Revisiting the classification of schizophrenia and bipolar disorder as separate clinical entities with distinct etiology and pathophysiologies has gained momentum recently. Infusion of a growing literature has drawn attention to shared aspects of psychopathology, neurobiology, and treatment efficacy across the 2 disorders. Linkage findings offer a substantial challenge to the traditional Kraepelinian model of the 2 disorders as having fully discrete underlying disease processes. Empirical support for similar pathoetiology in these disorders comes from genetic studies demonstrating shared genetic susceptibility. Yields from linkage studies indicate several loci that may represent risk genes for schizophrenia and bipolar disorder including 18p11.2, 13q32, 22q11–13, and 10p14.1–4
Candidate association studies have specified several genes (eg, G72/G30, BDNF, DISC1, COMT, neuregulin 1
, and dysbindin
) that appear to confer risk for both disorders. Importantly, these shared genetic factors appear to be more common in psychotic bipolar patients and their family members, suggesting that there may be common causes for psychosis across bipolar disorder and schizophrenia.5–8
Although differences between the disorders are established, especially the relatively specific familial aggregation of the disorders,9
shared deficits in neuropsychology,10–13
gross brain anatomy,17
and responsivity of both disorders to antipsychotic medications are consistent with the view that these disorders may share aspects of pathophysiology. Genetic models considering both common and unique genetic features of the disorders are of interest, for they bear on fundamental questions about the causes and interrelationship of the 2 most common, serious mental illnesses in adult psychiatry.
Unraveling the role of numerous contributing genetic factors to disease risk, including commonalities and differences across clinical syndromes, requires novel linkage strategies. The allied phenotype approach attempts to break down complex genetic disorders into their component parts by isolating intermediate expression/effects of individual genes. This approach is based on the premise that genetic determination of neurobiological alterations linked to illnesses may be more readily tracked than the genetic causes of overt expression of disorders. Relative to the clinical expression of psychiatric syndromes, this might be due to either an enhanced ability to resolve illness heterogeneity or a more direct genetic determination of specific biological traits. As in other medical disorders, this strategy in psychiatric genetics is based on the hope that improved understanding of the genetic causes of variation in allied phenotype expression will accelerate progress in understanding the genetics of complex psychiatric disorders. Given the possibility that schizophrenia and bipolar disorder share overlapping etiologic determinants, the endophenotypic approach may be helpful for delineating shared and unique causal pathways from genetic variation, to altered neural systems and neurobehavioral function, to the overt clinical expression of both disorders.
Useful allied phenotypes help to resolve questions about etiology in part by helping track down illness-related gene variants and also by filling gaps in the causal chain between gene expression and clinical expression. Consistent with suggested criteria for identification of endophenotypic markers,18–20
allied phenotypes should be: (1) heritable, (2) associated with the illness, (3) stable traits that can be reliably assessed, (4) cosegregated within families, and (5) higher in prevalence for unaffected relatives compared with the general population.
Based on current knowledge of both schizophrenia and bipolar disorder, genetic influence is likely to impact both structural and functional aspects of brain systems in ways that increase risk for the disorder. Atypical patterns in the organization of brain anatomy can be neurodevelopmental in origin,21–23
resulting in a cascade of events that manifest across a wide range of neurocognitive and affective abilities such as attention, executive function, working memory, affect regulation, affect-cognition integration, declarative memory, spatial processing, and psychomotor function. Consequently, neuropsychological measures are promising allied phenotypes, as are neurophysiological assessments of brain systems that subserve specific neurocognitive processes. The established heritability of cognitive abilities24,25
and the availability of highly reliable procedures for assessment of most cognitive skills highlight the potential of neurocognitive performance measures as candidate allied phenotypes for schizophrenia and bipolar disorder. To date, the allied phenotype approach has been used much more widely in studies of schizophrenia than bipolar disorder. Yet, patient studies with schizophrenia and bipolar patients have begun to show interesting patterns of separate and overlapping abnormalities in putative allied phenotypes.
The present review was organized to illustrate promising neuropsychological and neurocognitive candidate allied phenotypes with an eye toward guiding future work by identifying potential confounds and other critical factors that highlight areas where more work is needed. To this end, we review neurodevelopmental accounts of schizophrenia and bipolar disorder and the implications for allied phenotype research. Next, we examine the pediatric bipolar disorder and early-onset schizophrenia literatures for indicators of neurodevelopmental disruption, which may represent core allied phenotypic deficits. Finally, we review promising approaches from clinical cognitive and affective neuroscience research that have been used in studies of probands with schizophrenia and bipolar disorder and to a much more limited degree with their family members.