Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

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

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

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

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

Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study.

BACKGROUND: Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis. METHODS: We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up. RESULTS: Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05). CONCLUSIONS: Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Outcomes following first-episode psychosis - Why we should intervene early in all ages, not only in youth.

OBJECTIVE: To compare baseline demographics and 10-year outcomes of a first-episode psychosis patient incidence cohort in order to establish whether current youth-focussed age-based criteria for early intervention services are justified by patient needs. The patients in this cohort were treated prior to the establishment of early intervention services. The study aimed to test the hypothesis that those who develop psychosis at a younger age have worse outcomes than those who develop psychosis at an older age. METHODS: Data on first-episode psychosis patients from the ÆSOP-10 longitudinal follow-up study were used to compare baseline characteristics, and 10-year clinical, functional and service use outcomes between those patients who would and would not have met age-based criteria for early intervention services, in Australia or in the United Kingdom. RESULTS: In total, 58% men and 71% women with first-episode psychosis were too old to meet current Australian-early intervention age-entry criteria (χ2 = 9.1, p = 0.003), while 21% men and 34% women were too old for UK-early intervention age-entry criteria (χ2 = 11.1, p = 0.001). The 10-year clinical and functional outcomes did not differ significantly between groups by either Australian- or UK-early intervention age-entry criteria. Service use was significantly greater among the patients young enough to meet early intervention age-criteria (Australia: incidence rate ratio = 1.35 [1.19, 1.52], p < 0.001; United Kingdom: incidence rate ratio = 1.65 [1.41, 1.93], p < 0.001). CONCLUSION: Current early intervention services are gender- and age-inequitable. Large numbers of patients with first-episode psychosis will not receive early intervention care under current service provision. Illness outcomes at 10-years were no worse in first-episode psychosis patients who presented within the age range for whom early intervention has been prioritised, though these patients had greater service use. These data provide a rationale to consider extension of early intervention to all, rather than just to youth.

An automatic analysis framework for FDOPA PET neuroimaging.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

BACKGROUND: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. METHODS: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. RESULTS: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). CONCLUSIONS: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.

Cariprazine as a treatment for negative psychotic symptoms in first-episode psychosis: case series.

Negative psychotic symptoms are among the most disabling features of schizophrenia, and are strongly associated with relatively poor clinical and functional outcomes. However, there are no effective treatments for negative symptoms, and this represents a major unmet clinical need. Recent research has shown that negative symptoms are already present in many patients at illness onset. There is evidence that cariprazine may improve negative symptoms in patients with chronic schizophrenia. However, its utility in treating negative symptoms in the early stage of the disorder is unclear. Here, we report six cases of patients with first-episode psychosis who were treated with cariprazine.

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.

IMPORTANCE: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. OBJECTIVE: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). MAIN OUTCOMES AND MEASURES: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. RESULTS: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCE: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium.

INTRODUCTION: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. METHODS: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. RESULTS: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). IMPLICATIONS: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

Assessment of posttraumatic symptoms in patients with first-episode psychosis.

Posttraumatic stress disorder is common among patients with psychotic disorders. The present study examined the internal reliability and comparability of the Impact of Event Scale (IES) in a sample of 38 patients with first-episode psychosis and 47 controls exposed to severe physical and/or sexual abuse. The IES total score and both subscales showed high internal consistency in both groups (Cronbach's alpha coefficients of approximately 0.9 or higher). Given their equivalent trauma reporting, the lack of differences in IES scores between patients and controls seems to indicate that patients are likely to report accurately and neither exaggerate nor minimize their posttraumatic symptoms. Overall, the findings suggest that the IES can be used to assess symptoms of posttraumatic stress in patients with psychotic disorders as in other populations.

A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach.

[18F]FDOPA PET imaging has shown dopaminergic function indexed as Kicer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both [18F]FDOPA PET approaches had good test-rest reproducibility across striatal regions (Kicer ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: Kicer = 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (Kicer: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of [18F]FDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate [18F]FDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.

Lower speech connectedness linked to incidence of psychosis in people at clinical high risk.

BACKGROUND: Formal thought disorder is a cardinal feature of psychotic disorders, and is also evident in subtle forms before psychosis onset in individuals at clinical high-risk for psychosis (CHR-P). Assessing speech output or assessing expressive language with speech as the medium at this stage may be particularly useful in predicting later transition to psychosis. METHOD: Speech samples were acquired through administration of the Thought and Language Index (TLI) in 24 CHR-P participants, 16 people with first-episode psychosis (FEP) and 13 healthy controls. The CHR-P individuals were then followed clinically for a mean of 7 years (s.d. = 1.5) to determine if they transitioned to psychosis. Non-semantic speech graph analysis was used to assess the connectedness of transcribed speech in all groups. RESULTS: Speech was significantly more disconnected in the FEP group than in both healthy controls (p < .01) and the CHR-P group (p < .05). Results remained significant when IQ was included as a covariate. Significant correlations were found between speech connectedness measures and scores on the TLI, a manual assessment of formal thought disorder. In the CHR-P group, lower scores on two measures of speech connectedness were associated with subsequent transition to psychosis (8 transitions, 16 non-transitions; p < .05). CONCLUSION: These findings support the utility and validity of speech graph analysis methods in characterizing speech connectedness in the early phases of psychosis. This approach has the potential to be developed into an automated, objective and time-efficient way of stratifying individuals at CHR-P according to level of psychosis risk.

Natural Language Processing markers in first episode psychosis and people at clinical high-risk.

Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most strongly associated with psychosis, how different measures are related to each other and what the best strategies are to collect speech data from participants. Here, we assessed whether twelve automated Natural Language Processing markers could differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis, first episode psychosis patients and healthy control subjects (total N = 54). In-line with previous work, several measures showed significant differences between groups, including semantic coherence, speech graph connectivity and a measure of whether speech was on-topic, the latter of which outperformed the related measure of tangentiality. Most NLP measures examined were only weakly related to each other, suggesting they provide complementary information. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future clinical applications.

Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

The test-retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function.

Brain presynaptic dopaminergic function can be assessed using 18F-DOPA positron emission tomography (PET). Regional 18F-DOPA utilization may be used to index dopaminergic abnormalities over time or dopaminergic response to treatment in clinical populations. Such studies require prior knowledge of the stability of the 18F-DOPA signal in the brain regions of interest. Test-retest reliability was examined in eight healthy volunteers who each received two 18F-DOPA PET scans, approximately 2 years apart. 18F-DOPA utilization (k(i)(cer)) was determined using graphical analysis relative to a reference tissue input (Patlak and Blasberg, 1985). Reproducibility (measured as the within-subjects variation) and reliability (measured as intraclass correlation coefficients, ICCs) of 18F-DOPA k(i)(cer) were assessed in the structural and functional subdivisions of the striatum and select extrastriatal brain regions. Voxel-based median ICC maps were used to visualize the distribution of 18F-DOPA k(i)(cer) reliability across the brain. The caudate and putamen, and associative and sensorimotor, striatal subdivisions showed good reliability across the two scan sessions with bilateral ICCs ranging from 0.681 to 0.944. Reliability was generally lower in extrastriatal regions, with bilateral ICCs ranging from 0.235 in the amygdala to 0.894 in the thalamus. These data confirm the utility of 18F-DOPA PET in assessing dopaminergic function in the striatum and select extrastriatal areas but highlight the limitations in using this approach to measure dopaminergic function in low uptake extrastriatal brain areas. This information can be used to optimize the experimental design of future studies investigating changes in brain dopaminergic function with 18F-DOPA.

Glyceryl trinitrate in first-episode psychosis unmedicated with antipsychotics: A randomised controlled pilot study.

BACKGROUND: There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. AIMS: We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis. METHODS: This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond-Lader Visual Analogue Scales). RESULTS: Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms. CONCLUSIONS: We found no indication of an effect of GTN on symptoms of psychosis or cognition.

Rasch analysis of the PANSS negative subscale and exploration of negative symptom trajectories in first-episode schizophrenia - data from the OPTiMiSE trial.

The observed heterogeneity in negative symptom treatment response may be partly attributable to inadequate measurement tools or limitations in methods of analysis. Previous Item Response Theory models of the Positive and Negative Syndrome Scale (PANSS) have only examined samples of chronic patients and with mixed results. We examined the scalability of the negative subscale embedded in the PANSS and subsequently explored negative symptom trajectories across four weeks of amisulpride treatment. Data were derived from the OPTiMiSE trial comprising 446 patients with first-episode schizophrenia or schizophreniform disorder. Using the Rasch Model to examine psychometric properties of the PANSS negative subscale, we found that the composite score across items was not an adequate measure of negative symptom severity. Consequently, we chose an exploratory statistical approach involving Principal Component Analysis which yielded one significant component clustering into two significant symptom trajectories: 1) Subtle but constant decrease in negative symptom severity (N = 323; 72%), and 2) symptom instability across visits (N = 19; 4%). Explorative analytic methods as presented here may pave the way for more efficient and sensitive methods of analyzing negative symptom response in research and in clinical practice.

Persistent negative symptoms in recent-onset psychosis: Relationship to treatment response and psychosocial functioning.

Negative symptoms are associated with poor clinical and psychosocial outcome in schizophrenia. Their prevalence and identification in first-episode patients remains controversial. In a large cohort of patients in the early stage of schizophrenia, schizophreniform or schizoaffective disorder, we investigated, over the different phases of the OPTiMiSE trial (baseline, 4, 10 and 22 weeks of treatment), the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline. Moreover, we assessed symptomatic remission, attrition rate and psychosocial functioning in subjects with short-term (4 weeks) persistent unconfounded negative symptoms (PNS) and in those with negative symptoms that did not persist at follow-up and/or were confounded at baseline (N-PNS). Negative symptoms of moderate severity were observed in 59% of subjects at baseline. They were associated with worse psychosocial functioning and longer duration of psychosis at intake in the study. Eleven percent of subjects had PNS unconfounded at baseline and 7.9% had PNS unconfounded at both baseline and end of 4-week treatment. Psychosocial functioning was comparable in PNS and N-PNS subjects at baseline but it was significantly worse in the former group after 4-weeks. PNS subjects showed lower remission and higher attrition rates at the end of all treatment phases. Fifty-six percent of subjects completing phase 3 (clozapine treatment) had PNS, and 60% of them were non-remitters at the end of this phase. The presence of short-term PNS during the first phases of psychosis was associated with poor clinical outcome and resistance to antipsychotic treatment, including clozapine.