Patricia K. Latham

Sertraline and cognitive behavioral therapy for depressed alcoholics: Results of a placebo-controlled trial

Alcoholism and depression are common disorders that frequently cooccur in the same individual. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and also had decreased drinking in some studies of heavy drinkers and alcoholics. The reported effect of serotonergic medications on alcohol intake in depressed alcoholics has not been consistent. Most previous studies have not investigated the use of an SSRI in the context of cognitive behavioral therapy (CBT), a known efficacious treatment of both alcoholism and depression. The study presented here was a randomized placebo-controlled 12-week trial of sertraline combined with individual CBT focused on both alcoholism relapse prevention and depressive symptoms. Subjects were 82 currently depressed, actively drinking alcohol-dependent individuals. Subjects had either primary (independent) major depression (70 subjects) or substance-induced mood disorder and at least 1 first-degree relative (parent, sibling, or child) with an affective disorder (12 subjects). Depression and alcohol consumption outcomes were measured weekly over 12 weeks. Sertraline was well tolerated and all subjects had decreases in both depression and alcohol use during the study compared with baseline. Subjects who received sertraline had fewer drinks per drinking day than subjects who received placebo, but other drinking outcomes were not different between the 2 treatment groups. Treatment with sertraline was associated with less depression at the end of treatment in female subjects compared with female subjects who received placebo. Less drinking during the study was associated with improved depression outcome. The findings in this study suggest that sertraline, compared with placebo, may provide some modest benefit in terms of drinking outcome and also may lead to improved depression in female alcohol-dependent subjects. Additionally, alcohol relapse prevention CBT, delivered according to manual guidelines with modifications that provide specific attention to depression, appeared to be of benefit to subjects, although this interpretation is limited by the design of the study.

Naltrexone combined with either cognitive behavioral or motivational enhancement therapy for alcohol dependence.

Abstract: Although naltrexone has been shown to be effective in the treatment of alcohol dependence, less is known about its efficacy when combined with different behavioral therapies. Previous work has suggested that naltrexone works best when combined with weekly cognitive behavioral therapy (CBT). This study examined the efficacy of naltrexone when combined with CBT or a motivational enhancement therapy involving less patient contact. Outpatient alcoholics (N = 160) were randomly assigned to either naltrexone (50 mg/d) or placebo and either CBT (12 sessions) or motivational enhancement therapy (4 sessions), in a 4-cell design, and treated over a 12-week period. Subjects were evaluated periodically for alcohol consumption, craving, and biologic markers of drinking (carbohydrate-deficient transferrin and γ-glutamyltransferase). There was high retention and adherence to therapy and medication in the trial with no significant difference across the treatment groups. Naltrexone, independent of therapy assignment, increased the time to first relapse. However, the CBT-naltrexone group did better than the other groups on a variety of outcome measures. Fewer CBT-naltrexone-treated subjects relapsed, and those that did had both fewer, and more time between, subsequent relapses. This randomized controlled trial is consistent with previous reports about the utility of combining naltrexone with CBT. Despite being more efficient to administer, the combination of motivational enhancement therapy and naltrexone is less effective than CBT and naltrexone. Because CBT and naltrexone share common mechanisms of action, such as craving reduction and relapse prevention, these therapies are likely to be well suited to use in combination.

Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence

OBJECTIVE Naltrexone, an efficacious medication for alcohol dependence, does not work for everyone. Symptoms such as insomnia and mood instability that are most evident during early abstinence might respond better to a different pharmacotherapy. Gabapentin may reduce these symptoms and help prevent early relapse. This clinical trial evaluated whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo during the early drinking cessation phase (first 6 weeks), and if so, whether this effect persisted. METHOD A total of 150 alcohol-dependent individuals were randomly assigned to a 16-week course of naltrexone alone (50 mg/day [N=50]), naltrexone (50 mg/day) with gabapentin (up to 1,200 mg/day [N=50]) added for the first 6 weeks, or double placebo (N=50). All participants received medical management. RESULTS During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone-alone group and the placebo group. These differences faded over the remaining weeks of the study. Poor sleep was associated with more drinking in the naltrexone-alone group but not in the naltrexone-gabapentin group, while a history of alcohol withdrawal was associated with better response in the naltrexone-gabapentin group. CONCLUSIONS The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first 6 weeks after cessation of drinking. This effect did not endure after gabapentin was discontinued.

Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism.

Naltrexone, an opiate antagonist medication, has been reported to be efficacious in the treatment of alcohol dependence when added to psychosocial treatments. Although the within-treatment efficacy of naltrexone has received primary attention, there has been little published on the outcome of individuals once the medication is discontinued. Animal studies have led to concern regarding a quick rebound to heavy drinking. This report extends the data previously reported by evaluating the outcome in alcoholic subjects during the 14 weeks after a 12-week treatment with naltrexone or placebo in conjunction with cognitive behavioral therapy. Of the 131 subjects evaluated during the treatment phase, 124 (95%) had up to 14 weeks of posttreatment drinking data available for analysis. Measures of craving and blood markers of heavy drinking were also evaluated. By the end of treatment, naltrexone demonstrated significantly greater efficacy than placebo. However, once the medication was discontinued, there was a gradual increase in relapse rates, heavy drinking days, and drinks per drinking day, and fewer days of abstinence were reported. By the end of the 14-week follow-up period, although naltrexone-treated subjects were, on average, still doing better than control subjects, the effectiveness of naltrexone was no longer statistically significant. There was no evidence that naltrexone subjects had an immediate return to heavy alcohol use as suggested in animals. These data suggest that, for a number of alcoholic subjects, continued treatment with naltrexone, or perhaps psychosocial intervention, for longer than 3 months is indicated. Future research should identify which alcohol-dependent individuals may need prolonged treatment to improve treatment success in the long term.

Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms.

Improved treatment of alcohol dependence is a high priority, including defining subtypes that might respond differently. We evaluated a medication combination of intravenous flumazenil (FMZ) and oral gabapentin (GBP) in alcoholics who did and did not exhibit pretreatment alcohol withdrawal (AW) symptoms. Sixty alcohol-dependent individuals (44 with low AW and 16 with high AW) were randomized to receive FMZ (2 mg of incremental bolus for 20 minutes for 2 consecutive days) and GBP (up to 1200 mg nightly for 39 days) or their inactive placebos. Alcohol withdrawal was measured for the first 2 days, and drinking, sleep parameters, and adverse events were monitored during weekly evaluations, along with behavioral counseling sessions. Percent days abstinent (PDA) during treatment and time to first heavy drinking (TFHD) day were primary outcome variables. There was an interaction between the pretreatment AW status and the medication group on PDA (P = 0.0006) and TFHD (P = 0.06). Those in the high AW group had more PDA and more TFHD if treated with active medications, whereas those in the low AW group had more PDA and more TFHD if treated with placebo. This interaction remained for those totally abstinent (P = 0.03) and was confirmed by percent carbohydrate-deficient transferrin values. In addition, the pattern of response remained up to 8 weeks after treatment. In addition, in those with high AW, greater improvement in AW symptoms was observed in the active medication group compared with the placebo group. These results suggest a differential response to FMZ/GBP treatment, depending on pretreatment AW status that should be taken into account during future treatment trials.

Psychosocial and psychopathology differences in hospitalized male and female cocaine abusers: a retrospective chart review.

While considerable amounts of psychological and pharmacological data have been collected on male substance abusers in public treatment facilities, relatively little information is available about the psychosocial characteristics of men in private treatment settings and of women presenting for substance abuse treatment. The present study reviewed the records of 100 male and female cocaine abusers admitted to a private substance abuse treatment program between 1987 and 1989. Patterns of cocaine use and levels of impairment were found to be similar for men and women, with male cocaine abusers more likely to abuse additional substances. Male cocaine abusers were employed more frequently than women and held higher status jobs despite equivalent levels of education. Female cocaine abusers were more likely to be diagnosed with concurrent psychiatric disorders and were more likely to report family histories of substance abuse. Both groups produced elevations on MMPI scales indicating depression, anxiety, paranoid features, and acting-out tendencies. These data suggest that while male and female cocaine abusers show similarities on some measures, there are significant gender differences that may have implications for both research and treatment.

Blood pressure reduction during treatment for alcohol dependence: results from the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study.

AIMS Heavy drinking is associated with hypertension. This study evaluated blood pressure changes occurring during treatment for alcohol dependence. PARTICIPANTS Subjects included 1383 people participating in the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study, a large multi-center treatment study for alcohol dependence. MEASUREMENTS Methods appropriate for repeated-measures data were used to assess the relationship of percentage of drinking days (PDD) to systolic and diastolic blood pressure over a 16-week treatment period. Modification of these associations by demographic and other variables was assessed. FINDINGS Blood pressure reduction was evident only in people who were above the median blood pressure at baseline. In this group, systolic blood pressure decreased by an average of 12 mmHg and diastolic blood pressure decreased by an average of 8 mmHg. Blood pressure reduction occurred during the first month of treatment. This effect was similar regardless of age, sex, body mass index, reported history of hypertension and use of anti-hypertensive medications. An observed association between blood pressure and PDD in Caucasians was not evident in African Americans due largely to their lower pre-treatment blood pressure. CONCLUSIONS Reduction in alcohol consumption has a potent anti-hypertensive effect in alcoholics with higher blood pressure. For hypertensive, alcohol-dependent people, treatment for alcoholism should be considered a major component of anti-hypertensive therapy.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status

Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50 mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.

Neurocognitive performance, alcohol withdrawal, and effects of a combination of flumazenil and gabapentin in alcohol dependence.

BACKGROUND Among some alcohol-dependent individuals, early alcohol abstinence is marked by alcohol withdrawal (AW), a phenomenon mediated by GABA and glutamate signaling. We previously reported that a combination of 2 medications that affect GABA and glutamate tone, gabapentin and flumazenil, more effectively reduced drinking among individuals with higher pretreatment AW (Anton et al., 2009). This study evaluated whether this finding is related to changes in neurocognitive performance, which is also affected by cortical GABA and glutamate tone. METHODS Neurocognitive performance was assessed at baseline and twice during the first week of treatment among 60 alcohol-dependent participants in the previously published clinical trial. RESULTS AW was associated with poorer baseline performance on 4 of 8 measures, and individuals with higher baseline AW who received the gabapentin and flumazenil combination demonstrated greater improvement on a measure of response inhibition than those with lower AW or those who received a combination of placebos. Improvement in response inhibition during the first week and medication group interacted in their effect on subsequent drinking, such that improvement predicted greater abstinence only among individuals who received gabapentin and flumazenil. Improvement on other neurocognitive measures was neither differentially impacted by medication or baseline AW nor related to subsequent drinking. CONCLUSIONS Taken together, these data suggest that acute AW accounts for a small proportion of variance in neurocognitive performance, that gabapentin and flumazenil slightly improve response inhibition during early abstinence, and that such improvement may somewhat reduce later drinking. However, these medications may not affect other neurocognitive domains.