Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Minor tranquillizers for short-term treatment of newly onset symptoms of anxiety and distress: a systematic review with network meta-analysis of randomized trials.

Unspecific symptoms of anxiety and distress are frequently encountered in patients in both general practice and acute psychiatric services. Minor tranquillizers may be a treatment option when non-pharmacological interventions are insufficient or unavailable. We conducted a systematic review with network meta-analysis of the evidence for short-term (1-4 weeks) pharmacological treatment of newly onset symptoms of anxiety and distress. We searched the PsycInfo, MEDLINE, EMBASE and Cochrane Library databases and extracted data following a predefined hierarchy of outcomes. We assessed risk of bias using the Cochrane Risk of Bias tool and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). We included 34 randomized trials comprising a total of 7044 patients with adjustment disorders or anxiety spectrum disorders. The network meta-analysis showed that regarding the critical outcome symptoms of anxiety within 1-4 weeks benzodiazepines (SMD - 0.58, 95% CI - 0.77 to - 0.40), quetiapine (SMD - 0.51, 95% CI - 0.90 to - 0.13) and pregabalin (SMD - 0.58, 95% CI - 0.87 to - 0.28) all performed better than placebo with no statistically significant difference between the drugs. Data on other important outcomes were inconsistently reported. Adverse effects varied, but overall, it was uncertain whether adverse effects differed between interventions. The evidence regarding the risk of dependence was uncertain, but dependence may be a concern in susceptible individuals even with short-term treatment. Overall, the certainty of the evidence according to GRADE was rated as low to very low across outcomes. Despite the limitations in the evidence, the results of this review can inform treatment guidelines, supporting clinicians in the choice of minor tranquillizer in this prevalent and help-seeking, clinically heterogeneous population.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Dimensional profiling of psychopathology in children and adolescents based on the K-SADS-PL and an analysis of the construct validity of two ADHD symptom dimensions.

OBJECTIVES: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification. METHODS: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls). RESULTS: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale. CONCLUSIONS: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.

Negative symptoms in First-Episode Schizophrenia related to morphometric alterations in orbitofrontal and superior temporal cortex: the OPTiMiSE study.

BACKGROUND: Negative symptoms are one of the most incapacitating features of Schizophrenia but their pathophysiology remains unclear. They have been linked to alterations in grey matter in several brain regions, but findings have been inconsistent. This may reflect the investigation of relatively small patient samples, and the confounding effects of chronic illness and exposure to antipsychotic medication. We sought to address these issues by investigating concurrently grey matter volumes (GMV) and cortical thickness (CTh) in a large sample of antipsychotic-naïve or minimally treated patients with First-Episode Schizophrenia (FES). METHODS: T1-weighted structural MRI brain scans were acquired from 180 antipsychotic-naïve or minimally treated patients recruited as part of the OPTiMiSE study. The sample was stratified into subgroups with (N = 88) or without (N = 92) Prominent Negative Symptoms (PMN), based on PANSS ratings at presentation. Regional GMV and CTh in the two groups were compared using Voxel-Based Morphometry (VBM) and FreeSurfer (FS). Between-group differences were corrected for multiple comparisons via Family-Wise Error (FWE) and Monte Carlo z-field simulation respectively at p < 0.05 (2-tailed). RESULTS: The presence of PMN symptoms was associated with larger left inferior orbitofrontal volume (p = 0.03) and greater CTh in the left lateral orbitofrontal gyrus (p = 0.007), but reduced CTh in the left superior temporal gyrus (p = 0.009). CONCLUSIONS: The findings highlight the role of orbitofrontal and temporal cortices in the pathogenesis of negative symptoms of Schizophrenia. As they were evident in generally untreated FEP patients, the results are unlikely to be related to effects of previous treatment or illness chronicity.

Fibre density and fibre-bundle cross-section of the corticospinal tract are distinctly linked to psychosis-specific symptoms in antipsychotic-naïve patients with first-episode schizophrenia.

Multiple lines of research support the dysconnectivity hypothesis of schizophrenia. However, findings on white matter (WM) alterations in patients with schizophrenia are widespread and non-specific. Confounding factors from magnetic resonance image (MRI) processing, clinical diversity, antipsychotic exposure, and substance use may underlie some of the variability. By application of refined methodology and careful sampling, we rectified common confounders investigating WM and symptom correlates in a sample of strictly antipsychotic-naïve first-episode patients with schizophrenia. Eighty-six patients and 112 matched controls underwent diffusion MRI. Using fixel-based analysis (FBA), we extracted fibre-specific measures such as fibre density and fibre-bundle cross-section. Group differences on fixel-wise measures were examined with multivariate general linear modelling. Psychopathology was assessed with the Positive and Negative Syndrome Scale. We separately tested multivariate correlations between fixel-wise measures and predefined psychosis-specific versus anxio-depressive symptoms. Results were corrected for multiple comparisons. Patients displayed reduced fibre density in the body of corpus callosum and in the middle cerebellar peduncle. Fibre density and fibre-bundle cross-section of the corticospinal tract were positively correlated with suspiciousness/persecution, and negatively correlated with delusions. Fibre-bundle cross-section of isthmus of corpus callosum and hallucinatory behaviour were negatively correlated. Fibre density and fibre-bundle cross-section of genu and splenium of corpus callosum were negative correlated with anxio-depressive symptoms. FBA revealed fibre-specific properties of WM abnormalities in patients and differentiated associations between WM and psychosis-specific versus anxio-depressive symptoms. Our findings encourage an itemised approach to investigate the relationship between WM microstructure and clinical symptoms in patients with schizophrenia.

Clustering of antipsychotic-naïve patients with schizophrenia based on functional connectivity from resting-state electroencephalography.

Schizophrenia is associated with aberrations in the Default Mode Network (DMN), but the clinical implications remain unclear. We applied data-driven, unsupervised machine learning based on resting-state electroencephalography (rsEEG) functional connectivity within the DMN to cluster antipsychotic-naïve patients with first-episode schizophrenia. The identified clusters were investigated with respect to psychopathological profile and cognitive deficits. Thirty-seven antipsychotic-naïve, first-episode patients with schizophrenia (mean age 24.4 (5.4); 59.5% males) and 97 matched healthy controls (mean age 24.0 (5.1); 52.6% males) underwent assessments of rsEEG, psychopathology, and cognition. Source-localized, frequency-dependent functional connectivity was estimated using Phase Lag Index (PLI). The DMN-PLI was factorized for each frequency band using principal component analysis. Clusters of patients were identified using a Gaussian mixture model and neurocognitive and psychopathological profiles of identified clusters were explored. We identified two clusters of patients based on the theta band (4-8 Hz), and two clusters based on the beta band (12-30 Hz). Baseline psychopathology could predict theta clusters with an accuracy of 69.4% (p = 0.003), primarily driven by negative symptoms. Five a priori selected cognitive functions conjointly predicted the beta clusters with an accuracy of 63.6% (p = 0.034). The two beta clusters displayed higher and lower DMN connectivity, respectively, compared to healthy controls. In conclusion, the functional connectivity within the DMN provides a novel, data-driven means to stratify patients into clinically relevant clusters. The results support the notion of biological subgroups in schizophrenia and endorse the application of data-driven methods to recognize pathophysiological patterns at earliest stage of this syndrome.

Value of gym-based group exercise versus usual care for young adults receiving antipsychotic medication: study protocol for the multicenter randomized controlled Vega trial.

BACKGROUND: Exercise is recommended to protect physical health among people with severe mental illness and holds the potential to facilitate long-term recovery. An inclusive exercise community provides an opportunity for life skill training and social connectedness and may reduce the experience of loneliness and internalized stigmatization which together may improve personal recovery. Using a pragmatic randomized design, we aim to examine the effectiveness of a gym-based exercise intervention tailored to young adults in antipsychotic treatment (i.e., Vega Exercise Community) compared to usual care. It is hypothesized that the Vega Exercise Community will be superior to usual care for personal recovery at four months. METHODS: The trial will be conducted at four sites in Denmark from which 400 participants, aged 18 to 35 years, who are in current treatment with antipsychotic medications for the management of schizophrenia spectrum or affective disorders, will be recruited. Participants will be randomized (2:1) to Vega Exercise Community or usual care. Vega Exercise Community includes three weekly group-based exercise sessions hosted in commercial functional training centers delivered by certified Vega instructors. After four months, participants in Vega Exercise Community will be randomized (1:1) to minimal versus extended support with regards to sustained physical activity. Data will be collected at baseline, four, six and 12 months. The primary outcome is personal recovery assessed by Questionnaire about the Process of Recovery at four months. Behavioral symptoms, health-related quality of life, metabolic health, and program costs will be evaluated to further determine the effectiveness and cost-effectiveness of the Vega Exercise Community. Finally, the quality of life and physical and mental health of the participants' primary relative will be evaluated. DISCUSSION: The results of this trial may have important implications for health, sustained physical activity, and recovery for individuals in treatment with antipsychotics. Given the pragmatic design, positive results may readily be implemented by mental health care professionals to promote exercise as an integrated part of treatment of severe mental illness. TRIAL REGISTRATION: Clinical Trials.gov (NCT05461885, initial registration June 29th, 2022). WHO Universal Trial Number (UTN): U1111-1271-9928.

Lower Vitamin C Levels Are Associated With Less Improvement in Negative Symptoms in Initially Antipsychotic-Naïve Patients With First-Episode Psychosis.

Low levels of vitamin C have been observed in patients with schizophrenia and psychosis, and vitamin C may affect the dopaminergic system. Likewise, antipsychotic medication modulates striatal dopamine D2 receptors. We measured vitamin C levels in 52 patients with first-episode psychoses (24 females, age 23.1 ± 5.2 years) and 57 matched HCs (20 females, age 22.7 ± 4.3 years) before and after 6 weeks where patients received aripiprazole monotherapy (mean dose 10.4 mg ± 4.8 mg). At baseline, patients displayed lower levels of vitamin C (57.4 ± 25.9 µM) than controls (72.7 ± 21.4 µM) (t = 3.4, P = .001). Baseline symptoms and vitamin C levels were not correlated. Higher baseline vitamin C levels were associated with more improvement in negative symptoms (n = 39, R2 = 0.20, F = 8.2, P = .007), but not with age, sex, or p-aripiprazole. Because negative symptoms are generally considered challenging to alleviate, a potential adjunctive effect of vitamin C on treatment response should be tested in future randomized clinical trials.

Scalability of the Positive and Negative Syndrome Scale in first-episode schizophrenia assessed by Rasch models.

OBJECTIVE: Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30-item PANSS total score as well as the scalability of a shorter version (PANSS-6) of the scale. METHODS: A composite data set of 1073 patients with first-episode schizophrenia or schizophrenia spectrum disorder was subjected to Rasch analysis of PANSS data from baseline and 4-6 weeks follow-up. RESULTS: The central tests of fit of the Rasch model failed to satisfy the statistical requirements behind item homogeneity for the PANSS-30 as well as the PANSS-6 total score. For the PANSS-30, Differential Item Functioning was pronounced both for the 7-point Likert scale rating categories and when dichotomizing the rating categories. Subsequently, the Rasch structure analysis in the context of dichotomized items was used to isolate and estimate a systematic error because of item inhomogeneity, as well as a random error. The size of the combined sources of error for the PANSS-30 total score approximated 20% which is often regarded as clinical cut-off between response versus no-response. CONCLUSION: The results demonstrate the operational consequences of a lack of statistical fit of the Rasch model and suggest that the calculated measure of uncertainty needs to be considered when using the PANSS-30 total score.

Differential effects of age at illness onset on verbal memory functions in antipsychotic-naïve schizophrenia patients aged 12-43 years.

BACKGROUND: The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition. METHODS: The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12-43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates. RESULTS: There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs. CONCLUSIONS: Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

Global fractional anisotropy predicts transition to psychosis after 12 months in individuals at ultra-high risk for psychosis.

OBJECTIVE: Psychosis spectrum disorders are associated with cerebral changes, but the prognostic value and clinical utility of these findings are unclear. Here, we applied a multivariate statistical model to examine the predictive accuracy of global white matter fractional anisotropy (FA) for transition to psychosis in individuals at ultra-high risk for psychosis (UHR). METHODS: 110 UHR individuals underwent 3 Tesla diffusion-weighted imaging and clinical assessments at baseline, and after 6 and 12 months. Using logistic regression, we examined the reliability of global FA at baseline as a predictor for psychosis transition after 12 months. We tested the predictive accuracy, sensitivity and specificity of global FA in a multivariate prediction model accounting for potential confounders to FA (head motion in scanner, age, gender, antipsychotic medication, parental socioeconomic status and activity level). In secondary analyses, we tested FA as a predictor of clinical symptoms and functional level using multivariate linear regression. RESULTS: Ten UHR individuals had transitioned to psychosis after 12 months (9%). The model reliably predicted transition at 12 months (χ2  = 17.595, p = 0.040), accounted for 15-33% of the variance in transition outcome with a sensitivity of 0.70, a specificity of 0.88 and AUC of 0.87. Global FA predicted level of UHR symptoms (R2  = 0.055, F = 6.084, p = 0.016) and functional level (R2  = 0.040, F = 4.57, p = 0.036) at 6 months, but not at 12 months. CONCLUSION: Global FA provided prognostic information on clinical outcome and symptom course of UHR individuals. Our findings suggest that the application of prediction models including neuroimaging data can inform clinical management on risk for psychosis transition.

Fish Oil Supplementation in Pregnancy and Neurodevelopment in Childhood-A Randomized Clinical Trial.

A double-blind randomized controlled trial of n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation or matching placebo during third trimester of pregnancy was conducted within the COPSAC2010 mother-child cohort consisting of 736 women and their children. The objective was to determine if maternal n-3 LCPUFA pregnancy supplementation affects offspring neurodevelopment until 6 years. Neurodevelopment was evaluated in 654 children assessing age of motor milestone achievement, language development, cognitive development, general neurodevelopment, and emotional and behavioral problems. Maternal n-3 LCPUFA supplementation during pregnancy improved early language development and reduced the impact of emotional and behavioral problems. The n-3 LCPUFA supplementation was in boys associated with the earlier achievement of gross motor milestones, improved cognitive development, and a reduced impact of emotional and behavioral problems.

Risk factors for long-term cognitive impairment in ICU survivors: A multicenter, prospective cohort study.

PURPOSE: To describe the incidence of and risk factors for impaired cognitive function in intensive care unit (ICU) survivors. We hypothesized that age, severity of illness, and days in coma, delirium, mechanical ventilation in the ICU would be associated with impaired cognitive function. METHODS: We included all adults, alive 6 months after acute admission to one of the 24 Danish ICUs participating in the AID-ICU cohort study. Trained professionals assessed cognitive function in patients' homes or in outpatient clinics using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 6 months after ICU admission. Potential risk factors for cognitive impairment were analyzed with linear regression models. RESULTS: In total, 237 ICU patients were alive 6 months after ICU admission and did not meet the exclusion criteria. A total of 106 patients completed the cognitive assessment. The median RBANS global cognitive score was 76 (interquartile range, 62-91), and 52% had a global cognitive score 1.5 SD below the normative mean and 36% displayed a global cognitive score 2 SD below the normative mean, similar to that of Alzheimer's disease. Higher age was associated with poorer RBANS global cognitive score (estimate -0.35 [95% confidence interval -0.63 to -0.07] per year). CONCLUSIONS: In this multicenter study of adult ICU survivors, cognitive impairment was frequent and severe in those assessed at 6 months. Higher age was a risk factor for cognitive impairment, but events related to the ICU stay were not associated with poorer cognitive performance at 6 months.

Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis.

BACKGROUND: Poor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs). METHODS: Thirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response. RESULTS: Before treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ. CONCLUSION: Glutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

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.

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.

BACKGROUND: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial. METHODS: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables. CONCLUSION: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.

Increased use of coercive procedures and prolonged hospitalization in compulsory admitted psychotic patients, who refuse antipsychotic medication.

Objective: Current Danish legislation imposes that compulsory admitted psychotic patients have the right to refuse antipsychotic medication, which markedly delays pertinent medical treatment.Material and methods: In a retrospective, observational cohort study, we analyzed data from a 1-year period on 34 consecutively admitted patients with schizophrenia, who had been compulsory admitted due to need of treatment, or because they were judged to constitute an acute danger to themselves or others. We compared the use of other coercive procedures and hospitalization time.Results: Twenty-three patients accepted to commence antipsychotic treatment immediately, and 11 patients submitted an official complaint, which significantly delayed initiation of antipsychotic treatment (1 day ±0.9 versus 14 days ±10.1, p = 0.002). The 11 complaining patients were subjected to 6.8 times more coercive procedures of forced sedative medication compared to the 23 patients without delay (2.7 ± 2.3 episodes versus 0.4 ± 0.7 episodes, p = 0.007). Moreover, the treatment-delay prolonged duration of hospitalization by a factor 2.3 (73.3 ± 28.3 days versus 31.7 ± 22.0 days, p < 0.001).Conclusion: The current legislation intends to preserve patient rights and promote voluntary treatment alliance but may instead lead to prolonged hospitalization and increased use of other coercive measures such as forced sedative medication. Modification of current legislation may therefore be considered.