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IN THIS CHAPTER AND THE NEXT, we examine disorders that affect perception, thought, mood, emotion, and motivation: schizophrenia, depression, bipolar disorder, and anxiety disorders. These have been challenging to understand, but recent progress in genetic analysis has begun to yield significant clues to their pathogenesis.

Mental illness has damaging effects on individuals, families, and society. The World Health Organization reports that mental illnesses, in the aggregate, constitute the leading cause of disability worldwide and are the leading risk factors for the 800,000 annual suicides reported by the World Health Organization. In addition, depression and anxiety disorders frequently co-occur with and worsen the outcomes of diabetes mellitus, coronary artery disease, stroke, and several other illnesses.

Medications such as antipsychotic drugs, lithium, and antidepressant drugs discovered during the mid-20th century made it possible to close large and often substandard mental hospitals; however, halfway houses and other less restrictive treatment settings did not materialize in sufficient numbers. As a result, many people with schizophrenia and severe bipolar disorder become homeless at some time in their lives, and in many countries, individuals with severe mental disorders compose a large fraction of prison populations.

In addition, although antipsychotic drugs, lithium, and antidepressant drugs have played important roles in controlling symptoms of mental disorders, significant limitations in treatment efficacy remain. For example, there are no effective treatments for the highly disabling cognitive impairments and deficit symptoms of schizophrenia. Even for symptoms that benefit from existing medications, such as hallucinations and delusions, residual symptoms remain and relapses are the rule. Because of significant scientific challenges posed by the human brain and limitations in animal models of mental disorders, there has been little advance in the efficacy of psychiatric drugs for more than 50 years. However, recent progress in human genetics and neural science has created significant opportunities to improve upon this unfortunate state of affairs.

Schizophrenia Is Characterized by Cognitive Impairments, Deficit Symptoms, and Psychotic Symptoms

In medicine, the understanding of a disease, and therefore its diagnosis, is ultimately based on identification of two features: (1) etiological factors (eg, microbes, toxins, or genetic risks) and (2) mechanism of pathogenesis (the processes by which etiologic agents produce disease). While human genetics and neural science are beginning to provide insights into the etiology and pathogenesis of disorders such as schizophrenia, bipolar disorder, and autism spectrum disorders, this research has not yet yielded objective diagnostic tests or biomarkers. As a result, psychiatric diagnoses still rely on a description of the patient’s symptoms, the examiner’s observations, and the course of the illness over time.

Schizophrenia is a very severe illness. Its symptoms can be divided into three clusters: (1) cognitive symptoms; (2) deficit, or negative, symptoms; and (3) psychotic symptoms. These symptom clusters exhibit different temporal patterns of onset—with cognitive impairments and deficit symptoms typically the earliest. The different timing of ...

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