First-episode Schizophrenia Spectrum Research Articles

D-serine and D-amino acid oxidase levels in patients with schizophrenia spectrum disorders in the first episode and 6-month follow-up

BackgroundD-serine and the D-amino acid oxidase (DAO) enzyme, which breaks down d-amino acids, may be involved in the pathophysiology of schizophrenia by affecting the N-methyl-D-aspartate (NMDA) receptor. The exact role of D-serine and DAO, as well as the consequences of increased DAO activity in patients with schizophrenia, remain unclear. We aimed to investigate D-serine and DAO levels in patients with first-episode schizophrenia spectrum disorders before treatment and after six months of treatment. MethodComparisons for the serum levels of D-serine and DAO were made between 81 healthy controls and 89 patients with first-episode schizophrenia spectrum disorders without a history of treatment. Further comparisons were made after 6 months for changes in these levels in the 41 patients in follow-up. The Positive and Negative Syndrome Scale (PANNS), Calgary Scale for Depression in Schizophrenia (CDSS), Montreal Cognitive Assessment Scale (MoCA), Global Assessment Scale (GAS), and Clinical Global Impression Scale (CGI) were used to evaluate the symptom severity and functionality. Secondary results included comparisons related to antipsychotic equivalent doses. ResultsBefore treatment, patients had significantly lower levels of D-serine, DAO, and D-serine/DAO ratio compared to healthy individuals (p < 0.001; p < 0.001; p = 0.004). DAO and D-serine levels of the patients were higher after six months of treatment (p = 0.025; p = 0.001). There was correlation of DAO levels with antipsychotic dosage and with PANSS negative and total subscale scores (rho = 0.421, p = 0.01; rho = 0.280, p = 0.008; rho = 0.371, p = 0.000). No correlation was found between serum D-serine level, DAO level, and the D-serine/DAO ratio with cognitive function. ConclusionsThe results suggest that D-serine and DAO may play a role that is sensitive to treatment effects in schizophrenia spectrum disorders. To gain a more comprehensive understanding of the impact antipsychotic drugs have on NMDA receptor dysfunction, there is a requirement for studies that directly evaluates the activity of the DAO enzyme.

Metabolic syndrome associations with neurocognitive function in first-episode schizophrenia spectrum disorders

We examined the associations between metabolic syndrome (MetS) and neurocognitive function in patients with first-episode schizophrenia spectrum disorders (FES) compared to controls assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. In patients, psychopathology was assessed using the Positive and Negative Syndrome Scale and Calgary Depression Scale for Schizophrenia. First, we found illness- and domain-specific associations between the individual MetS features and neurocognitive performance in patients, but not in controls. Second, body mass index and total cholesterol levels were lower in patients than controls, which in turn correlated with increased global psychopathology severity and cognitive deficits. Third, negative symptoms moderated the association between low HDL cholesterol and poorer immediate verbal memory performance in patients. Our findings suggest that distinct lipid profile alterations are associated with cognitive performance and psychopathology severity in patients with FES. Further studies are needed to explore the associations of MetS with neurocognition over time, as well as how these relationships are affected by socio-demographic and clinical factors, including depression, anxiety, and related psychopathology.

Time is the enemy: Negative symptoms are related to even slight differences in the duration of untreated psychosis

BackgroundNegative symptoms (NS) represent a detrimental symptomatic domain in schizophrenia affecting social and occupational outcomes. AimsWe aimed to identify factors from the baseline visit (V1) — with a mean illness duration of 0.47 years (SD = 0.45) — that predict the magnitude of NS at the follow-up visit (V3), occurring 4.4 years later (mean +/− 0.45). MethodUsing longitudinal data from 77 first-episode schizophrenia spectrum patients, we analysed eight predictors of NS severity at V3: (1) the age at disease onset, (2) age at V1, (3) sex, (4) diagnosis, (5) NS severity at V1, (6) the dose of antipsychotic medication at V3, (7) hospitalisation days before V1 and; (8) the duration of untreated psychosis /DUP/). Secondly, using a multiple linear regression model, we studied the longitudinal relationship between such identified predictors and NS severity at V3 using a multiple linear regression model. ResultsDUP (Pearson's r = 0.37, p = 0.001) and NS severity at V1 (Pearson's r = 0.49, p < 0.001) survived correction for multiple comparisons. The logarithmic-like relationship between DUP and NS was responsible for the initial stunning incremental contribution of DUP to the severity of NS. For DUP < 6 months, with the sharpest DUP/NS correlation, prolonging DUP by five days resulted in a measurable one-point increase in the 6-item negative symptoms PANSS domain assessed 4.9 (+/− 0.6) years after the illness onset. Prolongation of DUP to 14.7 days doubled this NS gain, whereas 39 days longer DUP tripled NS increase. ConclusionThe results suggest the petrification of NS during the early stages of the schizophrenia spectrum and a crucial dependence of this symptom domain on DUP. These findings are clinically significant and highlight the need for primary preventive actions.

Inflammation and cognitive performance in first-episode schizophrenia spectrum disorders: The moderating effects of childhood trauma.

In this study, we aimed to determine whether childhood trauma moderated the relationship between inflammation and cognitive functioning in persons with first-episode schizophrenia spectrum disorders (SSDs). We included data from 92 individuals who participated in the nationwide Early-Stage Schizophrenia Outcome study. These individuals completed the Childhood Trauma Questionnaire, provided a fasting blood sample for high-sensitivity C-reactive protein analysis, and underwent extensive neuropsychological testing. The intervening effects of age, sex, education, smoking status, and body mass index were controlled. Results indicated that childhood trauma levels significantly moderated the relationship between inflammation and four cognitive domains: speed of processing, working memory, visual memory, and verbal memory. Inflammation also predicted verbal memory scores irrespective of childhood trauma levels or the covariates. Upon further exploration, the significant moderation effects appeared to be primarily driven by males. In conclusion, a history of childhood trauma may be an important determinant in evaluating how inflammation relates to the cognitive performance of people with first-episode SSDs, particularly in speed of processing, working memory, visual memory, and verbal memory. We recommend that future researchers examining the effect of inflammation on cognitive functioning in SSDs include trauma as a moderating variable in their models and further examine additional moderating effects of sex.

20-year trajectories of positive and negative symptoms after the first psychotic episode in patients with schizophrenia spectrum disorder: results from the OPUS study.

This study aimed to identify the 20-year trajectories of positive and negative symptoms after the first psychotic episode in a sample of patients with an ICD-10 diagnosis of schizophrenia spectrum disorder, and to investigate the baseline characteristics and long-term outcomes associated with these trajectories. A total of 373 participants in the OPUS trial were included in the study. Symptoms were assessed at baseline and after 1, 2, 5, 10 and 20 years using the Scales for the Assessment of Positive and Negative Symptoms. We used latent class growth mixture modelling to identify trajectories, and multinominal regression analyses to investigate predictors of membership to identified trajectories. Five trajectories of positive symptoms were identified: early continuous remission (50.9% of the sample), stable improvement (18.0%), intermittent symptoms (10.2%), relapse with moderate symptoms (11.9%), and continuous severe symptoms (9.1%). Substance use disorder (odds ratio, OR: 2.83, 95% CI: 1.09-7.38, p=0.033), longer duration of untreated psychosis (OR: 1.02, 95% CI: 1.00-1.03, p=0.007) and higher level of negative symptoms (OR: 1.60, 95% CI: 1.07-2.39, p=0.021) were predictors of the relapse with moderate symptoms trajectory, while only longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.030) predicted membership to the continuous severe symptoms trajectory. Two trajectories of negative symptoms were identified: symptom remission (51.0%) and continuous symptoms (49.0%). Predictors of the continuous symptoms trajectory were male sex (OR: 3.03, 95% CI: 1.48-6.02, p=0.002) and longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.034). Trajectories displaying continuous positive and negative symptoms were linked to lower neurocognition, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) (z-score: -0.78, CI: -1.39 to -0.17, for continuous positive symptoms; z-score: -0.33, CI: -0.53 to -0.13, for continuous negative symptoms). The same trajectories were also linked to higher use of antipsychotic medication at 20-year follow-up (continuous positive symptoms: 78%; continuous negative symptoms: 67%). These findings suggest that the majority of patients with first-episode schizophrenia spectrum disorder have a trajectory with early stable remission of positive symptoms. Long duration of untreated psychosis and comorbid substance abuse are modifiable predictors of poor trajectories for positive symptoms in these patients. In about half of patients, negative symptoms do not improve over time. These symptoms, in addition to being associated with poor social and neurocognitive functioning, may prevent patients from seeking help.

Cognitive flexibility in schizophrenia: A confirmatory factor analysis of neuropsychological measures

Cognitive flexibility (CF) is the ability to adapt cognitive strategies according to the changing environment. The deficit in CF has often been linked to various neurological and psychiatric disorders including schizophrenia. However, the operationalization and assessment of CF have not been unified and the current research suggests that the available instruments measure different aspects of CF. The main objective of the present study was to compare three frequently used neuropsychological measures of CF-Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and Stroop Color and Word Test (SCWT) in a population of patients (N = 220) with first-episode schizophrenia spectrum disorders in order to evaluate their convergent validity. The hypothesis of an underlying latent construct was tested via a confirmatory factor analysis. We used a one-factor CF model with scores from WCST, SCWT and TMT as observed variables. The established model showed a good fit to the data (χ2 = 1.67, p = 0.43, SRMR = 0.02, RMSEA = 0.0, CFI = 1.00). The highest factor loading was found in WCST as CF explained most of the variance in this neuropsychological measure compared to the other instruments. On the other hand, a TMT ratio index and a SCWT interference demonstrated lowest loadings in the model. The findings suggest that not all the frequently used measures share an underlying factor of CF or may capture different aspects of this construct.

Impact of early negative symptom patterns on the long-term outcomes of patients with first-episode schizophrenia-spectrum disorders: A 12-year follow up study

Given the strong prognostic value of early negative symptoms (NS), understanding their associations with long-term outcomes of schizophrenia is essential. The study examined early NS patterns in trajectory, severity and variability and their association with 12-year outcomes. NS in the first 36 months after onset and the symptomatology, cognitive function, and functioning at 12 years were examined in 330 patients with first-episode schizophrenia spectrum disorders. The relationships and pathways between the outcomes at 12 years and the trajectory, severity, and variability of early NS were examined. We found that the prediction of trajectory of early NS to long-term outcomes was limited, whereas variability was negatively associated with the patient's long-term executive function, and severity was positively associated with long-term symptomatology and negatively associated with long-term functioning. Path modelling revealed that the severity and variability of early NS influenced patients’ long-term functioning via cognitive function and/or clinical symptom pathways. Our findings support the notion that severity of early NS influences the prognosis of schizophrenia and the closer examination revealed that the severity and variability of early NS are differentially associated with long-term clinical symptoms, executive function, and functional outcomes via distinct pathways.

Clinical Recovery and Long-Term Association of Specialized Early Intervention Services vs Treatment as Usual Among Individuals With First-Episode Schizophrenia Spectrum Disorder

The OPUS 20-year follow-up is the longest follow-up of a randomized clinical trial testing early intervention services (EIS) among individuals with first-episode schizophrenia spectrum disorder. To report on long-term associations of EIS compared with treatment as usual (TAU) for first-episode schizophrenia spectrum disorder. A total of 547 individuals were included in this Danish multicenter randomized clinical trial between January 1998 and December 2000 and allocated to early intervention program group (OPUS) or TAU. Raters who were blinded to the original treatment performed the 20-year follow-up. A population-based sample aged 18 to 45 years with first-episode schizophrenia spectrum disorder were included. Individuals were excluded if they were treated with antipsychotics (>12 weeks prior to randomization), had substance-induced psychosis, had mental disability, or had organic mental disorders. Analysis took place between December 2021 and August 2022. EIS (OPUS) consisted of 2 years of assertive community treatment including social skill training, psychoeducation, and family involvement by a multidisciplinary team. TAU consisted of the available community mental health treatment. Psychopathological and functional outcomes, mortality, days of psychiatric hospitalizations, number of psychiatric outpatient contacts, use of supported housing/homeless shelters, symptom remission, and clinical recovery. Of 547 participants, 164 (30%) were interviewed at 20-year follow-up (mean [SD] age, 45.9 [5.6] years; 85 [51.8%] female). No significant differences were found between the OPUS group compared with the TAU group on global functional levels (estimated mean difference, -3.72 [95% CI, -7.67 to 0.22]; P = .06), psychotic symptom dimensions (estimated mean difference, 0.14 [95% CI, -0.25 to 0.52]; P = .48), and negative symptom dimensions (estimated mean difference, 0.13 [95% CI, -0.18 to 0.44]; P = .41). The mortality rate was 13.1% (n = 36) in the OPUS group and 15.1% (n = 41) in the TAU group. Likewise, no differences were found 10 to 20 years after randomization between the OPUS and TAU groups on days of psychiatric hospitalizations (incidence rate ratio, 1.20 [95% CI, 0.73-1.20]; P = .46) or number of outpatient contacts (incidence rate ratio, 1.20 [95% CI, 0.89-1.61]; P = .24). Of the entire sample, 53 participants (40%) were in symptom remission and 23 (18%) were in clinical recovery. In this follow-up study of a randomized clinical trial, no differences between 2 years of EIS vs TAU among individuals with diagnosed schizophrenia spectrum disorders at 20 years were found. New initiatives are needed to maintain the positive outcomes achieved after 2 years of EIS and furthermore improve very long-term outcomes. While registry data was without attrition, interpretation of clinical assessments are limited by high attrition rate. However, this attrition bias most likely confirms the lack of an observed long-term association of OPUS with outcomes. ClinicalTrials.gov Identifier: NCT00157313.

Stage-Specific Brain Aging in First-Episode Schizophrenia and Treatment-Resistant Schizophrenia.

Brain age is a popular brain-based biomarker that offers a powerful strategy for using neuroscience in clinical practice. We investigated the brain-predicted age difference (PAD) in patients with schizophrenia (SCZ), first-episode schizophrenia spectrum disorders (FE-SSDs), and treatment-resistant schizophrenia (TRS) using structural magnetic resonance imaging data. The association between brain-PAD and clinical parameters was also assessed. We developed brain age prediction models for the association between 77 average structural brain measures and age in a training sample of controls (HCs) using ridge regression, support vector regression, and relevance vector regression. The trained models in the controls were applied to the test samples of the controls and 3 patient groups to obtain brain-based age estimates. The correlations were tested between the brain PAD and clinical measures in the patient groups. Model performance indicated that, regardless of the type of regression metric, the best model was support vector regression and the worst model was relevance vector regression for the training HCs. Accelerated brain aging was identified in patients with SCZ, FE-SSDs, and TRS compared with the HCs. A significant difference in brain PAD was observed between FE-SSDs and TRS using the ridge regression algorithm. Symptom severity, the Social and Occupational Functioning Assessment Scale, chlorpromazine equivalents, and cognitive function were correlated with the brain PAD in the patient groups. These findings suggest additional progressive neuronal changes in the brain after SCZ onset. Therefore, pharmacological or psychosocial interventions targeting brain health should be developed and provided during the early course of SCZ.

Sexual dysfunction in first-episode schizophrenia spectrum disorders

Sexual dysfunction (SD) is common in patients with schizophrenia. In this study, we examined the prevalence and correlates of SD in a sample of patients with first-episode schizophrenia spectrum disorders (FES) (n = 77). Sexual functioning was examined using the Arizona Sexual Experiences Scale. Clinical measures of interest included the duration of untreated psychosis, psychopathology, depressive symptoms, functionality, and quality of life. Biochemical testing was also performed to measure prolactin, lipid profiles, and fasting glucose levels. In total, 27 (35%) patients met the criteria for SD, which was significantly more prevalent in females than males (p = 0.027). Higher depression scores, poorer social and occupational functioning, and lower high-density lipoprotein cholesterol levels predicted overall SD. Female sex, more pronounced global psychopathology, and poorer quality of life were also predictors of domain-specific SD, adjusting for the extent of antipsychotic exposure. SD has a high prevalence in patients with FES, particularly females. There is a need for a more nuanced understanding of SD in recent-onset schizophrenia, and to establish its relevance in terms of comorbid depressive symptoms and poor quality of life. SD may require specific attention and tailored treatment in females with FES. • We examined the prevalence and correlates of SD in FES. • SD was assessed in 77 patients with FES using the ASEX. • Female sex and depressive symptoms predicted SD. • Females had worse SD across multiple ASEX domains (1, 2, 4, 5). • FES characteristics were associated with SD in a sex- and domain-specific manner.

Differences in white matter microstructure in first-episode schizophrenia spectrum disorders vs healthy volunteers and their association with cognition

Objective: Both cognitive impairment and alterations in white matter tissue microstructure are well recognised in schizophrenia. We investigated whether differences in white matter microstructure underpin cognitive impairments in patients with first-episode schizophrenia spectrum disorders when controlling for multiple confounding factors. Methods: We employed a cross-sectional study design and compared fractional anisotropy (FA) between individuals diagnosed with first- episode schizophrenia spectrum disorders (FES) (n = 68) and matched healthy controls (n = 120). We conducted multiple analyses of covariance (ANCOVAs) to compare the mean FA values for patients and controls across 27 white matter tracts. We conducted exploratory correlation analyses to determine if white matter tract differences were associated with global cognitive impairment as well as deficits across seven cognitive domains. Results: We found widespread reductions in FA in patients compared to controls, after controlling for confounding variables, such as age, biological sex, education, substances, and childhood adversities. We found a significant positive correlation between the attention/vigilance domain and the splenium of the corpus collosum and external capsule after correction for multiple comparisons. In the control group we found no significant correlations between FA and cognition. Conclusion: Our findings provide a neurobiological basis for attentional cognitive deficits in schizophrenia, highlighting a potential role for the splenium of the corpus collosum and external capsule.

Computational Modeling of Oddball Sequence Processing Exposes Common and Differential Auditory Network Changes in First-Episode Schizophrenia-Spectrum Disorders and Schizophrenia.

Differences in sound relevance filtering in schizophrenia are proposed to represent a key index of biological changes in brain function in the illness. This study featured a computational modeling approach to test the hypothesis that processing differences might already be evident in first-episode, becoming more pronounced in the established illness. Auditory event-related potentials to a typical oddball sequence (rare pitch deviations amongst regular sounds) were recorded from 90 persons with schizophrenia-spectrum disorders (40 first-episode schizophrenia-spectrum, 50 established illness) and age-matched healthy controls. The data were analyzed using dynamic causal modeling to identify the changes in effective connectivity that best explained group differences. Group differences were linked to intrinsic (within brain region) connectivity changes. In activity-dependent measures these were restricted to the left auditory cortex in first-episode schizophrenia-spectrum but were more widespread in the established illness. Modeling suggested that both established illness and first-episode schizophrenia-spectrum groups expressed significantly lower inhibition of inhibitory interneuron activity and altered gain on superficial pyramidal cells with the data indicative of differences in both putative N-methyl-d-aspartate glutamate receptor activity-dependent plasticity and classic neuromodulation. The study provides further support for the notion that examining the ability to alter responsiveness to structured sound sequences in schizophrenia and first-episode schizophrenia-spectrum could be informative to uncovering the nature and progression of changes in brain function during the illness. Furthermore, modeling suggested that limited differences present at first-episode schizophrenia-spectrum may become more expansive with illness progression.

Load-dependent functional connectivity deficits during visual working memory in first-episode psychosis

IntroductionAberrant network connectivity is a core deficit in schizophrenia and may underlie many of its associated cognitive deficits. Previous work in first-episode schizophrenia spectrum illness (FESz) suggests preservation of working memory network function during low-load conditions with dysfunction emerging as task complexity increases. This study assessed visual network connectivity and its contribution to load-dependent working memory impairments. MethodsMagnetoencephalography was recorded from 35 FESz and 28 matched controls (HC) during a lateralized change detection task. Impaired alpha desynchronization was previously identified within bilateral dorsal occipital (Occ) regions. Here, whole-brain alpha-band connectivity was examined using phase-locking (PLV) and bilateral Occ as connectivity seeds. Load effects on connectivity were assessed across participants, and PLV modulation within networks was compared between groups. ResultsOcc exhibited significant load modulated connectivity with six regions (FDR-corrected). HC exhibited PLV enhancement with load in all connections. FESz failed to show PLV modulation between right Occ and left inferior frontal gyrus, lateral occipito-temporal sulcus, and anterior intermediate parietal sulcus. Smaller PLVs in all three network connections during both memory load conditions were associated with increased reality distortion in FESz (FDR-corrected.) ConclusionExamination of functional connectivity across the visual working memory network in FESz revealed an inability to enhance communication between perceptual and executive networks in response to increasing cognitive demands. Furthermore, the degree of network communication impairment was associated with positive symptoms. These findings provide insights into the nature of brain dysconnectivity and its contribution to symptoms in early psychosis and identify potential targets for future interventions.

Associations between BMI and brain structures involved in food intake regulation in first-episode schizophrenia spectrum disorders and healthy controls

Structural brain differences have been described in first-episode schizophrenia spectrum disorders (FES), and often overlap with those evident in the metabolic syndrome (MetS). We examined the associations between body mass index (BMI) and brain structures involved in food intake regulation in minimally treated FES patients (n = 117) compared to healthy controls (n = 117). The effects of FES diagnosis, BMI and their interactions on our selected prefrontal cortical thickness and subcortical gray matter volume regions of interest (ROIs) were investigated with hierarchical multivariate regressions, followed by post-hoc regressions for the individual ROIs. In a secondary analysis, we examined the relationships of other MetS risk factors and psychopathology with the brain ROIs. Both illness and BMI significantly predicted the grouped prefrontal cortical thickness ROIs, whereas only BMI predicted the grouped subcortical volume ROIs. For the individual ROIs, schizophrenia diagnosis predicted thinner left and right frontal pole and right lateral OFC thickness, and increased BMI predicted thinner left and right caudal ACC thickness. There were no significant main or interaction effects for diagnosis and BMI on any of the individual subcortical volume ROIs. Secondary analyses suggest associations between several brain ROIs and individual MetS risk factors, but not with psychopathology. Our findings indicate differential, independent effects for FES diagnosis and BMI on brain structures. Limited evidence suggests that the BMI effects are more prominent in FES. Exploratory analyses suggest associations between other MetS risk factors and some brain ROIs.

Dynamic Patterns of Symptoms and Functioning in Predicting Deliberate Self-harm in Patients with First-Episode Schizophrenia-Spectrum Disorders Over 3 Years.

Patients with schizophrenia have a significant risk of self-harm. We aimed to explore the dynamic relationship between symptomatology, functioning and deliberate self-harm (DSH) and evaluate the feasibility of developing a self-harm risk prediction tool for patients with first-episode schizophrenia (FES). Patients with FES (n = 1234) were followed up for 36 months. Symptomatology, functioning, treatment adherence and self-harm information were obtained monthly over the follow-up period. A time-varying vector autoregressive (VAR) model was used to study the contribution of clinical variables to self-harm over the 36th month. Random forest models for self-harm were established to classify the individuals with self-harm and predict future self-harm events. Over a 36-month period, 187 patients with FES had one or more self-harm events. The depressive symptoms contributed the most to self-harm prediction during the first year, while the importance of positive psychotic symptoms increased from the second year onwards. The random forest model with all static information and symptom instability achieved a good area under the receiver operating characteristic curve (AUROC = 0.77 ± 0.023) for identifying patients with DSH. With a sliding window analysis, the averaged AUROC of predicting a self-event was 0.65 ± 0.102 (ranging from 0.54 to 0.78) with the best model being 6-month predicted future 6-month self-harm for month 11-23 (AUROC = 0.7). Results highlight the importance of the dynamic relationship of depressive and positive psychotic symptoms with self-harm and the possibility of self-harm prediction in FES with longitudinal clinical data.

Aberrant attentional modulation of the auditory steady state response (ASSR) is related to auditory hallucination severity in the first-episode schizophrenia-spectrum

The 40-Hz auditory steady state response (ASSR) is reduced early in schizophrenia, with differences evident even at the first episode of schizophrenia-spectrum psychosis (FESz). Although robust, there is high variability in effect size across studies, possibly due to differences in experimental control of attention and heterogeneity of symptom profiles across studies, both of which may affect the ASSR. We investigated the relationships among ASSR deficits, attention-mediated sensory gain, and auditory hallucinations in 25 FESz (15 male; 23.3 ± 4.5 years) and 32 matched healthy comparison subjects (HC, 22 male; 24.7 ± 5.8 years). ASSR was measured to 40-Hz click trains at three intensities (75, 80, and 85 dB) while participants attended or ignored stimuli. ASSR evoked power and inter-trial phase coherence (ITPC) were measured using the Morlet wavelet transform. FESz did not show overall ASSR power reduction (p > 0.1), but power was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.1). Likewise, FESz did not evince overall ASSR ITPC reduction (p > 0.1), and ITPC was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.09). Attention-related change in ASSR correlated with auditory hallucination severity for power (r = −0.49, p < 0.05) and ITPC (r = −0.58, p < 0.01). FESz with auditory hallucinations may have pathologically increased basal excitability of auditory cortex and consequent reduced ability to further increase auditory cortex sensory gain with focused attention. These findings indicate hallucination-related pathophysiology early in schizophrenia and may guide novel intervention strategies aimed to modulate basal activity levels.

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

ObjectiveHistorically, 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.MethodsA 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.ResultsThe 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.ConclusionThe 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.

Guidelines for Discontinuation of Antipsychotics in Patients Who Recover From First-Episode Schizophrenia Spectrum Disorders: Derived From the Aggregated Opinions of Asian Network of Early Psychosis Experts and Literature Review.

ObjectiveAntipsychotic discontinuation has been a long-standing clinical and medicolegal issue. The Asian Network of Early Psychosis developed guidelines for antipsychotic discontinuation in patients who recover from first-episode non-affective psychosis. We reviewed the existing studies and guidelines on antipsychotic discontinuation to develop guidelines for antipsychotic discontinuation in such patients.MethodsWe reviewed the relevant studies, reviews, guidelines, and ongoing trials related to antipsychotic discontinuation in patients with first-episode psychosis or schizophrenia. The quality of randomized controlled trials was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.ResultsMost studies had low to very low quality, and 2 had moderate quality. All studies, except 1, advised against antipsychotic discontinuation because of higher relapse rates in the antipsychotic discontinuation group (19%–82% at 1-year follow-up) than the treatment maintenance group compared with the maintenance group. Based on expert opinion and Grading of Recommendations Assessment, Development, and Evaluation evidence of trials, guidelines have been recommended for future discontinuation studies on patients with first-episode schizophrenia spectrum disorders.ConclusionsCurrently, there are no recommendations for antipsychotic discontinuation in patients with first-episode schizophrenia spectrum disorders. However, there is a pressing need to conduct more rigorous research in remitted patients using more stringent criteria of full recovery, which can form the basis of guidelines on when and how antipsychotics should be tapered and discontinued. Studies that evaluate the patient characteristics and biomarkers that predict successful antipsychotic discontinuation are also needed.

The relationships between cognitive reserve, cognitive functioning and quality of life in first-episode schizophrenia spectrum disorders

Cognitive reserve (CR) has been conceptualized as an individual's ability to optimize or maximize performance through differential recruitment of brain networks. As such, CR may contribute to the heterogeneity of cognitive deficits observed in schizophrenia. This study aimed to assess the relationships between CR, cognition and quality of life in first-episode (FES) patients. A total of 137 patients with either ICD-10 schizophrenia or “acute and transient psychotic disorders” diagnosis, and 62 healthy controls had completed a comprehensive assessment of six cognitive domains: speed of processing, attention, working memory/flexibility, verbal memory, visual memory, and abstraction/executive functioning. CR was calculated from the participants’ education, premorbid IQ, and socioeconomic status. The results suggested that in patients, CR was positively related to cognitive performance in all domains, explaining 42.6% of the variance observed in cognition overall. Effects of CR in the control group were limited to three domains: speed of processing, abstraction/executive function and working memory/flexibility. These results suggest that CR largely contributes to cognitive variations present in FES patients. In addition, CR was negatively related to the social construct of patients’ quality of life, and positively to symptom severity and general functioning.

The associations of cannabis and methamphetamine use with cognitive performance over the first 2 years of treatment in schizophrenia spectrum disorders.

Cognitive deficits are a core feature of schizophrenia, and comorbid substance use may be a contributory factor. Methamphetamine use has been associated with cognitive impairment in schizophrenia, while associations with cannabis use are less clear-cut. This study aimed to investigate the associations of cannabis and methamphetamine use with cognitive performance in first-episode schizophrenia spectrum disorders over the first 2 years of treatment. This was a longitudinal cohort study in 81 patients treated with flupenthixol decanoate according to a standardized protocol over 24 months. Cognitive performance was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Cognitive Consensus Battery at four time points, and urine testing for cannabis and methamphetamine was conducted at six time points. We used linear mixed-effect models for repeated measures to assess visit-wise changes in composite cognitive scores in patients (n= 91) compared to matched controls without psychiatric or medical disorders (n= 100). Linear regression models were constructed to examine pre-treatment and end-point effects in patients. Compared to controls, patients exhibited greater cognitive impairments at baseline, which improved with treatment, but remained significantly lower throughout. The number of positive methamphetamine, but not cannabis, tests predicted less cognitive improvement in patients. Our findings suggest a negative association between methamphetamine and cognition, but not cannabis.