Cinthia Higuchi

Effects of depression on the cytokine profile in drug naïve first-episode psychosis

Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.

Factor structure of the Positive and Negative Syndrome Scale (PANSS) in Brazil: convergent validation of the Brazilian version

OBJECTIVES The Positive and Negative Syndrome Scale (PANSS) was developed to assess the symptoms of schizophrenia dimensionally. Although it is widely used in clinical trials in Brazil, it is not fully validated. The aim of this study is to assess the factor structure of the Brazilian PANSS and generate validation data for its current version. METHODS A total of 292 patients diagnosed with schizophrenia were enrolled. RESULTS Principal component analysis suggested a forced five-factor final model that accounted for 58.44% of the total variance, composed of negative, disorganization/cognition, excitement, positive, and depression/anxiety. CONCLUSION The Brazilian PANSS has a similar factor structure and internal consistency compared to versions in several other languages.

Peripheral immuno-inflammatory abnormalities in ultra-high risk of developing psychosis

BACKGROUND Immuno-inflammatory imbalances have been documented in schizophrenia, but very little is known about the immunological changes prior to the onset of disease. OBJECTIVE This work aimed to compare serum levels of pro- and anti-inflammatory cytokines in young subjects at ultra-high risk (UHR) of developing psychosis with age- and sex-matched healthy controls. METHODS A total of 12 UHR and 16 age- and sex-matched healthy controls (HC) subjects were enrolled in this study. Clinical profile was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS), Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or Kiddie-SADS-Present and Lifetime Version (K-SADS-PL), and Global Assessment of Functioning (GAF) scale. Serum interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, IFN-γ, and IL-17 were measured by flow cytometry using the Th1/Th2/Th17 cytometric bead array. RESULTS Compared with the healthy control group, patients in UHR showed increased IL-6 levels (Z=-2.370, p=0.018) and decreased IL-17 levels in serum (Z=-1.959, p=0.050). Levels of IL-17 positively correlated to the values in GAF symptoms (rho=0.632, p=0.028). CONCLUSION Our results suggest that immunological imbalances could be present in the early stages of psychosis, including in at-risk stages. Future studies should replicate and expand these results.

Increased expression of NDEL1 and MBP genes in the peripheral blood of antipsychotic-naïve patients with first-episode psychosis

Schizophrenia is a multifactorial neurodevelopmental disorder with high heritability. First-episode psychosis (FEP) is a critical period for determining the disease prognosis and is especially helpful for identifying potential biomarkers associated with the onset and progression of the disorder. We investigated the mRNA expression of 12 schizophrenia-related genes in the blood of antipsychotic-naïve FEP patients (N=73) and healthy controls (N=73). To evaluate the influences of antipsychotic treatment and progression of the disorder, we compared the gene expression within patients before and after two months of treatment with risperidone (N=64). We observed a significantly increased myelin basic protein (MBP) and nuclear distribution protein nudE-like 1 (NDEL1) mRNA levels in FEP patients compared with controls. Comparing FEP before and after risperidone treatment, no significant differences were identified; however; a trend of relatively low NDEL1 expression was observed after risperidone treatment. Animals chronically treated with saline or risperidone exhibited no significant change in Ndel1 expression levels in the blood or the prefrontal cortex (PFC), suggesting that the trend of low NDEL1 expression observed in FEP patients after treatment is likely due to factors other than risperidone treatment (i.e., disease progression). In addition to the recognized association with schizophrenia, MBP and NDEL1 gene products also play an essential role in the functions that are deregulated in schizophrenia, such as neurodevelopment. Our data strengthen the importance of these biological processes in psychotic disorders, indicating that these changes can be detected peripherally and potentially represent putative novel blood biomarkers of susceptibility and disorder progression.

Disorganized symptoms predicted worse functioning outcome in schizophrenia patients with established illness.

Most patients with schizophrenia will have subsequent relapses of the disorder, with continuous impairments in functioning. However, evidence is lacking on how symptoms influence functioning at different phases of the disease. This study aims to investigate the relationship between symptom dimensions and functioning at different phases: acute exacerbation, nonremission and remission. METHODS Patients with schizophrenia were grouped into acutely ill (n=89), not remitted (n=89), and remitted (n=69). Three exploratory stepwise linear regression analyses were performed for each phase of schizophrenia, in which the five PANSS factors and demographic variables were entered as the independent variables and the total Global Assessment of Functioning Scale (GAF) score was entered as the dependent variable. An additional exploratory stepwise logistic regression analysis was performed to predict subsequent remission at discharge in the inpatient population. RESULTS The Disorganized factor was the most significant predictor for acutely ill patients (p<0.001), while the Hostility factor was the most significant for not-remitted patients and the Negative factor was the most significant for remitted patients (p=0.001 and p<0.001, respectively). In the logistic regression, the Disorganized factor score presented a significant negative association with remission (p=0.007). CONCLUSIONS Higher disorganization symptoms showed the greatest impact in functioning at acute phase, and prevented patients from achieving remission, suggesting it may be a marker of symptom severity and worse outcome in schizophrenia.

New evidence in support of staging approaches in schizophrenia: Differences in clinical profiles between first episode, early stage, and late stage

Few studies have examined the progression of symptom dimensions in schizophrenia patients over the course of the illness. The objective of this study was to investigate whether clinical and psychopathological differences exist between first-episode schizophrenia (FES) and multiple-episode patients in an inpatient setting. Patients (N=203) were evaluated using the Positive and Negative Syndrome Scale (PANSS) over time. Five different generalized estimating equations were built for the PANSS factors using the following as covariates: sex, patients age, assessment time point (i.e., moment of patients evaluation, with a minimum of two and a maximum of four assessments throughout the study timeframe). The FES group was used as the reference to which the groups with up to five years of illness and more than five years of illness were compared. Remission rates and treatment resistance (TRS) rates were also compared. Generalized estimating equations were used to allow for different numbers of assessments over the study period. Patients with FES showed significantly milder severity in positive, disorganized, and hostility factors. Also, FES patients were more likely to achieve remission (P=0.002) and had lower rates of TRS (P=0.001). First-episode schizophrenia seems to be the critical period to improve outcome, as multiple-episode patients were similar in clinical characteristics regardless of illness duration.

What are the PANSS items most related with global improvements in patients with schizophrenia? Toward a reduced version of the PANSS.

The most commonly used response criteria in clinical trials for the treatment of schizophrenia is a combination of the percentage of decrease in the total score of the Positive and Negative Syndromes Scale (PANSS; Kay et al., 1987) and the Clinical Global Impression (CGI; Guy, 1976) scale (Leucht et al., 2007). The peak of effect of antipsychotics typically occurs within 2–4 weeks, which means that satisfactory subsequent clinical response is highly unlikely (Kinon et al., 2009). The PANSS consists of 30 items and generally produce a five-factor solution (Wallwork et al., 2012; Higuchi et al., in press), that are regarded as “symptom dimensions”, which are the positive, negative, cognitive/disorganized, mood/depression and excitement/hostility. However, few items poorly correlate to the factors (Lehoux et al., 2009). In addition, the PANSS demands carefully directed interviews lasting 40–60 min and, recent studies have proposed a modification to the PANSS in order to improve its application time and efficiency (Obermeier et al., 2010). Here, we compared reductions in the scores of each item of the PANSS with corresponding reductions in the CGI-S score after 4 weeks of treatment with antipsychotic medication to ascertain which items of the PANSS best explained global improvements. The sample comprised 106 inpatients with schizophrenia from the Inpatient Psychiatric Unit of Hospital das Clínicas Luzia de Pinho Melo (Mogi das Cruzes, Brazil) between 2011 and 2013. The inclusion criteria were: a diagnosis of schizophrenia as defined by the DSM-IV (American Psychiatric Association, 1994), age between 14 and 65 years and absence of demonstrable organic brain diseases assessed with computed tomography, or severe intellectual disability. Patients were assessed by the first author with the Structured Clinical Interview for DSM-IVAxis I Disorders (SCID-I) (First et al., 1996), the PANSS, and the CGI-S. The local ethic committee approved the study (2013/01), and all subjects and their relatives provided written informed consent for participation in the study. Each psychopathological dimension was disclosed by factor analysis. To estimate the association between each item of the PANSS and CGI-S scores, the baseline scores of each item and the scores of the CGI-S were subtracted from the 4th week scores. For a fair comparison between the items (positive symptoms respond better than negative symptoms), we performed an exploratory stepwise linear regression analysis for each dimension, in which the delta PANSS items were entered as the independent variables and the corresponding delta CGI-S score was entered as the dependent variable. To compare the variance explained by the final model with the traditional 30-item model, a linear regression analysis was performed for bothmodels with the delta CGI-S scores as the dependent variable. P-

S129. DOES TREATMENT RESISTANT SCHIZOPHRENIA PRESENT A CHARACTERISTIC SYMPTOMATIC SIGNATURE

Abstract Background Treatment-resistant schizophrenia (TRS) may underlie a specific biological signature among patients with schizophrenia. The main lines of evidence suggest a glutamatergic rather than dopaminergic dysfunction in TRS, with lower levels of striatal dopamine and higher levels of glutamate in anterior cingulate. Whether this biological signature relates to a distinct symptomatic profile remains unclear. Our objective is to define a symptom profile of patients with TRS. Methods We used two samples of patients with schizophrenia. First, we followed a discovery sample of inpatients (n=203) to prospectively identify TRS predictors, then we tested the predictors in a replication sample of outpatients (n=207). The samples were collected independently. All patients were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity Scale (CGI-S) and the Global Assessment of Functioning Scale (GAF). Diagnosis was confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). TRS was defined according the criteria of the Schizophrenia Algorithm of the International Psychopharmacology Algorithm Project (IPAP). Initially, we tested if patients with disorganized subtype were more likely to be TRS, and grouped the patients into disorganized or non-disorganized schizophrenia according to SCID-I. Then, we checked which PANSS items at the baseline predicted TRS at the follow-up through multiple logistic regression analyses. A receiver operating characteristic (ROC) curve with the best items was performed at the follow-up. Results TRS was more common in disorganized schizophrenia in the inpatient sample (73.8% vs 22.4%, P < 0.001) and in the outpatient sample (68.2% vs 28.2%, P < 0.001) in comparison to non-disorganized schizophrenia. They also presented worse scores on PANSS, CGI-S and GAF (P < 0.001). In the second step, three PANSS items, P2 (conceptual disorganization), N5 (difficulty in abstract thinking) and G9 (unusual thought content), predicted TRS with 78.4% accuracy (P = 0.011, P = 0.010 and P <0.001). The ROC analysis using the sum of PE+N5G+G9 predicted TRS with a sensitivity of 72.3%, and a specificity of 82.4%. In the outpatient sample, logistic regression analysis of the model P2+N5+G9 discriminated TRS with 69.3% accuracy (P <0.001). Discussion Non-paranoid clinical presentations, specially disorganized characteristics, may consist in clinical markers of TRS. Further Cross-validation of such clinical findings and biological features may improve prediction of TRS

T97. CANNABIS USE IMPACTS SYMPTOM PRESENTATION IN ANTIPSYCHOTIC NAIVE PATIENTS IN FIRST EPISODE OF PSYCHOSIS (FEP)

Abstract Background Psychotic disorders induced by cannabis may present distinct symptomatic profile, course and underlying biology. Most studies on symptomatic effects of cannabis exposure are limited by examining patients after antipsychotic treatment. We investigated if antipsychotic naive FEP patients that reported cannabis use present higher symptom’s severity and if affects deferentially any of standard psychosis dimensions (positive, negative, disorganized, excitement and depressive). Methods The sample comprised 194 antipsychotic naive FEP individuals. The baseline assessment was performed right after the admission at the emergency room and the follow-up assessment two months after antipsychotic treatment. The cannabis exposure was measured by ASI-6 (Addiction Severity Index) and additional questions addressing the relation to onset of psychotic disorders and how many times cannabis has been used. Cannabis use was reported by 41,2% of patients, and 25.8% reported heavy use (more than 50 times). Dimensional psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the symptom dimensions were constructed based on previous studies (positive, negative, disorganized, depressive, excitement). Considering cannabis use, we analyzed the following variables: 1 - Number of days of cannabis consumption in the last 30 days (Acute Use); 2 – Age of first cannabis use; 3 – Total cannabis use lifetime, categorized in no use, less than 50, more than 50 (total use). Results The mean age was 25.52 (sd=7.17), mean duration of untreated psychosis was 176 days (sd= 291) and most of the subjects were male (63%). Acute use of cannabis was associated with higher scores in the positive symptom dimension (p =0.017, df= 40, R-squared = 0.132). Also, the earlier age of first cannabis use was related to higher presentation scores of the negative symptom dimension (p = 0.002, df = 33, R-squared = 0.238). No significant association was found between any cannabis exposure variable and other symptomatic dimensions excitement, depressive and disorganized symptoms′ dimensions. Cannabis use did not associate with duration of untreated psychosis (p=0.443, W= 2709.5). All the analyses were controlled by gender, age and duration of untreated psychosis. Discussion Acute and total exposure to cannabis affected deferentially the symptoms dimensions in patients at first episode of psychosis. Previous studies on the relationship between cannabis use and negative symptoms produced mixed results. This may be biased by antipsychotic exposure prior to first assessment. We will investigate the course of the symptoms of those patients to verify if the symptomatic differences are maintained.

F119. MULTILEVEL ANALYSIS IMPROVES THE MODEL FIT OF THE DIMENSIONAL STRUCTURE OF THE PANSS IN PATIENTS WITH SCHIZOPHRENIA

Abstract Background Principal component analyses (PCA) studies show that schizophrenia symptoms are usually grouped into five domains. However, to infer a latent dimensional structure, confirmatory factor analysis (CFA) is more appropriate than PCA. Most CFA studies addressing the five-factor model yielded poor fit indices. One single study achieved a good fit using a multilevel CFA structure with the interviewers as level. Other possible reasons for sample heterogeneity and subsequent poor model adjustments, such as differences in patients’ clinical profiles across clinical units and clinical staging, were not measured in this study. We aimed to replicate the effect of the CFA multilevel analyses and evaluate the possible influence of other heterogeneity sources as levels, i.e., clinical staging, on the Positive and Negative Syndrome Scale (PANSS) five-factor structure. Methods 700 patients with schizophrenia at four different centers had their PANSS analyzed. A Confirmatory Factor Analysis (CFA) was conducted using the following fit index: Comparative Fit Index (CFI) and Non-Normed Fit Index (NNFI) >0.95, the Root Mean Square Errors of Approximation (RMSEA) <0.06, and Weighted Root Mean Square Residual (WRMR) <1.0. Thereafter, we performed multilevel analyses considering the following levels: i) centers, ii) interviewers and iii) clinical staging for schizophrenia (first episode, treatment-resistant schizophrenia and non-treatment resistant schizophrenia). Results The mean (SD) age was 34.9 (10.3) years, mean age of onset was 21.7 (7.5), mean duration of illness means was 13.2 (9.7) years, and 64.3% of the sample was male. The CFA model without multilevel analyses yielded poor fit indices: RMSEA = 0.102 (90% CI: 0.097 – 0.107; Cfit was <0.001), CFI = 0.921 and NNFI = 0.906 and WRMR = 1.952. When the multilevel analysis was applied, all models reached an acceptable fit: i) centers: RMSEA = 0.044 (90% CI: 0.038 – 0.049; CFit = 0.964), CFI = 0.981, NNFI = 0.977, and WRMR = 1.860; ii) interviewers: RMSEA = 0.047 (90% CI: 0.041 – 0.053; CFit = 0.765), CFI = 0.947, NNFI = 0.938, and WRMR = 1.531; iii) clinical stage: RMSEA = 0.052 (90% CI: 0.046 – 0.058; CFit = 0.274), CFI = 0.988, NNFI = 0.985, and WRMR = 2.433. Discussion Good CFA model fits were only achieved when the multilevel structure was applied. Besides the bias generated by data collection (i.e., local of data collection and raters), the clinical staging is a potential source of variability to consider in schizophrenia dimensional structure. As dimensional approaches gain relevance to reduce heterogeneity in schizophrenia and to investigate their biological substrates, reliable methods to address latent dimensions are required.