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Studies on New Pharmacological Treatments for Alcohol Dependence - and the Importance of Objective Markers of Alcohol Consumption

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Studies on New Pharmacological Treatments for Alcohol Dependence - and the Importance of Objective Markers of Alcohol Consumption Studies on new pharmacological treatments for alcohol dependence - and the importance of objective markers of alcohol consumption Andrea de Bejczy 2016 Addiction Biology Unit Section of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at University of Gothenburg Sweden Cover illustration: by A. de Bejczy Inspired by Stan Lee’s “The Invincible Ironman. The empty shell”, Marvel Comics “…HIS VOICE IS HOARSE, HIS HAND TREMBLING AS HE REACHES FOR THE GLEAMING OBJECT THAT SEEMS BOTH WONDERFUL AND TERRIBLE TO HIM…” Studies on new pharmacological treatments for alcohol dependence ©Andrea de Bejczy [email protected] ISBN: 978-91-628-9788-8 (printed publication) ISBN: 978-91-628-9789-5 (e-publication) http://hdl.handle.net/2077/42349 Printed in Gothenburg, Sweden 2016 By INEKO ii La familia iii iv Studies on new pharmacological treatments for alcohol dependence - and the importance of objective markers of alcohol consumption Andrea de Bejczy Addiction Biology Unit Section of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at University of Gothenburg ABSTRACT This thesis will guide you through three randomized controlled trials (RCT) on three pharmacotherapies for alcohol dependence; the antidepressant drug mirtazapine, the smoking cessation drug varenicline and the glycine-uptake inhibitor Org 25935. The mirtazapine study was an investigator initiated single- center harm-reduction study with alcohol consumption measured by self-report in a diary as main outcome. The results indicated that mirtazapine reduced alcohol consumption in males with heredity for alcohol use disorder (AUD). The Org 25935 study was an international multi-center study with abstinence as treatment goal, main time to relapse and alcohol consumption was measured by self-report collected by the Time Line Follow Back method (TLFB). All subjects reduced their drinking compared to baseline, but Org 25935 failed to show superiority over placebo. The varenicline study was an investigator initiated multi-center harm- reduction study. In this study alcohol consumption was measured both by self- report in a diary and by alcohol biomarkers. In the analysis of self-reported data, varenicline failed to show efficacy, however, in the biomarker analysis varenicline reduced alcohol consumption compared to placebo. The direct alcohol marker phosphatidylethanol (PEth) was superior to the indirect biomarkers CDT and GGT in measuring alcohol consumption. Keywords: Alcohol dependence, RCT, mirtazapine, glycine-transporter inhibitor, varenicline, alcohol marker, phosphatidylethanol, PEth ISBN: 978-91-628-9788-8 (printed publication) ISBN: 978-91-628-9789-5 (e-publication) v LIST OF PAPERS This thesis is based on the following studies, referred to in the text by their Roman numerals. Papers I. The Effects of Mirtazapine Versus Placebo on Alcohol Consumption in Male High Consumers of Alcohol; A Randomized, Controlled Trial. Andrea de Bejczy, MD and Bo Söderpalm, MD, PhD. Journal of Clinical Psychopharmacology, Vol. 35, No.1, pp 43-50, February 2015 II. Efficacy and Safety of the Glycine Transporter-1 Inhibitor Org 25935 for the Prevention of Relapse in Alcohol-Dependent Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. Andrea de Bejczy, Kari R. Nations, Armin Szegedi, Joep Schoemaker, Frank Ruwe and Bo Söderpalm. Alcoholism: Clinical and Experimental Research, Vol.38, No.9, pp. 2427-2435, September 2014 III. Varenicline for treatment of alcohol dependence: a randomized, placebo-controlled trial. Andrea de Bejczy*, MD, Elin Löf*, PhD, Lisa Walther, MD, Joar Guterstam, MD, Anders Hammarberg, PhD, Gulber Asanovska, MD, Johan Franck, prof., Anders Isaksson, associate prof., and Bo Söderpalm, prof. *shared first author Alcoholism: Clinical and Experimental Research, Vol.39, No.11, pp. 2189-2199, November 2015 IV. Phosphatidylethanol is Superior to Carbohydrate-Deficient Transferrin and γ-Glutamyltransferase as an Alcohol Marker and is a Reliable Estimate of Alcohol Consumption Level. Lisa Walther, Andrea de Bejczy, Elin Löf, Therese Hansson, Anders Andersson, Joar Guterstam, Anders Hammarberg, Gulber Asanovska, Johan Franck, Bo Söderpalm and Anders Isaksson. Alcoholism: Clinical and Experimental Research, Vol.39, No.11, pp. 2200-2208, November 2015 vi POPULÄRVETENSKAPLIG SAMMANFATTNING Alkoholberoende innebär ett stort lidande för de drabbade och deras närstående. Alkohol orsakar också stora kostnader för samhället och ca. 4 % av den totala sjukdomsbördan i världen orsakas av alkohol. Idag finns i Europa fyra godkända läkemedel för alkoholberoende. Disulfiram, som verkar genom att påverka nedbrytningen av alkohol och orsaka symptom som kräkning och huvudvärk om man dricker alkohol när man tagit medicinen. Akamprosat, naltrexon och nalmefen verkar genom olika mekanismer för att minska suget efter alkohol och öka kontrollen över hur mycket man dricker. Tyvärr fungerar inte läkemedlen för alla och det skulle behövas fler behandlingar. Den här avhandlingen baseras på tre kliniska randomiserade placebokontrollerade prövningar som undersöker tre olika läkemedels effekter på alkoholkonsumtionen. Den första studien visade att mirtazapin, ett välkänt antidepressivt läkemedel (Remeron®) kan ha effekt på alkoholkonsumtionen hos högkonsumerande män med ärftlighet för alkoholberoende. Den andra studien undersökte hur en glycintransportör-blockare, Org 25935, påverkade återfallsfrekvensen hos avgiftade alkoholberoende individer. Båda grupperna drack mycket mindre under studien, men läkemedlet hade inte bättre effekt jämfört med placebo. På grund av övertygande resultat i djurstudier behövs det fler studier som utvärderar glycintransportör-blockerare innan man med säkerhet kan säga att de inte har en effekt på alkoholkonsumtionen. Studien var gjord i samarbete med ett läkemedelsföretag (MSD) men det underliggande konceptet kom från gruppens prekliniska forskning. Den tredje studien var också en fortsättning på gruppens prekliniska forskning. I den undersöktes vareniklin, den verksamma substansen i ett läkemedel mot rökning (Champix®), påverkar kolinerga system i hjärnan och som visat sig sänka alkoholkonsumtion hos råttor och hos rökare med hög alkoholkonsumtion. I vår studie mättes alkoholkonsumtionen på två sätt, dels genom att försökspersonerna fick anteckna vad de druckit i en dagbok, dels genom ett blodprov där man mätte phosphatidylethanol (PEth), som bildas då man druckit alkohol och är en markör för hur mycket man har druckit. När man analyserade alkoholkonsumtionen som rapporterats i dagböckerna så fanns det ingen skillnad mellan gruppen som fått vareniklin och gruppen som fått placebo, men när man analyserade uppmätta nivåer av PEth i blodet så hade de som fått vareniklin sänkt sin konsumtion. Eftersom flera markörer för alkoholkonsumtion mättes i studien, jämfördes dessa med varandra och med den mängd alkohol som uppgivits i dagböckerna. Den markör som verkade ge den mest korrekta uppskattningen av alkoholkonsumtionen var PEth. Det var större skillnad mellan den uppgivna konsumtionen och PEth-nivåer i blodet i placebogruppen än i gruppen som fått vareniklin. Förklaringen kan vara att om man starkt önskar att dricka mindre och man också förväntar sig en effekt av det läkemedel man får, så underrapporterar man omedvetet sin konsumtion. Hos de som fått vareniklin och vii faktiskt har sänkt sin konsumtion under studien blev inte underrapporteringen lika tydlig. Det är möjligt att det finns en nivå av alkoholkonsumtion som känns accepterad av samhället och också upplevs som en acceptabel förbättring, och att det är på den nivån som placebogruppen OCH vareniklingruppen (som rapporterar lite mindre än den med PEth uppmätta konsumtionen) hamnar. Den sammanlagda slutsatsen från de tre studierna är att det är viktigt att mäta utfallet, dvs. alkoholkonsumtionen, på ett så objektivt sätt som möjligt, t.ex. med en alkoholmarkör. Av de markörer som utvärderades i studierna var PEth den som mätte alkoholkonsumtionen bäst. I KORTHET Alkohol orsakar lidande, för tidig död och stora kostnader. Tre kliniska studier på tre möjliga nya läkemedel genomfördes. Mirtazapin, ett antidepressivt läkemedel, minskade alkoholkonsumtion hos män med ärftlighet för alkoholkonsumtion. Org 25935, som påverkar glycinnivåer i hjärnan, förlängde inte tiden till återfall efter avgiftning, men fler studier behöver göras. Vareniklin, ett läkemedel mot rökning, sänkte alkoholkonsumtionen när man mätte med en objektiv alkoholmarkör, men inte när man mätte med självrapporterad alkoholkonsumtion. Alkoholkonsumtion i studier bör hellre mätas med ett objektivt mått, som t.ex. en alkoholmarkör, än med ett subjektivt mått. I jämförelse med två andra vanliga alkoholmarkörer visade sig phosphatidylethanol (PEth) vara den som mätte alkoholkonsumtion bäst. viii LIST of CONTENTS LIST OF ABBREVIATIONS 1 DEFINITIONS IN SHORT 6 CALCULATION FORMULAS 8 BACKGROUND ALCOHOL AND ITS HISTORY 10 Global history of alcohol 10 The history of alcohol in Sweden 14 ALCOHOL AND SOCIETY 16 Alcohol consumption in the Swedish population 16 The monetary costs of alcohol 16 Global burden of disease (GBD) and mortality 17 CONSEQUENCES OF ALCOHOL CONSUMPTION 19 Neurological complications 19 Somatic complications 20 RISK FACTORS FOR ALCOHOL DEPENDENCE 23 THE ALCOHOL USE DISORDER (AUD) 25 Diagnose criteria 25 The AUD diagnose and heavy drinking 26 SUBTYPING OF A HETEROGENEOUS DISEASE 29 ALKOHOL AND THE REWARD PATHWAY 33 ix TREATMENTS 39 History of treatments 39
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