Maria Inês Rodrigues Lobato

Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young persons life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5 ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population.

Improvement of Negative and Positive Symptoms in Treatment-Refractory Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Trial With Memantine as Add-On Therapy to Clozapine

BACKGROUND Glutamate deregulation may be involved in the neuropathology of schizophrenia, mainly through N-methyl-d-aspartate (NMDA) receptor dysfunction. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimers disease, acts as a weak nonselective NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to clozapine in patients with refractory schizophrenia. METHOD In this double-blind, placebo-controlled study, outpatients with refractory schizophrenia according to DSM-IV clinical criteria were randomly assigned, from March 2005 to February 2008, to receive either 20 mg/d memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. The primary outcome measure was the total score on the 18-item Brief Psychiatry Rating Scale (BPRS) and BPRS subscales of positive and negative symptoms. Secondary outcomes were global severity of disease as measured by the Clinical Global Impressions scale (CGI), cognition as assessed by the Mini-Mental State Examination (MMSE), and extrapyramidal symptoms as assessed by the Simpson-Angus Scale (SAS). RESULTS Twenty-one participants completed the study and were used in the analysis. Significant improvement (P < .01) on the total BPRS score, its subscales of positive (effect size [ES] = -1.38) and negative (ES = -3.33) symptoms, the CGI score (ES = 1.56), and the MMSE score was observed with memantine as compared with placebo. No significant changes in extrapyramidal symptoms were observed. CONCLUSIONS Memantine add-on to clozapine therapy was associated with improvement in negative and positive symptoms in refractory schizophrenia patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00757978.

Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients.

Refractory depression is a highly debilitating mental condition that originates major social and economic burden. About 50% of the patients experience a chronic course of illness and up to 20% show an insufficient response to drug treatments. Electroconvulsive therapy (ECT) is the most effective treatment method in refractory depression, although its mechanism of action is still unknown. Brain-derived neurotrophic factor (BDNF) is decreased in depressive episodes, and increases with antidepressant treatment, being suggested as a biomarker of response to ECT. We report the findings of a study on the effects of ECT on BDNF and clinical outcomes in a group of drug resistant depressive patients before and after ECT. The patients post-ECTs have shown an important improvement of depressive symptomatology on the HDRS (p=0.001), of psychotic features on the BPRS (p=0.001) and of the severity of illness on the CGI (p=0.001). There were no changes in the serum BDNF before and after the ECT treatment (p=0.89). These results do not support the hypothesis that the clinical improvement following ECT is due to changes in the BDNF.

The association of child abuse and neglect with adult disability in schizophrenia and the prominent role of physical neglect

OBJECTIVE To assess long-lasting effects of childhood trauma on the functional outcome of adult patients diagnosed with schizophrenia. METHOD Ninety-nine stable patients with schizophrenia followed in an outpatient program at a public university hospital in Porto Alegre, southern Brazil, were investigated for childhood traumatic experiences by the Childhood Trauma Questionnaire (CTQ) and for functional impairment by the World Health Organization Disability Assessment Schedule (WHO/DAS). The schizophrenia diagnosis was assessed by ICD-10 and DSM-IV criteria according to the Operational Criteria Checklist for Psychotic Illness (OPCRIT). RESULTS Childhood trauma in general was associated with increased disability in adulthood, reflected by impaired Overall Behavior (p=.023) and Global Evaluation (p=.032). Analysis of specific traumatic domains revealed that increased childhood physical neglect was associated with functional impairment in Overall Behavior (p<.000), Social Role Performance (p=.037) and Global Evaluation (p=.014). Higher emotional abuse was associated with impaired Overall Behavior (p=.026), and higher emotional neglect with poor Global Evaluation (p=.047). Additionally, earlier onset of illness was associated with lower level of functioning evidenced by impairment in Overall Behavior (p=.042). Linear regression using WHO/DAS sections (Overall Behavior, Social Role Performance and Global Evaluation) as dependent variables and CTQ subscales indicated that only physical neglect had an effect on adult functionality. CONCLUSIONS Childhood trauma was associated with functional and social impairment in adult patients with schizophrenia. Specific types of abuse and neglect, such as physical neglect and emotional abuse and neglect, influenced disability, and the most robust association was physical neglect. Studies involving more patients, with normal controls and additional measurements of biological liability, should be conducted to confirm this association and to increase the understanding of gene-environment relationship in schizophrenia and pathways to disability. PRACTICE IMPLICATIONS Further investigation is warranted to clarify the association between childhood trauma and disability in schizophrenia, as well as to develop standardized instruments for the assessment of trauma and earlier detection of risk along with education of patients and families about adequate care, in an effort to reduce the incidence of disability in schizophrenia.

Serum brain-derived neurotrophic factor and clozapine daily dose in patients with schizophrenia: A positive correlation

Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n=44), on treatment with clozapine (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings.

Elevated serum thiobarbituric acid reactive substances in clinically symptomatic schizophrenic males

Impaired antioxidant defenses are suggested to participate in the pathophysiology of schizophrenia. Altered superoxide dismutase (SOD) and increased lipid peroxidation, measured by the thiobarbituric acid reactive substances (TBARS), are increased in schizophrenia. The aim of this study was to determine the effects of clinical course and subtype on oxidative stress parameters. In this study, 68 male patients, classified according to DSM-IV schizophrenia subtypes and clinical course (partial remission, marked symptoms, and deteriorated), were studied, and TBARS and SOD measured. Mean serum SOD and mean serum TBARS concentrations were similarly not significantly different among different subtypes (paranoid, disorganized and undifferentiated). However, marked symptoms status was associated with higher TBARS levels compared to the deteriorated group. This suggests a possible relationship between symptom acuity and oxidative stress in males.

Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics

Objectives This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia. Methods One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia. Results From the nine studied CYP3A4 single nucleotide polymorphisms, only the −392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the −392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the −392G variant. The CYP3A5 low expressor genotype (CYP3A5*3/CYP3A5*3) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (χ2=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A5*3 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A5*3 homozygotes+non-T/A/G/A/C carriers (χ2=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08–5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms. Conclusion Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia.

Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet

Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia.

Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians

AIMS The delineation of allele distribution and frequency is required to effectively translate pharmacogenetics to the clinic and given the paucity of CYP2D6 data in the Brazilian population, the purpose of this research was to characterize CYP2D6 alleles and genotype frequencies in Brazilians of European and African ancestries. Moreover, since it is suggested in the literature that CYP2D6 poor metabolism might be involved with susceptibility to schizophrenia, we included data from Brazilian schizophrenic patients to verify if CYP2D6 poor metabolism phenotypes are associated with susceptibility to schizophrenia. MATERIALS & METHODS We investigated 24 CYP2D6 polymorphisms, gene deletions and gene multiplications in 179 healthy individuals from Brazil, 92 of European descent and 87 African Brazilians. CYP2D6 gene polymorphisms were genotyped by a MassARRAY SNP genotyping system. RESULTS A total of 19 different alleles and five allele duplications were identified in African and European Brazilians. No significant differences in CYP2D6 allele function or poor metabolizer predicted phenotype frequencies were observed between healthy controls and schizophrenic patients, but the predicted metabolic phenotype distribution showed a significant higher frequency of intermediate metabolizers in African Brazilians than in European Brazilians (p = 0.001). CONCLUSIONS CYP2D6 poor metabolizer genotype seems not to be a determining factor of schizophrenia susceptibility in Brazilians. The characterization of CYP2D6 variability will be very useful for future pharmacogenetic studies in the Brazilian population.