Mental disorders such as schizophrenia, bipolar illness, depression, and autism are the number one source of medical disability for people 15–44 years of age in the U.S. and Canada. In the past, these disorders have been considered psychological conflicts or chemical imbalances, but, as highlighted in this Review series, recent research indicates they are brain disorders, developmental disorders, and complex genetic disorders.
Mental disorders such as schizophrenia, bipolar illness, and depression have become the predominant chronic diseases of young people, accounting for approximately 40% of the medical burden for people aged 15–44 in the United States and Canada. Research is transforming our understanding of these disorders, as exemplified in the articles in this Review Series. Important, “disruptive” insights into pathophysiology are emerging from studies addressing these illnesses as brain disorders, developmental disorders, and complex genetic disorders — rather than only as psychological conflicts or chemical imbalances, as they were considered in the past. Current medications are not sufficient for most patients. A new and deep understanding of the pathophysiology of these disabling disorders is our best hope for a new generation of treatments that will help patients to recover.
Thomas R. Insel
Schizophrenia is a severe disorder that disrupts the function of multiple brain systems, resulting in impaired social and occupational functioning. The etiology and pathogenesis of schizophrenia appear to involve the interplay of a potentially large number of genetic liabilities and adverse environmental events that disrupt brain developmental pathways. In this Review, we discuss a strategy for determining how particular common and core clinical features of the illness are associated with pathophysiology in certain circuits of the cerebral cortex. The identification of molecular alterations in these circuits is providing critical insights for the rational development of new therapeutic interventions.
David A. Lewis, Robert A. Sweet
During the last 20 years of neuroscience research, we have witnessed a fundamental shift in the conceptualization of psychiatric disorders, with the dominant psychological and neurochemical theories of the past now complemented by a growing emphasis on developmental, genetic, molecular, and brain circuit models. Facilitating this evolving paradigm shift has been the growing contribution of functional neuroimaging, which provides a versatile platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment. Discussed here are converging imaging findings that established a rationale for testing a targeted neuromodulation strategy, deep brain stimulation, for treatment-resistant major depression.
Helen S. Mayberg
Bipolar disorder (BPD) is a devastating illness that is characterized by recurrent episodes of mania and depression. In addition to these cyclic episodes, individuals with BPD exhibit changes in psychovegetative function, cognitive performance, and general health and well being. In this article we draw from neuroimaging findings in humans, postmortem data, and human genetic and pharmacological studies as well as data from animal models of behavior to discuss the neurobiology of BPD. We conclude with a synthesis of where the field stands and with suggestions and strategies for future areas of study to further increase our conceptual understanding of this complex illness.
Keri Martinowich, Robert J. Schloesser, Husseini K. Manji
Childhood-onset obsessive-compulsive disorder (OCD) affects 1%–2% of children and adolescents. It is characterized by recurrent obsessions and compulsions that create distress and interfere with daily life. The symptoms reported by children are similar to those seen among individuals who develop OCD in adulthood, and the two groups of patients are treated with similar symptom-relieving behavior therapies and medications. However, there are differences in sex ratios, patterns of comorbidity, and the results of neuroimaging studies that might be important. Here we review the diagnosis and treatment of childhood-onset OCD in light of pediatric and adult studies. We also discuss current knowledge of the pathophysiology of the disorder. Despite advances in this area, further research is needed to understand better the etiopathogenesis of the disorder and to develop new, more effective therapeutic options.
Simran K. Kalra, Susan E. Swedo
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.
Pat Levitt, Daniel B. Campbell