A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder.

OBJECTIVE: To determine clinical predictors of lithium response in bipolar disorder. METHODS: Systematic review of studies examining clinical predictors of lithium response was conducted. Meta-analyses were performed when ≥2 studies examined the same potential predictor. RESULTS: A total of 71 studies, including over 12 000 patients, identified six predictors of good response: mania-depression-interval sequence [odds ratio (OR): 4.27; 95% CI: 2.61, 6.97; P < 0.001], absence of rapid cycling (OR for rapid cycling: 0.30; 95% CI: 0.17, 0.53; P < 0.001), absence of psychotic symptoms (OR for psychotic symptoms: 0.52; 95% CI: 0.34, 0.79; P = 0.002), family history of bipolar disorder (OR: 1.61; 95% CI: 1.03, 2.52; P = 0.036), shorter prelithium illness duration [standardised mean difference (SMD): -0.26; 95% CI: -0.41, -0.12; P < 0.001] and later age of onset (SMD: 0.17; 95% CI: 0.02, 0.36; P = 0.029). Additionally, higher body mass index was associated with poor response in two studies (SMD: -0.61; 95% CI: -0.90, -0.32; P < 0.001). There was weak evidence for number of episodes prior to lithium treatment (SMD: -0.42; 95% CI: -0.84, -0.01; P = 0.046), number of hospitalisations before lithium (SMD: -0.40; 95% CI: -0.81, 0.01; P = 0.055) and family history of lithium response (OR: 10.28; 95% CI: 0.66, 161.26; P = 0.097). CONCLUSIONS: The relative importance of these clinical characteristics should be interpreted with caution because of potential biases and confounding.

Variability in phase and amplitude of diurnal rhythms is related to variation of mood in bipolar and borderline personality disorder.

Variable mood is an important feature of psychiatric disorders. However, its measurement and relationship to objective measureas of physiology and behaviour have rarely been studied. Smart-phones facilitate continuous personalized prospective monitoring of subjective experience and behavioural and physiological signals can be measured through wearable devices. Such passive data streams allow novel estimates of diurnal variability. Phase and amplitude of diurnal rhythms were quantified using new techniques that fitted sinusoids to heart rate (HR) and acceleration signals. We investigated mood and diurnal variation for four days in 20 outpatients with bipolar disorder (BD), 14 with borderline personality disorder (BPD) and 20 healthy controls (HC) using a smart-phone app, portable electrocardiogram (ECG), and actigraphy. Variability in negative affect, positive affect, and irritability was elevated in patient groups compared with HC. The study demonstrated convincing associations between variability in subjective mood and objective variability in diurnal physiology. For BPD there was a pattern of positive correlations between mood variability and variation in activity, sleep and HR. The findings suggest BPD is linked more than currently believed with a disorder of diurnal rhythm; in both BPD and BD reducing the variability of sleep phase may be a way to reduce variability of subjective mood.

Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial.

After psychological trauma, recurrent intrusive visual memories may be distressing and disruptive. Preventive interventions post trauma are lacking. Here we test a behavioural intervention after real-life trauma derived from cognitive neuroscience. We hypothesized that intrusive memories would be significantly reduced in number by an intervention involving a computer game with high visuospatial demands (Tetris), via disrupting consolidation of sensory elements of trauma memory. The Tetris-based intervention (trauma memory reminder cue plus c. 20 min game play) vs attention-placebo control (written activity log for same duration) were both delivered in an emergency department within 6 h of a motor vehicle accident. The randomized controlled trial compared the impact on the number of intrusive trauma memories in the subsequent week (primary outcome). Results vindicated the efficacy of the Tetris-based intervention compared with the control condition: there were fewer intrusive memories overall, and time-series analyses showed that intrusion incidence declined more quickly. There were convergent findings on a measure of clinical post-trauma intrusion symptoms at 1 week, but not on other symptom clusters or at 1 month. Results of this proof-of-concept study suggest that a larger trial, powered to detect differences at 1 month, is warranted. Participants found the intervention easy, helpful and minimally distressing. By translating emerging neuroscientific insights and experimental research into the real world, we offer a promising new low-intensity psychiatric intervention that could prevent debilitating intrusive memories following trauma.

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.

Remote mood monitoring for adults with bipolar disorder: An explorative study of compliance and impact on mental health service use and costs.

BACKGROUND: Remote monitoring of mood disorders may be an effective and low resource option for patient follow-up, but relevant evidence remains very limited. This study explores real-life compliance and health services impacts of mood monitoring among patients with bipolar disorder in the UK. METHODS: Patients with a diagnosis of bipolar disorder who were registered users of the True Colours monitoring system for at least 12months at study assessment were included in this retrospective cohort study (n=79). Compliance was measured as the proportion of valid depression and mania scale messages received in comparison to their expected numbers over the first 12months of monitoring. Mental health service use data were extracted from case notes, costed using national unit costs, and compared 12months before (pre-TC period) and 12months after (TC period) patients' engagement with monitoring. Associations with relevant patient factors were investigated in a multiple regression model. RESULTS: Average compliance with monitoring was 82%. Significant increases in the annual use and costs of psychiatrist contacts and total mental health services were shown for patients newly referred to the clinic during the pre-TC period but not for long-term patients of the clinic. Psychiatric medication costs increased significantly between the pre-TC and TC periods (£235, P=0.005) unrelated to patients' referral status. CONCLUSIONS: Remote mood monitoring has good compliance among consenting patients with bipolar disorder. We found no associations between observed changes in mental health service costs and the introduction of monitoring except for the increase in psychiatric medication costs.

Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).

BACKGROUND: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Detecting Bipolar Depression From Geographic Location Data.

OBJECTIVE: This paper aims to identify periods of depression using geolocation movements recorded from mobile phones in a prospective community study of individuals with bipolar disorder (BD). METHODS: Anonymized geographic location recordings from 22 BD participants and 14 healthy controls (HC) were collected over 3 months. Participants reported their depressive symptomatology using a weekly questionnaire (QIDS-SR16). Recorded location data were preprocessed by detecting and removing imprecise data points and features were extracted to assess the level and regularity of geographic movements of the participant. A subset of features were selected using a wrapper feature selection method and presented to 1) a linear regression model and a quadratic generalized linear model with a logistic link function for questionnaire score estimation; and 2) a quadratic discriminant analysis classifier for depression detection in BD participants based on their questionnaire responses. R esults: HC participants did not report depressive symptoms and their features showed similar distributions to nondepressed BD participants. Questionnaire score estimation using geolocation-derived features from BD participants demonstrated an optimal mean absolute error rate of 3.73, while depression detection demonstrated an optimal (median ± IQR) [Formula: see text] score of 0.857 ± 0.022 using five features (classification accuracy: 0.849 ± 0.016; sensitivity: 0.839 ± 0.014; specificity: 0.872 ± 0.047). CONCLUSION: These results demonstrate a strong link between geographic movements and depression in bipolar disorder. S ignificance: To our knowledge, this is the first community study of passively recorded objective markers of depression in bipolar disorder of this scale. The techniques could help individuals monitor their depression and enable healthcare providers to detect those in need of care or treatment.

Experiences of remote mood and activity monitoring in bipolar disorder: A qualitative study.

BACKGROUND: Mobile technology enables high frequency mood monitoring and automated passive collection of data (e.g. actigraphy) from patients more efficiently and less intrusively than has previously been possible. Such techniques are increasingly being deployed in research and clinical settings however little is known about how such approaches are experienced by patients. Here, we explored the experiences of individuals with bipolar disorder engaging in a study involving mood and activity monitoring with a range of portable and wearable technologies. METHOD: Patients were recruited from a wider sample of 50 individuals with Bipolar Disorder taking part in the Automated Monitoring of Symptom Severity (AMoSS) study in Oxford. A sub-set of 21 patients participated in a qualitative interview that followed a semi-structured approach. RESULTS: Monitoring was associated with benefits including increased illness insight, behavioural change. Concerns were raised about the potential preoccupation with, and paranoia about, monitoring. Patients emphasized the need for personalization, flexibility, and the importance of context, when monitoring mood. CONCLUSIONS: Mobile and electronic health approaches have potential to lend new insights into mental health and transform healthcare. Capitalizing on the perceived utility of these approaches from the patients' perspective, while addressing their concerns, will be essential for the promise of new technologies to be realised.

Associations between mood instability and emotional processing in a large cohort of bipolar patients.

BACKGROUND: Aberrant emotional biases have been reported in bipolar disorder (BD), but results are inconsistent. Despite the clinical relevance of chronic mood variability in BD, there is no previous research investigating how the extent of symptom fluctuations in bipolar disorder might relate to emotional biases. This exploratory study investigated, in a large cohort of bipolar patients, whether instability in weekly mood episode symptoms and other clinical and demographic factors were related to emotional bias as measured in a simple laboratory task. METHOD: Participants (N = 271, BDI = 206, BDII = 121) completed an 'emotional categorization and memory' task. Weekly self-reported symptoms of depression and mania were collected prospectively. In linear regression analyses, associations between cognitive bias and mood variability were explored together with the influence of demographic and clinical factors, including current medication. RESULTS: Greater accuracy in the classification of negative words relative to positive words was associated with greater instability in depressive symptoms. Furthermore, greater negative bias in free recall was associated with higher instability in manic symptoms. Participants diagnosed with BDII, compared with BDI, showed overall better word recognition and recall. Current antipsychotic use was associated with reduced instability in manic symptoms but this did not impact on emotional processing performance. CONCLUSIONS: Emotional processing biases in bipolar disorder are related to instability in mood. These findings prompt further investigation into the underpinnings as well as clinical significance of mood instability.

A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation.

UNLABELLED: The opportunistic fungal pathogen Cryptococcus neoformans causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA) signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in C. neoformans showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis. IMPORTANCE: Fungi cause life-threatening diseases, but very few drugs are available to effectively treat fungal infections. The pathogenic fungus Cryptococcus neoformans causes a substantial global burden of life-threatening meningitis in patients suffering from HIV/AIDS. An understanding of the mechanisms by which fungi deploy virulence factors to cause disease is critical for developing new therapeutic approaches. We employed a quantitative proteomic approach to define the changes in the protein complement that occur upon modulating the cAMP signaling pathway that regulates virulence in C. neoformans. This approach identified a conserved role for cAMP signaling in the regulation of the ubiquitin-proteasome pathway and revealed a link between this pathway and elaboration of a major virulence determinant, the polysaccharide capsule. Targeting the ubiquitin-proteasome pathway opens new therapeutic options for the treatment of cryptococcosis.

The iTreAD project: a study protocol for a randomised controlled clinical trial of online treatment and social networking for binge drinking and depression in young people.

BACKGROUND: Depression and binge drinking behaviours are common clinical problems, which cause substantial functional, economic and health impacts. These conditions peak in young adulthood, and commonly co-occur. Comorbid depression and binge drinking are undertreated in young people, who are reluctant to seek help via traditional pathways to care. The iTreAD project (internet Treatment for Alcohol and Depression) aims to provide and evaluate internet-delivered monitoring and treatment programs for young people with depression and binge drinking concerns. METHODS: Three hundred sixty nine participants will be recruited to the trial, and will be aged 18-30 years will be eligible for the study if they report current symptoms of depression (score 5 or more on the depression subscale of the Depression Anxiety Stress Scale) and concurrent binge drinking practices (5 or more standard drinks at least twice in the prior month). Following screening and online baseline assessment, participants are randomised to: (a) online monthly self-assessments, (b) online monthly self-assessments + 12-months of access to a 4 week online automated cognitive behaviour therapy program for binge drinking and depression (DEAL); or (c) online monthly assessment + DEAL + 12-months of access to a social networking site (Breathing Space). Independent, blind follow-up assessments occur at 26, 39, 52 and 64-weeks post-baseline. DISCUSSION: The iTreAD project is the first randomised controlled trial combining online cognitive behaviour therapy, social networking and online monitoring for young people reporting concerns with depression and binge drinking. These treatments represent low-cost, wide-reach youth-appropriate treatment, which will have significantly public health implications for service design, delivery and health policy for this important age group. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000310662. Date registered 24 March 2014.

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines.

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.

The development of a designated dental pathway for looked after children.

OBJECTIVE: To explore the impact of a community-based dental care pathway on the dental care of children entering residential or foster care. DESIGN: The study used qualitative data collected during interviews with children who used the service, their carers and key professionals involved in the pathway, and routine quantitative data concerned with care entry and the dental service use. RESULTS: The dental pathway facilitated dental care access for children entering statutory care, met the dental needs of service users even when dental care provision proved challenging, and offered a consistent dental service regardless of care moves. Improved interagency integration and support was reported by key professionals as was better dissemination and documentation of dental assessments and outcomes. CONCLUSION: The dental care pathway had a beneficial impact on the dental access and experiences of children who used it, promoted better interagency working and facilitated record keeping. These findings call for extension of the service to a wider population to allow further evaluation of its impact and efficacy in different regional areas and contexts.

Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels.

BACKGROUND: Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers. METHOD: Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period. RESULTS: Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness. CONCLUSIONS: Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Clinical and regulatory implications of active run-in phases in long-term studies for bipolar disorder.

OBJECTIVE: The integration of new treatments into the market and routine clinical practice should be dependent on robustness of evidence from randomised controlled trials (RCTs). We assessed study designs of long-term studies for bipolar disorder of all second-generation antipsychotics (SGAs) submitted to the Food and Drug Administration (FDA) and the completeness of evidence submitted to the regulatory agency. METHOD: Systematic review of double-blind RCTs comparing SGAs with placebo or active drugs in adults. FDA website and electronic databases were searched until July 2013. RESULTS: Six placebo-controlled trials comparing aripiprazole, olanzapine, quetiapine and ziprasidone were found in the FDA website. Electronic searches found four additional RCTs about aripiprazole, olanzapine or quetiapine. All RCTs (either submitted to FDA or not) selected patients who responded to acute treatment to increase the treatment effect observed in the long-term phase (enrichment design). By contrast, in the prescribing information sheets for all SGAs, the reported indication was 'maintenance treatment of bipolar disorder'. CONCLUSION: Extrapolation of results from enrichment studies to the more general population of patients should be carried out cautiously because average treatment benefits are likely to be less in unselected patients. Clear guidance for regulatory submission of RCTs is needed.

Fenbendazole improves pathological and functional recovery following traumatic spinal cord injury.

During a study of spinal cord injury (SCI), mice in our colony were treated with the anthelmintic fenbendazole to treat pinworms detected in other mice not involved in the study. As this was not part of the original experimental design, we subsequently compared pathological and functional outcomes of SCI in female C57BL/6 mice who received fenbendazole (150 ppm, 8 mg/kg body weight/day) for 4 weeks prior to moderate contusive SCI (50 kdyn force) as compared to mice on the same diet without added fenbendazole. The fenbendazole-treated mice exhibited improved locomotor function, determined using the Basso mouse scale, as well as improved tissue sparing following contusive SCI. Fenbendazole may exert protective effects through multiple possible mechanisms, one of which is inhibition of the proliferation of B lymphocytes, thereby reducing antibody responses. Autoantibodies produced following SCI contribute to the axon damage and locomotor deficits. Fenbendazole pretreatment reduced the injury-induced CD45R-positive B cell signal intensity and IgG immunoreactivity at the lesion epicenter 6 weeks after contusive SCI in mice, consistent with a possible effect on the immune response to the injury. Fenbendazole and related benzimadole antihelmintics are FDA approved, exhibit minimal toxicity, and represent a novel group of potential therapeutics targeting secondary mechanisms following SCI.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Use of self-administered instruments to assess psychiatric disorders in older people: validity of the General Health Questionnaire, the Center for Epidemiologic Studies Depression Scale and the self-completion version of the revised Clinical Interview Schedule.

BACKGROUND: Diagnosis of depressive disorder using interviewer-administered instruments is expensive and frequently impractical in large epidemiological surveys. The aim of this study was to assess the validity of three self-completion measures of depressive disorder and other psychiatric disorders in older people against an interviewer-administered instrument. METHOD: A random sample stratified by sex, age and social position was selected from the Whitehall II study participants. This sample was supplemented by inclusion of depressed Whitehall II participants. Depressive disorder and other mental disorders were assessed by the interviewer-administered structured revised Clinical Interview Schedule (CIS-R) in 277 participants aged 58-80 years. Participants also completed a computerized self-completion version of the CIS-R in addition to the General Health Questionnaire (GHQ) and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: The mean total score was similar for the interviewer-administered (4.43) and self-completion (4.35) versions of the CIS-R [95% confidence interval (CI) for difference -0.31 to 0.16]. Differences were not related to sex, age, social position or presence of chronic physical illness. Sensitivity/specificity of self-completion CIS-R was 74%/98% for any mental disorder and 75%/98% for depressive episode. The corresponding figures were 86%/87% and 78%/83% for GHQ and 77%/89% and 89%/86% for CES-D. CONCLUSIONS: The self-completion computerized version of the CIS-R is feasible and has good validity as a measure of any mental disorder and depression in people aged ≥ 60 years. GHQ and CES-D also have good criterion validity as measures of any mental disorder and depressive disorder respectively.