MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

[Lifestyle in young adults with and without a psychotic disorder]. / Leefstijl bij jongvolwassenen met en zonder psychotische stoornis.

Background Patients with psychotic disorders have a higher risk of physical illnesses on account of genetic predisposition, poorer access to healthcare, medication use, environmental factors and lifestyle. Because healthy lifestyle behaviour is established at young age, it is important to signal problems in good time. A lifestyle screening might be useful in this respect. Aim To describe the lifestyle characteristics of patients in a mental health clinic for young adults (age: 18-28 years) with early psychotic disorder based on parts of the instrument ‘Lifestyle-in-the-picture’ compared to healthy controls. We also discuss experiences of lifestyle coaches in applying ‘Lifestyle-in-the-picture’. Method Lifestyle characteristics and lifestyle behaviour of 90 patients with a psychotic disorder and 137 young adults from the general population were compared quantitatively. Additionally, interviews were held with lifestyle coaches as to the use of the instrument ‘Lifestyle-in-the-picture’. Results The young adult patients had considerably poorer results on lifestyle aspects than controls: increased body mass index (BMI 53% versus 18%), smoking, addiction and unhealthy eating and activity patterns. They were more dissatisfied with their physical and mental health. According to the lifestyle coaches, the ‘Lifestyle-in-the-picture’ instrument was a good starting point to work on improvement with patients since the instrument provided insight in the healthy and unhealthy aspects of their lifestyle and gave directions to set goals. Conclusions Young adults with a psychotic disorder have an unhealthy lifestyle and also more risk factors compared to controls. Lifestyle screening programmes are important to discuss health risks in time and which steps for improvement can be taken. The step from insight to actual more healthy behaviour is challenging.

'I am proud of how I handled it'. Exploring the impact of the COVID-19 pandemic and related restrictions on well-being of adults with severe mental illness using qualitative methods.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and related restrictions globally impacted mental health, particularly for those with pre-existing severe mental illness (SMI). This qualitative study examined how adults with SMI perceived the effects of the COVID-19 pandemic and related restrictions in the Netherlands, focusing on their personal recovery, well-being and daily life, including an exploration of factors influencing these effects. METHODS: Semi-structured interviews were conducted, audio-recorded and transcribed verbatim. Reflexive thematic analysis was applied. Purposive sampling was used to ensure diversity of individuals with SMI (i.e., age, gender, diagnosis, cultural background and mental healthcare institution). RESULTS: Twenty participants (median age: 45 years [SD: 12, 8]; 11 females) were interviewed between May and July 2023. Findings revealed a wide range of experiences: while some individuals reported a negative impact on their existing psychiatric symptoms, others described adaptability, resilience and even positive effects of COVID-19 restrictions on their mental health and well-being. Factors influencing the heterogeneic perceptions of the COVID-19 pandemic and related restrictions include the availability of trusted social relationships and enduring interactions with health professionals. CONCLUSION: Personalised support, both socially and professionally, is crucial for addressing fears, building resilience, reducing isolation and encouraging positive coping strategies for individuals with SMI during external crises. In this project, a participatory research approach that integrated the lived experience perspective helped uncover the unique perceptions of people with SMI with regard to the pandemic and related restrictions. PATIENT OR PUBLIC CONTRIBUTION: The study used a participatory action research approach, with experts-by-experience involved in every stage of the project as part of the research team. This included engagement with the funding application process, recruitment strategies for interviews, developing the interview guide, piloting the interview, interpreting findings, and knowledge dissemination activities.

fMRI connectivity as a biomarker of antipsychotic treatment response: A systematic review.

BACKGROUND: Antipsychotic drugs are the first-choice therapy for psychotic episodes, but antipsychotic treatment response (AP-R) is unpredictable and only becomes clear after weeks of therapy. A biomarker for AP-R is currently unavailable. We reviewed the evidence for the hypothesis that functional magnetic resonance imaging functional connectivity (fMRI-FC) is a predictor of AP-R or could serve as a biomarker for AP-R in psychosis. METHOD: A systematic review of longitudinal fMRI studies examining the predictive performance and relationship between FC and AP-R was performed following PRISMA guidelines. Technical and clinical aspects were critically assessed for the retrieved studies. We addressed three questions: Q1) is baseline fMRI-FC related to subsequent AP-R; Q2) is AP-R related to a change in fMRI-FC; and Q3) can baseline fMRI-FC predict subsequent AP-R? RESULTS: In total, 28 articles were included. Most studies were of good quality. fMRI-FC analysis pipelines included seed-based-, independent component- / canonical correlation analysis, network-based statistics, and graph-theoretical approaches. We found high heterogeneity in methodological approaches and results. For Q1 (N = 17) and Q2 (N = 18), the most consistent evidence was found for FC between the striatum and ventral attention network as a potential biomarker of AP-R. For Q3 (N = 9) accuracy's varied form 50 till 93%, and prediction models were based on FC between various brain regions. CONCLUSION: The current fMRI-FC literature on AP-R is hampered by heterogeneity of methodological approaches. Methodological uniformity and further improvement of the reliability and validity of fMRI connectivity analysis is needed before fMRI-FC analysis can have a place in clinical applications of antipsychotic treatment.

[Psychiatric symptoms and COVID-19: results of a national case register]. / Psychiatrische symptomen en COVID-19: resultaten uit een landelijk register.

BACKGROUND: Psychiatric disorders are associated with a more severe course of COVID-19. COVID-19 can also lead to psychiatric symptoms. AIM: To gain insight into vulnerabilities and protective factors for the course of COVID-19 in a Dutch (neuro)psychiatric population. METHOD: Patients were divided into three groups: patients with pre-existent mental disorders without and with new (neuro)psychiatric symptoms (NPS) during COVID-19 and patients without pre-existent mental disorders who developed de novo NPS during COVID-19. We summarize the characteristics of each group and compare the subgroups with inferential statistics. RESULTS: 186 patients were included in the case register. Patients with NPS showed a more severe course of COVID-19. Mortality in patients with NPS was higher in patients with pre-existent mental disorders compared to patients without pre-existent mental disorders. The most frequently reported de novo psychiatric symptoms during COVID-19 were delirium (46-70%), anxiety (53-54%) and insomnia (18-42%). CONCLUSION: NPS might be an expression of a more severe COVID-19 episode. In patients who developed NPS during COVID-19 we found evidence for a higher mortality risk in patients with pre-existent mental disorders. Extra vigilance for neuropsychiatric symptoms during COVID-19 is warranted.

[Tapering of psychotropic drugs: current practice and needs of patients and their relatives]. / Deprescriptie van psychofarmaca; praktijk en behoeften van patiënten en naasten.

BACKGROUND: The prevalence of mental illness has remained stable in recent decades, yet the use of psychotropic drugs has increased. This trend suggests that psychotropic drugs are being prescribed with an unnecessary frequency. Internationally, there is growing attention for deprescribing. AIM: To investigate what experiences and needs patients and their loved ones/relatives have with regard to deprescribing of psychotropics. METHOD: An online questionnaire was distributed among members of the MIND mental health care panel, which consists of (former) patients with a psychiatric disorder and their loved ones. RESULTS: A total of 564 respondents took part in this survey. Most patients have phased out/stopped their psychotropic drugs (83.8%). This was usually done at the initiative of the patient (66.7%), in consultation with the practitioner (72.9%). The practitioner only took the initiative to deprescribe in 15.1% of the cases. In 68.6% tapering was not discussed at the start of psychotropic drug use. Patients did not experience willingness from practitioners in deprescribing, and would like to discuss deprescribing more often (79.5%). CONCLUSION: There is an undeniable demand among patients and near ones for more emphasis on deprescribing of psychotropic drugs. We advise to include this topic in the shared decision making process.

Effectiveness and implementation of a multidisciplinary lifestyle focused approach in the treatment of inpatients with mental illness (MULTI +): a stepped wedge study protocol.

BACKGROUND: People with mental illness have a reduced life expectancy compared to the general population. Despite the increasing evidence for the efficacy of lifestyle interventions there is little change in routine clinical care. This discrepancy is often referred to as the implementation gap and has caused a need for effectiveness and implementation research in real-world settings. Our study assesses the effectiveness and implementation of a multidisciplinary lifestyle focused approach in the treatment of inpatients with mental illness (MULTI +). METHODS: An open cohort stepped wedge cluster randomized trial in inpatients psychiatric wards of GGz Centraal, the Netherlands. The wards are divided into three clusters based on geographical region. These clusters are randomly allocated to one of the three pre-defined steps to integrate MULTI + . MULTI + can be tailored to fit individual psychiatric wards and includes 10 core components aimed at improving lifestyle factors. The primary outcome is to investigate the difference in the mean QRISK3 score of patients receiving MULTI + compared to patients receiving TAU. Secondary outcomes include somatic and mental health outcomes, lifestyle factors, and implementation factors. Findings will be analysed using mixed model analyses. DISCUSSION: The MULTI + study is the first large-scale study evaluating the long-term effects of a multidisciplinary, multicomponent approach aimed at improving lifestyle factors in routine inpatient mental health care. A limitation of this study is the risk of missing data due to the large-scale, real-world setting of this study. Furthermore, implementation monitoring and external events that may influence outcomes could be difficult to account for. Strengths of this study are the focus on effectiveness as well as implementation and the inclusion of both patient and health care professionals' perspectives. Effectiveness studies in routine clinical care can advance our knowledge on lifestyle interventions in real-world settings. TRIAL REGISTRATION: ClinicalTrials.gov registration. Identifier: NCT04922749 . Retrospectively registered 3th of June 2021.

Beloop van covid-19-infecties en impact op mentale gezondheid; opzet van een landelijk casusregister.

Course of covid-19 infections and impact on mental health; setting up a national case register.

[Evidence based eHealth applications targeting improvement of lifestyle habits of people with severe mental illness]. / Evidence-based e-healthtoepassingen op het gebied van leefstijl in de psychiatrie.

BACKGROUND: People with severe mental illness (smi) often suffer from long lasting psychiatric symptoms, have a lower quality of life and a worse physical condition compared to the general population. Healthy lifestyle habits improve mental and physical health. EHealth (digital applications in healthcare) could play a role in the improvement of lifestyle habits in this population.
AIM: To provide an overview of evidence based eHealth applications targeting improvement of lifestyle habits of people with smi.
METHOD: We performed a narrative rapid review.
RESULTS: There are many eHealth applications targeting improvement of lifestyle habits, but few are specifically targeting the psychiatric population and evidence based. Most studies concerned small pilot studies.
CONCLUSION: EHealth applications might be used as a support in the guidance and treatment of unhealthy lifestyle habits in people with smi, however more research is needed.

[Regional healthcare labels: differences in care needs and psychosocial functioning]. / Regionale zorgvignetten: verschillen in zorgbehoeften en psychosociaal functioneren.

BACKGROUND: Severe mental illnesses (SMI) are associated with high mental healthcare and other healthcare costs. In 2012, mental healthcare labels were developed to create more transparency between insurance companies, municipalities, and mental healthcare. The labels are based on care intensity, and should provide a regional overview of the present groups of patients with SMI.
AIM: Explore the functionality and validity of the used labels in relation to needs for care and psychosocial functioning.
METHOD: The ROM data (needs for care, functioning) from 706 patients were tested per label by Chi-square tests and ANOVAs. For two high complex labels (alarming care avoiders and persons with safety risks), repeated measures ANOVAs and McNemar tests were used to analyse changes in functioning and needs over time.
RESULTS: To a limited extent, the labels were distinctive in care needs and functioning. The most restrictions in functioning and (unfulfilled) needs were present in the labels 'alarming care avoiders' and 'avoiding danger'. These findings were stable over time.
CONCLUSION: The labels are not sufficiently distinctive. To enhance regional care planning, it is desirable to combine existing information on healthcare labels with information on care needs and functioning. KEY WORDS functioning, mental healthcare labels, needs for care, routine outcome monitoring, severe mental illness.

[Integral care necessary for patients with complex somatic, psychic and social problems]. / Integrale zorg vereist voor patiënten met complexe somatische, psychische en sociale problematiek.

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[Residents in supported housing and factors related to moving towards independent living]. / RIBW-bewoners en de factoren die samenhangen met een overgang naar een andere woonsituatie.

BACKGROUND: Few data are available on predictors for the transition of individuals with mental illness to more independent forms of housing.
AIM: To analyse which variables predict the transition of individuals with severe mental illness from supported housing within the Dutch community housing programs (CHP) to more independent ways of living.
METHOD: Data of 1569 participants were analysed using Cox regression analysis.
RESULTS: Individuals with a personality disorder, current alcohol misuse or who received ambulant care prior to admission in CHP had the highest probability of moving to a more independent way of living. Individuals who received clinical care prior to admission in CHP, individuals with admission in Supported Housing, and individuals with a history of substance dependency had the highest probability of clinical relapse.
CONCLUSION: The predictors found in this study can be used as a starting point both for hypotheses for additional aetiological research and for guidelines covering specific interventions.

Reward-related brain structures are smaller in patients with schizophrenia and comorbid metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MS) is highly prevalent in schizophrenia and often a consequence of unhealthy behaviour. Reward-related brain areas might be associated with MS, since they play a major role in regulating health behaviour. This study examined the relationship between MS and brain volumes related to the reward system in schizophrenia. METHOD: We included patients with schizophrenia, with MS (MS+; n = 23), patients with schizophrenia, without MS (MS-; n = 48), and healthy controls (n = 54). Global brain volumes and volumes of (sub)cortical areas, part of the reward circuit, were compared between patients and controls. In case of a significant brain volume difference between patients and controls, the impact of MS in schizophrenia was examined. RESULTS: Patients had smaller total brain (TB; P = 0.001), GM (P = 0.010), larger ventricles (P = 0.026), and smaller reward circuit volume (P < 0.001) than controls. MS+ had smaller TB (P = 0.017), GM (P = 0.008), larger ventricles (P = 0.015), and smaller reward circuit volume (P = 0.002) than MS-. MS+ had smaller orbitofrontal cortex (OFC; P = 0.002) and insula volumes (P = 0.005) and smaller OFC (P = 0.008) and insula cortical surface area (P = 0.025) compared to MS-. CONCLUSION: In schizophrenia, structural brain volume reductions in areas of the reward circuitry appear to be related to comorbid MS.

Neural correlates of exercise training in individuals with schizophrenia and in healthy individuals: A systematic review.

A body of evidence has revealed positive effects of physical exercise on behavioral, cognitive and physical outcomes in patients with schizophrenia. Notably, the effect of exercise at the neural level may be particularly relevant as well as it is hypothesized that exercise may stimulate the brain in a way that might normalize neural alterations related to the disorder. The aim of the current systematic review was to provide an up to date overview of studies investigating the neural effects of exercise in individuals with a schizophrenia spectrum disorder and healthy individuals. The majority of included studies focused on hippocampal effects, reporting beneficial effects of exercise. In addition, in schizophrenia increased extrastriate body area (EBA) activation and increased white matter fiber integrity in tracts relevant to the disorder were found and in healthy individuals decreased connectivity of the dorsolateral prefrontal cortex (DLPFC) indicating greater cognitive efficiency was reported. Comparing individuals with a schizophrenia spectrum disorder and healthy individuals within a similar age range, most studies found similar effects on hippocampal volume and white matter tracts for both groups, although the effect in schizophrenia spectrum disorders may be attenuated which is in line with previous literature on brain plasticity. The current review indicates a lack of studies investigating neural correlates other than the hippocampus. Although those studies that did focus on other neural correlates revealed promising results, these have not been replicated in other studies and call for replication. Furthermore, future studies should expand their focus, by investigating neural mechanisms underlying positive effects of physical exercise on positive symptoms, negative symptoms and symptoms such as depression, social withdrawal and social cognition.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia.

Emerging evidence suggests schizophrenia to involve widespread alterations in the macroscale wiring architecture of the human connectome. Recent findings of attenuated connectome alterations in unaffected siblings of schizophrenia patients suggest that altered connectome organization may relate to the vulnerability to develop the disorder, but whether it relates to progression of illness after disease onset is currently unknown. Here, we examined the interaction between connectome structure and longitudinal changes in general functioning, clinical symptoms and IQ in the 3years following MRI assessment in a group of chronically ill schizophrenia patients. Effects in patients were compared to associations between connectome organization and changes in subclinical symptoms and IQ in healthy controls and unaffected siblings of schizophrenia patients. Analyzing the patient sample revealed a relationship between structural connectivity-particularly among central 'brain hubs'-and progressive changes in general functioning (p=0.007), suggesting that more prominent impairments of hub connectivity may herald future functional decline. Our findings further indicate that affected local connectome organization relates to longitudinal increases in overall PANSS symptoms (p=0.013) and decreases in total IQ (p=0.003), independent of baseline symptoms and IQ. No significant associations were observed in controls and siblings, suggesting that the findings in patients represent effects of ongoing illness, as opposed to normal time-related changes. In all, our findings suggest connectome structure to have predictive value for the course of illness in schizophrenia.