5 July 2013. Schizophrenia and bipolar disorder with psychosis share cognitive features and connectivity patterns, according to two studies from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) published online June 17 in the American Journal of Psychiatry. The first study, led by Scot Kristian Hill of Rosalind Franklin University, Chicago, Illinois, finds cognitive impairments in psychotic disorders relative to controls, with schizophrenia subjects worse off than those with schizoaffective disorder, which in turn were worse than subjects with psychotic bipolar disorder. In the second study, Pawel Skudlarski of Yale University, New Haven, Connecticut, and colleagues report differences in the brain’s communication byways relative to controls, with degradation of white matter integrity somewhat more pronounced for schizophrenia than for bipolar disorder. Both studies also found less severe cognitive and white matter impairments in unaffected relatives, which could flag inherited features amenable to gene finding.
The results suggest that boundaries between schizophrenia and bipolar disorder with psychosis reflect differences in degree rather than kind. Although overlaps between the two disorders have long been recognized (e.g., see SRF related news story), the studies reflect the first attempts of the B-SNIP group, consisting of six centers across the United States, to pinpoint similarities and differences between the two in a standardized setting. Distilling the symptoms of these disorders into specific component parts (also called intermediate phenotypes), such as a working memory impairment or an abnormal brain structure, could reveal underlying brain pathologies more clearly than a direct comparison of the two disorders (Meyer-Lindenberg et al., 2006).
Finding these component parts also marks the first step in looking for endophenotypes—those distilled features of an illness that are also inherited. Endophenotypes may lie closer to an originating genetic glitch than the complicated symptoms that define a diagnosis, making it easier to link genotype to phenotype. To this end, the B-SNIP project also examines unaffected relatives of people with schizophrenia and bipolar disorder.
Hill and colleagues assembled 293 participants with schizophrenia and 316 of their first-degree relatives, 227 with psychotic bipolar disorder and 259 of their relatives, 165 with schizoaffective disorder and 197 relatives, and 295 healthy controls. The researchers evaluated all participants with the Brief Assessment of Cognition in Schizophrenia (BACS), a 30-minute test of verbal memory, processing speed, reasoning, and working memory. The average scores for schizophrenia, schizoaffective disorder, and psychotic bipolar disorder were lower than those for healthy controls, indicating cognitive impairments. But within the psychotic disorders, the scores fell off progressively, with the psychotic bipolar group scoring highest, followed by schizoaffective disorder, then schizophrenia. Across the six different domains tested by the BACS, the psychotic disorders shared a similar profile of performance, differing only in the magnitude of impairment. Scores on the Schizo-Bipolar Scale revealed that more prominent mood symptoms and less persistent psychosis were associated with less severe cognitive impairments.
Among the first-degree relatives with no history of psychosis, those related to someone with schizophrenia showed cognitive impairments, whereas those related to someone with schizoaffective or bipolar disorder did not, as their scores were not significantly different from controls. Heritability testing revealed that performance on the BACS was potentially inherited, with heritability estimated at 0.5 for the schizophrenia families and 0.61 in the psychotic bipolar families. This indicates that these cognitive abilities might be worthy endophenotypes.
The researchers further parsed the relatives according to their personality traits, as measured by the DSM-IV. Among relatives of participants with schizophrenia, those who showed elevated personality traits for cluster A (odd or eccentric) or cluster B (dramatic, emotional, or erratic) performed just as poorly on the BACS as those who did not meet these personality criteria. Among relatives of participants with psychotic bipolar disorder, however, only the groups with elevated cluster A or cluster B traits showed cognitive impairments. This difference hints at a qualitative difference between the disorders and suggests that, for psychotic bipolar disorder, tracking both cognitive impairments and personality traits would be important for unearthing the relevant risk factors.
In the second study, Skudlarski and colleagues used brain imaging to try to discern features of brain structure that characterize psychotic disorders. Prompted by their previous findings of impaired functional connectivity in schizophrenia and psychotic bipolar disorder (Meda et al., 2012), the researchers used diffusion-tensor imaging to delineate the structure of the white matter tracts that connect different brain regions in 513 participants total, including first-degree relatives.
The researchers found signs of disrupted white matter structure—as indicated by lower than normal fractional anisotropy (FA) values, which measure how aligned connections are within a tract. These disruptions mapped to 29 of 76 regions analyzed, with the genu, or anterior bend, of the corpus callosum showing the greatest difference relative to controls. The pattern of disruption mostly overlapped between the two disorders, and the magnitude of the disruptions was largely the same. But schizophrenia registered more low FA regions, suggesting a slightly worse pattern. White matter differences also showed up in the relatives in attenuated form, and whole-brain FA had a heritability of 0.45, along with several individual regions weighing in with similar heritability. This suggests that white matter structure as reflected by FA might warrant pursuing as an endophenotype for psychotic disorders.
The findings in both studies obscure diagnostic boundaries and add heft to the idea that differences among psychiatric disorders are more quantitative than qualitative in nature. Though the search space for the core pathological components is vast, the studies here take steps toward defining them. Even if the cognitive and white matter features explored here do not turn out to be core features of psychotic disorders, they may still help define useful disease subtypes that can inform genetic studies as well as treatment plans.—Michele Solis.
Hill SK, Reilly JL, Keefe RS, Gold JM, Bishop JR, Gershon ES, Tamminga CA, Pearlson GD, Keshavan MS, Sweeney JA. Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study. Am J Psychiatry. 2013 Jun 17. Abstract
Skudlarski P, Schretlen DJ, Thaker GK, Stevens MC, Keshavan MS, Sweeney JA, Tamminga CA, Clementz BA, O'Neil K, Pearlson GD. Diffusion Tensor Imaging White Matter Endophenotypes in Patients With Schizophrenia or Psychotic Bipolar Disorder and Their Relatives. Am J Psychiatry. 2013 Jun 17. Abstract