Andrea F. Mello

Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis

Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology.

Maus-tratos na infância e psicopatologia no adulto: caminhos para a disfunção do eixo hipotálamo-pituitária-adrenal

OBJECTIVE The aim of this paper was to examine the relationship between childhood maltreatment and adult psychopathology, as reflected in hypothalamic-pituitary-adrenal axis dysfunction. METHOD A selective review of the relevant literature was undertaken in order to identify key and illustrative research findings. RESULTS There is now a substantial body of preclinical and clinical evidence derived from a variety of experimental paradigms showing how early-life stress is related to hypothalamic-pituitary-adrenal axis function and psychological state in adulthood, and how that relationship can be modulated by other factors. DISCUSSION The risk for adult psychopathology and hypothalamic-pituitary-adrenal axis dysfunction is related to a complex interaction among multiple experiential factors, as well as to susceptibility genes that interact with those factors. Although acute hypothalamic-pituitary-adrenal axis responses to stress are generally adaptive, excessive responses can lead to deleterious effects. Early-life stress alters hypothalamic-pituitary-adrenal axis function and behavior, but the pattern of hypothalamic-pituitary-adrenal dysfunction and psychological outcome in adulthood reflect both the characteristics of the stressor and other modifying factors. CONCLUSION Research to date has identified multiple determinants of the hypothalamic-pituitary-adrenal axis dysfunction seen in adults with a history of childhood maltreatment or other early-life stress. Further work is needed to establish whether hypothalamic-pituitary-adrenal axis abnormalities in this context can be used to develop risk endophenotypes for psychiatric and physical illnesses.

Depressão e estresse: existe um endofenótipo?

OBJECTIVE To review the new findings about stress, hypothalamic-pituitary-adrenal axis and depression trying to explain a possible endophenotype prone to depression. METHOD Nonsystematic review of the literature based on the endophenotype hypothesis. RESULTS Depression is linked to hypercortisolemia in many patients, but not all patients present these hypothalamic-pituitary-adrenal axis dysfunction. The dexamethasone suppression test is not the most accurate test to measure the hypothalamic-pituitary-adrenal axis function, and its use in the first studies published probably jeopardized the results. Hypercortisolemia frequently occurs in patients with severe depression, melancholic, either psychotic or nonpsychotic type; it is linked to the presence of a polymorphism in the promoter of the serotonin transporter gene, with a history of childhood abuse or neglect, or other significant stressful experiences like the loss of a parent during childhood and temperament leading to alterations in the response to stress. CONCLUSIONS The alterations of the hypothalamic-pituitary-adrenal axis depend on many factors like severity and type of depression, genotype, history of exposure to stress, temperament, and probably resilience. All these factors together result in an endophenotype thought to be prone to depression.

Treinamento de clínicos para o diagnóstico e tratamento da depressão

OBJECTIVE The American Regional Office of the WHO has launched a major initiative to reduce the prevalence of affective disorders region-wide that includes focusing on the primary health care system. This study evaluated the results of an educational training program for Brazilian primary care physicians that measured changes in knowledge, attitudes, and practice. METHODS A total of 17 primary care physicians and 1,224 patients participated in the study. Physicians knowledge, attitudes, and clinical practice were assessed one-month prior and one-month following the training program. In addition, the patients that visited the clinic during a typical week completed depression symptom self-ratings, including the Zung and a DSM-IV/ICD-10 major depression checklist at both times. RESULTS The training program showed limited benefits in this small sample of physicians. The program was unable to demonstrate benefit in improving knowledge about depression and in changing disorder-related attitudes. There were no changes in the diagnostic rates of major depression. There was some evidence to support improvement in psychopharmacological management. The physicians seemed more confident in treating patients, as there was a reduction of referrals to the specialists. Lack of statistical power prevented the latter two findings from reaching statistical significance. CONCLUSIONS The inclusion of primary care physicians is a central component of any initiative to reduce the treatment gap and lag of depression. However, more effective methods of training Brazilian primary care physicians in the management of major depression need to be tested.

Estudo de revisão dos fatores biológicos, sociais e ambientais associados com o comportamento agressivo

OBJECTIVES To study the risk factors related to the development of aggressive behavior. METHOD A search was carried out in two electronic databases, Medline and SciElo by retrospective studies, longitudinal and review that assessed risk factors for the development of aggressive behavior. RESULTS There were selected 11 longitudinal studies (8 prospective and 3 case-control studies) and a cross sectional study that evaluated the risk factors and socio-biological related to aggressive behavior. Five studies have evaluated gene expression, five evaluated exposure to tobacco, alcohol and cocaine in the prenatal period, one evaluated the effect of early malnutrition on the development of aggressive behavior and one assessed the impact of child maltreatment. CONCLUSION The main biological factors were: genetic (low expression of the monoamine oxidase gene and serotonin transporter gene, variations in transporter and dopamine receptor genes), exposure to substances during intrauterine development (tobacco, alcohol and cocaine) and nutrition (malnutrition). The main environmental factors were: child abuse, poverty, crime and antisocial behavior in childhood, while the highest level of evidence was related to early neglect. The interaction between biological and environmental factors can be catalyzed by a hostile environment, increasing the risk for the development of aggressive behavior.OBJETIVOS: Estudar os fatores de risco relacionados ao desenvolvimento do comportamento agressivo. METODO: Foi realizada uma busca em duas bases de dados eletronicas, Medline e SciElo, por estudos retrospectivos, longitudinais e de revisao que avaliaram fatores de risco para o desenvolvimento do comportamento agressivo. RESULTADOS: Foram selecionados 11 estudos longitudinais (8 prospectivos e 3 de casos-controle) e um transversal que avaliaram os fatores de risco biologicos e socioambientais relacionados ao comportamento agressivo. Cinco estudos avaliaram a expressao genica, cinco a exposicao ao tabaco, ao alcool e a cocaina no periodo pre-natal, um avaliou as implicacoes da desnutricao precoce no desenvolvimento do comportamento agressivo e um avaliou o impacto dos maus tratos na infância. CONCLUSAO: os principais fatores biologicos encontrados foram: geneticos (baixa expressao do gene monoaminaoxidase e do gene transportador de serotonina, variacoes nos genes transportador e receptor de dopamina), exposicao a substâncias durante o desenvolvimento intrauterino (tabaco, alcool e cocaina) e nutricionais (desnutricao infantil). os principais fatores socioambientais encontrados foram: maus tratos na infância, pobreza, criminalidade e comportamento antissocial na infância, sendo que o maior nivel de evidencia esteve relacionado a negligencia precoce. A interacao entre fatores biologicos e ambientais pode ser catalisada por um ambiente hostil aumentando os riscos para o desenvolvimento de comportamentos agressivos.

Psychotic major depression : A benefit-risk assessment of treatment options

Numerous studies in the past three decades have characterised ‘psychotic major depression’, a subtype of major depression which is accompanied by delusions or other psychotic features. Evidence from phenomenological and neurobiological investigations indicates that this is a unique disorder with clinical and biological characteristics that are distinct from those of nonpsychotic depression and from other psychotic disorders. Treatment studies have provided evidence of small placebo effects and good responses to electroconvulsive therapy or combination treatment with an antidepressant plus an antipsychotic agent. However, until recently, there were only a few small, prospective, double-blind, controlled trials investigating the efficacy of antidepressant-antipsychotic combination pharmacotherapy, yet this constitutes the currently accepted and most universally applied ‘standard of care’ for psychotic depression. Treatment guidelines have been based largely on uncontrolled investigations of electroconvulsive therapy and studies using tricyclic antidepressants and first-generation antipsychotic drugs, which are not frequently chosen as first-line agents today because of concerns regarding tolerability and risks. However, recent open-label studies and large controlled trials of newer antidepressants and antipsychotics have yielded very divergent results thus far, so that the best treatment approach remains elusive. This review discusses the phenomenology and treatment of psychotic depression with a focus on the benefits and risks of various treatment approaches. Problems with this literature are highlighted, and strategies for future research are suggested.

Exposure to maltreatment and urban violence in children working on the streets in São Paulo, Brazil: factors associated with street work

OBJECTIVE To quantitatively study the exposure to childhood maltreatment and urban violence in children from families with at least one child working on the streets and to investigate the relationship between these factors and street work. METHODS Families who participated in a nongovernmental organization (NGO) program to eliminate child labor were included. Data concerning sociodemographic characteristics, punishment methods used in the family environment against the children, five types of abuse and neglect perpetrated by the caregivers, urban violence exposure and family functioning were collected. RESULTS The sample included 126 children who were working on the streets and 65 siblings who were not working on the streets. Caregivers reported high levels of severe physical punishment. The children reported high levels of abuse and neglect, and high levels of urban violence exposure. The families showed a predominance of dysfunctional and unsatisfactory relationships. A multiple logistic regression model showed that age older than 12 years and severe physical punishment at home were associated with street work. CONCLUSION Interventions to decrease the risk of child street work should be family-focused and should aim to reduce violence in the family environment.

Quality of life of mothers whose children work on the streets of São Paulo, Brazil.

The present study evaluated the perceived quality of life of the mothers of street children and investigated the association with their history of childhood violence, the occurrence of current domestic violence, their current mental states and that of their children, and family functioning. The applied instruments were as follows: Strengths and Difficulties Questionnaire, WorldSAFECore Questionnaire, Instrument for the Assessment of Quality of Life of the WHO, Global Assessment of Relational Functioning Scale, Childhood Trauma Questionnaire and a socio-demographic questionnaire. The sample of convenience consisted of 79 low-income mothers who raised their children alone, and most of whom had a positive screening for mental illness. The multiple regression analysis showed that the perception of quality of life of these women was associated with the presence of psychopathology either in themselves or their children and family dysfunction. Thus any program aimed at improving the quality of life of such mothers should consider addressing their mental problems as well as those of their children, besides offering educational and psychotherapeutic approaches to these families to improve the social environment.

Lack of association between the 5-HTTLPR and positive screening for mental disorders among children exposed to urban violence and maltreatment

OBJECTIVE To ascertain whether genetic variations in the serotonin transporter gene (5-HTTLPR 44-bp insertion/deletion polymorphism) influence an increase in depressive and anxiety symptoms in children and adolescents exposed to high levels of violence. METHODS Saliva samples were collected from a group of children who were working on the streets and from their siblings who did not work on the streets. DNA was extracted from the saliva samples and analyzed for 5-HTTLPR polymorphism genotypes. RESULTS One hundred and seventy-seven children between the ages of 7 and 14 years were analyzed (114 child workers and 63 siblings). Data on socioeconomic conditions, mental symptoms, and presence and severity of maltreatment and urban violence were collected using a sociodemographic inventory and clinical instruments. There was no positive correlation between the 5-HTTLPR polymorphism and presence of mental symptoms in our sample, although the children were exposed to high levels of abuse, neglect, and urban violence. CONCLUSIONS Despite previous studies that associated adult psychiatric disorders with the 5-HTTLPR polymorphism and a history of childhood maltreatment, no such association was found in this sample of children at risk.

Factors related to the cortisol awakening response of children working on the streets and siblings, before and after 2 years of a psychosocial intervention.

The study objective was to observe the cortisol awakening response (CAR) pattern before and after a psychosocial intervention with children from dysfunctional families who had at least one child working on the streets, and to verify factors related to it. Two hundred and eleven children between 7 and 14 years old were selected and 191 were included, 178 were re-evaluated 2 years after, of whom 113 had cortisol measures completed. Besides cortisol, they were evaluated at baseline and at end point regarding: abuse/neglect, mental health symptoms, exposure to urban violence and family environment. There was no significant difference between the CAR area under the curve (AUC) before and after the intervention. Two regression analysis models were built to evaluate factors related to the CAR before and after intervention. Before the intervention, working on the streets (vs. not) was related to a greater cortisol increase after awakening, at follow-up, having suffered physical punishment (vs. not) was related to a flattened cortisol response. The intervention was not associated with changes in the magnitude of the CAR AUC, though the CAR was associated with psychosocial stressors pre- and post-intervention. Effective interventions for children at risk that might shape a physiological cortisol response are still needed.