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Background: Supplementation of omega-3 fatty acids has shown efficacy to prevent conversion to schizophrenia in ultra-high risk population. In this study we evaluated the efficacy of omega-3 in preventing ketamine-induced effects in an animal model of schizophrenia and its effect on BDNF serum levels. Methods: Forty-eight Wistar male rats were included. Twenty-four received 0.8g/kg omega-3 and 24 tween, both groups at the 30Th day of life for 15 days. Each group was split in two 12-animals groups to receive along the following 7 days 25 mg/kg of ketamine or saline intra-peritoneal. The total treatment period was 22 days. Locomotor and exploratory activity (open-field task), memory test (inhibitory avoidance test) and social interaction between pairs (latency time to first contact, number and time of contacts) were evaluated at the 52nd day of life. Bloods for BDNF were withdrawal at the 53rd day of life. Results: Social interactions were decreased in time and number of contacts, and latency time to first contact was increased in ketamine group. Ketamine increased covered distances in 5, 10 and 15 minutes. Ketamine+omega-3 were not different than controls and omega-3 alone in 10 and 15 minutes. On the inhibitory avoidance memory test, omega-3 has prevented ketamine-induced impairment on working, short and late memories. BDNF levels were higher in ketamine+omega-3 group (p=0.009). Conclusions: Omega-3, in a ketamine-induced model of schizophrenia, prevents in adolescents Wistar male rats the equivalent in humans of positive, negative and, cognitive symptoms of schizophrenia. Moreover it increases BDNF in prevention treatment of ketamine effects.

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.

clinicaltrials.gov Identifier: NCT00757978.

Schizophrenia (SCZ) is a mental disorder arising from a complex interaction of genetic and environmental factors. It has been suggested that treatment-resistant schizophrenia (TRS) is a distinct, more severe, and homogenous subgroup of schizophrenia that could present specific biological markers. Our aim was to characterize expression of target genes in blood of TRS patients compared with non-TRS (NTRS) patients and healthy controls (HC). TRS has been defined using failure to respond to two previous antipsychotic trials. We hypothesized that genes involved in neurodevelopment, myelination, neuroplasticity, neurotransmission, and miRNA processing could be involved in treatment resistance; then, we investigated 13 genes related to those processes in 256 subjects, being 94 healthy controls and 162 schizophrenia patients treated with antipsychotics. Of those, 78 were TRS patients and 84 were NTRS patients. Peripheral blood samples were collected from all subjects and RNA was isolated. Gene expression analysis was performed using the TaqMan low-density array (TLDA) technology. To verify the influence of expression quantitative trait loci (eQTLs), we evaluated single-nucleotide polymorphism (SNP) of all genes using data from GTEx Project. SNP genotypes were obtained from HumanOmniExpress BeadChip. We did not detect gene expression differences between TRS and NTRS subjects, indicating candidate genes specific to treatment resistance. We detected an upregulation of CNR1 and UFD1L gene expression in patients (TRS and NTRS groups) when compared to controls, that may be associated with the release of neurotransmitters, which can influence neuronal plasticity, or with a stress response-activating protein degradation. DICER1 and AKT1 expression increased slightly across the groups and could differentiate only the extreme opposite groups, HC and TRS. Both genes act in heterogeneous pathways, such as cell signaling and miRNA processing, and seem to have an increased demand in the TRS group. We did not detect any eQTLs in our sample that could explain differences in mRNA levels, suggesting a possible regulation by other mechanism, not driven by genotypes. Our data strengthen the importance of several biological pathways involved in the schizophrenia refractoriness and severity, adding knowledge to develop more effective treatments in the future.

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AbstractMajor depressive disorder (MDD) and bipolar disorder (BD) are among the leading causes of burden and disability worldwide. Despite intensified research efforts to improve the treatment options and remission rates in mood disorders, no disease modifying treatment exists for these disorders. Accumulating evidence implicates the involvement of the gut microbiota in processes relevant to etiopathology of central nervous system-based disorders. The objective of this article was to critically evaluate the evidence supporting the link between gastrointestinal microbiota and mood disorders and to discuss the potential benefits of using probiotics in the treatment of MDD and BD. The concept of psychobiotics, which is bacterial-based interventions with mental health benefit, is emerging in the field. On the other hand, while probiotics might potentially represent a significant advance, specific roles of microbiota in the pathophysiology of mood disorders still need further investigation along with intervention studies.

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