Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology

AbstractDeficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.</jats:p

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin.</p

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score &lt; −2, and 23% of patients (17% of women and 29% of men) displayed −2.5 &lt; T-scores &lt; –1 indicating osteopenia, but none had osteoporosis. After treatment, PINP decreased at trend level significance (P = 0.05), and body mass index BMD increased for L2–L4 (P = 0.016). No changes in bone markers were significant after correction for mean prolactin levels.Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin

Effect of GLP-1 Receptor Agonist Treatment on Body weight in Obese Antipsychotic-treated Patients with Schizophrenia:a Randomized, Placebo-controlled Trial Byline

AIMS: Schizophrenia is associated with cardiovascular co‐morbidity and a reduced life‐expectancy of up to 20 years. Antipsychotics are dopamine D(2) receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP‐1RA, exenatide once‐weekly, in non‐diabetic, antipsychotic‐treated, obese patients with schizophrenia. MATERIAL AND METHODS: Antipsychotic‐treated, obese, non‐diabetic, schizophrenia spectrum patients were randomized to double‐blinded adjunctive treatment with once‐weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. RESULTS: Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. CONCLUSIONS: Treatment with exenatide once‐weekly did not promote weight loss in obese, antipsychotic‐treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight‐lowering effect of GLP‐1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti‐obesity regimens effective in the general population may not be readily implemented in antipsychotic‐treated patients with schizophrenia

Widespread higher fractional anisotropy associates to better cognitive functions in individuals at ultra-high risk for psychosis

In schizophrenia patients, cognitive functions appear linked to widespread alterations in cerebral white matter microstructure. Here we examine patterns of associations between regional white matter and cognitive functions in individuals at ultra-high risk for psychosis. One hundred and sixteen individuals at ultra-high risk for psychosis and 49 matched healthy controls underwent 3 T magnetic resonance diffusion-weighted imaging and cognitive assessments. Group differences on fractional anisotropy were tested using tract-based spatial statistics. Group differences in cognitive functions, voxel-wise as well as regional fractional anisotropy were tested using univariate general linear modeling. Multivariate partial least squares correlation analyses tested for associations between patterns of regional fractional anisotropy and cognitive functions. Univariate analyses revealed significant impairments on cognitive functions and lower fractional anisotropy in superior longitudinal fasciculus and cingulate gyrus in individuals at ultra-high risk for psychosis. Partial least squares correlation analysis revealed different associations between patterns of regional fractional anisotropy and cognitive functions in individuals at ultra-high risk for psychosis compared to healthy controls. Widespread higher fractional anisotropy was associated with better cognitive functioning for individuals at ultra-high risk for psychosis, but not for the healthy controls. Furthermore, patterns of cognitive functions were associated with an interaction-effect on regional fractional anisotropy in fornix, medial lemniscus, uncinate fasciculus, and superior cerebellar peduncle. Aberrant associations between patterns of cognitive functions to white matter may be explained by dysmyelination

Macroscale EEG characteristics in antipsychotic-naïve patients with first-episode psychosis and healthy controls

Electroencephalography in patients with a first episode of psychosis (FEP) may contribute to the diagnosis and treatment response prediction. Findings in the literature vary due to small sample sizes, medication effects, and variable illness duration. We studied macroscale resting-state EEG characteristics of antipsychotic naïve patients with FEP. We tested (1) for differences between FEP patients and controls, (2) if EEG could be used to classify patients as FEP, and (3) if EEG could be used to predict treatment response to antipsychotic medication. In total, we studied EEG recordings of 62 antipsychotic-naïve patients with FEP and 106 healthy controls. Spectral power, phase-based and amplitude-based functional connectivity, and macroscale network characteristics were analyzed, resulting in 60 EEG variables across four frequency bands. Positive and Negative Symptom Scale (PANSS) were assessed at baseline and 4–6 weeks follow-up after treatment with amisulpride or aripiprazole. Mann-Whitney U tests, a random forest (RF) classifier and RF regression were used for statistical analysis. Our study found that at baseline, FEP patients did not differ from controls in any of the EEG characteristics. A random forest classifier showed chance-level discrimination between patients and controls. The random forest regression explained 23% variance in positive symptom reduction after treatment in the patient group. In conclusion, in this largest antipsychotic- naïve EEG sample to date in FEP patients, we found no differences in macroscale EEG characteristics between patients with FEP and healthy controls. However, these EEG characteristics did show predictive value for positive symptom reduction following treatment with antipsychotic medication

Maternal dietary patterns, breastfeeding duration, and their association with child cognitive function and head circumference growth:A prospective mother-child cohort study

Background Early life is a critical period for neurodevelopment, where factors such as maternal nutrition and breastfeeding duration significantly impact the growth of head circumference and cognitive development in children. Our study aimed to explore the associations between maternal dietary patterns during pregnancy, duration of breastfeeding, and their impacts on child head circumference and cognitive outcomes. Methods and findings Our study utilised data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort, which enrolled 700 mother–child pairs between 2008 and 2010 with 86% clinical follow-up at age 10. Pregnancy dietary patterns, described as ‘Varied’ and ‘Western,’ were derived from food frequency questionnaires and used to model quantitative metabolite scores via sparse partial least squares modelling of blood metabolome data. Cognitive development was assessed using the Bayley Scales of Infant Development at 2.5 years and the Wechsler Intelligence Scale for Children at age 10. Head circumference was measured from 20 weeks gestation to 10 years, and calibrated using related anthropometric measures. Growth trajectories were evaluated using linear mixed models and latent class trajectory models. Parental and child genetic influences for cognition and head circumference were controlled by including polygenic risk scores derived from genomic data. We found that a Western dietary pattern during pregnancy was associated with lower cognitive scores at age 2.5 (β −1.24 [−2.16, −0.32], p=0.008) and reduced head circumference growth (p-interaction &lt;0.0001). We found that a Varied dietary pattern during pregnancy was associated with higher estimated intelligence quotient (IQ) at age 10 (β 1.29 [0.27, 2.3], p=0.014). Additionally, head circumference growth was associated with higher cognitive scores at age 10 (β 3.40 [1.21, 5.60], p=0.002), and it partly mediates the association between the Varied dietary pattern and estimated IQ (proportion mediated 13.5% [0.01, 0.71], p=0.034). Extended breastfeeding duration was also independently associated with increased head circumference growth (p-interaction &lt;0.0001). These patterns and correlations were consistent even after adjusting for potential confounders and accounting for genetic influences. Conclusions Our findings reveal that a Western dietary pattern during pregnancy is associated with lower cognitive scores at age 2.5 and decreased head circumference growth, suggesting potential adverse impacts on early neurodevelopment. Conversely, a Varied dietary pattern is linked with a higher estimated IQ at age 10, with head circumference growth contributing to this positive outcome. These findings highlight the critical role of maternal nutrition during pregnancy, and duration of breastfeeding, in promoting optimal neurodevelopmental outcomes. Effective public health strategies should therefore focus on enhancing maternal dietary practices to support better cognitive and physical development in children.</p

Mortality and HRQoL in ICU patients with delirium : Protocol for 1-year follow-up of AID-ICU trial

Background Intensive care unit (ICU)-acquired delirium is frequent and associated with poor short- and long-term outcomes for patients in ICUs. It therefore constitutes a major healthcare problem. Despite limited evidence, haloperidol is the most frequently used pharmacological intervention against ICU-acquired delirium. Agents intervening against Delirium in the ICU (AID-ICU) is an international, multicentre, randomised, blinded, placebo-controlled trial investigates benefits and harms of treatment with haloperidol in patients with ICU-acquired delirium. The current pre-planned one-year follow-up study of the AID-ICU trial population aims to explore the effects of haloperidol on one-year mortality and health related quality of life (HRQoL). Methods The AID-ICU trial will include 1000 participants. One-year mortality will be obtained from the trial sites; we will validate the vital status of Danish participants using the Danish National Health Data Registers. Mortality will be analysed by Cox-regression and visualized by Kaplan-Meier curves tested for significance using the log-rank test. We will obtain HRQoL data using the EQ-5D instrument. HRQoL analysis will be performed using a general linear model adjusted for stratification variables. Deceased participants will be designated the worst possible value. Results We expect to publish results of this study in 2022. Conclusion We expect that this one-year follow-up study of participants with ICU-acquired delirium allocated to haloperidol vs. placebo will provide important information on the long-term consequences of delirium including the effects of haloperidol. We expect that our results will improve the care of this vulnerable patient group.Peer reviewe

COVID-19 lockdown, genetic ADHD susceptibility, and mental health in 10- year-old children

Previous studies report that the COVID-19 lockdown had an impact on the mental health of the pediatric population. In this study, we harness the deep neuropsychiatric phenotyping of the population-based COPSAC2010 (n = 700) cohort at age 10 to study the impact of the COVID-19 lockdown on mental health outcomes with focus on the role of the genetic vulnerability to attention-deficit/hyperactivity disorder (ADHD), in the form of polygenic risk scores (PRS). A total of 593 children were examined between 2019 and 2021, resulting in two groups of different children, those evaluated before the lockdown (n = 230) and those evaluated after (n = 363). Children assessed after the lockdown presented higher odds of being diagnosed with ADHD and had significantly higher scores in most neuropsychiatric scales, particularly in subscales pertaining to behavior and attention problems. We observed a significant interaction between the lockdown and ADHD PRS on several neuropsychiatric dimensions, with a large post-lockdown increase in children with a high PRS, while there was little to no pre-post difference in children with low PRS. These results indicate mental health consequences of the lockdown in children and suggest that genetically susceptible individuals are more affected by such stressors in childhood.</p