New insights into the endophenotypic status of cognition in bipolar disorder: genetic modelling study of twins and siblings.

BACKGROUND: Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder. AIMS: To quantify the shared genetic variability between bipolar disorder and cognitive measures. METHOD: Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder. RESULTS: Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|-|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|-|1.00|), which remained significant after covarying for affective symptoms. CONCLUSIONS: Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.

Executive functioning in familial bipolar I disorder patients and their unaffected relatives.

OBJECTIVE: To compare the executive function of patients with familial bipolar I disorder (BP-I) with a history of psychotic symptoms to their first-degree relatives and normal controls. METHODS: Three domains of executive function: response inhibition, working memory, and cognitive set shifting were assessed in 44 familial patients with a lifetime diagnosis of BP-I who had experienced psychotic symptoms, 42 of their unaffected first-degree relatives, and 47 controls. RESULTS: Bipolar disorder patients and their unaffected relatives had significantly worse scores for response inhibition compared to healthy controls. The groups did not differ in working memory or cognitive set shifting. CONCLUSIONS: Impairments in response inhibition are associated with both psychotic bipolar disorder and genetic liability for this illness. Our results indicate that deficits in this specific domain of executive functioning are a promising candidate endophenotype for psychotic bipolar disorder.

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.

Auditory P300 in patients with bipolar disorder and their unaffected relatives.

OBJECTIVES: There is evidence that genetic susceptibility may be shared between bipolar disorder (BD) and schizophrenia, but electrophysiological phenotypes which have been extensively used in studies of genetic susceptibility for schizophrenia remain far less explored in bipolar illness. This study assesses whether auditory P300 latency delays and amplitude reductions, which have been demonstrated in patients with schizophrenia and their unaffected first-degree relatives, are associated with familial liability to psychotic bipolar illness. METHODS: The P300 auditory evoked potential was obtained using an oddball task from 37 participants with BD who had a history of psychotic symptoms, 38 of their unaffected first-degree relatives and 42 healthy unrelated comparison subjects. Patients and relatives came from families multiply affected with BD or another functional psychotic disorder. P300 amplitude and latency at midline sites were compared between the groups, using linear regression analyses and robust variance estimators for clustered data, including age and gender as covariates. RESULTS: Bipolar disorder patients with a history of psychosis and their unaffected relatives showed significantly delayed P300 latency at Pz compared to controls. The groups did not differ in P300 amplitude. CONCLUSIONS: P300 latency delays are associated with both psychotic BD and familial liability for this illness. Sample size limited our ability to test for multimodal distribution of P300 measures among relatives, which might be expected if only a subgroup inherits any deficits. In future it will be of interest to directly compare groups of families with psychotic and non-psychotic forms of BD to explore further the role of psychotic symptoms with regard to P300 measures in the disorder. Our results indicate that delayed P300 latency is a promising candidate endophenotype for psychotic BD, as well as schizophrenia, and may reflect the impact of shared susceptibility genes for both types of psychosis.

P50 auditory evoked potential suppression in bipolar disorder patients with psychotic features and their unaffected relatives.

BACKGROUND: Diminished suppression of the P50 response, a consistent finding in schizophrenia, has also been reported in patients with psychotic bipolar disorder. It is a promising endophenotype for schizophrenia, but its relationship to genetic liability in bipolar disorder is unknown. We therefore assessed whether diminished P50 suppression is associated with familial risk for psychotic bipolar disorder. METHODS: The P50 response was collected in a conditioning (C)--testing (T) paradigm from 42 outpatients with bipolar 1 disorder who had experienced psychotic symptoms and 44 of their unaffected first-degree relatives, all from families multiply affected with bipolar disorder or another non-organic psychotic disorder; 48 healthy control subjects were also studied. The T/C ratio was compared between the groups, with linear regression analyses and robust variance estimators for clustered data. RESULTS: Both patients (estimated mean difference in T/C ratio to control subjects, 32, 95% confidence interval [CI] 15-48, p=.001) and unaffected relatives (20, 95% CI 7-32, p=.002) demonstrated higher T/C ratio, thus indicating diminished P50 suppression compared with control subjects. CONCLUSIONS: To our knowledge, this is the first report of diminished P50 gating in unaffected relatives of psychotic bipolar disorder patients from multiply affected families. Our results suggest that impaired P50 gating is a putative endophenotype for psychotic bipolar disorder and thus might reflect the impact of susceptibility genes across psychosis.