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.

Hemoencephalography self-regulation training and its impact on cognition: A study with schizophrenia and healthy participants.

BACKGROUND: Cognitive impairments in schizophrenia are strongly correlated to functional outcome and recovery rates, with no pharmacological agent approved for its treatment. Neurofeedback has emerged as a non-pharmacological approach to enhance neuroplasticity, which consists in inducing voluntary control of brain responses through operant conditioning. METHOD: The effects of hemoencephalography neurofeedback (HEG-NFBK) in 4 brain sites (F7, Fp1, Fp2 and F8) was studied in 8 patients with schizophrenia (SCH, mean age 36.5±9.98) and 12 health controls (mean age 32.17±5.6). We analyzed groups' performance (10 sessions) and cognitive differences in 3 time points (baseline, after training and follow-up) with generalized estimated equations. For SCH we also evaluate the impact on psychopathology. RESULTS: We found a group∗time interaction for HEG-NFBK performance in the left hemisphere sites (F7 an Fp1) and a near-to-significant in the right frontotemporal region (F8), with no group differences and a significant time effect. Most of cognitive domains improved after intervention, including information processing speed, attention processing, working memory, executive functioning, verbal and visual learning. No group∗time interaction was found. Results suggest that both groups benefit from HEG-NFBK training regardless of cognitive differences at baseline. No significant time effects were found for Calgary and PANSS total scale and subscales (positive, negative neither general). CONCLUSION: To our knowledge, this is the first controlled trial showing effects of NFBK on cognitive performance improvement in schizophrenia. Further research investigating the effects of HEG-NFBK training in schizophrenia should be performed.

Gene expression alterations related to mania and psychosis in peripheral blood of patients with a first episode of psychosis.

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system.

Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy-Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose-response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS "top-down" antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis.

The serotonin transporter (5-HTT) is a candidate gene for bipolar disorder (BPD). It has been investigated for association with the illness in a series of studies, but overall results have been inconsistent and its role in the disorder remains controversial. Systematic reviews using meta-analytical techniques are a useful method for objectively and reproducibly assessing individual studies and generating combined results. We performed two meta-analyses of published studies--both population-based and family-based studies--investigating the association between BPD and the 5-HTT gene-linked polymorphic region (5-HTTLPR) and the intron 2 variable numbers of tandem repeats (VNTR) polymorphisms. The literature was searched using Medline and Embase to identify studies for inclusion. We statistically joined population-based and family-based studies into a single meta-analysis. For both polymorphisms, our review revealed significant pooled odds ratios (ORs): 1.12 (95% CI 1.03-1.21) for the 5-HTTLPR and 1.12 (95% CI 1.02-1.22) for the intron 2 VNTR. Meta-regression showed that neither the study type (population-based vs family-based; P=0.41 for the 5-HTTLPR and P=0.91 for the intron 2 VNTR) nor the sample ethnicity (Caucasian vs non-Caucasian; P=0.35 for the 5-HTTLPR and P=0.66 for the intron 2 VNTR) significantly contributed to the heterogeneity of the meta-analyses. The observed ORs could be regarded simply as a very small but detectable effect of the 5-HTT, which has an additive effect when combined with other susceptibility loci. Alternative hypotheses on this finding were also discussed: a stronger effect of the haplotypes involving the two polymorphisms or other SNP markers; a more direct effect of these polymorphisms on specific phenotypes of BPD; and the presence of gene-environment interaction as a mediator of the genetic effects of 5-HTT.

Late-life depression, heart failure and frontal white matter hyperintensity: a structural magnetic resonance imaging study.

The relevance of the relationship between cardiac disease and depressive symptoms is well established. White matter hyperintensity, a bright signal area in the brain on T2-weighted magnetic resonance imaging scans, has been separately associated with cardiovascular risk factors, cardiac disease and late-life depression. However, no study has directly investigated the association between heart failure, major depressive symptoms and the presence of hyperintensities. Using a visual assessment scale, we have investigated the frequency and severity of white matter hyperintensities identified by magnetic resonance imaging in eight patients with late-life depression and heart failure, ten patients with heart failure without depression, and fourteen healthy elderly volunteers. Since the frontal lobe has been the proposed site for the preferential location of white matter hyperintensities in patients with late-life depression, we focused our investigation specifically on this brain region. Although there were no significant group differences in white matter hyperintensities in the frontal region, a significant direct correlation emerged between the severity of frontal periventricular white matter hyperintensity and scores on the Hamilton scale for depression in the group with heart failure and depression (P = 0.016, controlled for the confounding influence of age). There were no significant findings in any other areas of the brain. This pattern of results adds support to a relationship between cardiovascular risk factors and depressive symptoms, and provides preliminary evidence that the presence of white matter hyperintensities specifically in frontal regions may contribute to the severity of depressive symptoms in cardiac disease.

Late-life depression, heart failure and frontal white matter hyperintensity: a structural magnetic resonance imaging study

The relevance of the relationship between cardiac disease and depressive symptoms is well established. White matter hyperintensity, a bright signal area in the brain on T2-weighted magnetic resonance imaging scans, has been separately associated with cardiovascular risk factors, cardiac disease and late-life depression. However, no study has directly investigated the association between heart failure, major depressive symptoms and the presence of hyperintensities. Using a visual assessment scale, we have investigated the frequency and severity of white matter hyperintensities identified by magnetic resonance imaging in eight patients with late-life depression and heart failure, ten patients with heart failure without depression, and fourteen healthy elderly volunteers. Since the frontal lobe has been the proposed site for the preferential location of white matter hyperintensities in patients with late-life depression, we focused our investigation specifically on this brain region. Although there were no significant group differences in white matter hyperintensities in the frontal region, a significant direct correlation emerged between the severity of frontal periventricular white matter hyperintensity and scores on the Hamilton scale for depression in the group with heart failure and depression (P = 0.016, controlled for the confounding influence of age). There were no significant findings in any other areas of the brain. This pattern of results adds support to a relationship between cardiovascular risk factors and depressive symptoms, and provides preliminary evidence that the presence of white matter hyperintensities specifically in frontal regions may contribute to the severity of depressive symptoms in cardiac disease.

Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil.

Linkage and association studies in five independently ascertained samples have suggested that polymorphisms of the regulator of G-protein signaling 4 (RGS4) may confer risk for schizophrenia (SCZ). Suggestive evidence for association with bipolar disorder (BD) has also been presented. However, the associated alleles and haplotypes have differed among the samples. Data from other independent samples may clarify the putative associations. Hence, we investigated an independent, ethnically diverse Brazilian population comprising patients with SCZ (n=271) or BD1 (n=306), who were contrasted with 576 community-based controls. Parents of 49 SCZ cases and 44 BD cases were available for transmission disequilibrium tests (TDTs). Four RGS4 single-nucleotide polymorphisms (SNPs) 1, 4, 7 and 18 putatively associated with SCZ were investigated. In the SCZ samples, significant case-control differences were not observed for individual SNPs or haplotypes, though the TDT suggested transmission distortion similar to that observed in the initial report. For the BD sample, case-control comparisons revealed no significant differences for individual SNPs, but an omnibus test suggested differences in the overall distribution of haplotypes bearing all four SNPs (SNP-EM Omnibus likelihood ratio test; P=0.003). The TDT revealed over-transmission of allele A at SNP7 (P=0.016), as well as haplotypes incorporating this allele. However, global tests incorporating all haplotypes yielded only suggestive trends for association (P=0.19). In conclusion, association with SCZ was not detected in the present analyses. The failure to detect an association may be related to inadequate power or to confounds related to ethnic admixture. Suggestive associations with BD detected here require further investigation in a larger sample.

[Study of association between the ser-9-gly polymorphism of the D3 dopaminergic receptor and schizophrenia]. / Estudo de associação entre o polimorfismo serina-9-glicina do receptor dopaminérgico D3 e esquizofrenia.

Two molecular genetic studies were undertaken to investigate the association between a ser-9-gly polymorphism in the dopamine D3 receptor gene and schizophrenia. The first study analysed 141 schizophrenic patients and 189 matched controls. In addition, an haplotype relative risk study was performed using 35 trios (mother, father, affected offspring). No allelic or genotype association was found in both studies. We conclude that this D3 polymorphism is not a risk factor for schizophrenia in our sample.

[Parkinsonian, cerebellar, psychotic and demential symptoms in ex-boxer: case report]. / Sintomas parkinsonianos, cerebelares, psicóticos e demenciais em ex-pugilista: relato de caso.

67 years-old male patient, ex-boxer, after the end of his sportive career, began to present neuropsychiatric manifestations possibly due to the successive brain injuries related to the boxing. In report to this case, we discuss the mean organic psychosyndromes related to the boxing.

Darier's disease: a new paradigm for genetic studies in psychiatric disorders.

CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12.