Risk of suicide attempt and suicide associated with benzodiazepine: A nationwide case crossover study.

BACKGROUND: Previous studies that found an association between benzodiazepines and suicidal behaviours were confounded by indication bias. AIMS: To limit this bias, a case crossover study (CCO) was conducted to estimate the risk of suicide attempt and suicide associated with benzodiazepines. METHOD: Patients ≥16 years, with hospitalised suicide attempt or suicide between 2013 and 2016, and at least one benzodiazepine dispensing within the 120 days before their act were selected in the nationwide French reimbursement healthcare system databases (SNDS). For each patient, frequency of benzodiazepine dispensing was compared between a risk period (days -30 to -1 before the event) and two matched reference periods (days -120 to -91, and -90 to -61). RESULTS: A total of 111,550 individuals who attempted suicide and 12,312 suicide victims were included, of who, respectively, 77,474 and 7958 had recent psychiatric history. Benzodiazepine dispensing appeared higher in the 30-day risk period than in reference ones. The comparison yielded adjusted odds ratios of 1.74 for hospitalised suicide attempt (95% confidence interval 1.69-1.78) and 1.45 for suicide (1.34-1.57) in individuals with recent psychiatric history, and of 2.77 (2.69-2.86) and 1.80 (1.65-1.97) for individuals without. CONCLUSION: This nationwide study supports an association between recent benzodiazepine use and both suicide attempt and suicide. These results strengthen the need for screening for suicidal risk carefully before initiation and during treatment when prescribing benzodiazepines. REGISTRATION NO: EUPAS48070 (http://www.ENCEPP.eu).

The risk of dementia in patients using psychotropic drugs: Antidepressants, mood stabilizers or antipsychotics.

OBJECTIVE: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case-control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics. METHODS: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five-year lag time and diagnosis of dementia was assessed by conditional logistic regression models. RESULTS: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First- and second-generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06-3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10-2.67; p = 0.02 and OR 1.84; 1.03-3.32; p = 0.04, respectively). CONCLUSION: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them.

A safety signal of somnambulism with the use of antipsychotics and lithium: A pharmacovigilance disproportionality analysis.

AIMS: Antipsychotics and lithium are widely used in psychiatry, particularly in schizophrenia and bipolar disorders. Recently, some cases of somnambulism or sleep-related eating disorder (SRED) have been reported in patients treated with these drugs. This study investigated the risk of reporting somnambulism or SRED associated with the use of antipsychotics and lithium. METHODS: The World Health Organization pharmacovigilance database (VigiBase), comprising >18 million adverse events, was queried. All somnambulism or SRED reports related to antipsychotics or lithium were identified. The association between antipsychotics or lithium and somnambulism or SRED was computed using the proportional reporting ratio (PRR) and information component. RESULTS: Among the 5784 cases reporting somnambulism or SRED, 508 suspected at least 1 antipsychotic or lithium. Most patients were aged 18-64 years (62.0%), and 37.0% were men. In most cases (77.6%), antipsychotic or lithium were the only drug class involved, and 53.3% of cases suspected quetiapine. Somnambulism was reported in 88.6% of cases and SRED in 18.1%. A significant association was found for second-generation antipsychotics (PRR 3.44, 95% confidence interval 3.13) and lithium (PRR 2.03, [1.22; 3.37]), but not for first-generation antipsychotics (PRR 0.99, [0.68; 1.44]). CONCLUSIONS: We found a significant signal of somnambulism or SRED related to second-generation antipsychotics and lithium. While case reports mentioned mostly quetiapine and olanzapine, almost all second-generation antipsychotics were associated with somnambulism or SRED.

Trajectories of antidepressant drugs during pregnancy: A cohort study from a community-based sample.

AIMS: The aim of this study was to monitor the trajectories of antidepressant use during pregnancy and the postpartum period among women chronically treated with antidepressants before their pregnancy, and to assess characteristics associated with each trajectory. METHODS: This cohort study included all pregnant women whose data were included in the General Sample of Beneficiaries (EGB) database affiliated with the French Health Insurance System, from 2009 to 2014. Women were followed up until 6 months after childbirth. Chronic treatment was defined as exposure over the 6-month period preceding pregnancy. A group-based trajectory model (GBMT) was estimated to identify distinctive longitudinal profiles of antidepressant use. RESULTS: Among 760 women chronically treated with antidepressants before their pregnancy, 55.8% stopped their treatment permanently in the first trimester, 20.4% discontinued it for a minimum of 3 months and resumed it postpartum, and 23.8% maintained it throughout pregnancy and postpartum. No sociodemographic or medical characteristics were associated with any trajectory group. Women who maintained treatment presented more frequent obstetric complications and postpartum psychiatric disorders. Among women who interrupted treatment, prescription of benzodiazepines and anxiolytics decreased initially but rose postpartum to a higher level than before pregnancy. CONCLUSIONS: Pregnant women treated with antidepressant require a re-evaluation of psychiatric treatment. It is necessary to pay attention to obstetric complications for severely depressed women. Additionally, as relapse was associated with increased benzodiazepine use, it is important to carefully monitor all women who stop antidepressant treatment during pregnancy.

Long-term risk of hip or forearm fractures in older occasional users of benzodiazepines.

AIMS: This article sought to study the association between patterns of benzodiazepine (BZD) use and the risk of hip and forearm fractures in people aged 50 and 75 years or more. METHODS: In a representative cohort of the French National Health Insurance Fund of individuals aged 50 years or older (n = 106 437), we followed up BZD dispensing (reflecting their patterns of use) and the most frequent fall-related fractures (hip and forearm) for 8 years. We used joint latent class models to simultaneously identify BZD dispensing trajectories and the risk of fractures in the entire cohort and in those 75 years or older). We used a survival model to estimate the adjusted hazard ratios (aHRs) between these trajectories and the risk of fractures. RESULTS: In the entire cohort, we identified 5 BZD trajectories: non-users (76.7% of the cohort); occasional users (15.2%); decreasing users (2.6%); late increasing users (3.0%); and early increasing users (2.4%). Compared with non-users, fracture risk was not increased in either occasional users (aHR = 0.99, 95% confidence interval [CI] 0.99-1.00) or in decreasing users (aHR = 0.90, 95% CI 0.74-1.08). It was significantly higher in early increasing users (aHR = 1.86, 95% CI 1.62-2.14) and in late increasing users (aHR = 1.39, 95% CI 1.15-1.60). We observed similar trajectories and risk levels in the people older than 75 years. CONCLUSION: Occasional BZD use, which is compatible with current recommendations, was not associated with an excess risk of the most frequent fall-related fractures in people older than 50 or 75 years.

Misuse of benzodiazepines: Prevalence and impact in an inpatient population with psychiatric disorders.

AIMS: Use and misuse of benzodiazepine might be very prevalent in patients with acute psychiatric symptoms, whereas they might be associated with specific adverse events in this population. The study investigated their prevalence in these patients. Secondary objectives were to identify risk factors for misuse of benzodiazepines, and its impact. METHODS: A cohort study was based on the hospital's electronic patient records and conducted in patients aged 18 years and over and admitted to a psychiatric hospital. They were followed up for 84 days or until the end of hospitalisation. Four variables of misuse were built: excessive duration of treatment, type of product, excessive dosage and concomitant benzodiazepines. Backward stepwise multivariate logistic regression analysis was used to assess risk factors for each misuse criterion, on the 1 hand, and impact of benzodiazepine misuse, on the other. RESULTS: In total, 511 psychiatric inpatients were included with 89.0% of them exposed to benzodiazepine. Discharge prescription included no benzodiazepine or a dosage lower than the maximum dosage prescribed during hospitalisation for 78.2% of patients exposed to benzodiazepine during their stay. Of benzodiazepine treatments, 31.4% were associated with at least 1 misuse criterion. Excessive dosage was associated with age ≥65 years (OR 11.57; 95% confidence interval 4.92-27.17), substance/alcohol use disorders (3.35; 95% confidence interval 1.70-6.62) and parenthood (0.49; 0.25-0.97). Some criteria of benzodiazepine misuse were associated with a higher frequency of adverse events occurring after treatment initiation. CONCLUSIONS: Misuse of benzodiazepines is very common in inpatients with psychiatric disorders. These findings should alert clinicians to comply with clinical recommendations.

Use of benzodiazepines and z-drugs not compliant with guidelines and associated factors: a population-based study.

Benzodiazepines and z-drugs are primarily indicated for the treatment of sleep disorders and anxiety symptoms. Their frequent long-term use contrasts with the international guidelines that limit treatment duration to a maximum of 4 weeks. The objective of this study was to assess the frequency of their use that was not in accordance with guidelines in the French general population between 2007 and 2012 and associated characteristics. A cohort of 67,550 benzodiazepine new users was set up in an exhaustive database for health-care reimbursements and representative of the French population. Benzodiazepine use not in accordance with guidelines was defined as the concomitant dispensation of several benzodiazepines, the dispensation of treatment over a period longer than recommended, or a new dispensing within the 2 months following the end of a previous treatment of maximum recommended duration, considering that French recommendations distinguish between hypnotic (4 weeks) and anxiolytic benzodiazepines (12 weeks). Benzodiazepine use not in accordance with guidelines was high, in about 30% of new hypnotic users and 20% of new anxiolytic users. Its frequency was stable over the study period. Associated characteristics were similar for new hypnotic or anxiolytic users, i.e.. older age, treatment initiation by a psychiatrist, presence of a chronic disease, hospitalization, or another psychotropic treatment. These findings provide a solid basis for establishing a public health policy to reduce benzodiazepine use not compliant with guidelines. They should be further explored in patients most at risk in the present study, e.g., patients treated by a psychiatrist.

Trajectories of Antipsychotic Drug Use Over 10 Years in a French Community-Based Sample of Persons Aged 50 and Older.

OBJECTIVE: To identify the temporal prescribing patterns of antipsychotics among persons aged 50 and older and to explore the demographic and clinical characteristics associated with each trajectory of antipsychotic drug use. METHODS: This was a historical fixed cohort study on a community-based sample of persons affiliated with the French Insurance Healthcare system. Data from community drug reimbursement claims were collected by the French Insurance Healthcare system over the period 2006-2015. The study included 160,853 persons aged 50 and older. Trajectories of antipsychotic drug use were identified by examining the distribution of antipsychotic use within consecutive 3-month periods over the entire follow-up period. Latent class analyses were used to identify distinct trajectories. Multivariate polynomial logistic regression models were used to explore the characteristics independently associated with trajectories. RESULTS: Five trajectories of antipsychotic use were identified: null or very low use (93.8%), occasional use (2%), decreasing use (1.6%), chronic use (1.5%), and increasing use (1.1%). Occasional users were older and had a lower use of other psychotropic drugs and a high use of health resources. Chronic users had the highest frequency of chronic psychiatric diseases and were less likely to present with dementia or Parkinson disease. Persons with increasing use of antipsychotics were more frequently males and had a high frequency of dementia; half of them died over the follow-up period compared with 20% in the total sample. CONCLUSION: Further studies should explore whether the benefit-risk ratio of antipsychotic drugs in older adults differs according to trajectories of use.

Antipsychotics use: 2006-2013 trends in prevalence and incidence and characterization of users.

PURPOSE: The present study was conducted to describe antipsychotic (AP) prevalent and incident use, characteristics of AP users, and their trends in the French population. METHODS: A cross-sectional study was repeated yearly from January 1, 2007 to December 31, 2013 (for prevalence analysis) or to December 31, 2012 (for incidence analysis) using the French Health Insurance reimbursement database (Echantillon Généraliste de Bénéficiaires, EGB). For each year studied, prevalent and incident AP users were described in terms of age and gender overall, and according to the type of AP (FGAPs or SGAPs) used at index date. In addition, concurrent medications and comorbidities that a priori contraindicate the use of drugs having atropinic properties were researched. RESULTS: Prevalence and incidence remained relatively stable along the 2007-2013 period. Trends slightly decreased, from 2.07% (n = 10,252) to 2.05% (n = 11,015) for prevalence, and from 0.73% (n = 3461) to 0.66% (n = 3363) for incidence, especially in elderly, in contrast of children and adolescents (+ 39% for prevalence, from 184 to 271). The number of coprescribed drugs was found high (median = 5) and remained constant over time. In 2013, about 7% of prevalent AP users presented with a comorbidity increasing the risk of atropinic ADRs, and 36% used at least one concurrent atropinic drug. In incident AP users, these numbers were of 8 and 29%, respectively. CONCLUSIONS: The present study highlighted a marked shift from FGAPs toward SGAPs, as well as an increase in AP use in children and adolescents in France.

Perceived parental support in childhood and adolescence and suicidal ideation in young adults: a cross-sectional analysis of the i-Share study.

BACKGROUND: Suicidal ideation and suicidal risk assessment are major concerns for health professionals. The perception of a low level of parental support is a risk factor for suicidal tendencies among adolescents, but little is known about its long-term impact on the vulnerability to suicidal behavior in young adults. We investigated whether the perceived level of parental support during childhood and adolescence was associated with current suicidal ideation in young adults. METHODS: We retrieved data collected in the i-Share study from February 1st, 2013 through January 30, 2017. This cross-sectional study included 10,015 French students, aged 18-24 years that completed an on-line self-reported questionnaire about suicidal ideation in the last 12 months and their perceived parental support in childhood and adolescence. We performed multinomial logistic regressions and sensitivity analyses to assess associations between the degree of perceived parental support and the frequency suicidal thoughts, after adjusting for the main known risk factors of suicidal ideation. We employed multiple imputations to account for missing data. RESULTS: The study sample included 7539 female (75.7%) and 2436 male (24.3%) students (mean [SD] age 20.0 [1.8] years). About one in five students reported occasional suicidal thoughts (n = 1775, 17.7%) and 368 students (3.7%) reported frequent suicidal thoughts. The adjusted multinomial logistic regression revealed a significant negative association between perceived parental support and suicidal thoughts. A lack of perceived parental support in childhood and adolescence was associated with > 4-fold elevated risk of occasional (adjusted OR, 4.55; 95% CI: 2.97-6.99) and nearly 9-fold elevated risk of frequent (adjusted OR, 8.58; 95% CI: 4.62-15.96) suicidal thoughts, compared to individuals that perceived extremely strong parental support. This association was strongest among students with no personal history of depression or suicide attempts. CONCLUSIONS: Students that perceived low levels of past parental support had a higher risk of suicidal ideation. Past perceived parental support appeared to be a potent marker of suicidal risk in young adults. This marker should be routinely collected in studies on suicidal risk in young adults, and it could be considered an additional screening tool.

Trends in patterns of antidepressant use in older general population between 2006 and 2012 following publication of practice guidelines.

OBJECTIVE: The French regulatory agency published in 2006 practice guidelines related to the management of depressive and anxiety disorders. The main objective of the study was to assess their impact regarding use and monitoring of antidepressant drug treatment in older patients. The secondary objective was to identify factors associated with compliance with practice guidelines. METHODS: A historical fixed cohort study with dynamic follow-up time was conducted in 16,144 subjects aged 65 years and over, initiating antidepressant treatment and registered in the National Health Insurance Database between 2006 and 2012. Compliance with guidelines was assessed from year to year using segmented regression analysis. Multiple logistic regressions were used to identify factors associated with compliance with guidelines. RESULTS: Duration of antidepressant treatment was compliant with guidelines in 13.0% of patients aged 65-74 years and 18.5% of patients aged 75 years and over. Biological monitoring was performed in 12.6% of patients aged 65-74 years and 18.5% of patients aged 75 years and over. No significant change of rate of compliance with guidelines was observed over the study period. Compliance of prescriptions with guidelines was associated with patient's age, specialty of the prescriber, presence of chronic disease, year of treatment initiation, and presence of a university hospital in the area of residence. CONCLUSION: While treatment duration and biological monitoring were often inadequate in older patients, the publication of guidelines by the French health regulatory authorities did not lead to any significant and sustained improvement in their patterns of antidepressant use. Copyright © 2016 John Wiley & Sons, Ltd.

Trends in incident use of benzodiazepines and Z-drugs in France from 2006 to 2012: a population-based study.

PURPOSE: To study trends in incident use of benzodiazepines in France between 2006 and 2012. METHODS: A cross-sectional study repeated yearly was conducted using data from the French national healthcare insurance system. New benzodiazepine users were defined as users without any benzodiazepine dispensing in the year prior to the first dispensing of benzodiazepine in each year. Relative changes in incidence of use were calculated with the year 2006 as reference; confidence intervals for changes were estimated using the bootstrap method. RESULTS: Over the study period, the incident use of benzodiazepines decreased from 6.2% to 5.9%; this corresponded to a 5.1% decrease (95%CI: -6.8% to -4.2%) for 2012 compared to 2006. The decrease mainly concerned hypnotics (-15.5%; -21.2% to -15.3%) and appeared more pronounced in people aged 18-44 years. Incident use of anxiolytics remained stable overall during the period (4.0% of the population). Within anxiolytics, incident use of long half-life benzodiazepines (bromazepam, prazepam) decreased in favor of short half-life benzodiazepines (alprazolam, oxazepam). This change concerned patients aged 65-79 and patients aged 80 years and over. Nevertheless, in 2012, nearly one third of incident users aged 65 years and over started a treatment with a long half-life benzodiazepine, mostly bromazepam. CONCLUSIONS: A limited decrease in incident benzodiazepine use was observed in France between 2006 and 2012 that concerned only hypnotics. Although congruent with recommendations, this improvement appears insufficient with regard to the level of exposure to these drugs in France. New actions especially targeting anxiolytic benzodiazepine use should be undertaken to consolidate these results. Copyright © 2016 John Wiley & Sons, Ltd.

Comorbidities and concurrent medications increasing the risk of adverse drug reactions: prevalence in French benzodiazepine users.

PURPOSE: To estimate benzodiazepine prevalence of use and to quantify, in benzodiazepine users, the prevalence of comorbidities and concurrent medications increasing the risk of adverse drug reactions (ADRs). METHODS: Cross-sectional study performed using data from the French national healthcare insurance system. The prevalence of use was estimated by considering as users, patients who had at least one benzodiazepine reimbursement during the year 2013. Patients at increased risk for benzodiazepine ADRs were those who had (i) drug-drug interactions at risk for central nervous system and respiratory depression and (ii) comorbidities at risk for adverse respiratory effects, or for falls or fractures. RESULTS: Overall, the prevalence of benzodiazepine use in 2013 was estimated to be 13.8 %; it was higher among women and increased with age. This prevalence was 10.6 % for anxiolytic benzodiazepines, and 6.1 % for hypnotic benzodiazepines. Approximately half of the benzodiazepine users (48.1 %) were at increased risk for benzodiazepine ADRs; this proportion increased with age. Drug-drug interactions represented the most prevalent condition (39.3 % of benzodiazepine users). The drugs most frequently involved were opioids: analgesics (15.9 %) and antitussives (6.8 %). Overall, 11.3 % of benzodiazepine users had comorbidities at increased risk for adverse respiratory effects (13.9 % in those aged 65-79), and 7.0 % comorbidities at increased risk for falls or fractures (13.4 % in those aged ≥80). CONCLUSIONS: This study found that benzodiazepine use remained high in France, and that roughly half of the users presented with comorbidities and concurrent medications increasing the risk of ADRs. These findings are of concern, given that benzodiazepines are frequently used, and especially among the elderly.

Antipsychotic prescribing in youths: a French community-based study from 2006 to 2013.

The objectives were to explore in a community-based sample of persons aged 0-25 years: (1) trends in antipsychotic prescribing, (2) characteristics of the zone of residence associated with antipsychotic prescribing rates, and (3) the pattern of antipsychotic prescribing. The study was performed using reimbursement data from the French Insurance Healthcare system. Prescribing trends were investigated over the period 2006-2013. An ecological design was used to assess the impact of the socio-economical and health resource characteristics of the zone of residence (n = 96 administrative subdivisions of French territory) on antipsychotic prescribing rates. The pattern of antipsychotic prescribing was explored in a cohort of youths newly treated with antipsychotics. Over the period 2006-2013, antipsychotic dispensing rates were stable in persons aged 0-25 years (4.8 per 1,000 in 2006 and 4.9 per 1,000 in 2013). First-generation antipsychotic dispensing rates decreased from 3.1 to 2.6 per 1,000 (OR = 0.96, 95% CI 0.94-0.98), while second-generation antipsychotic dispensing rates increased from 2.7 to 3.4 per 1,000 (OR = 1.03, 95% CI 1.01-1.05). Antipsychotic prescribing rates were impacted by health resource characteristics of the zone of residence in children aged 10 years and under and by socio-economical characteristics in those aged 16-20 years. In all the age groups, antipsychotics were principally started by hospital practitioners (47%) and general practitioners (34%). The rates of psychostimulants concomitantly prescribed with antipsychotics were lower than 5%. In conclusion, rates of youths exposed to second-generation antipsychotics are still rising. The impact of environmental characteristics on antipsychotics prescribing and appropriateness of these prescriptions in youths should be further investigated.

Antidepressant treatment patterns in younger and older adults from the general population in a real-life setting.

OBJECTIVE: The treatment of depression in real-life settings appears to be influenced by health care systems. Antidepressant drugs have been found to be underused in the older population relative to younger adults when refunding of such drugs is poor. No study assessed the pattern of antidepressant use according to age in a universal health care system. The objective is to assess whether the pattern of antidepressant drug use differs between younger and older adults with respect to treatment duration, adherence to treatment, coprescription of other psychotropic drugs, switch, or combination of antidepressant drugs. METHODS: A historical cohort study included 7747 older (65+ years) and 27,306 younger (younger than 65 years) adults representative of the beneficiaries of the French national health care insurance system who initiated a new antidepressant treatment. Follow-up after treatment initiation was at least 6 months. RESULTS: Older patients had a significantly longer duration of treatment than younger adults (hazard ratio = 0.90; 95%CI[0.88-0.93]). Adherence was more often good in older than in younger adults when the treatment was initiated by a general practitioner (23.4% vs. 16.7%; Odds ratio (OR) = 1.35[1.25-1.46]), a hospital practitioner (OR = 1.68[1.40-2.03]) or another specialist (OR = 1.60[1.19-2.17]). The coprescription of psychotropic drugs decreased with older age in men (OR = 0.77[0.70-0.85]) and increased with older age in women (OR = 1.14[1.07-1.22]). Switches and combinations of antidepressants were not associated with age. CONCLUSION: In a universal health care system, with similar reimbursement of drugs regardless of age, treatment duration, and adherence were better in the older patients than in the younger ones.

Trajectories of Benzodiazepine Use among Older Adults from a Concordance-with-Guidelines Perspective: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVE: Benzodiazepines (including zolpidem and zopiclone) are often associated with higher-than-recommended intake and durations of use, especially in older adults. The objective of this study was to characterize trajectories of benzodiazepine use according to recommended patterns in older adults, and to assess predictors of the risk of developing each of these trajectories. METHODS: Using the French Health Insurance database, we constituted a cohort of adults aged ≥ 65 years who initiated benzodiazepines in 2007 and were followed for up to 8 years. Concordance with benzodiazepine use guidelines was assessed on a quarterly basis according to a "concordance-with-guideline score" with values 1-5. Group-based trajectory modeling was then applied as implemented in the Proc Traj procedure in SAS to define guideline-concordant trajectories based on seven baseline patient-centered characteristics: sex, complementary health insurance coverage, treated alcohol and tobacco use disorder, polypharmacy, hospital stay, and registered chronic diseases. RESULTS: Among 5080 new users (64.1% women, median age 74 years), six trajectories of benzodiazepine use were identified. Three, representing 70% of users, were concordant with guidelines, whereas three implied non-concordant benzodiazepine use for part or all of the benzodiazepine use follow-up. Polymedicated patients were more prone to develop chronic non-guideline-concordant initially guideline-concordant use, whereas those with a history of long-term disease and hospitalization were more likely to develop chronic non-guideline-concordant use. The number of prescribers during the first quarter, number of daily defined doses, use of loperamide, and use of psychostimulants were associated with a higher risk of developing an initial and persistent non-guideline-concordant use. Treatment initiation by a psychiatrist, initial use of World Health Organization (WHO) step-2 opioids and non-benzodiazepine anxiolytics or sedatives were associated with a higher risk of late non-guideline-concordant use. CONCLUSIONS: Concordance with guidelines varied over time during benzodiazepine use in older adults. A third of these adults will hypothetically follow one of the identified non-guideline-concordant trajectories, consisting of initial and/or late non-guideline concordance. This was associated with modifiable and nonmodifiable factors that clinicians should be aware of for tailoring the monitoring of patients.

Psychoactive substance intoxication leading to general hospital admission in young and middle-aged people during and after the first lockdown.

INTRODUCTION: Incidence of hospitalisations related to psychoactive substance (H-PS) intoxication has been strongly decreased during the coronavirus disease 2019 (COVID-19) pandemic especially in young adult and French region of Nouvelle-Aquitaine was mostly concerned. This study aimed to describe (i) the incidence of H-PS in Bordeaux teaching hospital during and after the first 2020 lockdown in adults aged 18-29 years or 30+ then (ii) their characteristics specifically associated with the pandemic period by comparing 2020 with 2017-2019 baseline period. MATERIAL AND METHODS: This historical cohort study was conducted in adults admitted to the Bordeaux teaching hospital with main or associated diagnosis codes of intoxication with benzodiazepine, methadone, buprenorphine, codeine, morphine, heroin, cocaine, ecstasy and alcohol. Data were collected locally through the discharge database. Incidence and characteristics of H-PS were described according to patients' age, in 2020 before (01/01-16/03), during (17/03-10/05), and after the first lockdown (11/05-31/07). RESULTS: Among the 5,824 stays included over the study period, PS most involved were alcohol and benzodiazepines. Compared to baseline, the decrease in H-PS's incidence was more important in young adults (-40%; nbaseline=450) in comparison to those aged 30+ (-18%; nbaseline=1,101) during the pandemic period, especially during the lockdown compared to 2017 (-59%; n2017=145 vs. -35%; n2017=166) with far decrease in alcohol and ecstasy intoxications. Seriousness of hospitalisation indications was increased regardless of age during the pandemic. Particularly in young adults, the proportion of suicides attempts increased during lockdown compared to the baseline period (almost 50% vs. 29%) and the period after lockdown was associated with 1.7 more-time road accident increased and 3 more-time fights compared with pre-lockdown period. DISCUSSION/CONCLUSION: The period following lockdown should be considered at risk H-PS due to accident. Recreational use of alcohol and ecstasy could be a target for minimize serious consequences associated to PS use in young adult.

Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences. WHAT THIS PAPER ADDS: • The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. • Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. • Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings. AIMS: To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration). METHODS: A historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug. RESULTS: A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20). CONCLUSIONS: The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results.

General practitioners' compliance with benzodiazepine discontinuation guidelines in patients treated with long-term lorazepam: A case-vignette cross-sectional survey.

AIM: To study determinants associated with GPs' compliance with benzodiazepine discontinuation guidelines through a case-vignette of a patient with multimorbidity treated with long-term lorazepam for insomnia. METHODS: This cross-sectional survey was performed in a sample of French GPs. The questionnaire included items on their characteristics and questions related to the management of a case-vignette with long-term lorazepam use consulting for a prescription renewal. GPs who proposed a dedicated consultation to discuss discontinuation or progressive discontinuation were considered as "following guidelines", while they were considered as "out-of-guidelines" if they proposed immediate discontinuation or decided not to discontinue lorazepam. A backward selection process was used to select factors to be included in the final logistic regression model. The probabilities of out-of-guidelines practice and their 95% confidence interval (95% CI) were then plotted using a heatmap graph. RESULTS: Of 1,177 GPs, the majority (92.2%) were aware of the necessity to discontinue lorazepam and reported practice consistent with good practice guidelines. Women GPs aged under 50 years had the lowest estimated probability of out-of-guidelines practice. Conversely, men aged over 58 years with high consideration of patient preferences and low concern about the benefit-risk ratio of lorazepam had the highest probability of out-of-guidelines practice (27.3% [18.7%; 34.7%]). CONCLUSION: GPs largely reported practice compliant with benzodiazepine discontinuation guidelines, although some GPs, mainly older men who overemphasise patient preferences, were more likely to adopt out-of-guidelines practice.

Oral Morphine as an Alternative Substitution Treatment for Opioid Use Disorder, a Rare but Non-risk-free Use.

Background: National health monitoring agencies have reported the alternative use of morphine sulfate painkiller for maintenance treatment of opioid use disorder (OUD), associated with a potential increase in overdose risk. Objectives: This study sought to assess the prevalence of regular and occasional legally prescribed morphine use in patients treated for OUD and compare their characteristics to those of patients receiving conventional opioid maintenance treatment (OMT), buprenorphine or methadone. Then, we assessed the factors associated with opioid overdose risk. Methods: Data were extracted from the French national healthcare system database, covering the entire population in 2015. Diagnosis associated with hospital discharge and long-term disease codes were extracted to select the population and identify outcomes and covariates. OUD non-chronic pain patients were divided into regular (≤35 days between dispensing and ≥3 months of continuous treatment duration) morphine users, and occasional users. Their sociodemographic and health characteristics were compared to OMT controls. A multivariate logistic regression model was performed to determine factors associated with opioid overdose. Results: In patients treated for OUD, 2,237 (2.2%) morphine users (1,288 regular and 949 occasional), 64,578 (63.7%) buprenorphine and 34,638 (34.1%) methadone controls were included. The prevalence of regular morphine use among patients treated for OUD regularly receiving an opioid was 1.3%. Compared to users who receive morphine regularly, occasional users had an increased risk of overdose [OR = 2.2 (1.5-3.3)], while the risk was reduced in the buprenorphine group [OR = 0.5 (0.4-0.7)] and not significantly different for methadone [OR = 1.0 (0.7-1.4)]. Other overdose risk factors were low-income, comorbidity, i.e., psychiatric conditions, alcohol use disorder or complications related to intravenous drug use, and coprescription with benzodiazepines or pregabalin. These factors were more frequent in morphine groups. Conclusions: Patients that were prescribed oral morphine represented a small minority of the treated for OUD. The poorer health condition affected by numerous comorbidities and higher risk of opioid overdose in patients treated with oral morphine compared with OMT controls points toward the need to better supervise the practices of these patients, to strengthen multidisciplinary care and risk reduction measures.