Is treatment-resistant schizophrenia associated with distinct neurobiological callosal connectivity abnormalities?

BACKGROUND: Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non-treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values. METHODS: TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB's Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05. RESULTS: We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC. CONCLUSION: Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

Cognitive and Psychiatric Evaluation in SYNE1 Ataxia.

SYNE1 gene mutations were identified as a cause of late-onset pure cerebellar syndrome. Non-cerebellar symptoms, including cognitive impairment, were already described in this condition. The aim of this study was to perform a detailed cognitive and psychiatric description of patients with SYNE1 gene mutations. We performed neuropsychological and psychiatric evaluations of six patients with SYNE1 ataxia and compared their performance with 18 normal controls paired for age and education level. SYNE1 ataxia patients present cognitive dysfunction, characterized by impairment in attention and processing speed domains. Otherwise, the psychiatric assessment reported low levels of overall behavioral symptoms with only some minor anxiety-related complaints. Although this is a small sample of patients, these results suggest that SYNE1 ataxia patients may represent a model to investigate effects of cerebellar degeneration in higher hierarchical cognitive functions. For further studies, abstract thinking impairment in schizophrenia may be related to dysfunction in cerebellum pathways.

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, patient's age, assessment time point (i.e., moment of patient's 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.

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.

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.

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.

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. .

Estimulação magnética transcraniana de repetição associada a antidepressivo: início e intensidade da resposta antidepressiva / Repetitive transcranial magnetic stimulation associated with antidepressant: start and intensive of the antidrepressant answer

OBJETIVOS: Avaliar diferentes estudos que analisam o grau de eficácia da resposta antidepressiva entre a associação de estimulação magnética transcraniana de repetição (EMTr) com antidepressivos em pacientes deprimidos graves. MÉTODOS: Os autores revisaram vários estudos em que a EMTr foi usada concomitantemente a antidepressivos em pacientes deprimidos graves. Adicionalmente, relatou-se um estudo feito no Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Estudo duplo-cego, randomizado, unicêntrico, placebo-controlado com 46 pacientes atendendo aos critérios diagnósticos da DSM-IV para episódio depressivo severo. Os pacientes estavam em uso de amitriptilina. RESULTADOS: De forma geral, a maioria dos estudos mostra que a EMTr apresenta boa eficácia antidepressiva quando associada a antidepressivos. Há grande diversidade de parâmetros técnicos utilizados, tipos de bobina, diferentes técnicas de placebo e uso de diferentes antidepressivos. O estudo realizado no Instituto de Psiquiatria mostrou que o emprego da EMTr de alta freqüência aumentou a resposta antidepressiva à amitriptilina e diminuiu o tempo para o início da resposta antidepressiva em relação ao grupo placebo. CONCLUSÕES: EMTr é um método novo, promissor e com grande potencial para o tratamento da depressão. Apesar disso, observa-se que não há ainda uniformidade no emprego dos parâmetros técnicos, nem tampouco das técnicas de placebo. O estudo realizado no Instituto de Psiquiatria do HC- FMUSP mostrou grandes taxas de resposta e remissão em relação ao grupo com estimulação sham e amitriptilna.