Jorge Mota-Pereira

Entrapment and Defeat Perceptions in Depressive Symptomatology: Through an Evolutionary Approach.

The social rank and arrested defenses model for mood disorders bridges between animal and human models of psychopathology. There is increasing evidence that depression is associated with subordinated and loss of social rank, feeling inferior, shame, submissive behavior, and feeling defeated. These stressful states activate threat coping responses of fight and flight. If these are aroused but blocked, feelings of entrapment emerge with a negative impact on mood. The current study builds on previous studies and explores the association between depressive symptoms, social rank variables (of social comparison and submissive behavior), entrapment, and defeat in a sample of patients (n = 106) with major depression and in a sample of healthy controls (n = 116). Results showed that social rank variables, entrapment, and defeat were strongly associated with depressive symptoms in both samples. Entrapment and defeat showed significant association with other social rank variables. Logistic regression analysis revealed that defeat and internal entrapment were significant predictors of the belonging to the clinical or control groups. The present study extends previous research and supports the importance of defeat and external entrapment in clinical depression.

Common genetic polymorphisms in the ABCB1 gene are associated with risk of major depressive disorder in male Portuguese individuals.

Major 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.

FAS -670A>G genetic polymorphism Is associated with Treatment Resistant Depression.

BACKGROUND Hippocampal 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. METHODS 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. RESULTS 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. LIMITATIONS Small sample size. Patients used antidepressants with different mechanisms of action. CONCLUSION 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.

The role of IL18-607C > A and IL18-137G > C promoter polymorphisms in antidepressant treatment phenotypes: A preliminary report

Recent studies suggest that immune activation and cytokines, such as IL-18, are involved in depression. IL-18 is expressed in brain and is increased in patients with moderate to severe depression. In this study we aim to evaluate the role of IL18-607C>A and IL18-137G>C promoter polymorphisms in antidepressant treatment phenotypes, specifically relapse and treatment resistant depression (TRD). We genotyped the referred polymorphisms in a subset of 80 MDD patients followed at Hospital Magalhães Lemos, Portugal, within a period of 27 months. Patients carrying IL18-607 CA or AA genotypes were significantly more prone to relapse after AD treatment and present a significantly lower time to relapse than patients carrying CC genotype. Similarly, patients carrying IL18-137 GC or CC genotypes have a significantly higher risk of relapse and display relapse significantly earlier than the ones carrying GG genotype. Due to the low number of IL18-607 CC and IL18-137 GG in the relapse subgroup (n=3 and n=5, respectively), results were validated by bootstrapping analysis, and remained significant. No association was found between the evaluated genetic polymorphisms and TRD. IL18 peripheral mRNA levels were upregulated in IL18-607 CA or AA carriers. This preliminary report indicates that IL18-607C>A and IL18-137G>C genetic polymorphisms seem to influence depression relapse after antidepressant treatment in our subset of depressed patients, and may possibly contribute to the disregulated IL-18 levels found in patients with depression.

IL6-174G > C genetic polymorphism influences antidepressant treatment outcome

Abstract Background: Major 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. Objectives: This study aims to evaluate the role of IL6-174G > C and IL6R D358A A > C functional polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse, and treatment resistant depression (TRD). Methods: The referred polymorphisms were genotyped in 80 MDD patients followed at Hospital Magalhães Lemos, Portugal, within a period of 27 months. Results: It was found that patients carrying IL6-174 GC genotype present a protection towards the development of TRD (OR = 0.242; 95% CI = 0.068–0.869; p = .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 = .030, Log-rank test). No association was found between IL6R D358A genetic polymorphism and any of the treatment phenotypes evaluated. Conclusions: 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 Il-18 Genetic Polymorphisms in Antidepressant Treatment Phenotypes

Introduction Recent studies suggested that immune activation and cytokines might be involved in depression. The proinflammatory cytokine interleukin-18 (IL-18) is less reported in depression but is still relevant since it is expressed in the brain and serum levels of IL-18 have been found to be increased in patients with moderate to severe depression. Therefore, it seems reasonable that IL-18 promoter SNPs may have an effect in antidepressant response phenotypes. Objectives We aim to evaluate the role of IL18-607C>A and IL18-137G>Cpromoter polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse and treatment resistant depression (TRD). Methods We genotyped the referredpolymorphisms in a subset of 80 MDD patients followed at Hospital Magalhaes Lemos, Portugal, within a period of 27 months. Results We found that patients carrying IL18-607CA or AA genotypes are more prone to relapse after AD treatment (OR=4.145; 95%CI: [1.038-16.555]; p=0.043) and present a lower time to relapse than patients carrying CC genotype (69 vs 115 weeks, p=0.019, Log-rank test). We also observed that patients carrying IL18-137GC or CC genotypes have a higher risk of relapse (OR=3.988; 95%CI: [1.176-13.516]; p=0.022) and display relapse earlier than the ones carrying GG genotype (64 vs 112 weeks, p=0.006, Log-rank test). No association was found between the evaluated genetic polymorphisms and remission or TRD. Conclusions The IL18-607A>C and IL18-137G>Cpolymorphisms seems to influence relapse after antidepressant treatment in our subset of depressed patients. These polymorphisms may possibly contribute to the elevated IL-18 levels found in patients with moderate to severe depression.

EPA-1313 - Influence of il6-174g>c, il6-6331t>c and il6r d358a a>c il-6 genetic polymorphisms in antidepressant treatment phenotypes

Introduction Several 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. Objectives We aim to evaluate the role of IL6-174G>C, IL6-6331T>C and IL6R D358A A>C functional polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse and TRD. Methods We genotyped the referred polymorphisms in a subset of 80 MDD patients followed at Hospital Magalhaes Lemos, Portugal, within a period of 18 months. Results We found that patients carrying IL6-174 GG genotype are more prone to develop TRD (OR=4.125; 95%CI: [1.151-14.786]; p=0.038). We also observed that patients carrying IL6-6331 TC genotype have a higher risk of relapse (OR=3.988; 95%CI: [1.176-13.516]; p=0.022), and present a lower time to relapse, TC: 26 weeks vs. TT: 45 weeks (p=0.041, Log-rank test). No association was found between IL6R D358A genetic polymorphism and any of treatment phenotypes. Conclusions The IL6-174G>C and IL6-6331T>C polymorphisms influence antidepressant treatment response in our subset of MDD patients. These polymorphisms may possibly contribute to the elevated IL-6 levels found in patients with TRD. This research was partially supported by an AstraZeneca Grant