Attempting to disentangle the relationship between impulsivity and longitudinal self-harm: Epidemiological analysis of UK household survey data

Background: Impulsivity may be an important risk factor in terms of future self-harm. However, the extent of this, whether it may relate to self-harm that is new in onset and/or repetition of self-harm, and the detail of any interaction with mood instability (MI) and childhood sexual abuse (CSA) requires detailed examination. Aims: We used the 2000 Adult Psychiatry Morbidity Survey and an 18-month follow-up data to test hypotheses relating to the role of impulsivity, CSA and MI in the inception and persistence of self-harm. Methods: We assessed associations of impulsivity with (1) suicidal self-harm (SSH) and (2) non-SSH (NSSH) at baseline and follow-up, controlling for confounders including MI. Finally, we tested whether impulsivity mediated the relationship between CSA and self-harm. Results: A total of 8,580 respondents were assessed at baseline and 2,406 at follow-up as planned. Impulsivity significantly predicted emergence of new NSSH at 18-month follow-up even after adjustment for MI and other confounders. Impulsivity did not significantly predict repetition of NSSH, or repetition or new inception of SSH, even before inclusion of MI in the model. However, the absolute numbers involved were small. Cross-sectionally, impulsivity was a stronger mediator of the link between CSA and SSH (13.1%) than that between CSA and NSSH (4.8%). Conclusion: Impulsivity may increase the risk of future development of NSSH independently of MI, which is clinically important for risk assessment. The involvement of impulsivity in the repetition of self-harm generally appears less certain. However, impulsivity may have a role in SSH in the context of previous CSA

Mother-infant interactions and regional brain volumes in infancy: an MRI study

Background: It is generally agreed that the human brain is responsive to environmental influences, and that the male brain may be particularly sensitive to early adversity. However, this is largely based on retrospective studies of older children and adolescents exposed to extreme environments in childhood. Less is understood about how normative variations in parent-child interactions are associated with the development of the infant brain in typical settings. Method: To address this, we used magnetic resonance imaging to investigate the relationship between observational measures of mother-infant interactions and regional brain volumes in a community sample of 3-6 month old infants (N=39). In addition, we examined whether this relationship differed in male and female infants. Results: We found that lower maternal sensitivity was correlated with smaller subcortical grey matter volumes in the whole sample, and that this was similar in both sexes. However, male infants who showed greater levels of positive communication and engagement during early interactions had smaller cerebellar volumes. Conclusion These preliminary findings suggest that variations in mother-infant interaction dimensions are associated with differences in infant brain development. Although the study is cross-sectional and causation cannot be inferred, the findings reveal a dynamic interaction between brain and environment that may be important when considering interventions to optimize infant outcomes

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Can we use neurocognition to predict repetition of self-harm, and why might this be clinically useful? a perspective

Over 800,000 people die by suicide each year globally, with non-fatal self-harm 20 times more common. With each episode of self-harm, the risks of future self-harm and suicide increase, as well as personal and healthcare costs. Therefore, early delineation of those at high risk of future self-harm is important. Historically, research has focused on clinical and demographic factors, but risk assessments based on these have low sensitivity to predict repetition. Various neurocognitive factors have been associated with self-harming behavior, but it is less certain if we can use these factors clinically (i) as risk markers to predict future self-harm and (ii) to become therapeutic targets for interventions. Recent systematic reviews and meta-analyses of behavioral tasks and fMRI studies point to an emerging hypothesis for neurocognition in self-harm: an underactive pre-frontal cortex is unable to respond appropriately to non-emotional stimuli, or inhibit a hyperactive emotionally-/threat-driven limbic system. However, there is almost no imaging data examining repetition of self-harm. Extrapolating from the non-repetition data, there may be several potential neurocognitive targets for interventions to prevent repeat self-harm: cognitive training; pharmacological regimes to promote non-emotional neurocognition; or other techniques, such as repetitive transcranial magnetic stimulation. Hence, there is an urgent need for imaging studies examining repetition and to test specific hypotheses. Until we investigate the functional neurocognitive basis underlying repetition of self-harm in a systematic manner using second-generational imaging techniques, we will be unable to inform third-generational imaging and potential future clinical applications

Adjunctive benzodiazepines in depression: a clinical dilemma with no recent answers from research

Comorbid anxiety symptoms are common in depression, and adding benzodiazepines to antidepressant treatment may seem a rational clinical solution. Benzodiazepines also have potential to reduce the initial anxiety that may be caused by early antidepressant treatment (owing to their inhibitory effect via GABAA receptor binding). This month's Cochrane Corner review examines the evidence behind combination treatment versus antidepressants alone in major depressive disorder, in terms of both the clinical and neuroscientific context. The review provides evidence that, in the first 4 weeks of treatment, additional medication with a benzodiazepine may lead to greater improvements than antidepressant alone on ratings of severity, response rates and remission rates for depression, but not on measures of anxiety

Self-harm, suicidal ideation, and the positive symptoms of psychosis: Cross-sectional and prospective data from a national household survey

Background Schizophrenia is associated with premature mortality, partly through increased suicide rates. Aims To examine (1) if persecutory ideas, auditory hallucinations, and probable cases of psychosis are associated with suicidal thoughts or attempts cross-sectionally and prospectively, and (2) if such links are mediated by specific affective factors (depression, impulsivity, mood instability). Method We analysed the 2000, 2007, and 2014 British Adult Psychiatric Morbidity Surveys (APMS) separately. Measures of psychosis provided independent variables for multi-stage logistic regressions, with suicidal thoughts and attempts as dependent variables. We also conducted analyses to assess mediation by affective variables, and longitudinal analyses on a subset of the 2000 dataset. Results In every dataset, persecutory ideas, auditory hallucinations and probable psychosis were associated cross-sectionally with lifetime suicidal attempts and thoughts, even after controlling for confounders, with a single exception (persecutory ideation and suicide attempts were unconnected in APMS 2014). Cross-sectional associations between auditory hallucinations and suicidal phenomena were moderated by persecutory ideation. In the 2000 follow-up, initial persecutory ideas were associated with later suicidal thoughts (O.R. 1.77, p Conclusions Improving psychotic symptoms and ameliorating co-morbid distress may in itself be effective in reducing suicidal risk in schizophrenia. Given their potential mediating role, mood instability and depression may also be targets for intervention.</p

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases

Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed‐dose combination of blood pressure‐ and cholesterol‐lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD. Objectives To determine the effect of fixed‐dose combination therapy on all‐cause mortality, fatal and non‐fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed‐dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health‐related quality of life, and costs. Search methods We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed‐dose combination therapy including at least one blood pressure‐lowering and one lipid‐lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre‐existing ASCVD. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed‐effect models when heterogeneity was low (I2 and#60; 50%) and random‐effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence. Main results In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed‐dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow‐up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow‐up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed‐dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I2 = 0%, 5 studies, N = 5300) and fatal and non‐fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low‐quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed‐dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed‐dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate‐quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was ‐6.34 mmHg (95% CI ‐9.03 to ‐3.64, 13 trials, 7638 participants, moderate‐quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were ‐0.61 mmol/L (95% CI ‐0.88 to ‐0.35, 11 trials, 6565 participants, low‐quality evidence) and ‐0.70 mmol/L (95% CI ‐0.98 to ‐0.41, 12 trials, 7153 participants, moderate‐quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed‐dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate‐quality evidence). Authors' conclusions The effects of fixed‐dose combination therapy on all‐cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed‐dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer‐term trials of fixed‐dose combination therapy will help demonstrate whether short‐term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases

Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed‐dose combination of blood pressure‐ and cholesterol‐lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD. Objectives To determine the effect of fixed‐dose combination therapy on all‐cause mortality, fatal and non‐fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed‐dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health‐related quality of life, and costs. Search methods We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed‐dose combination therapy including at least one blood pressure‐lowering and one lipid‐lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre‐existing ASCVD. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed‐effect models when heterogeneity was low (I2 &lt; 50%) and random‐effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence. Main results In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed‐dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow‐up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow‐up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed‐dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I2 = 0%, 5 studies, N = 5300) and fatal and non‐fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low‐quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed‐dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed‐dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate‐quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was ‐6.34 mmHg (95% CI ‐9.03 to ‐3.64, 13 trials, 7638 participants, moderate‐quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were ‐0.61 mmol/L (95% CI ‐0.88 to ‐0.35, 11 trials, 6565 participants, low‐quality evidence) and ‐0.70 mmol/L (95% CI ‐0.98 to ‐0.41, 12 trials, 7153 participants, moderate‐quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed‐dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate‐quality evidence). Authors' conclusions The effects of fixed‐dose combination therapy on all‐cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed‐dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer‐term trials of fixed‐dose combination therapy will help demonstrate whether short‐term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes

Translating the promise of 5HT4 receptor agonists for the treatment of depression

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic