ABCB1 C1236T, G2677TA and C3435T Genetic Polymorphisms and Antidepressant Response Phenotypes: Results from a Portuguese Major Depressive Disorder Cohort.

P-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.

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.

Attachment Style and Insight in Schizophrenia: a Cross-Sectional Study.

Attachment theory provides a model for understanding impairments in social and interpersonal functioning. Schizophrenia is a neuropsychiatry disorder frequently associated with compromised social functioning and limited social support networks. However, the relationship between attachment style and psychopathology dimensions, including insight, isn't fully understood To determine whether there is a relationship between the attachment style and markers for severity of schizophrenia and insight. We conducted a cross-sectional study of 41 patients with schizophrenia and 34 patients with non-psychotic disorders used as a control group. Patients were assessed using semi-structured diagnostic interviews and self-reporting questionnaires, including Adult Attachment Scale-Revised. The schizophrenia group was also given the Positive and Negative Syndrome Scale and the Markova and Berrios Insight Scale. Insecure attachment was overrepresented in the schizophrenic group, and this difference was mainly accounted for lower levels of dependence, representing a moderate effect size (Cohen's d = 0.32). In the schizophrenia group, the closeness and the dependence subscale were negatively correlated with psychopathology severity. Using a multiple regression analysis, the insight was predicted by attachment anxiety, accounting for 20% of the total variance (R2 = 0.199, p <0.05). Our data confirm previous evidence that insecure attachment is associated with schizophrenia and suggest that the less comfortable the patient is with closeness and intimacy the greater the severity of symptoms. Furthermore, our findings indicate that higher separation anxiety might predict a better insight.

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.

Treatment-Resistant Depression in Portugal: Perspective From Psychiatry Experts.

Guidance about treatment-resistant depression (TRD) in Portugal is very limited, even though depression prevalence is among the highest in European countries. A questionnaire was conducted, followed by two advisory boards with seven Portuguese psychiatry experts, to characterize and discuss MDD and TRD epidemiology, diagnosis, patient journey, treatment options, and unmet clinical needs. Consensus was reached on the main issues. In daily practice, TRD can be defined as moderate to severe MDD episodes with insufficient clinical improvement after two antidepressant treatments, taken in adequate doses and duration. TRD diagnosis and treatment are mostly decided by psychiatrists at public hospitals. Treatment type and duration must be adjusted to characteristics of the patient and the depressive episode, including symptoms, number of previous episodes, comorbidities, and previous treatment response and side effects. The most relevant objectives of TRD treatment are reaching response and remission, prevention of suicide, and improvement of quality of life, functionality, and wellbeing. Regarding pharmacotherapy, antidepressant switch occurs more frequently with non-response, while optimization, combination, and augmentation are considered for patients with partial response. Psychotherapy should be considered in parallel to pharmacological treatment. Brain stimulation techniques are underused. Lifelong treatment is required for recurrent or more chronic TRD episodes, but patient adherence is also poorer in these cases. In Portugal, TRD management is limited by lack of access to specialist care and to many treatment options. These aspects highlight that conventional pharmacotherapy does not lead to remission in many patients and that optimization strategies are frequently necessary to achieve satisfactory treatment outcomes.

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.

Consultation-Liaison Psychiatry Literature Database (2003 update). Part I: Consultation - Liaison Literature Database: 2003 update and national lists.

Every day there are 10,000 scientific articles published. Since the Consultation-Liaison ("C-L") psychiatrist may be asked to consult on a patient with any medical illness, e.g., severe acute respiratory syndrome (SARS), malaria, cancer, stroke, amytrophic, lateral sclerosis, and a patient who may be on any medical drug, methods need to be developed to review the recent literature and have an awareness of key and essential current findings. At the same time, teachers need to develop a current listing of seminal papers for trainees and practitioners of this newest cross-over subspecialty of psychiatry-now called Psychosomatic Medicine. Experts selected because of their writings and acknowledged contributions to a specific clinical area or problem hope examined thousands of citations to choose those articles, chapters, books, or letters that they regard as most important to Psychosomatic Medicine. In addition, psychiatric specialists in six countries have provided their national Psychosomatic Medicine (Consultation-Liaison) lists as examples of what they regard as the most important teaching materials journals: Australia, Brazil, Greece, Mexico, Portugal, and Taiwan. It is our belief that a cogent, international, systematic review will provide the greatest success in creating a "regionally appropriate" teaching and consultation literature database with world-wide applicability. We review our current progress on this literature database and software, the technical system and data organization involved, the approach used to populate the literature system, and ongoing development plans to bring this system to the physician via mobile technologies.

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.

Psychiatry training towards a global future: trainees' perspective in Portugal.

INTRODUCTION: Psychiatry is influenced by society changes, so it should be permanently updating itself, foreseeing future behaviours and pathologies. This study aims to describe psychiatry trainee's opinion in Portugal concerning their training and the modifications they would want to witness in the near future. MATERIAL AND METHODS: A structured questionnaire of 26 questions was developed by the Portuguese Association of Psychiatry Trainees and sent via email. RESULTS: The percentage of responses was 41.5%. The majority of the trainees were satisfied with their formation. However, some changes were pointed out concerning obligatory and optional placements. Most trainees claimed psychotherapy should be included in their training, along with an easier access to investigational procedures and clinical training opportunities abroad. DISCUSSION AND CONCLUSION: This detailed perspective can facilitate the transformation of the curricula throughout Portugal and Europe, allowing the improvement of psychiatry training, as well as the enhancement of mental health care.

Introdução: A psiquiatria é influenciada pelas mudanças que ocorrem na sociedade, devendo estar em constante renovação, antevendo futuros comportamentos e doenças. Este estudo pretende descrever a opinião dos internos de psiquiatria em Portugal relativamente ao seu internato e às modificações que nele gostariam de assistir no futuro próximo.Material e Métodos: Um questionário estruturado de 26 perguntas foi desenvolvido pela Associação Portuguesa de Internos de Psiquiatria e enviado por email.Resultados: A percentagem de respostas obtidas foi de 41,5%. A maioria dos internos estava satisfeita com a sua formação. Contudo, algumas mudanças foram sugeridas no que diz respeitos aos estágios obrigatórios e opcionais. A maior parte dos internos requer que as psicoterapias sejam incluídas no âmbito do internato, solicitando também um acesso mais fácil à investigação e a oportunidades de estágio no estrangeiro.Discussão e Conclusão: Esta perspectiva detalhada pode facilitar a transformação dos currículos do internato em Portugal e naEuropa, permitindo a melhoria do internato de psiquiatria, bem como dos cuidados de saúde mental.

[Drug induced movement disorders: role of antipsychotic drugs]. / Doenças do movimento induzidas por fármacos: a importância dos psicofármacos.

This article reviews the current knowledge on drug-induced movement disorders (DIMD) epidemiology, pathophysiology, phenomenology and treatment. This review is justified by its high prevalence in certain medical specialties, the need to include them on movement disorders etiologic differential diagnosis and the potential economical burden. The acronym DIMD refers to a heterogeneous group of neurological syndromes, the most prevalent being parkinsonism, dystonia, dyskinesia and akathisia. Soon after neuroleptics (D2 dopamine receptor blocking agents) introduction in clinical practice, the first acute dystonic reactions were reported. Later, was recognized that extrapyramidal symptoms could occur in association with their chronic use. Nowadays, several non dopamine receptor blocking drugs and drugs of abuse are recognized as potential inductors of extrapyramidal reactions.

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.

[Evolutionary medicine: the future looking at the past]. / Medicina evolucionária: o futuro olhando o pasado.

Evolutionary medicine is an emergent basic science that offers new and varied perspectives to the comprehension of the human health and disease, considering them as a result of a gap between our modern lives and the environment where human beings evolve. This work's goals are to understand the importance of the evolutionary theories on concepts of health and disease, providing a new insight on medicine investigation. This bibliography review is based on Medline and PsycINFO articles research between 1996 and 2007 about review and experimental studies published in English, using the key words evolutionary and medicine, psychiatry, psychology, behaviour, health, disease, gene. There were selected forty-five articles based on and with special interest on the authors' practice. There were also consulted some allusive books. The present human genome and phenotypes are essentially Palaeolithic ones: they are not adapted to the modern life style, thus favouring the so called diseases of civilization. Fitting evolutionary strategies, apparently protective ones, when excessive, are the core syndromes of many emotional disruptive behaviours and diseases. Having the stone age's genes, we are obliged to live in the space age. With the evolutionary approach, postmodern medicine is detecting better the vulnerabilities, restrictions, biases, adaptations and maladaptations of human body, its actual diseases and its preventions and treatment.