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.

Predictors of abstinence maintenance after cocaine inpatient detoxification: A prospective study.

BACKGROUND AND OBJECTIVES: Cocaine is a highly addictive substance, and with no approved medication for cocaine use disorder (CUD), leading to a heavy burden. Despite validated psychosocial treatments, relapse rates after detoxification are very high in CUD. Few consistent factors can predict abstinence after detoxification. Our study, therefore, aimed at identifying factors predicting abstinence among CUD patients after inpatient detoxification. METHODS: Eighty-one CUD inpatients were included during detoxification and characterized for clinical and sociodemographic data at baseline and at a follow-up of 3 months after discharge, including a standard measure of their abstinence duration from cocaine. We performed Cox univariate analyzes to determine the factors associated with abstinence maintenance, followed by a multivariate Cox regression to identify independent predictors. RESULTS: Abstinence maintenance was shorter in patients injecting cocaine (hazard ratio [HR] = 5.16, 95% confidence interval [CI]: 2.01-13.27, p < .001) and using cocaine heavily in the month before inclusion (HR = 1.03, 95% CI: 1.00-1.06, p = .046). Conversely, abstinence maintenance was longer in patients with longer inpatient detoxification stays (HR = 0.96, 95% CI: 0.94-0.99, p = .015) and prescribed with selective serotonin reuptake inhibitors (SSRIs) (HR = 0.30, 95% CI: 0.16-0.56, p < .001). DISCUSSION AND CONCLUSIONS: Patients with severe CUD may require longer inpatient stays to achieve abstinence. Regarding SSRI prescription, more specific studies are needed to provide stronger recommendations about their use in clinical practice. SCIENTIFIC SIGNIFICANCE: Our findings suggest several modifiable factors to improve inpatient treatment response in CUD. As there are no specific recommendations about the optimal duration of inpatient stay, our results could pave the way for evidence-based guidelines.

Lamotrigine in mood disorders: Flash survey on prescribing habits and blood tests practices.

OBJECTIVE: Therapeutic drug monitoring for lamotrigine is poorly documented in bipolar and depressive disorders. In order to evaluate its use among French psychiatrists, we explored prescribing habits, therapeutic monitoring and dosage adjustment of lamotrigine through a flash survey. METHODS: A survey was broadcasted by the network of Expert Centers for Bipolar Disorder and Resistant Depression and by the Collegial of Psychiatry of the Assistance publique des Hôpitaux de Paris. Questions concerned the frequency of prescribing depending on the mood disorder, the frequency of plasma levels, therapeutic monitoring, dosage adjustment and the limitation represented by dermatological risk. RESULTS: Of the 99 hospital psychiatrists who responded, 66 practiced in a university hospital and 62 for more than 5years. Overall, lamotrigine was more frequently prescribed for type 2 bipolar disorder (often: 51%) than for type 1 bipolar disorder (often: 22%). Dermatotoxicity was a major barrier to prescribing for 15% (n=13) of respondents. Nearly two-thirds of prescribers (61%, n=59) measured lamotrigine, of which 50% (n=29) systematically. However, 40% of them did not have an opinion on the optimal plasma concentration. In total, 22% (n=13) always adjusted the dosage according to the result. The first argument for dosage adjustment was clinical response for 80% (n=47) of prescribers, adverse effects for 17% (n=10) and plasma levels for only 4% (n=2). CONCLUSION: While many psychiatrists report using plasma dosage of lamotrigine, few use the plasma level result to adapt dosage and many have no opinion of the target values for plasma concentrations. This illustrates the lack of data and recommendations regarding the use of therapeutic pharmacological monitoring of lamotrigine in bipolar and depressive disorders.

Plasma tau, NfL, GFAP and UCHL1 as candidate biomarkers of alcohol withdrawal-associated brain damage: A pilot study.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.

Childhood trauma and the severity of past suicide attempts in outpatients with cocaine use disorders.

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.

[Continuity of medication after hospitalisation in geriatric follow-up and rehabilitation care]. / Continuité médicamenteuse après une hospitalisation en soins de suite et de réadaptation gériatrique.

After one year of practice, the medication reconciliation approach in follow-up and rehabilitation care was evaluated. The aim of the activity was to identify changes in treatment (CT). Three hundred and two patients benefited from the process. Some 82.2% of drug lines had voluntary TCs at discharge and all of patients had at least one TC at discharge. What are the consequences of so many TCs and what are the levers to limit these effects?

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side.

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.

Biomarkers to predict staging and treatment response in opioid dependence: A narrative review.

Opioid use disorder is a devastating disorder with a high burden in terms of overdose mortality, with an urgent need for more personalized prevention or therapeutic interventions. For this purpose, the description and validation of biological measures of staging or treatment response is a highly active research field. We conducted a narrative review on the pathophysiology of opioid use disorder to propose staging of the disease and search for research studies proposing or demonstrating the predictive value of biomarkers. We propose a IV stage description of opioid use disorder, from (I) vulnerability stage to (II) disease progression, (III) constituted opioid dependence and were several type of treatments can be applied, to the reach a (IV) modified health state. We classified biomarkers studies according to the stage of the disorder they were intended to predict, and to the three categories of methods they used: anatomical and functional aspects of the brain, genetic/transcriptomic/epigenetic studies, and lastly biomarkers of systemic modifications associated with opioid use disorder, especially regarding the immune system. Most studies predicting Stage III that we reviewed collected data from small samples sizes and were cross-sectional association studies comparing opioid dependent patients and control groups. Pharmacogenetic biomarkers are proposed to predict treatment response. Future research should now emphasize prospective studies, replication in independent samples, and predictive value calculation of each biomarker. The most promising results are multimodal evaluations to be able to measure the state of the brain reward system in living individuals.

[Continuity of medication management after hospitalization in geriatric subacute rehabilitation care]. / La continuité médicamenteuse après une hospitalisation en soins de suite et de réadaptation gériatrique.

After one year of practice, a medication reconciliation process in geriatric aftercare was evaluated. The objective of the activity was to identify treatment changes (TC). 302 patients benefited from approach, 82.2% of changes was voluntary at hospitalization discharge and 100% of patients benefited from at least one change at hospitalization discharge. What are the consequences of so many changes and what are the measures to limit these consequences?

Acceptability of oral liquid pharmaceutical products in older adults: palatability and swallowability issues.

BACKGROUND: In institutional care, oral liquid pharmaceutical products are widely prescribed for older patients, especially for those with swallowing disorders. As medicines acceptability is a key factor for compliance in the older population, this study investigated the acceptability of oral liquid pharmaceutical products in this targeted population. METHODS: An observational, multicenter, prospective study was conducted in eight geriatric hospitals and eight nursing homes in France. Observers reported several behaviours/events describing the many aspects of acceptability for various pharmaceutical products' uses in patients aged 65 and older. Acceptability scores of oral liquid pharmaceutical products were obtained using an acceptability reference framework (CAST - ClinSearch Acceptability Score Test®): a 3D-map summarizing the different users' behaviors, with two clusters defining the positively and negatively accepted profiles materialized by the green and red zones, respectively. RESULTS: Among 1288 patients included in the core study and supporting the acceptability reference framework, 340 assessments were related to the administration of an oral liquid pharmaceutical product. The mean age of these patients was 87 (Range [66-104y]; SD = 6.7), 68% were women and 16% had swallowing disorders. Globally, the oral liquid pharmaceutical products were classified as "positively accepted," the barycenter of the 340 assessments, along with the entire confidence ellipses surrounding it, were positioned on the green zone of the map. Sub-populations presenting a different acceptability profile have also been identified. For patients with swallowing disorders, the oral liquid pharmaceutical products were classified as "negatively accepted," the barycenter of the 53 assessments along with 87% of its confidence ellipses were associated with this profile. A gender difference was observed for unflavored oral liquids. In women, they were classified "negatively accepted," the barycenter of the 68 assessments with 75% of its confidence ellipses were located in the red zone, while they were classified "positively accepted" in men. CONCLUSION: This study showed that oral liquid pharmaceutical products are a suboptimal alternative to solid oral dosage forms in patients with swallowing disorders. To ensure an optimal acceptability, prescribers should also consider the presence of a taste-masker in these oral liquids. As highlighted herein, palatability remains crucial in older populations, especially for women.

A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population.

PURPOSE: Medicine acceptability, which is of the utmost importance for vulnerable patients' adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population. METHODS: An observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model's reliability. RESULTS: A three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients' ability to swallow, we have highlighted the tool's efficacy in demonstrating the impact of user features on medicine acceptability. CONCLUSIONS: This multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.

Opinion of health professionals and drug users before the forthcoming opening of the first drug consumption room in Paris: a quantitative cross-sectional study.

BACKGROUND: On the brink of the opening of the first French drug consumption room in Paris, the general opinion of the local involved health care professionals and drug users was not known. The objective of this study was to determine their expectations and to search for influencing factors. METHOD: We carried out a quantitative cross-sectional study. A multiple choice questionnaire was proposed to the surrounding willing general practitioners (GPs) and pharmacists, to the emergency doctors of Lariboisière hospital, and to the professionals of the harm reduction facilities and their drug users (PWUD). For each question, there was a choice between seven answers, from "- 3" (very negative impact) to "+ 3" (very positive impact). The influence of the characteristics of each group on its mean answers was explored by Mann-Whitney, Kruskal-Wallis, and Spearman's tests. RESULTS: The median expectations among the groups of responding GPs (N = 62), other health care professionals (N = 82), and PWUD (N = 57) were mainly positive. They thought that the drug consumption room (DCR) would improve the health of PWUD, reduce their at-risk behaviors, would not increase drug use or drug dealing in the neighborhood, and would reduce nuisance in the public space. Only the group of GPs expressed that the DCR could decrease the quietness of the neighborhood, and only the group of PWUD had higher expectations that the DCR would decrease the number of arrests and the number of violent behavior. GPs' expectations were significantly better in terms of health improvement of PWUD and reducing their precariousness if they had a previous experience in addiction medicine (Mann-Whitney, p = 0.004 and p = 0.019), with a longer practice (Spearman's rho, p = 0.021 and p = 0.009), and if they were currently prescribing opioid substitution treatments (Mann-Whitney, p = 0.030 and p = 0.002). Among non-GPs, those who were working in addiction medicine centers had significantly better expectations than pharmacists, and the professionals of the local emergency department had intermediate expectations. CONCLUSIONS: Health care professionals and drug users had a positive opinion of the to-be-created Parisian drug consumption room. Experience in addiction medicine influenced positively health professionals' expectations.

[Temporary approval for intranasal naloxone: Setting up in a French addiction center]. / Pratique de l'ATU de cohorte de la naloxone intranasale (Nalscue®) : mise en place dans un CSAPA parisien.

Intranasal naloxone aims at preventing opioid overdose related deaths in active drug users. In France, it has been available since July 2016 through a temporary approval which requires a hospital-based pharmacy and a nominative registration of each patient. We present the characteristics of the first patients who could receive this prescription in our hospital-based addiction center and how they used naloxone during follow-up. Results favor a larger dispensing of naloxone. Patients' as well as peers' and families' education is needed.

Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.

AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

Anxiety and substance use disorders: co-occurrence and clinical issues.

The co-occurrence of substance use disorders (SUDs) and anxiety disorders has been now well established. This association is frequent and can be explained by three models: the shared vulnerability factors model, the self-medication model, and the substance-induced model. General population epidemiological studies provide strong evidence of the frequency of the association for the most used substances: tobacco, alcohol, cannabis, and to a lesser extent sedatives, opiates, and cocaine. For substances that are less commonly used in the general population, the frequency of the co-occurrence can more precisely be studied in clinical samples. We provide the most recent literature results on the association of SUDs and anxiety, and evidence for one explicative model or the other when available. For substances with sedative properties (alcohol, benzodiazepines, cannabis, opioids), both evidence for a self-medication and for a toxic effect exist. For substances with psychostimulant properties (tobacco, cocaine, and amphetamines), the literature favors the toxic hypothesis to explain the association with anxiety disorders. We give practical steps for the recognition of these dual diagnoses and present therapeutic issues, although the strategies are rarely evidence based.

Self-reported cue-induced physical symptoms of craving as an indicator of cocaine dependence.

BACKGROUND: The presence of cocaine dependence is under-recognized by cocaine users and requires a careful standardized interview to be ascertained by clinicians. OBJECTIVE: To test if past experiences of cue-induced physical symptoms of craving (nausea, vomiting, sweating, shaking, nervousness) before cocaine use could be a useful way to boost the diagnosis of cocaine dependence. METHODS: A cross-sectional study of 221 cocaine users from several outpatient addiction treatment services in France, addressing the most severe period of cocaine use. DSM-IV cocaine dependence was determined with the MINI International Neuropsychiatric Interview (MINI). Physical symptoms before using cocaine were retrospectively assessed with a single item rated on a 0-5 scale. RESULTS: The prevalence of DSM-IV cocaine dependence was 84.6%. The mean score on the physical symptoms item was 1.3 (SD 1.3). A cut-off score of ≥ 1 on this item alone resulted in a sensitivity of 62%, a specificity of 88.2%, a positive predictive value of 96.6% and a negative predictive value of 29.7% to detect DSM IV cocaine dependence in this sample. Adding this item to a model with the frequency of cocaine use significantly increased the predictive power: Nagelkerke's R(2) increased from .149 to .326 (p < .001). DISCUSSION AND CONCLUSION: Recalling past experiences of cue-induced physical signs of cocaine craving is associated with a clinical diagnosis of lifetime cocaine dependence and could be a simple way to improve its detection in clinical settings.

A cannabinoid receptor 1 polymorphism is protective against major depressive disorder in methadone-maintained outpatients.

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.

Are empty methadone bottles empty? An analytic study.

BACKGROUND: Methadone maintenance treatment is the most widely prescribed treatment for opiate dependence with proven benefits for patients. In naïve users or in case of recreational misuse, methadone can be a source of potentially lethal intoxications, resulting in fatal overdoses. A few cases of infantile intoxications have been described in the literature, some of which resulted in death. Nowadays, more than 50,000 bottles are used every day in France, most of which are thrown away in the bin. Relatives at home, especially children, can have access to these empty bottles. This study aims to determine whether the residual quantity of methadone in the bottles is associated with a risk of intoxication for someone who has a low tolerance to opiates, such as a child. METHODS: The methadone dosage left in a sample of 175 bottles recapped after use by the patients taking their maintenance treatment in an addiction treatment program centre was analysed during a 2-week period in March 2013. RESULTS: The mean residual quantity of methadone left in each bottle after use is 1.9 ± 1.8 mg and 3.3 ± 2.4 mg in the sample of 60 mg bottles. CONCLUSIONS: There is a potential danger of accidental overdose with empty bottles of methadone syrup, especially for children. To take into account this hazard, several harm reduction strategies can be proposed, such as favouring the taking of the treatment within the delivery centres rather than the 'take home' doses, asking methadone users to bring back their used bottles, and raising patients' awareness of the intoxication risks and the necessary everyday precautions. For stable patients with take home methadone, the use of capsules could be considered.

Brain alterations in Cocaine Use Disorder: Does the route of use matter and does it relate to the treatment outcome?

AIMS: Cocaine Use Disorder (CUD) is an important health issue, associated with structural brain abnormalities. However, the impact of the route of administration and their predictive value for relapse remain unknown. METHODS: We conducted an anatomical MRI study in 55 CUD patients (26 CUD-Crack and 29 CUD-Hydro) entering inpatient detoxification, and 38 matched healthy controls. In patients, a 3-months outpatient follow-up was carried out to specify the treatment outcome status (relapser when cocaine was consumed once or more during the past month). A Voxel-Based Morphometry approach was used. RESULTS: Compared with controls, CUD patients had widespread gray matter alterations, mostly in frontal and temporal cortices, but also in the cerebellum and several sub-cortical structures. We then compared CUD-Crack with CUD-Hydro patients and found that crack-cocaine use was associated with lower volume in the right inferior and middle temporal gyri, and the right fusiform gyrus. Cerebellar vermis was smaller during detoxification in subsequent relapsers compared to three-months abstainers. CONCLUSIONS: Patients with CUD display widespread cortical and subcortical brain shrinkage. Patients with preferential crack-cocaine use and subsequent relapsers showed specific gray matter volume deficits, suggesting that different patterns of cocaine use and different clinical outcome are associated with different brain macrostructure.

Valproate, divalproex, valpromide: Are the differences in indications justified?

In many countries, valproate is indicated for epilepsy only, whereas its derivative divalproex (DVP) and valpromide (VPM) are indicated for bipolar disorders only. DVP is composed of sodium valproate and valproic acid (VA) in a 1:1 molar ratio and VPM is a prodrug completely hydrolyzed in the gastric tract to VA. Whatever the drug, the absorbed and active substance is the valproate ion. In this article, we reviewed the potential reasons that might justify these different indications. We performed a literature review of comparative studies of efficacy, pharmacokinetic parameters, side effects and costs for VPA, DVP, and VPM. We found only studies comparing VA with DVP. None of the eight efficacy studies found differences in epilepsy or mood disorders. The ten studies of side effects reported a difference in terms of gastrointestinal effects, but inconsistently. The United States (US) summary of product characteristics and kinetic comparison studies reported bioequivalence between DVP and VA, but a longer Tmax for DVP, likely due to its gastro-resistant galenic form. VPM summary of product characteristics and pharmacokinetic studies revealed a lower bioavailability (80% vs. 100% for VA) and a delayed Tmax. There is an additional cost for using DVP or VPM as compared to VA (respectively +177% and +77% in France). The differences in indications between valproate derivatives do not seem justified. Interchangeability between VA and DVP in bipolar disorders seems possible, at identical dosage. VPM would require a closer dosing schedule and a 20% reduction in dosage when switching to valproate.