Browsing by Subject "depression"

Tiivistelmä – Referat – Abstract Mental disorders are among the leading causes of global disease burden and years lived with disability. Their pathogenesis is poorly understood and there are enormous challenges in the development of biomarkers to aid in diagnosis and more effective therapeutic options. It has been documented that the microbiota-gut-brain axis shows alterations in mental disorders such as anxiety, depression, autism spectrum disorders, bipolar disorder and schizophrenia. Here we study the gut microbiota of individuals with axis I mental disorders and their unaffected siblings by 16S RNA gene amplicon sequencing. In the Central Valley of Costa Rica, a total of 37 participants were recruited and diagnosed using a Best Estimate Diagnosis protocol. For each of the individuals diagnosed with a mental disorder a healthy sibling was selected after matching by age and gender. A total of 13 pairs of 26 siblings, affected and unaffected, was used for the analysis. In a subsequent analysis, individuals were also divided into the three categories of “unaffected” (UA), “affected without psychosis” (AA) and “affected with psychosis” (AP). They underwent clinical assessments about their habits and diet and about resilience (Connor-Davidson Resilience Scale), current status (SADS-C) and disability (WHODAS 2.0). Their fecal samples were collected freshly and stored at -80°C. DNA was extracted, libraries constructed by PCR and subjected for Illumina MiSeq 300 paired-end 16S RNA amplicon sequencing for analysis of the gut microbiota. The sequencing data were analyzed using the R packages mare and vegan for gut microbiota composition, diversity and richness, taking into account the identified confounders. All participants were of Hispanic ethnicity, residents of the San José Greater Metropolitan Area, adults and 69% of them were women. Affected individuals had major depression, bipolar affective disorder, psychosis non-otherwise specified or schizoaffective disorder. Based on beta-diversity analysis as a measure of the community-level microbiota variation, it was found that the use of levothyroxine (R2=0.08, p=0.005) and of irbesartan (R2=0.068 ,p=0.001) had a significant impact on the microbiota composition and hence the use of these drugs was included as confounder in further analyses. Several statistically significant differences in the relative abundance of intestinal bacteria were identified: Differences were found in the relative abundance of bacterial families Peptostreptococcaceae, Ruminococcaceae, Porphyromonadaceae, and in bacterial genera Pseudomonas, Barnesiella, Odoribacter, Paludibacter, Lactococcus, Clostridium, Acidaminococcus and Haemophilus. Our results indicate that affected individuals have more pro-inflammatory Proteobacteria (Pseudomonas) and less bacteria associated to healthy phenotype, such as Barnesiella and Ruminococcaceae, the former being dose-dependently depleted in AP and AA compared to UA. Furthermore, we documented decreased bacterial richness among affected participants while no significant differences were detected in alpha diversity. Our study identified significant differences in the microbiota of individuals affected by mental illness when comparing to their healthy siblings. The results may have important implications for the holistic understanding of mental health and its diagnosis and therapeutics. Larger studies to confirm these findings would be justified.

While weeks of continuous treatment is required for conventional antidepressant drugs (e.g. fluoxetine) to bring their full therapeutic effects, a subanesthetic dose of ketamine alleviates the core symptoms of depression (anhedonia, depressed mood) and suicidal thinking within just few hours and the effects may last for days. Nitrous oxide (N2O, “laughing gas”), another NMDAR antagonist, has recently been shown to have similar rapid antidepressant effects in treatment-resistant depressed patients (Nagele et al. 2015). We previously found using naïve mice ketamine and N2O treatment to upregulate five mRNAs related to the MAPK pathway and synaptic plasticity, both implicated as being important in the action of rapid-acting antidepressants. In the current study, these shared mechanisms were further investigated in C57BL/6JHsd mice, using behavioral test batteries to study depressive-like behaviour and RT-qPCR for biochemical analyses. We first aimed to demonstrate behavioral differences between naïve mice and a chronic corticosterone-induced animal model of depression, and to use this model to investigate antidepressant-like effects of ketamine and N2O. According to the results, chronic corticosterone produced some behaviors typical of a depressive-like phenotype, namely significant worsening of coat state and decreased saccharin consumption in the saccharin preference test. Both ketamine and N2O exhibited antidepressant-like effects by reverting decreased saccharin preference. We then aimed to elucidate the effects of ketamine and N2O on five previously found shared mRNAs: Arc, Dusp1, Dusp5, Dusp6 and Nr4a1. N2O significantly upregulated all targets in the vmPFC, except Dusp5, two hours after beginning of N2O treatment. Neither ketamine nor sole chronic corticosterone produced any significant changes. The results of this study suggest that N2O is a potential candidate for rapid alleviation of depressive symptoms. We suggest that the action of rapid-acting antidepressants, more specifically N2O, is based on a homeostatic response of the brain to a presented challenge. Here this challenge would be cortical excitation previously been shown to be caused by N2O, which leads to activation of pathways such as MAPK and subsequent Arc, Dusp and Nr4a1 signaling. The level of expression of these markers would then depend on which phase this response is in and hence, the differences in time between treatment and brain sample dissection could be a reason for conflicting results to previous research. Future studies would benefit from detailed investigation of the chronic corticosterone-induced model due to its potential in controlling for behavioral variability, thus reducing the number of animals needed for preclinical research. Overall the preliminary findings of this study could be one of the first steps in the search for the mechanisms underlying the potential antidepressant effect of N2O, how these molecular markers are related to its action and how it differs from the action of ketamine.