Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.

BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders.

This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015-December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18-34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = -0.19, -0.26 and -0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = -0.20, -0.24, -0.21, respectively) and ED admissions (SMD = -0.15, -0.13, -0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.

How can we improve the care of patients with schizophrenia in the real-world? A population-based cohort study of 456,003 patients.

An important step to improve outcomes for patients with schizophrenia is to understand treatment patterns in routine practice. The aim of the current study was to describe the long-term management of patients with schizophrenia treated with antipsychotics (APs) in real-world practice. This population-based study included adults with schizophrenia and who had received ≥3 deliveries of an AP from 2012-2017, identified using a National Health Data System. Primary endpoints were real-life prescription patterns, patient characteristics, healthcare utilization, comorbidities and mortality. Of the 456,003 patients included, 96% received oral APs, 17.5% first-generation long-acting injectable APs (LAIs), and 16.1% second generation LAIs. Persistence rates at 24 months after treatment initiation were 23.9% (oral APs), 11.5% (first-generation LAIs) and 20.8% (second-generation LAIs). Median persistence of oral APs, first-generation LAIs and second-generation LAIs was 5.0, 3.3, and 6.1 months, respectively. Overall, 62.1% of patients were administered anxiolytics, 45.7% antidepressants and 28.5% anticonvulsants, these treatments being more frequently prescribed in women and patients aged ≥50 years. Dyslipidemia was the most frequent metabolic comorbidity (16.2%) but lipid monitoring was insufficient (median of one occasion). Metabolic comorbidities were more frequent in women. Standardized patient mortality remained consistently high between 2013 and 2015 (3.3-3.7 times higher than the general French population) with a loss of life expectancy of 17 years for men and 8 years for women. Cancer (20.2%) and cardiovascular diseases (17.2%) were the main causes of mortality, and suicide was responsible for 25.4% of deaths among 18-34-year-olds. These results highlight future priorities for care of schizophrenia patients. The global persistence of APs used in this population was low, whereas rates of psychiatric hospitalization remain high. More focus on specific populations is needed, such as patients aged >50 years to prevent metabolic disturbances and 18-34-year-olds to reduce suicide rates.

Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis-findings from the EU-GEI study.

ABTRACT: Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10-5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.

Variation of subclinical psychosis as a function of population density across different European settings: Findings from the multi-national EU-GEI study.

BACKGROUND: Urbanicity is a well-established risk factor for psychosis. Our recent multi-national study found an association between urbanicity and clinical psychosis in Northern Europe but not in Southern Europe. In this study, we hypothesized that the effect of current urbanicity on variation of schizotypy would be greater in North-western Europe countries than in Southern Europe ones. METHODS: We recruited 1080 individuals representative of the populations aged 18-64 of 14 different sites within 5 countries, classified as either North-western Europe (England, France, and The Netherlands) with Southern Europe (Spain and Italy). Our main outcome was schizotypy, assessed through the Structured Interview for Schizotypy-Revised. Our main exposure was current urbanicity, operationalized as local population density. A priori confounders were age, sex, ethnic minority status, childhood maltreatment, and social capital. Schizotypy variation was assessed using multi-level regression analysis. To test the differential effect of urbanicity between North-western and Southern European, we added an interaction term between population density and region of recruitment. RESULTS: Population density was associated with schizotypy (ß = 0.248,95%CI = 0.122-0.375;p < 0.001). The addition of the interaction term improved the model fit (likelihood test ratio:χ2 = 6.85; p = 0.009). The effect of urbanicity on schizotypy was substantially stronger in North-western Europe (ß = 0.620,95%CI = 0.362-0.877;p < 0.001) compared with Southern Europe (ß = 0.190,95%CI = 0.083-0.297;p = 0.001). CONCLUSIONS: The association between urbanicity and both subclinical schizotypy and clinical psychosis, rather than being universal, is context-specific. Considering that urbanization is a rapid and global process, further research is needed to disentangle the specific factors underlying this relationship.

Parkinson's Disease: Coping Strategies, Cognitive Restructuring and Deep Brain Stimulation.

OBJECTIVE: Less is known concerning the evolution of coping strategies before and after deep brain stimulation (DBS) in Parkinson's disease (PD) patients. METHODS: In a randomized controlled trial, coping was measured with the neurological version of the CHIP (Coping with Health Injuries and Problem) and the BriefCOPE in PD patients before ( T1: DBS - 2 months) and after (T2: + 3 months, T3: + 6 months) DBS. Patients (N = 50, age 59 ± 5.7 years, disease duration 9.54 ± 3.7 years) were randomised in 3 groups: CRTG (preoperative psychological preparation with cognitive restructuring), PIG (preoperative non structured interviews), and CG (no psychological preparation). RESULTS: Coping strategies are modulated by the time of evaluation. Some strategies are significantly more used preoperatively than postoperatively, as strategies about the research for information (CHIP: F = 16.14; P = .000; η2 = .095; BriefCOPE F = 5.71; P = .005; η2 = .066), emotional regulation (F = 3.29; P = .042; η2 = .029), and well-being searching (F = 4.59; P = .013; η2 = .043). Some other strategies appear more used post than preoperatively, as palliative coping (F = 5.57; P = .005; η2 = .064), humour (F = 3.35; P = .041; η2 = .0.35), and use of substance (F = 4.43; P = .015; η2 = .070). No other specific time, group or time per group interaction effect was found. CONCLUSION: Coping strategies are crucial for PD patients to adapt to the evolution of their parkinsonian state. Their consideration should be more systematic in the neurosurgical process, particularly when neurological symptoms would remain after DBS. More insights are needed concerning the evolution of coping strategies through DBS and the impact of a preoperative psychotherapy over them in preoperative PD patients.

Adherence to clinical practice guidelines for using electroconvulsive therapy in elderly depressive patients.

OBJECTIVES: Electroconvulsive therapy (ECT) is one of the most effective treatments in mood disorders, mainly in major depressive episode (MDE) in the context of either unipolar (MDD) or bipolar disorder (BD). However, ECT remains a neglected and underused treatment. Older people are at high risk patients for the development of adverse drug reactions. In this context, we sought to determine the duration of MDEs and the number of lines of treatment before the initiation of ECT in patients aged 65 years or over according to the presence or absence of first-line indications for using ECT from international guidelines. METHODS: In this multicenter, retrospective study including patients aged 65 years or over with MDEs in MDD or BD who have been treated with ECT for MDEs, data on the duration of MDEs and the number of lines of treatment received before ECT were collected. The reasons for using ECT, specifically first-line indications (suicidality, urgency, presence of catatonic and psychotic features, previous ECT response, patient preference) were recorded. Statistical comparisons between groups used standard statistical tests. RESULTS: We identified 335 patients. The mean duration of MDEs before ECT was about 9 months. It was significantly shorter in BD than in MDD- about 7 and 10 months, respectively. The co-occurrence of chronic medical disease increased the duration before ECT in the MDD group. The presence of first-line indications for using ECT from guidelines did not reduce the duration of MDEs before ECT, except where there was a previous response to ECT. The first-line indications reduced the number of lines of treatment before starting ECT. CONCLUSION: Even if ECT seems to be a key treatment in the elderly population due to its efficacity and safety for MDEs, the delay before this treatment is still too long.

Anorexia nervosa: Enhancing motivation to change with self-determination theory.

Motivational deficits (little or no motivation to change) are often reported in patients with eating disorders, particularly anorexia nervosa. The motivational approaches frequently used by French clinicians rely solely on a dichotomous view of motivation (intrinsic vs. extrinsic). In self-determination theory, certain forms of extrinsic motivation can strengthen an individual's commitment to an activity, providing they are self-determined. This theory therefore extends and enriches the dual motivational approach by highlighting potentially useful forms of extrinsic motivation and by emphasizing the importance of behavioral regulation. Empirical work is now needed to assess how clinicians can use self-determination theory to enhance motivation to change among patients with anorexia nervosa and encourage their adherence to care management plans.

French Society for Biological Psychiatry and Neuropsychopharmacology (AFPBN) guidelines for the management of patients with partially responsive depression and treatment-resistant depression: Update 2024.

INTRODUCTION: The purpose of this update is to add newly approved nomenclatures and treatments as well as treatments yet to be approved in major depressive disorder, thus expanding the discussions on the integration of resistance factors into the clinical approach. METHODS: Unlike the first consensus guidelines based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) developed an update of these guidelines for the management of partially responsive depression (PRD) and treatment-resistant depression (TRD). The expert guidelines combine scientific evidence and expert clinicians' opinions to produce recommendations for PRD and TRD. RESULTS: The recommendations addressed three areas judged as essential for updating the previous 2019 AFPBN guidelines for the management of patients with TRD: (1) the identification of risk factors associated with TRD, (2) the therapeutic management of patients with PRD and TRD, and (3) the indications, the modalities of use and the monitoring of recent glutamate receptor modulating agents (esketamine and ketamine). CONCLUSION: These consensus-based guidelines make it possible to build bridges between the available empirical literature and clinical practice, with a highlight on the 'real world' of the clinical practice, supported by a pragmatic approach centred on the experience of specialised prescribers in TRD.

Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: A national population-based cohort study.

BACKGROUND: Patients with severe mental illness (SMI) (i.e., schizophrenia, bipolar disorder, or major depressive disorder) have been reported to have excess mortality rates from infection compared to patients without SMI, but whether SMI is associated with higher or lower case fatality rates (CFRs) among infected patients remains unclear. The primary objective was to compare the 90-day CFR in septic shock patients with and without SMI admitted to the intensive care unit (ICU), after adjusting for social disadvantage and physical health comorbidity. METHODS AND FINDINGS: We conducted a nationwide, population-based cohort study of all adult patients with septic shock admitted to the ICU in France between January 1, 2014, and December 31, 2018, using the French national hospital database. We matched (within hospitals) in a ratio of 1:up to 4 patients with and without SMI (matched-controls) for age (5 years range), sex, degree of social deprivation, and year of hospitalization. Cox regression models were conducted with adjustment for smoking, alcohol and other substance addiction, overweight or obesity, Charlson comorbidity index, presence of trauma, surgical intervention, Simplified Acute Physiology Score II score, organ failures, source of hospital admission (home, transfer from other hospital ward), and the length of time between hospital admission and ICU admission. The primary outcome was 90-day CFR. Secondary outcomes were 30- and 365-day CFRs, and clinical profiles of patients. A total of 187,587 adult patients with septic shock admitted to the ICU were identified, including 3,812 with schizophrenia, 2,258 with bipolar disorder, and 5,246 with major depressive disorder. Compared to matched controls, the 90-day CFR was significantly lower in patients with schizophrenia (1,052/3,269 = 32.2% versus 5,000/10,894 = 45.5%; adjusted hazard ratio (aHR) = 0.70, 95% confidence interval (CI) 0.65,0.75, p < 0.001), bipolar disorder (632/1,923 = 32.9% versus 2,854/6,303 = 45.3%; aHR = 0.70, 95% CI = 0.63,0.76, p < 0.001), and major depressive disorder (1,834/4,432 = 41.4% versus 6,798/14,452 = 47.1%; aHR = 0.85, 95% CI = 0.81,0.90, p < 0.001). Study limitations include inability to capture deaths occurring outside hospital, lack of data on processes of care, and problems associated with missing data and miscoding in medico-administrative databases. CONCLUSIONS: Our findings suggest that, after adjusting for social disadvantage and physical health comorbidity, there are improved septic shock outcome in patients with SMI compared to patients without. This finding may be the result of different immunological profiles and exposures to psychotropic medications, which should be further explored.

Mortality among inpatients with bipolar disorders and COVID-19: a propensity score matching analysis in a national French cohort study.

BACKGROUND: It remains unknown whether coronavirus disease 2019 (COVID-19) patients with bipolar disorders (BDs) are at an increased risk of mortality. We aimed to establish whether health outcomes and care differed between patients infected with COVID-19 with BD and patients without a diagnosis of severe mental illness. METHODS: We conducted a population-based cohort study of all patients with identified COVID-19 and respiratory symptoms who were hospitalized in France between February and June 2020. The outcomes were in-hospital mortality and intensive care unit (ICU) admission. We used propensity score matching to control for confounding factors. RESULTS: In total, 50 407 patients were included, of whom 480 were patients with BD. Patients with BD were 2 years older, more frequently women and had more comorbidities than controls without a diagnosis of severe mental illness. Patients with BD had an increased in-hospital mortality rate (26.6% v. 21.9%; p = 0.034) and similar ICU admission rate (27.9% v. 28.4%, p = 0.799), as confirmed by propensity analysis [odds ratio, 95% confidence interval (OR, 95% CI) for mortality: 1.30 (1.16-1.45), p < 0.0001]. Significant interactions between BD and age and between BD and social deprivation were found, highlighting that the most important inequalities in mortality were observed in the youngest [OR, 95% CI 2.28 (1.18-4.41), p = 0.0015] and most deprived patients with BD [OR, 95% CI 1.60 (1.33-1.92), p < 0.001]. CONCLUSIONS: COVID-19 patients with BD were at an increased risk of mortality, which was exacerbated in the youngest and most deprived patients with BD. Patients with BD should thus be targeted as a high-risk population for severe forms of COVID-19, requiring enhanced preventive and disease management strategies.

Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways: insights from the FACE-BD study.

BACKGROUND: Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways. METHODS: We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning. RESULTS: A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions. CONCLUSIONS: Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.

Current (but not ex) cigarette smoking is associated with worse cognitive performances in schizophrenia: results from the FACE-SZ cohort.

BACKGROUND: Tobacco use is common in subjects with schizophrenia (SZ) and has sometimes been associated with better functioning in short-term studies. Only few studies embrace an extensive examination of tobacco influence on clinical, cognitive and therapeutic characteristics in stabilized SZ outpatients. The objective of the present study was to assess the association between cognitive performances and smoking status in SZ subjects. METHODS: In total, 1233 SZ participants (73.9% men, mean age 31.5) were included and tested with a comprehensive battery. Tobacco status was self-declared (never-, ex-, or current smokers). Multivariable analyses including principal component analyses (PCA) were used. RESULTS: In total, 53.7% were smokers with 33.7% of them nicotine-dependent. Multiple factor analysis revealed that current tobacco smoking was associated with impaired general intellectual ability and abstract reasoning (aOR 0.60, 95% IC 0.41-0.88, p = 0.01) and with a lifetime alcohol use disorder (p = 0.026) and a lifetime cannabis use disorder (p < 0.001). Ex- and never-smokers differed for age, mean outcome, cannabis history and medication [ex-smokers being older (p = 0.047), likely to have higher income (p = 0.026), a lifetime cannabis use disorder (p < 0.001) and higher CPZeq doses (p = 0.005)]. Premorbid IQ in the three groups significantly differed with, from higher to lower: ex-smokers, never-smoker, current smokers (all p < 0.001). CONCLUSIONS: This study is the largest to date providing strong evidence that chronic smoking is associated with cognitive impairment in SZ, arguing against the self-medication hypothesis as a contributor to the high prevalence of smoking in SZ. Ex-smokers may also represent a specific subgroup. Longitudinal studies are warranted to determine the developmental impact of tobacco on neurocognition.

Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study.

BACKGROUND: Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). METHODS: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. RESULTS: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74). CONCLUSIONS: Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

Cannabis use as a potential mediator between childhood adversity and first-episode psychosis: results from the EU-GEI case-control study.

BACKGROUND: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis. METHODS: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use. RESULTS: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord. CONCLUSIONS: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

Child maltreatment, migration and risk of first-episode psychosis: results from the multinational EU-GEI study.

BACKGROUND: Child maltreatment (CM) and migrant status are independently associated with psychosis. We examined prevalence of CM by migrant status and tested whether migrant status moderated the association between CM and first-episode psychosis (FEP). We further explored whether differences in CM exposure contributed to variations in the incidence rates of FEP by migrant status. METHODS: We included FEP patients aged 18-64 years in 14 European sites and recruited controls representative of the local populations. Migrant status was operationalized according to generation (first/further) and region of origin (Western/non-Western countries). The reference population was composed by individuals of host country's ethnicity. CM was assessed with Childhood Trauma Questionnaire. Prevalence ratios of CM were estimated using Poisson regression. We examined the moderation effect of migrant status on the odds of FEP by CM fitting adjusted logistic regressions with interaction terms. Finally, we calculated the population attributable fractions (PAFs) for CM by migrant status. RESULTS: We examined 849 FEP cases and 1142 controls. CM prevalence was higher among migrants, their descendants and migrants of non-Western heritage. Migrant status, classified by generation (likelihood test ratio:χ2 = 11.3, p = 0.004) or by region of origin (likelihood test ratio:χ2 = 11.4, p = 0.003), attenuated the association between CM and FEP. PAFs for CM were higher among all migrant groups compared with the reference populations. CONCLUSIONS: The higher exposure to CM, despite a smaller effect on the odds of FEP, accounted for a greater proportion of incident FEP cases among migrants. Policies aimed at reducing CM should consider the increased vulnerability of specific subpopulations.

Synergistic effects of childhood adversity and polygenic risk in first-episode psychosis: the EU-GEI study.

BACKGROUND: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone. METHODS: We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case-control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS - ORexposure - ORPRS + 1] with adjustment for potential confounders. RESULTS: There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) -1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI -6.25 to 20.88). CONCLUSIONS: Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

Associations of white blood cell and platelet counts with specific depressive symptom dimensions in patients with bipolar disorder: Analysis of data from the FACE-BD cohort.

Evidences suggest that inflammation is increased in a subgroup of patients with depression. Moreover, increased peripheral inflammatory markers (cells and proteins) are associated with some, but not all depressive symptoms. On the other hand, similar studies on bipolar disorders mainly focused on blood cytokines. Here, we analysed data from a large (N = 3440), well-characterized cohort of individuals with bipolar disorder using Kendall partial rank correlation, multivariate linear regression, and network analyses to determine whether peripheral blood cell counts are associated with depression severity, its symptoms, and dimensions. Based on the self-reported 16-Item Quick Inventory of Depressive Symptomatology questionnaire scores, we preselected symptom dimensions based on literature and data-driven principal component analysis. We found that the counts of all blood cell types were only marginally associated with depression severity. Conversely, white blood cell count was significantly associated with the sickness dimension and its four components (anhedonia, slowing down, fatigue, and appetite loss). Platelet count was associated with the insomnia/restlessness dimension and its components (initial, middle, late insomnia and restlessness). Principal component analyses corroborated these results. Platelet count was also associated with suicidal ideation. In analyses stratified by sex, the white blood cell count-sickness dimension association remained significant only in men, and the platelet count-insomnia/restlessness dimension association only in women. Without implying causation, these results suggest that peripheral blood cell counts might be associated with different depressive symptoms in individuals with bipolar disorder, and that white blood cells might be implicated in sickness symptoms and platelets in insomnia/agitation and suicidal ideation.

Impact of the COVID-19 pandemic on non-COVID-19 hospital mortality in patients with schizophrenia: a nationwide population-based cohort study.

It remains unknown to what degree resource prioritization toward SARS-CoV-2 (2019-nCoV) coronavirus (COVID-19) cases had disrupted usual acute care for non-COVID-19 patients, especially in the most vulnerable populations such as patients with schizophrenia. The objective was to establish whether the impact of the COVID-19 pandemic on non-COVID-19 hospital mortality and access to hospital care differed between patients with schizophrenia versus without severe mental disorder. We conducted a nationwide population-based cohort study of all non-COVID-19 acute hospitalizations in the pre-COVID-19 (March 1, 2019 through December 31, 2019) and COVID-19 (March 1, 2020 through December 31, 2020) periods in France. We divided the population into patients with schizophrenia and age/sex-matched patients without severe mental disorder (1:10). Using a difference-in-differences approach, we performed multivariate patient-level logistic regression models (adjusted odds ratio, aOR) with adjustment for complementary health insurance, smoking, alcohol and substance addiction, Charlson comorbidity score, origin of the patient, category of care, intensive care unit (ICU) care, major diagnosis groups and hospital characteristics. A total of 198,186 patients with schizophrenia were matched with 1,981,860 controls. The 90-day hospital mortality in patients with schizophrenia increased significantly more versus controls (aOR = 1.18; p < 0.001). This increased mortality was found for poisoning and injury (aOR = 1.26; p = 0.033), respiratory diseases (aOR = 1.19; p = 0.008) and for both surgery (aOR = 1.26; p = 0.008) and medical care settings (aOR = 1.16; p = 0.001). Significant changes in the case mix were noted with reduced admission in the ICU and for several somatic diseases including cancer, circulatory and digestive diseases and stroke for patients with schizophrenia compared to controls. These results suggest a greater deterioration in access to, effectiveness and safety of non-COVID-19 acute care in patients with schizophrenia compared to patients without severe mental disorders. These findings question hospitals' resilience pertaining to patient safety and underline the importance of developing specific strategies for vulnerable patients in anticipation of future public health emergencies.