Graccielle R. Cunha

Cytokines in schizophrenia: possible role of anti-inflammatory medications in clinical and preclinical stages.

Aims:  In this paper, we review the literature on the efficacy of anti‐inflammatory agents as neuroprotectors in clinical and preclinical stages of schizophrenia.

N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals

Abstract Schizophrenia is a chronic and often severe psychotic disorder. Its causes include imbalances in mediators involved in neuroplasticity, apoptosis, cell resilience and dendritic arborization. Among these mediators, oxidative species are particularly relevant for the pathophysiology of the disease, and this is the rationale for experimental use of antioxidant medications, such as N-acetylcysteine (NAC). Onset of schizophrenia is usually preceded by a period of subtle and unspecific symptoms, the prodrome, in which preventive interventions could delay or even stop the progression to full-blown psychosis. In this article, we propose that NAC could be a useful medication to prevent evolution of schizophrenia in individuals at risk for psychosis.

Abnormalities in sleep patterns in individuals at risk for psychosis and bipolar disorder

AIM To compare patterns of sleep and the presence of sleep disturbances in individuals in at-risk mental states (ARMS) for psychosis and bipolar disorder (BD) with a healthy control (HC) group. METHODS This was a comparative study involving 20 individuals in ARMS for psychosis or BD, according to the Comprehensive Assessment of At-Risk Mental States, and 20 age- and sex-matched healthy controls. Quality of sleep in the previous month was assessed using the Pittsburgh Sleep Quality Index, diurnal somnolence was evaluated using The Epworth Sleepiness Scale, and chronotype was determined using the Questionnaire of Morningness/Eveningness (QME). All of the participants underwent polysomnography (PSG) during the entire night for two consecutive nights. The first night aimed to adapt the subject to the environment, and only the data from the second night were used for the analysis. RESULTS Compared with the HC group, individuals in the ARMS group reported significantly worse sleep quality, as measured by the Pittsburgh Sleep Quality Index. Both groups had scores consistent with daytime sleepiness on the Epworth Sleepiness Scale, and there were no differences with regard to chronotype between the groups, with a predominance of the indifferent type in both groups. In the PSG assessment, we observed increased Sleep Latency (SL) and increased Rapid Eye Movement Sleep Onset Latency (REMOL) in the ARMS group, compared to the HC group. CONCLUSION The results of this study indicated that sleep abnormalities could be found early in the course of mental diseases, even in at-risk stages, and support the further investigation of their predictive value in the transition to psychosis and BD.

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.

Impaired glucose metabolism moderates the course of illness in bipolar disorder

BACKGROUND The longitudinal course of bipolar disorder (BD) is highly heterogeneous, and is moderated by the presence of general medical comorbidities. This study aimed to investigate the moderating effects of impaired glucose metabolism (IGM) on variables of illness course and severity in a BD population. METHODS Fifty-five patients with BD were evaluated. All subjects were evaluated with respect to current and past psychiatric and medical disorders, as well as lifetime use of any medication. Body mass index (BMI) and metabolic parameters were obtained. IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. RESULTS Thirty (54.5%) individuals had IGM. After adjustment for age, gender, ethnicity, alcohol use, smoking, BMI and past and current exposure to psychotropic medications, individuals with IGM, when compared to euglycemic participants, had an earlier age of onset (RR: 0.835, p=0.024), longer illness duration (RR: 1.754, p=0.007), a higher number of previous manic/hypomanic episodes (RR: 1.483, p=0.002) and a higher ratio of manic/hypomanic to depressive episodes (RR: 1.753, p=0.028). Moreover, we observed a moderating effect of IGM on the association between number of mood episodes and other variables of illness course, with the correlation between lifetime mood episodes and frequency of episodes being significantly greater in the IGM subgroup (RR: 1.027, p=0.029). All associations observed herein remained significant after adjusting for relevant confounding factors (e.g. age, alcohol and tobacco use, exposure to psychotropic agents, BMI). LIMITATIONS Cross-sectional design, small sample size. CONCLUSIONS Comorbid IGM may be a key moderator of illness progression in BD.

Brain‐derived neurotrophic factor, impaired glucose metabolism, and bipolar disorder course

OBJECTIVES The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism (IGM) on plasma levels of BDNF in individuals with BD, and on the relationship between BDNF and variables of illness course. METHODS We measured and compared the plasma levels of BDNF in individuals with BD (n=57) and healthy controls (n=26). IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured. RESULTS Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking, alcohol use, and IGM (P=.046). There was no effect of IGM (P=.860) and no interaction between BD diagnosis and IGM (P=.893). Peripheral BDNF levels were positively correlated with lifetime depressive episodes (P<.001), psychiatric hospitalizations (P=.001) and suicide attempts (P=.021). IGM moderated the association between BDNF and the number of previous mood episodes (P<.001), wherein there was a positive correlation in euglycemic participants and a negative correlation in individuals with IGM. CONCLUSIONS BD is independently associated with lower levels of BDNF; IGM may modify the relationship between BDNF and BD course, suggesting an interactive effect of BDNF with metabolic status on illness progression.

Gene expression analysis in blood of ultra-high risk subjects compared to first-episode of psychosis patients and controls

Abstract Objectives. This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC). Methods. We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons. Results. We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10–6 ; P = 9.41 × 10–6). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10–6). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age. Conclusions. These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies.

Shorter leukocyte telomere length in patients at ultra high risk for psychosis

Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population.

Brain tumor in a patient with attenuated psychosis syndrome

Universidade Federal de Sao Paulo, Program Intervent Risk Mental States PRISMA, Dept Psychiat, BR-04039032 Sao Paulo, Brazil

Inflammation, neurotrophism and oxidative stress and childhood psychopathology in a large community sample

To investigate the association between peripheral biomarkers and child psychopathology in a large community sample.