CNS Drug Research Articles

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR.

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT1B receptor (5-HT1BR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates (n = 3), we used positron emission tomography (PET) imaging with the radioligand [11C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT1BR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT1BR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT1BR occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT1BR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HT1BR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT1BR cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT1BR and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin.SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT1B receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT1B receptor density. The technique lends itself to a comprehensive in vivo investigation and understanding of drugs' effects in the brain.

No Occultation in the International Association for Hospice and Palliative Care Position Statement on Palliative Care and Assisted Suicide

Journal of Palliative MedicineVol. 20, No. 12 Letters to the EditorNo Occultation in the International Association for Hospice and Palliative Care Position Statement on Palliative Care and Assisted SuicideLiliana De Lima, Roberto Wenk, Katherine Pettus, and Lukas RadbruchLiliana De LimaInternational Association for Hospice and Palliative Care, Houston, Texas.Search for more papers by this author, Roberto WenkInternational Association for Hospice and Palliative Care, Houston, Texas.Fundacion FEMEBA, San Nicolas, Argentina.Search for more papers by this author, Katherine PettusInternational Association for Hospice and Palliative Care, Houston, Texas.Search for more papers by this author, and Lukas RadbruchInternational Association for Hospice and Palliative Care, Houston, Texas.Department of Palliative Medicine, Malteser Hospital, Bonn, Germany.Palliative Care Centre, Malteser Hospital Bonn/Rhein-Sieg, Bonn, Germany.Search for more papers by this authorPublished Online:1 Dec 2017https://doi.org/10.1089/jpm.2017.0364AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"No Occultation in the International Association for Hospice and Palliative Care Position Statement on Palliative Care and Assisted Suicide." Journal of Palliative Medicine, 20(12), pp. 1309–1310FiguresReferencesRelatedDetailsCited byPalliative Sedation for the Terminally Ill Patient27 September 2018 | CNS Drugs, Vol. 32, No. 10 Volume 20Issue 12Dec 2017 InformationCopyright 2017, Mary Ann Liebert, Inc.To cite this article:Liliana De Lima, Roberto Wenk, Katherine Pettus, and Lukas Radbruch.No Occultation in the International Association for Hospice and Palliative Care Position Statement on Palliative Care and Assisted Suicide.Journal of Palliative Medicine.Dec 2017.1309-1310.http://doi.org/10.1089/jpm.2017.0364Published in Volume: 20 Issue 12: December 1, 2017Online Ahead of Print:September 8, 2017PDF download

CNS Drug Development: Lessons Learned Part 3: Psychiatric and Central Nervous System Drugs Developed Over the Last Decade-Implications for the Field.

This column reviews the divergence between the approach to drug development in infectious disease, oncology, and immunology versus psychiatry. Between 2009 and 2016, 254 new drugs were approved. Of those, only 9 were for a psychiatric indication; another 5 were labeled to treat central nervous system disorders that are not considered psychiatric per se but are frequently found in individuals with psychiatric illnesses (eg, substantial weight gain). There were 2 additional new products for psychiatric indications that involved either a combination product (Contrave) or a prodrug for the production of aripiprazole (Aristada). The column discusses the reasons behind these different rates of development of psychiatric and/or central nervous system drugs compared with drugs in the areas of infectious disease, oncology, and immunology, and it predicts that this situation will change over the next century as we develop an improved understanding of the neurobiology underlying specific psychiatric illnesses.

Modeling consequences of prolonged strong unpredictable stress in zebrafish: Complex effects on behavior and physiology

Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience research and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we present a new zebrafish model of clinically relevant, prolonged unpredictable strong chronic stress (PUCS). The 5-week PUCS induced overt anxiety-like and motor retardation-like behaviors in adult zebrafish, also elevating whole-body cortisol and proinflammatory cytokines - interleukins IL-1β and IL-6. PUCS also elevated whole-body levels of the anti-inflammatory cytokine IL-10 and increased the density of dendritic spines in zebrafish telencephalic neurons. Chronic treatment of fish with an antidepressant fluoxetine (0.1mg/L for 8days) normalized their behavioral and endocrine phenotypes, as well as corrected stress-elevated IL-1β and IL-6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, PUCS elevated whole-body BDNF levels and the telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in-vivo model of chronic stress, also calling for further cross-species studies of both shared/overlapping and distinct neurobiological responses to chronic stress.

A PLATFORM FOR NOVEL IN VIVO MOLECULAR PROBES FOR ATTENUATION OF SYNAPTIC DYSFUNCTION AND PROINFLAMMATORY CYTOKINE OVERPRODUCTION

Diverse CNS disorders display common pathophysiology themes. Efforts to develop disease-modifying therapeutics reflect the increasing appreciation of these core mechanisms. Major challenges include identification of disease progression time windows amenable to intervention, the identification of druggable targets linked to disease related phenotypes, and the need for pharmacodynamic (PD) landmarks that can be taken from preclinical studies to clinical trials. Retrospective analyses of new molecular entity drug approvals reveal the differing impact of phenotypic vs single molecular target drug discovery approaches. The less biased phenotypic approach allows probing for new or alternative intervention approaches in areas of critical unmet medical need when there are no validated single molecular targets, whereas single molecular target approaches provide exceptional efficiencies when used in the context of established PD endpoints. As part of a multi-site collaboratorium focused on synaptic dysfunction and innate immunity as a common pathophysiology progression theme, we developed a platform that delivers new in vivo molecular probes of different potential therapeutic intervention mechanisms. The platform is based on highly focused organic syntheses of new chemical entities designed by risk reduction using pharmacoinformatics combined with project-specific considerations. Key among pharmacoinformatic restrictions were multi-property profiles based on curated databases of in vivo CNS drugs and drug candidates. Initial sets of synthesized compounds were taken through non-GLP ADMET-based pharmacological screens as a Go or NoGo decision point. Compounds passing Go were taken through hierarchical screens of activity related to pharmacological mechanism and in vivo efficacy. A prototype single molecular target approach for CNS protein kinases was brain p38αMAPK, an established target whose activity is up-regulated in glia and neurons in stress responses. The phenotypic approach focused on early stage overproduction of proinflammatory cytokines causally linked to synaptic dysfunction. The case study presentations are those based on an aminoarylpyridazine molecular fragment and its chemical diversification. Novel small molecule deliverables for each pharmacological intervention approach show efficacy in AD-relevant mouse models. Our validated discovery platform has generated efficacious, CNS-active, in vivo molecular probes. ADMET-optimized versions of these probes are in late stage, investigational new drug (IND) development or early stage first-in-human clinical trials.

Abstract 5215: Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery

Abstract Introduction: Efforts to transiently increase blood brain barrier permeability would facilitate improved CNS delivery of chemotherapy agents. Previous studies demonstrated that vascular endothelial factor (VEGF) increases permeability in traumatic brain injury and ischemic brain disease. Exogenously administered VEGF increases barrier permeability in the non-diseased CNS. In our study, we investigated the role for exogenous VEGF therapy to modulate blood-brain barrier permeability Methods: For in vitro studies, confluent mouse brain endothelial cells (BEND.3) were treated with VEGF165. Trans-endothelial electrical resistance measured cell impedance changes and immunofluorescence was used to assess qualitative expression of tight and adherens junction proteins at key time points. Western blotting and qPCR were done to evaluate the effect of VEGF on expression of protein and RNA associated with tight and adherens junctions. Results: Confluent endothelial cells treated with rVEGF165 (200ng/mL) evaluated by TEER show a significant drop in cell impedance approximately 6 hours post treatment, compared to control (more than 10-fold) reflecting increased permeability of the monolayer. Treatment with progressively higher doses of VEGF (200, 400, and 600ng/mL) showed a progressively greater drop in cell impedance. Immunofluorescence of endothelial cells treated with rVEGF165 (200ng/mL) shows disassembly of both tight junctions and adherens junctions between 4 and 8 hours post-treatment compared to controls. Western blots and qPCR demonstrate that rVEGF165 treatment induces down-regulation of genes associated with tight junctions, such as Claudin5, beginning as early as 4 hours post treatment and continuing up to 24 hours post treatment. Conclusion: Our results suggest that VEGF is capable of inducing transient breakdown of the blood-brain barrier, which may facilitate improved CNS delivery of chemotherapeutic agents. Our in vitro data warrants further investigations of the applicability of VEGF therapy to induce endothelial cell permeability in animal tumor models, potentially improving delivery of chemotherapeutic drugs. Citation Format: Matthew McCord. Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2017-5215

Connexin-Dependent Neuroglial Networking as a New Therapeutic Target.

Astrocytes and neurons dynamically interact during physiological processes, and it is now widely accepted that they are both organized in plastic and tightly regulated networks. Astrocytes are connected through connexin-based gap junction channels, with brain region specificities, and those networks modulate neuronal activities, such as those involved in sleep-wake cycle, cognitive, or sensory functions. Additionally, astrocyte domains have been involved in neurogenesis and neuronal differentiation during development; they participate in the “tripartite synapse” with both pre-synaptic and post-synaptic neurons by tuning down or up neuronal activities through the control of neuronal synaptic strength. Connexin-based hemichannels are also involved in those regulations of neuronal activities, however, this feature will not be considered in the present review. Furthermore, neuronal processes, transmitting electrical signals to chemical synapses, stringently control astroglial connexin expression, and channel functions. Long-range energy trafficking toward neurons through connexin-coupled astrocytes and plasticity of those networks are hence largely dependent on neuronal activity. Such reciprocal interactions between neurons and astrocyte networks involve neurotransmitters, cytokines, endogenous lipids, and peptides released by neurons but also other brain cell types, including microglial and endothelial cells. Over the past 10 years, knowledge about neuroglial interactions has widened and now includes effects of CNS-targeting drugs such as antidepressants, antipsychotics, psychostimulants, or sedatives drugs as potential modulators of connexin function and thus astrocyte networking activity. In physiological situations, neuroglial networking is consequently resulting from a two-way interaction between astrocyte gap junction-mediated networks and those made by neurons. As both cell types are modulated by CNS drugs we postulate that neuroglial networking may emerge as new therapeutic targets in neurological and psychiatric disorders.

Monomeric Octahedral Ruthenium(II) Complex Enabled meta-C-H Nitration of Arenes with Removable Auxiliaries.

A removable oxime-assisted meta-C-H nitration of arenes is reported. Mechanistic investigations and DFT calculations reveal a new monomeric octahedral ruthenium(II) complex is responsible for the meta-selective nitration. Dioxygen as a cooxidant is crucial for achieving high conversion and good yields. Moreover, the utility of the present reaction protocol is further showcased by the late-stage modification of the clinical CNS drugs Diazepam and Fluvoxamine.

TRTH-06. CHILDREN’S BRAIN TUMOUR DRUG DELIVERY CONSORTIUM

INTRODUCTION: Whilst there is an urgent need to expedite the development of new or repurposed drugs for children’s cancer, the additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non toxic concentrations for sufficient duration to achieve the biological effect. This is the necessary focus for personalised medicine agendas in children’s brain tumours as they account for over 20% of childhood cancer and differ significantly in their biological characteristics from their adult counterparts. METHODS: The authors took part in an international CNS drug delivery London workshop funded by the charity Children with Cancer UK (CwC) in February 2016 where different experimental techniques aimed at optimising CNS drug delivery in children’s brain tumours were presented and discussed. RESULTS: The workshop was reported (1) and promoted through e-cancer (2). We were encouraged to develop a proposal, to establish an international research consortium to raise awareness and promote collaboration in the field. This is now to be funded for two years by Children with Cancer. The Children’s Brain Tumour Drug Delivery Consortium will organise and host discussions between an international, multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders. This Consortium seeks to strengthen collaborative developments by working closely with the international children’s brain tumour community. CONCLUSION: We present this abstract to the SNO Pediatric conference to launch this initiative in North America and invite collaborators to promote this research priority for children across the world and to consider joining the consortium, which will be presented at the conference.

Burden of neurological diseases in the US revealed by web searches.

BackgroundAnalyzing the disease-related web searches of Internet users provides insight into the interests of the general population as well as the healthcare industry, which can be used to shape health care policies.MethodsWe analyzed the searches related to neurological diseases and drugs used in neurology using the most popular search engines in the US, Google and Bing/Yahoo.ResultsWe found that the most frequently searched diseases were common diseases such as dementia or Attention Deficit/Hyperactivity Disorder (ADHD), as well as medium frequency diseases with high social impact such as Parkinson’s disease, MS and ALS. The most frequently searched CNS drugs were generic drugs used for pain, followed by sleep disorders, dementia, ADHD, stroke and Parkinson’s disease. Regarding the interests of the healthcare industry, ADHD, Alzheimer’s disease, MS, ALS, meningitis, and hypersomnia received the higher advertising bids for neurological diseases, while painkillers and drugs for neuropathic pain, drugs for dementia or insomnia, and triptans had the highest advertising bidding prices.ConclusionsWeb searches reflect the interest of people and the healthcare industry, and are based either on the frequency or social impact of the disease.

Medication-Assisted Treatment in the Perianesthesia Setting

IN 2015, one in 10 Americans (27 million) ages 12 or older used an illicit drug in the past month, and opioid pain relievers were the second most commonly used drug (3.8 million). 1 Center for Behavioral Health Statistics and QualityKey Substance Use and Mental Health Indicators in the United States: Results From the 2015 National Survey on Drug Use and Health. 2016https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH-FFR1-2015.htm Google Scholar Current trends in opiate morbidity and mortality include increased use of heroin and illicit synthetic fentanyl. 2 Centers for Disease Control and PreventionHeroin Overdose Data. 2017https://www.cdc.gov/drugoverdose/data/heroin.html Google Scholar , 3 Gladden R.M. Martinez P. Seth P. Fentanyl law enforcement submissions and increases in synthetic opioid-involved overdose deaths - 27 States, 2013-2014. MMWR Morbidity Mortality Weekly Rep. 2016; 65: 837-843 Crossref PubMed Scopus (286) Google Scholar More than 2 million people with a substance use disorder that included pain relievers (opioids) sought treatment in 2015. 1 Center for Behavioral Health Statistics and QualityKey Substance Use and Mental Health Indicators in the United States: Results From the 2015 National Survey on Drug Use and Health. 2016https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH-FFR1-2015.htm Google Scholar Treatment of opioid use disorder (OUD) may include the use of medications such as methadone, buprenorphine, and naltrexone. The use of these substances to treat OUD is referred to as medication-assisted treatment (MAT). In 2011, about 300,000 people received methadone in opioid treatment programs and more than 32,000 individuals were treated with buprenorphine. 4 Alderks C.E. Trends in the Use of Methadone and Buprenorphine at Substance Abuse Treatment Facilities: 2003 to 2011. The CBHSQ Report. Substance Abuse and Mental Health Services Administration (US), Rockville (MD)2013 Google Scholar Because of recent legislation, nurse practitioners and physician assistants are able to prescribe buprenorphine as part of MAT, 5 American Society of Addiction MedicineSummary of the Comprehensive Addiction and Recovery Act. 2016http://www.asam.org/advocacy/issues/opioids/summary-of-the-comprehensive-addiction-and-recovery-act Google Scholar so the number of individuals receiving buprenorphine is expected to grow. Naltrexone is another emerging treatment option for OUD that may be effective for other types of addiction such as alcohol use disorder. 6 Aboujaoude E. Salame W.O. Naltrexone: A pan-addiction treatment?. CNS Drugs. 2016; 30: 719-733 Crossref PubMed Scopus (41) Google Scholar Kathleen Broglio, DNP, ANP-BC, Palliative Care, Dartmouth Hitchcock Medical Center, Lebanon, NH Maureen F. Cooney, DNP, FNP-BC, Pain Management, Westchester Medical Center, Valhalla, NY

Rationale for Assessing Safety and Efficacy of Drug Candidates Alone and in Combination with Medical Devices: The Case Study of SpinalonTM.

The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary 'reflex' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjects was designed to compare the effects of repeated administration in different conditions (arms). Tests with a motorized treadmill, a harness for body weight support, a transdermal spinal cord stimulator and/or an exoskeleton were proposed because: 1) these devices are unlikely to alter safety but, 2) they are reasonably expected to increase spinal locomotor neuron activation, reflex walking induction, and musculoskeletal/cardiovascular benefits. This approach would normally allow the phase III study to demonstrate clearly, with fewer subjects and at lower costs, long-term benefits on health of SpinalonTM used in optimized conditions and settings. This innovative strategy in drug development may contribute to further describe the mechanisms of action as well as optimized conditions of use for patients. Adapted to the development of other products, such an approach may enable greater safety, efficacy, clinical utility and compliance to be sought for next-generation CNS drugs.

Neurovascular Alterations in Alzheimer's Disease: Transporter Expression Profiles and CNS Drug Access.

Despite a century of steady and incremental progress toward understanding the underlying biochemical mechanisms, Alzheimer's disease (AD) remains a complicated and enigmatic disease, and greater insight will be necessary before substantive clinical success is realised. Over the last decade in particular, a large body of work has highlighted the cerebral microvasculature as an anatomical region with an increasingly apparent role in the pathogenesis of AD. The causative interplay and temporal cascade that manifest between the brain vasculature and the wider disease progression of AD are not yet fully understood, and further inquiry is required to properly characterise these relationships. The purpose of this review is to highlight the recent advancements in research implicating neurovascular factors in AD, at both the molecular and anatomical levels. We begin with a brief introduction of the biochemical and genetic aspects of AD, before reviewing the essential concepts of the blood-brain barrier (BBB) and the neurovascular unit (NVU). In detail, we then examine the evidence demonstrating involvement of BBB dysfunction in AD pathogenesis, highlighting the importance of neurovascular components in AD. Lastly, we include within this review research that focuses on how altered properties of the BBB in AD impact upon CNS exposure of therapeutic agents and the potential clinical impact that this may have on people with this disease.

71. Improving the Regional Specificity of CNS Drugs by Targeting Accessory Proteins: Proof-of-Concept Using Glutamate Receptors

71. Improving the Regional Specificity of CNS Drugs by Targeting Accessory Proteins: Proof-of-Concept Using Glutamate Receptors

Acute effects of amitriptyline on adult zebrafish: Potential relevance to antidepressant drug screening and modeling human toxidromes

The need to develop novel antidepressants is an emerging problem in biomedicine. An aquatic vertebrate species, the zebrafish (Danio rerio) may serve as a useful in-vivo screen for CNS drugs, and displays high sensitivity to a wide range of antidepressants. Amitriptyline is a commonly used tricyclic antidepressant which acts primarily as a serotonin and noradrenaline reuptake inhibitor. Here, we characterize drug-induced behavioral and neurochemical responses in adult zebrafish following their acute exposure to amitriptyline. Overall, the drug at 1 and 5mg/L significantly increased time spent in top and shortened the latency to enter it, thereby paralleling recent reports on zebrafish ‘serotonin toxicity-like behavior’ caused by various serotonergic agents. The 10mg/L dose of the drug also significantly decreased top entries and maximal velocity and evoked overt ataxia, likely due to emerging non-specific toxic effects. Amitriptyline at 5 and 10mg/L also dose-dependently increased serotonin turnover, but not noradrenaline levels, in zebrafish whole-brain samples. Overall, zebrafish high sensitivity to acute effects of amitriptyline can help improve our understanding of psychopharmacological profiles of this compound and the related CNS drugs, and contributes further to the development of aquatic experimental models of human toxidromes.

Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening

Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62–1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

Zebrafish models in neuropsychopharmacology and CNS drug discovery.

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets.

Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.

The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.

Psychotropic use in elderly with cognitive impairment living in nursing homes

IntroductionElderly patients in nursing homes (NH) are often prescribed medications for many physical and mental health problems, with polypharmacy. There is a considerable number of studies documenting this extensive prescription of psychotropic medication, despite the raised concerns about their overuse/misuse, due to serious adverse effects, including increased rate of cognitive decline associated with antipsychotics.AimsTo characterize the prescription of psychotropics in elderly sample with cognitive impairment living in NH.MethodsElderly living in three Portuguese NH were included in this cross-sectional study. All residents were eligible, unless they were unwilling or unresponsive. Participants’ medication was obtained from medical records. Guidelines of ATC were used to categorize the drugs. Participants were assessed with MMSE and GDS.ResultsThe sample included 172 elderly, mostly women (90%), with average of 81(sd = 10) years and median lengths of stay of 3 years. Overall, 79.1% used ≥ 1 nervous system-acting drugs. Anxiolytics (54.7%), antidepressants (29.1%) and antipsychotics (23.3%) were the most frequent. The majority (58%) presented cognitive impairment (MMSE). Among those, 46.2% presented depression (GDS) and 79.6% took at least one drug for the CNS and 41.9% ≥ 3. Antipsychotics were received by 26.5%, while 57.1% used anxiolytics, 31.6% antidepressants and 16.3% anti-dementia drugs. No significant relation between GDS and antidepressants was found.ConclusionThis study confirms the high usage of CNS drugs in patients with cognitive impairment in NH. These rates were comparable with previous studies. Antidepressants appear to be under-used, which can be related to the under-recognition of depression. Also, potential harmful psychotropic drugs such as anxiolytics and antipsychotics are overused.Disclosure of interestThe authors have not supplied their declaration of competing interest.

PET microdosing of CNS drugs

Purpose Positron emission tomography (PET) is an important tool in the discovery and development of drugs targeting the central nervous system. The current review purports to give a brief overview of methods used in the labeling and quantitative evaluation of brain disposition and kinetics of radiolabeled drug molecules. These radiolabeled drug molecules are typically administered in microgram amounts, hence the concept microdosing.