Shared and distinct neurocognitive endophenotypes of schizophrenia and psychotic bipolar disorder.

Original Article pISSN 1738-1088 / eISSN 2093-4327 Copyrightⓒ 2015, Korean College of Neuropsychopharmacology http://dx.doi.org/10.9758/cpn.2015.13.1.94 Clinical Psychopharmacology and Neuroscience 2015;13(1):94-102 Shared and Distinct Neurocognitive Endophenotypes of Schizophrenia and Psychotic Bipolar Disorder Dohoon Kim, Jiwoo Kim, Taehoon Koo, Hyerim Yun, Seunghee Won Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, Korea Objective: Schizophrenia and bipolar disorder are characterized by the presence of neurocognitive impairments on the psychosis continuum. The present study aimed to explore the shared and distinct endophenotypes between these disorders. Methods: The study included 34 probands with remitted schizophrenia and 34 probands with euthymic bipolar disorder who had a history of psychotic symptoms that met the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria, unaffected first-degree relatives of probands (31 relatives of probands with schizophrenia and 29 relatives of probands with bipolar disorder), and 34 healthy controls. Cognitive assessments were performed using the digit span, continuous performance, Rey auditory and visual learning, complex figure, verbal fluency, Wisconsin card sorting, and finger tapping tests. Results: Probands with schizophrenia showed the most generalized and severe cognitive deficits across cognitive domains (working memory, verbal learning and memory, visual memory, verbal fluency, and executive function). Some domains of cognitive function (working memory, verbal learning, and memory) were also impaired in probands with bipolar disorder, but to a lesser degree than in probands with schizophrenia. All probands and relatives showed a common deficit in working memory compared to healthy controls. Relatives of probands with schizophrenia also showed verbal fluency dysfunction. Cognitive performance of all relatives was intermediate to the performance of both patients and healthy controls. Conclusion: These findings suggest that a deficit in working memory could be a shared endophenotype of genetic vulnerability to schizophrenia and psychotic bipolar disorder, and verbal fluency could be a candidate endophenotype for schizophrenia specifically. KEY WORDS: Schizophrenia; Bipolar disorder; Endophenotypes; Cognition. INTRODUCTION susceptibility loci uncovered within recent genome-wide association studies.4,5) Because of these challenges, some researchers have suggested a dimensional approach to the psychosis continuum; the relative admixture of psychotic and affective symptoms would show a continuous distribution between SZ and psychotic BD.1) Many researchers have tried to identify whether SZ and BD should be considered as separate diseases or different manifestations of the same pathophysiological process. Establishing similarities and differences in the biological markers of SZ and BD may provide important insights for future genetic studies, and may improve conceptualizations about the common and distinct aspects of the pathophysiology, about clinical heterogeneity, and about the clinical boundaries of the two disorders. To overcome these clinical limitations, many researchers have tried to find endophenotypes that are specific to each disorder. These intermediate phenotypes are disease-associated traits that more strongly indicate the underlying molecular genetic background than the clinical phenotype itself. According to the “Kraepelinian dichotomy”, schizophrenia (SZ) and bipolar disorder (BD) have been regarded as different nosologic categories. This conception has been maintained in the current versions of the diagnostic classifications for mental disorders. However, several issues challenge the dichotomous paradigm of psychotic disorders with respect to SZ and BD.1) These issues include the overlapping organic basis and blurred boundaries between psychoses, as indicated by emerging biological data2,3); the non-specificity of psychopathological features, such as perceptual disturbances and affective symptoms, between SZ and BD; and the shared genetic Received: January 25, 2015 / Revised: March 18, 2015 Accepted: March 24, 2015 Address for correspondence: Seunghee Won, MD, PhD Department of Psychiatry, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Korea Tel: +82-53-200-5747, Fax: +82-53-426-5361 E-mail: This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 94 Neurocognitive Endophenotypes of Schizophrenia and Bipolar Disorder 95 Consistent with the suggested criteria for the identification of endophenotypic markers, allied phenotypes should be (a) associated with illness, (b) heritable, (c) state-independent, (d) co-segregated with illness within families, and (e) also found in unaffected relatives at a higher rate than in the general population.6) One of the widely studied putative endophenotypes in psychiatric syndromes is cognitive dysfunction. The established heritability of cognitive function and the neural networks mediating specific aspects of cognition, as well as the availability of objective measurement tools to assess cognitive performance provide support for examining cognitive 7) function as a promising endophenotype for SZ and BD. The literature reports that the generalized cognitive deficit in probands with SZ is present at the first episode of psychosis, relatively stable over time, largely independent of clinical status or antipsychotic treatment, and is an important cause of functional disability. Probands with BD also exhibit cognitive dysfunction even when in a euthymic state, and this tendency is preserved between mood episodes and is generally stable in chronic patients. Moreover, the cognitive impairments of BD can be strongly related to poor functional outcomes and present before illness onset.8) A meta-analysis on direct comparison studies of cognitive dysfunction have reported that probands with BD tend to show generalized cognitive impairment, although it is less severe than that of probands with SZ.9) As there is a high genetic influence on the development of SZ and BD, unaffected relatives are also anticipated to show some cognitive dysfunction. In this context, many studies of first relatives of probands with SZ and BD have explored whether cognitive impairment qualifies as a good candidate for an endophenotype for SZ or BD. Some recent studies of probands with SZ and their relatives have proposed verbal memory, executive function, working memory, verbal fluency, and sustained attention as poten10,11) tial endophenotypes for SZ. For BD, executive function, verbal memory, response inhibition, processing speed, and working memory were (...truncated)