Longitudinal alterations in mRNA expression of the BDNF neurotrophin signaling cascade in blood correlate with changes in depression scores in patients undergoing electroconvulsive therapy.

Electroconvulsive therapy (ECT) appears to be the most effective treatment for severe depression. However, its mechanisms of action are incompletely understood. Evidence suggests ECT enhances neuroplasticity and neurogenesis. While studies on ECT-induced neuroplasticity focused on brain-derived neurotrophic factor (BDNF), other factors of the BDNF/TrkB signaling cascade remain underinvestigated. We assessed longitudinal changes in depression scores, serum BDNF protein levels, and mRNA expression of BDNF/TrkB related genes (BDNF, AKT1, ERK1, CREB), NR3C1 and IGF1 in peripheral blood in 19 treatment-resistant depressed patients undergoing ECT. We also analysed DNA methylation patterns at various timepoints to explore possible epigenetic regulation of mRNA expression. Using multilevel regression, we found a negative association between depression scores and blood-based mRNA expression of BDNF/TrkB related genes and NR3C1. Expression of BDNF, ERK1 and NR3C1 increased significantly over time (BDNF: ß = 0.0295, p = 0.003; ERK1: ß = 0.0170, p = 0.034; NR3C1: ß = 0.0035, p = 0.050). For these three genes changes in mRNA expression were highly correlated (R = 0.59 - 0.88) with changes in DNA methylation for multiple CpG sites in the respective genes. Also, serum BDNF protein levels increased across the study period (ß = 0.11, p = 0.001). Our findings show that the antidepressant effects of ECT are associated with changes in expression of BDNF and its signaling molecules and that these molecular markers can be detected in peripheral blood. Alterations in DNA methylation could be a key mechanism whereby ECT influences gene expression.

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. METHODS: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. RESULTS: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. CONCLUSIONS: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry.

Successful electroconvulsive therapy for depression in a man with cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a condition characterised by accumulation of amyloid beta protein (Aß) in the wall of cerebral blood vessels which increases the risk of intracranial haemorrhage and contributes to cognitive impairment. We describe the case of a man around the age of 70 with 'probable' CAA according to the modified Boston criteria and severe depression whose depression was treated successfully with electroconvulsive therapy (ECT). To the best of our knowledge, there are no earlier published reports of ECT in a patient with CAA. We briefly discuss possible safety measures for these patients, the impact of ECT on cognition in CAA and a possible influence of ECT on Aß clearance.

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.

Comparative study of clinical and neuropsychological characteristics between early-, late and very-late-onset schizophrenia-spectrum disorders.

OBJECTIVE: To compare the clinical and neurocognitive profile of early-onset (EOP, <40 years), late-onset (LOP, 40-59 years) and very-late-onset (VLOP, ≥60 years) psychosis. DESIGN: Cross-sectional observational study. SETTING: Secondary, tertiary, and community mental health care. PARTICIPANTS: Patients with a DSM-IV diagnosis of non-affective psychotic disorder were included from two complementary studies (GROUP and PSITE) on genetic and environmental risk factors of psychosis in the Netherlands and Belgium. MEASUREMENTS: Main outcome measures were the severity of positive and negative symptoms, quality of life, and age-corrected scores on measures of general intelligence, verbal memory, attention, and executive function. One-year follow-up data were used to validate diagnoses and exclude participants with possible or probable dementia. RESULTS: 286 EOP (85%), 24 LOP (7%) and 28 VLOP (8%) participated. VLOP patients reported significantly more positive symptoms than EOP patients. Age-at-onset groups had similar age-corrected scores on IQ, verbal memory, attention and executive functions. A significantly better performance was found in VLOP compared with LOP on the CAMCOG total score, though scores were still within the normal range. After controlling for possible confounding, however, VLOP differed significantly on an attention accuracy task compared with LOP patients. Re-entering data for probable dementia patients (N = 4) did change the results regarding cognition outcomes. CONCLUSIONS: VLOP patients show more positive symptoms but do not appear to differ on neuropsychological tests from EOP and LOP when age is controlled for. This questions the idea that VLOP is the expression of underlying neurodegeneration.

Epigenetic effects of electroconvulsive seizures.

Electroconvulsive therapy (ECT) is one of the most effective methods for managing treatment-resistant depression. Although the proposed mechanisms of action have thus far mainly been investigated at the cellular level, recent observations and developments in the field of molecular biology and genomics have provided novel insights in the actual molecular underpinnings of dynamic alterations in gene expression, particularly in response to environmental exposures, and experience-dependent plasticity, both of which are highly relevant to ECT. Here, we provided a brief background on epigenetics and we reviewed the current state of knowledge on epigenetic mediation of ECT-related therapeutic effects. We performed a systematic search on the effects of ECT on epigenetics and found only a limited number on animal studies relevant to our search. These studies, however, support the notion of a robust impact of ECT on epigenetic mechanisms and set the stage for human ECT studies on the epigenetic machinery.

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.

Depressive symptoms in Crohn's disease: relationship with immune activation and tryptophan availability.

Crohn's 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), Crohn's 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.

Antipsychotic medications and cognitive functioning in bipolar disorder: moderating effects of COMT Val108/158 Met genotype.

BACKGROUND: There is a negative association between the use of antipsychotics and cognitive functioning in bipolar patients, which may be mediated by altered dopamine signaling in selected brain areas, and moderation thereof by genetic sequence variation such as COMT Val108/158Met. The interaction between antipsychotic drug use and the COMT Val108/158Met genotype on two-year cognitive functioning in bipolar patients was examined. METHODS: Interaction between the COMT Val108/158Met and antipsychotics on a composite cognitive measure was examined in 51 bipolar patients who were assessed 12 times at two-monthly intervals over a period of two years (379 observations). RESULTS: There was a significant negative effect of the interaction between antipsychotic medications and Val allele load on the composite cognitive measure in bipolar patients (p < 0.001). CONCLUSIONS: The negative effects of antipsychotics on cognitive functioning in bipolar disorder may be moderated by the COMT Val 108/158 Met genotype, with a negative effect of Val allele load. If replicated, the results may be indicative of pharmacogenetic interactions in bipolar disorder.

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.

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.

Attentional bias and general orienting processes in bipolar disorder.

Attentional biases for emotional stimuli and general orienting processes were examined in bipolar disorder, using a modified dot-probe task with a spatial cueing paradigm incorporated in it. Bipolar patients in a euthymic state (i.e., remission), bipolar patients in a mildly depressed state, and non-psychiatric controls participated. General orienting results showed that within the patient group as a whole, measures of depressed mood were positively associated with a relative inability to disengage attention. Attentional bias results showed that bipolar patients in a mildly depressed state, in comparison with controls, directed their attention away from depression-related words and positive words. The bias away from positive words was equally present in both patient groups and part of a trait effect, demonstrated by the comparison of patients in a euthymic state and controls. The bias away from depression-related words was mood state-dependent and within the patient group as a whole correlated negatively with measures of depressed mood. It is proposed that biases for emotional stimuli are related to the transition of mood states, characteristic 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.

Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review.

OBJECTIVE: Evidence suggests that cognitive functioning in bipolar disorder may be impaired even in euthymic states, but it is unclear if the pattern of deficits is similar to the deficits found in schizophrenia. The aim of this study was to review quantitatively the studies on cognitive performance in schizophrenia and bipolar disorder. METHODS: Articles for consideration were identified through a literature search in MEDLINE and PsycLIT in the period between 1985 and October 2004, using the keywords "schizophrenia" combined with "bipolar disorder", or "manic-depress*" or "manic" combined with "cogniti*" or "neuropsycholog*". Thirty-one studies were included that: i) evaluated cognitive performance using standardized and reliable neuropsychological testing procedures; ii) compared adult patients with schizophrenia and with bipolar disorder; iii) reported test scores of both patient groups, or exact p-values, t-values, or F-values; and iv) were published as an original article in a peer-reviewed English language journal. RESULTS: Meta-analyses of all studies indicated that patients with bipolar disorder generally perform better than patients with schizophrenia, but the distribution of effect sizes showed substantial heterogeneity. Results based on a more homogeneous subset of studies that matched patient groups on clinical and demographic characteristics pointed in the same direction, with effect sizes in the moderate range. CONCLUSIONS: Patients with bipolar disorder show better cognitive performance than patients with schizophrenia, even when matched for clinical and demographic characteristics.

Brain- and heart-type fatty acid-binding proteins in the brain: tissue distribution and clinical utility.

BACKGROUND: Detection of brain injury by serum markers is not a standard procedure in clinical practice, although several proteins, such as S100B, neuron-specific enolase (NSE), myelin basic protein, and glial fibrillary acidic protein, show promising results. We investigated the tissue distribution of brain- and heart-type fatty acid-binding proteins (B-FABP and H-FABP) in segments of the human brain and the potential of either protein to serve as plasma marker for diagnosis of brain injury. METHODS: B-FABP and H-FABP were measured immunochemically in autopsy samples of the brain (n = 6) and in serum samples from (a) patients with mild traumatic brain injury (MTBI; n = 130) and (b) depressed patients undergoing bilateral electroconvulsive therapy (ECT; n = 14). The protein markers S100B and NSE were measured for comparison. Reference values of B-FABP and H-FABP were established in healthy individuals (n = 92). RESULTS: The frontal, temporal, and occipital lobes, the striatum, the pons, and the cerebellum had different tissue concentrations of B-FABP and of H-FABP. B-FABP ranged from 0.8 microg/g wet weight in striatum tissue to 3.1 microg/g in frontal lobe. H-FABP was markedly higher, ranging from 16.2 microg/g wet weight in cerebellum tissue to 39.5 microg/g in pons. No B-FABP was detected in serum from healthy donors. H-FABP serum reference value was 6 microg/L. In the MTBI study, serum B-FABP was increased in 68% and H-FABP in 70% of patients compared with S100B (increased in 45%) and NSE (increased in 51% of patients). In ECT, serum B-FABP was increased in 6% of all samples (2 of 14 patients), whereas H-FABP was above its upper reference limit (6 microg/L) in 17% of all samples (8 of 14 patients), and S100B was above its upper reference limit (0.3 microg/L) in 0.4% of all samples. CONCLUSIONS: B-FABP and H-FABP patterns differ among brain tissues, with the highest concentrations in the frontal lobe and pons, respectively. However, in each part of the brain, the H-FABP concentration was at least 10 times higher than that of B-FABP. Patient studies indicate that B-FABP and H-FABP are more sensitive markers for minor brain injury than the currently used markers S100B and NSE.