DOCSLIB.ORG

New Molecular Targets for Antidepressant Drugs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Molecular Targets for Antidepressant Drugs pharmaceuticals Review New Molecular Targets for Antidepressant Drugs Johannes Kornhuber 1,* and Erich Gulbins 2,3 1 Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054 Erlangen, Germany 2 Department of Molecular Biology, University of Duisburg-Essen, 45117 Essen, Germany; [email protected] 3 Department of Surgery, University of Cincinnati, Cincinnati, OH 45267, USA * Correspondence: [email protected] Abstract: Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF). Keywords: acid sphingomyelinase; ceramide; sphingomyelin; FIASMA; antidepressant drug; lyso- some; neurogenesis; hippocampus; autophagy; brain-derived neurotrophic factor (BDNF) Citation: Kornhuber, J.; Gulbins, E. New Molecular Targets for 1. Introduction Antidepressant Drugs. Pharmaceuticals 2021, 14, 894. https:// For many clinically successful drugs, new and relevant mechanisms of action have doi.org/10.3390/ph14090894 been discovered over time. For example, we have demonstrated relevant antagonistic effects of memantine, amantadine and budipine, which until then had been considered Academic Editor: Marco Scarselli dopaminomimetic substances, on N-methyl-D-aspartate (NMDA) receptors [1–3]. A new mechanism of action has only recently been demonstrated for the very well established Received: 16 August 2021 and effective drug metformin in the treatment of type 2 diabetes [4]. This is also true for an- Accepted: 25 August 2021 tidepressants, which have been used successfully to treat major depressive disorder (MDD) Published: 2 September 2021 since 1957 [5]. These compounds were initially used clinically without the knowledge of their molecular targets. Over time, their mechanisms of action were initially discovered to Publisher’s Note: MDPI stays neutral be the inhibition of monoamine oxidases and the inhibition of monoaminergic transporters. with regard to jurisdictional claims in Later, other molecular mechanisms were discovered, such as the inhibition of postsynaptic published maps and institutional affil- serotonin receptors, the inhibition of presynaptic alpha 2 receptors, and the activation of iations. melatonergic receptors. In recent years, a number of new antidepressants with novel mechanisms of action have been developed and clinically evaluated. The inhibition of NMDA receptors by esketamine shows a rapid antidepressant effect [6]. However, NMDA receptor inhibition Copyright: © 2021 by the authors. as an antidepressant mode of action is in doubt, since a ketamine metabolite has low Licensee MDPI, Basel, Switzerland. affinity for the NMDA receptor but has antidepressant activity [7]. A single i.v. adminis- This article is an open access article tration of brexanolone, a neuroactive steroid (SAGE-547) with gamma-aminobutyric acid distributed under the terms and (GABA)A receptor-positive allosteric modulatory activity, shows a rapid antidepressant conditions of the Creative Commons effect that lasts more than a week in postpartum depression [8,9]. Zuranolone, an orally Attribution (CC BY) license (https:// available neuroactive steroid with a comparable mechanism of action (SAGE-217), also creativecommons.org/licenses/by/ shows antidepressant effects on MDD [10] and postpartum depression [11]. In addition, 4.0/). Pharmaceuticals 2021, 14, 894. https://doi.org/10.3390/ph14090894 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 16 Pharmaceuticals 2021, 14, 894 2 of 15 number of other compounds, each with different molecular targets and potential antide- therepressant are aeffects, number that of otherare currently compounds, being each evaluated with different [12]. molecular targets and potential antidepressantIn parallel effects, with the that development are currently of being new evaluated compounds [12]. and the exploitation of new molecularIn parallel targets, with important the development cellular and of newsystemic compounds mechanisms and theof action exploitation of antidepres- of new molecularsants have targets, been discovered, important such cellular as neurog and systemicenesis [13], mechanisms neuroplasticity of action and ofinflammation. antidepres- santsHowever, have it been is not discovered, yet clear through such as which neurogenesis molecular [13 targets], neuroplasticity neurogenesis, and neuroplasticity inflammation. However,and inflammation it is not yet are clear affected. through which molecular targets neurogenesis, neuroplasticity and inflammationThe focus of this are affected.review is relatively narrow. We discuss only novel molecular targets otherThe than focus the ofpreviously this review described is relatively targets narrow. for the We groups discuss of onlylicensed novel antidepressants molecular targets (i.e., otherGroup than N06A the in previously the ATC system), described and targets we only for consider the groups developments of licensed during antidepressants the last 10 (i.e.,years. Group The mechanisms N06A in the should ATC system), apply not and only we to only individual consider substances developments but also during to many the lastantidepressants, 10 years. The even mechanisms structura shouldlly different apply ones. not We only discuss to individual in detail substances the effect of but antide- also topressants many antidepressants, on the sphingolipid even system structurally and the different tyrosine ones. kinase We receptor discuss in 2 detail(TRKB) the receptor effect offor antidepressants BDNF. on the sphingolipid system and the tyrosine kinase receptor 2 (TRKB) receptor for BDNF. 2. MDD as a Whole-Body Multisystem Disease 2. MDD as a Whole-Body Multisystem Disease MDD is a common mental disorder with a lifetime prevalence of approximately 10%. PatientsMDD suffer is a common a high overall mental burden disorder of with disease a lifetime due to prevalence severe impairment of approximately during 10%.each Patientsepisode sufferof illness, a high long overall individual burden episodes of disease of illness, due to an severe often impairmentearly age of onset, during and each an episodeoften recurrent of illness, course long individual[14]. MDD episodesis a risk fa ofctor illness, for anthe oftendevelopment early age of of cardiovascular onset, and an oftendisease, recurrent diabetes, course metabolic [14]. MDD syndrome, is a risk osteoporosis, factor for the Alzheimer’s development disease, of cardiovascular and hippocam- dis- ease, diabetes, metabolic syndrome, osteoporosis, Alzheimer’s disease, and hippocampal pal atrophy. The adrenocortical stress axis is activated, and changes in serum lipids occur; atrophy. The adrenocortical stress axis is activated, and changes in serum lipids occur; pe- peripheral proinflammatory cytokines, including interleukin-1β (IL-1β), markers of oxi- ripheral proinflammatory cytokines, including interleukin-1β (IL-1β), markers of oxidative dative stress and inflammation, and serum phospholipase A2 activity are increased. Inde- stress and inflammation, and serum phospholipase A2 activity are increased. Independent pendent of suicide, life expectancy is reduced in patients with MDD. Therefore, MDD is of suicide, life expectancy is reduced in patients with MDD. Therefore, MDD is considered considered not only a mental disorder but also a multisystem whole-body disease [15–19] not only a mental disorder but also a multisystem whole-body disease [15–19] (Figure1). (Figure 1). FigureFigure 1.1. MDD is is a a risk risk factor factor for for the the development development of ofmultiple multiple disorders disorders and and diseases, diseases, such such as met- as metabolicabolic syndrome, syndrome, osteoporosis, osteoporosis, an andd cardiovascular cardiovascular disease. disease. MDD MDD can can therefore bebe conceptualizedconceptualized asas aa multisystem,multisystem, whole-body whole-body disease. disease. TheThe diagnosticdiagnostic criteriacriteria forfor majormajor depressiondepression accordingaccording toto thethe DSM-5DSM-5 [[20]20] includeinclude pre-pre- dominantlydominantly psychologicalpsychological symptomssymptoms apart apart from from fatigue fatigue and and weight weight change. change. The The physical physical illnessesillnesses listed listed here, here, which which occur occur frequently frequently as as a follow-upa follow-up to to depression, depression, do do not not belong belong to theto the diagnostic diagnostic criteria. criteria. Pharmaceuticals 2021, 14, 894 3 of 15 3. Current Pharmacological Treatments for MDD The group of antidepressants defined in the ATC system (N06A) includes substances with very different structures and mechanisms of action.
Load more

Recommended publications
  • Zuranolone | Medchemexpress
    Inhibitors Product Data Sheet Zuranolone • Agonists Cat. No.: HY-103040 CAS No.: 1632051-40-1 Molecular Formula: C₂₅H₃₅N₃O₂ • Molecular Weight: 409.56 Screening Libraries Target: GABA Receptor Pathway: Membrane Transporter/Ion Channel; Neuronal Signaling Storage: Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 100 mg/mL (244.16 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 2.4416 mL 12.2082 mL 24.4164 mL Stock Solutions 5 mM 0.4883 mL 2.4416 mL 4.8833 mL 10 mM 0.2442 mL 1.2208 mL 2.4416 mL Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: 2.5 mg/mL (6.10 mM); Suspended solution; Need ultrasonic 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (6.10 mM); Clear solution 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 2.5 mg/mL (6.10 mM); Clear solution 4. Add each solvent one by one: 5% DMSO >> 40% PEG300 >> 5% Tween-80 >> 50% saline Solubility: 2.5 mg/mL (6.10 mM); Suspended solution; Need ultrasonic 5. Add each solvent one by one: 5% DMSO >> 95% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (6.10 mM); Clear solution BIOLOGICAL ACTIVITY Description Zuranolone is an orally active and potent neuroactive steroid positive allosteric modulator of GABAA receptor, with EC50s of [1] 296 and 163 nM for α1β2γ2 and α4β3δ GABAA receptors, respectively .
    [Show full text]
  • Mrna Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases Upon Antidepressant Treatment
    International Journal of Molecular Sciences Article mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment Cosima Rhein 1,2,* , Iulia Zoicas 1 , Lena M. Marx 1, Stefanie Zeitler 1, Tobias Hepp 2,3, Claudia von Zimmermann 1, Christiane Mühle 1 , Tanja Richter-Schmidinger 1, Bernd Lenz 1,4 , Yesim Erim 2, Martin Reichel 1,† , Erich Gulbins 5 and Johannes Kornhuber 1 1 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; [email protected] (I.Z.); [email protected] (L.M.M.); [email protected] (S.Z.); [email protected] (C.v.Z.); [email protected] (C.M.); [email protected] (T.R.-S.); [email protected] (B.L.); [email protected] (M.R.); [email protected] (J.K.) 2 Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany; [email protected] (T.H.); [email protected] (Y.E.) 3 Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany 4 Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany 5 Department of Molecular Biology, University Hospital, University of Duisburg-Essen, D-45147 Essen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-9131-85-44542 Citation: Rhein, C.; Zoicas, I.; Marx, † Current address: Department of Nephrology and Medical Intensive Care, Charité—Universitätsmedizin L.M.; Zeitler, S.; Hepp, T.; von Berlin, Berlin, Germany.
    [Show full text]
  • K+ Channel Modulators Product ID Product Name Description D3209 Diclofenac Sodium Salt NSAID; COX-1/2 Inhibitor, Potential K+ Channel Modulator
    K+ Channel Modulators Product ID Product Name Description D3209 Diclofenac Sodium Salt NSAID; COX-1/2 inhibitor, potential K+ channel modulator. G4597 18β-Glycyrrhetinic Acid Triterpene glycoside found in Glycyrrhiza; 15-HPGDH inhibitor, hERG and KCNA3/Kv1.3 K+ channel blocker. A4440 Allicin Organosulfur found in garlic, binds DNA; inwardly rectifying K+ channel activator, L-type Ca2+ channel blocker. P6852 Propafenone Hydrochloride β-adrenergic antagonist, Kv1.4 and K2P2 K+ channel blocker. P2817 Phentolamine Hydrochloride ATP-sensitive K+ channel activator, α-adrenergic antagonist. P2818 Phentolamine Methanesulfonate ATP-sensitive K+ channel activator, α-adrenergic antagonist. T7056 Troglitazone Thiazolidinedione; PPARγ agonist, ATP-sensitive K+ channel blocker. G3556 Ginsenoside Rg3 Triterpene saponin found in species of Panax; γ2 GABA-A agonist, Kv7.1 K+ channel activator, α10 nAChR antagonist. P6958 Protopanaxatriol Triterpene sapogenin found in species of Panax; GABA-A/C antagonist, slow-activating delayed rectifier K+ channel blocker. V3355 Vindoline Semi-synthetic vinca alkaloid found in Catharanthus; Kv2.1 K+ channel blocker and H+/K+ ATPase inhibitor. A5037 Amiodarone Hydrochloride Voltage-gated Na+, Ca2+, K+ channel blocker, α/β-adrenergic antagonist, FIASMA. B8262 Bupivacaine Hydrochloride Monohydrate Amino amide; voltage-gated Na+, BK/SK, Kv1, Kv3, TASK-2 K+ channel inhibitor. C0270 Carbamazepine GABA potentiator, voltage-gated Na+ and ATP-sensitive K+ channel blocker. C9711 Cyclovirobuxine D Found in Buxus; hERG K+ channel inhibitor. D5649 Domperidone D2/3 antagonist, hERG K+ channel blocker. G4535 Glimepiride Sulfonylurea; ATP-sensitive K+ channel blocker. G4634 Glipizide Sulfonylurea; ATP-sensitive K+ channel blocker. I5034 Imiquimod Imidazoquinoline nucleoside analog; TLR-7/8 agonist, KCNA1/Kv1.1 and KCNA2/Kv1.2 K+ channel partial agonist, TREK-1/ K2P2 and TRAAK/K2P4 K+ channel blocker.
    [Show full text]
  • Rediscovery of Fexinidazole
    New Drugs against Trypanosomatid Parasites: Rediscovery of Fexinidazole INAUGURALDISSERTATION zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Marcel Kaiser aus Obermumpf, Aargau Basel, 2014 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz“ (CC BY-NC-ND 3.0 CH) lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licenses/by-nc-nd/3.0/ch/ eingesehen werden. 1 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel auf Antrag von Prof. Reto Brun, Prof. Simon Croft Basel, den 10. Dezember 2013 Prof. Dr. Jörg Schibler, Dekan 2 3 Table of Contents Acknowledgement .............................................................................................. 5 Summary ............................................................................................................ 6 Zusammenfassung .............................................................................................. 8 CHAPTER 1: General introduction ................................................................. 10 CHAPTER 2: Fexinidazole - A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness ........ 26 CHAPTER 3: Anti-trypanosomal activity of Fexinidazole – A New Oral Nitroimidazole Drug Candidate for the Treatment
    [Show full text]
  • Ceramide and Related Molecules in Viral Infections
    International Journal of Molecular Sciences Review Ceramide and Related Molecules in Viral Infections Nadine Beckmann * and Katrin Anne Becker Department of Molecular Biology, University of Duisburg-Essen, 45141 Essen, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-201-723-1981 Abstract: Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit. Keywords: ceramide; acid sphingomyelinase; sphingolipids; lipid-rafts; α-galactosylceramide; viral Citation: Beckmann, N.; Becker, K.A.
    [Show full text]
  • No Involvement of Acid Sphingomyelinase in the Secretion of IL-6 From
    1 No Involvement of Acid Sphingomyelinase in the Secretion of IL-6 from Alveolar Macrophages in Rat Tomoo Ito, Chikako Oyama, Hirokazu Arai, Tsutomu Takahashi Department of Pediatrics, Akita University Graduate School of Medicine, Akita-shi, Akita, 010-8543, Japan Correspondence: Tsutomu Takahashi, M.D. Department of Pediatrics, Akita University Graduate School of Medicine, 1-1-1 hondo, Akita 010-8543, Japan Tel: 018-884-6159 FAX: 018-836-2620 E-mail: [email protected] 1 2 Key words: chronic lung disease of the newborn, alveolar macrophage, acid sphingomyelinase, Running title: Acid Sphingomyelinase in CLD of the Newborn 2 3 Abstract Chronic lung disease (CLD) of the newborn is a major problem in neonatology. Activation of alveolar macrophages has been implicated in the pathogenesis of CLD. Acid sphingomyelinase (ASM) responds to diverse cellular stressors, including lipopolysaccharide (LPS) stimulation. Recently, functional inhibitors of acid sphingomyelinase (FIASMAs) have been described as a large group of compounds that inhibit ASM. Here, we used maternal intra-peritoneal LPS injection to model CLD in the infant rat lung. Using this model, we studied ASM activity in the infant rat lung and the effects of FIASMAs on release of interleukin-6 (IL-6) from LPS-stimulated alveolar macrophages. Maternal exposure to LPS non-significantly increased ASM activities in the infant rat lung. FIASMAs significantly decreased ASM activity of LPS-stimulated alveolar macrophages. In addition, some FIASMAs suppressed the release of IL-6 from LPS-stimulated alveolar macrophages during the early response phase. However, FIASMAs did not suppress the release of IL-6 from LPS-stimulated alveolar macrophages.
    [Show full text]
  • Konzentrationsabhängige Funktionelle Hemmung Der Sauren Sphingomyelinase Durch Antidepressiva
    Friedrich-Alexander-Universität Erlangen-Nürnberg Universitätsklinikum Erlangen Psychiatrische und Psychotherapeutische Klinik Direktor: Prof. Dr. Johannes Kornhuber Konzentrationsabhängige funktionelle Hemmung der sauren Sphingomyelinase durch Antidepressiva Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg vorgelegt von Sven Städtler aus Kulmbach Gedruckt mit Erlaubnis der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen Nürnberg Dekan: Prof. Dr. med. Dr. h.c. Jürgen Schüttler Referent: Prof. Dr. med. Johannes Kornhuber Korreferent: PD Dr. med. Juan Manuel Maler Tag der Mündlichen Prüfung: 30. März 2011 Meinen Eltern gewidmet Inhaltsverzeichnis 1 Zusammenfassung ..................................................................................................... 7 1.1 Hintergrund und Ziele ........................................................................................ 7 1.2 Material und Methode ........................................................................................ 7 1.3 Ergebnisse .......................................................................................................... 8 1.4 Schlussfolgerungen ............................................................................................ 8 2 Abstract ..................................................................................................................... 9 2.1 Background and Aims .......................................................................................
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • View Presentation
    Investor Presentation June 2020 Safe Harbor Statement • The slides presented today and the accompanying oral presentations contain forward-looking statements, which may be identified by the use of words such as “may,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “opportunity”, “goal”, “potential,” or “continue,” and other similar expressions. • Forward-looking statements in this presentation include statements regarding: our plans and expectations for ZULRESSO, including our revenue expectations and the factors that may impact revenues; our expectations as to the development and regulatory path forward and filing requirements for zuranolone; our development plans, goals and strategy for our product candidates and the potential results of our development efforts; the anticipated timing of clinical trial initiation and reporting of results, including our belief as to our ability to mitigate the possible impact of the COVID-19 pandemic on our clinical development timelines; the potential profile and benefit of our product candidates; our belief in the potential of our product candidates in various indications; the estimated number of patients with the disorders and diseases we are studying or plan to study; our financial expectations, including with respect to year-end cash; our belief that existing cash will support operations into 2022; and our expectations as to the goals, opportunity and potential for our business. • These forward-looking statements are neither promises
    [Show full text]
  • Zuranolone—An Investigational Oral Neuroactive Steroid and Positive
    Expert Interview Psychiatric Disorders Zuranolone—An Investigational Oral Neuroactive Steroid and Positive Allosteric Modulator of GABA Type A Receptors for Postpartum Depression and Major Depressive Disorder Handan Gunduz-Bruce Sage Therapeutics, Inc., Cambridge, MA, USA Handan Gunduz-Bruce Handan Gunduz-Bruce is Senior Medical Director at Sage Therapeutics, Inc. and Assistant Clinical Professor of Psychiatry at Yale School of Medicine. She received her medical degree from the Istanbul Medical Faculty in 1991 and then completed her residency in psychiatry, followed by a fellowship in clinical neuroscience at the Long Island Jewish Medical Center of Albert Einstein College of Medicine. Earlier in her academic career, Dr. Gunduz-Bruce’s research focused on the longitudinal course and pharmacological treatment of schizophrenia. Her later research included pathophysiology studies of schizophrenia and depression with a focus on the N-methyl-D-aspartate (NMDA) receptor function and GABAergic mechanisms using electrophysiological, imaging and biomarker approaches. More recently, she received her MBA degree in Leadership in Healthcare from Yale School of Management. Since the beginning of her tenure at Sage Therapeutics, Dr. Gunduz-Bruce has contributed to the approval of ZULRESSOTM, the first pharmacological treatment for postpartum depression in adults, and continues to oversee the development of zuranolone, an investigational oral neuroactive steroid and positive allosteric modulator of GABAA receptors, for postpartum depression and major
    [Show full text]
  • Video Course Evaluation Form My Name Is
    Garden State CLE 2000 Hamilton Avenue Hamilton, New Jersey 08619 (609) 584-1924 – Phone (609) 584-1920 - Fax Video Course Evaluation Form My Name is: __________________________________________ Name of Course: ______________________________________ My Street address: _____________________________________ City: _____________________ State: _____ Zip Code: ____ Email Address: ________________________________________ Please Circle the Appropriate Answer Instructors: Poor Satisfactory Good Excellent Materials: Poor Satisfactory Good Excellent CLE Rating: Poor Satisfactory Good Excellent Required: Secret words that appeared on the screen during the seminar. 1) __________________________ 2) _______________________ 3) __________________________ 4) _______________________ What did you like most about the seminar? _____________________________________________________________ _____________________________________________________________ What criticisms, if any, do you have? _____________________________________________________________ _____________________________________________________________ I certify that I watched, in its entirety, the above-listed CLE Course. Signature ___________________________________ Date_________ In order to receive your CLE credits, please send our payment and this completed form to Garden State CLE, 2000 Hamilton Avenue, Hamilton, New Jersey, 08619. BURLINGTON COUNTY BAR ASSOCIATION --- Interpreting Your Client’s Drug Lab Results: Were They Impaired? © Chris Baxter 2020 DO LAB RESULTS MATTER IN A DUI-D? YES ➢State
    [Show full text]
  • Horizon Scanning Status Report Volume 2, Issue 1 March 2020
    PCORI Health Care Horizon Scanning System Horizon Scanning Status Report Volume 2, Issue 1 March 2020 Prepared for: Patient-Centered Outcomes Research Institute 1828 L St., NW, Suite 900 Washington, DC 20036 Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12 Prepared by: ECRI Institute 5200 Butler Pike Plymouth Meeting, PA 19462 Investigators: Randy Hulshizer, MA, MS Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, PA-C Marcus Lynch, PhD Misha Mehta, MS Brian Wilkinson, MA Donna Beales, MLIS Jennifer De Lurio, MS Eloise DeHaan, BS Eileen Erinoff, MSLIS Maria Middleton, MPH Diane Robertson, BA Kelley Tipton, MPH Rosemary Walker, MLIS Karen Schoelles, MD, SM Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.
    [Show full text]