Browsing by Author "Carvalho, Serafim"
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- ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms and antidepressant response phenotypes: results from a portuguese major depressive disorder cohortPublication . Santos, Marlene; Lima, Luís; Carvalho, Serafim; Brandão, Andreia; Barroso, Fátima; Cruz, Agostinho; Medeiros, RuiP-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood–Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.
- Bdnf-NRF2 crosstalk in depression disorderPublication . Santos, Marlene; Caldevilla, Renato; Morais, Stephanie; Carvalho, Serafim; Medeiros, Rui; Barroso, Maria FátimaThe World Health Organization estimates that major depressive disorder (MDD) affects over 264 million individuals globally, posing a significant public health challenge. Treatment-resistant depression (TRD) represents a severe form of MDD with poor treatment outcomes. Genetic variations are known to impact MDD treatment responses, yet genome-wide association studies have struggled to identify consistent marker alleles. Previous research has linked the Brain Derived Neurotrophic Factor (BDNF) genetic polymorphism with TRD. BDNF is essential for neuronal survival and neuroplasticity, processes influenced by antidepressant treatment, and regulated by transcription factors like Nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 regulates antioxidant and anti-inflammatory responses and plays a crucial role in depression pathogenesis. NRF2 knockout mice exhibit reduced BDNF levels and depression-like behaviors, indicating that NRF2activation enhances BDNF expression and antidepressant efficacy. The BDNF rs6265 (Val66Met) polymorphism is associated with variations in antidepressant response rates. Research suggests that the interaction between BDNF and NRF2 pathways could enhance antidepressant effectiveness. NRF2 activation, such as through the compound sulforaphane, has demonstrated rapid antidepressant effects by increasing BDNF expression. Lower levels of NRF2 and BDNF are observed in stress-induced depression models, and ketamine treatment influences NRF2-related genes. Simultaneously, there is a growing need for efficient genotyping methods, and genosensors offer a promising solution. This presentation will address the interplay between BDNF and NRF2 in depression, explore its relationship in antidepressant response, and present a putative genosensor for BDNF rs6265 (Val66Met) polymorphism identification, improving antidepressant treatment outcome.
- Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individualsPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Nogueira, Augusto; Assis, Joana; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiMajor depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus–pituitary–adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR) = 0.360, 95% confidence interval [CI]: [0.140– 0.950], p = 0.022; C3435T: OR= 0.306, 95% CI: [0.096–0.980], p = 0.042; and G2677TA: OR= 0.300, 95% CI: [0.100– 0.870], p = 0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR = 0.313, 95% CI: [0.118–0.832], p = 0.016, FDR p = 0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.
- Design of an electrochemical genosensor for the BDNF gene polymorphism sequence detection using an enzymatic labelled DNA probePublication . Caldevilla, Renato; Morais, Stephanie; Carvalho, Serafim; Medeiros, Rui; Delerue-Matos, Cristina; Cruz, Agostinho; Santos, Marlene; Barroso, M. FátimaThe BDNF gene is associated with high degrees of variability in antidepressant treatments. The Val66Met polymorphism is widely known as a source of this variability, warranting growing interest in genotyping patients that undergo antidepressant treatment to better suit their needs. This paper reports on an electrochemical genosensing platform, based on gold electrodes, capable of detecting this polymorphism, through the use of synthetic enzymatic labelled DNA-probes for 2 different BDNF alleles. The sensor showed promising results, and its applicability to real samples is currently being tested.
- FAS -670A>G genetic polymorphism Is associated with treatment resistant depressionPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiHippocampal neurogenesis has been suggested as a downstream event of antidepressants (AD) mechanism of action and might explain the lag time between AD administration and the therapeutic effect. Despite the widespread use of AD in the context of Major Depressive Disorder (MDD) there are no reliable biomarkers of treatment response phenotypes, and a significant proportion of patients display Treatment Resistant Depression (TRD). Fas/FasL system is one of the best-known death-receptor mediated cell signaling systems and is recognized to regulate cell proliferation and tumor cell growth. Recently this pathway has been described to be involved in neurogenesis and neuroplasticity. Since FAS -670A>G and FASL -844T>C functional polymorphisms never been evaluated in the context of depression and antidepressant therapy, we genotyped FAS -670A>G and FASL -844T>C in a subset of 80 MDD patients to evaluate their role in antidepressant treatment response phenotypes. We found that the presence of FAS -670G allele was associated with antidepressant bad prognosis (relapse or TRD: OR=6.200; 95% CI: [1.875–20.499]; p=0.001), and we observed that patients carrying this allele have a higher risk to develop TRD (OR=10.895; 95% CI: [1.362–87.135]; p=0.008). Moreover, multivariate analysis adjusted to potentials confounders showed that patients carrying G allele have higher risk of early relapse (HR=3.827; 95% CI: [1.072–13.659]; p=0.039). FAS mRNA levels were down-regulated among G carriers, whose genotypes were more common in TRD patients. No association was found between FASL-844T>C genetic polymorphism and any treatment phenotypes. Small sample size. Patients used antidepressants with different mechanisms of action. To the best of our knowledge this is the first study to evaluate the role of FAS functional polymorphism in the outcome of antidepressant therapy. This preliminary report associates FAS -670A>G genetic polymorphism with Treatment Resistant Depression and with time to relapse. The current results may possibly be given to the recent recognized role of Fas in neurogenesis and/or neuroplasticity.
- IL6-174G > C genetic polymorphism influences antidepressant treatment outcomePublication . Carvalho, Serafim; Santos, Marlene; Lima, Luís; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiMajor depressive disorder is a condition associated with dysregulated cytokine levels; among these, IL6. Furthermore, genetic variations within cytokine genes have been proposed to predict antidepressant treatment outcome. This study aims to evaluate the role of IL6-174G > C and IL6R D358A A > C functional poly-morphisms in antidepressant treatment phenotypes, specifically remission, relapse, and treatment resistant depression (TRD). The referred polymorphisms were genotyped in 80 MDD patients followed at Hospital Magalh~aes Lemos, Portugal, within a period of 27 months. It was found that patients carrying IL6-174 GC genotype present a protection towards the development of TRD (OR ¼ 0.242; 95% CI ¼ 0.068–0.869; p ¼ .038), when compared with GG genotype. Additionally, carriers of IL6-174 CC genotype remit earlier than patients with IL6-174 GG/GC genotypes, with a median time to remission of 6 weeks for CC carriers and 15 weeks for GG or GC carriers (p ¼ .030, Log-rank test). No association was found between IL6R D358A genetic polymorphism and any of the treatment phenotypes evaluated. The IL6-174G > C polymorphism influences antidepressant treatment outcome in this sub-set of MDD patients, providing a putative mechanistic link for the dysregulated IL-6 levels described in the literature in patients with TRD.
- Influence of common ABCB1 genetic polymorphisms in the risk of Major Depressive Desorder and ntidepressant treatment phenotypesPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Nogueira, Augusto; Assis, Joana; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiMajor depressive Disorder (MDD) is a highly prevalent disorder, which has been associated with na abnormal response of hypothalamus-pituitary-adrenal (HPA) axis.
- Influence of il6-174g>c, il6-6331t>c and il6r d358a a>c il-6 genetic polymorphisms in antidepressant treatment phenotypesPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiSeveral studies associated Major Depressive Disorder (MDD) with an increased production of pro-inflammatory cytokines, such as interleukin 6 (IL-6). Serum IL-6 levels were found to be significantly increased in subjects with MDD and with Treatment Resistant Depression (TRD). Moreover, ketamine, a drug with fast-acting antidepressant properties, has proven to reduce IL-6 levels in rat prefrontal cortex and hippocampus. However, despite the clear influence of IL-6 in the pathophysiology of depression and in antidepressant response, studies evaluating the impact of IL-6 functional genetic polymorphisms on treatment response phenotypes are scarce.
- Role of pharmacogenomics in predicting antidepressant response and individualizing therapyPublication . Santos, Marlene; Carvalho, Serafim; Lima, Luís; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiMajor Depressive Disorder (MDD) is a highly prevalent chronic psychiatric condition with significant morbidity. Despite several antidepressants drugs (AD) available, a wide fraction of patients fail to respond, present relapse or display treatment resistant depression (TRD). Pharmacogenomics could help identify patients at risk of relapse or TRD and possibly have a direct impact on personalizing therapy. Additionally, recent studies suggested that immune activation and cytokines may be involved in depression, and its normalization occurs after antidepressant treatment. The proinflammatory cytokines interleukin-18 (IL-18) and IL-6 are less reported in depression, but considered to be relevant since they have been found to be increased in patients with depression.
- The impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 genetic polymorphisms in antidepressant treatment response phenotypesPublication . Santos, Marlene; Lima, Luis; Carvalho, Serafim; Mota-Pereira, Jorge; Pimentel, Paulo; Maia, Dulce; Correia, Diana; Barroso, M. Fátima; Gomes, Sofia; Cruz, Agostinho; Medeiros, RuiThis study aimed to investigate the influence of genetic variants in neuroplasticity-related genes on antidepressant treatment phenotypes. The BDNF-TrkB signaling pathway, as well as the downstream kinases Akt and ERK and the mTOR pathway, have been implicated in depression and neuroplasticity. However, clinicians still struggle with the unpredictability of antidepressant responses in depressed patients. We genotyped 26 polymorphisms in BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 in 80 patients with major depressive disorder treated according to the Texas Medical Algorithm for 27 months at Hospital Magalhães Lemos, Porto, Portugal. Our results showed that BDNF rs6265, PTEN rs12569998, and SYN1 rs1142636 SNP were associated with treatment-resistant depression (TRD). Additionally, MAPK1 rs6928 and GSK3B rs6438552 gene polymorphisms were associated with relapse. Moreover, we found a link between the rs6928 MAPK1 polymorphism and time to relapse. These findings suggest that the BDNF, PTEN, and SYN1 genes may play a role in the development of TRD, while MAPK1 and GSK3B may be associated with relapse. GO analysis revealed enrichment in synaptic and trans-synaptic transmission pathways and glutamate receptor activity with TRD-associated genes. Genetic variants in these genes could potentially be incorporated into predictive models of antidepressant response.