Feasibility and Acceptability of Using a Mobile Phone App for Characterizing Auditory Verbal Hallucinations in Adolescents With Early-Onset Psychosis: Exploratory Study

Background: Auditory verbal hallucinations (AVH) are the most frequent symptom in early-onset psychosis (EOP) and a risk factor for increased suicide attempts in adolescents. Increased knowledge of AVH characteristics can lead to better prediction of risk and precision of diagnosis and help identify individuals with AVH who need care. As 98% of Norwegian adolescents aged 12 to 16 years own a mobile phone, the use of mobile phone apps in symptom assessment and patient communication is a promising new tool. However, when introducing new technology to patients, their subjective experiences are crucial in identifying risks, further development, and potential integration into clinical care. Objective: The objective was to explore the feasibility and acceptability of a newly developed mobile phone app in adolescents with EOP by examining compliance with the app and user experiences. Indication of validity was explored by examining associations between AVH dimensions, which were correlated and analyzed. Methods: Three adolescents with EOP and active AVH were enrolled. Real-time AVH were logged on an iPod touch using the experience sampling method (ESM), for seven or more consecutive days. The app included five dimensions of AVH characteristics and was programmed with five daily notifications. Feasibility and acceptability were examined using the mean response rate of data sampling and by interviewing the participants. Validity was assessed by examining associations between the AVH dimensions using nonparametric correlation analysis and by visual inspection of temporal fluctuations of the AVH dimensions. Results: One participant was excluded from the statistical analyses but completed the interview and was included in the examination of acceptability. The sampling period of the two participants was mean 12 (SD 6) days with overall completed sampling rate of 74% (SD 30%), indicating adequate to high compliance with the procedure. The user experiences from the interviews clustered into four categories: (1) increased awareness, (2) personal privacy, (3) design and procedure, and (4) usefulness and clinical care. One participant experienced more commenting voices during the sampling period, and all three participants had concerns regarding personal privacy when using electronic devices in symptom assessment. The AVH dimensions of content, control, and influence showed moderate to strong significant correlations with all dimensions (P<.001). Days of data sampling showed weak to moderate correlations with localization (P<.001) and influence (P=.03). Visual inspection indicated that the app was able to capture fluctuations within and across days for all AVH dimensions. Conclusions: This study demonstrates the value of including patients’ experiences in the development and pilot-testing of new technology. Based on the small sample size, the use of mobile phones with ESM seems feasible for patients with EOP, but the acceptability of using apps should be considered. Further investigation with larger samples is warranted before definitive conclusions are made.publishedVersio

Previous hospital admissions and disease severity predict the use of antipsychotic combination treatment in patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Although not recommended in treatment guidelines, previous studies have shown a frequent use of more than one antipsychotic agent among patients with schizophrenia. The main aims of the present study were to explore the antipsychotic treatment regimen among patients with schizophrenia in a catchment area-based sample and to investigate clinical characteristics associated with antipsychotic combination treatment.</p> <p>Methods</p> <p>The study included 329 patients diagnosed with schizophrenia using antipsychotic medication. Patients were recruited from all psychiatric hospitals in Oslo. Diagnoses were obtained by use of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Additionally, Global Assessment of Functioning (GAF), Positive and Negative Syndrome Scale (PANSS) and number of hospitalisations and pharmacological treatment were assessed.</p> <p>Results</p> <p>Multiple hospital admissions, low GAF scores and high PANSS scores, were significantly associated with the prescription of combination treatment with two or more antipsychotics. The use of combination treatment increased significantly from the second hospital admission. Combination therapy was not significantly associated with age or gender. Regression models confirmed that an increasing number of hospital admission was the strongest predictor of the use of two or more antipsychotics.</p> <p>Conclusions</p> <p>Previous hospital admissions and disease severity measured by high PANSS scores and low GAF scores, predict the use of antipsychotic combination treatment in patients with schizophrenia. Future studies should further explore the use of antipsychotic drug treatment in clinical practice and partly based on such data establish more robust treatment guidelines for patients with persistently high symptom load.</p

Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder

AbstractBackgroundPrevious studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics.MethodsPlasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations.ResultsAfter controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures.ConclusionsThis supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s d = 0.37), posterior corona radiata (d = 0.32), and superior fronto‐ occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness

Task-based functional connectivity reveals aberrance with the salience network during emotional interference in late-life depression

Objectives Late-life depression (LLD) is a common and debilitating disorder. Previously, resting-state studies have revealed abnormal functional connectivity (FC) of brain networks in LLD. Since LLD is associated with emotional-cognitive control deficits, the aim of this study was to compare FC of large-scale brain networks in older adults with and without a history of LLD during a cognitive control task with emotional stimuli. Methods Cross-sectional case-control study. Twenty participants diagnosed with LLD and 37 never-depressed adults 60–88 years of age underwent functional magnetic resonance imaging during an emotional Stroop task. Network-region-to-region FC was assessed with seed regions in the default mode, the frontoparietal, the dorsal attention, and the salience networks. Results FC between salience and sensorimotor network regions and between salience and dorsal attention network regions were reduced in LLD patients compared to controls during the processing of incongruent emotional stimuli. The normally positive FC between these networks were negative in LLD patients and inversely correlated with vascular risk and white matter hyperintensities. Conclusions Emotional-cognitive control in LLD is associated with aberrant functional coupling between salience and other networks. This expands on the network-based LLD model and proposes the salience network as a target for future interventions.publishedVersio

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from crosssectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns

Patterns of childhood adverse events are associated with clinical characteristics of bipolar disorder

Background Previous studies in bipolar disorder investigating childhood trauma and clinical presentations of the illness have mainly focused on physical and sexual abuse. Our aim was to explore further the relationship between childhood trauma and disease characteristics in bipolar disorder to determine which clinical characteristics were most strongly associated with childhood trauma total score, as well as subtypes of adverse childhood events, including physical, sexual, emotional abuse and neglect. Methods 141 Patients with bipolar disorder were consecutively recruited, and disease history and clinical characteristics were assessed. History of childhood abuse was obtained using the Childhood Trauma Questionnaire (CTQ). Statistical methods used were factor analysis, Poisson and linear regression, and generalized additive modeling (GAM). Results The factor analysis of CTQ identified three factors: emotional abuse/neglect, sexual abuse and physical abuse. There were significant associations between CTQ total score and earlier onset of illness, reduced level of psychosocial functioning (GAF; Global Assessment of Functioning) and decreased number of hospitalization, which mainly were due to the factor emotional abuse/neglect. Physical abuse was significantly associated with lower GAF scores, and increased number of mood episodes, as well as self-harm. Sexual abuse was significantly associated with increased number of mood episodes. For mood episodes and self-harm the associations were characterized by great variance and fluctuations. Conclusions Our results suggest that childhood trauma is associated with a more severe course of bipolar illness. Further, childhood abuse (physical and sexual), as well as emotional abuse and neglect were significantly associated with accelerating staging process of bipolar disorder. By using specific trauma factors (physical abuse, sexual abuse and emotional abuse/neglect) the associations become both more precise, and diverse

Cortical thickness across the lifespan: Data from 17,075healthy individuals aged 3–90 years

Delineating the association of age and cortical thickness in healthy individuals is criti-cal given the association of cortical thickness with cognition and behavior. Previousresearch has shown that robust estimates of the association between age and brainmorphometry require large-scale studies. In response, we used cross-sectional datafrom 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Geneticsthrough Meta-Analysis (ENIGMA) Consortium to infer age-related changes in corticalthickness. We used fractional polynomial (FP) regression to quantify the associationbetween age and cortical thickness, and we computed normalized growth centilesusing the parametric Lambda, Mu, and Sigma method. Interindividual variability wasestimated using meta-analysis and one-way analysis of variance. For most regions,their highest cortical thickness value was observed in childhood. Age and corticalthickness showed a negative association; the slope was steeper up to the thirddecade of life and more gradual thereafter; notable exceptions to this general patternwere entorhinal, temporopolar, and anterior cingulate cortices. Interindividual vari-ability was largest in temporal and frontal regions across the lifespan. Age and its FPcombinations explained up to 59% variance in cortical thickness. These results mayform the basis of further investigation on normative deviation in cortical thicknessand its significance for behavioral and cognitive outcomes.Instituto de Salud Carlos III PI02049

Limited association between infections, autoimmune disease and genetic risk and immune activation in severe mental disorders

Background Low-grade inflammation may be part of the underlying mechanism of schizophrenia and bipolar disorder. We investigated if genetic susceptibility, infections or autoimmunity could explain the immune activation. Methods Seven immune markers were selected based on indicated associations to severe mental disorders (IL-1Ra, sIL-2R, IL-18, sgp130, sTNFR-1, APRIL, ICAM-1) and measured in plasma of patients with schizophrenia (SCZ, N = 732) and bipolar spectrum disorders (BD, N = 460) and healthy controls (HC, N = 938). Information on rate of infections and autoimmune diseases were obtained from Norwegian national health registries for a twelve-year period. Polygenic risk scores (PRS) of SCZ and BD were calculated from genome-wide association studies. Analysis of covariance were used to test effects of infection rate, autoimmune disease and PRS on differences in immune markers between patients and HC. Results Infection rate differed between all groups (BD > HC > SCZ, all p < 0.001) whereas autoimmune disease was more frequent in BD compared to SCZ (p = 0.004) and HC (p = 0.003). sIL-2R was positively associated with autoimmune disease (p = 0.001) and negatively associated with PRS of SCZ (p = 0.006) across SCZ and HC; however, associations represented only small changes in the difference of sIL-2R levels between SCZ and HC. Conclusion There were few significant associations between rate of infections, autoimmune disease or PRS and altered immune markers in SCZ and BD, and the detected associations represented only small changes in the immune aberrations. The findings suggest that most of the low-grade inflammation in SCZ and BD is explained by other factors than the underlying PRS, autoimmunity and infection rates.publishedVersio

Boosting Schizophrenia Genetics by Utilizing Genetic Overlap With Brain Morphology

Background Schizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome. Methods We ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls. Results We found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios. Conclusions Our results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue–specific genetic variants and its use in polygenic risk frameworks.publishedVersio