Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome.

INTRODUCTION: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. METHODS: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. RESULTS: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. CONCLUSION: SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.

Indirect effect of impulsivity on suicide risk through self-esteem and depressive symptoms in a population with treatment-resistant depression: A FACE-DR study.

INTRODUCTION: Suicide is a major health issue. Its prevalence is particularly high in subjects presenting major depression disorder (MDD), making this a key suicide-related risk factor. Suicide attempts in severe forms of MDD were assumed to be linked to impulsivity and loss of control. Nevertheless, we failed to find data specifically investigating the link between impulsivity and suicide risk in treatment-resistant depression (TRD). This study seeks to review this relationship. METHOD: Patients were recruited for a prospective cohort. Suicide risk and impulsivity were assessed using the International Neuropsychiatric Interview and Barratt Impulsiveness Scale, Version 10, respectively, while the severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale, anxiety with the State-Trait Anxiety Inventory and childhood maltreatment using the Childhood Trauma Questionnaire. RESULTS: 220 TRD patients were enrolled in the study. The impulsivity score was correlated with self-esteem, marital status, professional status and anxiety. There was no direct link to suicide risk. However, impulsivity was associated with self-esteem (coefficient: -0.24; p value 0.043) and depressive symptom severity (coefficient: 0.; p value 0.045). The suicide risk was significantly correlated with depressive symptom severity (coefficient = 0.38, p < 0.001) and self-esteem (coefficient = -0.34, p = 0.01). Considering these correlations, we postulated that the effect of impulsivity on suicide risk could be mediated by self-esteem in terms of depressive symptom severity and we finally found a relevant mediation model within impulsivity having an indirect effect on suicide risk by impacting self-esteem and depressive symptoms with anxiety also playing a significant role as a covariable. CONCLUSION: We found that impulsivity could play an indirect role with the involvement of self-esteem and depressive symptoms and the contributing role of anxiety.

Changes in suicide-related tweets before and during the COVID-19 pandemic in France: The importance of social media monitoring in public health prediction.

INTRODUCTION: The COVID-19 pandemic impacted mental health, as demonstrated by numerous studies. In recent years, especially during the pandemic, the use of social networks, including Twitter, increased. This suggests that this media could help with mental health monitoring, as attested by previous studies. METHOD: We conducted a multidisciplinary study on French tweets that were posted between January 1, 2019, and December 31, 2021. We selected the tweets via the Twitter API (Application Programming Interface) using five keywords relating to suicide: want to die, suicidal ideation, commit suicide, suicidal, and suicide attempt. A word frequency analysis was performed, and the data were compared with the number of emergency visits for suicidal ideation before and during the COVID-19 pandemic as recorded by the French national suicide observatory. RESULTS: We observed that 189,005 tweets were related to suicide in 2019, 261,993 in 2020 (+38.62% of that observed in 2019), and 301,177 in 2021 (+59.35% of that observed in 2019). We also observed an increase in the number of tweets containing control words in 2020 (+30.07% of that observed in 2019), but in 2021, the number almost fell back to the level of that in 2019 (+5.96% of that observed in 2019). Furthermore, the difference between both ratios (of suicide-related tweets and of tweets containing control words) was most significant during the third lockdown. The change in the number of suicide-related tweets followed a curve that overlapped with the change in the number of emergency visits following suicidal ideations, as reported by the French national suicide observatory. In conclusion, Twitter can be an adequate and reliable tool for screening for suicidal ideation in the general population.

Amygdala hyperactivation relates to eating behaviour: a potential indicator of food addiction in Prader-Willi syndrome.

Prader-Willi syndrome is a rare neurodevelopmental genetic disorder characterized by various endocrine, cognitive and behavioural problems. The symptoms include an obsession for food and reduced satiety, which leads to hyperphagia and morbid obesity. Neuropsychological studies have reported that Prader-Willi patients display altered social interactions with a specific weakness in interpreting social information and responding to them, a symptom close to that observed in autism spectrum disorders. In the present case-control study, we hypothesized that brain regions associated with compulsive eating behaviour would be abnormally activated by food-related odours in Prader-Willi syndrome, as these can stimulate the appetite and induce hunger-related behaviour. We conducted a brain imaging study using the olfactory modality because odours have a high-hedonic valence and can cause stronger emotional reactions than other modalities. Further, the olfactory system is also intimately associated with the endocrine regulation of energy balance and is the most appropriate modality for studies of Prader-Willi syndrome. A total of 16 Prader-Willi participants were recruited for this study, which is a significant achievement given the low incidence rate of this rare disease. The second group of 11 control age-matched subjects also participated in the brain imaging study. In the MRI scanner, using an MRI-compatible olfactometer during 56 block sessions, we randomly presented two odours (tulip and caramel), which have different hedonic valence and a different capacity to arouse hunger-related behaviour. Our results demonstrate that Prader-Willi participants have abnormal activity in the brain reward system that regulates eating behaviour. Indeed, we found that these patients had right amygdala activity up to five times higher in response to a food odour (caramel) compared with the tulip odour. In contrast, age-matched control participants had similar activity levels in response to both odours. The amygdala activity levels were found to be associated with the severity of the hyperphagia in Prader-Willi patients. Our results provide evidence for functional alteration of the right amygdala in Prader-Willi syndrome, which is part of the brain network involved in food addiction modulated by the ghrelin and oxytocin systems, which may drive the hyperphagia. Our study provides important new insights into the functioning of emotion-related brain circuits and pathology, and it is one of the few to explore the dysfunction of the neural circuits involved in emotion and addiction in Prader-Willi syndrome. It suggests new directions for the exploration and remediation of addictive behaviours.

The association between reattempted suicide and incoming calls to the brief contact intervention service, VigilanS: a study of the clinical profile of callers.

BACKGROUND: Suicide is a major health problem globally. As attempted suicide is a major risk factor for suicide, specific prevention strategies have been designed for use thereafter. An example is the brief contact intervention (BCI). In this regard, France employs a composite BCI, VigilanS, which utilizes three types of contact: phone calls, postcards and a 'who to contact in a crisis' card. Previous studies have found that this system is effective at preventing suicide. Nevertheless, VigilanS was not effective in the same way for all the patients included. This observation raises the question of specific adaptation during follow-up for populations that were less receptive to the service. In consideration of this issue, we identified one study which found that incoming calls to the service were linked with a higher risk of suicide reattempts. However, this study did not document the profiles of the patients who made these calls. Better understanding of why this population is more at risk is important in terms of identifying factors that could be targeted to improve follow-up. This research therefore aims to bring together such data. METHODS: We performed a retrospective analysis of 579 patients referred to VigilanS by Toulouse University Hospital (France). We examined the sociodemographics, clinical characteristics, and follow-ups in place and compared the patients who made incoming calls to the service versus those who did not. Subsequently, we conducted a regression analysis using the significantly associated element of patients calling VigilanS. Then, in order to better understand this association, we analyzed the factors, including such calls, that were linked to the risk of suicide reattempts. RESULTS: We found that 22% of the patients in our sample called the VigilanS service. These individuals: were older, at 41.4 years versus 37.9 years for the non-callers; were more likely to have a borderline personality disorder (BPD) diagnosis (28.9% versus 19.3%); and had a history of suicide attempts (71.9% versus 54.6%). Our analysis confirmed that incoming calls to VigilanS (OR = 2.9) were associated with reattempted suicide, as were BPD (OR = 1.8) and a history of suicide attempts (OR = 1.7). CONCLUSION: There was a high risk that the patients calling VigilanS would make another suicide attempt. However, this association was present regardless of the clinical profile. We postulate that this link between incoming calls and reattempted suicide may arise because this form of contact is, in fact, a way in which patients signal that a further attempt will be made.

Personal Identity and Narrativity in Borderline Personality Disorder: A Phenomenological Reconfiguration.

Borderline personality disorder (BPD) is a complex condition marked by heterogeneity. People with BPD have a profusion of symptoms spread across various levels of lived experience, such as identity, affectivity, and interpersonal relationships. Researchers and clinicians have often resorted to the structuring concept of Self to organize the fragmentation of their experience at the identity level. Notably, using the concept of the narrative self, Fuchs proposed to interpret BPD as a fragmentation of narrative identity. This interpretation of BPD, widely shared, has been challenged by Gold and Kyratsous, who have proposed a complementary understanding of the self through the idea of agency, and to which Schmidt and Fuchs in turn have countered. This article proposes to contribute to this discussion from a phenomenological perspective. First, we will briefly review the discussions around narrative interpretation of BPD. From the problems left unresolved by the discussion, we will then justify the necessity to proceed with a stratification of the self from a phenomenology method. Third, from the thought of the Hungarian phenomenologist László Tengelyi, we will continue with an archaeology of the self, in three layers - self-institution, self-formation, and minimal self - integrating Schmidt and Fuchs' concepts of self, in addition to those of Gold and Kyratsous, but also, to a lesser extent, those of Dan Zahavi. Finally, we will proceed with a phenomenological reconfiguration of the experiences and manifestations associated with the identity axis of BPD.

Factors associated with a borderline personality disorder diagnosis in the emergency department.

Introduction: Research on borderline personality disorder (BPD) has shown that less intensive care is especially effective when patients have been told about their condition. However, problems with diagnosing the disorder are also described in the literature. This study thus aims to explore the factors associated with the challenges of identifying and then communicating a BPD diagnosis to patients. Methods: We analyzed a database of 202 patients of Toulouse University Hospital (France) who had a CIM-10 F60.3 diagnosis. This data was used to identify the sociodemographic and clinical benchmarks associated with patients who had received an established BPD diagnosis prior to their attendance at the hospital's emergency department (ED) in the study period. Results: Sixty-three percentage of the patients admitted to our psychiatric ED had been given an earlier diagnosis of BPD. Those who had not been diagnosed were more likely to: not have undergone any psychiatric follow-up; not have been hospitalized in the psychiatry department; and not have previously attended at the ED. Patients with BPD and a comorbidity of MDD were also less likely to have received a BPD diagnosis before their ED admission. Conclusion: This study found that patients without an established BPD diagnosis who present at the ED are more likely to not be known to the psychiatric care system. This suggests that EDs have a specific role to play in making a diagnosis and the subsequent orientation of care.

An Innovative, Nurse-Led Service for Appropriate Management of Psychiatric Emergencies: Initial Findings.

The emergency department (ED) physicians working for the French Service d'Aide Medicale d'Urgence (SAMU) refer about 84% of individuals who contact SAMU for psychiatric problems to the psychiatric ED (PED), compared with only 20% of those calling with other medical emergencies. Physicians' lack of psychiatric knowledge may contribute to the high PED referral rate. The authors created a new psychiatric nurse-led service to improve the identification of psychiatric emergencies and assessed PED referrals and inpatient hospitalization rates before and after the new service commenced. After service implementation, the proportion of PED-referred patients fell from 84% to 38%, and inpatient hospitalization rates for those referred to the PED increased from 27% to 36%.

Changes in Cannabis Consumption During the Global COVID-19 Lockdown: The International COVISTRESS Study.

Introduction: COVID-19 lockdown measures have been sources of both potential stress and possible psychological and addiction complications. A lack of activity and isolation during lockdown are among the factors thought to be behind the growth in the use of psychoactive substances and worsening addictive behaviors. Previous studies on the pandemic have attested to an increase in alcohol consumption during lockdowns. Likewise, data suggest there has also been a rise in the use of cannabis, although it is unclear how this is affected by external factors. Our study used quantitative data collected from an international population to evaluate changes in cannabis consumption during the lockdown period between March and October, 2020. We also compared users and non-users of the drug in relation to: (1) socio-demographic differences, (2) emotional experiences, and (3) the information available and the degree of approval of lockdown measures. Methods: An online self-report questionnaire concerning the lockdown was widely disseminated around the globe. Data was collected on sociodemographics and how the rules imposed had influenced the use of cannabis and concerns about health, the economic impact of the measures and the approach taken by government(s). Results: One hundred eighty two respondents consumed cannabis before the lockdown vs. 199 thereafter. The mean cannabis consumption fell from 13 joints per week pre-lockdown to 9.75 after it (p < 0.001). Forty-nine respondents stopped using cannabis at all and 66 admitted to starting to do so. The cannabis users were: less satisfied with government measures; less worried about their health; more concerned about the impact of COVID-19 on the economy and their career; and more frightened of becoming infected in public areas. The risk factors for cannabis use were: age (OR = 0.96); concern for physical health (OR = 0.98); tobacco (OR = 1.1) and alcohol consumption during lockdown (OR = 1.1); the pre-lockdown anger level (OR = 1.01); and feelings of boredom during the restrictions (OR = 1.1). Conclusion: In a specific sub-population, the COVID-19 lockdown brought about either an end to the consumption of cannabis or new use of the drug. The main risk factors for cannabis use were: a lower age, co-addictions and high levels of emotions.

Teaching emergency situations during a psychiatry residency programme using a blended learning approach: a pilot study.

BACKGROUND: Emergency psychiatry is an essential component in the training of psychiatry residents who are required to make patient-centred orientation decisions. This training calls for specific knowledge as well as skills and attitudes requiring experience. Kolb introduced a theory on experiential learning which suggested that effective learners should have four types of abilities: concrete experience, reflective observation, abstract conceptualisation and active experimentation. We aimed to evaluate a resident training programme that we designed for use in an emergency psychiatry setting based on the experimental learning theory. METHODS: We designed a four-step training programme for all first-year psychiatry residents: (i) theoretical teaching of psychiatric emergency knowledge, (ii) concrete experience of ability teaching involving an initial simulation session based on three scenarios corresponding to clinical situations frequently encountered in emergency psychiatry (suicidal crisis, hypomania and depressive episodes), (iii) reflective observation and abstract conceptualisation teaching based on videos and clinical interview commentary by a senior psychiatrist for the same three scenarios, (iv) active experimentation teaching during a second simulation session based on the same three frequently encountered clinical situations but with different scenarios. Training-related knowledge acquisition was assessed after the second simulation session based on a multiple-choice quiz (MCQ), short-answer questions and a script concordance test (SCT). The satisfaction questionnaire was assessed after the resident had completed his/her initial session in order to evaluate the relevance of teaching in clinical practice. The descriptive analyses were described using the mean (+/- standard deviation). The comparative analyses were conducted with the Wilcoxon or Student's t tests depending on data distribution. RESULTS: The residents' mean MCQ and short-answer question scores and SCT were 7.25/10 (SD = 1.2) 8.33/10 (SD = 1.4), 77.5/100 (SD = 15.8), respectively. The satisfaction questionnaire revealed that 67 % of residents found the teaching consistent. CONCLUSION: We designed a blended learning programme that associated, classical theoretical learning to acquire the basic concepts, a learning with simulation training to experiment the clinical situations and a video support to improve learning of interview skills and memory recall. The residents indicate that this training was adequate to prepare them to be on duty. However, despite this encouraging point, this program needs further studies to attest of its efficiency.

Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory.

BACKGROUND: Prader-Willi syndrome is a rare genetic neurodevelopmental disorder caused by a paternal deficiency of maternally imprinted gene expression located in the chromosome 15q11-q13 region. Previous studies have demonstrated that several classes of neurodevelopmental disorders can be attributed to either over- or under-expression of specific genes that may lead to impairments in neuronal generation, differentiation, maturation and growth. Epigenetic changes that modify gene expression have been highlighted in these disorders. One recent study focused on epigenetic analysis and compared patients with PWS with patients with other imprinting disorders. No study, however, has yet focused on epigenetics in patients with PWS specifically by comparing the mutations associated with this syndrome. OBJECTIVE: This study investigated the epigenetic modifications in patients with PWS and patients with PWS-related disorders caused by inactivation of two genes of the PWS chromosomal region, SNORD116 and MAGEL2. Our approach also aimed to compare the epigenetic modifications in PWS and PWS-related disorders. METHODS: We compared genome-wide methylation analysis (GWAS) in seven blood samples from patients with PWS phenotype (five with deletions of the PWS locus, one with a microdeletion of SNORD116 and one with a frameshift mutation of MAGEL2 presenting with Schaaf-Yang syndrome), as well as two control patients. Controls were infants that had been studied for suspicion of genetic diseases that was not confirmed by the genetic analysis and the clinical follow-up. RESULTS: The analysis identified 29,234 differentially methylated cytosines, corresponding to 5,308 differentially methylated regions (DMRs), which matched with 2,280 genes. The DMRs in patients with PWS were associated with neurodevelopmental pathways, endocrine dysfunction and social and addictive processes consistent with the key features of the PWS phenotype. In addition, the separate analysis for the SNORD116 and MAGEL2 deletions revealed that the DMRs associated with the SNORD116 microdeletion were found in genes implicated in metabolic pathways and nervous system development, whereas MAGEL2 mutations mostly concerned genes involved in macromolecule biosynthesis. CONCLUSION: The PWS is associated with epigenetic modifications with differences in SNORD116 and MAGEL2 mutations, which seem to be relevant to the different associated phenotypes.

SNORD116 and growth hormone therapy impact IGFBP7 in Prader-Willi syndrome.

PURPOSE: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS. METHODS: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness. RESULTS: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1. CONCLUSION: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.

Developing and Testing a Local Expert-Based Reading Process for Use to Examine Discrepancies Between Guidelines and Current Clinical Practices.

The use of relevant guidelines is critical in psychiatric clinical practice to ensure the homogeneity of the global care provided. Consequently, it is important to identify whether they are utilized successfully and, if not, why. This would enable pragmatic solutions to be agreed to improve the organization of care and the removal of any barriers to the guidelines' implementation. The first step in this process, before any exploration of the limitations of the guidelines themselves, involves a determination of whether they are actually applied in clinical practice. We therefore evaluated discrepancies between the guidelines relating to patients with borderline personality disorder and current practices in the psychiatric Emergency Department at Toulouse University Hospital. This was achieved using a reading process involving a panel of eight local experts who analyzed relevant medical files extracted from a database. They were guided by, and instructed to answer, six standardized questions in relation to each file to determine the method's feasibility. A total of 333 files were analyzed to determine whether, in the local experts' judgment, the care provided reflected current guidance. This reading process revealed substantial agreement (0.85%; Fleiss Kappa -0.69), which is a promising outcome and suggests that such methods could be used in future protocols. Moreover, the process is practical and reliable and requires very few materials.

What can we learn from PWS and SNORD116 genes about the pathophysiology of addictive disorders?

Addictive disorders have been much investigated and many studies have underlined the role of environmental factors such as social interaction in the vulnerability to and maintenance of addictive behaviors. Research on addiction pathophysiology now suggests that certain behavioral disorders are addictive, one example being food addiction. Yet, despite the growing body of knowledge on addiction, it is still unknown why only some of the individuals exposed to a drug become addicted to it. This observation has prompted the consideration of genetic heritage, neurodevelopmental trajectories, and gene-environment interactions in addiction vulnerability. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which children become addicted to food and show early social impairment. PWS is caused by the deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene was identified as the minimal gene responsible for the PWS phenotype. Several studies have also indicated the role of the Snord116 gene in animal and cellular models to explain PWS pathophysiology and phenotype (including social impairment and food addiction). We thus present here the evidence suggesting the potential involvement of the SNORD116 gene in addictive disorders.

Evidence of practice gaps in emergency psychiatric care for borderline personality disorder: how can this be explained?

BACKGROUND: Recent research has highlighted that patients with borderline personality disorder (BPD) could experience symptomatic remissions. This led to the production of guidelines concerning the most appropriate care. In addition, as BPD patients frequently present at an emergency department (ED), specific recommendations concerning how they should be cared for there have also been developed. The recommendations include the referral of patients to inpatient, outpatient or specific crisis care. However, an issue that has not been addressed is the capacity of ED services to apply the care recommendations. The objective of our study, therefore, was to identify the factors limiting their use in the ED of Toulouse University Hospital. METHODS: A panel of psychiatrists specializing in BPD care examined the medical files of 298 patients with a BPD diagnosis to determine which referrals were consistent or not, according to the care recommendations. A logistic regression was then performed to identify which sociodemographic, clinical, organizational or professional-training factors were associated with inconsistent referrals. RESULTS: 32% of patients experienced an inconsistent referral. Consultations performed during an on-call or day-off schedule were linked with inconsistent referrals, while an active follow-up was associated with the provision of consistent care. CONCLUSION: Changing how evaluations of BPD patients in the ED are organized during on-call and day-off schedules could improve the application of the care recommendations regarding the most appropriate referrals.

The RDoC approach for translational psychiatry: Could a genetic disorder with psychiatric symptoms help fill the matrix? the example of Prader-Willi syndrome.

The Research Domain Criteria project (RDoc) proposes a new classification system based on information from several fields in order to encourage translational perspectives. Nevertheless, integrating genetic markers into this classification has remained difficult because of the lack of powerful associations between targeted genes and RDoC domains. We hypothesized that genetic diseases with psychiatric manifestations would be good models for RDoC gene investigations and would thereby extend the translational approach to involve targeted gene pathways. To explore this possibility, we reviewed the current knowledge on Prader-Willi syndrome, a genetic disorder caused by the absence of expression of some of the genes of the chromosome 15q11-13 region inherited from the father. Indeed, we found that the associations between genes of the PW locus and the modification identified in the relevant behavioral, physiological, and brain imaging studies followed the structure of the RDoC matrix and its six domains (positive valence, negative valence, social processing, cognitive systems, arousal/regulatory systems, and sensorimotor systems).