Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an alpha-secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPPalpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer’s disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-Plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy. Here we screened a FDA-approved drug library and identified disulfiram as a novel ADAM10 gene expression enhancer. Disulfiram increased ADAM10 production as well as sAPP-alpha in SH-SY5Y human neuronal cells and additionally prevented A-beta aggregation in an in vitro assay in a dose-dependent fashion. In addition, acute disulfiram treatment of Alzheimer model mice induced ADAM10 expression in peripheral blood cells, reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits. Alcohol-dependent patients are subjected to disulfiram-treatment to discourage alcohol-consumption. In such patients, enhancement of ADAM10 by disulfiram-treatment was demonstrated in peripheral blood cells. Our data suggest that disulfiram could be repurposed as an ADAM10 enhancer and AD therapeutic. However, efficacy and safety has to be analyzed in Alzheimer patients in the future

Prevalence Estimates of ADHD in a Sample of Inpatients With Alcohol Dependence

Objective: ADHD is common in patients with alcohol dependence, but prevalence results are inconsistent. We investigated ADHD prevalence in a complex design to avoid over- or underdiagnosing. Method: Patients with alcohol dependence starting long-term residential treatment were included. A structured interview (Diagnostic Interview for ADHD in Adults [DIVA]) was conducted on all patients. DIVA results indicating childhood or adulthood ADHD were assessed in successive diagnostic interviews by two expert clinicians. Results: 415 of 488 patients had completed the entire diagnostic assessment. ADHD prevalence was 20.5%. DIVA results correlated moderately with experts’ diagnoses. In patients with ADHD, a higher comorbid illicit substance use was prevalent and alcohol dependence started earlier and was more severe. Conclusion: This study provides the largest sample on ADHD prevalence in alcohol dependent inpatients. Despite great efforts to avoid overestimation, we found every fifth patient to have ADHD. ADHD diagnosis should not be based solely on a structured interview but should be clinically confirmed. (J. of Att. Dis. 2020; 24(14) 2072–2083

The clinical course of comorbid substance use disorder and attention deficit/hyperactivity disorder: protocol and clinical characteristics of the INCAS study

Abstract Background: Substance use disorders (SUD) often co-occur with attention deficit hyperactivity disorder (ADHD). Although the short-term effects of some specific interventions have been investigated in randomized clinical trials, little is known about the long-term clinical course of treatment-seeking SUD patients with comorbid ADHD. Aims: This paper presents the protocol and baseline clinical characteristics of the International Naturalistic Cohort Study of ADHD and SUD (INCAS) designed and conducted by the International Collaboration on ADHD and Substance Abuse (ICASA) foundation. The overall aim of INCAS is to investigate the treatment modalities provided to treatment-seeking SUD patients with comorbid ADHD, and to describe the clinical course and identify predictors for treatment outcomes. This ongoing study employs a multicentre observational prospective cohort design. Treatment-seeking adult SUD patients with comorbid ADHD are recruited, at 12 study sites in nine different countries. During the follow-up period of nine months, data is collected through patient files, interviews, and self-rating scales, targeting a broad range of cognitive and clinical symptom domains, at baseline, four weeks, three months and nine months. Results: A clinically representative sample of 578 patients (137 females, 441 males) was enrolled during the recruitment period (June 2017-May 2021). At baseline, the sample had a mean age (SD) of 36.7 years (11.0); 47.5% were inpatients and 52.5% outpatients; The most prevalent SUDs were with alcohol 54.2%, stimulants 43.6%, cannabis 33.1%, Abstract Background: Substance use disorders (SUD) often co-occur with attention deficit hyperactivity disorder (ADHD). Although the short-term effects of some specific interventions have been investigated in randomized clinical trials, little is known about the long-term clinical course of treatment-seeking SUD patients with comorbid ADHD. Aims: This paper presents the protocol and baseline clinical characteristics of the International Naturalistic Cohort Study of ADHD and SUD (INCAS) designed and conducted by the International Collaboration on ADHD and Substance Abuse (ICASA) foundation. The overall aim of INCAS is to investigate the treatment modalities provided to treatment-seeking SUD patients with comorbid ADHD, and to describe the clinical course and identify predictors for treatment outcomes. This ongoing study employs a multicentre observational prospective cohort design. Treatment-seeking adult SUD patients with comorbid ADHD are recruited, at 12 study sites in nine different countries. During the follow-up period of nine months, data is collected through patient files, interviews, and self-rating scales, targeting a broad range of cognitive and clinical symptom domains, at baseline, four weeks, three months and nine months. Results: A clinically representative sample of 578 patients (137 females, 441 males) was enrolled during the recruitment period (June 2017-May 2021). At baseline, the sample had a mean age (SD) of 36.7 years (11.0); 47.5% were inpatients and 52.5% outpatients; The most prevalent SUDs were with alcohol 54.2%, stimulants 43.6%, cannabis 33.1%, and opioids 14.5%. Patients reported previous treatments for SUD in 71.1% and for ADHD in 56.9%. Other comorbid mental disorders were present in 61.4% of the sample: major depression 31.5%, post-traumatic stress disorder 12.1%, borderline personality disorder 10.2%. Conclusions: The first baseline results of this international cohort study speak to its feasibility. Data show that many SUD patients with comorbid ADHD had never received treatment for their ADHD prior to enrolment in the study. Future reports on this study will identify the course and potential predictors for successful pharmaceutical and psychological treatment outcomes

[ADHD in adult patients with substance use disorders].

Hintergrund: Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist eine häufige Komorbidität bei erwachsenen Patienten mit Substanzkonsum-Störungen (SKS). Die Diagnostik und Behandlung der ADHS bei SKS stellt dabei oft eine Herausforderung dar, auch in Hinblick auf die Verordnung von Stimulanzien. Vor kurzem erstellte eine Gruppe internationaler Experten ein Konsensus-Papier zu Diagnostik und Therapie der Komorbidität ADHS und SKS. Außerdem wurden die S3-Leitlinien «ADHS» veröffentlicht, die auch Hinweise zur Behandlung der ADHS bei komorbider SKS geben. Auch die S3-Leitlinien zu alkohol- bzw. methamphetaminbezogenen Störungen gehen auf ADHS als Komorbidität ein. Methoden: Zusammenfassung der Konsensus- und Leitlinien-Empfehlungen, ergänzt um die aktuelle Literatur. Schlussfolgerung: In den letzten Jahren haben sich neue Erkenntnisse zur Komorbidität ADHS bei Patienten mit SKS ergeben. Eine Reihe von Screening- und Diagnostik-Instrumenten wurden mittlerweile in dieser Patientengruppe untersucht. Das Konsensus-Papier und verschiedene Leitlinien geben dem Kliniker daher konkrete Hilfestellungen beim Erkennen von ADHS bei Sucht-Patienten sowie bei der Durchführung der weiteren Diagnostik und der Behandlung beider Erkrankungen. Hier hat sich beispielsweise der Stellenwert von Stimulanzien bei der Behandlung von Patienten mit SKS und ADHS deutlich verändert und es gibt erste Studien zu psychotherapeutischen Interventionen spezifisch für diese Komorbidität

Stop What You're Doing!—An fMRI Study on Comparisons of Neural Subprocesses of Response Inhibition in ADHD and Alcohol Use Disorder

Rationale: Both attention deficit-/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) are accompanied by deficits in response inhibition. Furthermore, the prevalence of comorbidity of ADHD and AUD is high. However, there is a lack of research on whether the same neuronal subprocesses of inhibition (i.e., interference inhibition, action withholding and action cancellation) exhibit deficits in both psychiatric disorders. Methods: We examined these three neural subprocesses of response inhibition in patient groups and healthy controls: non-medicated individuals with ADHD (ADHD; N = 16), recently detoxified and abstinent individuals with alcohol use disorder (AUD; N = 15), and healthy controls (HC; N = 15). A hybrid response inhibition task covering interference inhibition, action withholding, and action cancellation was applied using a 3T functional magnetic resonance imaging (fMRI). Results: Individuals with ADHD showed an overall stronger hypoactivation in attention related brain areas compared to AUD or HC during action withholding. Further, this hypoactivation was more accentuated during action cancellation. Individuals with AUD recruited a broader network, including the striatum, compared to HC during action withholding. During action cancellation, however, they showed hypoactivation in motor regions. Additionally, specific neural activation profiles regarding group and subprocess became apparent. Conclusions: Even though deficits in response inhibition are related to both ADHD and AUD, neural activation and recruited networks during response inhibition differ regarding both neuronal subprocesses and examined groups. While a replication of this study is needed in a larger sample, the results suggest that tasks have to be carefully selected when examining neural activation patterns of response inhibition either in research on various psychiatric disorders or transdiagnostic questions

Agomelatine is effective in reducing insomnia in abstinent alcohol-dependent patients

OBJECTIVES: Sleep disorders are a widespread, persistent problem among alcohol-dependent patients and have been implicated in an increased risk for alcohol relapse. The melatonin-agonist agomelatine has been shown to improve overall sleep quality without daytime sedation. METHODS: In an off-label therapeutic setting, 9 alcohol-dependent patients with chronic sleep disorders received nightly doses of between 25 and 50 mg of agomelatine. RESULTS: After 6 weeks of agomelatine treatment, the Pittsburgh Sleep Quality Index global score for all patients had decreased significantly from a mean (SD) of 13.1 (1.7) to 7.8 (1.7) (t = 12.8; P = 0.00). CONCLUSIONS: Agomelatine is a preparation that is not prone to abuse. The current pilot investigation shows that agomelatine might offer the prospect of becoming a valuable addition to the pharmacological repertoire for the treatment of alcohol-dependence-associated insomnia

Common and distinct neural connectivity in attention deficit/hyperactivity disorder and alcohol use disorder: a study using resting-state functional magnetic resonance imaging.

BACKGROUND: The relation between Attention Deficit/Hyperactivity Disorder (ADHD) and Alcohol Use Disorder (AUD) has been widely demonstrated. In this study, we aimed to investigate the connectivity traits that would help to understand the strong link between both disorders using a neuroimaging perspective. METHODS: The study included an AUD group (N = 18), an ADHD group (N = 17), a group with AUD+ADHD comorbidity individuals (N = 12) and a control group (N = 18). We used resting-state functional connectivity in a seed-based approach in the Default Mode Networks, the Dorsal Attention Network and the Salience Network. RESULTS: Within the Default Mode Networks, all groups shared increased connectivity towards the Temporal Gyrus when compared to the control group. Regarding the Dorsal Attention Network, the Brodmann Area 6 presented increased connectivity for each disorder group in comparison with the control group, displaying the strongest aberrations in the AUD+ADHD group. In the Salience Network, the Prefrontal Cortex showed decreased connectivity in every disorder group compared to the control group. CONCLUSIONS: Despite the small and unequal sample size, our study suggests common neurobiological alterations in AUD and ADHD, supporting the hypothesis that ADHD might be a risk factor for the development of an AUD. The results highlight the importance of an early ADHD diagnosis and treatment to reduce this risk for a subsequent AUD

Common and distinct neural connectivity in attention-deficit/hyperactivity disorder and alcohol use disorder studied using resting-state functional magnetic resonance imaging

Background: A link between attention-deficit/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) has been widely demonstrated. In this study, we used neuroimaging to investigate the connectivity traits that may contribute to the comorbidity of these disorders. Methods: The study included an AUD group (N = 18), an ADHD group (N = 17), a group with AUD + ADHD comorbidity (N = 12) and a control group (N = 18). We used resting-state functional connectivity in a seed-based approach in the default mode networks, the dorsal attention network, and the salience network. Results: Within the default mode networks, all affected groups shared greater connectivity toward the temporal gyrus when compared to the control group. Regarding the dorsal attention network, the Brodmann area 6 presented greater connectivity for each affected group in comparison with the control group, displaying the strongest aberrations in the AUD + ADHD group. In the salience network, the prefrontal cortex showed decreased connectivity in each affected group compared to the control group. Conclusions: Despite the small and unequal sample sizes, our findings show evidence of common neurobiological alterations in AUD and ADHD, supporting the hypothesis that ADHD could be a risk factor for the development of AUD. The results highlight the importance of an early ADHD diagnosis and treatment to reduce the risk of a subsequent AUD

International consensus statement on screening, diagnosis and treatment of substance use disorder patients with comorbid attention deficit/hyperactivity disorder

Contains fulltext : 191273.pdf (publisher's version ) (Closed access)Adult attention deficit/hyperactivity disorder (ADHD) often co-occurs with substance use disorders (SUD) and is associated with early onset and more severe development of SUD and with reduced treatment effectiveness. Screening tools allow for a good recognition of possible ADHD in adults with SUD and should be used routinely, followed by an ADHD diagnostic process initiated as soon as possible. Simultaneous and integrated treatment of ADHD and SUD, using a combination of pharmaco- and psychotherapy, is recommended. Long-acting methylphenidate, extended-release amphetamines, and atomoxetine with up-titration to higher dosages may be considered in patients unresponsive to standard doses. This paper includes evidence- and consensus-based recommendations developed to provide guidance in the screening, diagnosis and treatment of patients with ADHD-SUD comorbidity.9 p