Prescribing Trends for Valproate Among Pregnant Women: A Cross-sectional Study in 2013 and 2016 Using the French Health Insurance Database.

BACKGROUND AND OBJECTIVE: To describe the prescribing trends for sodium valproate (VPA) and alternative drugs during and around pregnancy, comparing 2016 (after the recommendations on valproate for women were reinforced by the European Medicines Agency [EMA]) with 2013 (before the recommendations). METHODS: Using the French National Health Insurance Database, a cross-sectional study was carried out in 2013 and in 2016, including women who became pregnant and had at least 1 reimbursement claim for VPA in the 2 years prior to pregnancy or during pregnancy. Exposure to VPA and its alternatives was then measured for each quarter, in the 2 years before pregnancy (preconception), during pregnancy, and in the year after pregnancy (postpartum). RESULTS: Among pregnant women with epilepsy (n = 2,607 pregnancies), the proportion exposed to VPA during pregnancy decreased from 26.4% to 9.3% between 2013 and 2016, alongside an increase in lamotrigine and levetiracetam use. Among pregnant women with bipolar disorder (n = 4,278 pregnancies), the proportion of women exposed during pregnancy decreased from 3.7% in 2013 to 1.9% in 2016, without any switch to alternative drugs. In both populations, fewer than one third had consulted a specialist before pregnancy. DISCUSSION: As recommended by the EMA, a change in practice over the 2013-2016 period was observed, with fewer women exposed to VPA during pregnancy and before pregnancy. However, in 2016, a large number of women were exposed to VPA in the first trimester of pregnancy (n = 471), which could suggest that the timing of pregnancy should be better planned when possible.

Impact of recommendations on sodium valproate prescription among women with epilepsy: An interrupted time-series study.

BACKGROUND: The European Medicines Agency (EMA) has developed risk minimization measures (RMMs) to reduce the use of the teratogenic drug, sodium valproate (VPA). The objective was to assess the impact of these RMMs among females with epilepsy in France. METHODS: We used data from the French National Health Insurance Database (SNDS), including 114,936 females aged under 50, with a reimbursement claim for an antiepileptic drug from January 2011 to December 2017, and identified as people with epilepsy. We used a controlled interrupted time series stratifying on age: girls (0-14 years old) and women of childbearing age (15-49 years), and with 129,917 males as controls. RESULTS: VPA prevalent use among girls and women of childbearing age with epilepsy decreased significantly after the issue of the RMMs (trend changes of, respectively, -5 and -4 users per 1000 females at-risk per quarter in comparison to the control group). We did not detect any significant change in VPA incident use. CONCLUSIONS: VPA use decreased over the study period among females with epilepsy but there were still 317 women and 206 girls started on VPA therapy VPA in 2017 (8 per 1000 at-risk and 18 per 1000, respectively). This suggests that either the measures should be strengthened or that the lowest level of VPA use has been reached. In this context, the introduction of a new RMM (in 2018) needs to be evaluated.

Prevalence of mental disorders is higher in patients with multiple sclerosis than in the general population or in patients with rheumatoid arthritis in France.

BACKGROUND: Mental disorders (MDs) in multiple sclerosis (MS) patients decreases treatment adherence and quality of life, and increases the risk of disability progression and care consumption. OBJECTIVE: This study was to assess the prevalence of MDs in MS patients compared with healthy controls (HC) of the French general population and rheumatoid arthritis (RA) patients. METHODS: The 2015 prevalence of MDs for MS patients, RA patients and general population was estimated using a random population-based data sample from 'National Inter-Scheme Information System on Health Insurance' in the 2011-2015 period. Two control groups (1:5 ratio for the HC and 1:1 for the RA group) were matched to the MS group for year of birth, gender, area of residence and health insurance scheme. RESULTS: A total of 1145 MS patients were identified (sex ratio of 2.5 (F/M); median age 50 years). The prevalence of MDs was higher in the population of patients with MS (37.3%) than in the French general population (13.6%), and to a lesser extent in the RA group (21.1%) leading to the prevalence ratios of 2.8 (95% confidence intervals (CIs) 2.5-3.0) and 1.9 (95% CI 1.7-2.3), respectively. CONCLUSIONS: This study confirmed that MS patients are at a higher risk of MDs than the French general population or RA patients.

Risk of suicide attempt associated with isotretinoin: a nationwide cohort and nested case-time-control study.

BACKGROUND: Isotretinoin is the only effective treatment for severe acne. An isotretinoin-related suicide risk is still debated and under scrutiny by regulatory agencies. Our objectives were: to assess the risk of suicide attempt before, during and after isotretinoin treatment; to detect any potential triggering effect of isotretinoin initiation on suicide attempt. METHODS: We implemented a cohort and nested case-time-control study of subjects treated with oral isotretinoin (course or initiation) aged 10-50 years, using the Nationwide French Health Insurance data (2009-2016). The main outcome was hospitalized suicide attempt. Standardized incidence ratios for hospitalized suicide attempts were calculated before, during and after isotretinoin treatment. The number of isotretinoin initiations was compared in risk and control periods of 2 months using a case-time-control analysis. RESULTS: In all, 443 814 patients (median age 20.0 years; interquartile range 17.0-27.0 years) were exposed to isotretinoin, amounting to 244 154 person-years, with a marked seasonality for treatment initiation. Compared with the French general population, the occurrence of suicide attempts under isotretinoin treatment was markedly lower, with a standardized incidence ratio of 0.6 [95% confidence interval (CI) = 0.53-0.67]; the same applied, to a lesser extent, before and after isotretinoin treatment. In the case-time-control analysis, among cases of suicide attempt, 108 and 127 isotretinoin initiations were observed in the risk and control periods respectively (i.e. 0-2 months and 2-4 months before the date of suicide attempt). The comparison with the 1199 and 1253 initiations observed among matched controls in the same two periods yielded a case-time-control odds ratio of 0.89 (95% CI = 0.68-1.16). A sensitivity analysis using three-month periods and a complementary analysis adding completed suicides for case definition showed consistent results. CONCLUSION: Compared with the general population, a lower risk of suicide attempt was observed among patients exposed to isotretinoin and there was no evidence for a triggering effect of isotretinoin initiation on suicide attempt. A selection of patients at lower risk for suicidal behaviour and appropriate treatment management could explain these findings. Risk management plans should therefore be maintained.

Combining Postcards, Crisis Cards, and Telephone Contact Into a Decision-Making Algorithm to Reduce Suicide Reattempt: A Randomized Clinical Trial of a Personalized Brief Contact Intervention.

BACKGROUND: There is growing evidence in the literature that brief contact interventions (BCIs) might be reliable suicide prevention strategies. OBJECTIVE: To assess the effectiveness of a decision-making algorithm for suicide prevention (ALGOS) combining existing BCIs in reducing suicide reattempts in patients discharged after a suicide attempt. METHODS: A randomized, multicenter, controlled, parallel trial was conducted in 23 hospitals. The study was conducted from January 26, 2010, to February 28, 2013. People who had made a suicide attempt were randomly assigned to either the intervention group (ALGOS) or the control group. The primary outcome was the rate of participants who reattempted suicide (fatal or not) within the 6-month study period. RESULTS: 1,040 patients were recruited. After 6 months, 58 participants in the intervention group (12.8%) reattempted suicide compared with 77 (17.2%) in the control group. The difference between groups (4.4%; 95% CI, -0.7% to 9.0%) was not significant (complete-case analysis, P = .059). CONCLUSIONS: These results may help researchers better integrate BCIs into routine health care and provide new insights concerning personalized suicide prevention strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01123174.

Preoperative factors of apathy in subthalamic stimulated Parkinson disease: a PET study.

OBJECTIVE: The current literature provides discrepant results regarding preoperative sociodemographic and clinical factors, and no information about preoperative cerebral metabolic patterns associated with apathy after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: To resolve this issue, we set out to identify preoperative metabolic patterns and sociodemographic and clinical factors associated with increased apathy after STN-DBS. Forty-four patients with Parkinson disease were enrolled in this study. They all underwent STN-DBS. Metabolic activity was assessed with F-18 fluorodeoxyglucose PET 3 months before surgery. Apathy was assessed on the Apathy Evaluation Scale 3 months before and after STN-DBS. We controlled for preoperative age, levodopa therapy, and overall cognitive functions. RESULTS: Increased apathy after STN-DBS was significantly associated with reduced preoperative metabolism within the right ventral striatum. None of the sociodemographic and clinical variables tested were associated with apathy after STN-DBS. CONCLUSIONS: Preoperative PET, but not sociodemographic or clinical factors, is associated with apathy after STN-DBS.

Pallidal stimulation in Parkinson's disease does not induce apathy.

BACKGROUND: Whereas apathy is known as a common consequence of subthalamic nucleus deep brain stimulation in Parkinson's disease, few studies have investigated the psychiatric consequences of internal globus pallidus deep brain stimulation. METHOD: Twenty consecutive parkinsonian patients who underwent bilateral pallidal stimulation were assessed 3 months prior to surgery (M‒3) and at both 3 (M3) and 6 months (M6) after surgery, using psychiatric, neuropsychological, and motor scales. Apathy, mood state, and anxiety state were scored using the Apathy Evaluation Scale, the Montgomery-Åsberg Depression Rating Scale, and the anxiety scale from the Association for Methodology and Documentation in Psychiatry, respectively. RESULTS: The mean apathy score remained stable between the preoperative M‒3 assessment (37.2±6.2) and both the postoperative M3 (36.9±7.5) and M6 (37.2±5.0) assessments. The mean depression score did not differ between the M‒3 assessment and M3 and M6 assessments. There was no difference between the preoperative mean anxiety score and both the postoperative M3 and M6 scores. The mean score for the Mattis Dementia Rating Scale remained stable at each study visit. CONCLUSIONS: The main result of this study is the absence of deterioration in psychiatric and cognitive scores 3 months and 6 months after pallidal stimulation.

Apathy and impaired emotional facial recognition networks overlap in Parkinson's disease: a PET study with conjunction analyses.

Apathy is a disabling non-motor symptom that is frequently observed in Parkinson's disease (PD). Its description and physiopathology suggest that it is partially mediated by emotional impairment, but this research issue has never been addressed at a clinical and metabolic level. We therefore conducted a metabolic study using (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in 36 PD patients without depression and dementia. Apathy was assessed on the Apathy Evaluation Scale (AES), and emotional facial recognition (EFR) performances (ie, percentage of correct responses) were calculated for each patient. Confounding factors such as age, antiparkinsonian and antidepressant medication, global cognitive functions and depressive symptoms were controlled for. We found a significant negative correlation between AES scores and performances on the EFR task. The apathy network was characterised by increased metabolism within the left posterior cingulate (PC) cortex (Brodmann area (BA) 31). The impaired EFR network was characterised by decreased metabolism within the bilateral PC gyrus (BA 31), right superior frontal gyrus (BAs 10, 9 and 6) and left superior frontal gyrus (BA 10 and 11). By applying conjunction analyses to both networks, we identified the right premotor cortex (BA 6), right orbitofrontal cortex (BA 10), left middle frontal gyrus (BA 8) and left posterior cingulate gyrus (BA 31) as the structures supporting the association between apathy and impaired EFR. These results confirm that apathy in PD is partially mediated by impaired EFR, opening up new prospects for alleviating apathy in PD, such as emotional rehabilitation.

Apathy in patients with Parkinson disease without dementia or depression: a PET study.

OBJECTIVE: We sought to identify apathy metabolic bases in Parkinson disease (PD). METHODS: A total of 45 patients with PD who were not clinically depressed (Montgomery-Åsberg Depression Rating Scale [MADRS] <21) and had no dementia (Mattis Dementia Rating Scale [MDRS] >130) were assessed with the Apathy Evaluation Scale (AES) and underwent a resting-state F-18 fluorodeoxyglucose PET (FDG-PET) scan. A motor assessment comprising the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) was conducted and total levodopa equivalent daily dose (LEDD) was calculated. Imaging data were analyzed with statistical parametric mapping. Age, LEDD, and MDRS scores were introduced as covariates. RESULTS: Positive correlations were observed between the AES score and cerebral metabolism in the right inferior frontal gyrus (Brodmann area [BA] 47), right middle frontal gyrus (BA 10), right cuneus (BA 18), and right anterior insula (BA 13). Negative correlations were observed between the AES score and cerebellar metabolism in the semilunar lobules bilaterally, within the posterior lobe. Using an AES score equal to or above 42 to define clinical apathy, prevalence in our patient group was 17.8%. The AES score was negatively correlated with the MDRS score and positively correlated with the "retardation" subscore of the MADRS. It was not correlated with either UPDRS III or LEDD. CONCLUSIONS: Results indicate that the frontal, temporal, and cerebellar areas known to be involved in reward, emotion, and cognition are also implicated in apathy in patients with PD without dementia or depression. Their roles in the etiopathology of apathy are discussed.

Major depressive disorder skews the recognition of emotional prosody.

OBJECTIVE: Major depressive disorder (MDD) is associated with abnormalities in the recognition of emotional stimuli. MDD patients ascribe more negative emotion but also less positive emotion to facial expressions, suggesting blunted responsiveness to positive emotional stimuli. To ascertain whether these emotional biases are modality-specific, we examined the effects of MDD on the recognition of emotions from voices using a paradigm designed to capture subtle effects of biases. METHODS: Twenty-one MDD patients and 21 healthy controls (HC) underwent clinical and neuropsychological assessments, followed by a paradigm featuring pseudowords spoken by actors in five types of emotional prosody, rated on continuous scales. RESULTS: Overall, MDD patients performed more poorly than HC, displaying significantly impaired recognition of fear, happiness and sadness. Compared with HC, they rated fear significantly more highly when listening to anger stimuli. They also displayed a bias toward surprise, rating it far higher when they heard sad or fearful utterances. Furthermore, for happiness stimuli, MDD patients gave higher ratings for negative emotions (fear and sadness). A multiple regression model on recognition of emotional prosody in MDD patients showed that the best fit was achieved using the executive functioning (categorical fluency, number of errors in the MCST, and TMT B-A) and the total score of the Montgomery-Asberg Depression Rating Scale. CONCLUSIONS: Impaired recognition of emotions would appear not to be specific to the visual modality but to be present also when emotions are expressed vocally, this impairment being related to depression severity and dysexecutive syndrome. MDD seems to skew the recognition of emotional prosody toward negative emotional stimuli and the blunting of positive emotion appears not to be restricted to the visual modality.