Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

Mundo de Pólus serious game for people with bipolar disorder.

BACKGROUND: Serious games are play-based technologies designed to teach users a wide range of concepts and skills applicable in the non-virtual environment. OBJECTIVES: This paper describes the process of developing a serious game for people with bipolar disorder to promote symptom recognition and the safe use of medications. METHODS: This study was based on the User-Centered Design methodological model and the theoretical framework for Participatory Design. We conducted interviews with health professionals and discussion circles with people with bipolar disorder and their family members in order to identify the learning needs related to symptom recognition and safe medication use. A categorical analysis was completed of the participants' reports and the scientific literature and formed the basis for the design of Mundo de Pólus. RESULTS: The game development process had three pillars (detailed in this manuscript): missions, simulation, and journal. The serious game focuses on the users' perceptions about their experience with the disorder, their interpersonal relationships, coping strategies, use of medications, and non-pharmacological treatments. CONCLUSIONS: These scientific and technological outcomes are useful to promote literacy and safety in medication therapy for people with bipolar disorder.

The Association of Biochemical and Genetic Biomarkers in VEGF Pathway with Depression.

VEGF is an important neurotrophic and vascular factor involved in mental disorders. The objective of this study was to verify the effect of genetic polymorphisms in the VEGF pathway on the risk for depression, symptom intensity, and suicide attempts. To examine the association between the VEGF pathway and depression, we genotyped polymorphisms and measured the plasma concentrations of VEGF, KDR, and FLT1 proteins. The participants were 160 patients with depression and 114 healthy controls. The questionnaires that assessed the clinical profile of the patients were the MINI-International Neuropsychiatric Interview, GRID-HAMD21, CTQ, BSI, and the number of suicide attempts. Genotyping of participants was performed using the real-time PCR and protein measurements were performed using the enzyme-linked immunosorbent assay (ELISA). VEGF and its inhibitors were reduced in depression. Individuals with depression and displaying the homozygous AA of the rs699947 polymorphism had higher plasma concentrations of VEGF (p-value = 0.006) and were associated with a greater number of suicide attempts (p-value = 0.041). Individuals with depression that were homozygous for the G allele of the FLT1 polymorphism rs7993418 were associated with lower symptom severity (p-value = 0.040). Our results suggest that VEGF pathway polymorphisms are associated with the number of suicide attempts and the severity of depressive symptoms.

Evaluation of the HPA Axis' Response to Pharmacological Challenges in Experimental and Clinical Early-Life Stress-Associated Depression.

Early-life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (PND)1 to PND21. On PND65 animals were behaviorally evaluated through the forced-swimming test (FST). At PND68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone, or fludrocortisone, and corticosterone levels were determined 3 h after injections. Cortisol response of the patients did not differ significantly from healthy subjects, regardless of their ELS history, and it was lower after fludrocortisone, prednisolone, and dexamethasone compared with placebo, indicating the suppression of plasma cortisol by all these treatments. Animals exposed to ELS presented altered phenotype as indicated by an increased immobility time in the FST when compared with control, but no significant long-lasting effects of ELS were observed on the HPA axis response. Limitations on the way the volunteers were sampled may have contributed to the lack of ELS effects on the HPA axis, pointing out the need for further research to understand these complex phenomena.

Relationship Between Depression and Subtypes of Early Life Stress in Adult Psychiatric Patients.

Numerous studies have researched the aggravating and maintainer effect of Early Life Stress in patients adults with psychiatric disorders. This study examined the relationship between depression and subtypes of early life stress among 81 psychiatric patients treated at the inpatient Day Hospital Unit of a University General Hospital. Psychiatric diagnosis was confirmed according to the MINI International Neuropsychiatric Interview (MINI). The Childhood Trauma Questionnaire (CTQ) was used for evaluating as retrospective assessment of the presence of ELS on these patients, and we also evaluated the severity of hopelessness with the Beck Hopelessness Scale (BHS). Our results suggested that the occurrence of depression in adulthood is related to situations of emotional abuse, sexual, and physical neglect during childhood. The analysis between depression and childhood emotional abuse was significant after a multiple logistic regression analysis OR (IC 95%): 4.4 (1.7-11.2), even accounting for gender adjusted OR [AOR] 4.0; (IC 1.5-10.5); psychiatry family history AOR 3.8 (1.4-10.5); previous suicide attempted AOR 3.7; (1.4-10.5) and Hopelessness AOR 3.2 (1.11-9.4). Thus, these findings demonstrate emotional abuse as a significant risk factor to be part of the mechanism involved in the pathogenesis of depression related to early life stress.

Psicofarmacoterapia para o clínico geral / Pharmacotherapy for general practitioners

O objetivo deste artigo é introduzir o aluno de graduação na área da saúde, em especial o aluno de Medicina, no campo da psicofarmacoterapia para o tratamento dos transtornos mentais. Para isso, serão revisados os principais psicofármacos utilizados na atualidade, seus mecanismos de ação, suas indica- ções e contra-indicações, seus efeitos colaterais, oferecendo ainda diretrizes para o seu uso na prática clínica diária.(AU)

The objective of this article is to introduce the graduate students of healthcare courses, especially medical students, into the psychopharmacotherapy field for the treatment of mental disorders. To this aim, we performed a comprehensive review of the main psychoactive drugs used today, their mechanisms of action, indications and contraindications, side effects. We also provided guidelines for their use in daily clinical practice. (AU)

Early Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist.

BACKGROUND: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. METHODS: We included 30 subjects, 20 patients with current major depression (HAM-D21 ≥ 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). RESULTS: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p < 0.05) but not after GR agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p < 0.05); but now as well placebo vs. GR agonist (R = 0.53; p < 0.05). CONCLUSION: Our findings indicate that MR activity is impaired in depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction.

Effectiveness of psychoeducation for depression: a systematic review.

OBJECTIVE: Pharmacological treatment is considered indispensable to major depressive disorder. In spite of this, a significant number of patients do not respond adequately to treatment based only on medication, presenting high relapse and recurrence rates. Therefore, psychosocial interventions, such as psychoeducation, have been increasingly recognized as an essential component in the treatment of depression, associated with pharmacological strategies. Thus, the aim of the present systematic review was to evaluate the effectiveness of psychoeducation for patients with unipolar depression, analyzing the evidence from the literature. METHOD: Searches were undertaken from April to October 2012 in LILACS, PsycINFO, PubMed, SCOPUS and ISI Web of Knowledge with keywords including 'psychoeducation', 'psychoeducational intervention' and 'depression', with no restriction regarding publishing dates. RESULTS: Fifteen studies were included in the review, 13 of which evaluated the effectiveness of psychoeducation for patients with depression: 10 papers evaluated in-person psychoeducation approaches and three papers evaluated long-distance approaches. In addition to these 13 papers, one evaluated psychoeducational interventions for patients' families and patients' responses and another evaluated psychoeducational interventions for patients' families and families' responses. Findings suggest that increased knowledge about depression and its treatment is associated with better prognosis in depression, as well as with the reduction of the psychosocial burden for the family. CONCLUSIONS: Psychoeducation is a psychosocial treatment that has been well documented as an adjunct to pharmacological therapy. However, there are only a few studies regarding its effectiveness on adult patients with major depressive disorder. Although the publications in this area are still very limited, the articles selected in this review suggest that psychoeducation is effective in improving the clinical course, treatment adherence, and psychosocial functioning of depressive patients.

Efficacy of psychoeducation in bipolar patients: systematic review of randomized trials

Bipolar disorder is a recurrent and chronic disorder with significant morbidity and mortality. Currently, pharmacological treatment is considered indispensable in bipolar disorder. However, despite advances in this area, treatment remains suboptimal. A large body of research has shown that innumerable psychosocial factors influence the emergence of mood disorders. Therefore, in addition to pharmacological strategies, psychological interventions are increasingly recognized as an essential component in the treatment of bipolar patients. Among the various approaches of psychosocial interventions, psychoeducation (PE) has been one of the most used. Thus, the aim of this review was to evaluate the efficacy of PE in the clinical course, treatment adherence, and psychosocial functioning of bipolar patients by collecting data from controlled trials that used solely PE as a psychosocial approach. A systematic review of the literature was performed in the PubMed and SCOPUS databases, without date limits, using the following keywords: Psychoeducation and Bipolar disorder. We found 13 randomized controlled trials. Psychoeducation significantly improved the clinical course, treatment adherence, and psychosocial functioning of bipolar patients. It also reduced the number of relapses and recurrences per patient and increased the time to depressive, manic, hypomanic, and mixed recurrences. The number and length of hospitalizations per patient were also lower in patients who received PE. Although we found a limited number of randomized controlled trials that evaluated the efficacy of PE in bipolar disorder, the studies showed positive results in reducing relapse rates and improving long-term treatment adherence. Additionally, PE intervention improves the knowledge of the illness for both patients and caregivers to reduce their distress and improve overall social functioning.

Efficacy of psychoeducation in bipolar patients: systematic review of randomized trials

Bipolar disorder is a recurrent and chronic disorder with significant morbidity and mortality. Currently, pharmacological treatment is considered indispensable in bipolar disorder. However, despite advances in this area, treatment remains suboptimal. A large body of research has shown that innumerable psychosocial factors influence the emergence of mood disorders. Therefore, in addition to pharmacological strategies, psychological interventions are increasingly recognized as an essential component in the treatment of bipolar patients. Among the various approaches of psychosocial interventions, psychoeducation (PE) has been one of the most used. Thus, the aim of this review was to evaluate the efficacy of PE in the clinical course, treatment adherence, and psychosocial functioning of bipolar patients by collecting data from controlled trials that used solely PE as a psychosocial approach. A systematic review of the literature was performed in the PubMed and SCOPUS databases, without date limits, using the following keywords: Psychoeducation and Bipolar disorder. We found 13 randomized controlled trials. Psychoeducation significantly improved the clinical course, treatment adherence, and psychosocial functioning of bipolar patients. It also reduced the number of relapses and recurrences per patient and increased the time to depressive, manic, hypomanic, and mixed recurrences. The number and length of hospitalizations per patient were also lower in patients who received PE. Although we found a limited number of randomized controlled trials that evaluated the efficacy of PE in bipolar disorder, the studies showed positive results in reducing relapse rates and improving long-term treatment adherence. Additionally, PE intervention improves the knowledge of the illness for both patients and caregivers to reduce their distress and improve overall social functioning.(AU)

Analysis of the occurrence of early life stress in adult psychiatric patients: a systematic review

The purpose of the paper was to conduct a systematic review of early life stress and its association with psychiatric disorders in adulthood. The occurrence of early stress has lasting negative consequences on the individual, with psychopathology onset one of the most important consequences. The degree of early life stress is associated with the severity of psychiatric disorders and disability in adulthood. Methodology: We conducted a search of two databases (PubMed and SciELO), limited to the time span 1990-2010, using the following keywords: child abuse, maltreatment, early stress, and psychiatric disorders. Thirty-one papers were selected for this review. Results: We found that the subtypes of early life stress such as emotional and physical neglect and sexual, emotional, and physical abuse have associations with several psychiatric disorders, but the Borderline Personality Disorder and Mood Disorders are more associated with the categories listed. Conclusions: Exposure to adversities in childhood and adolescence is predictive of psychiatric disorders in adulthood. More studies are needed to understand the mechanisms by which early life stress is a risk factor for future psychopathology.

Early life stress, HPA axis, and depression

Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue.

Early life stress, HPA axis, and depression

Considerable evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that early life stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of early life stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue.(AU)

Analysis of the occurrence of early life stress in adult psychiatric patients: a systematic review

The purpose of the paper was to conduct a systematic review of early life stress and its association with psychiatric disorders in adulthood. The occurrence of early stress has lasting negative consequences on the individual, with psychopathology onset one of the most important consequences. The degree of early life stress is associated with the severity of psychiatric disorders and disability in adulthood. Methodology: We conducted a search of two databases (PubMed and SciELO), limited to the time span 1990-2010, using the following keywords: child abuse, maltreatment, early stress, and psychiatric disorders. Thirty-one papers were selected for this review. Results: We found that the subtypes of early life stress such as emotional and physical neglect and sexual, emotional, and physical abuse have associations with several psychiatric disorders, but the Borderline Personality Disorder and Mood Disorders are more associated with the categories listed. Conclusions: Exposure to adversities in childhood and adolescence is predictive of psychiatric disorders in adulthood. More studies are needed to understand the mechanisms by which early life stress is a risk factor for future psychopathology.(AU)

Efeitos das células tronco adultas de medula óssea e do plasma rico em plaquetas na regeneração e recuperação funcional nervosa em um modelo de defeito agudo em nervo perfiférico em rato

OBJETIVOS: Foram avaliados os efeitos do uso de células tronco da medula óssea (CTM) e do plasma rico em plaquetas (PRP) na regeneração de nervos periféricos, utilizando um modelo estabelecido de regeneração de nervo ciático em ratos. MÉTODOS: Um defeito nervoso de 10 mm foi reconstruído com a utilização de um tubo de silicone preenchido com CTM, PRP ou ambos. O grupo controle recebeu somente o tubo de silicone. Foi realizado ainda um quinto grupo no qual o intervalo foi reconstruído utilizando o segmento ressecado do nervo. A função motora foi testada seis semanas após a cirurgia utilizando teste de marcha. Após o teste motor, os ratos foram anestesiados, o nervo ciático e o tubo foram ressecados e foi realizada microscopia eletrônica de transmissão. RESULTADOS: A análise quantitativa demonstra uma melhora na recuperação funcional no grupo CTM em comparação com os demais grupos. Regeneração nervosa foi demonstrada no grupo CTM por microscopia eletrônica de trasmissão com uma recuperação praticamente completa da anatomia neural. CONCLUSÃO: Nossos resultados sugerem que o uso de CTM associado com a técnica de tubulização promove uma satisfatória recuperação da função motora e regeneração nervosa.

OBJECTIVES: The effects of the use of bone marrow stem cells (MSC) and platelet-rich plasma (PRP) on peripheral nerves regeneration were assessed by using an established model of sciatic nerve regeneration in rats. METHODS: A 10-mm nervous defect was reconstructed by using a silicone tube filled with MSC, PRP or both. The control group received only the silicone tube. A fifth group was also set, in which the interval was reconstructed by using a dried segment of the nerve. Motor function was tested six weeks after surgery, by means of a gait test. After motor test, the rats were anesthetized, the sciatic nerve and the tube were dried, and the transmission electronic microscopy was performed. RESULTS: The quantitative analysis shows an improved functional recovery in MSC group compared to the other groups. Nervous regeneration was reported for MSC group by means of transmission electronic microscopy with an almost full recovery of the neural anatomy. CONCLUSION: Our results suggest that the use of MSC combined with tubing technique yields a satisfactory recovery of motor function and nervous regeneration.

[Ocular aspergillosis--case report]. / Aspergilose orbitária: relato de caso.

Presence of fungus in the conjunctiva is a constant threat to the eyes, because these microorganisms, defined as opportunistic, may provoke severe ocular infections, in situations as low organic resistance, use of immunosuppressants, antibiotics and epithelial alteration. Our goal here is to report a case of ocular aspergillosis in an immunosuppressed patient where paroxysmal nocturnal hemoglobinuria was diagnosed. A 51-year-old immunosuppressed, thrombocytopenic patient was hospitalized with a diagnosis of paroxysmal nocturnal hemoglobinuria. On examination, she had a visual acuity of 20/40 in the right eye (RE) and light perception in the left (LE). She presented hyposphagma, bilateral conjunctival edema on biomicroscopy and had some multiple and circumscribed conjunctival abscesses in both eyes; clear cornea in both eyes. Fundoscopy of the RE did show any particularity, in the LE there was a smear hemorrhage. Computed tomograph showed a fat periocular infiltration. Magnetic resonance lead to the same finding, compatible with orbital cellulitis. Hemoculture showed Aspergillus growth and direct smears of conjunctival material was negative. There was great improvement while treating her with amphotericin B, but there was complete remission after using 5% natamicyn eye drops. Orbital infections caused by Aspergillus are uncommon, usually appearing in immunosuppressed patients. Frequently they progress insidiously, and can be confounded with other orbital processes. Immunological impairment can inhibit the expression of local and systemic symptoms, resulting in diagnostic confusion. The diagnosis is established by laboratory tests, but culture can be negative in spite of the classical presentation, making the beginning of treatment difficult. In these cases management starts according to the symptoms.

Aspergilose orbitária: relato de caso / Ocular aspergillosis: case report

A presença de fungos na conjuntiva representa constante ameaça para os olhos, pois estes microrganismos, definidos como oportunistas, podem provocar infecções oculares graves, em situações como baixa resistência orgânica, uso de medicações imunossupressoras, antibióticos e alteração epitelial. O objetivo desta, é relatar um caso de aspergilose ocular em paciente imunodeprimida com diagnóstico de hemoglobinúria paroxística noturna. Paciente feminina de 51 anos, internou imunossuprimida e plaquetopênica com diagnóstico de hemoglobinúria paroxística noturna. Ao exame, apresentava acuidade visual de 20/40 OD (olho direito) e percepção luminosa OE (olho esquerdo). Apresentava à biomicroscopia hiposfagma, edema conjuntival bilateral e abscessos conjuntivais múltiplos em ambos os olhos; córnea transparente AO (ambos os olhos). Boa motilidade ocular. A fundoscopia em OD não demonstrava particularidades, em OE havia hemorragia macular. A tomografia computadorizada de órbita revelou infiltração de gordura periocular. A ressonância nuclear magnética mostrou os mesmos achados da tomografia computadorizada, compatível com celulite orbitaria. Foi realizada hemocultura que demonstrou crescimento de Aspergillus sp e a cultura do raspado conjuntival foi negativa. O tratamento sistêmico com anfotericina B demonstrou melhora do quadro ocular, que regrediu completamente após a introdução de colírio de natamicina a 5 por cento. As infecções orbitárias causadas por Aspergillus são incomuns, aparecendo usualmente em pacientes imunodeprimidos. Com freqüência têm curso insidioso, podendo ser confundidas com outros processos orbitarios. O comprometimento imunológico pode inibir a expressão dos sintomas locais e sistêmicos, resultando em confusão diagnóstica. O diagnóstico é feito com exames laboratoriais, mas a cultura pode ser negativa apesar do quadro clínico clássico, dificultando assim, o início do tratamento. Nesses casos inicia-se o manejo, segundo o quadro de sintomas.