Living the life you want following a diagnosis of bipolar disorder: A grounded theory approach.

Bipolar disorder (BD) is considered a severe and lifelong mental health diagnosis. However, there is growing evidence of people defying the odds and recovering. Processes underlying recovery remain poorly understood. This study aimed to explore these recovery processes and extend on the length of recovery defined within previous research. Twelve people previously diagnosed with BD, who had not experienced an episode of depression and/or mania for four or more years, were interviewed. Standardised diagnostic interviews (Structured Clinical Interview for Diagnostic and Statistical Manual-V, Research version) confirmed past diagnosis and recovery time. Qualitative methodology via grounded theory was used to analyse these personal accounts. The analysis revealed 10 overarching categories of what participants reported to be important in their recovery: support, recognition of the problem, believing that things can change and not giving up, instinctive curiosity, medication, psychological therapy, becoming the director of your own life, changing how I think, accepting who I am and how I feel, and looking after me. A model was developed to represent how categories were related. The study was limited by recruitment not leading to the inclusion of people who had distanced themselves from the label of BD. Potential transdiagnostic recovery processes also require further direct exploration. Critically, the study highlights that following a diagnosis of BD, people do experience long-term recovery achieved through self-determined pathways and that being able to live the life you want is therefore achievable. This challenges current diagnostic perspectives and societal messages of lifelong conditions.

'What people diagnosed with bipolar disorder experience as distressing': A meta-synthesis of qualitative research.

BACKGROUND: Bipolar disorder (BD) is considered to have a significantly negative impact on functioning and prognosis is considered poor. Current treatments are modestly effective and predominantly focus on reducing extreme mood fluctuations and symptoms, yet less is known about what patients themselves describe as distressing. Therefore we aimed to assess this through a systematic review. METHODS: A comprehensive literature search was conducted in four major bibliographic databases in August 2017, updated in July 2018. Qualitative studies exploring BD were included if they contained themes related to distress. First person accounts from people with BD discussing what they experience as distressing were extracted and synthesised using thematic synthesis. Author interpretations were also extracted to support the synthesis. RESULTS: Twenty-four studies were included. Five main analytical themes were developed: 1) diagnosis, 2) loss, 3) uncertainty, 4) threat and 5) relationships. Two further crosscutting themes were identified as 1) stigma and 2) fear of relapse. Implications for interventions to focus on these causes of distress also emerged. LIMITATIONS: The included studies did not adequately examine the authors' potential own biases and influences within their interpretations of the data. One author predominantly undertook data extraction and coding for the current review, although research team discussions led to an agreed consensus on themes. CONCLUSIONS: This was the first qualitative study to specifically explore distress in BD. The meta-synthesis highlights important areas that people with BD experience as distressing. Adaptations to current interventions, to focus on what people find distressing could seek to improve treatment outcomes.

Complete recovery from anxiety disorders following Cognitive Behavior Therapy in children and adolescents: A meta-analysis.

Cognitive Behavior Therapy (CBT) is a well-established treatment for childhood anxiety disorders. Meta-analyses have concluded that approximately 60% of children recover following treatment, however these include studies using a broad range of diagnostic indices to assess outcomes including whether children are free of the one anxiety disorder that causes most interference (i.e. the primary anxiety disorder) or whether children are free of all anxiety disorders. We conducted a meta-analysis to establish the efficacy of CBT in terms of absence of all anxiety disorders. Where available we compared this rate to outcomes based on absence of primary disorder. Of 56 published randomized controlled trials, 19 provided data on recovery from all anxiety disorders (n=635 CBT, n=450 control participants). There was significant heterogeneity across those studies with available data and full recovery rates varied from 47.6 to 66.4% among children without autistic spectrum conditions (ASC) and 12.2 to 36.7% for children with ASC following treatment, compared to up to 20.6% and 21.3% recovery in waitlist and active treatment comparisons. The lack of consistency in diagnostic outcomes highlights the urgent need for consensus on reporting in future RCTs of childhood anxiety disorders for the meaningful synthesis of data going forwards.

Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.

Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.

The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease.

Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.

Group I metabotropic glutamate receptors, mGlu1a and mGlu5a, couple to cyclic AMP response element binding protein (CREB) through a common Ca2+ - and protein kinase C-dependent pathway.

Coupling of the group I metabotropic glutamate receptors, mGlu1a and mGlu5a, to the cAMP response element binding protein (CREB) has been studied in Chinese hamster ovary cell lines where receptor expression is under the control of an inducible promoter. Both receptors stimulate CREB phosphorylation with similar time courses, and agonist potency was also comparable between the two receptors. Stimulation of cells in Ca(2+)-free medium containing EGTA (100 microm), with or without the additional depletion of intracellular stores, caused marked decreases in agonist-mediated responses in both cell lines. Down-regulation of protein kinase C (PKC) activity by phorbol ester treatment, or treatment with the broad spectrum PKC inhibitor Ro 31-8220, partially attenuated both mGlu1a and mGlu5a receptor-mediated responses. Furthermore, stimulation of cells in the absence of extracellular Ca(2+) following prior PKC down-regulation resulted in additive inhibitory effects. The involvement of extracellular signal-regulated kinases (ERK1/2), Ca(2+)/calmodulin or Ca(2+)/calmodulin-dependent protein kinases was assessed using pharmacological inhibitors. Results indicated that coupling of the group I mGlu receptors to CREB phosphorylation occurs independently of these pathways. Thus, although the [Ca(2+)](i) signatures activated by these mGlu receptors differ, they couple to CREB with comparable potency and recruit similar downstream components to execute CREB phosphorylation.

The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death.

The stress-activated protein kinase p38 and nitric oxide (NO) are proposed downstream effectors of excitotoxic cell death. Although the postsynaptic density protein PSD95 can recruit the calcium-dependent neuronal NO synthase (nNOS) to the mouth of the calcium-permeable NMDA receptor, and depletion of PSD95 inhibits excitotoxicity, the possibility that selective uncoupling of nNOS from PSD95 might be neuroprotective is unexplored. The relationship between excitotoxic stress-generated NO and activation of p38, and the significance of the PSD95-nNOS interaction to p38 activation also remain unclear. We find that NOS inhibitors reduce both glutamate-induced p38 activation and the resulting neuronal death, whereas NO donor has effects consistent with NO as an upstream regulator of p38 in glutamate-induced cell death. Experiments using a panel of decoy constructs targeting the PSD95-nNOS interaction suggest that this interaction and subsequent NO production are critical for glutamate-induced p38 activation and the ensuing cell death, and demonstrate that the PSD95-nNOS interface provides a genuine possibility for design of neuroprotective drugs with increased selectivity.

Involvement of the Arp2/3 complex and Scar2 in Golgi polarity in scratch wound models.

Cell motility and cell polarity are essential for morphogenesis, immune system function, and tissue repair. Many animal cells move by crawling, and one main driving force for movement is derived from the coordinated assembly and disassembly of actin filaments. As tissue culture cells migrate to close a scratch wound, this directional extension is accompanied by Golgi apparatus reorientation, to face the leading wound edge, giving the motile cell inherent polarity aligned relative to the wound edge and to the direction of cell migration. Cellular proteins essential for actin polymerization downstream of Rho family GTPases include the Arp2/3 complex as an actin nucleator and members of the Wiskott-Aldrich Syndrome protein (WASP) family as activators of the Arp2/3 complex. We therefore analyzed the involvement of the Arp2/3 complex and WASP-family proteins in in vitro wound healing assays using NIH 3T3 fibroblasts and astrocytes. In NIH 3T3 cells, we found that actin and Arp2/3 complex contributed to cell polarity establishment. Moreover, overexpression of N-terminal fragments of Scar2 (but not N-WASP or Scar1 or Scar3) interfere with NIH 3T3 Golgi polarization but not with cell migration. In contrast, actin, Arp2/3, and WASP-family proteins did not appear to be involved in Golgi polarization in astrocytes. Our results thus indicate that the requirement for Golgi polarity establishment is cell-type specific. Furthermore, in NIH 3T3 cells, Scar2 and the Arp2/3 complex appear to be involved in the establishment and maintenance of Golgi polarity during directed migration.