Mario Francisco Juruena

The Role of Early Life Stress in Adult Psychiatric Disorders A Systematic Review According to Childhood Trauma Subtypes

Abstract Early life stress (ELS; sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect) has been the focus of numerous studies. It has been associated with the onset and the severity of psychiatric disorders in adults. The objective of this study was to review the literature on ELS associated with psychiatric disorders in adulthood, seeking to identify whether there are independent effects between subtypes of early stress in triggering psychopathology in adults. We reviewed articles from 2001 to 2011 in four databases (PubMed, SciELO, LILACS, and PsycINFO), with the following key words: child abuse, maltreatment, early life stress, psychiatric disorders, mental disease, and psychopathology. Forty-four articles were selected, and most of these articles demonstrate that the subtypes of ELS are associated with several psychiatric disorders, more specifically: physical abuse, sexual abuse, and unspecified neglect with mood disorders and anxiety disorders; emotional abuse with personality disorders and schizophrenia; and physical neglect with personality disorders. Physical neglect had the weakest association between the subtypes. ELS subtypes in childhood and adolescence can predict the development of psychopathology in adults. Scientific evidence shows that ELS triggers, aggravates, maintains, and increases the recurrence of psychiatric disorders. These results demonstrate the importance of a deeper understanding about the unique effects of ELS subtypes, especially for mental health professionals.

Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance

BACKGROUND People with severe depressive illness have raised levels of cortisol and reduced glucocorticoid receptor function. AIMS To obtain a physiological assessment of hypothalamic-pituitary-adrenal (HPA) axis feedback status in an in-patient sample with depression and to relate this to prospectively determined severe treatment resistance. METHOD The prednisolone suppression test was administered to 45 in-patients with depression assessed as resistant to two or more antidepressants and to 46 controls, prior to intensive multimodal in-patient treatment. RESULTS The patient group had higher cortisol levels than controls, although the percentage suppression of cortisol output after prednisolone in comparison with placebo did not differ. Non-response to in-patient treatment was predicted by a more dysfunctional HPA axis (higher cortisol levels post-prednisolone and lower percentage suppression). CONCLUSIONS In patients with severe depression, HPA axis activity is reset at a higher level, although feedback remains intact. However, prospectively determined severe treatment resistance is associated with an impaired feedback response to combined glucocorticoid and mineralocorticoid receptor activation by prednisolone.

Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system

Despite the evidence of an association between depression and increased inflammatory markers, still little is known in relation to the most severe cases of the disorder i.e., those who fail to respond to antidepressants. We have assessed the cytokine profile and cortisol levels in 21 healthy controls (HC) and 19 medicated patients with depression with treatment-resistance (TRD) moderately ill. As an initial exploratory analysis, we have also related cytokine profile to the patients clinical treatment outcome after an inpatient admission. Cytokine profile was measured in the serum by the Cytokine Array I kit (Randox). Plasma cortisol was carried out using a commercially available for the IMMULITE system. When compared to healthy controls, depressed patients had higher levels of cortisol, IL-6, IL-10, but lower levels of IL-4 and VEGF. Our exploratory analysis showed subjects who did not go on to respond to the inpatient admission treatment package had lower levels of MCP-1, and a trend toward lower levels of VEGF. Taking together, these data suggest that lack of clinical therapeutic benefit of antidepressants is associated with overall activation of the inflammatory system.

The ratio of cortisol/DHEA in treatment resistant depression

OBJECTIVE Hypercortisolaemia has been well described in depression and may be a factor associated with treatment resistance. The role of the more abundant adrenal steroid dehydroepiandrosterone (DHEA) has been recently investigated, with some evidence that it may have an antiglucocorticoid effect. This study measured cortisol, DHEA and their ratio in treatment resistant depression (TRD) and healthy controls and also related these measures to treatment outcome. METHOD Plasma cortisol, DHEA and cortisol/DHEA ratio were determined at 0900h in 28 patients with TRD and 40 healthy controls. The measures were repeated following inpatient treatment in a subgroup of 21 patients and related to the outcome of such treatment. The stability of cortisol/DHEA ratios was assessed with 2 hourly samples from 0900 to 1700h in a subgroup of 15 controls. RESULTS Basal levels of cortisol and the cortisol/DHEA ratio were higher in patients compared to controls. Whilst cortisol levels were lower after treatment, there was no relationship between cortisol levels and treatment outcome. In contrast, treatment responders had significantly lower DHEA on admission and a higher cortisol/DHEA ratio both on admission and on discharge. Cortisol/DHEA ratios were stable between 9 a.m. and 5 p.m. CONCLUSIONS In addition to cortisol, the cortisol/DHEA ratio is raised in TRD; thus, there is no evidence that DHEA levels could negate the increased glucocorticoid activity in TRD. Patients with a more abnormal cortisol/DHEA ratio, possibly indicating greater biological dysfunction, responded preferentially to inpatient therapy, though the raised cortisol/DHEA ratio persisted after response. The cortisol/DHEA ratio is stable throughout the day and may be a more practical biological marker of TRD.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression

BACKGROUND Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

Evaluation of hippocampal volume based on MR imaging in patients with bipolar affective disorder applying manual and automatic segmentation techniques.

To compare the hippocampal volumes in patients with bipolar disorder (BD) and healthy controls, obtained by applying different segmentation methods (manual, Freesurfer [FS], and FSL).

Clomipramine In Vitro Reduces Glucocorticoid Receptor Function in Healthy Subjects but not in Patients with Major Depression

Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 μM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.

Revisão das diretrizes da Associação Médica Brasileira para o tratamento da depressão (Versão integral)

OBJECTIVE Depression is a frequent and chronic condition with high levels of functional disability. Brazilian Medical Association Guidelines project proposed guidelines for diagnosis and treatment of the most common medical disorders. The objective of this paper is to present the original document that originated the abbreviated version available at the electronic address of Brazilian Medical Association. METHODS This paper was based on guidelines developed in other countries and systematic reviews, randomized clinical trials and when absent, observational studies and recommendations from experts. Brazilian Medical Association proposed this methodology for the whole project. RESULTS The following aspects are presented: prevalence, demographics, disability, diagnostics and sub-diagnosis, efficacy of pharmacological and psychotherapeutic treatment, costs and side-effects of different classes of available drugs in Brazil. Planning of different phases of treatment is22 also discussed. CONCLUSIONS Guidelines are a good tool helping clinical decisions and are a reference for an attitude based on levels of evidence.OBJECTIVE Depression is a frequent, recurrent and chronic condition with high levels of functional disability. The Brazilian Medical Association Guidelines project proposed guidelines for diagnosis and treatment of the most common medical disorders. The objective of this paper is to present a review of the Guidelines Published in 2003 incorporating new evidence and recommendations. METHOD This review was based on guidelines developed in other countries and systematic reviews, randomized clinical trials and when absent, observational studies and recommendations from experts. The Brazilian Medical Association proposed this methodology for the whole project. The review was developed from new international guidelines published since 2003. RESULTS The following aspects are presented: prevalence, demographics, disability, diagnostics and sub-diagnosis, efficacy of pharmacological and psychotherapeutic treatment, costs and side-effects of different classes of available drugs in Brazil. Strategies for different phases of treatment are also discussed. CONCLUSION The Guidelines are an important tool for clinical decisions and a reference for orientation based on the available evidence in the literature.

[Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome].

OBJECTIVE We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category. METHOD The literature data on the overlap between the key-words were reviewed, summarized and discussed. RESULTS Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems. CONCLUSIONS Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning common symptom clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin realising factor activity.

Treatment of psychosis: 30 years of progress

Background:  Thirty years ago, psychiatrists had only a few choices of old neuroleptics available to them, currently defined as conventional or typical antipsychotics, as a result schizophrenics had to suffer the severe extra pyramidal side effects. Nowadays, new treatments are more ambitious, aiming not only to improve psychotic symptoms, but also quality of life and social reinsertion. Our objective is to briefly but critically review the advances in the treatment of schizophrenia with antipsychotics in the past 30 years. We conclude that conventional antipsychotics still have a place when just the cost of treatment, a key factor in poor regions, is considered. The atypical antipsychotic drugs are a class of agents that have become the most widely used to treat a variety of psychoses because of their superiority with regard to extra pyramidal symptoms. We can envisage different therapeutic strategies in the future, each uniquely targeting a different dimension of schizophrenia, be it positive, negative, cognitive or affective symptoms.