Comparing Genes and Phenomenology in the Major Psychoses: Schizophrenia and Bipolar 1 Disorder

Abstract

For the last several decades, diagnosis in psychiatry has been rule based, related to phenomenology and standardized. It has given psychiatry an unearned advantage in communicating about its illnesses, unearned because the molecular basis for this standardization has remained elusive. However, it has provided a language for successful communication about psychiatric syndromes and supported practical functions for which categorization is helpful; functions as disparate as insurance reimbursement and drug development have been enabled with this language. Moreover, this standardization has had additional practical advantages beyond communication and labeling, specifically in terms of public familiarity. Further, these standardized categories have been postulated without any real knowledge about the biological nature of the underlying brain disturbances or their mechanisms. Imagine categorizing diabetes by phenomenology before 1922 or infectious disease before the microscope and antibiotics. It is hard to intuit how one might successfully use nonspecific illness descriptors of phenomenology to sort affected individuals into homogeneous enough categories to discover molecular disease mechanisms, whether the diseases involve disorders of the pancreas, heart, or brain. In psychiatry, despite the practical importance of the Diagnostic and Statistical Manual of Mental Disorder (DSM) nomenclature, the diagnostic system remains a hypothesis of disease categories, awaiting a refinement of categorization based on mechanisms and molecules. Not that we should be persuaded to discard this current system, until another one, more biologically based, is in place. But, because this current system may not provide the final correct illness categories, it may be time to experiment with other systems, within research indications. In this context, scientists and clinicians alike have developed an informed skepticism, whose goal is to promote mechanism-oriented research into the major psychoses with the goal of defining the mechanistic basis of the brain diseases with cognitive and affective expression. There is consistent evidence that genes contribute to the etiology of psychosis. Recent findings from genetic studies provide evidence for an overlap in genetic susceptibility across the traditional psychosis categories. Candidate genes show strong associations with component symptom complexes, such as psychosis, that are not projected directly onto Kraepelinian disease entities. Genetic studies suggest that psychosis may be conceptualized as a clinical phenotype with specific genetic etiologies. Hypothetically genes or sets of genes, interacting with environmental factors, may predetermine vulnerability to psychosis. Depending on additional syndrome-specific genetic influence and environmental interactions, psychosis may coexist with other clinical phenotypes, eg, mood symptoms or cognitive dysfunction, composing categorical diagnoses. This conceptualization of psychosis is well illustrated by epidemiological and molecular genetic studies. In this chapter, we will review the phenomenology and genetics of psychosis, across different diagnoses. Other aspects of the psychosis overlap will be presented in other articles in this volume.