Neurobiological and psychiatric consequences of child abuse and neglect.

The effects of early-life trauma and its consequences for the treatment of depression are reviewed. The prevalence and clinical sequelae of early sexual and physical abuse, neglect and parental loss are described. An overview of preclinical studies that help guide clinical research and practice is presented.

The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology.

Anxiety disorders are highly comorbid with each other and with major depressive disorder. As syndromes, anxiety and mood disorders share many symptoms, and several treatments are effective for both. Despite this overlap, there exist many distinguishing features that support the continued classification of individual anxiety disorders that are distinct from each other and from major depression.

Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression.

Background: Depression will be the second largest burden of disease by 2020. Developing new tools for identifying risk and ultimately prevention of depression relies on elucidating the integrative relationships between susceptibility markers from gene-stress interactions and how they impact emotional brain and arousal systems. They have largely been studied in isolation.

Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood.

Background: The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing.

Methods: Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database.

Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: a pilot study.

Recent studies have indicated a gene-by-environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress.

Asymmetrical contribution of brain structures to treatment-resistant depression as illustrated by effects of right subgenual cingulum stimulation.

Major depressive disorder is one of the most common psychiatric disorders, with a worldwide lifetime prevalence rate of 10%-20% in women and a slightly lower rate in men. While many patients are successfully treated using established therapeutic strategies, a significant percentage of patients fail to respond. This report describes the successful recovery of a previously treatment-resistant patient following right unilateral deep brain stimulation of Brodmann's area 25.

Early life programming and neurodevelopmental disorders.

For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects.

Tolerability of the dexamethasone-corticotropin releasing hormone test in major depressive disorder.

Background: The dexamethasone-corticotropin releasing hormone (Dex-CRH) test may differentially predict which depressed patients will respond to antidepressant medication. However, a comprehensive analysis of the safety of this test in psychiatric patients has not previously been performed.

Methods: We conducted a pooled analysis of depressed patients in four clinical studies.

Changes in the vascular area fraction of the hippocampus and amygdala are induced by prenatal dexamethasone and/or adult stress.

In addition to the neuronal and behavioral consequences of excess glucocorticoid exposure, the cerebrovascular system can also be adversely affected by stressors. This study determined that chronic stress in adulthood decreased the vascular area fraction of the hippocampus and increased the vascular area fraction of the amygdala. In addition, the data indicated that prenatal exposure to synthetic glucocorticoids modulated the effects of adult stress on vascular area fraction of the hippocampus and amygdala.

Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response.

Context: The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment.

Objective: To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N = 1768).

Design: Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial.

A novel transgenic mouse for gene-targeting within cells that express corticotropin-releasing factor.

Corticotropin-releasing factor (CRF) orchestrates the mammalian endocrine, autonomic, and behavioral stress response and has been implicated in the pathophysiology of illnesses ranging from irritable bowel syndrome to mood and anxiety disorders. CRF is produced and released from a variety of cell types, making it difficult to distinguish the specific role of CRF from other neurotransmitters with which it colocalizes. To clarify the basic biology of the CRF neuron, we must be able to manipulate selectively CRFergic cells.

Effect of Childhood Trauma on Adult Depression and Neuroendocrine Function: Sex-Specific Moderation by CRH Receptor 1 Gene.

Variations of the corticotropin-releasing hormone receptor 1 (CRHR1) gene appear to moderate the development of depression after childhood trauma. Depression more frequently affects women than men. We examined sex differences in the effects of the CRHR1 gene on the relationship between childhood trauma and adult depression.

Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms.

Gene x environment (G x E) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene x gene (G x G) interactions between CRHR1 and 5-HTTLPR polymorphisms. We used an association study examining G x G x E interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology.

The CRF system, stress, depression and anxiety-insights from human genetic studies.

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology.

The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology.

Anxiety disorders are highly comorbid with each other and with major depressive disorder. As syndromes, anxiety and mood disorders share many symptoms, and several treatments are effective for both. Despite this overlap, there exist many distinguishing features that support the continued classification of individual anxiety disorders that are distinct from each other and from major depression.

The neurobiological toll of child abuse and neglect.

Exposure to interpersonal violence or abuse affects the physical and emotional well-being of affected individuals. In particular, exposure to trauma during development increases the risk of psychiatric and other medical disorders beyond the risks associated with adult violence exposure. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis, a major mediating pathway of the stress response, contribute to the long-standing effects of early life trauma.

Effects of a cognitive stress challenge on myocardial perfusion and plasma cortisol in coronary heart disease patients with depression.

Although it is well established that coronary heart disease (CHD) patients with depression exhibit increased mortality compared with equally ill cardiac patients without depression, the mechanisms mediating this effect remain obscure. Depression is characterized by vulnerability to stress and heightened stress responsiveness, and stress can theoretically act through several biological pathways to contribute to excess mortality from CHD. Mechanisms connecting stress, depression and cardiovascular mortality have not been previously explored in detail.

Cardiac arrest and cardiopulmonary resuscitation dysregulates the hypothalamic-pituitary-adrenal axis.

Cardiac arrest and cardiopulmonary resuscitation (CA/CPR) increase the risk for affective disorders in human survivors. Postischemic anxiety- and depressive-like behaviors have been documented in animal models of CA/CPR; however, the stability of post-CA/CPR anxiety-like behavior over time and the underlying physiologic mechanisms remain unknown. The hypothalamic-pituitary-adrenal (HPA) axis and the corticotropin releasing factor (CRF) system may mediate the pathophysiology of anxiety and depression; therefore, this study measured CA/CPR-induced changes in CRF receptor binding and HPA axis negative feedback.

Emerging targets for antidepressant therapies.

Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression.

Placebo-controlled inpatient comparison of venlafaxine and fluoxetine for the treatment of major depression with melancholic features.

The objective of this study was to compare venlafaxine and fluoxetine with placebo in treating major depressive disorder with melancholic features. Adult inpatients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder with melancholia and 21-item Hamilton Depression Rating Scale (HAM-D₂₁) scores > or =24 (n=289) were randomized to receive (double-blind) venlafaxine 225-375 mg/day, fluoxetine 60-80 mg/day, or placebo for 6 weeks. The primary outcome measures were HAM-D₂₁ total score, HAM-D depressed mood item, Montgomery Asberg Depression Rating Scale total score and the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scores.

Cape Town consensus on posttraumatic stress disorder.

The association between traumatic events and psychopathology has long been recognized, and the literature on posttraumatic stress disorder (PTSD) has burgeoned since this entity was introduced into the diagnostic nomenclature. This literature has been characterized by a range of clinical controversies about the optimal diagnosis and treatment of PTSD. In response, several systematic reviews of treatment, clinical guidelines, and consensus statements about PTSD have been generated, but their conclusions are not always consistent.

Neurobiology of posttraumatic stress disorder.

Exposure to a traumatic event is required for the diagnosis of posttraumatic stress disorder (PTSD). The symptoms of PTSD are believed to reflect stress-induced changes in neurobiological systems and/or an inadequate adaptation of neurobiological systems to exposure to severe stressors. More recently, there have been attempts to link the identified neurobiological changes to the specific features that constitute PTSD, such as altered mechanisms of learning and extinction, sensitization to stress, and arousal.

Exploratory structural equation modeling of resting-state fMRI: applicability of group models to individual subjects.

The extension of group-level connectivity methods to individual subjects remains a hurdle for statistical analyses of neuroimaging data. Previous group analyses of positron emission tomography data in clinically depressed patients, for example, have shown that resting-state connectivity prior to therapy predicts how patients eventually respond to pharmacological and cognitive-behavioral therapy. Such applications would be considerably more informative for clinical decision making if these connectivity methods could be extended into the individual subject domain.

Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.

Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants.