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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 ; Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Jose GoikoleaEduard Vieta
Submitted 18 July 2013
Posted 18 July 2013

The recent publication of two papers from the B-SNIP group in the American Journal of Psychiatry provides additional high-quality data supporting a dimensional model for psychotic disorders, different from the current Kraepelinian categorical model. These two papers focus on two different putative endophenotypes for schizophrenia and bipolar disorder, namely, cognitive performance and white matter integrity. Interestingly, both endophenotypes show quite similar results.

The work of the B-SNIP group is praiseworthy. Consisting of six centers across the United States, the group has studied quite a large sample of patients with psychotic disorders (schizophrenia, schizoaffective, and psychotic bipolar disorder) using both current categorical diagnostic criteria and a dimensional Schizo-Bipolar Scale approach. Besides that, the group assesses relatives without psychotic or affective disorders, which is essential for further understanding the underlying genetic basis and identifying endophenotypes for these disorders.

Both studies obtain similar results for each endophenotype: Both schizophrenia and bipolar disorder show abnormalities (in cognition and in white matter integrity) compared to healthy controls. There are no qualitative differences in these abnormalities; that is, they share a similar pattern of disturbance, although it is more severe (cognition) or widespread (white matter) in schizophrenia. These disturbances are shared to a lower degree by unaffected relatives, supporting their validity as endophenotypes, even if this is much clearer for relatives of schizophrenia subjects. Undoubtedly, these results support the notion of a single nosological entity with a dimensional nature. On the “schizophrenia edge” of the continuum, a more severe or widespread impairment as well as more abnormalities in unaffected relatives would be found.

However, there are some comments that should be taken into account for a fair interpretation of the results. First of all, the diagnosis of schizoaffective disorder has become somehow a test itself to validate the categorical versus dimensional model for psychotic disorders. The paper by Hill et al. compares the schizoaffective group with the healthy control group and with the other proband groups. The conclusions seem to support the dimensional model, as schizoaffective probands show an intermediate cognitive performance between schizophrenia and bipolar disorder without qualitative differences. Instead, for unclear reasons, the DTI paper splits the schizoaffective group in manic type merged with the bipolar group, and depressive type merged with the schizophrenia group, losing an opportunity to analyze this perspective.

Second, it is a shame that non-psychotic bipolar 1 patients have not been included in these studies. This represents a bias toward the psychotic view, whereas the inclusion of the non-psychotic bipolar subjects would have provided a second enriching view from the “affective” perspective. This second supplementary approach would be more likely to identify possible endophenotypic features that might differentiate schizophrenia from bipolar disorder. In fact, in light of these two papers, schizophrenia and bipolar disorder could be understood as the same disease, bipolar just being a less severe phenotype. Although there is quite large evidence that schizophrenia and bipolar disorder share different genetic, neurobiological, and cognitive features, and that a mixed categorical and dimensional approach may be much closer to reality, differences between both disorders should still be kept in mind. For instance, the unique clinical features of the most prototypical euphoric mania or the circadian rhythm disturbances in bipolar disorder are likely to be based on neurobiological features specific to bipolar disorder that are not yet completely understood or identified.

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Primary Papers: Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study.

Comment by:  Antonella Trotta
Submitted 5 August 2013
Posted 7 August 2013
  I recommend this paper

Despite Kraepelin’s nosological distinction between schizophrenia and bipolar disorder and the categorical classification of current diagnostic systems, recent advances indicate that there is considerable overlap between these disorders. In fact, epidemiological, genetic, and neuroimaging studies comparing schizophrenia and bipolar disorder show a complex range of pathophysiological and phenomenological similarities (Demjaha et al., 2012).

In line with previous findings, the two papers from the B-SNIP group in the American Journal of Psychiatry confirm, respectively, the role of potential cognitive and brain functioning endophenotypes in schizophrenia and bipolar disorder. The findings of Hill and colleagues on cognitive impairment in schizophrenia and psychotic bipolar disorder add an important contribution to a continuum model of cognitive deficits in psychotic disorders in which, on one hand, schizophrenia is characterized by the most severe cognitive impairment, and bipolar disorder, on the other hand, shows less severe but still significant deficits. Moreover, their findings confirm the familiality of cognitive impairment across schizophrenia, while cognitive dysfunction in first-degree relatives of bipolar disorder probands is linked with elevated cluster A or cluster B personality traits.

It seems likely that certain risk factors (i.e., susceptibility genes) may predispose an individual to developing psychosis, and then other genetic and/or environmental risks factors may determine if schizophrenia or bipolar disorder symptoms predominate. In fact, birth cohort and conscript studies have shown that schizophrenia and bipolar disorder are distinguished by premorbid cognitive impairment being found in the former but not in the latter. This may reflect a neurodevelopmental abnormality in schizophrenia but not bipolar disorder; thus, on the background of genetic susceptibility to psychosis, additional genes may interact with early environmental stressors, leading to schizophrenia.

However, the findings of Hill and colleagues should be considered in the light of some limitations. First, although they retrospectively assessed cognitive functioning before the illness onset using the WRAT-4 reading test, the authors do not pay much attention to cognitive trajectories in either probands or first-degree relatives. Their results show, in fact, that cognitive impairment precedes the onset of schizophrenia but not bipolar disorder, and a similar pattern is shown by their unaffected relatives. A recent meta-analysis of follow-up studies of cognition in first-episode psychosis and ultra-high-risk groups for psychosis reported no evidence of cognitive decline over, or after, the onset of first-episode psychosis (Bora and Murray, 2013). Therefore, these findings suggest that cognitive deficits are already established before the prodromal phase of psychosis, supporting a neurodevelopmental rather than neurodegenerative model of schizophrenia-like psychosis (Murray et al., 2004).

Moreover, Hill and colleagues underestimate the effect of other potential biological or environmental factors on the association between cognitive performance and schizophrenia or bipolar disorder, such as sociodemographic and clinical variables, as well as the influence of medication on cognitive functioning. Cognitive deficit could be intrinsic to the illnesses but could also be related to other factors such as substance misuse, physical ill health, or prescribed medications (Zipursky et al., 2012).

Therefore, future studies including examining longitudinal changes in cognition using a large sample size and controlling for potential confounders would advance our understanding in identifying the potential causes of the deficits.

References:

Bora E, Murray RM. Meta-analysis of Cognitive Deficits in Ultra-high Risk to Psychosis and First-Episode Psychosis: Do the Cognitive Deficits Progress Over, or After, the Onset of Psychosis? Schizophr Bull . 2013 Jun 14. Abstract

Demjaha A, Maccabe JH, Murray RM. How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull . 2012 Mar ; 38(2):209-14. Abstract

Murray RM, Sham P, van Os J, Zanelli J, Cannon M, McDonald C. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res . 2004 Dec 1 ; 71(2-3):405-16. Abstract

Zipursky RB, Reilly TJ, Murray RM. The Myth of Schizophrenia as a Progressive Brain Disease. Schizophr Bull . 2012 Dec 7. Abstract

View all comments by Antonella TrottaComment by:  Ole A. AndreassenMartin Tesli
Submitted 3 September 2013
Posted 4 September 2013

The two reports from the B-SNIP consortium elegantly address Kraepelin’s dichotomy in psychosis and provide evidence using a large sample that there are overlapping cognitive deficits across psychotic bipolar disorder and schizophrenia (Hill et al., 2013), and similar patterns of connectivity abnormalities (as measured by diffusion tensor imaging, or DTI) in the two disorders (Skudlarski et al., 2013). Both phenotypes are also found in relatives, supporting the idea that the cognitive and DTI measures are true "endophenotypes."

The finding that cognitive dysfunction in schizophrenia and psychotic bipolar disorder depends more on psychosis than a diagnostic group is a nice replication of our previous findings (Simonsen et al., 2011). This is reassuring and further suggests that it is a robust phenomenon, as the neuropsychological test batteries used in the two studies were quite different. The severity of the deficits is also comparable between the two studies.

The current study also investigated the familiality of cognitive dysfunction, which was quite high, with deficits also seen in non-psychotic relatives of both bipolar disorder and schizophrenia. Quite interestingly, the cognitive deficits were more associated with cluster A (psychosis-like) personality traits in relatives of bipolar disorder than in schizophrenia. This further strengthens the argument that there is a continuum of psychosis across these disorders which is heritable.

The paper by Skudlarski et al. reports brain imaging investigations (DTI) from the same sample. Decreased fractional anisotropy was found in multiple brain regions in schizophrenia and psychotic bipolar disorder subjects, and to a smaller extent in their relatives, than in healthy controls. These findings seem consistent, as 15 out of 18 regions have been previously reported in schizophrenia and 10 out of 21 in bipolar disorder. Further, the current results are in line with the continuum model of psychotic disorders and the polygenic architecture reported in recent mega-analyses (Lee et al., 2013).

Intriguingly, the authors found fractional anisotropy to be even better correlated with the "Schizo-Bipolar Scale" than with disease category. This proves the utility of cross-diagnostic clinical dimensions when investigating potential neurobiological mechanisms in psychiatric disorders. To bring this a step further, it would be interesting to know whether this clinical scale also correlates with fractional anisotropy (or neurocognition) within the bipolar disorder or the schizophrenia sub-sample separately.

In the perspective of the psychosis continuum model, it seems slightly contradictory that the investigators did not include schizoaffective disorder as a disease category on its own. Instead, they split this diagnostic group in two, classifying the depressed subgroup in the schizophrenia group and the manic subgroup in the psychotic bipolar disorder group. As a rationale for this classification, the authors reported controversial validity of the diagnostic status of schizoaffective disorder. If this controversy led to a split of the schizoaffective group in the paper by Skudlarski et al., why did the same controversy lead to the inclusion of schizoaffective disorder as its own category in the study by Hill et al.? Both approaches could potentially have been applied in both studies to actually explore this controversy in terms of neurocognition and white matter integrity.

Both studies support the hypothesis that reduced white matter integrity and impaired neurocognition are intermediate phenotypes in psychotic disorders. However, it might be debated whether these two features are causative in nature or merely correlate with the clinical symptomatology. Does reduced white matter integrity cause reduced neurocognition, which in turn gives rise to psychotic symptoms, or are the two latter phenomena independent but correlating effects of the former? Future studies should aim at disentangling these levels of correlating phenomena in biological psychiatric research. In line with this, it would be interesting to investigate the relationship between DTI measures and structural and functional MRI. Is the currently reported reduced white matter integrity reflected in the reductions identified with sMRI? And what consequences do these impairments have for brain activity as assessed with fMRI? Lastly, can these alterations be explained by genetic risk variants individually or in aggregate?

In summary, these two statistically well-powered studies have provided robust evidence for the continuum model in psychotic disorders. This is in accordance with findings from molecular genetics, brain imaging, and clinical studies. Now it is time to look for mechanisms behind these correlations.

References:

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

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