ATYPICAL ANTI-PSYCHOTICS IN ADULT BIPOLAR DISORDER: URRENT EVIDENCE AND UPDATES IN THE NICE GUIDELINES

Background: The introduction of atypical antipsychotics in the management of adult bipolar disorder has been increasingly adopted in clinical setting. While new studies continue to emerge, NICE has recently updated the guidelines on the assessment and management of bipolar disorder. Aim: To review the efficacy and tolerability profiles of atypical antipsychotics used to treat adult bipolar disorder in clinical practice, in relation to the latest NICE guidelines. Methods: The recent NICE guidelines (CG185), published in September 2014 was analysed to identify second generation antipsychotics (SGA) for the various presentations of bipolar disorder in adults. A qualitative literature search was conducted to review the evidence to support these changes, and identify randomized controlled trials on off-label and newer SGAs. Results and conclusions: With respect to atypical antipsychotics, NICE guidelines introduced olanzapine and fluoxetine combination therapy as first line treatment for moderate to severe bipolar depression; and improved clarity on the treatment of mania, hypomania and rapid cycling bipolar disorder. Evidence from our literature search favour these changes; and recognized other atypical antipsychotics such as aripiprazole, asenapine, lurasidone, ziprasidone and clozapine which could be of potential clinical benefit

ATYPICAL ANTIPSYCHOTICS FOR SCHIZOPHRENIA AND/OR BIPOLAR DISORDER IN PREGNANCY: CURRENT RECOMMENDATIONS AND UPDATES IN THE NICE GUIDELINES

Background: The gold standard pharmacological agents used to treat schizophrenia and bipolar disorder in adults are antipsychotics. Atypical or second-generation antipsychotics have superseded or used as alternatives to typical first-generation antipsychotics due to better tolerability and safety profile. However the efficacy and safety of these drugs are severely limited in pregnancy and/or women of childbearing potential. There are very few guidelines to guide the clinical management of schizophrenia and/or bipolar disorder in this subgroup. Aim: We aimed to review current evidence of atypical antipsychotics used in pregnancy where available, with considerations to its efficacy and safety to both the mother and fetus, in conjunction with the recently updated NICE guidelines. Methods: The latest NICE CG192 guidelines on antenatal and postnatal mental health, published in December 2014 was reviewed and summarized, and the BNF-approved list of atypical antipsychotics were identified. Clinically relevant MEDLINElinked publications were searched and selected where available using the PubMed search engine to identify evidence for or against the use of atypical antipsychotics in pregnancy. Results and Conclusions: NICE CG192 improved clarity on the prediction, support and holistic management of mental illness in pregnancy and puerperium; however there were no specific recommendations in terms of pharmacological agents used to treat schizophrenia and/or bipolar disorder in this subgroup. Evidence from the literature on atypical antipsychotics yielded discordant results. Nonetheless, our report presents preliminary findings of certain antipsychotics which appear to be effective and safe in pregnancy. Future research would benefit from larger, prospective randomized controlled trials, and perhaps include newer atypical antipsychotics for consideration in this subgroup

Investigating upper urinary tract urothelial carcinomas: a single-centre 10-year experience.

OBJECTIVES: Evidence of the accuracy of predictive tests in confirming the presence and grade of upper urinary tract urothelial carcinomas (UUTUC) is limited. We present the largest series evaluating the diagnostic value of pre- and intra-operative parameters in the detection of UUTUC. MATERIALS AND METHODS: We retrospectively analysed records of patients who underwent diagnostic ureteroscopy between 2005 and 2014 for suspected UUTUC. Pre-operative workup included voided urine cytology and CT imaging. Intra-operative assessments involved ureteroscopy to directly visualise suspicious lesions, and where possible selective cytology and biopsy. Primary outcomes were the visualisation of UUTUC and histopathological confirmation of tumour. RESULTS: Hundred out of 160 (63 %) patients presenting with suspected upper tract malignancy had UUTUC. Voided and selective urine cytology and CT individually predicted UUTUC with a sensitivity/specificity of 63/67, 76/73, and 95/26 %, respectively. Forty out of 48 (83 %) patients who had abnormal CT and abnormal voided urine cytology had UUTUC, while 100 % of those with normal CT and normal voided cytology (investigated for ongoing symptoms) were normal. Comparing endoscopic biopsy to nephroureterectomy specimen grade, 19 (46 %), 18 (44 %), and 4 (10 %) were identical, upgraded, and downgraded, respectively. CONCLUSION: Pre-operative investigations can predict UUTUCs. When these investigations were normal, the risk of UUTUC is negligible. In selective patients with abnormal investigations, ureteroscopy should be performed to confirm and predict the grade of UUTUC, in order to guide future management. Selective cytology is unlikely to significantly contribute to the diagnostic workup of UUTUC.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer

ATYPICAL ANTIPSYCHOTICS FOR SCHIZOPHRENIA AND/OR BIPOLAR DISORDER IN PREGNANCY: CURRENT RECOMMENDATIONS AND UPDATES IN THE NICE GUIDELINES

Background: The gold standard pharmacological agents used to treat schizophrenia and bipolar disorder in adults are antipsychotics. Atypical or second-generation antipsychotics have superseded or used as alternatives to typical first-generation antipsychotics due to better tolerability and safety profile. However the efficacy and safety of these drugs are severely limited in pregnancy and/or women of childbearing potential. There are very few guidelines to guide the clinical management of schizophrenia and/or bipolar disorder in this subgroup. Aim: We aimed to review current evidence of atypical antipsychotics used in pregnancy where available, with considerations to its efficacy and safety to both the mother and fetus, in conjunction with the recently updated NICE guidelines. Methods: The latest NICE CG192 guidelines on antenatal and postnatal mental health, published in December 2014 was reviewed and summarized, and the BNF-approved list of atypical antipsychotics were identified. Clinically relevant MEDLINElinked publications were searched and selected where available using the PubMed search engine to identify evidence for or against the use of atypical antipsychotics in pregnancy. Results and Conclusions: NICE CG192 improved clarity on the prediction, support and holistic management of mental illness in pregnancy and puerperium; however there were no specific recommendations in terms of pharmacological agents used to treat schizophrenia and/or bipolar disorder in this subgroup. Evidence from the literature on atypical antipsychotics yielded discordant results. Nonetheless, our report presents preliminary findings of certain antipsychotics which appear to be effective and safe in pregnancy. Future research would benefit from larger, prospective randomized controlled trials, and perhaps include newer atypical antipsychotics for consideration in this subgroup

ATYPICAL ANTI-PSYCHOTICS IN ADULT BIPOLAR DISORDER: URRENT EVIDENCE AND UPDATES IN THE NICE GUIDELINES

Background: The introduction of atypical antipsychotics in the management of adult bipolar disorder has been increasingly adopted in clinical setting. While new studies continue to emerge, NICE has recently updated the guidelines on the assessment and management of bipolar disorder. Aim: To review the efficacy and tolerability profiles of atypical antipsychotics used to treat adult bipolar disorder in clinical practice, in relation to the latest NICE guidelines. Methods: The recent NICE guidelines (CG185), published in September 2014 was analysed to identify second generation antipsychotics (SGA) for the various presentations of bipolar disorder in adults. A qualitative literature search was conducted to review the evidence to support these changes, and identify randomized controlled trials on off-label and newer SGAs. Results and conclusions: With respect to atypical antipsychotics, NICE guidelines introduced olanzapine and fluoxetine combination therapy as first line treatment for moderate to severe bipolar depression; and improved clarity on the treatment of mania, hypomania and rapid cycling bipolar disorder. Evidence from our literature search favour these changes; and recognized other atypical antipsychotics such as aripiprazole, asenapine, lurasidone, ziprasidone and clozapine which could be of potential clinical benefit

Investigating Upper Urinary Tract Urothelial Carcinomas: A single centre 10-year experience

OBJECTIVES Evidence of the accuracy of predictive tests in confirming the presence and grade of upper urinary tract urothelial carcinomas (UUTUC) is limited. We present the largest series evaluating the diagnostic value of pre- and intraoperative parameters in the detection of UUTUC. MATERIALS AND METHODS We retrospectively analysed records of patients who underwent diagnostic ureteroscopy between 2005 and 2014 for suspected UUTUC. Preoperative workup included voided urine cytology and CT imaging. Intra-operative assessments involved ureteroscopy to directly visualise suspicious lesions, and where possible selective cytology and biopsy. Primary outcomes were the visualisation of UUTUC and histopathological confirmation of tumour. RESULTS 100/160 (63%) of patients presenting with suspected upper tract malignancy had UUTUC. Voided and selective urine cytology and CT individually predicted UUTUC with a sensitivity/specificity of 63%/67%, 76%/73% and 95%/26% respectively. 40/48 (83%) of patients who had abnormal CT and abnormal voided urine cytology had UUTUC, while 100% of those with normal CT and normal voided cytology (investigated for ongoing symptoms) were normal. Comparing endoscopic biopsy to nephrouretectomy specimen grade, 19 (46%), 18 (44%), and 4 (10%) were identical, upgraded and downgraded respectively. CONCLUSIONS Pre-operative investigations can predict UUTUCs. When these investigations were normal, the risk of UUTUC is negligible. In selective patients with abnormal investigations, ureteroscopy should be performed to confirm and predict the grade of UUTUC, in order to guide future management. Selective cytology is unlikely to signfiicantly contribute to the diagnostic workup of UUTUC.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer

Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors

Grand Challenges for Global Brain Sciences

The next grand challenges for society and science are in the brain sciences. A collection of 60+ scientists from around the world, together with 10+ observers from national, private, and foundations, spent two days together discussing the top challenges that we could solve as a global community in the next decade. We eventually settled on three challenges, spanning anatomy, physiology, and medicine. Addressing all three challenges requires novel computational infrastructure. The group proposed the advent of The International Brain Station (TIBS), to address these challenges, and launch brain sciences to the next level of understanding