Negative Symptom Dimensions Research Articles

Cortical Gyrification, Psychotic-Like Experiences, and Cognitive Performance in Nonclinical Subjects.

Psychotic-like experiences (PLE) are present in nonclinical populations, yet their association with brain structural variation, especially markers of early neurodevelopment, is poorly understood. We tested the hypothesis that cortical surface gyrification, a putative marker of early brain development, is associated with PLE in healthy subjects. We analyzed gyrification from 3 Tesla MRI scans (using CAT12 software) and PLE (positive, negative, and depressive symptom dimensions derived from the Community Assessment of Psychic Experiences, CAPE) in 103 healthy participants (49 females, mean age 29.13 ± 9.37 years). A subsample of 63 individuals completed tasks from the Wechsler Adult Intelligence Scale and Controlled Oral Word Association Test. Estimated IQ and a composite neuropsychological score were used to explore mediation pathways via cognition. Positive PLE distress was negatively associated with gyrification of the left precuneus. PLE depression dimension showed a negative association with gyrification in the right supramarginal and temporal region. There was no significant mediating effect of cognition on these associations. Our results support a neurobiological psychosis spectrum, for the first time linking an early developmental imaging marker (rather than volume) to dimensional subclinical psychotic symptoms. While schizophrenia risk, neurodevelopment, and cognitive function might share genetic risk factors, additional mediation analyses did not confirm a mediating effect of cognition on the gyrification-psychopathology correlation.

M113. THE RELATIONSHIP BETWEEN ATTACHMENT STYLES AND CLINICAL PRESENTATION IN EARLY PSYCHOSIS PATIENTS

BackgroundResearch in both clinical and early psychosis samples is increasingly indicating that insecure attachment styles impact on psychosis symptom expression. Moreover, empirical support has been found for the assumption that specific types of insecure attachment predispose individuals to develop different symptom profiles. This study aimed to increase our understanding of the relevance of attachment styles in an early psychosis sample. To this end, we first examined the relationship of attachment styles with the severity of positive, negative and general symptom dimensions. Secondly, associations between attachment styles and specific positive psychotic symptoms were explored.MethodsA total of 96 (60 At-Risk Mental State and 36 First Episode Psychosis) patients participated in the study. Patients’ attachment style was assessed by the Psychosis Attachment Measure (PAM) and the Relationship Questionnaire (RQ). The PAM was used to evaluate attachment dimensions (i.e., anxiety and avoidance), whereas RQ was employed to classify participants into an attachment prototypes (i.e., secure, fearful, preoccupied or dismissive). In addition, patients were administered the Positive and Negative Syndromes Scale. Correlation analyses examined the associations of patients’ attachment dimensions and patients’ attachment prototypes with symptom dimensions (positive, negative and general psychopathology) and specific positive psychotic symptoms (delusions, conceptual disorganization, hallucinations, excitement, grandiosity, paranoia and hostility).ResultsPatients’ attachment anxiety was associated with positive symptoms and general psychopathology, whereas no associations were found between attachment avoidance and symptom dimensions. Moreover, only attachment anxiety was related with specific positive symptoms, such as hallucinations and paranoia. Regarding the associations between attachment prototypes and symptom dimensions, only secure attachment was significantly related to decreased levels of general symptoms. Besides, secure attachment was associated with decreased levels of paranoia, whereas fearful attachment was related with increased levels of paranoid symptoms. No significant relationships were observed between dismissing and preoccupied attachment with specific positive symptoms.DiscussionThese findings highlight the potential role of secure attachment as a protective factor against poor clinical outcomes and are consistent with previous studies indicating that secure attachment confers a form of resilience for psychopathology. In contrast, attachment anxiety and fearful attachment might represent risk factors for general and positive symptoms. The fact that neither attachment dimensions nor attachment prototypes were associated with the negative symptom dimension seems to confirm previous findings and might suggest that the association of attachment with psychotic symptoms is more robust for the positive dimension. These findings highlight the need of tailoring interventions to patients’ attachment needs. This would include assessing patients’ attachment patterns, as the specific subtypes of insecure attachment style should provide guidance in the context of psychological formulation and treatment planning with early psychosis patients.

Expressive deficits and amotivation as mediators of the associations between cognitive problems and functional outcomes: Results from two independent cohorts

Many individuals with severe mental disorders have difficulties in vocational and social functioning, which are regarded the most important outcomes, together with clinical symptoms. To understand the underlying mechanisms, research is increasingly focused on factors influencing functional outcomes. One established association has been shown between cognition and community functioning with negative symptoms as a possible mediator. Although it has been shown that negative symptoms consist of two subdomains, thus far negative symptoms have been assessed as one unitary construct. This study considers for the first time subdomains of negative symptoms as putative mediators (expressive deficits, amotivation) of the association between cognition (neuro- and social cognition) and functional outcome (living situation, occupation, social functioning). We expected that specific subdomains of negative symptoms (e.g. amotivation) would mediate the effect of cognition on specific functional outcomes (e.g. social functioning) independently from illness duration. To assess this, we included two independent cohorts, consisting of participants with different illness duration.These two independent cohorts consisted of patients with a recent-onset psychotic disorder: PROGR-S (first time treated; N = 1129) and GROUP (illness duration preferably <5 years; N = 1200). Using linear regression, mediation analyses were performed with two cognition domains (neurocognition and social cognition) as predictors, negative symptoms (Expressive deficits and Amotivation as indexed with items from the Positive and Negative Syndrome Scale) as mediators and three measures of functional outcomes (living situation, occupation and social functioning) as outcome measures. The analyses were repeated with the same outcome measures three years later.Three main results were obtained. I) Both in the cross-sectional and longitudinal analyses, the associations of neurocognition (both cohorts) and social cognition (GROUP) with social functioning were mediated by amotivation. II) The association between cognition and living situation was mediated by Expressive deficits in one cohort (GROUP) but not in the cohort assessing first-episode psychosis (PROGR-S). III) The association between cognition and occupation was mediated by Amotivation in PROGR-S and by Expressive deficits in GROUP. ConclusionThe current results show a less robust mediating role for specific negative symptom domains regarding the associations of cognition with occupation and living situation that may depend on the duration of psychotic illness. However, Amotivation, mediates the association between cognition and social functioning, which holds true for patients experiencing a first-onset and patients with a longer illness duration alike. The results may have implications for the development of therapeutic approaches focusing on amotivation to improve social functioning. General scientific summaryThis study stresses the importance of distinguishing subdomains of negative symptoms, cognition and functioning. Our results show that specific negative symptom dimensions mediate the effects of cognition on specific functional outcomes.

Negative symptom configuration in first episode Schizophrenia: findings from the “Parma Early Psychosis” program

Purpose: Identifying distinct dimensions of negative symptoms in First Episode Schizophrenia (FES) might result in a better understanding and treatment of this invalidating symptomatology. Aim of this study was to examine negative symptom structure in FES patients using the Positive and Negative Syndrome Scale (PANSS).Materials and Methods: All 147 participants, aged 12–35 years, completed the PANSS and the Global Assessment of Functioning (GAF) scale. A principal component analysis with varimax rotation was performed to investigate PANSS negative symptom structure in the FES total sample.Results: A 2-factor model (i.e. “Expressive Deficits” and “Asociality” dimensions) was identified. Only “Expressive Deficits” domain had a significant negative correlation with baseline GAF score.Conclusions: This bipartite solution seems to be adequate to describe the phenomenological variety of negative symptoms experienced by FES individuals at the point of entry in early intervention services.

Schizophrenia phenomenology comprises a bifactorial general severity and a single-group factor, which are differently associated with neurotoxic immune and immune-regulatory pathways

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity. Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia ("OSOS"); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

Prodopaminergic Drugs for Treating the Negative Symptoms of Schizophrenia: Systematic Review and Meta-analysis of Randomized Controlled Trials.

The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments. We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder.Medline, EMBASE, and several other databases as well as trial registries were searched for placebo-controlled trials. Ten randomized controlled trials were included in the meta-analysis, 6 trials on modafinil, 2 on armodafinil, 1 on L-dopa, and 1 on pramipexole. Overall, prodopaminergic agents did not significantly reduce negative symptoms. Restricting the analysis to studies requiring a minimum threshold for negative symptom severity, modafinil/armodafinil showed a significant but small effect on negative symptoms. A subset of studies allowed for calculating specific effects for the negative symptom dimensions diminished expression and amotivation, but no significant effect was found. Prodopaminergic agents did not increase positive symptom scores. The currently available evidence does not allow for formulating recommendations for the use of prodopaminergic agents for the treatment of negative symptoms. Nevertheless, the observed improvement in studies defining a minimum threshold for negative symptom severity in the absence of an increase in positive symptoms clearly supports further research on these agents.

Impact of duration of untreated psychosis in short-term response to treatment and outcome in antipsychotic naïve first-episode psychosis.

Duration of untreated psychosis (DUP) is one of the few potentially modifiable outcome predictors in psychosis. Previous studies have associated a longer DUP with a poor prognosis, but few of them were performed in countries with low and middle level of income. This study aimed to investigate the DUP in a Brazilian sample of antipsychotic-naïve first-episode psychosis (AN-FEP) patients and its association with clinical characteristics and treatment outcomes in a short-term follow-up. One hundred forty-five AN-FEP patients between 16 and 40 years were enrolled and were reassessed 10 weeks after risperidone treatment. We investigated the association between DUP and symptom severity, functionality and response to treatment, using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity Scale (CGI) and the Global Assessment of Functionality (GAF) scale. DUP was defined as the period between the onset of the first psychotic symptoms and the first effective antipsychotic treatment. For the analysis, we performed multivariate linear regressions. The DUP's median was 61 days. At baseline, we did not find any significant association between DUP and clinical characteristics. After treatment, the longer DUP predicted worse positive and negative symptom dimensions, worse total PANSS, GAF and CGI scores and poorer response to treatment. Our results showed that DUP is associated with worse outcomes after short treatment, but it does not modify the baseline clinical profile of the AN-FEP patients. Such results reinforce the need to develop early intervention strategies, reducing DUP.

Intersection of verbal memory and expressivity on cortical contrast and thickness in first episode psychosis.

Longitudinal studies of first episode of psychosis (FEP) patients are critical to understanding the dynamic clinical factors influencing functional outcomes; negative symptoms and verbal memory (VM) deficits are two such factors that remain a therapeutic challenge. This study uses white-gray matter contrast at the inner edge of the cortex, in addition to cortical thickness, to probe changes in microstructure and their relation with negative symptoms and possible intersections with verbal memory. T1-weighted images and clinical data were collected longitudinally for patients (N = 88) over a two-year period. Cognitive data were also collected at baseline. Relationships between baseline VM (immediate/delayed recall) and rate of change in two negative symptom dimensions, amotivation and expressivity, were assessed at the behavioral level, as well as at the level of brain structure. VM, particularly immediate recall, was significantly and positively associated with a steeper rate of expressivity symptom decline (r = 0.32, q = 0.012). Significant interaction effects between baseline delayed recall and change in expressivity were uncovered in somatomotor regions bilaterally for both white-gray matter contrast and cortical thickness. Furthermore, interaction effects between immediate recall and change in expressivity on cortical thickness rates were uncovered across higher-order regions of the language processing network. This study shows common neural correlates of language-related brain areas underlying expressivity and VM in FEP, suggesting deficits in these domains may be more linked to speech production rather than general cognitive capacity. Together, white-gray matter contrast and cortical thickness may optimally inform clinical investigations aiming to capture peri-cortical microstructural changes.

Hits and false alarms in recognition memory show differential impairment in positive and negative schizotypy.

The present study examined the extent to which positive and negative schizotypy are associated with impairment in recognition memory in 3 large samples of nonclinically ascertained adults (total n = 826). Schizophrenia is associated with a wide array of cognitive deficits, but the study of cognitive impairment in schizophrenia is confounded by generalized performance deficits related to symptoms and consequences of the disorder, and by failure to separately examine positive and negative symptom dimensions. Schizotypy provides a promising framework for examining these deficits relatively unconfounded by symptoms and sequelae of the disorder. The present study obtained recognition memory deficits in positive and negative schizotypy across verbal and figural stimuli in three different samples. Importantly, although discrimination accuracy is impaired across higher scores on both schizotypy dimensions, the mechanism of impairment differs across positive and negative schizotypy. Negative, but not positive, schizotypy was associated with impaired hit rates, whereas the false alarm rates remained unaffected. In contrast, positive, but not negative, schizotypy was associated with increased false alarm rates despite stable hit rates. The results are discussed from the perspective of a signal-detection theoretic model that accounts for negative schizotypy results through reduced signal mechanism, and accounts for positive schizotypy results through increased noise mechanism. These findings further support the utility of multidimensional schizotypy for assessing and understanding episodic memory impairment in the schizophrenia spectrum. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Thérapie comportementale et cognitive des symptômes négatifs de la schizophrénie. Revue de la question : pratiques actuelles et directions futures

Negative symptoms, such as a lack of motivation, anhedonia or poverty of speech, constitute a major difficulty in schizophrenia. Indeed, these symptoms have deleterious effects on quality of life and functional outcome of individuals with schizophrenia. However, although multiple interventions have been the subject of investigation, to date, including pharmacological strategies, brain stimulation, physical activity and psychosocial interventions, none reached the threshold for clinically significant improvement. Therefore the treatment of negative symptoms represents a major challenge for mental health care in schizophrenia. If recent advances in CBT have clearly shown their efficiency on positive symptom and are now recommended as first line treatment for schizophrenia, CBT trials mainly focused on positive symptoms and investigated change in negative symptoms only as a secondary outcome. The aim of this article is to describe and to provide a brief description of the different CBT interventions targeting negative symptoms, the theoretical models on which they are based and empirical evidence highlighting their effectiveness. Of the interventions reviewed, cognitive interventions, behavioral activations and social skills training appear to have the most empirical support. The cognitive approach suggests the role of negative cognitions, or dysfunctional attitudes in the maintenance and exacerbation of behaviors is associated with negative symptoms in schizophrenia (Rector et. al., 2005 ; Beck et. al., 2009). Consequently, cognitive therapy interventions focus primarily on changing generalized beliefs that prevent patients with prominent negative symptoms from goal attainment. Clinical trials showed improvements on apathy, avolition, and functioning but not on anhedonia, blunted affects, and alogia suggesting that cognitive models of negative symptoms would be valid for the dimension avolition but less for the dimension diminished expression. Regarding behavioral interventions, there is now clear evidence that social skills training should be routinely recommended in treatment guidelines for psychological intervention targeting negative symptoms as a whole (Turner et al., 2018). However, its distinct impact on the two main dimensions of negative symptoms is still unknown. Behavioral activation appears particularly promising in the treatment of negative symptoms secondary to depression. Although psychosocial treatments show promise for the treatment of negative symptoms, certain limitations exist, particularly regarding the conceptualization of the different negative symptoms and the lack of integrative psychological models proposed in the literature. However, cognitive and behavioral therapy offer interesting possibilities for the improvement of negative symptomatology, particularly recovery-oriented cognitive therapy, focusing on dysfunctional beliefs, and adaptations to circumvent neurocognitive and engagement difficulties. As recommendations, we emphasize the need for a detailed and integrative functional analysis of each negative symptom before any interventions in order to understand the influence of the different environmental factors and psychological processes. Specific CBT interventions have utility in ameliorating negative symptoms in psychosis but validated and integrative psychological models need to be developed to increase their effectiveness.

Examination of formal thought disorder and its clinical correlates with the Turkish Version of the Thought and Language Disorder Scale (TALD-TR) in schizophrenia

BackgroundFormal thought disorder (FTD) is considered to be a fundamental feature of schizophrenia. This study aims to analyze psychometric properties of the Turkish version of “Thought and Language Disorder Scale (TALD)” and investigate the relationship between FTD and various clinical characteristics in patients with schizophrenia. MethodsTALD was adapted into Turkish and applied to a total of 149 participants of which 114 had DSM-5 psychiatric diagnoses (schizophrenia N = 70, mania N = 20, depression N = 24) and 35 were healthy controls. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression were administered to detect illness severity. ResultsThe principal component analyses revealed that the Turkish version of TALD (TALD-TR) consisted of four factors including the Objective Positive (OP), Subjective Negative (SN), Objective Negative (ON) and Subjective Positive (SP) symptom dimensions which were in line with the original TALD factorial structure. It was concluded that TALD-TR shows strong construct validity and high interrater reliability. The correlation analyses with TALD-TR and PANSS showed that there are positive correlations between the TALD-TR total score and the PANSS total and subscale scores. Each diagnostic group showed the distinct pattern of FTD. The mania group exhibited the highest mean total score in the OP, whereas the schizophrenia group exhibited the highest mean total score in the ON factor. In the schizophrenia group, the severity of FTD correlated positively with duration of illness and negatively with age at onset of illness. ConclusionAdaptation of TALD into different languages seems to be possible, bringing in an international tool for research on FTD.

Psychiatric symptoms and quality of life in older adults with schizophrenia spectrum disorder: results from a multicenter study

The severity of psychopathology has a strong negative impact on quality of life (QoL) among older adults with schizophrenia spectrum disorder. However, because these subjects generally experience multiple psychiatric symptoms, it remains unclear whether decreased QoL in this population is due to specific symptoms (e.g., hallucinations), specific dimensions of psychopathology (e.g., negative symptoms), a general psychopathology dimension representing the shared effect across all psychiatric symptoms, or a combination of these explanations. Data were derived from the Cohort of individuals with Schizophrenia Aged 55years or more (CSA) study, a large (N = 353) multicenter sample of older adults with schizophrenia spectrum disorder recruited from French public-sector psychiatric departments. We used structural equation modeling to examine the shared and specific effects of psychiatric symptoms on QoL, while adjusting for sociodemographic characteristics, general medical conditions, global cognitive functioning and psychotropic medications. Psychiatric symptoms and QoL were assessed face-to-face by psychiatrists using the Brief Psychiatric Rating Scale (BPRS) and the Quality of Life Scale (QLS). Among older adults with schizophrenia spectrum disorder, effects of psychiatric symptoms on QoL were exerted mostly through a general psychopathology dimension (β = - 0.43, p < 0.01). Negative symptom dimension had an additional negative effect on QoL beyond the effect of that factor (β = - 0.28, p < 0.01). Because psychiatric symptoms affect QoL mainly through two dimensions of psychopathology, i.e., a general psychopathology dimension and a negative symptom dimension, mechanisms underlying those dimensions should be considered as promising targets for therapeutic interventions to substantially improve quality of life of this vulnerable population.

Differential gene expression analysis in blood of first episode psychosis patients

BackgroundPsychosis is a condition influenced by an interaction of environmental and genetic factors. Gene expression studies can capture these interactions; however, studies are usually performed in patients who are in remission. This study uses blood of first episode psychosis patients, in order to characterise deregulated pathways associated with psychosis symptom dimensions. MethodsPeripheral blood from 149 healthy controls and 131 first episode psychosis patients was profiled using Illumina HT-12 microarrays. A case/control differential expression analysis was performed, followed by correlation of gene expression with positive and negative syndrome scale (PANSS) scores. Enrichment analyses were performed on the associated gene lists. We test for pathway differences between first episode psychosis patients who qualify for a Schizophrenia diagnosis against those who do not. ResultsA total of 978 genes were differentially expressed and enriched for pathways associated to immune function and the mitochondria. Using PANSS scores we found that positive symptom severity was correlated with immune function, while negative symptoms correlated with mitochondrial pathways. ConclusionsOur results identified gene expression changes correlated with symptom severity and showed that key pathways are modulated by positive and negative symptom dimensions.

Cerebral blood flow in striatal regions is associated with apathy in patients with schizophrenia.

Striatal dysfunction has been proposed as a pathomechanism for negative symptoms in schizophrenia. There is consensus that negative symptoms can be grouped into 2 dimensions: apathy and diminished expression. Recent studies suggest that different neural mechanisms underlie these dimensions, but the relationship between regional resting-state cerebral blood flow (rCBF) and negative symptom dimensions has not been investigated. This study included 29 patients with schizophrenia and 20 healthy controls. We measured rCBF in the striatum using arterial spin labelling (ASL) MRI. We assessed negative symptoms using the Brief Negative Symptom Scale. In the ventral and dorsal striatum, rCBF was not different between patients with schizophrenia and controls. However, we did find a positive association between the severity of apathy and increased rCBF in the ventral and dorsal striatum in patients with schizophrenia. This effect was not present for diminished expression. All patients were taking atypical antipsychotics, so an effect of antipsychotic medication on rCBF could not be excluded, although we did not find a significant association between rCBF and chlorpromazine equivalents. The main finding of this study was a specific association between increased striatal rCBF and the negative symptom dimension of apathy. Our results further support the separate assessment of apathy and diminished expression when investigating the neural basis of negative symptoms. The ASL technique can provide a direct and quantitative approach to investigating the role of rCBF changes in the pathophysiology of negative symptoms.

The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors

BackgroundNegative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms. MethodsUsing post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227). ResultsChange from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P < .05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P < .01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P < .05). ConclusionsSince items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Transdiagnostic dimensions of psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP).

The validity of the classification of non-affective and affective psychoses as distinct entities has been disputed, but, despite calls for alternative approaches to defining psychosis syndromes, there is a dearth of empirical efforts to identify transdiagnostic phenotypes of psychosis. We aimed to investigate the validity and utility of general and specific symptom dimensions of psychosis cutting across schizophrenia, schizoaffective disorder and bipolar I disorder with psychosis. Multidimensional item-response modeling was conducted on symptom ratings of the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale in the multicentre Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, which included 933 patients with a diagnosis of schizophrenia (N=397), schizoaffective disorder (N=224), or bipolar I disorder with psychosis (N=312). A bifactor model with one general symptom dimension, two distinct dimensions of non-affective and affective psychosis, and five specific symptom dimensions of positive, negative, disorganized, manic and depressive symptoms provided the best model fit. There was further evidence on the utility of symptom dimensions for predicting B-SNIP psychosis biotypes with greater accuracy than categorical DSM diagnoses. General, positive, negative and disorganized symptom dimension scores were higher in African American vs. Caucasian patients. Symptom dimensions accurately classified patients into categorical DSM diagnoses. This study provides evidence on the validity and utility of transdiagnostic symptom dimensions of psychosis that transcend traditional diagnostic boundaries of psychotic disorders. Findings further show promising avenues for research at the interface of dimensional psychopathological phenotypes and basic neurobiological dimensions of psychopathology.

SU95 - GENOME-WIDE ANALYSES OF CLINICAL FEATURES OF SCHIZOPHRENIA IN THE PSYCHIATRIC GENOMICS CONSORTIUM

Background Schizophrenia (SCZ) is a clinically heterogeneous disorder. Individual patients may vary with respect to onset, course of illness, response to treatment, outcome, and the particular pattern of symptoms endorsed. Proposed revisions to DSM-5 included dimensional measurement of several different symptom domains. We sought to determine whether common genetic variants influence clinical heterogeneity including symptom severity, Age-Of-Onset (AOO), smoking behaviors, and suicide attempt. Methods The Psychiatric Genomics Consortium (PGC) study of SZ comprised 8,000 cases of European ancestry with available clinical phenotype data; >12,000 cases with available information on age-of-onset of illness; and >5,000 cases with data on smoking behaviors or suicide attempt(s). Symptoms averaged over the course of illness were assessed using the OPCRIT, PANSS, LDPS, SCAN, SCID, and CASH. Factor analyses of each constituent PGC study identified positive, negative, manic, and depressive symptom dimensions. Results We examined the relationship between clinical features and aggregate polygenic risk scores constructed from the results of the primary PGC-SCZ GWAS, and estimate SNP-based heritabilities from genome-wide summary-statistics methods. Of particular interest, we replicated our previous finding that polygenic risk explains at least some of the variance in negative symptoms, a core illness dimension, and demonstrate that AOO is influenced by the aggregate effects of common genetic variation. We observed and subsequently replicated the significant genetic correlation of SCZ with smoking behaviors; comparing smoking behaviors among SCZ cases to the general population, we observe positive genetic correlations for both smoking initiation and smoking quantity. Discussion By compiling detailed clinical information from over 20 constituent studies of the PGC, we have demonstrated a polygenic basis for clinical features of SCZ including AOO, negative symptom severity, and smoking behaviors. The efforts described herein underscore the importance of both detailed phenotyping and the collaborative efforts of large-scale research consortia.

Activation of the immune-inflammatory response system and the compensatory immune-regulatory system in antipsychotic naive first episode psychosis

Psychotic disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through increased levels of anti-inflammatory cytokines such as interleukin (IL)-4, IL-13 and IL-10. This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve first episode psychosis (AN-FEP) before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-12) as compared with the CIRS response. Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement after treatment. Our findings indicate that AN-FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that (a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and (b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS might be a new drug target to treat FEP.

Factor Analysis of Negative Symptom Items in the Structured Interview for Prodromal Syndromes.

Negative symptoms occur early in the clinical high risk (CHR) state and indicate increased risk of conversion to psychotic disorder and poor functional outcome. However, while the negative symptom domain has shown to be parsimoniously explained by a 2-factor construct in schizophrenia, there has yet to be an established factor structure of negative symptoms in CHR. 214 individuals meeting the Structured Interview for Psychosis-Risk Syndromes (SIPS) criteria for CHR were recruited through 3 active research programs in the United States. Exploratory Factor Analysis was conducted on the 6 negative symptom items of the SIPS, and factors were evaluated with respect to functional outcome and depression. Factor analysis indicated a 2-factor hierarchical model with 2 negative symptom dimensions reflecting volition (Occupational Functioning and Avolition) and emotion (Expression of Emotion, Experience of Emotion and Social Anhedonia). Linear Regression showed that the emotion factor was associated with poor social function, and the volition factor was associated with poor role function and depression. Similar to factor solutions identified in adults diagnosed with psychotic disorders, results indicated that the SIPS negative symptom subscale is not a unidimensional construct. Rather, the SIPS negative subscale has 2 distinct factors that have different associations with clinical outcome and should be interpreted independently. Results have significant relevance for informing the valid assessment and conceptual interpretation of early clinical phenomenology in the psychosis prodrome.

Transdiagnostic dimensions of psychopathology at first episode psychosis: findings from the multinational EU-GEI study.

The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment. This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions. A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions. Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.