In the past two decades, much evidence has accumulated unequivocally demonstrating that child abuse and neglect is associated with a marked increase in risk for major psychiatric disorders (major ...depression, bipolar disorder, post-traumatic stress disorder PTSD, substance and alcohol abuse, and others) and medical disorders (cardiovascular disease, diabetes, irritable bowel syndrome, asthma, and others). Moreover, the course of psychiatric disorders in individuals exposed to childhood maltreatment is more severe. Recently, the biological substrates underlying this diathesis to medical and psychiatric morbidity have been studied. This Review summarizes many of the persistent biological alterations associated with childhood maltreatment including changes in neuroendocrine and neurotransmitter systems and pro-inflammatory cytokines in addition to specific alterations in brain areas associated with mood regulation. Finally, I discuss several candidate gene polymorphisms that interact with childhood maltreatment to modulate vulnerability to major depression and PTSD and epigenetic mechanisms thought to transduce environmental stressors into disease vulnerability.
In this Review, Nemeroff describes clinical and neurophysiological consequences of early life stress, including neuroendocrine and immune alterations and functional and structural changes. Candidate gene polymorphisms and epigenetic mechanisms are discussed as potential mediators of the interaction between early adverse treatment and disease vulnerability.
Major depressive disorder is a remarkably common and often severe psychiatric disorder associated with high levels of morbidity and mortality. Patients with major depression are prone to several ...comorbid psychiatric conditions, including posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorder, and substance use disorders, and medical conditions, including cardiovascular disease, diabetes, stroke, cancer, which, coupled with the risk of suicide, result in a shortened life expectancy. The goal of this review is to provide an overview of our current understanding of major depression, from pathophysiology to treatment. In spite of decades of research, relatively little is known about its pathogenesis, other than that risk is largely defined by a combination of ill-defined genetic and environmental factors. Although we know that female sex, a history of childhood maltreatment, and family history as well as more recent stressors are risk factors, precisely how these environmental influences interact with genetic vulnerability remains obscure. In recent years, considerable advances have been made in beginning to understand the genetic substrates that underlie disease vulnerability, and the interaction of genes, early-life adversity, and the epigenome in influencing gene expression is now being intensively studied. The role of inflammation and other immune system dysfunction in the pathogenesis of major depression is also being intensively investigated. Brain imaging studies have provided a firmer understanding of the circuitry involved in major depression, providing potential new therapeutic targets. Despite a broad armamentarium for major depression, including antidepressants, evidence-based psychotherapies, nonpharmacological somatic treatments, and a host of augmentation strategies, a sizable percentage of patients remain nonresponsive or poorly responsive to available treatments. Investigational agents with novel mechanisms of action are under active study. Personalized medicine in psychiatry provides the hope of escape from the current standard trial-and-error approach to treatment, moving to a more refined method that augurs a new era for patients and clinicians alike.
Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established ...that dysregulation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibit inflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, or a combination of these and other factors.
In at least a subset of patients, depression is associated with dysregulated innate and adaptive immune response. Beurel et al. discuss how inflammation contributes to the pathophysiology of depression, acting as a disease modifier, hindering favorable prognosis and antidepressant response.
A large body of evidence has demonstrated that exposure to childhood maltreatment at any stage of development can have long-lasting consequences. It is associated with a marked increase in risk for ...psychiatric and medical disorders. This review summarizes the literature investigating the effects of childhood maltreatment on disease vulnerability for mood disorders, specifically summarizing cross-sectional and more recent longitudinal studies demonstrating that childhood maltreatment is more prevalent and is associated with increased risk for first mood episode, episode recurrence, greater comorbidities, and increased risk for suicidal ideation and attempts in individuals with mood disorders. It summarizes the persistent alterations associated with childhood maltreatment, including alterations in the hypothalamic-pituitary-adrenal axis and inflammatory cytokines, which may contribute to disease vulnerability and a more pernicious disease course. The authors discuss several candidate genes and environmental factors (for example, substance use) that may alter disease vulnerability and illness course and neurobiological associations that may mediate these relationships following childhood maltreatment. Studies provide insight into modifiable mechanisms and provide direction to improve both treatment and prevention strategies.
The role of stress in the origin and development of depression may be conceived as the result of multiple converging factors, including the chronic effect of environmental stressors and the ...long-lasting effects of stressful experiences during childhood, all of which may induce persistent hyperactivity of the hypothalamic-pituitary-adrenal axis. These changes, including increased availability of corticotropin-releasing factor and cortisol, are also associated with hyperactivity of the amygdala, hypoactivity of the hippocampus, and decreased serotonergic neurotransmission, which together result in increased vulnerability to stress. The role of other monoaminergic neurotransmitters, genetic polymorphisms, epigenetic mechanisms, inflammatory processes, and altered cognitive processing has also been considered in the development of a comprehensive model of the interactions between different factors of vulnerability. Further understanding of the underlying mechanisms that link these factors may contribute significantly to the development of more effective treatments and preventive strategies in the interface between stress and mood disorders.
The central theme of personalized medicine is the premise that an individual's unique physiologic characteristics play a significant role in both disease vulnerability and in response to specific ...therapies. The major goals of personalized medicine are therefore to predict an individual's susceptibility to developing an illness, achieve accurate diagnosis, and optimize the most efficient and favorable response to treatment. The goal of achieving personalized medicine in psychiatry is a laudable one, because its attainment should be associated with a marked reduction in morbidity and mortality. In this review, we summarize an illustrative selection of studies that are laying the foundation towards personalizing medicine in major depressive disorder, bipolar disorder, and schizophrenia. In addition, we present emerging applications that are likely to advance personalized medicine in psychiatry, with an emphasis on novel biomarkers and neuroimaging.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The need for novel agents for the treatment of major depression is evidenced by the relatively low remission rates reported with all the FDA-approved antidepressants as well as after treatment with ...evidence-based psychotherapies such as cognitive behavior therapy. After a remarkable hiatus in which no new drugs with any novel mechanisms of action were approved distinct from the SSRI and SNRI classes, a veritable explosion of novel treatments has recently emerged. These include novel neuromodulation approaches such as accelerated theta burst transcranial magnetic stimulation (TMS) and a host of new pharmacological approaches including the recently approved esketamine, which followed on a series of studies of intravenously administered ketamine in treatment-resistant depression. The use of opioid agonists in the treatment of depression has a very long and noteworthy history, with both Hippocrates and Galen being prescribers of opioids for depression and the "opium cure" being widely used in the latter part of the 19th century. More recently antidepressant effects of buprenorphine were reported.
Patients with major depression are at an increased risk for developing cardiovascular disease, respond more poorly to treatment, and exhibit worse outcomes, including increased morbidity and ...mortality. This article reviews the relationship between depression and heart disease, with an emphasis on epidemiology, biological substrates that likely underlie this relationship, and implications for treatment.
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