First-episode Psychosis Subjects Research Articles

Borderline personality disorder vs. schizophrenia spectrum disorders in young people recruited within an "Early Intervention in Psychosis" service: clinical and outcome comparisons.

Borderline Personality Disorder (BPD) is under-recognized in First-Episode Psychosis (FEP) and its psychotic manifestations are difficult to differentiate from Schizophrenia Spectrum Disorders (SSD). The aim of this investigation was to compare clinical, sociodemographic, and outcome characteristics between FEP patients with BPD vs. FEP subjects with SSD both at baseline and across a 2-year follow-up period. Participants completed the Health of the Nation Outcome Scale (HoNOS), the Positive And Negative Syndrome Scale (PANSS), and the Global Assessment of Functioning (GAF) scale both at entry and every 12months during the follow-up. A mixed-design ANOVA model was conducted to investigate the temporal stability of clinical scores within and between the two subgroups. Among 356 FEP participants, 49 had a BPD diagnosis. Compared to FEP/SSD (n = 307), FEP/BPD patients showed higher prevalence of employment, current substance use, and past attempted suicide. They had a lower equivalent dose of antipsychotic medication at entry and lower levels of negative symptoms. Finally, they had a higher 2-year drop-out rate and a significant improvement in psychopathological scores limited to the first year of treatment. BPD as categorical entity represents a FEP subgroup with specific clinical challenges. Appropriate treatment guidelines for this FEP subgroup are thus needed.

CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.

The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. CSF dopamine was reliably detected in 50% of healthy controls and in 65% of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.

A machine learning approach on whole blood immunomarkers to identify an inflammation associated psychosis onset subgroups

AbstractPsychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. Since several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. In this lecture, I will show the results of our recent study that tested the hypothesis of the existence of subgroups of first-episode psychosis (FEP) patients identified by distinct peripheral immunomarkers’ profiles, possibly underpinning a subgroup-specific immunopathogenesis. More in detail, I will show the results obtained by the unsupervised machine learning model that we applied to the set of 12 peripheral blood immune gene transcripts, which we recently demonstrated to classify with high accuracy a cohort of FEP patients and HC. Also, I will report the results obtained by performing post-hoc univariate analyses using selective clinical, cognitive, and brain structural phenotypes of FEP patients and HC belonging to each subgroup identified by the computational model. I will extensively discuss two key clusters identified and validated by our model: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes; 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). Therefore, in this lecture I will emphasize that our study has been the first to demonstrate the existence of a psychosis onset subgroup identified by a peculiar multivariate pattern of immunomarkers, independently of clinical features or categorical diagnosis. This is paramount as if validated in independent samples, our clustering model could enable the sample selection in clinical trials aiming to test the efficacy of novel immunomodulant or anti-inflammatory therapies tailored to the specific inflammatory subgroup of psychotic patients.Disclosure of InterestNone Declared

Individual psychotherapy may help to reduce suicidal ideation in first episode psychosis: results from a 2-year Italian follow-up study

IntroductionSuicidal thinking is relevant in patients with First Episode Psychosis (FEP). However, longitudinal studies specifically examining treatment response for suicidal ideation in FEP are still relatively scarce, especially with long-term design and in real-world clinical settings.ObjectivesThe aims of this research were (A) to longitudinally assess suicidal thoughts in people with FEP along a 2-year follow-up period and (B) to overtime investigate any significant association of suicidal ideation levels with the specific treatment components of an ‘Early Intervention in Psychosis’ (EIP) protocol along the 2 years of follow-up.MethodsAt entry, 232 FEP participants (aged 12–35 years) completed the Brief Psychiatric Rating Scale (BPRS), including a ‘Suicidality’ item subscore. Multiple linear regression analysis was then performed.ResultsAcross the follow-up, FEP subjects showed a relevant decrease in suicidal thinking levels overtime. This was specifically predicted by the total number of individual psychotherapy sessions offered within the 2-year EIP protocol and antidepressant dose (at least as regards the first year of our intervention).Image:ConclusionsSuicidal ideation is clinically relevant in FEP but seems to improve overtime together with the provision of specific, patient-tailored and integrated EIP treatments, especially individual psychotherapy.Disclosure of InterestNone Declared

Depressive Features in Individuals with First Episode Psychosis: Psychopathological and Treatment Considerations from A 2-Year Follow-Up Study.

Comorbid depression is quite common in early psychosis and specifically related to suicidal behavior and poor long-term outcomes. However, Depressive Symptoms (DS) are often neglected in both research and treatment, especially at the psychosis onset. The goals of this investigation were: (a) to longitudinally explore DS levels in patients with First Episode Psychosis (FEP) during 24 months of follow-up, and (b) to investigate the associations of DS with psychopathology and intervention components of an "Early Intervention in Psychosis" (EIP) program across the follow-up period. The Global Assessment of Functioning (GAF) and the Positive And Negative Syndrome Scale (PANSS) were completed by 266 FEP subjects. A linear regression analysis with DS as the dependent parameter and psychopathological and treatment characteristics as independent variables was performed (both at baseline and across the follow-up period). DS had enduring associations with PANSS "Positive Symptoms" and "Negative Symptoms" subscores. During the investigation, FEP subjects significantly improved their DS severity levels. This was related to the number of individual psychotherapy meetings supplied within the EIP protocol, as well as to a higher antidepressant dose and a lower antipsychotic dose prescribed during the follow-up. DS are quite prominent in FEP, even at the recruitment time in EIP services. Nevertheless, DS severity tends to diminish overtime, especially with the provision of specialized EIP treatments.

A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

Chaos analysis of the brain topology in first-episode psychosis and clinical high risk patients.

Structural MRI studies in first-episode psychosis (FEP) and in clinical high risk (CHR) patients have consistently shown volumetric abnormalities in frontal, temporal, and cingulate cortex areas. The aim of the present study was to employ chaos analysis for the identification of brain topology differences in people with psychosis. Structural MRI were acquired from 77 FEP, 73 CHR and 44 healthy controls (HC). Chaos analysis of the gray matter distribution was performed: First, the distances of each voxel from the center of mass in the gray matter image was calculated. Next, the distances multiplied by the voxel intensity were represented as a spatial-series, which then was analyzed by extracting the Largest-Lyapunov-Exponent (lambda). The lambda brain map depicts thus how the gray matter topology changes. Between-group differences were identified by (a) comparing the lambda brain maps, which resulted in statistically significant differences in FEP and CHR compared to HC; and (b) matching the lambda series with the Morlet wavelet, which resulted in statistically significant differences in the scalograms of FEP against CHR and HC. The proposed framework using spatial-series extraction enhances the between-group differences of FEP, CHR and HC subjects, verifies diagnosis-relevant features and may potentially contribute to the identification of structural biomarkers for psychosis.

Association between case management and longitudinal decrease in negative symptoms in patients with first episode psychosis: A 2-year follow-up.

Negative symptoms (NS) severely affect daily functioning already at the psychosis onset. However, most studies investigating beneficial effects of specific treatments for NS mainly included individuals with prolonged psychotic disorders. Furthermore, evidence on psychosocial rehabilitation for NS in early psychosis is still relatively poor. The aims of this study therefore were (A) to longitudinally examine NS stability in people with first episode psychosis (FEP) along a 2-year follow-up period, and (B) to overtime explore any relevant association of NS levels with the specific intervention components of an 'early intervention in psychosis' (EIP) protocol during the follow-up. At baseline, 266 FEP subjects (aged 12-35 years) completed the positive and negative syndrome scale (PANSS). Multiple linear regression analyses were then performed. Along the follow-up, FEP participants had a relevant improvement in NS levels. This was specifically predicted by the total number of case management sessions offered within our 2-year EIP protocol, as well as by shorter duration of untreated psychosis at entry and by longitudinal reduction in PANSS depressive and positive symptom dimension levels. No association with antipsychotic medication was found. NS are clinically relevant in FEP, already at the recruitment time in specialized EIP services. However, their severity appears to improve over time together with the delivery of patient-tailored, integrated EIP case management.

Individual psychotherapy can reduce suicidal ideation in first episode psychosis: Further findings from the 2-year follow-up of the 'Parma Early Psychosis' programme.

Suicidal thinking is relevant in patients with First Episode Psychosis (FEP). However, longitudinal studies specifically examining treatment response for suicidal ideation in FEP are still relatively scarce, especially with long-term design and in real-world clinical settings. The aims of this research were (A) to longitudinally assess suicidal thoughts in people with FEP along a 2-year follow-up period and (B) to overtime investigate any significant association of suicidal ideation levels with the specific treatment components of an 'Early Intervention in Psychosis' (EIP) protocol along the 2years of follow-up. At entry, 232 FEP participants (aged 12-35 years) completed the Brief Psychiatric Rating Scale (BPRS), including a 'Suicidality' item subscore. Multiple linear regression analysis was then performed. Across the follow-up, FEP subjects showed a relevant decrease in suicidal thinking levels overtime. This was specifically predicted by the total number of individual psychotherapy sessions offered within the 2-year EIP protocol and antidepressant dose (at least as regards the first year of our intervention). Suicidal ideation is clinically relevant in FEP but seems to improve overtime together with the provision of specific, patient-tailored and integrated EIP treatments, especially individual psychotherapy.

Contributions of Parasympathetic Arousal–Related Activity to Cognitive Performance in Patients With First-Episode Psychosis and Control Subjects

BackgroundCognitive impairment is integral to the pathophysiology of psychosis. Recent findings implicate autonomic arousal–related activity in both momentary fluctuations and individual differences in cognitive performance. Although altered autonomic arousal is common in patients with first-episode psychosis (FEP), its contribution to cognitive performance is unknown. MethodsA total of 24 patients with FEP (46% male, age = 24.31 [SD 4.27] years) and 24 control subjects (42% male, age = 27.06 [3.44] years) performed the Multi-Source Interference Task in-scanner with simultaneous pulse oximetry. First-level models included the cardiac-blood oxygen level–dependent regressor, in addition to task (congruent, interference, and error) and nuisance (motion and CompCor physiology) regressors. The cardiac-blood oxygen level–dependent regressor reflected parasympathetic arousal–related activity and was created by convolving the interbeat interval at each heartbeat with the hemodynamic response function. Group models examined the effect of group or cognitive performance (reaction times × error rate) on arousal-related and task activity, while controlling for sex, age, and framewise displacement. ResultsParasympathetic arousal–related activity was robust in both groups but localized to different regions for patients with FEP and healthy control subjects. Within both groups, arousal-related activity was significantly associated with cognitive performance across occipital and temporal cortical regions. Greater arousal-related activity in the bilateral prefrontal cortex (Brodmann area 9) was related to better performance in healthy control subjects but not patients with FEP. ConclusionsAutonomic arousal circuits contribute to cognitive performance and the pathophysiology of FEP. Arousal-related functional activity is a novel indicator of cognitive ability and should be incorporated into neurobiological models of cognition in psychosis.

Evaluation of relationships between presence of adhesio interthalamica and cannabis use in first-episode psychosis: a magnetic resonance imaging investigation

ABSTRACT Recent studies suggested that cannabis use influences on the emergence of psychosis by disrupting neurodevelopmental processes that occur during adolescence and early adulthood and which are reflected on brain anatomical changes detectable with MRI. However, no MRI studies have investigated whether intrauterine neurodevelopmental abnormalities also interact with later cannabis use to influence on psychosis risk. We investigated differences between first-episode psychosis (FEP) patients with history of cannabis use (FEPC+, n=28), FEP subjects without cannabis use (FEPC-, n=78) and healthy controls (n=80) in regard to the frequency of absent or short Adhesio Interthalamica (AI), a well-established marker of intrauterine neurodevelopment. The FEPC+ subgroup had a significantly lower prevalence of absent AI than FEPC- subjects, as well as a lack of a significantly shorter AI length compared to controls (as found in FEPC- subjects). These preliminary results show that psychosis subjects with cannabis use present a low rather than high frequency of absent AI, suggesting that fixed intrauterine neurodevelopmental abnormalities may not be associated with cannabis use later in life to influence on the emergence of psychosis. This is consistent with a view that multiple different etiological processes may lead to similar clinical presentations in patients with FEP.

Classification of first-episode psychosis using cortical thickness: A large multicenter MRI study

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulnerable due to variation in glutamate receptor densities. We investigated hippocampal anomalies in first-episode psychosis (FEP) in relation to receptor distributions by leveraging 4 sources of data: (1) ultra high-field (7-Tesla) structural neuroimaging, and (2) proton magnetic resonance spectroscopy (1H-MRS) of glutamate from 27 healthy and 41 FEP subjects, (3) gene expression data from the Allen Human Brain Atlas and (4) atlases of the serotonin receptor system. Automated methods delineated the hippocampus to map receptor density across subfields. We used gene expression data to correlate serotonin and glutamate receptor genes across the hippocampus. Measures of individual hippocampal shape-receptor alignment were derived through normative modelling and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). We found reduced hippocampal volumes in FEP, while CA4-dentate gyrus showed greatest reductions. Gene expression indicated 5-HT1A and 5-HT4 to correlate with AMPA and NMDA expression, respectively. Magnitudes of subfield volumetric reduction in FEP correlated most with 5-HT1A (R = 0.64, p = 4.09E-03) and 5-HT4 (R = 0.54, p = 0.02) densities as expected, and replicated using previously published data from two FEP studies. Right-sided 5-HT4-RSMS was correlated with MRS glutamate (R = 0.357, p = 0.048). We demonstrate a putative glutamate-driven hippocampal variability in FEP through a serotonin receptor-density gated mechanism, thus outlining a mechanistic interplay between serotonin and glutamate in determining the hippocampal morphology in schizophrenia.

Salience network glutamate and brain connectivity in medication-naïve first episode patients – A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

BackgroundSalience network (SN) connectivity is altered in schizophrenia, but the pathophysiological origin remains poorly understood. The goal of this multimodal neuroimaging study was to investigate the role of glutamatergic metabolism as putative mechanism underlying SN dysconnectivity in first episode psychosis (FEP) subjects. MethodsWe measured glutamate + glutamine (Glx) in the dorsal anterior cingulate cortex (dACC) from 70 antipsychotic-naïve FEP subjects and 52 healthy controls (HC). The dACC was then used as seed to define positive and negative resting state functional connectivity (FC) of the SN. We used multiple regression analyses to test main effects and group interactions of Glx and FC associations. ResultsdACC Glx levels did not differ between groups. Positive FC was significantly reduced in FEP compared to HC, and no group differences were found in negative FC. Group interactions of Glx-FC associations were found within the SN for positive FC, and in parietal cortices for negative FC. In HC, higher Glx levels predicted greater positive FC in the dACC and insula, and greater negative FC of the lateral parietal cortex. These relationships were weaker or absent in FEP. ConclusionsHere, we found that positive FC in the SN is already altered in medication-naïve FEP, underscoring the importance of considering both correlations and anticorrelations for characterization of pathology. Our data demonstrate that Glx and functional connectivity work differently in FEP than in HC, pointing to a possible mechanism underlying dysconnectivity in psychosis.

The Complement C4 Genetic Diversity in First Episode Psychosis of the OPTiMiSE Cohort

Abstract Recent findings implicate the complement C4 gene in gray matter loss in schizophrenia. In a large cohort of patients with first-episode psychosis (FEP), we aimed to (1) characterize the frequency of C4 gene copy number variations (CNVs) and HERV-K Ins/Del events as compared to that in healthy controls (HCs) and (2) evaluate whether C4 gene structural variants influence baseline clinical symptoms and treatment response to amisulpride. A total of 271 FEP subjects and 221 HCs were genotyped for C4 CNV and HERV-Ins/Del (C4A and C4B isoforms; C4-HERV structural forms [C4AL, C4AS, C4BL, C4BS] variations using droplet digital PCR. Overall, the gene frequencies of both C4 isoforms and C4-HERV structural forms did not significantly differ between groups. At the genotype level, we found that the C4 AL-AL-BL-BL genotype (AL-BL haplotype) was significantly more frequent in FEP as compared to HC. Apart from a marginal observation concerning the C4 AL-AL-BL-BL genotype (AL-BL haplotype), possibly reflecting a relationship with schizophrenia, we did not find any correlation between C4 genetic and clinical characteristics or treatment response in FEP.

Multimodal MRI assessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup.

Multi‐institutional brain imaging studies have emerged to resolve conflicting results among individual studies. However, adjusting multiple variables at the technical and cohort levels is challenging. Therefore, it is important to explore approaches that provide meaningful results from relatively small samples at institutional levels. We studied 87 first episode psychosis (FEP) patients and 62 healthy subjects by combining supervised integrated factor analysis (SIFA) with a novel pipeline for automated structure‐based analysis, an efficient and comprehensive method for dimensional data reduction that our group recently established. We integrated multiple MRI features (volume, DTI indices, resting state fMRI—rsfMRI) in the whole brain of each participant in an unbiased manner. The automated structure‐based analysis showed widespread DTI abnormalities in FEP and rs‐fMRI differences between FEP and healthy subjects mostly centered in thalamus. The combination of multiple modalities with SIFA was more efficient than the use of single modalities to stratify a subgroup of FEP (individuals with schizophrenia or schizoaffective disorder) that had more robust deficits from the overall FEP group. The information from multiple MRI modalities and analytical methods highlighted the thalamus as significantly abnormal in FEP. This study serves as a proof‐of‐concept for the potential of this methodology to reveal disease underpins and to stratify populations into more homogeneous sub‐groups.

Perceived stress, social functioning and quality of life in first-episode psychosis: A 1-year follow-up study.

Quality of life (QoL) has been widely studied in people with schizophrenia. In the early phases of psychosis, it remains often impaired even after the remission of psychotic symptoms. The aim of this study was to explore QoL and social functioning during the first year after a first-episode psychosis (FEP), and to study potential moderating effects of stress measures. Here, 61 FEP subjects and 55 healthy controls (HCs) were included. Sociodemographic data and clinical variables were collected through a semi-structured interview. Stress measures, social functioning and QoL were assessed with the Holmes-Rahe Social Readjustment Rating Scale, the Perceived Stress Scale, the Social Adaptation Self-Scale and the Euro-QoL-5D, respectively. Analysis of variance was employed with repeated measures and a mediation analysis at baseline and at 1-year follow-up was carried out. Patients reported lower QoL, poorer social functioning and more stress than HC. FEP patients significantly improved in QoL and stress measures over time, but not in social functioning. Perceived stress mediated the association between poorer social functioning and lower QoL. Social functioning at baseline may determine QoL over a 1-year follow-up period. Despite the improvement in most measures, patients do not achieve the level of well-being as the healthy group.

Negative symptom dimensions in first episode psychosis: Is there a difference between schizophrenia and non-schizophrenia spectrum disorders?

Identifying discrete dimensions that underline negative symptoms in First Episode Psychosis (FEP) could improve the understanding and the treatment of such invalidating symptomatology. The aim of this study is to examine the negative symptom structure in FEP individuals and to compare the resulting factor configurations between FEP subjects with and without Schizophrenia Spectrum Disorders (SSD vs non-SSD). One hundred and seventy participants (88 SSD and 82 non-SSD), aged 13-35 years, completed the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Positive and Negative Syndrome Scale (PANSS). A principal component analysis was then performed to investigate PANSS negative symptom structure in both non-SSD and SSD groups. Whereas in the SSD sample a 3-factor model solution (i.e., "Socio-Emotional Disengagement", "Motor/Thought Poverty", and "Avolition/Apathy" dimensions) was identified, a 2-factor model solution (with a mixed alogia/avolition domain in addition to a mixed socio-emotional disengagement/expressive deficits dimension) appeared more appropriate in the non-SSD group. Our results show a relevant difference in the negative symptom factor structure between SSD and non-SSD individuals. In particular, a different specificity and significance of negative symptom models in FEP populations with diagnoses other than schizophrenia (compared to those with SSD) must be realistically considered. Notably, a "Motor/Thought Poverty" domain, which specifically includes alogia and motor retardation separately from the other PANSS negative items, appears to specifically characterize FEP young patients with the schizophrenia spectrum.

M167. MACHINE LEARNING CLASSIFICATION OF FIRST-EPISODE PSYCHOSIS USING CORTICAL THICKNESS IN A LARGE MULTICENTER MRI STUDY

BackgroundMachine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness data, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between the predictions and clinical variables.Methods428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI (sMRI) session and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20484 vertices) were extracted. Supervised (linear Support Vector Machine) classification was used to differentiate FEP from HC, within a repeated nested Cross-Validation (CV) framework through the NeuroMiner software. In both inner and outer CVs, a 10-fold CV cycle was employed. We performed repeated nested CV at the outer cross-validation cycle by randomly permuting the participants within their groups (10 permutations) and repeating the CV cycle for each of these permutations. As feature preprocessing, regression of covariates (age, sex, and site), Principal Component Analysis and Scaling were applied. All preprocessing steps were implemented within the CV. Further analyses were conducted by stratifying the sample for MRI scanner, sex and by performing random resampling with increasingly reduced sample sizes.ResultsVertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy (BAC) of 66.2% and an Area Under the Curve of 72%, compared to a BAC of 59% and an Area Under the Curve of 61% obtained with the ROI-based approach. The two BACs were significantly different based on the McNemar’s Test. By stratifying our sample for MRI scanner, we increased the overall BAC to more than 70% and we also increased generalizability across sites. Temporal areas resulted the most influential regions in the classification. The predictive decision scores presented significant correlations with age at onset, duration of treatment and the presence of affective vs non-affective psychosis.DiscussionCortical thickness could represent a valid measure to classify FEP subjects, showing temporal areas as potential markers in the early stages of psychosis. The assessment of site-dependent variables allowed us to increase the across-site generalizability of the model, thus attempting to address an important machine learning limitation, especially in the framework of large multi-site cohort and big data analysis.

CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects

Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and in vitro modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.