Ceftriaxone reverses diet-induced deficits in goal-directed control.

RATIONALE: Obesity is associated with numerous health risks and ever-increasing rates are a significant global concern. However, despite weight loss attempts many people have difficulty maintaining weight loss. Previous studies in animals have shown that chronic access to an obesogenic diet can disrupt goal-directed behavior, impairing the ability of animals to flexibly adjust food-seeking behavior following changes in the value of earned outcomes. Changes in behavioral control have been linked to disruption of glutamate transmission in the dorsal medial striatum (DMS), a region critical for the acquisition and expression of goal-directed behavior. OBJECTIVES: The goal of this study was to test whether ceftriaxone, a beta-lactam antibiotic shown elsewhere to upregulate the expression of the glutamate transporter GLT-1, would improve goal-directed control following long-term exposure to an obesogenic diet. METHODS: Male and female rats were given access to either standard chow or chow plus sweetened condensed milk (SCM) for 6 weeks. Access to SCM was ended and rats received daily injections of either ceftriaxone or saline for 6 days. Rats were then trained to press a lever to earn a novel food reward and, finally, were assessed for sensitivity to outcome devaluation. Histological analyses examined changes to GLT-1 protein levels and morphological changes to astrocytes, within the DMS. RESULTS: We found that ceftriaxone robustly restored goal-directed behavior in animals following long-term exposure to SCM. While we did not observe changes in protein levels of GLT-1 in the DMS, we observed that SCM induced changes in the morphology of astrocytes in the DMS, and that ceftriaxone mitigated these changes. CONCLUSIONS: These results demonstrate that long-term access to a SCM diet impairs goal-directed behavior while also altering the morphology of astrocytes in the DMS. Furthermore, these results suggest that ceftriaxone administration can reverse the impairment of goal-directed behavior potentially through its actions on astrocytes in decision-making circuitry.

Neuropsychology and Neurobiology of Negative Schizotypy: A Selective Review.

Schizotypy refers to a latent personality organization that reflects liability to schizophrenia. Because schizotypy is a multidimensional construct, people with schizotypy vary in behavioral and neurobiological features. In this article, we selectively review the neuropsychological and neurobiological profiles of people with schizotypy, with a focus on negative schizotypy. Empirical evidence is presented for alterations of neuropsychological performance in negative schizotypy. We also cover the Research Domain Criteria domains of positive valence, social process, and sensorimotor systems. Moreover, we systematically summarize the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. The convergence and inconsistency of the evidence are critically reviewed. Regarding theoretical and clinical implications, we argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

This perspective paper provides empirical evidence to show that schizotypy, and especially negative schizotypy, are associated with alterations of positive valence, social process, and sensorimotor systems domains within the Research Domain Criteria (RDoC). This perspective paper also systematically summarizes the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. We argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

Neural substrates of the interaction between effort-expenditure reward decision-making and outcome anticipation.

OBJECTIVE: Reward anticipation is important for future decision-making, possibly due to re-evaluation of prior decisions. However, the exact relationship between reward anticipation and prior effort-expenditure decision-making, and its neural substrates are unknown. METHOD: Thirty-three healthy participants underwent fMRI scanning while performing the Effort-based Pleasure Experience Task (E-pet). Participants were required to make effort-expenditure decisions and anticipate the reward. RESULTS: We found that stronger anticipatory activation at the posterior cingulate cortex was correlated with slower reaction time while making decisions with a high-probability of reward. Moreover, the substantia nigra was significantly activated in the prior decision-making phase, and involved in reward-anticipation in view of its strengthened functional connectivity with the mammillary body and the putamen in trial conditions with a high probability of reward. CONCLUSIONS: These findings support the role of reward anticipation in re-evaluating decisions based on the brain-behaviour correlation. Moreover, the study revealed the neural interaction between reward anticipation and decision-making.

Whole-exome sequencing in a Chinese sample provides preliminary evidence for the link between rare/low-frequency immune-related variants and early-onset schizophrenia.

Rare and low-frequency variants contribute to schizophrenia (SCZ), and may influence its age-at-onset (AAO). We examined the association of rare or low-frequency deleterious coding variants in Chinese patients with SCZ. We collected DNA samples in 197 patients with SCZ spectrum disorder and 82 healthy controls (HC), and performed exome sequencing. The AAO variable was ascertained in the majority of SCZ participants for identify the early-onset (EOS, AAO<=18) and adult-onset (AOS, AAO>18) subgroups. We examined the overall association of rare/low-frequency, damaging variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels using Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was conducted. Resampling was used to obtain empirical p-values and to control for family-wise error rate (FWER). In binary-trait association tests, we identified 5 potential candidate risk genes and 10 gene ontology biological processes (GOBP) terms, among which PADI2 reached FWER-adjusted significance. In quantitative rare-variant association tests, we found marginally significant correlations of AAO with alterations in 4 candidate risk genes, and 5 GOBP pathways. Together, the biological and functional profiles of these genes and gene sets supported the involvement of perturbations of neural systems in SCZ, and altered immune functions in EOS.

Empathic accuracy in individuals with schizotypal personality traits.

Empirical research using the Empathic Accuracy Task (EAT) has suggested that schizophrenia patients and people with schizotypal personality disorder exhibit lower empathic accuracy than healthy people. However, empathic accuracy in a subclinical sample with high levels of schizotypy has seldom been studied. Our study aimed to investigate empathy in a subclinical sample using the Chinese version of the EAT and a self-report empathy measure. Forty participants with high levels of schizotypy (HS participants) and 40 with low levels of schizotypy (LS participants), as measured by the Schizotypal Personality Questionnaire (SPQ), were recruited. All participants completed the Chinese version of the EAT and the self-report Questionnaire of Cognitive and Affective Empathy. Empathic accuracy (EA) scores and the intra-individual variability of EA scores were calculated. Independent samples t tests and Pearson correlation analyses were performed to examine group differences in empathy and the relationship between empathy and schizotypy respectively. HS participants exhibited reduced EA for both positive and negative videos, and larger intra-individual variability of EA for negative videos than LS participants. However, HS and LS participants did not differ in self-report cognitive empathy. Moreover, the interpersonal dimension of the SPQ was negatively correlated with EAT performance and self-report cognitive empathy in LS participants. Individuals with HS show poorer performance-based EA but relatively intact self-report cognitive empathy. This study provides empirical evidence for the ontogeny of empathy deficits in subclinical populations at risk of developing schizophrenia, supporting early interventions for social cognitive deficits.

Bidirectional two-sample Mendelian randomization study of differential white blood cell counts and schizophrenia.

BACKGROUND: Schizophrenia and white blood cell counts (WBC) are both complex and polygenic traits. Previous evidence suggests that increased WBC are associated with higher all-cause mortality, and other studies have found elevated WBC in first-episode psychosis and chronic schizophrenia. However, these observational findings may be confounded by antipsychotic exposures and their effects on WBC. Mendelian randomization (MR) is a useful method for examining the directions of genetically-predicted relationships between schizophrenia and WBC. METHODS: We performed a two-sample MR using summary statistics from genome-wide association studies (GWAS) conducted by the Psychiatric Genomics Consortium Schizophrenia Workgroup (N = 130,644) and the Blood Cell Consortium (N = 563,946). The MR methods included inverse variance weighted (IVW), MR Egger, weighted median, MR-PRESSO, contamination mixture, and a novel approach called mixture model reciprocal causal inference (MRCI). False discovery rate was employed to correct for multiple testing. RESULTS: Multiple MR methods supported bidirectional genetically-predicted relationships between lymphocyte count and schizophrenia: IVW (b = 0.026; FDR p-value = 0.008), MR Egger (b = 0.026; FDR p-value = 0.008), weighted median (b = 0.013; FDR p-value = 0.049), and MR-PRESSO (b = 0.014; FDR p-value = 0.010) in the forward direction, and IVW (OR = 1.100; FDR p-value = 0.021), MR Egger (OR = 1.231; FDR p-value < 0.001), weighted median (OR = 1.136; FDR p-value = 0.006) and MRCI (OR = 1.260; FDR p-value = 0.026) in the reverse direction. MR Egger (OR = 1.171; FDR p-value < 0.001) and MRCI (OR = 1.154; FDR p-value = 0.026) both suggested genetically-predicted eosinophil count is associated with schizophrenia, but MR Egger (b = 0.060; FDR p-value = 0.010) and contamination mixture (b = -0.013; FDR p-value = 0.045) gave ambiguous results on whether genetically predicted liability to schizophrenia would be associated with eosinophil count. MR Egger (b = 0.044; FDR p-value = 0.010) and MR-PRESSO (b = 0.009; FDR p-value = 0.045) supported genetically predicted liability to schizophrenia is associated with elevated monocyte count, and the opposite direction was also indicated by MR Egger (OR = 1.231; FDR p-value = 0.045). Lastly, unidirectional genetic liability from schizophrenia to neutrophil count were proposed by MR-PRESSO (b = 0.011; FDR p-value = 0.028) and contamination mixture (b = 0.011; FDR p-value = 0.045) method. CONCLUSION: This MR study utilised multiple MR methods to obtain results suggesting bidirectional genetic genetically-predicted relationships for elevated lymphocyte counts and schizophrenia risk. In addition, moderate evidence also showed bidirectional genetically-predicted relationships between schizophrenia and monocyte counts, and unidirectional effect from genetic liability for eosinophil count to schizophrenia and from genetic liability for schizophrenia to neutrophil count. The influence of schizophrenia to eosinophil count is less certain. Our findings support the role of WBC in schizophrenia and concur with the hypothesis of neuroinflammation in schizophrenia.

Interoception, somatic symptoms, and somatization tendency in Chinese individuals with subsyndromal depression: A follow-up study.

Interoception refers to the sensation and perception of internal bodily sensations, and may be related to depressive symptoms. Schemata concerning the body vary across different cultures and may influence interoception and symptom presentations of depression. This study explored the relationship between interoception, depressive symptoms, and schema of somatic focus in Chinese people with subsyndromal depression. Thirty-nine individuals with subsyndromal depression (SD) and 40 healthy controls (HCs) were assessed at baseline and after 3 months. Participants completed the self-report questionnaires for assessing interoceptive sensibility, somatic and psychological symptoms of depression, and somatization tendency. They also completed the heartbeat perception behavioral task for estimating interoceptive accuracy. The results showed that both the SD and the HC groups showed similar interoceptive accuracy, although the SD group showed heightened interoceptive sensibility. The discrepancy between interoceptive sensibility and interoceptive accuracy is termed the interoceptive trait prediction error (ITPE). The ITPE was positive in SD participants but was negative in HCs. In the entire sample, interoceptive sensibility and the ITPE were correlated with somatic symptoms rather than with psychological symptoms of depression. Interoceptive sensibility partially mediated the relationship between somatization tendency and somatic symptoms, after controlling for psychological symptoms of depression. These results remained stable after 3 months. The shortcomings of the present study were a lack of clinical interview to ascertain diagnosis and a short follow-up duration. In conclusion, our study suggests that altered interoception occurs in subsyndromal depression. Interoception is related to somatic symptoms of depression. The schema of body was related to depressive symptoms, partially through interoception, in Chinese people with subsyndromal depression.

Optogenetic stimulation of the locus coeruleus enhances appetitive extinction in rats.

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery) or reintroduction of the reinforcement (i.e. reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction; however, the role and source of endogenous NA in these effects are unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery, suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopsin, it is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.

Individuals with high levels of autistic traits exhibit impaired cognitive but not affective theory of mind and empathy.

Theory of mind (ToM) and empathy are considered key components of social cognition that are often impaired in individuals with autism spectrum disorders (ASD). However, it remains unclear whether individuals with high levels of autistic traits exhibit similar impairments in these two functions. This study examined the affective and cognitive domains of ToM and empathy in individuals with high levels of autistic traits. We recruited 84 participants with high levels and 78 participants with low levels of autistic traits to complete a set of self-reported checklists and performance-based tasks capturing affective and cognitive components of ToM and empathy. The results showed that participants with high levels of autistic traits exhibited significant impairments in cognitive but not in affective ToM and empathy compared with their counterparts with low levels of autistic traits. We also found that empathy impairments in people with high levels of autistic traits were confounded by alexithymia and depressive traits.

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Identifying subgroups of attention-deficit/hyperactivity disorder from the psychopathological and neuropsychological profiles.

The Research Domain Criteria (RDoC) advocates the dimensional approach in characterizing mental disorders. We followed RDoC to characterize children with ADHD using profiling based on the cognitive and psychopathological domains. We aimed to identify and validate ADHD subtypes with different clinical characteristics and functional impairments. We recruited 362 drug-naïve children with ADHD and 103 typically developing controls. The cluster analysis was used to identify subgroups based on the Child Behaviour Checklist (CBCL) and the Behaviour Rating Inventory of Executive Function (BRIEF). The subgroups' clinical characteristics and functional impairments were assessed using the WEISS Functional Impairment Rating Scale-Parent Report (WFIRS-P) and the Conners Parent Symptom Questionnaire (PSQ). The cluster analysis yielded four subgroups: (1) ADHD with severe impairment in psychopathology and executive functions (EF), (2) ADHD with mild executive dysfunctions and normal-level psychopathology, (3) ADHD with severe externalizing problems and (4) ADHD with severe executive dysfunctions. These subgroups showed different clinical characteristics and degrees of functional impairment. The EF impairment group displayed more serious learning problems and worse life skills than the externalizing group. The two groups with externalizing problems (i.e. the severe impairment group and the externalizing group) both exhibited higher rates of the combined subtype of ADHD and higher rates of comorbid ODD. Different subtypes of ADHD displayed different profiles of internalizing and externalizing problems and levels of executive dysfunctions. In particular, the subtype with severe impairment in EF exhibited more learning problems and worse life skills, suggesting EF is a critical target for intervention in children with ADHD.

Social and non-social reward processing in subclinical depression.

This study applied two incentive delay tasks involving social and non-social incentive types to 76 pairs of participants with high and low depressive symptoms. The results suggest that higher levels of depressive symptoms are correlated with abnormalities in social and non-social reward processing even in the healthy populations.

The effect of noninvasive brain stimulation on anhedonia in patients with schizophrenia and depression: A systematic review and meta-analysis.

Anhedonia is a transdiagnostic symptom found in patients with schizophrenia and depression. Current pharmacological interventions for anhedonia are unsatisfactory in a considerable proportion of patients. There has been growing interest in applying noninvasive brain stimulation (NIBS) to patients with anhedonia. However, evidence for the efficacy of NIBS for anhedonia remain inconsistent. This study systematically identified all studies that measured anhedonia and applied NIBS in patients with schizophrenia or depression. We conducted a search using the various databases in English (PubMed, EBSCOHost (PsycInfo/PsycArticles), Web of Science) and Chinese (China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform) languages, and reviewed original research articles on NIBS published from January 1989 to July 2023. Our search had identified 15 articles for quantitative synthesis, with three concerning schizophrenia samples, 11 concerning samples with depression, and one concerning both clinical samples. We conducted a meta-analysis based on the 15 included studies, and the results suggested that NIBS could improve anhedonia symptoms in schizophrenia patients and patients with depression, with a medium-to-large effect size. Our findings are preliminary, given the limited number of included studies. Future NIBS research should measure anhedonia as a primary outcome and should recruit transdiagnostic samples.

Range adaptation in schizophrenia: A one-year longitudinal study.

Range adaptation refers to the representation of a stimulus value based on its relative position in the range of pre-experienced values. Altered range adaptation in value representation may be related to motivation and pleasure (MAP) deficit in schizophrenia (SCZ). This follow-up study examined the relationship between range adaptation performance and MAP symptoms in SCZ patients. We recruited 26 schizophrenia patients and followed them for 1 year. They completed an experimental task for estimating their range adaptation to outcome value (OV) and expected value (EV) at baseline and after 1 year. At baseline, we found a marginally significant and negative correlation between OV adaptation and avolition symptoms in SCZ patients. Moreover, the 1-year change of EV adaptation was significantly and negatively correlated with the change of self-report pleasure experience. Our results suggest that range adaptation may track the variations of MAP symptoms in SCZ.

Range adaptive value representations in schizophrenia and major depression.

Anhedonia and amotivation are core symptoms of schizophrenia (SCZ) and major depressive disorder (MDD). Reward processing involves constructing and contrasting the representations for expected value (EV) and outcome value (OV) of a given stimulus, a phenomenon termed range adaptation. Impaired range adaptation can lead to anhedonia and amotivation. This study aimed to examine range adaptation in SCZ patients and MDD patients. Fifty SCZ, 46 MDD patients and 56 controls completed the Effort-based Pleasure Experience Task to measure EV and OV adaptation. SCZ and MDD patients showed altered range adaptation, albeit in different patterns. SCZ patients exhibited over-adaptation to OV and reduced adaptation to EV. By contrast, MDD patients exhibited diminished OV adaptation but intact EV adaptation. Both OV and EV adaptation were correlated with anhedonia and amotivation in SCZ and MDD. Taken together, our findings suggest that range adaptation is altered in both SCZ and MDD patients. Associations of OV and EV adaptation with anhedonia and amotivation were consistently found in SCZ and MDD patients. Impaired range adaptation in SCZ and MDD patients may be putative neural mechanisms and potential intervention targets for anhedonia and amotivation.

Early-onset schizophrenia is associated with immune-related rare variants in a Chinese sample.

Background: Rare variants are likely to contribute to schizophrenia (SCZ), given the large discrepancy between the heritability estimated from twin and GWAS studies. Furthermore, the nature of the rare-variant contribution to SCZ may vary with the "age-at-onset" (AAO), since early-onset has been suggested as being indicative of neurodevelopment deviance. Objective: To examine the association of rare deleterious coding variants in early- and adult-onset SCZ in a Chinese sample. Method: Exome sequencing was performed on DNA from 197 patients with SCZ spectrum disorder and 82 healthy controls (HC) of Chinese ancestry recruited in Hong Kong. We also gathered AAO information in the majority of SCZ samples. Patients were classified into early-onset (EOS, AAO<18) and adult-onset (AOS, AAO>18). We collapsed the rare variants to improve statistical power and examined the overall association of rare variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels by Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was also conducted. We focused on variants which were predicted to have a medium or high impact on the protein-encoding process as defined by Ensembl. We applied a 100000-time permutation test to obtain empirical p-values, with significance threshold set at p < 1e -3 to control family-wise error rates. Moreover, we compared the burden of targeted rare variants in significant risk genes and gene sets in cases and controls. Results: Based on several binary-trait association tests (i.e., SCZ vs HC, EOS vs HC and AOS vs HC), we identified 7 candidate risk genes and 20 gene ontology biological processes (GOBP) terms, which exhibited higher burdens in SCZ than in controls. Based on quantitative rare-variant association tests, we found that alterations in 5 candidate risk genes and 7 GOBP pathways were significantly correlated with AAO. Based on biological and functional profiles of the candidate risk genes and gene sets, our findings suggested that, in addition to the involvement of perturbations in neural systems in SCZ in general, altered immune responses may be specifically implicated in EOS. Conclusion: Disrupted immune responses may exacerbate abnormal perturbations during neurodevelopment and trigger the early onset of SCZ. We provided evidence of rare variants increasing SCZ risk in the Chinese population.

Pathway-Specific Polygenic Scores Improve Cross-Ancestry Prediction of Psychosis and Clinical Outcomes.

Psychotic disorders are debilitating conditions with disproportionately high public health burden. Genetic studies indicate high heritability, but current polygenic scores (PGS) account for only a fraction of variance in psychosis risk. PGS often show poor portability across ancestries, performing significantly worse in non-European populations. Pathway-specific PGS (pPGS), which restrict PGS to genomic locations within distinct biological units, could lead to increased mechanistic understanding of pathways that lead to risk and improve cross-ancestry prediction by reducing noise in genetic predictors. This study examined the predictive power of genome-wide PGS and nine pathway-specific pPGS in a unique Chinese-ancestry sample of deeply-phenotyped psychosis patients and non-psychiatric controls. We found strong evidence for the involvement of schizophrenia-associated risk variants within "nervous system development" (p=2.5e-4) and "regulation of neuron differentiation" pathways (p=3.0e-4) in predicting risk for psychosis. We also found the "ion channel complex" pPGS, with weights derived from GWAS of bipolar disorder, to be strongly associated with the number of inpatient psychiatry admissions a patient experiences (p=1.5e-3) and account for a majority of the signal in the overall bipolar PGS. Importantly, although the schizophrenia genome-wide PGS alone explained only 3.7% of the variance in liability to psychosis in this Chinese ancestry sample, the addition of the schizophrenia-weighted pPGS for "nervous system development" and "regulation of neuron differentiation" increased the variance explained to 6.9%, which is on-par with the predictive power of PGS in European ancestry samples. Thus, not only can pPGS provide greater insight into mechanisms underlying genetic risk for disease and clinical outcomes, but may also improve cross-ancestry risk prediction accuracy.

Cognitive subgroups and the relationships with symptoms, psychosocial functioning and quality of life in first-episode non-affective psychosis: a cluster-analysis approach.

Introduction: Prior research examining cognitive heterogeneity in psychotic disorders primarily focused on chronic schizophrenia, with limited data on first-episode psychosis (FEP). We aimed to identify distinct cognitive subgroups in adult FEP patients using data-driven cluster-analytic approach, and examine relationships between cognitive subgroups and a comprehensive array of illness-related variables. Methods: Two-hundred-eighty-nine Chinese patients aged 26-55 years presenting with FEP to an early intervention program in Hong Kong were recruited. Assessments encompassing premorbid adjustment, illness-onset profile, symptom severity, psychosocial functioning, subjective quality-of-life, and a battery of cognitive tests were conducted. Hierarchical cluster-analysis was employed, optimized with k-means clustering and internally-validated by discriminant-functional analysis. Cognitive subgroup comparisons in illness-related variables, followed by multivariable multinominal-regression analyzes were performed to identify factors independently predictive of cluster membership. Results: Three clusters were identified including patients with globally-impaired (n = 101, 34.9%), intermediately-impaired (n = 112, 38.8%) and relatively-intact (n = 76, 26.3%) cognition (GIC, IIC and RIC subgroups) compared to demographically-matched healthy-controls' performance (n = 50). GIC-subgroup was older, had lower educational attainment, greater positive, negative and disorganization symptom severity, poorer insight and quality-of-life than IIC- and RIC-subgroups, and higher antipsychotic-dose than RIC-subgroup. IIC-subgroup had lower education levels and more severe negative symptoms than RIC-subgroup, which had better psychosocial functioning than two cognitively-impaired subgroups. Educational attainment and disorganization symptoms were found to independently predict cluster membership. Discussion: Our results affirmed cognitive heterogeneity in FEP and identified three subgroups, which were differentially associated with demographic and illness-related variables. Further research should clarify longitudinal relationships of cognitive subgroups with clinical and functional outcomes in FEP.