White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Same donor laparoscopic liver and kidney procurement for sequential living donor liver-kidney transplantation in primary hyperoxaluria type i

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages.

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine

Stress and functional neurological disorders: mechanistic insights

At the interface between mind and body, psychiatry and neurology, functional neurological disorder (FND) remains poorly understood. Formerly dominant stress-related aetiological models have been increasingly challenged, in part due to cases without any history of past or recent trauma. In this perspective article, we review current evidence for such models, and how research into the role of traumatic stress in other disorders and the neurobiology of the stress response can inform our mechanistic understanding of FND. First, we discuss the association between stress and the onset or exacerbation of a variety of physical and mental health problems. Second, we review the role of hypothalamic-pituitary-adrenal axis dysfunction in the neurobiology of ill-health, alongside evidence for similar mechanisms in FND. Third, we advocate a stress-diathesis model, in which biological susceptibility interacts with early life adversity, where FND can be precipitated by traumatic events later in life and maintained by psychological responses. We hypothesise that greater biological susceptibility to FND is associated with less severe remote and recent stress, and that FND precipitated by more severe stress is associated with lower biological vulnerability. This would explain clinical experience of variable exposure to historical and recent traumatic stress among people with FND and requires empirical investigation. A testable, evidence-based stress-diathesis model can inform nuanced understanding of how biological and psychological factors interact at the individual level, with potential to inform personalised treatment pathways. Much-needed research to establish the aetiology of FND will enhance clinical care and communication, facilitate effective treatment and inform prevention strategies

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3–10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27Kip1 and p57Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans

When one childhood meets another – maternal childhood trauma and offspring child psychopathology: a systematic review.

Background: Child maltreatment can have a long-term impact on mental health. Less is known about the consequences of child maltreatment on the next generation’s psychological wellbeing. Aim: This systematic review aimed to synthesise existing empirical literature on the association between a mother’s history of maltreatment in her own childhood and her children’s experience of psychopathology, and to characterise potential mediating pathways. Method: Electronic database and hand searches yielded 12 studies, with a combined sample size of 45,723 mother-child dyads, which met criteria for inclusion in the review. Results: There was evidence of an overall positive association between a mother’s history of child maltreatment and her child’s experience of emotional and behavioural difficulties across childhood and adolescence. Maternal psychological distress and poorer parenting practices were found to be key mediating pathways of this association. Conclusion: Children of mothers who were exposed to maltreatment in childhood appear to be at an increased risk for psychopathology. Mothers with traumatic childhood experiences should be offered improved access to psychological therapies and parenting programmes to help mitigate the potential impact of child maltreatment on future generations

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research &amp; Development, LLC., of Johnson &amp; Johnson, and hold stock in Johnson &amp; Johnson. The other authors report no financial disclosures or potential conflicts of interest.This work was funded by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of patients was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. SRC consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK. In the last three years PJC has served on an advisory board for Lundbeck. NAH consults for GSK. PdB, DJ and WCD are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson