Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization. They are highly heritable, with genetic risk comprising 20–90% of disease vulnerability. As a result of their prevalence, early onset, and persistence, they contribute substantially to the burden of illness worldwide. All psychiatric disorders are broad heterogeneous syndromes that currently lack well-defined neuropathology and bona fide biologic markers. Therefore, diagnoses continue to be made solely from clinical observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association, which is in its fifth edition as of 2013.
There is increasing agreement that the classification of psychiatric illnesses in DSM does not accurately reflect the underlying biology of these disorders. Uncertainties in diagnosis make it extremely difficult to study the neurobiologic and genetic basis of mental illness. This has led to the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoCs), which classifies mental illness on the basis of core abnormalities—e.g., psychosis (loss of reality) or anhedonia (decreased ability to experience pleasure), which are common symptoms of several illnesses—with the idea that such classifications will assist in defining the biologic basis of at least key symptoms. Other factors that have impeded progress in understanding mental illness include the lack of access to pathologic brain tissue except upon death and the inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations, delusions, guilt, suicidality) that are inaccessible in animals.
Despite these limitations, the past decade has seen significant advances. Neuroimaging methods are beginning to provide evidence of brain pathology, genome-wide association studies and high-throughput sequencing are at last revealing genes that confer risk for severe forms of mental illness, and investigations using better validated animal models are offering new insight into the molecular, cellular, and circuit mechanisms of disease pathogenesis. There is also excitement in the potential utility of neuron-like cells induced in vitro from a patient’s peripheral tissues (e.g., fibroblasts) providing novel ways of studying disease pathophysiology and screening for new treatments. There is consequently justified optimism that the field of psychiatry will transition from behaviorally defined syndromes to true biologic disease entities and that such advances will drive the development of improved treatments and eventually cures and preventive measures. This chapter describes several examples of recent discoveries in basic neuroscience that have informed our current understanding of disease mechanisms in psychiatry.
Because the human brain can only be examined indirectly during life, genome analyses have been extremely important for obtaining molecular clues about the pathogenesis of psychiatric disorders. A wealth of new information has been made possible by recent technological developments that have permitted affordable, large-scale genome-wide association studies and fine-scale sequencing. As an example, significant progress has been made in the genetics of autism spectrum disorders (ASDs), which are a heterogeneous group of neurodevelopmental diseases that share clinical ...