Baer Arts

Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives

BACKGROUND Previous work suggests that impairments in executive function and verbal memory in particular may persist in euthymic bipolar patients and serve as an indicator of genetic risk (endophenotype). METHOD A systematic review of the literature was undertaken. Effects sizes were extracted from selected papers and pooled using meta-analytical techniques. RESULTS In bipolar patients, large effect sizes (d>0.8) were noted for executive functions (working memory, executive control, fluency) and verbal memory. Medium effect sizes (0.5<d<0.8) were reported for aspects of executive function (concept shifting, executive control), mental speed, visual memory, and sustained attention. Small effect sizes (d<0.5) were found for visuoperception. In first-degree relatives, effect sizes were small (d<0.5), but significantly different from healthy controls for executive function and verbal memory in particular. CONCLUSIONS Executive function and verbal memory are candidate bipolar endophenotypes given large deficits in these domains in bipolar patients and small, but intermediate, cognitive impairments in first-degree relatives.

A 2‐year naturalistic study on cognitive functioning in bipolar disorder

Arts B, Jabben N, Krabbendam L, van Os J. A 2‐year naturalistic study on cognitive functioning in bipolar disorder.

Neurocognitive functioning as intermediary phenotype and predictor of psychosocial functioning across the psychosis continuum: studies in schizophrenia and bipolar disorder.

OBJECTIVE Neurocognitive functioning may represent an indicator of genetic risk and poor outcome in both schizophrenia and bipolar disorder. In this study, shared and nonshared characteristics in the cognitive domain in both disorders were analyzed to determine to what degree neurocognitive functioning may represent a predictor of the familial vulnerability and poor functioning that schizophrenia spectrum disorders and bipolar disorder share. METHOD Neurocognition, psychopathology, and psychosocial functioning were assessed in samples of patients with a schizophrenia spectrum disorder (n = 345) and bipolar disorder (n = 76) meeting DSM-IV criteria, first-degree relatives of both patient groups (n = 331 and n = 37, respectively), and healthy controls (n = 260 and n = 61, respectively). Multiple regression models were used to investigate the effect of group status on neurocognition and to explore associations between cognition, symptoms, and psychosocial functioning in the 2 groups. The schizophrenia spectrum study sample was recruited between September 2004 and January 2008, and the bipolar study sample was recruited between June 2004 and July 2007. RESULTS Cognitive deficits were more severe and more generalized in patients with a schizophrenia spectrum disorder compared to patients with bipolar disorder; cognitive alterations were present in relatives of patients with schizophrenia spectrum disorders but not in relatives of bipolar patients. The association between neurocognitive dysfunction and psychosocial functioning was more generalized in schizophrenia spectrum disorders than in bipolar disorder; for both disorders, associations were only partly mediated by symptoms. CONCLUSIONS The evidence for cognitive dysfunction as a marker of familial vulnerability is stronger for schizophrenia than for bipolar disorder. Although the presence of multiple cognitive deficits is shared by the 2 groups, the severity of cognitive deficits and its consequences appear to partly differ between schizophrenia and bipolar disorder, which is in line with a model that implies the specific presence of a neurodevelopmental impairment in the former but not in the latter.

Investigating the association between neurocognition and psychosis in bipolar disorder: further evidence for the overlap with schizophrenia

OBJECTIVES In schizophrenia, a distinction is made between psychosis with developmental and cognitive impairment on the one hand and psychosis without developmental impairment and positive symptoms on the other. In this study, we investigated whether this model can be extended to bipolar disorder by testing the hypothesis that neurocognitive functioning is inversely related to positive psychotic symptoms in bipolar disorder. METHODS Neurocognitive functioning and psychopathology were assessed in (i) 76 patients with bipolar disorder, (ii) 39 of their healthy first-degree relatives, and (iii) 61 healthy controls. Cognitive performance of bipolar patients and their first-degree relatives was investigated, taking into account the possible moderating effect of the level of expression of psychosis in patients and relatives. RESULTS Bipolar patients showed impaired cognitive performance on multiple cognitive domains, whereas performance of their relatives was comparable to that of controls. A history of psychotic symptoms in patients was suggestive of less likelihood of cognitive alterations in relatives, and the presence of subclinical psychotic symptoms within the group of relatives predicted better cognitive performance. CONCLUSIONS The finding of similar psychosis-cognition associations in bipolar disorder as implied by the two pathways leading to nonaffective psychotic disorders suggests that this model might be extended to the continuum spanning affective and nonaffective psychosis. This is in line with the idea of a partially overlapping vulnerability to bipolar disorder and schizophrenia and provides an explanation for the apparent differences in cognitive alterations in those at risk for the two disorders.

Depressive Symptoms in Crohn's Disease: Relationship with Immune Activation and Tryptophan Availability

Crohns disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohns Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability.

Cognitive processes and attitudes in bipolar disorder: A study into personality, dysfunctional attitudes and attention bias in patients with bipolar disorder and their relatives

BACKGROUND Research in cognitive processes and attitudes in bipolar disorder is scarce and has provided mixed findings, possibly due to differences in current mood state. It is unclear whether alterations in cognitive processes and attitudes are only related to the depressive mood states of bipolar patients or also represent a vulnerability marker for the development of future (depressive) episodes. This was investigated in the current study. METHODS Both implicit (attentional bias for emotional words) and explicit (dysfunctional attitudes and personality characteristics) measures of cognitive processes and attitudes were assessed in 77 bipolar patients with varying levels of depressive symptoms (depressed=17, euthymic n=60), their healthy first-degree relatives (n=39) and a healthy control group (n=61). Analyses of variance were used to investigate differences between groups. RESULTS Mildly depressed patients with bipolar disorder demonstrated an attentional bias away from positive emotional words and showed increased dysfunctional attitudes and higher levels of neuroticism. Euthymic patients were largely comparable to healthy controls and only differed from controls in higher levels of neuroticism. Relatives were similar to controls on all measures, although they significantly differed from bipolar patients in displaying less neuroticism and more extraversion. LIMITATIONS No firm conclusions regarding causality can be drawn from the associations that were found between cognitive processes and attitudes and the evolution of mood symptoms in bipolar disorder. CONCLUSION Alterations in cognitive processes and attitudes in bipolar patients appear to be mostly related to the expression of mood symptomatology rather than to the vulnerability for bipolar disorder.

S100 and impact of ECT on depression and cognition.

Objectives: The main side effects of electroconvulsive therapy (ECT) are in the realm of cognition. The S100-beta is a calcium-binding protein that is expressed by astrocytes in the central nervous system during depression and has been suggested to modulate the impact of ECT on cognition. Methods: Serum samples of S100-beta were taken before and 1 and 3 hours after each ECT session in 12 depressed patients (mean age, 54 years), treated with bilateral ECT twice weekly (mean, 6 sessions). Measures of depression (Symptom Checklist-90 depression dimension) and a neurocognitive test battery yielding 3 domains of general cognition, memory, and subjective cognitive impairment were administered 1 day before and 5 and 30 days post-ECT. Results: Electroconvulsive therapy was associated with a reduction in depression and subjective cognitive impairment at 5 and 30 days post-ECT. Electroconvulsive therapy was associated with a small but significant rise in S100-beta 1 hour post-ECT (adjusted B = 0.013, P = 0.035), with a directionally similar but reduced effect size at 3 hours post-ECT (adjusted B = 0.010, P = 0.10). Higher level of S100-beta at baseline was associated with poorer memory function at 5 and 30 days of follow-up (adjusted B per tertile group increase, 0.38, P = 0.013) but also with less subjective cognitive impairment (B = −28.2, P < 0.001) and less depression at follow-up (B = −15, P = 0.009). Conclusion: The S100-beta at baseline may be a marker predicting and possibly mediating the differential impact of ECT on cognition and depression.

The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway

BACKGROUND There is still limited knowledge about the mechanism of action of electroconvulsive therapy (ECT) in the treatment of depression. Substantial evidence suggests a role for the immune-moderated tryptophan (TRP)-kynurenine (KYN) pathway in depression; i.e. a depression-associated disturbance in the balance between the TRP-KYN metabolites towards a neurotoxic process. We, therefore, aimed to investigate the impact of ECT treatment on the TRP-KYN pathway, in association with ECT-related alterations in depressive symptoms. METHOD Twenty-three patients with unipolar or bipolar depression, treated with bilateral ECT twice a week were recruited. Blood serum samples, and depression scores using the Hamilton Depression Rating Scale-17 items (HDRS) as well as the Beck Depression Inventory (BDI) were collected repeatedly during the period of ECT and until 6 weeks after the last ECT session. TRP and KYN metabolites were analyzed in serum using the High Performance Liquid Chromatography. Four patients could not complete the study; thereby yielding data of 19 patients. Analyses were performed using multilevel linear regression analysis. RESULTS There was an increase in kynurenic acid (KYNA) (B=0.04, p=0.001), KYN/TRP ratio (B=0.14, p=0.001), KYNA/KYN ratio (B=0.07, p<0.0001), and KYNA/3-hydroxykynurenine ratio (B=0.01, p=0.008) over time during the study period. KYN (B=-0.02, p=0.003) and KYN/TRP (B=-0.19, p=0.003) were negatively associated with total HDRS over time. Baseline TRP metabolite concentrations did not predict time to ECT response. CONCLUSION Our findings show that ECT influences the TRP-KYN pathway, with a shift in TRP-KYN metabolites balance towards molecules with neuroprotective properties correlating with antidepressant effects of ECT; thereby providing a first line of evidence that the mechanism of action of ECT is (co)mediated by the TRP-KYN pathway.

The Immune System and Electroconvulsive Therapy for Depression

Background Electroconvulsive therapy (ECT) remains the most effective and fast-acting treatment option for several psychiatric conditions, including treatment-resistant depression. Although ECT has been in use for 75 years, the mechanism of action is unknown. There is emerging evidence that modulation of the hypothalamic-pituitary-adrenal axis may mediate, in part, the therapeutic action of ECT. A growing body of evidence points to links between disturbances in the immune system and depression. However, the impact of ECT on immune functioning and the possible role of alterations in the immune system as a mechanism of action of ECT remain elusive. Objectives To provide a literature overview on the effects of ECT on the immune system. Methods Relevant articles and abstracts in English were retrieved from PubMed/Medline using search terms related to ECT, inflammation, and immune system. The results of studies examining ECT-induced changes in immune functioning as well as the degree to which these represent possible mechanisms mediating the therapeutic action of ECT were summarized. Results Our search identified only a limited number of studies. The findings suggest that a single session of ECT induces an acute, transient immune activation, whereas repetitive ECT treatment results in long-term down-regulation of immune activation. However, inconsistency in findings and methodological issues, including sample size and lack of consideration of confounding factors affecting cytokine concentrations, precludes definitive conclusion. Conclusions To elucidate the possible role of immunological changes mediating the effect of ECT, more prospective controlled studies with larger sample sizes are required.

Evidence for the impact of the CACNA1C risk allele rs1006737 on 2-year cognitive functioning in bipolar disorder.

Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Centre Maastricht, GGzE, Institute for Mental Health Care Eindhoven en de Kempen, Eindhoven, The Netherlands and King’s College London, King’s Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, UK Correspondence to Baer Arts, MD, Department Psychiatry and Psychology, School for Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands Tel: + 31 43 3874130; fax: + 31 43 3875444; e-mail: b.arts@maastrichtuniversity.nl