Bruno Bertolucci Ortiz

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.

Changes in gene expression and methylation in the blood of patients with first-episode psychosis

Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was observed in FEP patients relative to controls. Also, when we compare the FEP patients after risperidone treatment with controls, this difference remains significant, and no significant differences were observed in GCH1 mRNA levels when comparing patients before and after risperidone treatment. Additionally, although the differences were non-significant after Bonferroni correction, the expression of GCH1 seemed to be correlated with PANSS scores, and the GCH1 promoter region was more methylated in FEP than in controls, thus corroborating the results obtained at the mRNA level. Few studies have been conducted on GCH1, and future studies are needed to clarify its potential role in the progression of schizophrenia.

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.

Evaluation of neurotransmitter receptor gene expression identifies GABA receptor changes: A follow-up study in antipsychotic-naïve patients with first-episode psychosis

A study of the gene expression levels in the blood of individuals with schizophrenia in the beginning of the disease, such as first-episode psychosis (FEP), is useful to detect gene expression changes in this disorder in response to treatment. Although a large number of genetic studies on schizophrenia have been conducted, little is known about the effects of antipsychotic treatment on gene expression. The aim of the present study was to examine differences in the gene expression in the blood of antipsychotic-naïve FEP patients before and after risperidone treatment (N = 44) and also to verify the correlation with treatment response. In addition, we determined the correlations between differentially expressed genes and clinical variables. The expression of 40 neurotransmitter and neurodevelopment-associated genes was assessed using the RT2 Profiler PCR Array. The results indicated that the GABRR2 gene was downregulated after risperidone treatment, but no genes were associated with response to treatment and clinical variables after Bonferroni correction. GABRR2 downregulation after treatment can both suggest an effect of risperidone treatment or processes related to disease progression, either not necessarily associated with the improvement of symptoms. Despite this change was observed in blood, this decrease in GABRR2 mRNA levels might be an effect of changes in GABA concentrations or other systems interplay consequently to D2 blockage induced by risperidone, for example. Thus, it is important to consider that antipsychotics or the progression of psychotic disorders might interfere with gene expression.

Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study

OBJECTIVE To investigate whether inpatients with disorganized schizophrenia are more resistant to treatment. METHOD Eighty-five inpatients were assessed at admission and at discharge for schizophrenia subtype, symptom severity, and treatment resistance criteria. RESULTS Disorganized patients were significantly more treatment-resistant than paranoid patients (60%, p = 0.001), and presented worse scores on the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI-S), and the Global Assessment of Functioning Scale (GAF) (p < 0.001). Although the difference was not significant, 80% of treatment-resistant patients with disorganized schizophrenia responded to clozapine. CONCLUSION Patients with the disorganized subtype of schizophrenia should benefit from clozapine as a second-line agent.

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-

Effects of transcranial direct current stimulation on working memory and negative symptoms in schizophrenia: a phase II randomized sham-controlled trial

Background The lack of efficacy of pharmacological treatments for cognitive and negative symptoms in schizophrenia highlights the need for new interventions. We investigated the effects of tDCS on working memory and negative symptoms in patients with schizophrenia. Method Double-blinded, randomized, sham-controlled clinical trial, investigating the effects of 10 sessions of tDCS in schizophrenia subjects. Stimulation used 2 mA, for 20 min, with electrodes of 25 cm2 wrapped in cotton material soaked in saline solution. Anode was positioned over the left DLPFC and the cathode in the contralateral area. Twenty-four participants were assessed at baseline, after intervention and in a three-months follow-up. The primary outcome was the working memory score from MATRICS and the secondary outcome the negative score from PANSS. Data were analyzed using generalized estimating equations. Results We did not find group ∗ time interaction for the working memory (p = 0.720) score or any other cognitive variable (p > 0.05). We found a significant group ∗ time interaction for PANSS negative (p < 0.001, d = 0.23, CI.95 = −0.59–1.02), general (p = 0.011) and total scores (p < 0.001). Exploratory analysis of PANSS 5 factors suggests tDCS effect on PANSS negative (p = 0.012), cognitive (p = 0.016) and depression factors (p = 0.029). Conclusion The results from this trial highlight the therapeutic effects of tDCS for treatment of persistent symptoms in schizophrenia, with reduction of negative symptoms. We were not able to confirm the superiority of active tDCS over sham to improve working memory performance. Larger sample size studies are needed to confirm these findings.

T176. REDUCED WHITE MATTER ‘CONNECTIVITY’ IN THE SPLENIUM OF THE CORPUS CALLOSUM IN TREATMENT-RESISTANT SCHIZOPHRENIA

Abstract Background Resistance to treatment affects up to 30% of patients with schizophrenia (SCZ). Current criteria for treatment-resistant schizophrenia (TRS) require failure to respond to two antipsychotic trials for adequate dose and duration. Clozapine is the only antipsychotic that is more effective to treatment resistant patients. Increasing evidence suggest that TRS may represent a subgroup of patients with distinct biological signature. Brain dysconnectivity was proposed as a major feature of schizophrenia and more intense in TRS patients. Earlier identification of TRS may anticipate the clozapine trial and, thus, reduce disability and treatment costs. In our study, we investigated whether there were differences in white matter integrity among first episode of psychosis (FEP), treatment-resistant schizophrenia (TRS), and non treatment-resistant schizophrenia (NTRS) patients. Methods Diffusion-tensor brain MRI images were obtained for 34 TRS (19 males), 50 NTRS (26 males) and 35 FEP individuals (18 males), on a Siemens 1.5T MRI scanner. Treatment resistance was defined as persistence of moderate to severe symptoms, after failure to respond to 4–6 week trials of at least two different antipsychotic medications in adequate doses (equivalent to at least 400 mg/day of chlorpromazine or 5 mg/day of risperidone). All participants were receiving antipsychotic medication. All TRS patients were in clozapine use. Analysis of diffusion parameters was performed using a tract-based spatial statistics (TBSS), yielding a total two contrasts: i) mean FA is lower (or higher) in the TRS compared to the FEP, ii) mean FA is lower (or higher) in the NTRS compared to the FEP corrected for multiple comparisons using family-wise error (FWE) < 0.05. Gender and age were used as covariates. Results FEP patients were younger than TRS (mean±SD; 27.2 ± 7.93 y/o vs 37.06 y ±7.98 y/o;t=5.08, p <0.001) and NTRS (27.2 ± 7.93 y/o vs 37.71 y ±11.18 y/o; t=4.57, p<0.001) patients. Reduced in FA value was observed in the splenium of the corpus callosum (CC) in TRS patients when compared to FEP (47,598 voxels and thresholded at p<0.05). No differences between NTRS and FEP patients were observed. Discussion Our results showed reduced FA value in the splenium of the CC in TRS when compared to FEP. The splenium of corpus callosum connects the temporal and occipital cortices, and have been previously associated with schizophrenia, but not specifically to treatment resistance in schizophrenia. Our data might suggest that patients with resistance to treatment have inefficiency in the connectivity of the white matter between these regions. Further studies will be required to replicate these findings and to explore the significance of white matter changes in the brain in order to determine if these are consequence of disease progression or related to clozapine exposure.