IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Efficacy, tolerability, and safety of low-dose and high-dose baclofen in the treatment of alcohol dependence: A systematic review and meta-analysis.

A systematic review of the current literature on the efficacy of baclofen, particularly the effect of dosing, for the treatment of alcohol dependence (AD) is missing. We therefore conducted a systematic review and meta-analysis of currently available randomized placebo-controlled trials (RCTs). A systematic literature search for RCTs in AD patients comparing baclofen to placebo was performed in September 2017. The effect of baclofen treatment, and the moderating effects of baclofen dosing (low-dose (LDB) 30-60 mg versus high-dose (HDB) targeted as >60 mg/day), and the amount of alcohol consumption before inclusion were studied. Three treatment outcomes were assessed: time to lapse (TTL), percentage days abstinent (PDA), and percentage of patients abstinent at end point (PAE). 13 RCTs from 39 records were included. Baclofen was superior to placebo with significant increases in TTL (8 RCTs, 852 patients; SMD=0.42; 95% CI 0.19-0.64) and PAE (8 RCTs, 1244 patients; OR=1.93; 95% CI 1.17-3.17), and a non-significant increase in PDA (7 RCTs, 457 patients; SMD=0.21; 95% CI -0.24 to 0.66). Overall, studies with LDB showed better efficacy than studies with HDB. Furthermore, tolerability of HDB was low, but serious adverse events were rare. Meta-regression analysis showed that the effects of baclofen were stronger when daily alcohol consumption before inclusion was higher. Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation.

Can baclofen change alcohol-related cognitive biases and what is the role of anxiety herein?

BACKGROUND: Baclofen has shown promise in the treatment of alcohol dependence. However, its precise (neuro-) psychological working mechanism is still under debate. AIMS: This study aimed to get a better understanding of baclofen's working mechanism by examining the effect of baclofen on cognitive biases. It was hypothesized that baclofen, compared to placebo, would lead to weaker cognitive biases. Furthermore, given a suggested anxiolytic effect of baclofen, we expected that anxiety would moderate this effect. METHODS: From a larger randomized clinical trial (RCT) with 151 participants, a subset of 143 detoxified alcohol-dependent patients, either taking baclofen or placebo, was examined. Attentional bias for alcohol (500 and 1500 ms), alcohol approach tendencies, implicit alcohol-relaxation associations and trait anxiety were assessed before the administration of baclofen or placebo. Four weeks later, 94 patients were still abstinent (53 in the baclofen and 41 in the placebo condition) and cognitive biases were assessed again. RESULTS: At baseline, patients showed a vigilance-avoidance pattern for the attentional bias (at 500 and 1500 ms, respectively) and alcohol-negative associations. After 4 weeks, an indication for an attentional bias away from alcohol at 500 ms was found only in the baclofen group; however, cognitive biases did not differ significantly between treatment groups. No moderating role of anxiety on cognitive biases was found. CONCLUSIONS: Baclofen did not lead to a differential change in cognitive biases compared with placebo, and trait anxiety levels did not moderate this. A better understanding of the working mechanism of baclofen and predictors of treatment success would allow prescribing of baclofen in a more targeted manner.

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Speaking fluently with baclofen?

Baclofen is a new and promising pharmacological compound for the treatment of alcohol dependence (AD). Although several randomised trials found a reduction of craving and higher abstinence rates with low and high doses of baclofen, others failed to show positive effects. In this case study, the successful treatment of a patient with AD with daily 120 mg of baclofen is described. In addition to a decrease in alcohol use, we observed the cessation of stuttering during treatment with baclofen, reoccurrence of stuttering following discontinuation, and cessation of stuttering after reinstatement of the treatment. Based on this observation, the direct effects of baclofen on muscle relaxation and anxiety reduction and its indirect effect on dopaminergic inhibition, we believe that baclofen might be a new treatment for stuttering. Further research into the effect of baclofen on stuttering is warranted.

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

Validation of the Amsterdam Beverage Picture Set: A Controlled Picture Set for Cognitive Bias Measurement and Modification Paradigms.

BACKGROUND: Alcohol research may benefit from controlled and validated picture sets. We have constructed the Amsterdam Beverage Picture Set (ABPS), which was designed for alcohol research in general and cognitive bias measurement and modification in particular. Here, we first formulate a position on alcohol stimulus validity that prescribes that alcohol-containing pictures, compared to nonalcohol-containing pictures, should induce a stronger urge to drink in heavy drinkers than in light drinkers. Because a perceptually simple picture might induce stronger cognitive biases but the presence of a drinking context might induce a stronger urge to drink, the ABPS contains pictures with and without drinking context. By limiting drinking contexts to simple consumption scenes instead of real-life scenes, complexity was minimized. A validation study was conducted to establish validity, to examine ABPS drinking contexts, and to explore the role of familiarity, valence, arousal, and control. METHODS: Two hundred ninety-one psychology students completed the Alcohol Use Disorders Identification Test, as well as rating and recognition tasks for a subset of the ABPS pictures. RESULTS: The ABPS was well-recognized, familiar, and heavy drinkers reported a greater urge to drink in response to the alcohol-containing pictures only. Alcohol presented in drinking context did not elicit a stronger urge to drink but was recognized more slowly than alcohol presented without context. CONCLUSIONS: The ABPS was found to be valid, although pictures without context might be preferable for measuring cognitive biases than pictures with context. We discuss how an explicit approach to picture construction may aid in creating variations of the ABPS. Finally, we describe how ABPS adoption across studies may allow more reproducible and comparable results across paradigms, while allowing researchers to apply picture selection criteria that correspond to a wide range of theoretical positions. The latter is exemplified by ABPS derivatives and adoptions that are currently under way.

Implicit Associations and Explicit Expectancies toward Cannabis in Heavy Cannabis Users and Controls.

Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations toward cannabis were measured with three Single Category Implicit Association Tests (SC-IAT's) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive-arousal associations but weaker implicit negative associations toward cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies toward cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users.

Hemispheric asymmetry for affective stimulus processing in healthy subjects--a fMRI study.

BACKGROUND: While hemispheric specialization of language processing is well established, lateralization of emotion processing is still under debate. Several conflicting hypotheses have been proposed, including right hemisphere hypothesis, valence asymmetry hypothesis and region-specific lateralization hypothesis. However, experimental evidence for these hypotheses remains inconclusive, partly because direct comparisons between hemispheres are scarce. METHODS: The present fMRI study systematically investigated functional lateralization during affective stimulus processing in 36 healthy participants. We normalized our functional data on a symmetrical template to avoid confounding effects of anatomical asymmetries. Direct comparison of BOLD responses between hemispheres was accomplished taking two approaches: a hypothesis-driven region of interest analysis focusing on brain areas most frequently reported in earlier neuroimaging studies of emotion; and an exploratory whole volume analysis contrasting non-flipped with flipped functional data using paired t-test. RESULTS: The region of interest analysis revealed lateralization towards the left in the medial prefrontal cortex (BA 10) during positive stimulus processing; while negative stimulus processing was lateralized towards the right in the dorsolateral prefrontal cortex (BA 9 & 46) and towards the left in the amygdala and uncus. The whole brain analysis yielded similar results and, in addition, revealed lateralization towards the right in the premotor cortex (BA 6) and the temporo-occipital junction (BA 19 & 37) during positive stimulus processing; while negative stimulus processing showed lateralization towards the right in the temporo-parietal junction (BA 37,39,42) and towards the left in the middle temporal gyrus (BA 21). CONCLUSION: Our data suggests region-specific functional lateralization of emotion processing. Findings show valence asymmetry for prefrontal cortical areas and left-lateralized negative stimulus processing in subcortical areas, in particular, amygdala and uncus.