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Biology of Psychiatric Disorders

INTRODUCTION

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, Fifth Edition (DSM-5), of the American Psychiatric Association.

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 complicate efforts to study the genetic basis and attendant neurobiological mechanisms underlying mental illness, though recent advances in genomic and neuroscience technologies along with the consolidation of very large patient cohorts have, for multiple disorders, led to major progress in these realms. In addition, there have been recent efforts to address the limitations of a categorical nosology directly through the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoC). This system classifies mental illness on the basis of core behavioral abnormalities shared across several syndromes—such as psychosis (loss of reality) or anhedonia (decreased ability to experience pleasure)—and the associated brain circuitry that controls these behavioral domains. It is anticipated that that such classifications will assist in defining the biologic basis of 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 been marked by real progress. Neuroimaging methods are beginning to provide evidence of brain pathology; genome-wide association studies and high-throughput sequencing are reliably identifying genes and genomic loci that confer risk for severe forms of mental illness; and investigations of better validated animal models, leveraging a host of new methods to study molecular, cellular and circuit level processes, are offering new insight into disease pathogenesis. There is also excitement in the utility of neurons and brain organoids induced in vitro from patient-derived pluripotent stem cells, providing novel ways to study disease pathophysiology and screen for new treatments. There is consequently justified optimism that the field of psychiatry will better integrate behaviorally defined syndromes with an understanding of biological substrates in a way that will drive the development of improved treatments and eventually cures and preventive measures. This chapter describes several examples of recent discoveries in basic neuroscience and genetics that have informed our current understanding of disease mechanisms in psychiatry.

NEUROGENETICS

Because the human brain can only be examined indirectly during life, genome ...

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