Opinions of French psychiatrists on the regulatory status of cannabis: Results from the "PsyCan - Encéphale" national online survey.

OBJECTIVE: To explore the opinions of French psychiatrists toward the legalization of medical or recreational use of cannabis in France. METHODS: Psycan was an anonymous Internet survey conducted between September 28, 2021 and March 29, 2022, among subscribers of the Encéphale Online community, i.e., approximately 4000 French psychiatrists. Participants were asked to complete a structured questionnaire, collecting their socio-demographic features, clinical experience, opinions toward cannabis legalization, and perceived impact of cannabis derivatives for psychiatric disorders. Logistic regression models were used to identify factors associated with being for or against cannabis legalization. RESULTS: In total, 413 psychiatrists answered the survey, of whom 253 (61.3%) declared being in favour of recreational cannabis, and 349 (84.4%) of medical cannabis. Being in favour of legalization of recreational cannabis was negatively associated with being female (odd ratio [OR]=0.61; 95% confidence interval [CI]=0.41-0.93), and with the frequency of meeting patients with cannabis use disorder (OR=0.60; 95%CI=0.43-0.83). Most respondents were concerned about the development of psychotic disorders. The most frequent pro-legalization arguments were improved prevention, better control of product content, and better protection of youth, respectively. Arguments against legalization were increased societal damages, increased impact on health, including mental health. CONCLUSIONS: A majority of French psychiatrists were in favour of the marketing of medical cannabis, and, to a lesser extent, the legalization of recreational cannabis. For recreational cannabis, the proportion of pro-legalization psychiatrists was slightly more elevated than that found in the French general population.

[Joint study of seclusion, mechanical restraint and chemical restraint: Pilot study in three French psychiatric hospitals]. / Étudier conjointement l'isolement, la contention mécanique et la contention chimique : étude pilote dans trois établissements psychiatriques français.

Psychiatric wards that only exceptionally use isolation and mechanical restraint may be suspected of using "chemical restraint". However, in the case of these services, the hypothesis of a reduction in the general level of restraint can also be formulated. Prior to a comprehensive study to test these hypotheses, the current research aims to assess indicators which define high levels of the use of these measures and a relevant sample. The study was conducted in three facilities with 254 hospitalized patients over a week. Five per cent experienced isolation, 2% mechanical restraint, and 13% received high doses of medication (including "as needed" treatments). These figures are below literature data and national averages. Variances exist among centers, with one showing higher percentages for all three measures. While confirming the feasibility of studying these measures together, the study suggests the need for longer observations and continuous evaluation of prescription practices to better reflect yearly isolation and restraint trends. Future studies should involve more centers and include case studies for a nuanced understanding of administration practices in relation to prescriptions.

Initiation of quarterly palmitate paliperidone in French clinical practice: Results from the observational, cross-sectional OPTIMUS study.

PURPOSE: Long-term antipsychotic treatment is key to a positive clinical outcome in schizophrenia. Recent guidelines recommend the prescription of long-acting antipsychotic formulations (LAIs) as early as the first episode in patients with schizophrenia. The OPTIMUS study evaluated real-world use of a new three-monthly paliperidone palmitate formulation (PP3M) in France. METHODS: For this observational cross-sectional study, all French psychiatrists were invited to enrol patients who had initiated PP3M in the previous 4 months. Snapshot data were collected at a routine consultation, without any modification of clinical practice. RESULTS: This population of 350 patients with schizophrenia started on PP3M predominantly included single men, living independently with a diagnosis of schizophrenia for a median of 9.3 years. Demographic characteristics were broadly comparable to those reported in other studies on LAIs. Investigators cited treatment simplification (96.9%) and patient comfort (93.3%) as the most common reasons for switching to PP3M; enhancing adherence was mentioned less often (61.1%) with most patients previously considered as adherent, and a majority of them expressing a positive attitude to their treatment. One-third of patients accepted the psychiatrist's proposal to initiate PP3M treatment without any discussion, and relatives were involved in the therapeutic decision-making process in only 23.7% of cases. After initiation, few changes were seen in professional follow-up frequency or concomitant pharmacological and non-pharmacological treatment modalities except for a decrease in antipsychotic polytherapy. CONCLUSIONS: PP3M is mostly prescribed in adherent patients with fairly stable schizophrenia, and the longer dosing interval does not substantially affect patient care.

Assessment of risk factors of treatment discontinuation among patients on paliperidone palmitate and risperidone microspheres in France, Germany and Belgium.

BACKGROUND: Long-acting antipsychotics (e.g. 1-monthly (PP1M) / 3-monthly (PP3M) injection forms of paliperidone palmitate) have been developed to improve treatment continuation in schizophrenia patients. We aim to assess risk factors of treatment discontinuation of patients on paliperidone palmitate and risperidone microsphere. Additionally, treatment discontinuation between patients with PP1M and PP3M was compared. METHODS: The IQVIA Longitudinal Prescription databases were used. Risk factors of treatment discontinuation were identified by a multilevel survival regression using Cox proportional hazards model. Kaplan Meier analyses were performed by identified significant risk factors. RESULTS: Twenty-five thousand three hundred sixty-one patients (France: 9,720; Germany: 14,461; Belgium: 1,180) were included. Over a one-year follow-up period, a significant lower treatment discontinuation was observed for patients newly initiated on paliperidone palmitate (53.8%) than those on risperidone microspheres (85.4%). Additionally, a significantly lower treatment discontinuation was found for 'stable' PP3M patients (19.2%) than 'stable' PP1M patients (37.1%). Patients were more likely to discontinue when drugs were prescribed by GP only (HR = 1.68, p < 0.001 vs. psychiatrist only) or if they were female (HR = 1.07, p < 0.001), whereas discontinuation decreased with age (31-50 years: HR = 0.95, p = 0.006 and > 50 years: HR = 0.91, p < 0.001 vs. 18-30 years). CONCLUSIONS: This study demonstrates that patients stay significantly longer on treatment when initiated on paliperidone palmitate as compared to risperidone microspheres. It also indicated a higher treatment continuation of PP3M over PP1M. Treatment continuation is likely to be improved by empowering GPs with mental health knowledge and managing patients by a collaborative primary care-mental health model. Further research is needed to understand why females and younger patients have more treatment discontinuation.

Place of the partial dopamine receptor agonist aripiprazole in the management of schizophrenia in adults: a Delphi consensus study.

BACKGROUND: Aripiprazole is a second-generation antipsychotic, efficacious in patients with schizophrenia during acute episodes. Due to its pharmacological profile, aripiprazole may be of interest in patients with specific clinical profiles who have not been studied extensively in randomised clinical trials. OBJECTIVES: To capture experience with aripiprazole in everyday psychiatric practice using the Delphi method in order to inform decision-making on the use of aripiprazole for the treatment of patients with schizophrenia in clinical situations where robust evidence from clinical trials is lacking. METHODS: The scope of the survey was defined as the management of schizophrenia in adults. A systematic literature review was performed to identify the different clinical situations in which aripiprazole has been studied, and to describe the level of clinical evidence. Clinical profiles to include in the Delphi survey were selected if there was a clear interest in terms of medical need but uncertainty over the efficacy of aripiprazole. For each clinical profile retained, five to seven specific statements were generated and included in a questionnaire. The final 41-item questionnaire was proposed to a panel of 406 French psychiatrists with experience in the treatment of schizophrenia. Panellists rated their level of agreement using a Likert scale. A second round of voting on eleven items was organised to clarify points for which a consensus was not obtained in the first round. RESULTS: Five clinical profiles were identified in the literature review (persistent negative symptoms, pregnancy, cognitive dysfunction, addictive comorbidity and clozapine resistance). Sixty-two psychiatrists participated in the first round of the Delphi survey and 33 in the second round. A consensus was obtained for 11 out of 41 items in the first round and for 9/11 items in the second round. According to the panellists' clinical experience, aripiprazole can be used as maintenance treatment for pregnant women, is relevant to preserve cognitive function and can be considered an option in patients with a comorbid addictive disorder or with persistent negative symptoms. CONCLUSION: These findings may help physicians in choosing relevant ways to use aripiprazole and highlight areas where more research is needed to widen the evidence base.

Multimodal brain imaging connectivity analyses of emotional and motivational deficits in depression among women.

BACKGROUND: Major depressive disorder (MDD) is characterized by impaired cortical-subcortical functional connectivity. Apathy adds to functional impairment, but its cerebral basis in MDD remains unknown. Our objective was to describe impairments in functional connectivity during emotional processing in MDD (with varying levels of congruency and attention), and to determine their correlation with apathy. METHODS: We used the Variable Attention Affective Task during functional MRI, followed by diffusion-weighted MRI, to assess 55 right-handed women (30 with MDD and 25 healthy controls) between September 2012 and February 2015. We estimated functional connectivity using generalized psychophysiologic interaction and anatomic connectivity with tract-based spatial statistics. We measured apathy using the Apathy Evaluation Scale. RESULTS: We found decreased functional connectivity between the left amygdala and the left anterior cingulate cortex (ACC) during negative stimuli in participants with MDD (t54 = 4.2; p = 0.035, family-wise error [FWE]-corrected). During high-attention stimuli, participants with MDD showed reduced functional connectivity between the right dorsolateral prefrontal cortex (dlPFC) and the right ACC (t54 = 4.06, pFWE = 0.02), but greater functional connectivity between the right dlPFC and the right amygdala (t54 = 3.35, p = 0.048). Apathy was associated with increased functional connectivity between the right dlPFC and the right ACC during high-attention stimuli (t28 = 5.2, p = 0.01) and increased fractional anisotropy in the right posterior cerebellum, the anterior and posterior cingulum and the bilateral internal capsule (all pFWE < 0.05). LIMITATIONS: Limitations included a moderate sample size, concomitant antidepressant therapy and no directed connectivity. CONCLUSION: We found that MDD was associated with impairments in cortical-subcortical functional connectivity during negative stimuli that might alter the recruitment of networks engaged in attention. Apathy-related features suggested networks similar to those observed in degenerative disorders, but possible different mechanisms.

Do Home-Based Psychiatric Services for Patients in Medico-Social Institutions Reduce Hospitalizations? Pre-Post Evaluation of a French Psychiatric Mobile Team.

World Health Organization recommends the implementation of alternatives to full-time hospitalizations. Psychiatric home-care has known a worldwide development in the last 20 years. The psychiatric mobile team for social and medico-social institutions in Saint-Etienne, France, (Equipe mobile d'intervention en établissements Sociaux et Médico-sociaux, ESMS) aims to support professionals from medico-social housing institutions (MSHI) in order to maintain people in housing. The objective of the study was to evaluate the efficiency of home-based interventions to reduce hospitalizations and improve collaboration between psychiatric hospital facilities and MSHI. We used a pre-post study design. A same cohort of patients living in a MSHI one year before intervention and one year after implementation of the ESMS was studied. Hospitalizations were compared between the two periods. A survey was conducted for qualitative evaluation among professionals in MHSI. Sixty-three patients were included. Most patients suffered from psychotic disorders (71%). We found a significant decrease in the mean number of admissions per year from 2,06 to 1,48 (Wilcoxon signed rank test; df64; p = 0,01). Mobile-team interventions included answering phone calls, home visits, coordination meetings, or clinical interviews with patients in inpatient and outpatient services, with an average of 9,3 interventions per patient (SD = 11,4). ESMS was evaluated as "essential" for 73% of 11 professionals from MSHI who answered the questionnaire in May 2017. Assertive Community Treatment and Crisis Resolution Teams are the most studied home-care models in psychiatry. Our results tend to show the efficiency of mobile-team interventions in MSHI, to enhance partnerships.

Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing.

The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Effect of trait anxiety on prefrontal control mechanisms during emotional conflict.

Converging evidence points to a link between anxiety proneness and altered emotional functioning, including threat-related biases in selective attention and higher susceptibility to emotionally ambiguous stimuli. However, during these complex emotional situations, it remains unclear how trait anxiety affects the engagement of the prefrontal emotional control system and particularly the anterior cingulate cortex (ACC), a core region at the intersection of the limbic and prefrontal systems. Using an emotional conflict task and functional magnetic resonance imaging (fMRI), we investigated in healthy subjects the relations between trait anxiety and both regional activity and functional connectivity (psychophysiological interaction) of the ACC. Higher levels of anxiety were associated with stronger task-related activation in ACC but with reduced functional connectivity between ACC and lateral prefrontal cortex (LPFC). These results support the hypothesis that when one is faced with emotionally incompatible information, anxiety leads to inefficient high-order control, characterized by insufficient ACC-LPFC functional coupling and increases, possibly compensatory, in activation of ACC. Our findings provide a deeper understanding of the pathophysiology of the neural circuitry underlying anxiety and may offer potential treatment markers for anxiety disorders.

[Affective disorders and eating disorders]. / Troubles affectifs et troubles des conduites alimentaires.

Epidemiologic studies show a frequent co-occurence of affective and eating disorders. The incidence of one disorder in patients suffering from the other disorder is well over the incidence in the general population. Several causes could explain this increased comorbidity. First, the iatrogenic origin is detailed. Indeed, psychotropic drugs, and particularly mood stabilizers, often lead to modification in eating behaviors, generally inducing weight gain. These drugs can increase desire for food, reduce baseline metabolism or decrease motor activity. Also, affective and eating disorders share several characteristics in semiology. These similarities can not only obscure the differential diagnosis but may also attest of conjoint pathophysiological bases in the two conditions. However, genetic and biological findings so far are too sparse to corroborate this last hypothesis. Nonetheless, it is noteworthy that comorbidity of affective and eating disorders worsens patients'prognosis and is associated with more severe forms of affective disorders characterized by an earlier age of onset in the disease, higher number of mood episodes and a higher suicidality. Lastly, psychotropic drugs used in affective disorders (lithium, antiepileptic mood stabilizers, atypical antipsychotics, antidepressants) are reviewed in order to weigh their efficacy in eating disorders. This could help establish the best therapeutic option when confronted to comorbidity.

Prospective Acceptability of Digital Therapy for Major Depressive Disorder in France: Multicentric Real-Life Study.

BACKGROUND: Major depressive disorder is one of the leading causes of disability worldwide. Although most international guidelines recommend psychological and psychosocial interventions as first-line treatment for mild to moderate depression, access remains limited in France due to the limited availability of trained clinicians, high costs for patients in the context of nonreimbursement, and the fear of stigmatization. Therefore, online blended psychological treatment such as Deprexis could improve access to care for people with depression. It has several advantages, such as easy accessibility and scalability, and it is supported by evidence. OBJECTIVE: This study aims to evaluate the real-life acceptability of Deprexis for people with depression in France outside of a reimbursement pathway. METHODS: Deprexis Acceptability Study Measure in Real Life (DARE) was designed as a multicenter cross-sectional study in which Deprexis was offered to any patient meeting the inclusion criteria during the fixed inclusion period (June 2022-March 2023). Inclusion criteria were (1) depression, (2) age between 18 and 65 years, (3) sufficient French language skills, and (4) access to the internet with a device to connect to the Deprexis platform. Exclusion criteria were previous or current diagnoses of bipolar disorder, psychotic symptoms, and suicidal thoughts during the current episode. The primary objective was to measure the prospective acceptability of Deprexis, a new digital therapy. Secondary objectives were to examine differences in acceptability according to patient and clinician characteristics and to identify reasons for refusal. All investigators received video-based training on Deprexis before enrollment to ensure that they all had the same level of information and understanding of the program. RESULTS: A total of 245 patients were eligible (n=159, 64.9% were women and n=138, 56.3% were single). The mean age was 40.7 (SD 14.1) years. A total of 78% (n=191) of the patients had moderate to severe depression (according to the Patient Health Questionnaire-9 [PHQ-9]). More than half of the population had another psychiatric comorbidity (excluding bipolar disorder, psychotic disorders, and suicidal ideation). A total of 33.9% (n=83) of patients accepted the idea of using Deprexis; the main reason for refusal was financial at 83.3% (n=135). Multivariate logistic regression identified factors that might favor the acceptability of Deprexis. Among these, being a couple, being treated with an antidepressant, or having a low severity level favored the acceptance of Deprexis. CONCLUSIONS: DARE is the first French study aiming at evaluating the prospective acceptability of digital therapy in the treatment of depression. The main reason for the refusal of Deprexis was financial. DARE will allow better identification of factors influencing acceptability in a natural setting. This study highlights the importance of investigating factors that may be associated with the acceptability of digital interventions, such as marital status, medication use, and severity of depression.

Blunted brain responses to neutral faces in healthy first-degree relatives of patients with schizophrenia: an image-based fMRI meta-analysis.

Schizophrenia is characterized by the misattribution of emotional significance to neutral faces, accompanied by overactivations of the limbic system. To understand the disorder's genetic and environmental contributors, investigating healthy first-degree relatives is crucial. However, inconsistent findings exist regarding their ability to recognize neutral faces, with limited research exploring the cerebral correlates of neutral face processing in this population. Thus, we here investigated brain responses to neutral face processing in healthy first-degree relatives through an image-based meta-analysis of functional magnetic resonance imaging studies. We included unthresholded group-level T-maps from 5 studies comprising a total of 120 first-degree relatives and 150 healthy controls. In sensitivity analyses, we ran a combined image- and coordinate-based meta-analysis including 7 studies (157 first-degree relatives, 207 healthy controls) aiming at testing the robustness of the results in a larger sample of studies. Our findings revealed a pattern of decreased brain responses to neutral faces in relatives compared with healthy controls, particularly in limbic areas such as the bilateral amygdala, hippocampus, and insula. The same pattern was observed in sensitivity analyses. These results contrast with the overactivations observed in patients, potentially suggesting that this trait could serve as a protective factor in healthy relatives. However, further research is necessary to test this hypothesis.

Molecular mapping of a core transcriptional signature of microglia-specific genes in schizophrenia.

Besides playing a central role in neuroinflammation, microglia regulate synaptic development and is involved in plasticity. Converging lines of evidence suggest that these different processes play a critical role in schizophrenia. Furthermore, previous studies reported altered transcription of microglia genes in schizophrenia, while microglia itself seems to be involved in the etiopathology of the disease. However, the regional specificity of these brain transcriptional abnormalities remains unclear. Moreover, it is unknown whether brain and peripheral expression of microglia genes are related. Thus, we investigated the expression of a pre-registered list of 10 genes from a core signature of human microglia both at brain and peripheral levels. We included 9 independent Gene Expression Omnibus datasets (764 samples obtained from 266 individuals with schizophrenia and 237 healthy controls) from 8 different brain regions and 3 peripheral tissues. We report evidence of a widespread transcriptional alteration of microglia genes both in brain tissues (we observed a decreased expression in the cerebellum, associative striatum, hippocampus, and parietal cortex of individuals with schizophrenia compared with healthy controls) and whole blood (characterized by a mixed altered expression pattern). Our results suggest that brain underexpression of microglia genes may represent a candidate transcriptional signature for schizophrenia. Moreover, the dual brain-whole blood transcriptional alterations of microglia/macrophage genes identified support the model of schizophrenia as a whole-body disorder and lend weight to the use of blood samples as a potential source of biological peripheral biomarkers.

Efficacy and auditory biomarker analysis of fronto-temporal transcranial direct current stimulation (tDCS) in targeting cognitive impairment associated with recent-onset schizophrenia: study protocol for a multicenter randomized double-blind sham-controlled trial.

BACKGROUND: In parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial direct current stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear. METHOD: The study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS. DISCUSSION: Besides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct a randomized controlled trial (RCT) with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov NCT05440955. Prospectively registered on July 1st, 2022.

EMDR for symptoms of depression, stress and burnout in health care workers exposed to COVID-19 (HARD): A study protocol for a trial within a cohort study.

Background: Stressful events during a pandemic are a major cause of serious health problems, such as burnout, depression and posttraumatic stress disorder (PTSD) among health care workers (HCWs). During three years, HCWs, on the frontline to fight the COVID-19 pandemic, have been at an increased risk of high levels of stress, anxiety, depression, burnout and PTSD. Regarding potential psychological interventions, Eye Movement Desensitization & Reprocessing (EMDR) is a structured, strongly recommended therapy based on its well-known efficacy in reducing PTSD symptoms and anxiety.Objectives: This study, designed as a trial within a cohort (TwiC), aims to 1) estimate the prevalence of depression, burnout and PTSD in a sample of HCWs after experiencing the COVID-19 emergency (cohort part) and 2) assess the efficacy and acceptability of 'EMDR + usual care' for HCWs from the cohort who report significant psychological symptoms (trial part).Methods: The study, designed as a TwiC, consists of a prospective cohort study (n = 3000) with an embedded, pragmatic, randomized open-label superiority trial with two groups (n = 900). Participants included in the trial part are HCWs recruited for the cohort with significant symptoms on at least one psychological dimension (depression, burnout, PTSD) at baseline, 3 months or 6 months, determined by using the Patient Health Questionnaire (PHQ-9), Professional Quality of Life (ProQOL) scale, and PTSD Checklist for the DSM-5 (PCL-5). The intervention consists of 12 separate EMDR sessions with a certified therapist. The control group receives usual care. The trial has three primary outcomes: changes in depression, burnout and PTSD scores from randomization to 6 months. All participants are followed up for 12 months.Conclusions: This study provides empirical evidence about the impact of the COVID-19 pandemic and the mental health burden it places on HCWs and assesses the effectiveness of EMDR as a psychological intervention.Trial registration NCT04570202.

Health care workers are at increased risk of stress, anxiety, depression, burnout and PTSD following the COVID-19 pandemic.In this study, the effectiveness of EMDR in reducing depression, burnout and PTSD in health care workers exposed to COVID-19 is investigated.In this study, an original 'trial within a cohort' (TwiC) design that consists of a cohort study with an embedded pragmatic randomized trial is used.The study is fully web-based, including online screening, consent and assessments.

Understanding the potential of digital therapies in implementing the standard of care for depression in Europe.

Depressive disorders represent the largest proportion of mental illnesses, and by 2030, they are expected to be the first cause of disability-adjusted life years [1]. The COVID-19 pandemic exacerbated prevalence and burden of depression and increased the occurrence of depressive symptoms in general population [2]. The urgency of implementing mental health services to address new barriers to care persuaded clinicians to use telemedicine to follow patients and stay in touch with them, and to explore digital therapeutics (DTx) as potential tools for clinical intervention [2]. The combination of antidepressants and psychotherapy is widely recommended for depression by international guidelines [3] but is less frequently applied in real-world practice. Commonly used treatments are pharmacological, but while being effective, some aspects such as adherence to the drug regimen, residual symptoms, resistance, lack of information, and stigma may hinder successful treatment. In case of less severe depression, standalone psychological therapies should be the first-line treatment option [3], but access to trained psychotherapists remains inequitable. DTx are evidence-based therapies driven by software programs to treat or complement treatment of a specific disease. DTx are classified as Medical Devices, and given their therapeutic purpose, they need to be validated through randomized controlled clinical trials, as for drug-based therapies. In the last 10 years, studies of digital interventions have proliferated; these studies demonstrate that digital interventions increase remission rates and lower the severity of depressive symptoms compared with waitlist, treatment as usual, and attention control conditions [4]. Despite the efficacy demonstrated in clinical trials, many of these tools never reach real-life patients; thus, it might be necessary to implement DTx in the public health system to expand access to valid treatment options. In this framework, DTx represent a good opportunity to help people with depression receive optimal psychotherapeutic care [5].

Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-Based Functional Magnetic Resonance Imaging Meta-analysis.

BACKGROUND: Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia. Functional magnetic resonance imaging studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular, decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the functional magnetic resonance imaging literature. METHODS: Functional magnetic resonance imaging studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy control subjects were identified. Frequentist and Bayesian voxelwise meta-analyses were performed separately, by implementing a random-effect model with unthresholded group-level T-maps from individual studies as input. RESULTS: In total, 17 studies with a cumulative total of 677 at-risk individuals and 805 healthy control subjects were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy control subjects. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. CONCLUSIONS: These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies instead focus on impaired functional connectivity as an alternative and promising endophenotype.

Association between cannabis use and symptom dimensions in schizophrenia spectrum disorders: an individual participant data meta-analysis on 3053 individuals.

Background: The association between cannabis use and positive symptoms in schizophrenia spectrum disorders is well documented, especially via meta-analyses. Yet, findings are inconsistent regarding negative symptoms, while other dimensions such as disorganization, depression, and excitement, have not been investigated. In addition, meta-analyses use aggregated data discarding important confounding variables which is a source of bias. Methods: PubMed, ScienceDirect and PsycINFO were used to search for publications from inception to September 27, 2022. We contacted the authors of relevant studies to extract raw datasets and perform an Individual Participant Data meta-analysis (IPDMA). Inclusion criteria were: psychopathology of individuals with schizophrenia spectrum disorders assessed by the Positive and Negative Syndrome Scale (PANSS); cannabis-users had to either have a diagnosis of cannabis use disorder or use cannabis at least twice a week. The main outcomes were the PANSS subscores extracted via the 3-factor (positive, negative and general) and 5-factor (positive, negative, disorganization, depression, excitement) structures. Preregistration is accessible via Prospero: ID CRD42022329172. Findings: Among the 1149 identified studies, 65 were eligible and 21 datasets were shared, totaling 3677 IPD and 3053 complete cases. The adjusted multivariate analysis revealed that relative to non-use, cannabis use was associated with higher severity of positive dimension (3-factor: Adjusted Mean Difference, aMD = 0.34, 95% Confidence Interval, CI = [0.03; 0.66]; 5-factor: aMD = 0.38, 95% CI = [0.08; 0.63]), lower severity of negative dimension (3-factor: aMD = -0.49, 95% CI [-0.90; -0.09]; 5-factor: aMD = -0.50, 95% CI = [-0.91; -0.08]), higher severity of excitement dimension (aMD = 0.16, 95% CI = [0.03; 0.28]). No association was found between cannabis use and disorganization (aMD = -0.13, 95% CI = [-0.42; 0.17]) or depression (aMD = -0.14, 95% CI = [-0.34; 0.06]). Interpretation: No causal relationship can be inferred from the current results. The findings could be in favor of both a detrimental and beneficial effect of cannabis on positive and negative symptoms, respectively. Longitudinal designs are needed to understand the role of cannabis is this association. The reported effect sizes are small and CIs are wide, the interpretation of findings should be taken with caution. Funding: This research did not receive any specific grant or funding. Primary financial support for authors was provided by Le Vinatier Psychiatric Hospital.

Association between formal thought disorder and cannabis use: a systematic review and meta-analysis.

Formal thought disorder (FTD) is a multidimensional syndrome mainly occurring along the psychosis continuum. Cannabis use is known to increase symptoms of psychosis, particularly positive symptoms. However, the impact of cannabis use on FTD in individuals presenting symptoms along the psychosis continuum remains unclear. To address this knowledge gap, we conducted a meta-analysis examining the association between cannabis use and FTD in those individuals. We hypothesized that cannabis would worsen FTD. We conducted a systematic search of the PubMed, ScienceDirect, PsycINFO, Web of Science, Embase and Google Scholar databases up to July 2022. The results were collated through a random-effects model using the statistical software R. Reference lists of included studies were searched for additional relevant publications. Nineteen studies were included, totalling 1840 cannabis users and 3351 non-cannabis users. The severity of FTD was found to be higher in cannabis users (SMD = 0.21, 95%CI [0.12-0.29], p = 0.00009). Subgroup analyses revealed that FTD severity was increased among cannabis users, regardless of the disorder severity: healthy individuals (SMD = 0.19, 95%CI [0.05-0.33], p = 0.02); patients with first-episode psychosis (SMD = 0.21, 95%CI [0.01-0.41], p = 0.04); patients with schizophrenia (SMD = 0.25, 95%CI [0.11-0.38], p = 0.005). Between-group differences were not significant. In line with its already known effect on positive symptoms in psychosis, cannabis use appears to be associated with increased FTD severity all along the psychosis continuum. Future research should consider potential confounding variables such as other substance use disorders and explore how FTD dimensions are impacted by cannabis use.

A Single Session of Bifrontal tDCS Can Improve Facial Emotion Recognition in Major Depressive Disorder: An Exploratory Pilot Study.

Emotional processing deficits are key features in major depressive disorder (MDD). Neuroimaging studies indicate that the dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in both depressive symptoms and emotional processing. Recently, transcranial Direct Current Stimulations (tDCS) applied over the DLPFCs have held the promise to alleviate the symptoms in patients with MDD, but the effect on emotional processing in the patients is unclear. Here, we investigated the effect of a single session of tDCS over the DLPFCs on the emotional processing in patients with treatment-resistant MDD. In a randomized sham-controlled study, 35 patients received a single 30 min session of either active (2 mA, n = 18) or sham tDCS (n = 17). The anode was placed over the left and the cathode over the right DLPFC. Emotional processing accuracy was measured by a facial emotion recognition (FER) task. We observed an overall improvement in FER performance after the active tDCS, but not the sham tDCS. These exploratory results suggest that a single session of tDCS over the DLPFCs may improve FER in MDD, a crucial function of social cognition. Further studies are needed to investigate whether this acute improvement of FER in response to a single tDCS session could translate into clinical benefits or predict remission following repeated sessions of stimulation.