High-dose baclofen attenuates insula activation during anticipatory anxiety in treatment-seeking alcohol dependant individuals: Preliminary findings from a pharmaco-fMRI study.

The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder.

"Extreme emotions" - the impact of reproductive life events for women living with bipolar disorder.

Little is known about how women with bipolar disorder construct and experience reproductive life events across the lifespan. We analyzed qualitative data from 29 semi-structured interviews with women aged 22-63 years (reproductive, menopause and post-menopause phases) using thematic analysis through a social constructionist framework. Themes of "Losing a sense of self-agency and self-worth" contained accounts of feeling out of control because of both bipolar disorder and reproductive life events. "Building a sense of personal autonomy and positive self-image" included accounts of acceptance and management of mood change over time, particularly for women in menopause and post-menopause life phases.

Quality of life and psychological symptoms for women with bipolar disorder - a comparison between reproductive, menopause transition and post-menopause phases.

OBJECTIVE: The menopause transition may be associated with increased symptoms for women living with bipolar disorder; however, few have explored how this compares with other reproductive phases. The aim of this study was to compare women at reproductive, menopause transition and post-menopause phases on measures of quality of life and psychological symptoms associated with bipolar disorder. STUDY DESIGN: Women with bipolar disorder took part in a large international survey conducted online and were categorised into reproductive stages using the STRAW and Monash criteria. The 498 participants were divided into three groups: 202 (41%) in the reproductive age group, 101 (20%) in the menopause transition group and 195 (39%) in the post-menopause group. MAIN OUTCOME MEASURES: The Menopause Rating Scale (MRS), the Depression Anxiety and Stress Scales - 21 (DASS-21), the Altman Mania Rating Scale (ASRM) and the Bipolar Disorder Quality of Life scale (BD-QoL). RESULTS: BD-QoL scores were significantly lower in the menopause transition group than in the other groups and that group was more likely to report being constantly depressed over the past year than the other groups. Anxiety was significantly higher in the menopause transition and post-menopause groups compared with the reproductive age group. CONCLUSIONS: Quality of life and depression are impacted by the menopause transition for women with bipolar disorder. However, anxiety may be a clinical issue for women in both the post-menopause and the menopause transition phases. Research is needed to determine how symptoms vary across the reproductive life cycle for women with bipolar disorder and if targeted treatments may assist.

Moderation of baclofen response by a GABAB receptor polymorphism: results from the BacALD randomized controlled trial.

BACKGROUND AND AIMS: Baclofen has been shown to reduce alcohol consumption in alcohol-dependent individuals, but there is marked heterogeneity in response. An association between GABBR1 rs29220 and alcohol dependence has been demonstrated previously. The present study evaluated whether the response to baclofen is moderated by a single nucleotide polymorphism (rs29220) in the GABAB receptor subunit 1 gene (GABBR1). DESIGN: Double-blind, placebo-controlled study. SETTING: Australia. PARTICIPANTS: Seventy-two alcohol-dependent men and women receiving 12 weeks of 30 mg/day of baclofen, 75 mg baclofen or placebo. MEASUREMENTS: Primary outcomes included time to lapse (any drinking) and relapse (> 5 drinks per day in men and > 4 in women). We also examined alcohol consumption at follow-up (drinks per drinking day, number of heavy drinking days and percentage days abstinent). FINDINGS: We observed significant medication × genotype interaction effect for time to relapse (P = 0.049) and a near-significant interaction effect for time to lapse (P = 0.055). For the CC genotype group, the relapse hazard ratio for baclofen versus placebo was 0.32 [95% confidence interval (CI) = 0.14-0.75] and for the G- group it was 1.07 (95% CI = 0.43-2.63). There was also a significant medication × genotype interaction for follow-up alcohol consumption (drinks per drinking day, heavy drinking days and days abstinent) (P = 0.02). Covarying for baseline levels of craving, aspartate aminotransferase and abstinence before enrolment reduced the medication × genotype effect for time to lapse and relapse but not for alcohol consumption at follow-up. CONCLUSIONS: The GABBR1 rs29220 polymorphism may influence treatment response and possibly predict adverse effects to baclofen in the treatment of alcohol dependence.

Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD).AimsTo conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125). METHOD: Patients (n = 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (≥5 drinks per day in men and ≥4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent. RESULTS: There was a significant effect of baclofen (composite groups) on time to lapse (χ2 = 6.44, P<0.05, Cohen's d = 0.56) and relapse (χ2 = 4.62, P<0.05, d = 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%; P<0.05). There was one serious adverse event (overdose) directly related to medication (75 mg). CONCLUSIONS: Baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services.Declaration of interestNone.