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

Bejczy, Andrea de; Nations, Kari R.; Szegedi, Armin; Schoemaker, Joep; Ruwe, Frank; Söderpalm, Bo

doi:10.1111/acer.12501

Cited by 30 publications

(22 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current results suggest that receptors containing the GlyRa2 subunit may be important for promoting ethanol consumption (Table 2). It is interesting to note that an inhibitor of glycine transporter-1 was not effective in preventing alcohol relapse in humans (de Bejczy et al, 2014). Based on our study, a selective inhibitor of receptors containing GlyRa2 subunits might be more effective in reducing alcohol consumption.…”

Section: Discussionmentioning

confidence: 68%

Glycine Receptors Containing α2 or α3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyRa1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyRa2 and a3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyRa2 or a3 subunits were distinct from effects previously observed in mice with knock-in mutations in the a1 subunit. We provide evidence that GlyRa2 and a3 subunits may regulate ethanol consumption and the aversive response to ethanol.

show abstract

Section: Discussionmentioning

confidence: 68%

Glycine Receptors Containing α2 or α3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…Many studies (38; 27.3%) defined relapse as a return to some level of "heavy drinking," where "heavy" was variously defined. Some studies focused on the 4+/5+ drinks per occasion for women/men (e.g., Agosti et al, 2012;Bujarski et al, 2013;de Bejczy et al, 2014;Garbutt et al, 2010); some studies focused on 4+, 5+, or 6+ drinks for males or females (e.g., Schellekens et al, 2015); and other studies focused on various levels of grams of alcohol per day (e.g., Bach et al, 2015;Berner et al, 2014;Charlet et al, 2014;Hartl et al, 2011;Kiefer et al, 2011). The distinction between lapse/slip (defined as "any use" or in some cases defined as less than the relapse criteria) and relapse (defined as a higher level of use, such as heavy drinking or consecutive days of use) was used by 13 (9.4%) of the studies.…”

Section: Summary Of Findings On Relapsementioning

confidence: 99%

Is the Construct of Relapse Heuristic, and Does It Advance Alcohol Use Disorder Clinical Practice?

Maisto

Witkiewitz

Moskal

et al. 2016

J. Stud. Alcohol Drugs

View full text Add to dashboard Cite

ABSTRACT. Objective: Alcohol use disorder (AUD) relapse is a construct that has been of major clinical and research interest but has been inconsistently defined. The purpose of this study was to review the definitions of AUD relapse that have been used in clinical research as a basis for drawing conclusions about its heuristic value. Method: A systematic review of the literature was conducted on empirical studies that (a) were published in peer-reviewed journals, (b) were published between 2010 and 2015, (c) were written in English, and (d) provided a definition of alcohol relapse (or lapse) that was used in the study. Results: The review yielded 139 individual studies that met inclusion criteria. The studies showed wide variability in how relapse was defined and interpreted in the literature, and there was little direct empirical or theoretical rationale provided for the definitions of relapse that were chosen. Furthermore, the concept of AUD relapse as a discrete state is not consistent with the empirical literature on the clinical course of alcohol consumption. Conclusions: We conclude that the heuristic value of AUD relapse as currently studied is low. An alternative approach that embeds the construct in theory and data on the clinical course of alcohol consumption and aligns with current trends in healthcare would seem to have a better chance of improving AUD clinical decision-making and knowledge about AUD in general. (J. Stud. Alcohol Drugs, 77, 849-858, 2016 T HE TERM RELAPSE is part of the common discourse with respect to addictive behaviors. For example, a simple Google search for either "relapse and addiction" or "relapse and alcohol" yields millions of results. The purpose of this article is to examine the use of the term relapse in the area of alcohol use/alcohol use disorder (AUD) change, whether by self-initiation, the use of mutual-help groups, formal treatment services, or some combination of the three. The ultimate goal of this line of inquiry is to appraise the heuristic value of the term relapse in advancing clinical research and treatment. Heuristic value in this article means value in aiding the discovery of knowledge about AUD clinical course through the generation of research. The article begins with an overview of conceptual definitions of AUD relapse followed by reporting the findings of a systematic review of recently published (2010)(2011)(2012)(2013)(2014)(2015) empirical studies that have included relapse as an independent or dependent variable. Definition of relapseAccording to the online edition of the Merriam-Webster Dictionary (n.d.), "relapse" is derived from the Latin word relabi, which means "to slide back." Relapse as a verb means "to become ill again after a period of improvement in health," or "to return to a bad condition, form of behavior, etc." The noun form of relapse simply means a return of illness or a return to a former and undesirable condition.The construct of relapse is often applied in reference to what typically are considered physical illnesses. In this conte...

show abstract

“…The previous preclinical studies justified a Proof of concept study and Org25935 was rapidly tested in AUD patients, allowing minimal time to address translational issues (De Bejczy et al 2014). Org25935 demonstrated no benefit over placebo in the interim analyses and the trial was stopped due to futility.…”

Section: Discussionmentioning

confidence: 99%

Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects

et al. 2017

Self Cite

View full text Add to dashboard Cite

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.

show abstract

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

Abstract: Org 25935 demonstrated no benefit over placebo in preventing alcohol relapse. Study limitations and implications are discussed.

Cited by 30 publications

References 44 publications

Glycine Receptors Containing α2 or α3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Glycine Receptors Containing α2 or α3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Is the Construct of Relapse Heuristic, and Does It Advance Alcohol Use Disorder Clinical Practice?

Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects

Contact Info

Product

Resources

About