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Highlights • GILZ is a downstream mediator of glucocorticoids. • GILZ mRNA levels are low in patients with depression versus controls. • GILZ mRNA levels are further reduced by ECT. • GILZ may play a role in antidepressant mechanism. Abstract Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA)-axis is commonly observed in patients with depression. The delayed feedback system that mediates inhibition of HPA-axis activation is regulated by glucocorticoid receptors (GRs) found in stress-responsive areas of the brain. Glucocorticoid-induced leucine zipper (GILZ) is a key molecule in glucocorticoid biology and is thought to mediate the downstream anti-inflammatory effects of GRs. Previous reports suggest that GILZ levels are altered in the blood and brains of patients with, and animal models of, depression. However, no study has yet investigated the effects of antidepressant treatment on GILZ. Therefore, our aim was to examine peripheral blood GILZ mRNA levels in patients with depression (n = 88) compared to age- and sex-matched healthy controls (n = 63), and in patients with depression following treatment with a course of electroconvulsive therapy (ECT). We also assessed the relationship between GILZ and mood and clinical outcomes following ECT. GILZ mRNA levels were assessed using qRT-PCR. GILZ levels were found to be significantly lower in patients with depression compared to controls (p < 0.002), and ECT further decreased GILZ levels (p = 0.05). Both of these results survived adjustment for potential covariates. However, we found no association between GILZ and mood scores. Overall, these results suggest that GILZ is involved in the pathophysiology of depression and the peripheral molecular response to ECT. [ABSTRACT FROM AUTHOR]

Background Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and the antidepressant response. Electroconvulsive therapy (ECT) is reported to increase BDNF levels in blood, though only a small number of studies have been conducted to date. Objective Our objectives were to: 1) compare plasma BDNF levels in medicated patients with depression and controls; 2) assess the effect of ECT on plasma BDNF levels in medicated patients with depression; 3) explore the relationship between plasma BDNF levels and the Val66Met (rs6265) BDNF polymorphism; and 4) examine the relationship between plasma BDNF levels and clinical symptoms and outcomes with ECT. Methods Plasma BDNF levels were analyzed in samples from 61 medicated patients with a major depressive episode and 50 healthy controls, and in patient samples following a course of ECT. Fifty-two samples from the depressed patient group were genotyped for the Val66Met BDNF polymorphism. Results There was no difference in plasma BDNF levels between the control and depressed groups, and there was no difference in plasma BDNF levels in patients following treatment with ECT. In line with previous reports, we show that, in medicated patients with depression, Met-carriers had higher plasma BDNF levels than Val-carriers, though genotype was not related to clinical response. We found no association between plasma BDNF levels and depression severity or the clinical response to ECT. Conclusions Our results suggest that plasma BDNF does not represent a suitable candidate biomarker for determining the therapeutic response to ECT. [ABSTRACT FROM AUTHOR]

Background It is not known whether results of clinical research in ECT can be used to guide treatment decisions for those having involuntary ECT, who are not represented in trial populations. Objective We aimed to compare courses of involuntary ECT with matched voluntary ECT courses in terms of clinical and demographic factors, treatment requirements, and outcomes. Method We performed a retrospective case-control study examining a five-year sample of involuntary ECT courses and an age-, gender- and time-matched voluntary ECT control sample. Results We examined 48 involuntary and 96 control voluntary ECT courses. While groups differed at baseline in terms of diagnosis, illness severity and illness characteristics, there were no differences in treatment outcomes after ECT or six-month readmission rates. Conclusion Our findings suggest that research on capacitous ECT patients is applicable to those having involuntary ECT. [ABSTRACT FROM AUTHOR]

BACKGROUND: To our knowledge, changes in steroid metabolism in subjects with anorexia nervosa (AN) after weight gain have not been elucidated. OBJECTIVE: We characterized urinary steroid excretion and metabolism in AN patients and investigated the effects of refeeding. DESIGN: In an intervention study, we recruited 7 women with life-threatening weight loss upon admission and after a median [interquartile range (IQR)] of 95 d (88-125 d) of intensive refeeding; 15 age-matched women were recruited as control subjects. The major urinary metabolites were quantified in 24-h collections by capillary gas chromatography. A single examiner measured weights, heights, and skinfold thicknesses. RESULTS: The median (IQR) age of patients was 24 y (21-26 y), and the duration of AN was 4.0 y (3.3-8.0 y). Body mass index (BMI; in kg/m(2)) increased from 12.8 (12.7-13.1) to 18.6 (18.0-19.6) after refeeding (P < 0.0001). Steroid values [median pre-, post-refeeding (P value)] were as follows: androgen metabolites [472, 1017 [mu]g/24 h (0.93)], cortisol metabolites [1960, 3912 [mu]g/24 h (0.60)], and ratios of androsterone (5[alpha])/etiocholanolone (5[beta]) [0.28, 0.63 (<0.001)], 5[alpha]-/5[beta]-tetrahydrocortisol [0.20, 0.48 (0.02)], tetrahydrocortisols/tetrahydrocortisone [0.87, 0.61 (0.09)], 20-hydroxy-/20-oxocortisol metabolites [0.29, 0.47 (0.01)], and 20[alpha]-/20[beta]-reduced cortisol metabolites [1.18, 1.89 (>=1.00)]. BMI change was positively correlated with 5[alpha]-/5[beta]-tetrahydrocortisol (r = 0.95, P < 0.001). Before refeeding, the following metabolites were lower in patients than in control subjects: androsterone, 5[alpha]-tetrahydrocortisol, [alpha]-cortolone and [alpha]-cortol, 5[alpha]-/5[beta]-tetrahydrocortisol, androsterone/etiocholanolone, and 20-hydroxy/20-oxocortisol (all P < 0.05). After refeeding, all steroid metabolites in patients were at concentrations that were comparable with those in control subjects. CONCLUSIONS: Significant changes in urine steroid-metabolite excretion occurred upon starvation, which were reversed upon refeeding. For cortisol, there were decreases in 5[alpha]-/5[beta]-tetrahydrocortisol and 20-hydroxy-/20-oxometabolites; for androgen, there was a decrease in androsterone/etiocholanolone. © 2011 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: To our knowledge, changes in steroid metabolism in subjects with anorexia nervosa (AN) after weight gain have not been elucidated. Objective: We characterized urinary steroid excretion and metabolism in AN patients and investigated the effects of refeeding. Design: In an intervention study, we recruited 7 women with life-threatening weight loss upon admission and after a median [interquartile range (IQR)] of 95 d (88-125 d) of intensive refeeding; 15 age-matched women were recruited as control subjects. The major urinary metabolites were quantified in 24-h collections by capillary gas chromatography. A single examiner measured weights, heights, and skinfold thicknesses. Results: The median (IQR) age of patients was 24 y (21-26 y), and the duration of AN was 4.0 y (3.3-8.0 y). Body mass index (BMI; in kg/m²) increased from 12.8 (12.7-13.1) to 18.6 (18.0-19.6) after refeeding (P < 0.0001). Steroid values [median pre-, post-refeeding (P value)] were as follows: androgen metabolites [472, 1017 μg/24 h (0.93)], cortisol metabolites [1960, 3912 μg/24 h (0.60)], and ratios of androsterone (5α)/etiocholanolone (5β) [0.28, 0.63 (<0.001)], 5α-/5β-tetrahydrocortisol [0.20, 0.48 (0.02)], tetrahydrocortisols/tetrahydrocortisone [0.87, 0.61 (0.09)], 20-hydroxy-/20-oxocortisol metabolites [0.29, 0.47 (0.01)], and 20α-/20β-reduced cortisol metabolites [1.18, 1.89 (e1.00)]. BMI change was positively correlated with 5α-/5β-tetrahydrocortisol (r = 0.95, P < 0.001). Before refeeding, the following metabolites were lower in patients than in control subjects: androsterone, 5α-tetrahydrocortisol, α-cortolone and α-cortol, 5α-/5β-tetrahydrocortisol, androsterone/etiocholanolone, and 20-hydroxy/20-oxocortisol (all P < 0.05). After refeeding, all steroid metabolites in patients were at concentrations that were comparable with those in control subjects. Conclusions: Significant changes in urine steroid-metabolite excretion occurred upon starvation, which were reversed upon refeeding. For cortisol, there were decreases in 5α-/5β-tetrahydrocortisol and 20-hydroxy-/20-oxometabolites; for androgen, there was a decrease in androsterone/etiocholanolone. [ABSTRACT FROM AUTHOR]

Background: Electroconvulsive therapy (ECT) is the most acutely effective treatment for depression, but is limited by cognitive side effects. However, research on their persistence, severity, and pattern is inconsistent. We aimed to quantify ECT-associated cognitive changes, specify their pattern, and determine progression. Methods: MEDLINE, EMBASE, PsycArticles, PsychINFO, PsychLIT, and reference lists were systematically searched through January 2009. We included all independent, within-subjects design studies of depressed patients receiving ECT where cognition was assessed using standardized tests. Main outcome was change in performance after ECT relative to pretreatment scores with respect to delay between finishing ECT and cognitive testing. We explored potential moderators'' influence, e.g., electrode placement, stimulus waveform. Results: Twenty-four cognitive variables (84 studies, 2981 patients) were meta-analyzed. No standardized retrograde amnesia tests were identified. Significant decreases in cognitive performance were observed 0 to 3 days after ECT in 72% of variables: effect sizes (ES) ranging from −1.10 (95% confidence interval [CI], −1.53 to −.67) to −.21 (95% CI, −.40 to .01). Four to 15 days post-ECT, all but one CI included zero or showed positive ES. No negative ES were observed after 15 days, with 57% of variables showing positive ES, ranging from .35 (95% CI, .07–.63) to .75 (95% CI, .43–1.08). Moderators did not influence cognitive outcomes after 3 days post-ECT. Conclusions: Cognitive abnormalities associated with ECT are mainly limited to the first 3 days posttreatment. Pretreatment functioning levels are subsequently recovered. After 15 days, processing speed, working memory, anterograde memory, and some aspects of executive function improve beyond baseline levels. [Copyright &y& Elsevier]

Abstract: Physician-assisted suicide (PAS) is the death of an individual that occurs as a result of deliberate, purposive actions taken by that individual, with the assistance of a physician. In the UK, assisting with the death of another individual is illegal, but other parts of the world, such as the state of Oregon in the USA, have laws that permit PAS in certain circumstances. In the Netherlands, PAS may be provided for either physical or psychiatric illness, although requests for PAS emanating from psychiatric practice rarely tend to be granted. PAS, especially in the context of psychiatric illness, raises a range of clinical, ethical, and legal issues for patients, families, healthcare providers. and society at large. Even in jurisdictions where PAS is not provided on the grounds of psychiatric illness alone, there is a range of other ways in which the issues surrounding PAS may come to the attention of psychiatrists and mental health teams. These include: requests to provide mental health care to individuals with terminal physical illness, who may or may not request PAS; requests to assess the capacity or capability of individuals with terminal physical illness who request PAS; and requests to assess, support, or treat families or staff members who have had involvement with PAS. There are important issues that merit close attention and point to a strong need for enhanced psychiatric liaison with terminal care providers. [Copyright &y& Elsevier]

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in elderly people, and the fourth most common cause of death in developed nations. Clinically, the disease is characterized by the deterioration of a patient’s cognitive and functional abilities, which may be accompanied by varying degrees of psychiatric and behavioural symptoms. The clinical decline is associated with a significant loss of neurons and synapses and ensuing neurochemical changes within the brain of an affected individual. In addition, two further microscopic pathologies are observed within the brain tissue: extracellular neuritic plaques and intracellular neurofibrillary tangles (NFTs). Both of these distinctive neuropathologies, regarded as hallmarks of the disease, are the result of abnormal aggregation of proteinaceous material. Neuritic plaques are largely formed from the aggregation of the 4 kDa β-amyloid peptide, which is released into the extracellular space following the metabolic breakdown of the larger amyloid precursor protein (APP). NFTs, which develop within neurons, are aggregates principally composed of the cytoskeletal protein tau and may be initiated by aberrant phosphorylation of tau. The prevailing view within the field is that mismetabolism of APP and abnormal production, aggregation and deposition of Aβ are central to the pathogenesis of AD, and that the Aβ pathology somehow leads to the tau/NFT pathology and the subsequent neuronal damage observed. In this article we review our current understanding of these molecular events and highlight how this knowledge is directing approaches to develop AD-modifying therapies. [Copyright &y& Elsevier]

Cerebral deposition of amyloid-β peptide (Aβ) within neuritic plaques is a hallmark pathology of Alzheimer''s disease. It is now generally believed that the development of this pathology is central to the pathogenesis of Alzheimer''s disease. As such, inhibiting Aβ deposition or removing Aβ deposits once they are formed represent therapeutic targets for Alzheimer''s disease. Aβ is derived from a precursor, the amyloid precursor protein (APP), and APP binds to the X11 family of adaptor proteins. Studies from several laboratories have now shown that X11α and X11β (the two neuronal X11s) inhibit APP processing and Aβ production. Exactly how this is achieved is not yet known but recent studies in which other X11 binding partners have been identified are beginning to reveal potential mechanisms. [Copyright &y& Elsevier]

Systemic inflammation is commonly reported in depression, with dysregulation of both the innate and adaptive arms of the immune system documented. Obtaining ratios of neutrophils, platelets, and monocytes to counts of lymphocytes (NLR, PLR, MLR, respectively) represents a low-cost and easily reproducible measure of an individual's inflammatory burden that can be calculated effortlessly from routine clinical full white blood cell counts. Electroconvulsive therapy (ECT) remains the most effective acute antidepressant treatment for depression but is often limited by its cognitive side-effects. Here, we examined differences in blood cell ratios in subgroups of depressed patients (unipolar/bipolar, psychotic/non-psychotic, early-onset/late-onset) and ECT-related subgroups (responder/non-responder, remitter/non-remitter). We also explored the relationships between blood cell ratios and depression severity and immediate cognitive outcomes post-ECT. Our results show baseline NLR was raised in patients with psychotic depression. In the entire group of patients, significant negative correlations were noted between the PLR and SII and baseline HAM-D24 score, signifying that lower systemic inflammation is associated with more severe depressive symptoms. Significant positive correlations were noted between various blood cell ratios and mean time to recovery of orientation in the entire group of patients and in depression subgroups, indicating that increased peripheral inflammation is linked to worse cognitive outcomes post-ECT. Overall, our results suggest that assessment of blood cell ratios could be useful for predicting mood changes in patients at risk of developing depressive episodes or relapse following successful treatment or for identifying those at risk for cognitive side-effects following ECT. [ABSTRACT FROM AUTHOR]

Abstract: Physician-assisted suicide (PAS) is permitted in only a few jurisdictions (e.g. Oregon, USA; The Netherlands). In The Netherlands, PAS can be provided for psychiatric illness alone, even though the underlying biological causes of most psychiatric illnesses are unknown and the prognoses tend to be uncertain. There is an important role for psychiatrists and mental health teams in assessing and treating individuals with terminal physical illness who also develop psychiatric illness. There are, however, no agreed criteria to guide mandatory psychiatric assessment of the competence of terminally ill individuals who request PAS. The majority of psychiatrists feel they would not be able to make such a decision after a single assessment and, moreover, there is evidence that psychiatrists’ moral views may affect their judgements. There are important roles for psychiatrists in terminal care settings but there is insufficient biological understanding of most common psychiatric illnesses to describe them as ‘terminal’, with the exception of certain neurodegenerative disorders (e.g. advanced Alzheimer''s disease). While there is an overwhelming case in favour of psychiatric liaison with terminal care providers, the introduction of mandatory psychiatric assessment for all individuals requesting PAS would be ill-advised. [Copyright &y& Elsevier]

Mitochondrial dysfunction may play a role in various psychiatric conditions. Mitochondrial DNA copy number (mtDNAcn), the ratio of mitochondrial DNA to nuclear DNA, represents an attractive marker of mitochondrial health that is easily measured from stored DNA samples, and has been shown to be altered in depression. In this study, we measured mtDNAcn in whole blood samples from medicated patients with depression (n = 100) compared to healthy controls (n = 89) and determined the relationship between mtDNAcn and depression severity and the therapeutic response to electroconvulsive therapy (ECT). We also explored the relationship between mtDNAcn and telomere length and inflammatory markers. Our results show that mtDNAcn was significantly elevated in blood from patients with depression when compared to control samples, and this result survived statistical adjustment for potential confounders (p = 0.002). mtDNAcn was significantly elevated in blood from subgroups of patients with non-psychotic or unipolar depression. There was no difference in mtDNAcn noted in subgroups of ECT remitters/non-remitters or responders/non-responders. Moreover, mtDNAcn was not associated with depression severity, telomere length, or circulating inflammatory marker concentrations. Overall, our results show that mtDNAcn is elevated in blood from patients with depression, though whether this translates to mitochondrial function is unknown. Further work is required to clarify the contribution of mitochondria and mtDNA to the pathophysiology of depression and the therapeutic response to antidepressant treatments. • mtDNAcn represents an attractive marker of measuring mitochondrial health. • mtDNAcn was elevated in whole blood from depressed patients versus controls. • mtDNAcn was not related to depression severity or clinical outcomes following ECT. • mtDNAcn was not associated with telomere length or circulating inflammatory markers. [ABSTRACT FROM AUTHOR]

Highlights: [•] Alterations in miRNAs may be informative about the mechanism of action of ECS/ECT. [•] We examined levels of selected BDNF-associated miRNAs in rat brain and blood following ECS. [•] miR-212 was significantly increased in dentate gyrus after acute and chronic ECS. [•] miR-212 levels in dentate gyrus positively correlated with levels in whole blood. [•] miRNAs may pose suitable biomarkers to predict the response to ECT. [Copyright &y& Elsevier]

Objectives: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice.Methods: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps.Results: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine.Limitations: The KSET has established face and content validity, however it has not been validated against other measures of safety.Conclusions: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects. [ABSTRACT FROM AUTHOR]

Abstract The E2F transcription factors are a group of proteins that bind to the promotor region of the adenovirus E2 gene. E2F1, the first family member to be cloned, is linked to functions including cell proliferation and apoptosis, DNA repair, cell senescence and metabolism. We recently performed a deep sequencing study of micro-RNA changes in whole blood following ECT. Two micro-RNAs (miR-126-3p and miR-106a-5p) were identified and gene targeting analysis identified E2F1 as a shared target of these miRNAs. To our knowledge, no studies have examined E2F1 mRNA levels in patients with depression. Peripheral blood E2F1 mRNA levels were therefore examined in patients with depression, compared to healthy controls, and the effects of a course of ECT on peripheral blood E2F1 mRNA was investigated. Depressed patient and healthy control groups were balanced on the basis of age and sex. E2F1 mRNA levels were significantly lower in depressed patients in comparison to controls (p =.009) but did not change with ECT. There was no relationship between baseline E2F1 levels and depression severity, response to treatment, presence of psychosis or polarity of depression. There were no significant correlations between E2F1 levels and mood scores based on the HAM-D24. These results indicate that reduced peripheral blood E2F1 mRNA could be a trait feature of depression. Highlights • Peripheral blood E2F1 mRNA levels are significantly lower in patients with depression than in healthy controls. • Peripheral blood E2F1 mRNA levels do not change following a course of ECT. • Peripheral blood E2F1 mRNA levels are not related to depression severity and are not associated with the response to ECT. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) plays important roles in both the physiological and pharmacological state of the brain. Transiently enhancing the permeability of the BBB may allow use of more types of medications for neuropsychiatric diseases. Several studies have demonstrated that seizures cause a transient decrease in BBB integrity. We studied the timing of BBB changes following seizures and the role of astrocytes in this process. Rats received 10 applications of electroconvulsive stimulation (ECS). They were then infused with sodium fluorescein, a fluorescent substance that rarely passes the BBB, via the inferior vena cava. After 120 min of circulation, the amount of sodium fluorescein in the brain was measured by two methods in vivo fluorescence imaging (total radiant efficiency) and the brain concentration of sodium fluorescein. To assess any changes to the BBB, we measured S100Β in serum, which is a standard marker of BBB breakdown that is expressed by astrocytes. We also examined ultrastructural changes following ECS. Total radiant efficiency and the brain concentration of sodium fluorescein were significantly increased in treated rats compared to controls when sodium fluorescein was injected immediately after ECS but not when the injection was performed more than 15 min after ECS. Astrocytic endfeet showed swelling around brain capillaries following ECS. In conclusion, ECS transiently enhances the permeability of the BBB, which may be accompanied by changes in astrocytic endfeet. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is the most acutely effective treatment available for severe depression. However, its mechanism of action is not fully understood. Elucidating the protein changes induced in the brain by ECT will enhance our understanding of this antidepressant therapy. Electroconvulsive stimulation (ECS), the animal analogue of ECT, was administered to rats to determine the proteomic changes induced in the hippocampus, a region of the brain implicated in the biology of depression and its treatment. Two-dimensional difference in gel electrophoresis (2D-DiGE) and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to identify differentially expressed proteins following acute (×1 treatment), chronic (×10 treatments) or chronic +4 weeks (×10 treatments plus 4 weeks later) ECS. Administration of acute, chronic and chronic +4 weeks ECS induced significant changes in multiple DiGE gel protein spots. Interestingly, the largest number of differentially expressed protein spots was identified following chronic +4 weeks ECS. Following protein identification by LC-MS/MS, gene ontology analysis primarily implicated proteins with cytoskeletal and metabolism-related roles in the action of ECS. Immunoblotting confirmed the changes in abundance of the cytoskeletal protein actin following chronic +4 weeks ECS. Overall, chronic +4 weeks ECS was particularly effective at inducing longer-lasting changes in the abundance of hippocampal proteins with cytoskeletal and metabolism roles. These results suggest a role for persisting cytoskeletal-related neuroplastic changes in the action of ECS and may be informative as to the antidepressant mechanisms of ECT in patients with depression. [ABSTRACT FROM AUTHOR]

Abstract: Autobiographical amnesia assessments in depression need to account for normal changes in consistency over time, contribution of mood and type of memories measured. We report herein validation studies of the Columbia Autobiographical Memory Interview — Short Form (CAMI-SF), exclusively used in depressed patients receiving electroconvulsive therapy (ECT) but without previous published report of normative data. The CAMI-SF was administered twice with a 6-month interval to 44 healthy volunteers to obtain normative data for retrieval consistency of its Semantic, Episodic-Extended and Episodic-Specific components and assess their reliability and validity. Healthy volunteers showed significant large decreases in retrieval consistency on all components. The Semantic and Episodic-Specific components demonstrated substantial construct validity. We then assessed CAMI-SF retrieval consistencies over a 2-month interval in 30 severely depressed patients never treated with ECT compared with healthy controls (n =19). On initial assessment, depressed patients produced less episodic-specific memories than controls. Both groups showed equivalent amounts of consistency loss over a 2-month interval on all components. At reassessment, only patients with persisting depressive symptoms were distinguishable from controls on episodic-specific memories retrieved. Research quantifying retrograde amnesia following ECT for depression needs to control for normal loss in consistency over time and contribution of persisting depressive symptoms. [Copyright &y& Elsevier]

Abstract: Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5–1.5ms) is a very effective treatment for severe depression but is associated with cognitive side-effects. It has been proposed that ultrabrief pulse (UBP; pulse width 0.25–0.30ms) ECT may be as effective as BP ECT but have less cognitive effects because it is a more physiological form of neuronal stimulation. To investigate this further, we treated normal rats with a 10 session course of either BP (0.5ms), UBP (0.3ms), or sham electroconvulsive stimulation (ECS) and measured antidepressant-related changes in dentate gyrus cell proliferation and hippocampal BDNF protein levels as well as hippocampal-dependant spatial reference memory using the water plus maze and immobility time on the forced swim test. Both BP and UBP ECS induced very similar types of motor seizures. However, BP ECS but not UBP ECS treatment led to a significant, near 3-fold, increase in cell proliferation (p=0.026) and BDNF levels (p=0.01). In the forced swim test, only BP ECS treated animals had a significantly lower immobility time (p=0.046). There was a trend for similarly reduced hippocampal-dependent memory function in both BP and UBP groups but overall there was not a significant difference between treatment and control animals when tested 10days after completing allocated treatment. These findings show that, even though both forms of ECS elicited similar motor seizures, UBP ECS was less efficient than BP ECS in inducing antidepressant-related molecular, cellular and behavioural changes. [Copyright &y& Elsevier]

Abstract: To clarify advantages of unilateral electrode placement as an optimisation technique for electroconvulsive therapy (ECT) for depression, aims were to meta-analyse unilateral ECT effects on cognitive performance relative to: (1) bitemporal electrode placement, (2) electrical dosage, and (3) time interval between final treatment and cognitive reassessment. Relevant electronic databases were systematically searched through May 2009, using the terms: "electroconvulsive therapy" and ["cogniti∗", "neuropsycholog∗", "memory", "attention", "executive", "spatial", or "intellectual"]. Inclusion criteria were: independent study of depressed patients receiving unilateral or bitemporal brief-pulse ECT; within-subjects design; use of objective cognitive assessments; available mean electrical dosage for unilateral samples. Standardized pre-post ECT weighted effect sizes were computed and pooled within 16 cognitive domains by a mixed-effects model. Thirty-nine studies (1415 patients) were meta-analysed. Up to three days after final treatment, unilateral ECT was associated with significantly smaller decreases in global cognition, delayed verbal memory retrieval, and autobiographical memory, compared to bitemporal ECT. Significant publication bias was found for autobiographical memory, favouring reporting of larger percentage loss. Higher unilateral ECT electrical dosage predicted larger decreases in verbal learning, delayed verbal memory retrieval, visual recognition, and semantic memory retrieval. When retested more than three days after completing ECT, no significant differences remained between the two electrode placements; for unilateral ECT, electrical dosage no longer predicted cognitive performance whereas increasing interval between final treatment and retesting predicted growing improvement in some variables. This interval is a more useful long-term predictor of cognitive function than electrode placement or electrical dosage following unilateral ECT. [Copyright &y& Elsevier]

Abstract: Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport. [Copyright &y& Elsevier]

Abstract: Neurofilaments are the intermediate filaments of neurons and are synthesised in neuronal cell bodies and then transported through axons. Neurofilament light chain (NFL) is a principal component of neurofilaments, and phosphorylation of NFL head domain is believed to regulate the assembly of neurofilaments. However, the role that NFL phosphorylation has on transport of neurofilaments is poorly understood. To address this issue, we monitored axonal transport of phosphorylation mutants of NFL. We mutated four known phosphorylation sites in NFL head domain to either preclude phosphorylation, or mimic permanent phosphorylation. Mutation to preclude phosphorylation had no effect on transport but mutation of three sites to mimic permanent phosphorylation inhibited transport. Mutation of all four sites together to mimic permanent phosphorylation proved especially potent at inhibiting transport and also disrupted neurofilament assembly. Our results suggest that NFL head domain phosphorylation is a regulator of neurofilament axonal transport. [Copyright &y& Elsevier]

Abstract: Background: Methohexitone has been the most widely used anaesthetic for electroconvulsive therapy (ECT). However, recent scarcity and erratic availability has led to use of other anaesthetics with differing effects upon ECT. We compared treatment parameters and response to ECT in patients anaesthetised with different anaesthetics in a routine clinical setting. Methods: This was a naturalistic retrospective casenote analysis of 81 consecutive courses of ECT (total 659 treatments) for major depression. Results: Three anaesthetics were compared: methohexitone (n =34), propofol (n =13) and etomidate (n =34). Mean seizure duration was lowest (p <0.0001) for propofol. However, mean stimulus charge was highest in the propofol group (p <0.0001) who required a greater increase in stimulus charge during the course of treatment and also experienced a greater proportion of failed seizures (≤15 s on EEG). Despite differing effects upon treatment parameters, choice of anaesthetic did not appear to significantly affect therapeutic response to ECT. Use of propofol may be associated with longer treatment course that could result in extra cost. Limitations: This was a retrospective casenote study, in which patients were not randomised to anaesthetic and standardised outcome measures were not used. The small sample size in the propofol group may have reduced the power of the study to demonstrate other differences between propofol and the other anaesthetic groups. A formal economic analysis was not performed. Conclusion: Individual anaesthetics differentially influence seizure duration and stimulus charge but final response to ECT appears not to be adversely affected. [Copyright &y& Elsevier]

FE65 is an adaptor protein that binds to and forms a transcriptionally active complex with the γ-secretase-derived amyloid precursor protein (APP) intracellular domain. The regulatory mechanisms of FE65-APP-mediated transcription are still not clear. In this report, we demonstrate that Dexras1, a Ras family small G protein, binds to FE65 PTB2 domain and potently suppresses the FE65-APP-mediated transcription. The suppression is not via competition for binding of FE65 between Dexrasl and APP because the two proteins can simultaneously bind to the FE65 PTB2 domain. Phosphorylation of FE65 tyrosine 547 within the PTB2 domain has been shown to enhance FE65-APP-mediated transcription but not to influence binding to APP. Here we find that this phosphorylation event reduces the binding between Dexras1 and FE65. We also demonstrate that Dexrasl inhibits the FE65-APP-mediated transcription of glycogen synthase kinase 3β (GSK3β). Moreover, small interfering RNA knockdown of Dexrasl enhances GSK3β expression and increases phosphorylation of Tau, a GSK3β substrate. Thus, Dexras1 functions as a suppressor of FE65-APP-mediated transcription, and FE65 tyrosine 547 phosphorylation enhances FE65-APP-mediated transcription, at least in part, by modulating the interaction between FE65 and Dexras1. These findings reveal a novel regulatory mechanism for FE65-APP-mediated signaling. [ABSTRACT FROM AUTHOR]

Abstract: Background: Electroconvulsive therapy (ECT) has a long history of use in treating depression. Repetitive transcranial magnetic stimulation (rTMS) has been introduced more recently to the treatment spectrum. Its cost-effectiveness has not been explored. Method: Forty-six right-handed people with severe depressive episodes referred for ECT were randomised to receive either ECT twice weekly or rTMS on consecutive weekdays. Health and other service use were recorded for retrospective periods of 3 months prior to initiation of treatment and during the 6 months following the end of allocated treatment. Costs were calculated for the treatment period and the subsequent 6 months, and comparisons made between groups after adjustment for any baseline differences. Cost-effectiveness analysis was conducted with incremental change on the 17-item Hamilton Rating Scale for Depression (HRSD) as the primary outcome measure, and quality-adjusted life years (based on SF6D-generated utility scores with societal weights) as secondary outcome, cost-effectiveness acceptability curves plotted. Results: Based on the HRSD scores and other outcome measures, rTMS was not as effective as ECT. The cost of a single session of rTMS was lower than the cost of a session of ECT, but overall there were no treatment cost differences. In the treatment and 6-month follow-up periods combined, health and other service costs were not significantly different between the two groups. Informal care costs were higher for the rTMS group. Total treatment, service and informal care costs were also higher for the rTMS group. The cost-effectiveness acceptability curves indicated a very small probability that decision-makers would view rTMS as more cost-effective than ECT. Limitations: Small sample size, some sample attrition and a relatively short follow-up period of 6 months for a chronic illness. Productivity losses could not be calculated. Conclusions: ECT is more cost-effective than rTMS in the treatment of severe depression. [Copyright &y& Elsevier]

Abstract: The X11 protein family are multidomain proteins composed of a conserved PTB domain and two C-terminal PDZ domains. They are involved in formation of multiprotein complexes and two of the family members, X11α and X11β, are expressed primarily in neurones. Not much is known about the principal function of X11s, but through interactions with other neuronal proteins, they are believed to be involved in regulating neuronal signaling, trafficking and plasticity. Furthermore, they have been shown to modulate processing of APP and accumulation of Aβ, making them potential therapeutic targets for Alzheimer''s disease. This article reviews the known interactions of the different X11s and their involvement in Alzheimer''s disease. [Copyright &y& Elsevier]

Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly under- stood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAKI activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS. [ABSTRACT FROM AUTHOR]

Accumulation of cerebral amyloid β-protein (Aβ) is believed to be part of the pathogenic process in Alzheimer's disease. Aβ is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11β, a neuronal adaptor protein. X11β has been shown to inhibit the production of Aβ in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11β can also inhibit the deposition of Aβ as amyloid plaques is not known. Here we show that transgenic overexpression of X11β in neurons leads to a decrease in cerebral Aβ levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11β retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11β function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The amyloid precursor protein (APP) is proteolytically processed to release a C-terminal domain that signals to the nucleus to regulate transcription of responsive genes. The APP C terminus binds to a number of phosphotyrosine binding (PTB) domain proteins and one of these, Fe65, stimulates APP nuclear signaling. Fe65 is an adaptor protein that contains a number of protein-protein interaction domains. These include two PTB domains, the second of which binds APP, and a WW domain that binds proline-rich ligands. One ligand for the Fe65WW domain is the tyrosine kinase c-Abl. Here, we show that active c-Abl stimulates APP/Fe65-mediated gene transcription and that this effect is mediated by phosphorylation of Fe65 on tyrosine 547 within its second PTB domain. The homologous tyrosine within the motif Tyr-(Leu/Met)-Gly is conserved in a variety of PTB domains, and this suggests that PTB tyrosine phosphorylation occurs in other proteins. As such, PTB domain phosphorylation may represent a novel mechanism for regulating the function of this class of protein. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the prefrontal cortex is implicated in craving for drugs and food. This study explores the effect of prefrontal cortex stimulation on food craving. Methods: In a randomized double-blind parallel group study, 28 women, who reported frequent cravings for food were exposed to foods that typically elicit strong cravings before and after a single session of real or sham 10-Hz repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex at an intensity of 110% individual motor threshold. Results: Self-reported food craving during exposure to the experimental foods remained stable before and after real stimulation compared with sham stimulation in which cravings increased over the experimental session. Consumption of snack foods within a 5-min period after stimulation did not differ between groups. Conclusions: Prefrontal stimulation inhibits the development of craving. A longer period of observation is necessary to establish whether there is an effect on food consumption. [Copyright &y& Elsevier]