To Örebro University

Antipsychotics are mainly used for severe psychiatric disorders. Risperidone is the only antipsychotic approved for younger children. Aripiprazole is approved for older children, ziprasidone and lurasidone for adolescents. To describe paediatric utilisation of antipsychotic drugs in Sweden. Dispensations of antipsychotic drugs to children aged 5-17 years from 2008 to 2021 were analysed using the National Prescribed Drug Register and recorded diagnoses were obtained from the National Patient Register. Overall, dispensations of antipsychotics to children increased from 16.7 to 36.9/10,000 between 2008 and 2021. The increase was larger in girls, from 12.3 to 36.6/10,000. New users of antipsychotics increased by 121% in the same period, from 7.9 to 17.5/10.000. In 2019, in children aged 12-17, 63% of girls and 71% of boys were dispensed had at least three dispensations of antipsychotics, while the corresponding proportion in children aged 5-11 were 52% for girls and 63% for boys. Risperidone was the most common drug in boys of all ages and in girls aged 5-11. In girls aged 12-17, aripiprazole and quetiapine were most common. The proportion of on-label antipsychotic use was 21% in girls and 15% in boys based in authorised product information and increased to 37% and 45%, respectively, when aligning with national guidelines. The use of antipsychotics has increased, with the proportion of girls starting treatment at the end of study period exceeding that of boys. A considerable proportion of prescriptions was off-label, even when considering national guidelines.

PURPOSE: This study aims to assess the risk of metabolic side effects among paediatric new users of antipsychotics in Sweden, focusing on differences between substances and sexes.

METHODS: Children aged 5-17 years, who were new users of antipsychotics between 2014 and 2021, were identified using Swedish national health registers. Cox' models were fitted for children during first treatment with an antipsychotic, excluding those with eating disorders, yielding hazard ratios (HRs) for metabolic side effects with 95% confidence intervals (CIs).

RESULTS: A total of 5441 children were new users of antipsychotics. Of these, 399 (7.3%; 42% girls) received a new diagnosis or new treatment indicating a metabolic side effect, of which 139 cases during first-line treatment and without an eating disorder diagnosis. Obesity was the most common metabolic side effect, accounting for 69% of the cases. In girls, significantly increased risks were observed for aripiprazole (HR 3.52, 95% CI 1.58-7.80), olanzapine (HR 6.99, 95% CI 2.34-20.93) and quetiapine (HR 4.87, 95% CI 1.97-12.04), compared with risperidone. Younger girls had higher risks. In boys, a significantly increased risk was found for aripiprazole (HR 2.21, 95% CI 1.37-3.56).

CONCLUSION: The overall risk of metabolic side effects is considerable, with higher relative risks in girls, especially younger girls. These findings highlight the need for carefully considered treatment and attentive monitoring when initiating antipsychotics in children.

BACKGROUND: One third of patients with schizophrenia do not achieve remission with current antipsychotic treatments. Converging data support an immune-mediated component in a subset of cases, overlapping with autoimmune CNS disorders. The B-cell-depleting monoclonal antibody rituximab is used in diseases such as multiple sclerosis and has been explored as an immunomodulatory strategy. We investigated plasma biomarkers, focusing on T-helper-related transcription factors, in relation to outcome after rituximab in schizophrenia.

METHODS: Nineteen severely ill, treatment-resistant patients (n = 9 with schizophrenia and n = 10 with obsessive-compulsive disorder [OCD]) included in an open-label pilot trial, received a single 1000 mg intravenous infusion of rituximab. Symptoms were assessed at baseline and week 12 using PANSS or Y-BOCS, global functioning with PSP, and improvement with CGI-I. Response was defined as "much" or "very much improved" on CGI-I at week 12. For the present analyses, we compared schizophrenia responders with a combined group of schizophrenia and OCD non-responders. Plasma and whole blood were collected at baseline and week 12. Multiplex cytokines and RT-qPCR for the expression of 13 genes coding for cytokines and T-cell-related transcription factors were analyzed, including Th1 and Th17 master regulators TBX21 (T-bet) and RORC (RORγt), respectively. We also constructed a composite rank score combining TBX21 and RORC expression (sum of their within-sample ranks).

RESULTS: Six out of eight schizophrenia patients were classified as responders and showed large symptomatic improvement (median PANSS change -70.1) and marked functional gain (median PSP +22.5). Within the analytic sample, schizophrenia responders (n = 6) had higher baseline TBX21 and RORC expression than non-responders (n = 8). Baseline TBX21 correlated with PSP improvement at week 12 (rs = 0.675, p < 0.01). The TBX21+RORC composite rank score showed the strongest association with outcome (higher in responders, p < 0.001; correlated with PSP gain, rs = 0.793, p < 0.001). Classical inflammatory markers, including IL-6, TNF-α and high-sensitivity C-reactive protein, did not differentiate responders.

DISCUSSION: Elevated baseline expression of the Th1- and Th17-associated transcription factors TBX21 and RORC - particularly their combined composite rank score - was associated with symptomatic and functional response to rituximab in treatment-resistant schizophrenia. The data suggest that a TBX21/RORC-defined, Th1/Th17-skewed T-cell signature may characterize a rituximab-responsive immunopsychiatric subtype of schizophrenia, in which B-cell depletion may secondarily modulate pathogenic T-cell response. These findings should be viewed as preliminary and hypothesis-generating for future controlled studies.

Low motor competence (MC) has been associated with lower physical activity (PA) and long-term health risks in children. Less is known about sex-specific patterns and associations during early school age. The aim of this study was to explore how motor difficulties are associated with PA levels, screen time, and organised sports participation (OSP). Data from 479 children, seven years of age, participating in the Swedish Environmental, Longitudinal, Mother and child, Asthma, and allergy (SELMA) pregnancy cohort study were used. MC and activity-related outcomes were assessed with questionnaires answered by parents. Associations between MC and outcomes were evaluated using logistic regression models adjusted for sex, overweight, and parental education level. Sex differences were investigated with interaction analyses and in stratified models. Children with motor difficulties had the same level of PA as their peers, but more screen time and lower OSP. Compared with children with normal MC, boys with motor difficulties had lower rates of OSP, but girls did not. This indicates that the identification and compensatory support for motor difficulties for boys at an early age, as well as the development of inclusive leisure time activities, are of importance to facilitate health-promoting activities on equal terms.

BACKGROUND: Some endocrine disrupting chemicals (EDC), are "obesogens" and have been associated with overweight and obesity in children. Daily exposure to different classes of EDCs demands for research with mixtures approach.

OBJECTIVES: This study evaluates the association, considering sex-specific effects, between prenatal exposure to EDC mixture and children's body fat at seven years of age. METHODS: A total of 26 EDCs were assessed in prenatal urine and serum samples from first trimester in pregnancy from 737 mother-child pairs participating in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. An indicator for children's "overall body fat" was calculated, using principal component analysis (PCA), based on BMI, percent body fat, waist, and skinfolds measured at seven years of age. Weighted quantile sum (WQS) regression was used to assess associations between EDC mixture and children's body fat.

RESULTS: Principal component (PC1) represented 83.6 % of the variance, suitable as indicator for children's "overall body fat", with positive loadings of 0.40-0.42 for each body fat measure. A significant interaction term, WQS*sex, confirmed associations in the opposite direction for boys and girls. Higher prenatal exposure to EDC mixture was borderline significant with more "overall body fat" for boys (Mean β = 0.20; 95 % CI: -0.13, 0.53) and less for girls (Mean β = -0.23; 95 % CI: -0.58, 0.13). Also, higher exposure to EDC mixture was borderline significant with more percent body fat (standardized score) for boys (Mean β = 0.09; 95 % CI: -0.04, 0.21) and less for girls (Mean β = -0.10 (-0.26, 0.05). The chemicals of concern included bisphenols, phthalates, PFAS, PAH, and pesticides with different patterns for boys and girls.

DISCUSSION: Borderline significant associations were found between prenatal exposure to a mixture of EDCs and children's body fat. The associations in opposite directions suggests that prenatal exposure to EDCs may present sex-specific effects on children's body fat.

AIM: Swedish guidelines for therapeutic hypothermia (TH) after perinatal asphyxia were established in 2007, following several randomised studies that demonstrated improved outcomes. We assessed the implementation of hypothermia treatment in a mid-Swedish region with a sizeable proportion of outborn infants.

METHOD: A population-based TH cohort from 2007 to 2015 was scrutinised for adherence to national guidelines, interhospital transport, including the use of a cooling mattress made of phase change material for thermal management, and outcomes.

RESULTS: Of 136 admitted infants, 99 (73 %) were born outside the hospital. Ninety-eight percent fulfilled the criteria for postnatal depression/acidosis, and all patients had moderate-to-severe encephalopathy. Treatment was initiated within 6 h in 85 % of patients; amplitude-integrated electroencephalography/electroencephalography was recorded in 98 %, cranial ultrasound in 78 %, brain magnetic resonance imaging in 79 %, hearing tests in all, and follow-up was performed in 93 %. Although target body temperature was attained later (p < 0.01) in outborn than in inborn infants, at a mean (standard deviations) age of 6.2 (3.2) h vs 4.4 (2.6) h, 40 % of those transported using the cooling mattress were already within the therapeutic temperature range on arrival, and few were excessively cooled. The mortality rate was 23 %, and 38 % of the survivors had neurodevelopmental impairment at a median of 2.5 years.

CONCLUSION: The regionalisation of TH, including interhospital transport, was feasible and resulted in outcomes comparable to those of randomised controlled studies.

AIM: Extremely premature infants receive nutrition and medication through nasogastric tubes. Breastmilk given accordingly is subject to fat loss. This study aimed to investigate whether this could also apply to vitamin D.

METHODS: A questionnaire investigated vitamin D administration at a level III neonatal intensive care unit in Sweden in 2021. Feeding simulations with breastmilk and various vitamin D mixtures were done accordingly. After administration, vitamin D3 concentration was analysed using chromatography with mass spectrometry, followed by repeated simulations with vitamin D mixtures without breastmilk in 2023.

RESULTS: The questionnaire was completed by 10 persons. Vitamin D was administered as drops using an enteral syringe and a nasogastric tube in conjunction with a breastmilk meal. In the feeding simulations, vitamin D3 concentration after administration was significantly higher using a syringe alone compared to standard administration. When vitamins were administered according to standard but without breastmilk, 100% of the vitamin D and 40% of the multivitamins were lost. The vitamins adhered to the material, mainly in the nasogastric tube.

CONCLUSION: Our findings indicate that standard vitamin D supplementation in the neonatal intensive care unit may be unpredictable when administered by enteral syringe and nasogastric tube. We suggest using direct oral administration whenever possible.

Background: Prenatal exposure to mixtures of endocrine disrupting chemicals (EDC) has the potential to disrupt human metabolism. Prenatal periods are especially sensitive as many developmental processes are regulated by hormones. Prenatal exposure to EDCs has inconsistently been associated with children's body mass index (BMI) and obesity. The objective of this study was to investigate if prenatal exposure to a mixture of EDCs was associated with children's BMI and overweight (ISO-BMI ≥ 25) at 5.5 years of age, and if there were sex-specific effects.

Methods: A total of 1,105 mother-child pairs with complete data on prenatal EDCs concentrations (e.g., phthalates, non-phthalate plasticizers, phenols, PAH, pesticides, PFAS, organochlorine pesticides, and PCBs), children's measured height and weight, and selected covariates in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study were included in this analysis. The mixture effect of EDCs with children's BMI and overweight was assessed using WQS regression with 100 repeated holdouts. A positively associated WQS index with higher BMI and odds of overweight was derived. Models with interaction term and stratified weights by sex was applied in order to evaluate sex-specific associations.

Results: A significant WQS*sex interaction term was identified and associations for boys and girls were in opposite directions. Higher prenatal exposure to a mixture of EDCs was associated with lower BMI (Mean β = -0.19, 95%CI: -0.40, 0.01) and lower odds of overweight (Mean OR = 0.72, 95%CI: 0.48, 1.04) among girls with borderline significance. However, the association among boys did not reach statistical significance. Among girls, the possible chemicals of concern were MEP, 2-OHPH, BPF, BPS, DPP and PFNA.

Conclusion: Prenatal exposure to a mixture of EDCs was associated with lower BMI and overweight among girls, and non-significant associations among boys. Chemicals of concern for girls included phthalates, non-phthalate plasticizers, bisphenols, PAHs, and PFAS.

BACKGROUND: The role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance. The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture.

METHODS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research.

DISCUSSION: This is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma.

TRIAL REGISTRATION: NCT05622201, EudraCT-nr 2022-000220-37 version 2.1. registered 14th of October 2022.

OBJECTIVES: Digit ratio (2D:4D) might reflect prenatal testosterone exposure and has been used as a putative marker for androgen related outcomes. However, such associations might be inflicted by confounders. Application of 2D:4D in epidemiological research motivate identification of biological background determinants. We examined sex, anthropometric measures, and maternal factors as determinants of 2D:4D in Swedish 7-year-old children.

METHODS: The study was embedded in the Swedish Environmental, Longitudinal, Mother and Child, Asthma and Allergy (SELMA) pregnancy cohort. A total of 870 pre-pubertal children, median 7.5 years of age, were studied. A single assessor performed digit measurements from scanned photocopies using computer software. Child anthropometric measurements investigated were hand size, birthweight, recumbent birth length, standing height, weight, BMI, body fat percentage, and waist/hip circumference. Maternal factors included age, pregnancy length, parity, and education.

RESULTS: We found a significant sexual dimorphism regarding digit lengths and 2D:4D, boys on average presenting a lower 2D:4D than girls also after adjustment for summed finger lengths and body fatness. In crude analyses, maternal age correlated with 2D:4D across the whole population and in females but not in adjusted models. No other study variables were associated with 2D:4D.

CONCLUSION: Digit ratio showed sexual dimorphism at the age of seven and seems to represent a true sex difference rather than an artifact and bias from hand size, body size or body fat content. Among the rest of our investigated variables, we found no determinants constituting important confounders in future research on 2D:4D ratio.