Obsessive-compulsive symptoms and disorder in clozapine-treated schizophrenia.

BACKGROUND: Obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) are commonly reported in patients with schizophrenia. Furthermore, the use of clozapine in treatment-resistant schizophrenia has been thought to induce or aggravate these disorders. To date, there is a paucity of research regarding the prevalence and associated factors. Hence, this study aims to report the prevalence of OCS and OCD, and examine potential risk factors, in clozapine-treated schizophrenia. METHODS: This is a cross-sectional study conducted in the only tertiary hospital for psychiatric patients in Singapore. In total, 162 patients on a stable dose of clozapine were recruited for this study; 159 patients with a diagnosis of schizophrenia or schizoaffective disorder were included in the current analysis. Sociodemographic, clinical and treatment factors were analysed to identify factors associated with OCS and OCD. RESULTS: The prevalence of OCS and OCD is 21.4% and 12.6% respectively. Factors associated with OCS include younger age (OR:0.96, p=0.033) and younger age of onset of psychosis (OR:0.92, p=0.017). There were no significant factors associated with OCD. However, in an analysis of both OCS and/or OCD, factors associated include younger age (OR:0.96, p=0.027) and younger age of onset of psychosis (OR:0.91, p=0.016). Severity of psychotic illness and Clozapine dose were not associated with OCS or OCD in clozapine-treated schizophrenia. DISCUSSION & CONCLUSIONS: Our results suggest a high prevalence of OCS and OCD in clozapine-treated schizophrenia which clinicians should routinely screen for. Further research is warranted to establish the link between the factors identified in this study and OCS/OCD in clozapine-treated schizophrenia.

Deconstructing the genetic architecture of treatment-resistant schizophrenia in East Asian ancestry.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. METHODS: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. RESULTS: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. CONCLUSION: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.

Once-daily versus divided dosing regimens of clozapine: A cross-sectional study in Singapore.

INTRODUCTION: Clozapine is recognized as the gold standard medication for treatment-resistant schizophrenia. Despite the general recommendation of administering in a divided dosing regimen, clozapine is often prescribed once daily at night in clinical practice. This study aims to compare patient characteristics, psychiatric symptoms, side effects, and plasma concentration of clozapine between once-daily dosing and divided dosing regimens. METHODS: This cross-sectional study included 159 participants with treatment-resistant schizophrenia or schizoaffective disorder. Participant's demographic information, anthropometric data, and medical history were collected. Their psychiatric symptoms, cognition, functioning, and side effects were evaluated. RESULTS: Once-daily dosing regimen was associated with younger age and competitive employment. Lower clinical symptom severity, better functioning and cognitive performance were observed in the once-daily dosing group. Lower daily dose of clozapine, trough plasma concentrations of clozapine and norclozapine were also significantly associated with once-daily dosing regimen. CONCLUSION: The study results support once-daily dosing of clozapine as a viable option to selected patients in clinical practice, as no association of severe symptoms or side effects were associated with once-daily dosing regimen. More studies are needed to examine the relationship between clinical outcomes and clozapine dosing regimen.

The Impact of Clozapine Delay on Clinical Outcomes in Schizophrenia.

Background: Clozapine is the drug of choice indicated for treatment-resistant schizophrenia (TRS), but delays in initiation and underutilization might have affected its effectiveness in practice. In this study, we sought to examine the clinical outcomes of patients on clozapine treatment and if a delay in initiation was associated with poorer outcomes.Methods: This study was conducted at a tertiary mental health institution in patients aged 21 to 80 years from January 2016 to October 2019 who were on a stable dose of clozapine for 2 weeks. All patients were assessed using the Structured Clinical Interview for DSM-IV-TR (SCID-I) to ascertain diagnoses of schizophrenia and schizoaffective disorder. Each patient was assessed on the Positive and Negative Syndrome Scale (PANSS) and Social Occupational Functioning Assessment Scale (SOFAS). Past antipsychotic treatment trials were obtained from the medical records. Symptom remission status was defined using the PANSS symptom criteria proposed by Andreasen and colleagues in 2005. Functional remission was defined as a SOFAS score ≥ 60.Results: A total of 159 individuals with schizophrenia or schizoaffective disorder were recruited. The mean age of patients was 40.01 years, and the majority of patients were male (64.2%) and Chinese (85.5%). Thirty-seven patients (23.3%) achieved symptom remission, and 101 (63.5%) achieved functional remission. The median number of antipsychotic trials before clozapine initiation was 6 (interquartile range, 5-8). Patients in either symptom or functional remission had shorter time periods and fewer numbers of antipsychotic trials before first clozapine initiation. However, the trend was statistically significant only for median number of antipsychotic trials in the functional remission (P = .027) and symptom remission (P = .011) groups.Conclusion: Our study found a significant delay in the initiation of clozapine despite current guidelines indicating it for TRS. This delay might have contributed to the poorer clinical outcomes. Further research is needed to provide a clearer understanding of clozapine delay, evaluate its impact on outcomes, and find ways to improve access to clozapine.

Metabolic syndrome and cardiovascular risk between clozapine and non-clozapine antipsychotic users with schizophrenia.

INTRODUCTION: Clozapine use is associated with higher risks of metabolic side effects and cardiovascular diseases (CVD). Thus, this study aims to establish and compare the cardiometabolic profiles between non-clozapine antipsychotic and clozapine users with schizophrenia. METHODS: Data from 88 non-clozapine and 166 clozapine users were extracted from existing databases - demographics, medications, smoking and medical histories, anthropometric parameters, serum lipid and fasting glucose levels. Prevalence of metabolic syndrome (MetS) was established using the AHA/NHLBI criteria. Cardiovascular risk profiles were established using the Framingham risk score (FRS). RESULTS: The clozapine group had significantly higher proportions of diagnosed hypertension (10.8 % vs. 3.4 %, p = 0.041), diabetes mellitus (15.7 % vs. 3.4 %, p = 0.003) and dyslipidemia (36.7 % vs. 12.5 %, p < 0.001). However, the non-clozapine antipsychotic group had poorer anthropometric, serum lipids and glucose levels. The prevalence rates of MetS in the clozapine and non-clozapine antipsychotic groups were not statistically significant at 42.8 % and 43.2 %, respectively. As for CVD risk, the non-clozapine antipsychotic group had significantly higher FRS (6.59 % vs. 6.12 %, p = 0.001). CONCLUSION: Although clozapine users had higher rates of diagnosed metabolic conditions, other cardiometabolic parameters appeared better compared to non-clozapine antipsychotic users, which could be due to greater awareness, earlier detection and treatment. Regardless of the type of antipsychotic used, metabolic abnormalities are prevalent in individuals with schizophrenia; physical healthcare should be prioritised alongside mental healthcare in this group.

Large-scale evaluation of the Positive and Negative Syndrome Scale (PANSS) symptom architecture in schizophrenia.

Although the Positive and Negative Syndrome Scale (PANSS) is widely utilized in schizophrenia research, variability in specific item loading exist, hindering reproducibility and generalizability of findings across schizophrenia samples. We aim to establish a common PANSS factor structure from a large multi-ethnic sample and validate it against a meta-analysis of existing PANSS models. Schizophrenia participants (N = 3511) included in the current study were part of the Singapore Translational and Clinical Research Program (STCRP) and the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE). Exploratory Factor Analysis (EFA) was conducted to identify the factor structure of PANSS and validated with a meta-analysis (N = 16,171) of existing PANSS models. Temporal stability of the PANSS model and generalizability to individuals at ultra-high risk (UHR) of psychosis were evaluated. A five-factor solution best fit the PANSS data. These were the i) Positive, ii) Negative, iii) Cognitive/disorganization, iv) Depression/anxiety and v) Hostility factors. Convergence of PANSS symptom architecture between EFA model and meta-analysis was observed. Modest longitudinal reliability was observed. The schizophrenia derived PANSS factor model fit the UHR population, but not vice versa. We found that two other domains, Social Amotivation (SA) and Diminished Expression (DE), were nested within the negative symptoms factor. Here, we report one of the largest transethnic factorial structures of PANSS symptom domains (N = 19,682). Evidence reported here serves as crucial consolidation of a common PANSS structure that could aid in furthering our understanding of schizophrenia.

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.

Correction: Progressive decline in hippocampal CA1 volume in individuals at ultra-high-risk for psychosis who do not remit: findings from the longitudinal youth at risk study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

A Systematic Review of the Effectiveness of Medical Cannabis for Psychiatric, Movement and Neurodegenerative Disorders.

The discovery of endocannabinoid's role within the central nervous system and its potential therapeutic benefits have brought forth rising interest in the use of cannabis for medical purposes. The present review aimed to synthesize and evaluate the available evidences on the efficacy of cannabis and its derivatives for psychiatric, neurodegenerative and movement disorders. A systematic search of randomized controlled trials of cannabis and its derivatives were conducted via databases (PubMed, Embase and the Cochrane Central Register of Controlled Trials). A total of 24 reports that evaluated the use of medical cannabis for Alzheimer's disease, anorexia nervosa, anxiety, dementia, dystonia, Huntington's disease, Parkinson's disease, post-traumatic stress disorder (PTSD), psychosis and Tourette syndrome were included in this review. Trial quality was assessed with the Cochrane risk of bias tool. There is a lack of evidence on the therapeutic effects of cannabinoids for amyotrophic lateral sclerosis and dystonia. Although trials with positive findings were identified for anorexia nervosa, anxiety, PTSD, psychotic symptoms, agitation in Alzheimer's disease and dementia, Huntington's disease, and Tourette syndrome, and dyskinesia in Parkinson's disease, definitive conclusion on its efficacy could not be drawn. Evaluation of these low-quality trials, as rated on the Cochrane risk of bias tools, was challenged by methodological issues such as inadequate description of allocation concealment, blinding and underpowered sample size. More adequately powered controlled trials that examine the long and short term efficacy, safety and tolerability of cannabis for medical use, and the mechanisms underpinning the therapeutic potential are warranted.

Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study.

Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at baseline and at 1-2 follow-up time points (at 12-month intervals) from 147 UHR and healthy control subjects. An automated method (based on an ex vivo atlas of ultra-high-resolution hippocampal tissue) was used to delineate the hippocampal subfields. Over time, a greater decline in bilateral CA1 subfield volumes was found in the subgroup of UHR subjects whose subthreshold symptoms persisted (n=40) and also those who developed clinical psychosis (n=12), compared with UHR subjects who remitted (n=41) and healthy controls (n=54). No baseline differences in volumes of the overall hippocampus or its subfields were found among the groups. Moreover, the rate of volume decline of CA1, but not of other hippocampal subfields, in the non-remitters was associated with increasing symptom severity over time. Thus, these findings indicate that there is deterioration of CA1 volume in persistently symptomatic UHR individuals in proportion to symptomatic progression.

Can Peripheral Blood-Derived Gene Expressions Characterize Individuals at Ultra-high Risk for Psychosis?

The ultra-high risk (UHR) state was originally conceived to identify individuals at imminent risk of developing psychosis. Although recent studies have suggested that most individuals designated UHR do not, they constitute a distinctive group, exhibiting cognitive and functional impairments alongside multiple psychiatric morbidities. UHR characterization using molecular markers may improve understanding, provide novel insight into pathophysiology, and perhaps improve psychosis prediction reliability. Whole-blood gene expressions from 56 UHR subjects and 28 healthy controls are checked for existence of a consistent gene expression profile (signature) underlying UHR, across a variety of normalization and heterogeneity-removal techniques, including simple log-conversion, quantile normalization, gene fuzzy scoring (GFS), and surrogate variable analysis. During functional analysis, consistent and reproducible identification of important genes depends largely on how data are normalized. Normalization techniques that address sample heterogeneity are superior. The best performer, the unsupervised GFS, produced a strong and concise 12-gene signature, enriched for psychosis-associated genes. Importantly, when applied on random subsets of data, classifiers built with GFS are "meaningful" in the sense that the classifier models built using genes selected after other forms of normalization do not outperform random ones, but GFS-derived classifiers do. Data normalization can present highly disparate interpretations on biological data. Comparative analysis has shown that GFS is efficient at preserving signals while eliminating noise. Using this, we demonstrate confidently that the UHR designation is well correlated with a distinct blood-based gene signature.

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.

Investigation of cigarette smoking among male schizophrenia patients.

Male schizophrenia patients are known to have a heavier smoking pattern compared with the general population. However, the mechanism for this association is not known, though hypothesis that smoking could alleviate symptomatology of schizophrenia and reduce side effects of antipsychotics has been suggested. The aims of this study were to validate the heavier smoking pattern among male schizophrenia patients and to investigate the possible mechanisms for the association. To enhance the reliability of the study, we recruited two large independent samples with 604 and 535 male Chinese schizophrenia patients, and compared their smoking pattern with that of 535 healthy male controls recruited from general population. Validated multiple indicators and multiple causes structure equation model and regression models were used to investigate the association of smoking with factors of schizophrenia symptomatology and with the usage of antipsychotics and their extra-pyramidal side effects (EPS). Schizophrenia patients had significantly heavier smoking pattern compared with healthy controls in our sample (42.4% vs. 16.8%, p<0.001 for current smoking prevalence; 23.5% vs. 43.3%, p<0.001 for smoking cessation rate; 24.5% vs. 3.0%, p<0.001 for heavy smoker proportion). Their smoking status was also found to be consistently and significantly associated with reduced negative factor scores for schizophrenia symptomatology (ß = -0.123, p = 0.051 for sample-A; ß = -0.103, p = 0.035 for sample-B; ß = -0.082, p = 0.017 for the combined sample). However, no significant association was found between smoking and antipsychotics usage or risk of EPS. These results support that smoking is associated with improved negative symptoms, which could account for the heavier smoking pattern among schizophrenia patients.