Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder
Introduction
Recent studies have reported that neurocognitive impairments in bipolar disorder (BD) persist during remission (Robinson and Ferrier, 2006, Robinson et al., 2006), particularly in the domains of sustained attention (Clark et al., 2002, Bora et al., 2006), verbal memory (Zubieta et al., 2001, Altshuler et al., 2004, Bora et al., 2005) and executive functions (Altshuler et al., 2004, Bora et al., 2007). While these findings raise the possibility that some neuropsychological deficits can be vulnerability factors for BD, other explanations, like the effects of disease process, cannot be ruled out. Indeed, there is evidence that demonstrates that some neurocognitive variables, particularly verbal memory, may be linked to disease progression (Robinson and Ferrier, 2006).
Defining the abnormal behavioral, electrophysiological and biochemical markers that are related to underlying neurobiological processes rather than overt clinical signs or symptoms (endophenotypes) in BD patients in remission and their relatives is essential to understand the genetic underpinnings of complex psychiatric disorders like BD. To be considered as an endophenotype, a neurobiological marker must possess some specific criteria: (a) must be associated with illness, (b) must be observable in asymptomatic patients, (c) should be heritable, (d) should segregate with illness within families, and (e) must be observed at a higher rate among unaffected family members compared with the general population (Gottesman and Gould, 2003). While cognitive deficits are heritable and has been observed in euthymic BD patients, the final criterion for an endophenotype, deficit in family members, has not been investigated extensively in BD.
One of the most likely candidates as a cognitive endophenotype of BD is executive dysfunction. In addition to neuropsychological studies in euthymic BD patients, evidence of brain-imaging and biochemical abnormalities in frontal cortex in BD also supports this possibility (Blumberg et al., 2003, Kronhaus et al., 2006, Scan et al., 2006, Xing et al., 2006). However, few studies have extensively investigated executive function in family members of BD patients. There is some evidence for the existence of executive function (Ferrier et al., 2004, Frangou et al., 2005, Clark et al., 2005) deficits in relatives of BD probands, and tryptophan depletion was also reported to impair frontal lobe functions of relatives of patients with BD (Sobczak et al., 2002). Investigating different cognitive skills that are grouped under the concept of executive function in unaffected relatives of patients with BD is important in the effort to describe the specific cognitive endophenotypes of BD disorder.
In this study, we aimed to investigate the neuropsychological performances of unaffected first-degree relatives of patients with BD. We predicted that unaffected relatives of BD patients would have impaired performance on cognitive tests of frontal-executive functions. We also assessed the effect of family history of mood disorder with psychotic features on neurocognitive measures.
Section snippets
Sample
This study was conducted at the Affective Disorders Unit of Ege University Medical School. In this cross-sectional study, 39 first-degree relatives of patients with BD I disorders were interviewed. The relatives were contacted through 25 DSM-IV diagnosed BD type I patients. Previous history of psychiatric treatment, affective disorders, psychotic disorders, anxiety disorders and history of substance dependence, brain trauma and chronic medical disorders were exclusion criteria. Only two
Results
Clinical ratings for the subjects' mood and demographic variables in the two groups were successfully matched (Table 1). Verbal IQ estimates of the two groups were not different. MANOVAs demonstrated that the relative group, compared with the controls, was significantly impaired on only two cognitive domains: verbal working memory and executive function (Table 2). The effect sizes of between-group differences were large (eta square values > 0.14) for these domains. Healthy control subjects also
Discussion
Unaffected first-degree relatives of patients with BD showed significant impairments in working memory and executive function tasks. Verbal IQ estimate, psychomotor speed, sustained attention and verbal memory performance of the relatives did not significantly differ from performance in control subjects. These findings suggest a selective rather than a general cognitive dysfunction in high-risk subjects at high risk subjects for BD. Since ratings of mood symptoms did not differ between groups
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