le diagnostic et le traitement des adolescents souffrant de TDAH et de TUS comorbides. Résultats Après trois tours de cotation et d’adaptation de 37 énoncés, un consensus a été atteint sur 36 d’entre eux, représentant six domaines : généralités (n = 4), risque de développer un TUS (n = 3), dépistage et diagnostic (n = 7), prise en charges psychosociales (n = 5), traitement pharmacologique (n = 11) et traitements complémentaires (n = 7). Le dépistage systématique du TDAH est recommandé auprès des patients adolescents vus en addictologie et du TUS auprès des patients adolescents souffrant de TDAH vus en santé mentale. Les stimulants à action prolongée sont recommandés comme traitement de première intention du TDAH chez les adolescents souffrant de la comorbidité TDAH-TUS et la pharmacothérapie doit de préférence être incluse dans une prise en charge psychosociale (psychoéducation, entretien motivationnel, thérapies comportementales et cognitives, prise en charge familiale). L’unique déclaration non consensuelle restante concerne l’exigence d’abstinence avant l’initiation d’un traitement pharmacologique chez les adolescents atteints de TDAH et de TUS concomitants. Contrairement à la majorité des experts, certains exigent une abstinence complète avant de débuter tout traitement pharmacologique, certains se positionnent contre l’utilisation de stimulants dans le traitement de ces patients (indépendamment de l’abstinence), tandis que d’autres n’approuvent pas l’utilisation alternative du bupropion. Conclusion Cette déclaration de consensus internationale peut être utilisée par les cliniciens et les patients dans un processus collaboratif de prise de décision partagée pour sélectionner les meilleures interventions et obtenir des résultats optimaux chez les patients adolescents souffrant de TDAH et de TUS comorbides.

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.

International audience; Optimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic markers. We operationalized Li response phenotypes using the Retrospective Assessment of Response to Lithium Scale (i.e., the Alda scale) in a sample of 164 cases with bipolar disorder (BD). Three phenotypes were defined using the established approaches, whilst two phenotypes were generated by machine learning algorithms. We examined whether these five different Li response phenotypes showed different levels of statistically significant associations with polymorphisms of three candidate circadian genes (RORA, TIMELESS and PPARGC1A), which were selected for this study because they were plausibly linked with the response to Li. The three original and two revised Alda ratings showed low levels of discordance (misclassification rates: 8–12%). However, the significance of associations with circadian genes differed when examining previously recommended categorical and continuous phenotypes versus machine-learning derived phenotypes. Findings using machine learning approaches identified more putative signals of the Li response. Established approaches to Li response phenotyping are easy to use but may lead to a significant loss of data (excluding partial responders) due to recent attempts to improve the reliability of the original rating system. While machine learning approaches require additional modeling to generate Li response phenotypes, they may offer a more nuanced approach, which, in turn, would enhance the probability of identifying significant signals in genetic studies.

International audience; Introduction: Suicide attempts have been associated with both cocaine use disorder (CocUD) and childhood trauma. We investigated how childhood trauma is an independent risk factor for serious and recurrent suicide attempts in CocUD. Method: 298 outpatients (23% women) with CocUD underwent standardized assessments of substance dependence (Diagnostic and Statistical Manual-mental disorders, fourth edition, text revised), impulsiveness, resilience, and childhood trauma, using validated tools. Suicide attempts history was categorized as single vs. recurrent or non-serious vs. serious depending on the lifetime number of suicide attempts and the potential or actual lethality of the worst attempt reported, respectively. Bivariate and multinomial regression analyses were used to characterize which childhood trauma patterns were associated with the suicide attempts groups. Results: 58% of CocUD patients reported childhood trauma. Recurrent and serious suicide attempts clustered together and were thus combined into "severe SA." Severe suicide attempt risk increased proportionally to the number of childhood traumas (test for trend, p = 9 × 10-7). Non-severe suicide attempt risk increased with impulsiveness and decreased with resilience. In multinomial regression models, a higher number of traumas and emotional abuse were independently and only associated with severe vs. non-severe suicide attempts (effect size = 0.82, AUC = 0.7). The study was limited by its cross-sectional design. Conclusion: These preferential associations between childhood trauma and severe suicide attempts warrant specific monitoring of suicide attempts risk in CocUD, regardless of the severity of addiction profiles.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity.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.Cocaine dependence (pOur 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.

International audience; Objectives: The comorbidity of alcohol use disorder (AUD) and bipolar disorder (BD) has been repeatedly associated with poorer clinical outcomes than BD without AUD. We aimed to extend these findings by focusing on the characteristics associated with the sequence of onset of BD and AUD. Methods: 3,027 outpatients from the Fondamental Advanced Centres of Expertise were ascertained for BD-1, BD-2 and AUD diagnoses, including their respective ages at onset (AAOs, N =2,804). We selected the variables associated with both the presence and sequence of onset of comorbid AUD using bivariate analyses corrected for multiple testing to enter a binary regression model with the sequence of onset of BD and AUD as the dependent variable (AUD first - which also included 88 same-year onsets, vs. BD first). Results: BD patients with comorbid AUD showed more severe clinical profile than those without. Compared to BD-AUD (N =269), AUD-BD (N =276) was independently associated with a higher AAO of BD (OR =1.1, p

International audience; Over the last decade, robust human genetic findings have been instrumental in elucidating the heritable basis of nicotine addiction (NA). They highlight coding and synonymous polymorphisms in a cluster on chromosome 15, encompassing the CHRNA5, CHRNA3 and CHRNB4 genes, coding for three subunits of the nicotinic acetylcholine receptor (nAChR). They have inspired an important number of preclinical studies, and will hopefully lead to the definition of novel drug targets for treating NA. Here, we review these candidate gene and genome-wide association studies (GWAS) and their direct implication in human brain function and NA-related phenotypes. We continue with a description of preclinical work in transgenic rodents that has led to a mechanistic understanding of several of the genetic hits. We also highlight important issues with regards to CHRNA3 and CHRNB4 where we are still lacking a dissection of their role in NA, including even in preclinical models. We further emphasize the use of human induced pluripotent stem cell-derived models for the analysis of synonymous and intronic variants on a human genomic background. Finally, we indicate potential avenues to further our understanding of the role of this human genetic variation. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

International audience; Cocaine addiction is a chronic and relapsing disorder with an important genetic component. Human candidate gene association studies showed that the single nucleotide polymorphism (SNP) rs16969968 in the α5 subunit (α5SNP) of nicotinic acetylcholine receptors (nAChRs), previously associated with increased tobacco dependence, was linked to a lower prevalence of cocaine use disorder (CUD). Three additional SNPs in the α5 subunit, previously shown to modify α5 mRNA levels, were also associated with CUD, suggesting an important role of the subunit in this pathology. To investigate the link between this subunit and CUD, we submitted rats knockout for the α5 subunit gene (α5KO), or carrying the α5SNP, to cocaine self-administration (SA) and showed that the acquisition of cocaine-SA was impaired in α5SNP rats while α5KO rats exhibited enhanced cocaine-induced relapse associated with altered neuronal activity in the nucleus accumbens. In addition, we observed in a human cohort of patients with CUD that the α5SNP was associated with a slower transition from first cocaine use to CUD. We also identified a novel SNP in the β4 nAChR subunit, part of the same gene cluster in the human genome and potentially altering CHRNA5 expression, associated with shorter time to relapse to cocaine use in patients. In conclusion, the α5SNP is protective against CUD by influencing early stages of cocaine exposure while CHRNA5 expression levels may represent a biomarker for the risk to relapse to cocaine use. Drugs modulating α5 containing nAChR activity may thus represent a novel therapeutic strategy against CUD.

Background people suffering from substance use disorders (SUD) often die by suicide, so that the prevention of suicide attempts (SA) remains a top priority in this population. SA recurrence is common and is associated with suicide death, but this phenotype has been overlooked in SUD populations. Thus, we aimed at identifying the risk factors of SA recurrence in SUD, controlling for both gender and levels of exposure to addictive substances, including tobacco. Methods we consecutively recruited 433 treatment-seeking outpatients with either opiate or cocaine use disorder and assessed their lifetime history of addictive and suicidal symptoms by standardized questionnaires. They were reliably classified as never, single or recurrent (≥ 2) suicide attempters, whose characteristics were identified by multinomial regression, stratified by gender; and compared to our previous work on serious SA in order to identify common or different risk profiles. Results 86/140 (61%) suicide attempters reported recurrence. The mean number of SA was 3.1. Recurrence was independently associated with psychiatric hospitalization in both genders, with nicotine dependence in men and with sedative use disorders in women. Limitations psychiatric diagnoses were derived from the current medication regimen. Conclusion specific and possibly avoidable/treatable risk factors for the recurrence of SA in SUD have been identified for the first time, opening new avenues for research and prevention in this high-risk population. Apart from nicotine dependence, these risk factors were very similar to those of serious SA. Although this comparison is indirect for now, it suggests a common liability towards suicidal behavior.

Psychiatric disorders, including schizophrenic spectrum disorders, are common in People Who Use Drugs (PWUD). Promoting adherence to medication among PWUD with dual diagnosis is challenging. We present the case of a treatment-disrupted patient suffering from schizophrenia with co-occuring multiple drug dependence to whom penfluridol - an oral long acting typical antipsychotic - was proposed at the Supervised Drug Consumption Room (SDCR) of Paris. Penfluridol quickly improved patient's psychotic symptoms, increased engagement in addiction care and helped maintaining the patient in “Housing First” program. In harm reduction structure, penfluridol can be seen as a “hook treatment” while maintaining therapeutic alliance and favoring patients’ engagement in specific care.

Background Suicide is a major public health concern and suicide attempts (SA) are frequent and burdensome in people suffering from substance use disorders (SUDs). In particular, serious SAs are a preoccupying form of attempt, which remain largely overlooked in these populations, especially regarding basic risk factors such as gender, addictive comorbidity and substance use patterns. Thus, we undertook a gender-specific approach to identify the risk factors for serious SAs in outpatients with multiple SUDs. Material and methods 433 Treatment-seeking outpatients were consecutively recruited in specialized care centers and reliably classified as serious, non-serious and non-suicide attempters. We also characterized lifetime exposure to SUDs, including tobacco smoking, with standardized instruments. Current medication, including psychotropic treatments were collected, which informed psychiatric diagnoses. Multinomial regression identified independent factors specifically associated with serious SAs in each gender, separately. Results 32% Participants (N = 139, 47% Women and 27% Men) reported lifetime SA. There were 82 serious attempters (59% of attempters), without significant gender difference. Sedative dependence was an independent risk factor for serious SA compared to non-SA in Women and compared to non-serious SA in Men, respectively. Other risk factors included later onset of daily tobacco smoking in Men and history of psychiatric hospitalizations in Women, whose serious SA risk was conversely lower when reporting opiate use disorder or mood disorder, probably because of treatment issues. Conclusions Despite several study limitations, we identified subgroups for a better-tailored prevention of serious SAs among individuals with SUDs, notably highlighting the need to better prevent and treat sedative dependence.

Background: Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment and is associated with poor treatment outcomes. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations. Objective: The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience. Method: A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD. Results: After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general (n = 4), risk of developing SUD (n = 3), screening and diagnosis (n = 7), psychosocial treatment (n = 5), pharmacological treatment (n = 11), and complementary treatments (n = 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion. Conclusion: This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD.

Introduction: Comorbid attention deficit/hyperactivity disorder (ADHD) is present in 15–25% of all patients seeking treatment for substance use disorders (SUDs). Some studies suggest that comorbid ADHD increases clinical severity related to SUDs, other psychiatric comorbidities, and social impairment, but could not disentangle their respective influences. Objectives: To investigate whether comorbid adult ADHD in treatment-seeking SUD patients is associated with more severe clinical profiles in these domains assessed altogether. Methods: Treatment-seeking SUD patients from 8 countries (N = 1,294: 26% females, mean age 40 years [SD = 11 years]) were assessed for their history of DSM-IV ADHD, SUDs, and other psychiatric conditions and sociodemographic data. SUD patients with and without comorbid ADHD were compared on indicators of severity across 3 domains: addiction (number of SUD criteria and diagnoses), psychopathological complexity (mood disorders, borderline personality disorder, lifetime suicidal thoughts, or behavior), and social status (education level, occupational and marital status, and living arrangements). Regression models were built to account for confounders for each severity indicator. Results: Adult ADHD was present in 19% of the SUD patients. It was significantly associated with higher SUD severity, more frequent comorbid mood or borderline personality disorder, and less frequent “married” or “divorced” status, as compared with the absence of comorbid ADHD. ADHD comorbidity was independently associated with a higher number of dependence diagnoses (OR = 1.97) and more psychopathology (OR = 1.5), but not marital status. Conclusions: In treatment-seeking SUD patients, comorbid ADHD is associated with polysubstance dependence, psychopathological complexity, and social risks, which substantiates the clinical relevance of screening, diagnosing, and treating ADHD in patients with SUDs.

International audience; Rationale Behavioral disturbances (BD) are prevalent in patients with substance use disorders (SUD). Objectives To test the hypothesis that chronic exposure to cocaine could favor the acquisition of BD that were not present in childhood. Methods We used child and adult ADHD self-report screening scales (WURS-25 and ASRS-6, respectively, with their usual threshold) as assessment tools for significant BD. In a cross-sectional assessment of 382 patients with multiple SUD, we investigated BD and then "de novo" BD (i.e., by restricting the sample to patients below the threshold for childhood BD) (N = 214). We also tested for a gradient effect between patients' lifetime DSM IV cocaine and opioid dependence status and the prevalence of BD. Results BD were found in 188/382 (42.9%) subjects and in 74/214 (34.6%) subjects. Three clinical factors were associated with BD in the whole sample: the number of cocaine dependence criteria (OR = 1.36 [1.14-1.64], p = 0.001), the number of opioid dependence criteria (OR = 0.69 [0.52-0.91], p = 0.010), and a personal history of using cocaine through rapid routes of administration (OR = 0.41 [0.19-0.88], p = 0.022). The same three factors were associated with "de novo" BD in the restricted sample: OR = 1.35 ([1.11-1.63], p = 0.002), OR = 0.83 ([0.70-0.99], p = 0.046), and OR 0.37 ([0.16-0.86], p = 0.022), respectively. There were significant gradients for BD according to the cocaine exposure categories in the whole (Mantel-Haenszel, p < 0.001) and in the restricted sample (Mantel-Haenszel, p = 0.002). Conclusions Cocaine exposure was positively associated with behavioral disturbances in a dose-dependent manner in this clinical sample, whilst opioid exposure showed a negative association.

Background Suicide attempts (SA) are more frequent in bipolar disorder (BD) than in most other mental disorders. Prevention strategies would benefit from identifying the risk factors of SA recurrence in BD. Substance use disorders (SUD) (including tobacco-related) are strongly associated with both BD and SA, however, their specific role for the recurrence of SA in BD remains inadequately investigated. Thus, we tested if tobacco smoking - with or without other SUDs – was independently associated with recurrent SA in BD. Methods 916 patients from France and Norway with ascertained diagnoses of BD and reliable data about SA and SUD were classified as having no, single, or recurrent (≥2) SA. Five SUD groups were built according to the presence/absence/combination of tobacco, alcohol (AUD) and cannabis use disorders. Multinomial logistic regression was used to identify the correlates of SA recurrence. Results 338 (37%) individuals reported at least one SA, half of whom (173, 51%) reported recurrence. SUD comorbidity was: tobacco smoking only, 397 (43%), tobacco smoking with at least another SUD, 179 (20%). Regression analysis showed that tobacco smoking, both alone and comorbid with AUD, depressive polarity of BD onset and female gender were independently associated with recurrent SA. Limitations Lack of data regarding the relative courses of SA and SUD and cross-national differences in main variables. Conclusion Tobacco smoking with- or without additional SUD can be important risk factors of SA recurrence in BD, which is likely to inform both research and prevention strategies.

BACKGROUND: Tobacco smoking increases the global burden of bipolar disorder (BD). We examined markers of physical and mental health that are associated with tobacco smoking, controlling for confounders that have not always been considered in previous studies of BD. METHODS: Over 600 individuals with BD I or II referred to the French Network for bipolar disorder (FACE-BD) who completed standardized assessments, and could be reliably classified as current (CS) or former smokers (FS), were compared with those who were never smokers (NS) on: BD symptom load and psychiatric comorbidities; prevalence of alcohol and substance use disorders (ASUD); medication usage; functioning and physical health parameters. The bivariate and multivariate analyses took into account age and gender. RESULTS: 300 cases (49%) were CS, 78 (13%) FS and 238 (39%) had never smoked. Rates were similar across genders regardless of BD subtype. Compared with NS, CS were more likely to have an ASUD (Odds Ratio (OR) 5.18), BD I (OR 2.09), and lower abdominal obesity (OR 0.97), and FS were more likely to have an ASUD (OR 6.32) and higher abdominal obesity (OR 1.03). LIMITATIONS: The sample comprised of white Europeans; the FS subgroup was relatively small and we did not apply any statistical correction for the bivariate analyses. CONCLUSIONS: The increased risk of physical and mental health burden in CS and FS compared to NS represents avoidable morbidity in BD. This study offers support to the argument that individuals with BD should be routinely offered support to prevent or stop tobacco smoking.

Objectives We investigated the feasibility and acceptability of an integrated group therapy (called HABIT) for comorbid bipolar disorder (BD) and alcohol and substance use disorders (ASUD) (BD-ASUD), a disabling clinical presentation for which no specific treatment has been validated. The 14-session HABIT programme employs psychoeducation-oriented cognitive-behaviour therapy (CBT) followed by mindfulness-based relapse prevention (MBRP) therapy. Method Potential group participants were recruited from adult clients with a DSM-IV diagnosis of BD and an ASUD who were referred by their treating clinician. Observer-rated changes in mood symptoms and ASUD, attendance rates and subjective feedback are reported. Results Eight of 12 clients referred to the programme initially agreed to join the group, six attended the first group session and five clients completed the programme. Group mean scores for mood symptoms improved over time, with slightly greater reductions in depression during the first module. About 50% of individuals showed clinically significant improvement (≥30% reduction) in alcohol and substance use. Attendance rates showed some variability between individuals and across sessions, but the average attendance rate of the group was marginally higher for the first module (86%) as compared with the second module (77%). Most clients reported high levels of general satisfaction with a group specifically targeted at individuals with BD-ASUD. Conclusion This small pilot study suggests our intensive group therapy is acceptable and feasible. If findings are replicated, we may have identified a therapy that, for the first time, leads to improvement in both mood and substance use outcomes in clients with difficult-to-treat comorbid BD-ASUD. Copyright © 2016 John Wiley & Sons, Ltd. Key Practitioner Message Comorbidity between bipolar and alcohol and substance use disorders (BD-ASUD) is frequent and highly disabling; Therapeutic research on approaches that can simultaneously help BD and ASUD is lacking; Previous research highlights the need for integrated treatment of both conditions but showed improvements limited to either element of the comorbid disorder; This pilot study supports the feasibility and acceptability of an intensive, 14-session group therapy programme that integrates CBT and mindfulness approaches.

L’usage et les troubles lies a l’usage de substances (TUS) sont la regle dans le trouble bipolaire (TB). Ils pejorent le pronostic du TB en aggravant les decompensations thymiques, en diminuant la reponse au traitement usuel et, surtout, en augmentant la mortalite toutes causes. L’epidemiologie descriptive des comorbidites addictives du TB est desormais mieux connue [1] , [2] , mais on connait mal l’influence de l’apparition ou de la remission des TUS sur l’evolution du TB, qui presente de probables specificites pronostiques par substance et selon la sequence d’installation [3] . Nous nous focaliserons sur la comorbidite entre TB et troubles lies a l’usage d’alcool (TUA), qui aggravent la polarite depressive du TB, le risque de cancer et, probablement, de suicide. Ces TUA concernent 20 % des 2945 participants de la cohorte du reseau national des centres experts du trouble bipolaire de la fondation Fondamental dont les donnees anonymisees sont disponibles. Les participants, diagnostiques TB1 (52 %) ou TB2 (48 %) (nous avons exclu les TB-NOS pour notre projet), sont a 61 % des femmes et leur âge moyen est de 41 ± 13 ans. Les âges de debut des TUA, contrairement a tabac et cannabis, ont une distribution multimodale tres etalee permettant l’etude de trois sous-groupes d’interet par des modeles multivaries stratifies sur le genre TUA precedant largement le TB, TUA et TB relativement concomitants, et TUA debutant largement apres le TB. Notre hypothese est que ces groupes ne montrent pas (1) la meme evolution du TB evaluee retrospectivement par le taux annuel d’episodes thymiques, le nombre de comorbidites addictives et le fonctionnement a l’inclusion (Romain ICICK) et (2) influencent differemment les symptomes anxieux et thymiques ainsi que le traitement medicamenteux du TB evalues prospectivement a un an (Ludovic SAMALIN). Pour conclure, Isabelle Biseul presentera une lecture critique des donnees de la litterature concernant les possibilites therapeutiques pour les patients avec TB + TUA, en interrogeant notamment leurs benefices sur l’usage d’alcool, l’humeur, ou les deux. Puis elle decrira les resultats encourageants d’un programme de therapie cognitive de groupe specifique developpe dans un centre expert parisien [4] . Ces presentations fourniront a l’auditoire une base solide pour discuter la prise en charge integree et personnalisee des individus souffrant d’une comorbidite TB + TUA, situation deletere et particulierement frequente.

Les patients souffrant de trouble bipolaire (TB) ont un risque augmente de souffrir egalement d’un trouble lie a l’usage d’alcool (AUD), qui pejore le pronostic du TB en augmentant notamment les symptomes depressifs et le risque suicidaire. La physiopathologie de cette comorbidite reste mal connue, meme si TB et AUD partagent certains facteurs de risque, notamment temperamentaux et environnementaux precoces. Le developpement de cette comorbidite pourrait avoir des consequences majeures sur la trajectoire des patients concernes, aussi bien en fonction de la sequence d’apparition des troubles que de leur delai de survenue respective. Les donnees de la litterature indiquent que la sequence « AUD puis TB » est associee a un âge plus eleve, a d’autres comorbidites addictives, au genre masculin et a la presence de troubles anxieux comorbides. Cependant, les donnees existantes n’ont pas evalue l’influence potentielle du delai d’apparition des deux troubles, ce que nous avons etudie au moyen d’analyses de survie appropriees chez 2515 patients diagnostiques TB-I ou TB-II dans les centres experts de la fondation Fondamental. Nous avons analyse les caracteristiques associees (i) a la presence d’un AUD et a sa sequence d’apparition avec le TB au moyen d’une regression multinomiale puis (ii) au delai de survenue entre les deux par un modele de survie. Nous avons confirme certaines caracteristiques associees a la presence d’un AUD : comorbidites addictives, troubles anxieux, debut maniaque du TB, genre masculin et augmentation de la prevalence des tentatives de suicide. Nous avons surtout pu mettre en avant : (i) que les trajectoires cliniques des patients comorbides sont surtout liees a l’âge de debut du TB, qui est toujours plus tardif en cas de sequence « AUD puis TB » comparee a « TB puis AUD », ces patients ayant ainsi des scores plus eleves de depression, (ii) : que ces resultats ont une portee methodologique et clinique importante concernant le reperage des comorbidites addictives chez les patients souffrant de TB et sur les priorites a donner dans le soin des patients souffrant de telles comorbidites.

Background and Objectives The burden of opiate dependence not only relies on somatic complications such as infectious diseases or acute intoxication but also on frequent psychiatric events such as major depressive disorder (MDD) and suicidal behavior (SB). Given the preclinical and clinical evidence regarding the associations between cannabinoid systems and both opiate dependence and psychiatric disorders, we chose to address whether one single nucleotide polymorphism (SNP) of the cannabinoid receptor type 1 gene (CNR1) named rs2023239 would be associated with lifetime MDD and SB in a population of opiate-dependent outpatients remitted under stable methadone treatment. Methods Sociodemographic and clinical data were included as independent factors in two logistic regression models aimed at predicting SB and MDD, respectively, performed with 85 Caucasian individuals. Results The minor C allele of rs2023239 showed an independent protective effect against lifetime MDD after adjustment for potential confounders. It was not associated with variables related to suicidal behavior. Conclusions and Scientific Significance Despite limitations due to the modest sample size, our results are consistent with previous research on the endocannabinoid system and suggest new leads for detecting subjects at risk of MDD, which remains insufficiently diagnosed and treated in patients suffering from severe addictive disorders. (Am J Addict 2015;XX:1 –8)

Major Depressive Disorder (MDD) is the 3rd source for burden worldwide according to the World Health Organization (WHO). This comes partly from unsatisfactory response rates after usual treatment, highlighting the need for early indicators such as early improvement of depressive symptoms to adapt treatment strategies, especially for severe inpatients. Thus our objective was to assess the predictive value of baseline partial resistance in early antidepressant response (EAR), hypothesizing that previous treatment failures would decrease the probability of early response.We included 122 consecutive inpatients with current unipolar MDE. The Mini-Neuropsychiatric Interview was used to ascertain DSM-IV diagnoses of MDD as well as psychiatric comorbidities, and to exclude patients with a history of bipolar disorder. A specifically designed questionnaire was used to collect data on previous treatment trials for the current episode so as to generate scores on the five existing methods for quantifying treatment resistance. We prospectively assessed EAR, defined as a 50% decrease in MADRS after 14 days of steady regimen of antidepressant.In the per protocol sample (N=76), multivariate analyses showed that psychotic features at baseline remained an independent predictor of absence of EAR (p.01), unlike baseline partial resistance, which may rather be associated with a lack of any improvement.Lack of data about further response and non-randomized treatment allocation.Available methods for quantifying treatment resistance are heterogeneous and do not predict short-term response among severely depressed inpatients, despite potential usefulness in predicting a lack of early improvement.

Introduction Les benzodiazepines (BZD) sont utilisees par 45 a 60 % des individus souffrant de troubles lies a l’usage de substances (SUD), dont au moins la moitie presentent un trouble lie a l’usage [1,2] selon le Diagnostic and Statistical Manual of Mental Disorders, 4th version (DSM-IV) [3]. Cela suggere que leur utilisation reste banalisee dans cette population, bien que des donnees recentes aient suggere l’existence de dommages specifiques aux BZD [4,5], y compris avec augmentation du risque de tentatives de suicide [6]. Ces donnees proviennent presqu’exclusivement d’echantillons d’individus en soins pour une addiction aux opiaces, la plupart du temps traites par la methadone, ce qui donne une vision tres partielle des enjeux du mesusage de BZD dans les populations en soins pour des SUD de facon generale. En outre, les phenotypes suicidaires – l’une des complications frequentes les plus redoutees dans la pratique addictologique – ont ete etudies dans leur ensemble. Or, un consensus recent suggere de les etudier distinctement selon leur severite/violence/dangerosite et/ou leur recurrence, qui presentent des facteurs de risque distincts des TS isolees ou moins severes [7,8]. Pour mieux caracteriser ces liens, nous avons voulu : • Decrire les modalites d’usage/mesusage de BZD dans une population consultant pour SUD severes ; • Etudier les associations entre BZD et trois familles de marqueurs de severite : 1/ psychiatrique, avec les phenotypes suicidaires, 2/ socio-demographique (logement-emploi-statut marital) et 3/ addictologique avec la frequence et la gravite des overdoses. L’objectif final etait de constituer un modele general du profil de severite associe au mesusage de BZD dans cette population. Nous faisons l’hypothese que les BZD sont associees a un risque suicidaire accru, en fonction du genre. Methodes Apres avoir signe un consentement eclaire, 539 patients en soins pour trouble lie a l’usage de cocaine ou d’opiaces, composes a 77 % d’Hommes âges en moyenne de 40 +/- 9 ans, ont ete evalues de facon standardisee pour les consommations de substances (modalites d’usage et SUD selon les criteres du DSM-IV), l’adversite developpementale et l’histoire sociale et suicidaire. Nous avons recherche les modalites d’usage de BZD associees 1/ aux tentatives de suicide dangereuses et recurrentes, respectivement, 2/ a un probleme severe de logement caracterise par le fait d’avoir ete sans domicile pendant au moins 3 mois, au fait d’etre actuellement celibataire, et de rapporter une periode de chomage dans l’annee ecoulee et 3/ aux overdoses aux opiaces. Apres une breve description de l’usage et ses troubles dans notre echantillon, nous avons compare les distributions entre les sujets avec et sans trouble lie a l’usage de BZD (TLUB) par analyses bivariees, en fonction du genre [significativite statistique a 5 % apres correction par le False Discovery Rate selon la methode de Benjamini-Hochberg (FDR-BH) [9]. Les variables associees aux troubles lies a l’usage de BZD ont ensuite ete integrees, apres verification de leur absence de collinearite, dans un modele de regression logistique multinomiale ayant pour variable dependante l’absence d’usage de BZD, la presence d’un usage sans TLUB, et la presence d’un TLUB. Notre etude etant retrospective, nous avons choisi ce modele pour identifier les facteurs independants classant le mieux les individus selon la presence ou l’absence de TLUB par rapport a l’usage non pathologique de BZD. Resultats : L’usage de BZD vie entiere concernait 91 % de notre cohorte, dont 54 % d’abus/dependance debutes en moyenne a 24 et 33 ans, respectivement. La dependance aux BZD etait independamment associee aux tentatives de suicide dangereuses mais pas recurrentes, la pire ayant lieu en moyenne a 26 ans, le plus souvent apres l’initiation des BZD. Avoir ete SDF et victime d’une overdose aux opiaces etait egalement associe aux TLUB en analyses bivariees. Discussion : Dans un large echantillon de patients consultant en soins addictologiques specialises, nous avons montre que le mesusage de BZD etait un facteur de gravite majeur au plan suicidaire et social. Ces resultats nous amenent a evoquer une prise en charge specifique de cette comorbidite dans cette population deja tres a risque au plan psychiatrique et social. En l’absence de recommandation claire sur la methode a adopter, et bien que notre etude retrospective ne permette pas d’etablir des liens de cause a effet directs, il semble que cette classe medicamenteuse ne doive pas etre prescrite dans cette population.

We investigated the feasibility and acceptability of an integrated group therapy (called HABIT) for comorbid bipolar disorder (BD) and alcohol and substance use disorders (ASUD) (BD-ASUD), a disabling clinical presentation for which no specific treatment has been validated. The 14-session HABIT programme employs psychoeducation-oriented cognitive-behaviour therapy (CBT) followed by mindfulness-based relapse prevention (MBRP) therapy.Potential group participants were recruited from adult clients with a DSM-IV diagnosis of BD and an ASUD who were referred by their treating clinician. Observer-rated changes in mood symptoms and ASUD, attendance rates and subjective feedback are reported.Eight of 12 clients referred to the programme initially agreed to join the group, six attended the first group session and five clients completed the programme. Group mean scores for mood symptoms improved over time, with slightly greater reductions in depression during the first module. About 50% of individuals showed clinically significant improvement (≥30% reduction) in alcohol and substance use. Attendance rates showed some variability between individuals and across sessions, but the average attendance rate of the group was marginally higher for the first module (86%) as compared with the second module (77%). Most clients reported high levels of general satisfaction with a group specifically targeted at individuals with BD-ASUD.This small pilot study suggests our intensive group therapy is acceptable and feasible. If findings are replicated, we may have identified a therapy that, for the first time, leads to improvement in both mood and substance use outcomes in clients with difficult-to-treat comorbid BD-ASUD. Copyright © 2016 John WileySons, Ltd. Key Practitioner Message Comorbidity between bipolar and alcohol and substance use disorders (BD-ASUD) is frequent and highly disabling; Therapeutic research on approaches that can simultaneously help BD and ASUD is lacking; Previous research highlights the need for integrated treatment of both conditions but showed improvements limited to either element of the comorbid disorder; This pilot study supports the feasibility and acceptability of an intensive, 14-session group therapy programme that integrates CBT and mindfulness approaches.

Bipolar disorder is a chronic, disabling, frequent and highly comorbid illness. It is often associated with addictive disorders (ADDs), another chronic and relapsing condition, with a lifetime prevalence three to five times higher than in the general population. However, knowledge is scarce about the possible mechanisms and the optimal treatment of this co-occurrence. Moreover, previous research has focused on separate ADDs, and few incidence data were available at the time. Our objective was, therefore, to evaluate the relevance of regrouping ADDs as classified in the preliminary version of the DSM-V in understanding the comorbidity of bipolar and ADDs.

Early onset of heroin use is a severity marker of heroin use disorder. We studied the interaction between early onset and rapid transition to heroin dependence recorded with retrospective interviews in 213 patients with severe heroin dependence and history of methadone maintenance treatment. General linear models were used to identify independent factors associated with early onset, factors associated with rapid transition to dependence, and a multivariate model was used to study the interaction of those two dimensions. Lifetime history of anxiety disorders and age at onset of cannabis use are shared common risk factors and are associated with the interaction.

Objective Cannabis use disorders (CUD) may influence the course of bipolar disorder (BD), but key confounding factors such as tobacco smoking have not been adequately addressed. This study examined whether CUD was associated with a more severe illness course in tobacco smoking BD patients. Methods A sample of French and Norwegian tobacco smoking patients with BD I and II (N=642) was investigated. DSM-IV diagnoses and other characteristics were obtained through personal interviews using structured questionnaires. The association between CUD and illness course was assessed in regression analyses. Results In bivariate analyses, CUD was associated with earlier BD onset, higher frequency of manic (in BD I) and depressive episodes and hospitalizations per illness year, and a higher occurrence of psychotic episodes. After controlling for potential confounders, the relationships with earlier BD onset (B=−5.60 95% CI=−7.65 to −3.64), and increased rates of manic episodes (OR=1.93, 95% CI: 1.15 to 3.23) and hospitalizations (OR=2.93, 95% CI: 1.85 to 4.64) remained statistically significant. Limitations Despite the multivariate approach, differences between the two samples may lead to spurious findings related to hidden confounders. Substance use and mood episode information was collected retrospectively, and potential birth cohort effects could not be controlled for. Conclusion Studies have found associations between tobacco smoking and poorer outcomes in BD. In this study on tobacco smoking BD patients we report an association between CUD and illness severity, suggesting that CUD exacerbates the disease evolution independently of tobacco smoking. Specific treatment and prevention programs addressing CUD in BD patients are warranted.