The Impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 Genetic Polymorphisms in Antidepressant Treatment Response Phenotypes.

This 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.

Predictors of poor 6-week outcome in a cohort of major depressive disorder patients treated with antidepressant medication: the role of entrapment.

BACKGROUND: Only a small number of consistent processes predict which depressed patients will achieve remission with antidepressant medication. One set of processes is that of social ranking strategies/variables that are related to life events and severe difficulties. Particularly, defeat and entrapment predict poorer response to antidepressants. However, results are inconsistent. AIM: The current study aimed to evaluate evolutionary strategies, childhood maltreatment, neglect and life events and difficulties (LEDs) as predictors of remission in depressed patients undergoing pharmacological treatment in a psychiatric outpatient sample. METHODS: A cohort of 139 depressed outpatients undergoing pharmacological treatment was followed prospectively in a naturalistic study for 6 weeks. Two major evaluations were considered at baseline and 6 weeks. We allocated patients to a pharmacological treatment algorithm for depression - the Texas Medication Algorithm Project. Variables evaluated at baseline and tested as predictors of remission included demographic and clinical data, severity of depression, social ranking, evolution informed variables, LEDs and childhood maltreatment. RESULTS: Of the 139 patients, only 24.5% were remitted at week 6. In univariate analyses, non-remitted patients scored significantly higher in all psychopathology and vulnerability scales except for submissive behaviour and internal entrapment. For the logistic regression, a higher load of LEDs of the entrapment and humiliation dimension in the year before the index episode (OR = 6.62), and higher levels external entrapment in the Entrapment Scale (OR = 1.10) predicted non-remission. These variables accounted for 28.7% of the variance. CONCLUSIONS: Multivariate analysis revealed that external entrapment was the only predictor of non-remission.

Pets enhance antidepressant pharmacotherapy effects in patients with treatment resistant major depressive disorder.

Treatment resistant major depressive disorder (TR-MDD) is a severe disease, with very low remission rates. The resistance to pharmacotherapy leads to the search of non-pharmacological alternative approaches. Animal therapy has been used in patients with psychiatric conditions and the results have been promising. However, there have been no studies in TR-MDD patients with pet adoption. This study assessed the impact of TR-MDD patients adopting a pet. Eighty patients were suggested to adopt a pet, and 33 accepted the challenge. Other 33 patients constituted the control group (did not accept the suggestion of pet adoption and did not already have a pet). All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline, 4, 8 and 12 weeks for depressive symptoms using HAMD17 and GAF. Results show that the pet group had an improvement in HAMD17 and GAF scores as well as higher response and remission rates compared to the control group, where no patient responded or remitted. Therefore, pets can be used as an effective adjuvant to pharmacotherapy with regular medical appointments.

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

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.

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.

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.

Facebook enhances antidepressant pharmacotherapy effects.

Treatment-resistant major depressive disorder (TR-MDD) is a complex condition, with very low remission rates. In recent years some studies have been conducted on the implementation of cognitive behavioral therapy and psychodynamic psychotherapy interventions via the Internet to MDD patients, and results have been promising. However, there have been no studies in patients with TR-MDD nor with the use of Facebook with the psychiatrist as "friend." 60 TR-MDD patients were randomized to one of three groups: Facebook group with psychiatrist as "friend," Facebook group without psychiatrist as "friend," and control group (no Facebook use). Both Facebook groups spent at least 1 hour/day on Facebook, 7 days/week, during the 3 months. All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline and at 1, 2, and 3 months for depressive symptoms using HAD17 and BDI-II. Results show that both Facebook groups had a decrease on HADM17 and BDI-II scores as well as higher remission and response rates than the control group, with better results if the psychiatrist was a "friend" on Facebook. Therefore, in TR-MDD, Facebook can be used as an effective enhancement therapy, adjuvant to pharmacological therapy with regular consultations, especially if the psychiatrist is the patient's online "friend."

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.

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.

Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder.

BACKGROUND: Treatment-resistant major depressive disorder (MDD) is a complex condition, with very low remission rates. Physical exercise has been used, with some encouraging results, as an alternative therapy in other depressive disorders. This study assessed the impact on depression and functioning parameters of a moderate intensity exercise program, as an adjuvant to pharmacotherapy, in treatment-resistant MDD patients. METHODS: 150 individuals with treatment-resistant MDD, defined as taking combined therapy in doses considered adequate for 9-15 months, without showing clinical remission, were initially screened. 33 were randomized to one of two groups: usual pharmacotherapy (N = 11) and usual pharmacotherapy plus aerobic exercise (N = 22). The exercise program consisted of home-based 30-45 min/day walks, 5 days/week, for 12 weeks, being 1 walk per week supervised. RESULTS: The exercise group showed improvement of all depression and functioning parameters, as indicated by lower HAMD17, BDI and CGI-S and higher GAF (p < 0.05) at last observation compared both to baseline values and to control group. At the end of the study none of the participants in the control group showed response or remission, whilst in the exercise group 21% of participants showed response and 26% remission, although these differences were not statistically significant. CONCLUSION: A 12 week, home-based exercise program of 30-45 min/day walks, 5 days/week, improved depression and functioning parameters in treatment-resistant MDD patients, and contributed to remission of 26% of these patients. Moderate intensity exercise may be a helpful and effective adjuvant therapy for treatment-resistant MDD.