Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Safety and compliance of long-term low-dose ondansetron in alcohol use disorder treatment.

BACKGROUND: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD. METHODS: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed. RESULTS: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment. CONCLUSIONS: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

A critical scientific evaluation of a purportedly negative data report - response to Seneviratne et al. 2022.

A core principle in the pursuit of scientific knowledge is that science is self-correcting and that important results should be replicable. Hypotheses need to be reinforced, adjusted, or rejected when novel results are obtained. Replication of results confirms hypotheses and enhances their integration into scientific practice. In contrast, publication of substantiated and replicated negative findings (i.e., non-significant or opposite findings) can be the basis to reject erroneous hypotheses or develop alternative strategies for investigation. Replication is a problem in all research fields. The Psychology Reproductivity Project reported that only 36% of 'highly influential' published research in highly ranked journals were reproduced. Similar to positive data, negative data can be flawed. Errors in a negative data set can be based on methodology, statistics, conceptual defects, and flawed peer review. The peer review process has received progressive scrutiny. A large-scale review of the peer review process of manuscripts submitted to the British Medical Journal group indicated that the process could be characterized as inconsistent, inaccurate, and biased. Further analysis indicated that the peer process is easily manipulated, indicative of a failed system, is a major factor behind the lack of replication in science (acceptance of flawed manuscripts), suppresses opposing scientific evidence and views, and causes gaps in and lack of growth of science. Complicating the integrity of scientific publication is the role of Editors/Researchers. Ethical guidelines exist for major publishing houses about editorial ethics, behavior, and practice.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

AIMS: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. METHODS: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. RESULTS: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. CONCLUSIONS: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. AIMS: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. METHODS: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. RESULTS: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. CONCLUSIONS: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648423.

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study.

Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration.

Post-marketing and clinical safety experience with sodium oxybate for the treatment of alcohol withdrawal syndrome and maintenance of abstinence in alcohol-dependent subjects.

Introduction: Sodium oxybate (SMO) has been approved in Italy and in Austria for the treatment of alcohol use disorder (AUD). This study describes the cumulative postmarketing and clinical safety experience with SMO in AUD.Areas covered: Safety data for SMO at approved posology in AUD were identified from: (i) the clinical trial registries of the US National Institutes of Health (NIH) and the European Medicines Agency (EMA), (ii) reports from the biomedical literature and (iii) available pharmacovigilance safety information from the EMA.Expert opinion: Safety data from 3 recent large randomized clinical studies (520 participants) and 43 earlier clinical studies (2547 participants) showed that SMO has a good safety profile in AUD patients. The safety profile was confirmed by pharmacovigilance data resulting from 299 013 patients exposed to SMO in Austria and Italy. Main adverse events were transitory dizziness and vertigo. Serious adverse events were rare. No death attributable to SMO has been reported. Risks of abuse or dependence are low in patients without psychiatric comorbidities or poly-drug use. The adverse events of SMO are transitory and do not require discontinuation of treatment. SMO abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.

Alcohol-Related Mortality in the WHO European Region: Sex-Specific Trends and Predictions.

AIMS: Alcohol is an important risk factor for morbidity and mortality, especially within the European region. Differences in per capita consumption and drinking patterns are possible reasons for regional differences and diverging trends in alcohol-related health outcomes. METHODS: Twenty-nine countries within the World Health Organization (WHO) European region were evaluated for trends and predictions in alcohol-related deaths within the last four decades using data available from the WHO Health for All database. RESULTS: Between 1979 and 2015, age-standardised death rates due to selected alcohol-related causes decreased significantly for both sexes in all assessed countries of the WHO European region, but regional differences are still pronounced. Assuming a similar trend in the future, the model predicted a further decrease until the year 2030. CONCLUSION: Even though alcohol-related mortality may have decreased within the last decades, the detrimental effects of alcohol consumption and alcohol dependence remain a considerable burden of disease within Europe.

Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level.

Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL.

No evidence of subgroups found in amphetamine consumers in Iran.

Amphetamine type substances are the second most commonly consumed illicit drug type and their use is an important contributor to the global burden of disease. This investigation set out to determine whether, similar to alcohol or nicotine addiction, subgroups of consumers can also be found in amphetamine addicts. 204 consumers of methamphetamine only (n = 50) or both methamphetamine and heroin (n = 154) have been investigated in Mashhad, Iran by means of "Lesch Alcoholism Typology". No significant differences in consumption pattern or age of onset have been found between the different types. Many subjects, however, reported symptoms of anxiety (n=78) or depression (n = 129) prior to drug use. These findings highlight the need for high quality epidemiological studies further addressing this issue.

The role of affective temperament as a predictor of relapse in alcohol dependence.

BACKGROUND: Personality traits have been proposed as relapse risk factors in alcohol use disorders. So far, no study has assessed the association between affective temperamental traits and the prospective relapse risk. METHODS: This was a 3-month prospective naturalistic study, designed to assess the impact of affective temperaments in relapse. A sample of 61 alcohol-dependent patients was collected from an ambulatory clinical setting. Socio-demographic information, drinking and substance use habits, drinking status, craving and affective temperament traits were assessed. RESULTS: Age, age of onset of alcohol abuse and dependence and drug consumption correlate with drinking status. Male alcohol-dependent patients who relapsed presented higher scores on cyclothymic temperament than patients with an alcohol dependence diagnosis who remain sober. Hierarchical logistic regression indicates that cyclothymic temperament predicted relapse in a 3-month follow-up. However, the coefficient was marginally significant after controlling for all potential confounding predictors. CONCLUSIONS: Our results provide new insights about the role of affective temperaments in alcohol use disorders, specifically in predicting short-term relapse in detoxified male alcohol-dependent patients. Copyright © 2017 John Wiley & Sons, Ltd.

Attention deficit hyperactivity disorder and substance abuse: An investigation in young Austrian males.

BACKGROUND: Many studies have found an association between Substance Use Disorders (SUDs) and Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents and adults. We intended to determine whether substance abuse and SUDs are associated with former and current ADHD symptomatology in a non-clinical sample of 17 and 18 year old males. METHOD: A representative sample of 3280 young men (6.8% of all males born in Austria in the respective year) was investigated during the examination for military service. We collected data on past (WURS) and current (ADHD symptom checklist) ADHD symptomatology, substance abuse, parental substance use and abuse and motives for substance use. RESULTS: Measured by WURS, 10.1% had scored positive for past ADHD symptoms. 2.7% of all subjects stated that they have been treated for ADHD and 1.5% reported that they had at one point received pharmacological treatment for the condition. Abuse of alcohol, nicotine and illicit substances was significantly (p<.01) more frequent in subjects with ADHD syndrome. Perceived parental alcohol abuse increased the risk for ADHD in the offspring. Motives for substance use differed greatly between groups. LIMITATIONS: The sample consists of men only. Subjects had to be fit enough to be enlisted military service, generating a possible bias towards healthier subjects. The cross-sectional design does not allow conclusions about the temporal relationships between ADHD symptoms and substance abuse. CONCLUSION: Identification of vulnerability factors for comorbid ADHD and SUD in adolescence should be intensified. Preventive strategies ought to be established.

The influence of reported ADHD and substance abuse on suicidal ideation in a non-clinical sample of young men.

This study intended to determine whether former and current ADHD symptomatology is associated with suicidal ideation in a non-clinical sample of 18 year old males. We performed a cross sectional descriptive study of 3280 men during the examination for military service. The investigation included a screening for substance abuse, past (WURS) and current (ADHD symptom checklist) ADHD symptomatology and an interview about suicidal ideations. We found a correlation of suicidal ideations with a history of ADHD symptomatology. ADHD symptoms were strongly consistent over time. These results indicate that a history of (diagnosed or undiagnosed) ADHD could be a predictor for suicidal ideations. Surveying a history of ADHD in primary care might help identify subjects at risk for suicidal tendencies.

Motivational factors and negative affectivity as predictors of alcohol craving.

Craving is thought to play an important role in alcohol use disorders. The recent inclusion of "craving" as a formal diagnostic symptom calls for further investigation of this subjective phenomenon with multiple dimensions. Considering that alcohol-dependent patients compensate negative physical/emotional states with alcohol, the aim of this study is to investigate alcohol craving and its correlation with drinking measures and affective personality dimensions. A sample of 135 alcohol-dependent patients (104 males and 31 females) was collected from a clinical setting. Subjects self-rated their cravings (Penn Alcohol Craving Scale) and the stage of change. Several personality scales were also administered. Craving was related to drinking status, abstinence time, age, and taking steps. After controlling for these conditions, psychological characteristics related to low self-concept, neuroticism, cyclothymic affective temperament, depression, and hostility were found to be predictors of craving in sober alcohol-dependent patients. Our results support craving as a component of the phenomenology of alcohol dependence and highlight the presence of unpleasant feelings as predictors of craving in sober alcohol-dependent patients without co-occurring psychiatric conditions. The predisposition to experience negative emotions may induce a stronger craving response and increase the likelihood of a first drink and a subsequent loss of control.

Case control study of ANKK1 Taq 1A polymorphism in patients with alcohol dependence classified according to Lesch's typology.

OBJECTIVE: The aim of this study was to examine the association between the Taq 1A polymorphism of the ANKK1 gene in homogeneous subgroups of patients with alcohol dependence syndrome divided according to Lesch's typology. MATERIAL/METHODS: DNA was provided from alcohol-dependent (AD) patients (n = 373) and healthy control subjects (n = 168), all of Polish descent. The history of alcoholism was obtained using the Polish version of the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). Samples were genotyped using the PCR method. RESULTS: We found no association between alcohol dependence and ANKK1 Taq 1A polymorphism. CONCLUSIONS: Lesch's typology is a clinical consequence of the disease, and its phenotypic description is too complex for simple genetic analysis.

Monoamine oxidase a promoter variable number of tandem repeats (MAOA-uVNTR) in alcoholics according to Lesch typology.

BACKGROUND: The aim of this study was to examine the association between the MAOA-uVNTR gene polymorphism in a homogeneous subgroups of patients with alcohol dependence categorized according to Lesch's typology. METHODS: DNA was provided from alcohol dependent (AD) patients (n=370) and healthy control subjects (n=168) all of Polish descent. The history of alcoholism was obtained using the Polish version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Samples were genotyped using PCR methods. RESULTS: We found no association between alcohol dependence and MAOA gene polymorphism. CONCLUSIONS: Lesch typology is a clinical consequence of the disease and its phenotypic description is too complex for a simple genetic analysis.