Evaluating the utility of digital phenotyping to predict health outcomes in schizophrenia: protocol for the HOPE-S observational study.

INTRODUCTION: The course of schizophrenia illness is characterised by recurrent relapses which are associated with adverse clinical outcomes such as treatment-resistance, functional and cognitive decline. Early identification is essential and relapse prevention remains a primary treatment goal for long-term management of schizophrenia. With the ubiquity of devices such as smartphones, objective digital biomarkers can be harnessed and may offer alternative means for symptom monitoring and relapse prediction. The acceptability of digital sensors (smartphone and wrist-wearable device) and the association between the captured digital data with clinical and health outcomes in individuals with schizophrenia will be examined. METHODS AND ANALYSIS: In this study, we aim to recruit 100 individuals with schizophrenia spectrum disorders who are recently discharged from the Institute of Mental Health (IMH), Singapore. Participants are followed up for 6 months, where digital, clinical, cognitive and functioning data are collected while health utilisation data are obtained at the 6 month and 1 year timepoint from study enrolment. Associations between digital, clinical and health outcomes data will be examined. A data-driven machine learning approach will be used to develop prediction algorithms to detect clinically significant outcomes. Study findings will inform the design, data collection procedures and protocol of future interventional randomised controlled trial, testing the effectiveness of digital phenotyping in clinical management of individuals with schizophrenia spectrum disorders. ETHICS AND DISSEMINATION: Ethics approval has been granted by the National Healthcare Group (NHG) Domain Specific Review Board (DSRB Reference no.: 2019/00720). The results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT04230590.

Predicting Real-World Functioning in Schizophrenia: The Relative Contributions of Neurocognition, Functional Capacity, and Negative Symptoms.

Neurocognition and functional capacity are commonly reported predictors of real-world functioning in schizophrenia. However, the additional impact of negative symptoms, specifically its subdomains, i.e., diminished expression (DE) and avolition-apathy (AA), on real-world functioning remains unclear. The current study assessed 58 individuals with schizophrenia. Neurocognition was assessed with the Brief Assessment of Cognition in Schizophrenia, functional capacity with the UCSD Performance-based Skills Assessment (UPSA-B), and negative symptoms with the Negative Symptom Assessment-16. Real-world functioning was assessed with the Multnomah Community Ability Scale (MCAS) with employment status as an additional objective outcome. Hierarchical regressions and sequential logistic regressions were used to examine the associations between the variables of interest. The results show that global negative symptoms contribute substantial additional variance in predicting MCAS and employment status above and beyond the variance accounted for by neurocognition and functional capacity. In addition, both AA and DE predict the MCAS after controlling for cognition and functional capacity. Only AA accounts for additional variance in employment status beyond that by UPSA-B. In summary, negative symptoms contribute substantial additional variance in predicting both real-world functioning and employment outcomes after accounting for neurocognition and functional capacity. Our findings emphasize both DE and AA as important treatment targets in functional recovery for people with schizophrenia.

Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia: A Systematic Review and Meta-analysis.

Importance: Schizophrenia is associated with cognitive dysfunction and cardiovascular risk factors, including metabolic syndrome (MetS) and its constituent criteria. Cognitive dysfunction and cardiovascular risk factors can worsen cognition in the general population and may contribute to cognitive impairment in schizophrenia. Objective: To study the association between cognitive dysfunction and cardiovascular risk factors and cognitive impairment in individuals with schizophrenia. Data Sources: A search was conducted of Embase, Scopus, MEDLINE, PubMed, and Cochrane databases from inception to February 25, 2020, using terms that included synonyms of schizophrenia AND metabolic adversities AND cognitive function. Conference proceedings, clinical trial registries, and reference lists of relevant publications were also searched. Study Selection: Studies were included that (1) examined cognitive functioning in patients with schizophrenia or schizoaffective disorder; (2) investigated the association of cardiovascular disease risk factors, including MetS, diabetes, obesity, overweight, obesity or overweight, hypertension, dyslipidemia, and insulin resistance with outcomes; and (3) compared cognitive performance of patients with schizophrenia/schizoaffective disorder between those with vs without cardiovascular disease risk factors. Data Extraction and Synthesis: Extraction of data was conducted by 2 to 3 independent reviewers per article. Data were meta-analyzed using a random-effects model. Main Outcomes and Measures: The primary outcome was global cognition, defined as a test score using clinically validated measures of overall cognitive functioning. Results: Twenty-seven studies involving 10 174 individuals with schizophrenia were included. Significantly greater global cognitive deficits were present in patients with schizophrenia who had MetS (13 studies; n = 2800; effect size [ES] = 0.31; 95% CI, 0.13-0.50; P = .001), diabetes (8 studies; n = 2976; ES = 0.32; 95% CI, 0.23-0.42; P < .001), or hypertension (5 studies; n = 1899; ES = 0.21; 95% CI, 0.11-0.31; P < .001); nonsignificantly greater deficits were present in patients with obesity (8 studies; n = 2779; P = .20), overweight (8 studies; n = 2825; P = .41), and insulin resistance (1 study; n = 193; P = .18). Worse performance in specific cognitive domains was associated with cognitive dysfunction and cardiovascular risk factors regarding 5 domains in patients with diabetes (ES range, 0.23 [95% CI, 0.12-0.33] to 0.40 [95% CI, 0.20-0.61]) and 4 domains with MetS (ES range, 0.15 [95% CI, 0.03-0.28] to 0.40 [95% CI, 0.20-0.61]) and hypertension (ES range, 0.15 [95% CI, 0.04-0.26] to 0.27 [95% CI, 0.15-0.39]). Conclusions and Relevance: In this systematic review and meta-analysis, MetS, diabetes, and hypertension were significantly associated with global cognitive impairment in people with schizophrenia.

Clinical determinants of physical activity and sedentary behaviour in individuals with schizophrenia.

INTRODUCTION: Modifiable lifestyle factors such as physical activity (PA) have ameliorative effects on commonly reported health conditions in schizophrenia like cardiovascular diseases and diabetes. Similarly, reduction in sedentary behaviour (SB) promotes better physical health. However, engaging individuals with schizophrenia in PA and less SB can be challenging because of symptoms of schizophrenia. The aims of the present study are (i) to examine the profiles of PA and SB in individuals with schizophrenia; and (ii) to identify their respective clinical determinants. METHOD: 157 individuals with schizophrenia were recruited. PA and SB were examined via the Global Physical Activity Questionnaire (GPAQ). Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Potential clinical predictors of PA and SB were identified via univariate regression analyses and subsequently included in the final multiple regression models for PA and SB respectively. RESULTS: 63.7% met the WHO PA guidelines. Work-related activity was the largest domain specific contribution towards PA. Mean duration of SB was approximately 9 h and about 57.3% reported at least 8 h or more of SB daily. Positive symptom was associated with engagement in PA and reduced duration of SB. Negative symptom was associated with greater SB. CONCLUSION: With emerging evidence of deleterious health effects of SB independent of PA, it is important to monitor SB in individuals with schizophrenia, particularly those presenting with negative symptoms. While the lack of treatment response for negative symptoms remains a challenge, effort should be made to reduce duration of SB.

Non-verbal speech cues as objective measures for negative symptoms in patients with schizophrenia.

Negative symptoms in schizophrenia are associated with significant burden and possess little to no robust treatments in clinical practice today. One key obstacle impeding the development of better treatment methods is the lack of an objective measure. Since negative symptoms almost always adversely affect speech production in patients, speech dysfunction have been considered as a viable objective measure. However, researchers have mostly focused on the verbal aspects of speech, with scant attention to the non-verbal cues in speech. In this paper, we have explored non-verbal speech cues as objective measures of negative symptoms of schizophrenia. We collected an interview corpus of 54 subjects with schizophrenia and 26 healthy controls. In order to validate the non-verbal speech cues, we computed the correlation between these cues and the NSA-16 ratings assigned by expert clinicians. Significant correlations were obtained between these non-verbal speech cues and certain NSA indicators. For instance, the correlation between Turn Duration and Restricted Speech is -0.5, Response time and NSA Communication is 0.4, therefore indicating that poor communication is reflected in the objective measures, thus validating our claims. Moreover, certain NSA indices can be classified into observable and non-observable classes from the non-verbal speech cues by means of supervised classification methods. In particular the accuracy for Restricted speech quantity and Prolonged response time are 80% and 70% respectively. We were also able to classify healthy and patients using non-verbal speech features with 81.3% accuracy.

Longitudinal Cognitive Changes in Young Individuals at Ultrahigh Risk for Psychosis.

Importance: Cognitive deficits are a key feature of risk for psychosis. Longitudinal changes in cognitive architecture may be associated with the social and occupational functioning in young people. Objectives: To examine longitudinal profiles of cognition in individuals at ultrahigh risk (UHR) for psychosis, compared with healthy controls, and to investigate the association of cognition with functioning. Design, Setting, and Participants: This study has a multiple-group prospective design completed in 24 months and was conducted from January 1, 2009, to November 11, 2012, as part of the Longitudinal Youth at-Risk Study conducted in Singapore. Participants either were recruited from psychiatric outpatient clinics, educational institutions, and community mental health agencies or self-referred. Follow-up assessments were performed every 6 months for 2 years or until conversion to psychosis. Individuals with medical causes for psychosis, current illicit substance use, or color blindness were excluded. Data analysis was conducted from June 2014 to May 2018. Main Outcomes and Measures: Neuropsychological, perceptual, and social cognitive tasks; semi-structured interviews, and the Structured Clinical Interview for DSM-IV Axis I disorders were administered every 6 months. The UHR status of nonconverters, converters, remitters, and nonremitters was monitored. Cognitive domain scores and functioning were investigated longitudinally. Results: In total, 384 healthy controls and 173 UHR individuals between ages 14 and 29 years were evaluated prospectively. Of the 384 healthy controls, 153 (39.8%) were female and 231 (60.2%) were male with a mean (SD) age of 21.69 (3.26) years. Of the 173 individuals at UHR for psychosis, 56 (32.4%) were female and 117 (67.6%) were male with a mean (SD) age of 21.27 (3.52) years). After 24 months of follow-up, 383 healthy controls (99.7%) and 122 individuals at UHR for psychosis (70.5%) remained. Baseline cognitive deficits were associated with psychosis conversion later (mean odds ratio [OR], 1.66; combined 95% CI, 1.08-2.83; P = .04) and nonremission of UHR status (mean OR, 1.67; combined 95% CI, 1.09-2.95; P = .04). Five cognitive components-social cognition, attention, verbal fluency, general cognitive function, and perception-were obtained from principal components analysis. Longitudinal component structure change was observed in general cognitive function (maximum vertical deviation = 0.59; χ2 = 8.03; P = .01). Group-by-time interaction on general cognitive function (F = 12.23; η2 = 0.047; P < .001) and perception (F = 8.33; η2 = 0.032; P < .001) was present. Changes in attention (F = 5.65; η2 = 0.013; P = .02) and general cognitive function (F = 7.18; η2 = 0.014; P = .01) accounted for longitudinal changes in social and occupational functioning. Conclusions and Relevance: Individuals in this study who met the UHR criteria appeared to demonstrate cognitive deficits, and those whose UHR status remitted were seen to recover cognitively. Cognition appeared as poor in nonremitters and appeared to be associated with poor functional outcome. This study suggests that cognitive dimensions are sensitive to the identification of young individuals at risk for psychosis and to the longitudinal course of those at highest risk.

Montreal Cognitive Assessment as a screening instrument for cognitive impairments in schizophrenia.

BACKGROUND: Cognitive impairment is one of the core features of schizophrenia. For its evaluation, current clinical practice relies on detailed neuropsychological batteries which require trained testers and considerable amount of time to administer. Therefore, a brief and reliable screening tool for identification of overall cognitive impairment prior to a detailed comprehensive neurocognitive assessment is needed in a busy clinical setting. This study evaluates the clinical utility of the Montreal Cognitive Assessment (MoCA) in detecting cognitive impairments in schizophrenia and its relationship with functional outcome and demographic characters. METHODS: The MoCA, the Brief Assessment of Cognition in Schizophrenia (BACS), and the Brief UCSD Performance-based Skills Assessment (UPSA-B) were administered to 64 patients with schizophrenia. Mild and severe cognitive impairments were defined as BACS Z-score (calculated with the age and gender adjustments using previously published local norm data) of one or two standard deviations below the mean, respectively. RESULTS: The results showed that the MoCA was significantly correlated with BACS (r=.61, p<.001) and sensitive to detect both mild (AUC=0.82, p<.001) and severe (AUC=0.81, p<.001) cognitive impairments in schizophrenia. The MoCA was significantly correlated with UPSA-B score (r=.51, p<.001), and accounted for significant additional variance in UPSA-B score beyond the BACS. CONCLUSION: These findings indicate that MoCA is a useful bedside cognitive screening instrument for people with schizophrenia.

The Impact of Medication Anticholinergic Burden on Cognitive Performance in People With Schizophrenia.

BACKGROUND: Cognitive deficits are prevalent in people with schizophrenia and associated with functional impairments. In addition to antipsychotics, pharmacotherapy in schizophrenia often includes other psychotropics, and some of these agents possess anticholinergic properties, which may impair cognition. The objective of this study was to explore the association between medication anticholinergic burden and cognition in schizophrenia. METHODS: Seven hundred five individuals with schizophrenia completed a neuropsychological battery comprising Judgment of Line Orientation Test, Wechsler Abbreviated Scale of Intelligence Matrix Reasoning, Continuous Performance Test-Identical Pairs Version, and the Brief Assessment of Cognition in Schizophrenia. Cognitive g and 3 cognitive factor scores that include executive function, memory/fluency, and speed of processing/vigilance, which were derived from a previously published analysis, were entered as cognitive variables. Anticholinergic burden was computed using 2 anticholinergic scales: Anticholinergic Burden Scale and Anticholinergic Drug Scale. Duration and severity of illness, antipsychotic dose, smoking status, age, and sex were included as covariates. RESULTS: Anticholinergic burden was associated with poorer cognitive performance in cognitive g, all 3 cognitive domains and most cognitive tasks in multivariate analyses. The associations were statistically significant, but the effect sizes were small (for Anticholinergic Burden Scale, Cohen f = 0.008; for Anticholinergic Drug Scale, Cohen f = 0.017). CONCLUSIONS: Although our results showed a statistically significant association between medications with anticholinergic properties and cognition in people with schizophrenia, the impact is of doubtful or minimal clinical significance.

Association between serum levels of bioavailable vitamin D and negative symptoms in first-episode psychosis.

Total vitamin D levels had been commonly reported to be lowered in patients with chronic psychotic illnesses in countries from the higher latitudes. However, studies on patients with first episode psychosis (FEP) are limited. In this study we investigated serum concentrations of total and bioavailable vitamin D levels in FEP patients compared to healthy controls and the association between symptom severity and vitamin D components. A total of 31 FEP patients and 31 healthy controls were recruited from Institute of Mental Health, Singapore. FEP patients were identified using Structured Clinical Interview for DSM-IV Axis I disorders (SCID-1) and severity symptoms were assessed using the positive and negative syndrome scale (PANSS). Sera from participants were analyzed for total vitamin D, vitamin D-binding protein (DBP) and bioavailable vitamin D. Linear regressions were performed to examine the associations between serum total and bioavailable vitamin D and the PANSS subscales. Current study noted a significantly lower bioavailable vitamin D was in the FEP group and an association between bioavailable vitamin D and negative symptoms in FEP patients in a population with a consistent supply of sun exposure throughout the year.

Baseline social amotivation predicts 1-year functioning in UHR subjects: A validation and prospective investigation.

Social amotivation and diminished expression have been reported to underlie negative symptomatology in schizophrenia. In the current study we sought to establish and validate these negative symptom domains in a large cohort of schizophrenia subjects (n=887) and individuals who are deemed to be Ultra-High Risk (UHR) for psychosis. Confirmatory factor analysis conducted on PANSS item domains demonstrate that the dual negative symptom domains exist in schizophrenia and UHR subjects. We further sought to examine if these negative symptom domains were associated with functioning in UHR subjects. Linear regression analyses confirmed that social amotivation predicted functioning in UHR subjects prospectively at 1 year follow up. Results suggest that the association between social amotivation and functioning is generalisable beyond schizophrenia populations to those who are at-risk of developing psychosis. Social amotivation may be an important dimensional clinical construct to be studied across a range of psychiatric conditions.