DOCSLIB.ORG

CER 235: Pharmacologic and Nonpharmacologic Treatments For

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CER 235: Pharmacologic and Nonpharmacologic Treatments For Comparative Effectiveness Review Number 235 R Pharmacologic and Nonpharmacologic Treatments for Posttraumatic Stress Disorder: An Update of the PTSD-Repository Evidence Base Comparative Effectiveness Review Number 235 Pharmacologic and Nonpharmacologic Treatments for Posttraumatic Stress Disorder: An Update of the PTSD-Repository Evidence Base Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. 290-2015-00009-I Prepared by: Pacific Northwest Evidence-based Practice Center Portland, OR Investigators: Maya E. O’Neil, Ph.D., M.C.R. Tamara P. Cheney, M.D. Frances C. Hsu, M.S. Kathleen F. Carlson, Ph.D., M.S. Erica L. Hart, M.S.T. Rebecca S. Holmes, M.D., M.S. Katrina M. Murphy, B.S. Elaine Graham, M.L.S. David C. Cameron, M.P.H. Julie Kahler, Ph.D. Meaghan Lewis, Ph.D. Josh Kaplan, Ph.D. Marian S. McDonagh, Pharm.D. AHRQ Publication No. 20(21)-EHC029 November 2020 This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2015-00009-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. The information in this report is intended to help healthcare decision makers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of healthcare services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report is made available to the public under the terms of a licensing agreement between the author and the Agency for Healthcare Research and Quality. This report may be used and reprinted without permission except those copyrighted materials that are clearly noted in the report. Further reproduction of those copyrighted materials is prohibited without the express permission of copyright holders. AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied. AHRQ appreciates appropriate acknowledgment and citation of its work. Suggested language for acknowledgment: This work was based on an evidence report, Pharmacologic and Nonpharmacologic Treatments for Posttraumatic Stress Disorder: An Update of the PTSD- Repository Evidence Base, by the Evidence-based Practice Center Program at the Agency for Healthcare Research and Quality (AHRQ). Suggested citation: O’Neil ME, Cheney TP, Hsu FC, Carlson KF, Hart EL, Holmes RS, Murphy KM, Graham E, Cameron DC, Kahler J, Lewis M, Kaplan J, McDonagh MS. Pharmacologic and Nonpharmacologic Treatments for Posttraumatic Stress Disorder: An Update of the PTSD-Repository Evidence Base. Comparative Effectiveness Review No. 235. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2015-00009-I.) AHRQ Publication No. 20(21)-EHC029. Rockville, MD: Agency for Healthcare Research and Quality; November 2020. DOI: https://doi.org/10.23970/AHRQEPCCER235. Posted final reports are located on the Effective Health Care Program search page. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of healthcare in the United States. The U.S. Department of Veterans Affairs requested this report from the EPC Program at AHRQ. The reports and assessments provide organizations with comprehensive, evidence-based information on common, costly medical conditions, and new healthcare technologies and strategies. This evidence report provides an overview of key issues related to the interventions included—for example, current indications, relevant patient populations and subgroups of interest, outcomes measured, and contextual factors that may affect decisions regarding the intervention. The report includes data abstracted from published randomized controlled trials on interventions for posttraumatic stress disorder. These data were adapted to support the development of a publicly available repository by the National Center for Posttraumatic Stress Disorder (NCPTSD). AHRQ expects that the EPC evidence reports and technology assessments, when appropriate, will be helpful to health plans, providers, purchasers, government programs, and the healthcare system as a whole. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the website (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an email list to learn about new program products and opportunities for input. If you have comments on this systematic review, they may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane, Rockville, MD 20857, or by email to [email protected]. Gopal Khanna, M.B.A Arlene S. Bierman, M.D., M.S. Director Director Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Kim Wittenberg, M.A. Director Task Order Officer Evidence-based Practice Center Program Center for Evidence and Practice Center for Evidence and Practice Improvement Improvement Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Jessica L. Hamblen, Ph.D. Sonya B. Norman, Ph.D. Deputy for Education, National Center for PTSD Consultation Program Director Posttraumatic Stress Disorder National Center for Posttraumatic Stress Department of Veterans Affairs Disorder Department of Veterans Affairs iii Acknowledgments The authors gratefully acknowledge the following individuals for their contributions to this project: Tracy Dana, M.L.S., and Leah Williams, B.S. Technical Expert Panel In designing the study questions and methodology at the outset of this report, the EPC consulted several technical and content experts. Broad expertise and perspectives were sought. Divergent and conflicted opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, methodologic approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. Technical Experts must disclose any financial conflicts of interest greater than $5,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified. The list of Technical Experts who provided input to this report follows: Content Technical Expert Panel Jonathan I. Bisson, D.M., F.R.C.Psych.* Professor, Division of Psychological Medicine and Clinical Neurosciences Cardiff University Cardiff, Wales Susan Borja, Ph.D.* Program Chief National Institute of Mental Health Bethesda, MD Lori Davis, M.D. Professor, Psychiatry and Behavioral Neurobiology University of Alabama Tuscaloosa VA Medical Center Tuscaloosa, AL Lauren Denneson, M.S., Ph.D.* Core Investigator, Center to Improve Veteran Involvement in Care VA Portland Health Care System Associate Professor, Psychiatry Oregon Health & Science University Portland, OR iv Tara Galovski, Ph.D.* Director, Women’s Health Sciences Division National Center for PTSD Associate Professor, Psychiatry Boston University School of Medicine VA Boston Healthcare System Boston, MA Denise Hien, Ph.D., A.B.P.P.* Director, Center of Alcohol & Substance Use Studies Rutgers University Piscataway, NJ David Kearney, M.D. Professor, Medicine and Gastroenterology University of Washington VA Puget Sound Health Care System Seattle, WA Ariel Lang, Ph.D., M.P.H.* Professor in Residence, Psychiatry University of California San Diego VA Center of Excellence for Stress and Mental Health La Jolla, CA Tracy Simpson, Ph.D.* Professor, Psychiatry and Behavioral Science University of Washington VA Puget Sound Health Care System Seattle, WA Risk of Bias Technical Expert Panel Nancy Berkman, Ph.D.* Fellow, Health Services Research RTI International Research Triangle Park, NC M. Hassan Murad, M.D.* Director Mayo Clinic Evidence-based Practice Center Rochester, MN Neil Roberts, M.D. Senior Research Fellow, Psychological Medicine and Clinical Neurosciences Cardiff University v Cardiff, Wales Todd Semla, Pharm.D.* Clinical Associate Professor, Psychiatry and Behavioral Sciences
Load more

Recommended publications
  • The Promise of Ketamine for Treatment-Resistant Depression: Current Evidence and Future Directions
    Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Qatar Clinical Neuroscience Conference The promise of ketamine for treatment-resistant depression: current evidence and future directions Kaitlin E. DeWilde,1 Cara F. Levitch,1 James W. Murrough,1 Sanjay J. Mathew,2 and Dan V. Iosifescu1 1Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai, New York, New York. 2Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas Address for correspondence: Dan V. Iosifescu, M.D., Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai,1 Gustave L. Levy Place, Box 1230, New York, NY 10029. [email protected] Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants.
    [Show full text]
  • Changes in Glutamate Levels Measured by Glutamate
    Changes in glutamate levels measured by glutamate voltammetry in the rat medial prefrontal cortex after treatment with N-methyl-D-aspartate receptor antagonists (P.1.g.023) Irina Ionescu, Kelly Allers, Roberto Arban, Cornelia Dorner-Ciossek and Lothar Kussmaul Boehringer Ingelheim, CNS Diseases Research Background Hypothesized antidepressant MoA of NMDA-R antagonists: Disinhibition of glutamatergic neurons in the PFC N-methyl-D-aspartate receptor (NMDA-R) have been described as potential novel treatment options in the therapy of treatment-reistant depression (TRD). A single sub-anesthetic dose of the noncompetitive NMDA-R antagonist GABA ketamine has been shown to exert rapid-onset and long-lasting antidepressant Glutamate Glutamate NMDA-R effects in TRD patients; these effects were accompanied by brief psychotic Increased glutamate release episodes. Fast-onset antidepressant effects without psychotic side effects have also been described in the clinic for the NR2B-selective negative allosteric modulator (NAM) traxoprodil. However, other unspecific NMDA-R blockers, Synaptic plasticity such as lanicemine, failed to show fast-onset long-lasting antidepressant NMDA-R antagonists (ketamine, traxoprodil) effects in the clinic after single application. Here, we used glutamate AMPA-R AMPA-R voltammetry in rats in order to identify a preclinical predictor of clinical efficacy The increase in glutamate release as proof of circuit by circuit engagement in the prefrontal cortex (PFC). engagement and antidepressant activity can be measured by glutamate voltammetry. Using glutamate voltammetry to show circuit engagement by clinically active NMDA-R antagonists in the PFC Glutamate biosensor (Pinnacle Technology Inc., USA) Advantages of glutamate voltammetry Experimental design - fast response time Experiments were performed in Wistar Han rats implanted with Recording site: PFC - fast sampling time (1 Hz) guide cannulae at the specified coordinates.
    [Show full text]
  • Ketamine: a Novel Antidepressant with a Fast Onset of Action?† COMMENTARY ON… COCHRANE CORNER Katharine Smith & Mary Jane Attenburrow
    BJPsych Advances (2016), vol. 22, 216–221 doi: 10.1192/apt.22.4.216 ROUND THE CORNER Ketamine: a novel antidepressant with a fast onset of action?† COMMENTARY ON… COCHRANE CORNER Katharine Smith & Mary Jane Attenburrow Katharine Smith is an honorary For bipolar depression, the treatment challenge SUMMARY consultant psychiatrist at the is even greater. There is scarce evidence that National Institute for Health Glutamate receptor modulators, including antidepressants are effective as a first-line Research (NIHR) Oxford cognitive ketamine, are possible candidates for new health Clinical Research Facility treatment (Sidor 2012), and mood instability is an antidepressants with a novel mode of action. and Oxford University Department additional challenge. Current recommendations The pair of reviews discussed in this month’s of Psychiatry. Mary Jane (Kendall 2014) focus on the use of quetiapine; Attenburrow is Clinical Lead at Round the Corner considered their use in treating the NIHR Oxford cognitive health unipolar major depression and bipolar depression. lamotrigine, fluoxetine plus olanzapine and Clinical Research Facility, a Senior Promising results were seen for ketamine, but lithium are also recommended. A recent trial Research Fellow at Oxford University further studies are needed, in particular to (CEQUEL) demonst ra ted that there may be benefit Department of Psychiatry and an investigate whether the benefits are sustained in the combination of lamotrigine with quetiapine honorary consultant psychiatrist. Correspondence Dr Katharine or can be extended by repeated or adjunctive (Geddes 2016). Smith, NIHR Oxford cognitive health treatment, whether ketamine is effective in Although the differences in treatment response Clinical Research Facility, Warneford treatment resistance, whether other modes of between unipolar and bipolar depression Hospital, Oxford OX3 7JX, UK.
    [Show full text]
  • Schifano, F., Napoletano, F., Chiappini, S., Orsolini, L., Guirguis, A., Corkery, J
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Hertfordshire Research Archive Citation for the published version: Schifano, F., Napoletano, F., Chiappini, S., Orsolini, L., Guirguis, A., Corkery, J. M., ... vento, A. (2019). New psychoactive substances (NPS), psychedelic experiences, and dissociation: clinical and clinical pharmacological issues. Current Addiction Reports, 6(2), 140-152. https://doi.org/10.1007/s40429-019-00249-z Document Version: Accepted Version The final publication is available at Springer Nature via https://doi.org/10.1007/s40429-019-00249-z © 2019 Springer Nature Publishing AG General rights Copyright© and Moral Rights for the publications made accessible on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (http://uhra.herts.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge. Take down policy If you believe that this document breaches copyright please contact us providing details, any such items will be temporarily removed from the repository pending investigation.
    [Show full text]
  • NMDA) Receptor Antagonist
    White Paper The Use of Robust Biomarkers in the Early Clinical Development of N-methyl-D-aspartate (NMDA) Receptor Antagonist Biotrial has extensive early clinical development experience with a high output of over 20 CNS studies per year. The experience and capabilities of Biotrial Neuroscience (now also incorporating the know-how of the legacy CNS CRO Forenap), enables the in-depth cognitive and neurophysiological assessment of NMDA antagonists. The aim of the present document is twofold. Firstly, to characterize the pharmacological effects of non-competitive NMDA antagonists in psychiatry and pain indications and to validate the use of ketamine as a positive control in the development of these compounds with this mechanism of action. Secondly, to present Biotrial’s strategy and rationale for the integration of surrogate endpoints, biomarkers and PD models into a Phase I program, in order to establish early proof of concept of new NMDA antagonist candidates. Pharmacological Effects of Non-Competitive NMDA Antagonists: The Example of Ketamine Glutamatergic antagonists, such as ketamine, acting at the NMDA open channel have a long history of use in neuropsychiatry – independently of their anesthetic or pain attenuating properties. The mechanism of action and pharmacological effects of ketamine have been extensively studied over the last 20 years. Ketamine was initially profiled as a reversible model of psychosis1, producing positive and negative symptoms of schizophrenia as well as cognitive impairment. As of today there are approximately one hundred publications on the symptoms, brain connectivity, imaging and cognitive function alterations induced by ketamine. The main hypothesis to explain the effect of ketamine was the reduction of the glutamatergic burst in the prefrontal cortex, secondarily enhancing AMPA α-(amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) signaling.
    [Show full text]
  • Correspondence
    Psychological Medicine (2016), 46, 2449–2451. © Cambridge University Press 2016 Correspondence Psychological Medicine, 46 (2016). Hashimoto, 2014;Yanget al. 2015). Furthermore, a sin- doi:10.1017/S0033291716000969 gle dose of esketamine, but not R-ketamine, resulted in First published online 10 June 2016 loss of parvalbumin (PV)-immunoreactivity in the pre- frontal cortex (Yang et al. 2015). A recent study using R-ketamine: a rapid-onset and sustained [11C]raclopride and positron emission tomography antidepressant without risk of brain toxicity showed a marked reduction of dopamine D2/3 receptor binding in the conscious monkey striatum after single infusion of esketamine, but not R-ketamine (Hashimoto et al. 2016). Singh et al. (2015) reported I read with great interest the recent article by Kishimoto that psychotomimetic side effects were the highest at et al. (2016) about meta-analysis of the antidepressant 40 min after single infusion of esketamine although a effects of the N-methyl-D-aspartate receptor (NMDA-R) rapid-onset antidepressant effect was shown in antagonist ketamine (racemate) and non-ketamine treatment-resistant patients with MDD. Considering NMDA-R antagonists (traxoprodil, lanicemine, rapasti- the role of dopamine release in psychosis, it is likely nel) in patients with major depressive disorder (MDD) that marked release of dopamine from presynaptic and bipolar disorder. The authors examined the time terminals in the striatum could be associated with trajectory of efficacy of ketamine and non-ketamine psychotomimetic side effects in humans after a single NMDA-R antagonists. The greater reduction in depres- infusion of ketamine or esketamine. sive symptoms by ketamine infusion started as early The authors also pointed out that the transient as within 40–60 min, peaking on day 1, and lasting efficacy lasting 1 week post-infusion of ketamine has sti- until days 5–8, with maintenance of superior remission mulated multi-infusion studies (Kishimoto et al.
    [Show full text]
  • 'Party Drug' Turned Antidepressant Approaches Approval
    NEWS & ANALYSIS Nature Reviews Drug Discovery | Published online 30 Oct 2018; doi:10.1038/nrd.2018.187 ‘Party drug’ turned anti depressant approaches approval Johnson & Johnson has submitted its esketamine for regulatory approval, but researchers still don’t understand how the fast-acting antidepressant lifts moods. DrAfter123/DigitalVision Vectors Sara Reardon Monteggia, a neuroscientist at Vanderbilt later learned that the antibiotic, at low doses, University. blocks the NMDA receptor, a glutamate When researchers showed in 2006 that the Yet it is far from clear how this work will receptor. Then in the late 1990s,Nature when Reviews | Drug Discovery anaesthetic ketamine — also known as the play out. Whereas early evidence suggested psychiatrist John Krystal of Yale University club drug Special K — was a rapid and potent that ketamine acted through the NMDA was curious about whether the antidepressant, big pharmaceutical receptor, many of the first-generation neurotransmitter glutamate contributed to companies quickly jumped into the game. ketamine mimetics that were designed to act schizophrenia, he decided to test the known Extensive efforts to improve on decades-old on this target failed in clinical trials (TABLE 1). NMDA receptor antagonist ketamine in nine antidepressants had floundered, but ketamine Accumulating evidence now suggests that depressed patients. finally promised a novel mechanism of action ketamine’s antidepressant activity may be At the time, glutamate had mostly been and the potential to help treatment-resistant more complicated. studied for its role in learning and memory. But patients. As a result, some companies are quietly Krystal’s group found that ketamine induced a Because ketamine is an old drug and going back to the drawing board.
    [Show full text]
  • Evidence That Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans
    11694 • The Journal of Neuroscience, August 19, 2015 • 35(33):11694–11706 Behavioral/Cognitive Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Suresh D. Muthukumaraswamy,1 XAlexander D. Shaw,2 XLaura E. Jackson,3 Judith Hall,3 Rosalyn Moran,4 and Neeraj Saxena3,5 1Schools of Pharmacy and Psychology, The University of Auckland, Auckland 1142, New Zealand, 2Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF103AT, United Kingdom, 3Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant CF72 8XR, United Kingdom, 4Virginia Tech Carilion Research Institute, Bradley Department of Electrical and Computer Engineering, Roanoke, Virginia 24016, and 5Department of Anaesthetics, Intensive Care and Pain Medicine, School of Medicine, Cardiff University, Cardiff CF144XW, United Kingdom Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine’s effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n ϭ 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effectsdemonstratedtheirownsetoftemporaldynamics.Dynamiccausalmodelingoffrontoparietalconnectivitychangeswithketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity.
    [Show full text]
  • Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in The
    cells Review Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia Veronika Prikhodko 1,2,3, Daria Chernyuk 1 , Yurii Sysoev 1,2,3,4, Nikita Zernov 1, Sergey Okovityi 2,3 and Elena Popugaeva 1,* 1 Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia; [email protected] (V.P.); [email protected] (D.C.); [email protected] (Y.S.); [email protected] (N.Z.) 2 Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical Pharmaceutical University, 197022 St. Petersburg, Russia; [email protected] 3 N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences, 197376 St. Petersburg, Russia 4 Institute of Translational Biomedicine, Saint Petersburg State University, 199034 St. Petersburg, Russia * Correspondence: [email protected] Received: 31 August 2020; Accepted: 20 October 2020; Published: 24 October 2020 Abstract: Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models.
    [Show full text]
  • Targeting Unmet Needs in the Treatment of Major Depressive Disorder
    SUPPLEMENT TO Release date: September 1, 2019 Expiration date: August 31, 2020 Estimated time to complete activity: FREE 1 CME 1 AMA Category 1 Credit™ CREDIT 1 ANCC contact hours SEPTEMBER 2019 | VOL 18, NO 9 Available at www.mdedge.com/MDD Jointly provided by Postgraduate Institute for Medicine and Global Medical Education. This activity is supported by an independent Targeting Unmet Needs educational grant from Allergan. TARGET AUDIENCE in the Treatment of Major This activity is intended for physicians, physician assistants, nurse practitioners and Depressive Disorder registered nurses engaged in the care of patients with major depression. Roger S. McIntyre, MD, FRCPC EDUCATIONAL OBJECTIVES After completing this activity, the participant should be better able to: BOTTOM LINE: Targeting Unmet Needs in • Treat major depression within 2 weeks. the Treatment of Major Depressive Disorder • Use evidence based treatments to achieve remission in major depression. Many of the unmet needs in Major Depressive Disorder are • Discuss novel targets including glutamate modifiable, including improving diagnostic accuracy, offering for treating major depression. treatments with faster onset of action, treatments with greater • Utilize treatments with innovative overall efficacy, and treatments that can improve patient mechanisms to treat major depression. functioning. Measurement based care guiding treatment wherein FACULTY the aim is to achieve remission, improve cognitive function, and Roger S. McIntyre, MD, general functioning, are key therapeutic objectives. FRCPC Professor of Psychiatry and Pharmacology, Introduction University of Toronto Major depressive disorder (MDD) is a common and severe disorder that is estimated to affect approximately 350 million people glob- ally.1 It is predicted that MDD debases human capital more than most other non-communicable disorders.2 In addition to substan- Michael E.
    [Show full text]
  • Brain Networks in Pharmacological Fmri of NMDA Antagonists
    Aus dem Zentralinstitut für Seelische Gesundheit (Direktor: Prof. Dr. Andreas Meyer-Lindenberg) Brain networks in pharmacological fMRI of NMDA antagonists Inauguraldissertation zur Erlangung des Doctor scientiarum humanarum (Dr.sc.hum.) der Medizinischen Fakultät Mannheim der Ruprecht-Karls-Universität zu Heidelberg vorgelegt von Diplom-Physiker Robert Becker aus Wiesbaden 2019 Dekan: Prof. Dr. med. Sergij Goerdt Referent: apl. Prof. Dr. med. Dipl. Phys. Alexander Sartorius Contents 1 Introduction 1 1.1 Aims . 3 2 Network methods in neuroscience 5 2.1 Network definition . 5 2.2 Network analysis . 7 2.3 Studies . 13 3 Study: Species-conserved reconfigurations of brain networks in- duced by Ketamine 15 3.1 Abstract . 15 3.2 Introduction . 16 3.3 Methods . 17 3.4 Results . 23 3.5 Discussion . 26 3.6 Conclusions . 30 3.7 Supplementary Information . 30 4 Study: NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward related net- works in rats 35 4.1 Abstract . 35 4.2 Introduction . 36 4.3 Methods . 37 4.4 Results . 41 4.5 Discussion . 47 4.6 Conclusion . 51 4.7 Supplementary material . 51 5 Discussion 55 5.1 Establishment of network methods in preclinical studies . 55 5.2 Effects of NMDA antagonists on rat brain networks . 56 5.3 Limitations . 58 5.4 Future work . 58 5.5 Conclusion . 60 Summary 61 Bibliography 63 Curriculum Vitae 77 Acknowledgements 81 1 Introduction In the last two decades blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) has become a widely used tool in neuro- scientific research. After the relation of neuronal activity and BOLD signal was discovered, fMRI was used to detect neuronal responses to various tasks compared to control periods during which the brain was considered inactive (Biswal, Zerrin Yetkin, Haughton, & Hyde, 1995).
    [Show full text]
  • Application and Assessment of Deep Learning for the Generation Of
    Application and Assessment of Deep Learning for the Generation of Potential NMDA Receptor Antagonists Katherine J. Schultz, Sean M. Colby, Yasemin Yesiltepe, Jamie R. Nuñez, Monee Y. McGrady, Ryan R. Renslow* Pacific Northwest National Laboratory, Richland, WA, USA. ABSTRACT. Uncompetitive antagonists of the N-methyl D-aspartate receptor (NMDAR) have demonstrated therapeutic benefit in the treatment of neurological diseases such as Parkinson’s and Alzheimer’s, but some also cause dissociative effects that have led to the synthesis of illicit drugs. The ability to generate NMDAR antagonists in silico is therefore desirable both for new medication development and for preempting and identifying new designer drugs. Recently, generative deep learning models have been applied to de novo drug design as a means to expand the amount of chemical space that can be explored for potential drug-like compounds. In this study, we assess the application of a generative model to the NMDAR to achieve two primary objectives: (i) the creation and release of a comprehensive library of experimentally validated NMDAR phencyclidine (PCP) site antagonists to assist the drug discovery community and (ii) an analysis of both the advantages conferred by applying such generative artificial intelligence models to drug design and the current limitations of the approach. We apply, and provide source code for, a variety of ligand- and structure-based assessment techniques used in standard drug discovery analyses to the deep learning-generated compounds. We present twelve candidate antagonists that are not 1 available in existing chemical databases to provide an example of what this type of workflow can achieve, though synthesis and experimental validation of these compounds is still required.
    [Show full text]