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.

The efficacy of behavioural activation treatment for co-occurring depression and substance use disorder (the activate study): a randomized controlled trial.

BACKGROUND: Epidemiological studies suggest that compared with the general population, mood disorders are up to 4.7 times more prevalent in substance dependent samples. Comorbid substance use disorder (SUD) and depression has been associated with a more severe and protracted illness course and poorer treatment outcomes. Despite this, the development and assessment of behavioural interventions for treating depression among individuals with SUDs have received little empirical attention. Behavioural Activation Treatment for Depression (BATD-R) is an empirically supported treatment for depression that has shown some efficacy among substance users. This paper describes the study protocol of a parallel, single blind, randomised controlled trial to determine the efficacy and feasibility of a modified version of the BATD-R (Activate) in reducing symptoms of depression and substance dependence among individuals in residential rehabilitation (RR) and opioid substitution therapy (OST). METHODS/DESIGN: A sample of approximately 200 individuals with depressive symptomatology in treatment for SUD will be recruited from RR and OST services in New South Wales, Australia. Dynamic random allocation following minimisation methodology will be used to assign participants to one of two groups. The control group will receive treatment as usual (TAU), which will be the model of care provided in accordance with standard practice at participating RR and OST services. The intervention group will receive Activate, comprising 10 individual 60-min therapy sessions with a psychologist employed on the research team, in addition to TAU. Data collection will occur at baseline (pre-intervention), and 3-months and 12-months post baseline. DISCUSSION: The association between depression and substance dependence has been well documented, yet practical and effective treatments are scarce. The findings of the present study will contribute significantly to understanding the types of programs that are effective in treating this comorbidity. TRIAL REGISTRATION: This trial is registered with the Australian and New Zealand Clinical Trials registry, ACTRN12613000876796 . Registered on 7 August, 2013.

Treatment Resistant and Resistant to Treatment? Evaluation of 40 Alcohol Dependent Patients Admitted for Involuntary Treatment.

AIMS: To describe the clinical outcomes for a group of patients with severe alcohol dependence discharged from an Involuntary Drug and Alcohol Treatment (IDAT) program. METHODS: Forty patients admitted to an inpatient IDAT program were prospectively followed up over 6 months using standardized questionnaires. RESULTS: Patients had high rates of mental health comorbidities (97.5%), cortical atrophy (40%) and socioeconomic disadvantage (92.5% were beneficiaries). Six months after discharge, 25% of patients were abstinent and living in the community and 17.5% had notably reduced alcohol use. A further 7.5% were abstinent due to involuntary hospitalization. A total of 10% of patients were deceased and 40% of patients had relapsed or were lost to follow-up. Number of admissions and admission days reduced by 51 and 45% respectively for the 17 abstinent or improved community-based patients. A total of 82% of this patient group were actively engaged with an Assertive Community Treatment (ACT) team. CONCLUSIONS: While patient numbers are small, treatment responsiveness was evident for 42.5% of patients, most of whom were followed up with ACT. Evaluation with a comparator group is required to determine whether outcomes are a function of involuntary treatment or an assertive treatment approach.

Cognitive dysfunction and functional disability in alcohol-dependent adults with or without a comorbid affective disorder.

INTRODUCTION: Little is known about the relationship between cognitive dysfunction and functional disability in alcohol dependence with comorbid affective disorders. We investigated the neuropsychology of alcohol dependence in detoxified adults with and without affective comorbidity and examined the factors associated with prolonged functional disability. METHODS: From a total of 42 participants (age range = 18-44 years), 12 out of 21 alcohol-dependent participants had a comorbid affective disorder, 12 had an affective disorder only, and 9 were healthy controls. Participants completed a semi-structured clinical interview, questionnaires and comprehensive neuropsychological assessment. RESULTS: Following detoxification (median = 35 days; M = 41.2 days, SD = 17.9), visual learning and memory functioning was worse in alcohol-dependent individuals. Comorbid affective disorders did not appear to exacerbate cognitive dysfunction. Psychiatric comorbidity and current depressive symptoms were predictive of poorer functional disability. Furthermore, learning and memory, and response inhibition, contributed significantly and independently to predicting functional disability over and above clinical and demographic factors. CONCLUSIONS: Psychiatric comorbidity does not appear to be associated with more pronounced neuropsychological dysfunction in alcohol dependence. Conversely, both comorbid affective disorders and cognitive factors were critical in determining the functional outcomes of alcohol-dependent adults recently undergoing medically supervised inpatient detoxification.

Sex as a Potential Moderator for Baclofen Response in the Treatment of Alcohol Dependence.

Background and Aims: Recent studies indicate that sex may moderate the response to baclofen in the treatment of alcohol use disorder (AUD). We conducted a secondary analysis of a double-blind randomized controlled trial, Baclofen in the treatment of Alcohol Liver Disease (BacALD), to examine the moderating role of sex on treatment response to baclofen in reducing alcohol consumption. Methods: Alcohol-dependent patients (n = 104 including 74 men and 30 women) were treated for 12 weeks with baclofen (30 mg/day or 75 mg) or placebo. Predefined primary outcomes included time to lapse (any drinking) and relapse (≥ 5 drinks per day in men and ≥ 4drinks per day in women). Other outcomes included drinks per drinking day, the number of heavy drinking days, and percentage of days abstinent. We also examined the frequency of adverse events with an exploratory dose-response analysis. Results: There was a main effect of baclofen for days to first lapse for women (Log Rank: χ2 = 6.23, p = 0.01, d = 0.49) but not for men (Log Rank: χ2 = 2.48, p = 0.12, d = 0.22) and a marginal effect of baclofen for days to first relapse for women (Log Rank: χ2 = 3.15, p = 0.08, d = 0.27) but not for men (Log Rank: χ2 = 2.03, p = 0.16, d = 0.17). There were no significant effects of sex on the frequency of adverse events reported for the combined-dose or between-dose analysis (all p > 0.44). Conclusion: Baclofen significantly delayed the time to lapse for women but not male participants. These findings provide some support for the hypothesis that sex may be a potential moderator of baclofen response in the treatment of AUD. Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01711125, identifier: NCT01711125.

In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation.

AIMS: To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients. METHODS: Human liver microsomes (n= 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ-RISP combination (n= 10 per group). RESULTS: (i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance. CONCLUSIONS: No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition.

Baclofen Response in Alcohol Dependent Patients Concurrently Receiving Antidepressants: Secondary Analysis From the BacALD Study.

Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients. Methods: Alcohol dependent patients (N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events. Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen × AD (Log Rank: χ2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15-1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen × AD (Log Rank: χ2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01-11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions (P's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported (P's > 0.19). Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required. Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125.

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.

Therapy preference and treatment outcome in clients with mild to moderate alcohol dependence.

The Brief Treatment Programme for Alcohol Dependence allocated 122 clients randomly to three different forms of brief therapy. Prior to allocation clients were asked what their preference would have been had allocation not been random. This study posed the question: did clients receiving their preferred treatment have a better outcome than those who did not? Also examined were differences in the treatment process variables of perceived effectiveness, satisfaction, rapport, engagement and number of sessions attended. The results were that there was no difference in either outcome or treatment process according to whether or not clients were allocated to their treatment of preference. It is concluded that these findings reinforce both the ethicality of the randomized controlled trial as a methodology for examining differential treatment outcomes in individual brief treatment of between one and five sessions for alcohol dependence and the validity of these findings as they might relate to real clinical settings. Finally, it is suggested that other researchers consider the inclusion of questions related to client preference.

Substance misuse in patients with schizophrenia: epidemiology and management.

Substance misuse in individuals with schizophrenia is very common, especially in young men, in communities where use is frequent and in people receiving inpatient treatment. Problematic use occurs at very low intake levels, so that most affected people are not physically dependent (with the exception of nicotine). People with schizophrenia and substance misuse have poorer symptomatic and functional outcomes than those with schizophrenia alone. Unless there is routine screening, substance misuse is often missed in assessments. Service systems tend to be separated, with poor inter-communication, and affected patients are often excluded from services because of their comorbidity. However, effective management of these disorders requires a fully integrated approach because of the close inter-relationship of the disorders. Use of atypical antipsychotics may be especially important in this population because of growing evidence (especially on clozapine and risperidone) that nicotine smoking, alcohol misuse and possibly some other substance misuse is reduced. Several pharmacotherapies for substance misuse can be used safely in people with schizophrenia, but the evidence base is small and guidelines for their use are necessarily derived from experience in the general population.

The feasibility and acceptability of a brief intervention for clients of substance use services experiencing symptoms of post traumatic stress disorder.

BACKGROUND: Trauma exposure and post traumatic stress disorder (PTSD) are common among clients of substance use services. Existing treatments for these co-occurring conditions tend to be lengthy, treatment retention is relatively poor, and they require extensive training and clinical supervision. The aim of the present study was to conduct a preliminary examination of the feasibility and acceptability of a brief intervention for PTSD symptoms among individuals seeking substance use treatment. METHODS: An uncontrolled open-label pilot study was conducted among 29 inpatients of a medicated detoxification unit in Sydney, Australia. All participants completed a baseline interview followed by the brief intervention. The intervention consists of a single, one-hour manualised session providing psychoeducation pertaining to common trauma reactions and symptom management. PTSD and substance use outcomes were assessed at 1-week, 1-month and 3-month post-intervention. RESULTS: PTSD symptom severity (assessed using the Clinicians Administered PTSD Scale) decreased significantly from baseline to 1-week follow up (ß -10.87, 95%CI: -19.75 to -1.99) and again between the 1-week and 3-month follow-ups (ß -15.38, 95%CI: -23.20 to -7.57). Despite these reductions, the majority of participants continued to meet criteria for a diagnosis of PTSD and there was no change in participants' negative post-traumatic cognitions. Participants expressed high levels of satisfaction with the intervention. CONCLUSIONS: Brief psychoeducation for traumatised clients attending substance use services appears to be feasible, acceptable, and may be of some benefit in reducing PTSD symptoms. However, participants continued to experience symptoms at severe levels; thus, brief intervention may best be conceptualised as a "stepping stone" to further trauma treatment.

Pathways to alcohol-induced brain impairment in young people: a review.

Classically, disorders associated with 'alcohol-related brain damage' (ARBD) occur as a result of chronic excessive alcohol misuse and confer significant physical and psychological disability to the individual as well as to the community. These phenotypes are often difficult to detect at early stages and therefore early intervention and treatment is limited. It remains unresolved as to whether there are neurobiological markers of the early stages of such brain damage in young 'at-risk' drinkers, who probably experience 'alcohol-induced brain impairment' prior to the onset of ARBD, per se. This review focuses on neurobiological (in particular, neuropsychological and neuroimaging) markers that are associated with alcohol misuse in young people (13-24 years of age). The findings from this review suggest that a clearer understanding of alcohol misuse (particularly with regards to binge drinking) is needed. Despite this, neurocognitive profile along with supporting neuroimaging evidence appears to be particularly important in the early detection of brain changes that result from excessive alcohol use. In young alcohol misusers, these preventable and potentially reversible deficits may be progressive but if left unresolved such deficits eventually become major contributors to poor outcome (long term) and hamper adherence to treatment. We address five key themes in this review: (i) there are specific drinking patterns in young people; (ii) youth represents a critical period in brain development that is particularly vulnerable to alcohol misuse; (iii) the extent to which there are pre-existing versus alcohol-induced neurobiological changes remains unclear; (iv) vulnerability markers may be mediated by mental health and substance use comorbidities; and (v) cognitive remediation would be a likely candidate for early prevention and treatment as it could help to develop efficient meta-cognitive skills to prevent relapse in young drinkers.

Post-traumatic stress disorder, depression and suicidality in inpatients with substance use disorders.

INTRODUCTION AND AIMS: The international literature suggests that traumatic events are common for patients with substance use disorders (SUDs), and are often associated with the development of post-traumatic stress disorder (PTSD) and other psychiatric comorbidities. However, limited research has been conducted among Australian SUD patients. The aim of the present study was to examine the prevalence of these disorders in a group of Australian patients admitted for detoxification. DESIGN AND METHODS: Data were collected from 253 inpatients using a modified version of the Composite International Diagnostic Interview, the 10-item Trauma Screening Questionnaire, the Zung Self-rating Depression Scale and questions from the PsyCheck. RESULTS: Approximately 20% of inpatients experienced moderate to severe depressive symptoms, and 37% had a lifetime history of self-harm or attempted suicide. Approximately 80% of patients had experienced at least one traumatic event, most experiencing multiple traumas. The mean age of first trauma was 14years. Almost 45% of patients screened positive for current PTSD symptoms. Women were nine times more likely to have been raped and five times more likely to have been sexually molested than men. PTSD symptoms were associated with greater trauma exposure, younger age of first trauma, specific trauma types, moderate to severe depressive symptoms and a history of self-harm or attempted suicide. Despite their difficulties, patients with PTSD symptoms had high rates of retention in treatment. DISCUSSION AND CONCLUSIONS: Patients entering treatment for SUDs should be assessed for PTSD, depression and suicidality. These conditions impact significantly on treatment outcomes, and require the development of appropriate treatment strategies.

Drug-induced psychosis associated with crystalline methamphetamine.

OBJECTIVE: A case of drug-induced psychosis related to crystalline methamphetamine is described, highlighting the phenomenology and relevant treatment. RESULTS: A 44-year-old woman with borderline personality traits and severe drug dependence developed a protracted drug-induced psychosis related to chronic high-dose crystalline methamphetamine use. Complete resolution of symptoms occurred with antipsychotic medication and abstinence from methamphetamine. Rapid recurrence of symptoms occurred at a time of high stress associated with minimal methamphetamine use and cessation of low-dose quetiapine. Symptoms rapidly resolved with abstinence, quetiapine and reduction of stressors. CONCLUSIONS: A drug-induced psychosis resembling paranoid schizophrenia can occur with repeated or high-dose use of methamphetamine. While this generally resolves rapidly with cessation of stimulant use, some cases of protracted drug-induced psychosis in vulnerable individuals have been documented. Behavioural sensitization can also occur, and neuroleptics may prevent the recurrence of further psychosis triggered by ongoing low-dose methamphetamine use.