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Background: Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence., Methods: Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study., Results: Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence., Conclusions: These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: Relatively few studies have examined gender differences in the effectiveness of specific behavioral or pharmacologic treatment of alcohol dependence. The aim of this study is to assess whether there were gender differences in treatment outcomes for specific behavioral and medication treatments singly or in combination by conducting a secondary analysis of public access data from the national, multisite NIAAA-sponsored COMBINE study., Methods: The COMBINE study investigated alcohol treatment among 8 groups of patients (378 women, 848 men) who received medical management (MM) with 16 weeks of placebo, naltrexone (100 mg/day), acamprosate (3 g/day), or their combination with or without a specialist-delivered combined behavioral intervention. We examined efficacy measures separately for men and women, followed by an overall analysis that included gender and its interaction with treatment condition in the analyses. These analyses were performed to confirm whether the findings reported in the parent trial were also relevant to women, and to more closely examine secondary outcome variables that were not analyzed previously for gender effects., Results: Compared to men, women reported a later age of onset of alcohol dependence by approximately 3 years, were significantly less likely to have had previous alcohol treatment, and drank fewer drinks per drinking day. Otherwise, there were no baseline gender differences in drinking measures. Outcome analyses of 2 primary (percent days abstinent and time to first heavy drinking day) and 2 secondary (good clinical response and percent heavy drinking days) drinking measures yielded the same overall pattern in each gender as that observed in the parent COMBINE study report. That is, only the naltrexone by behavioral intervention interaction reached or approached significance in women as well as in men. There was a naltrexone main effect that was significant in both men and women in reduction in alcohol craving scores with naltrexone-treated subjects reporting lower craving than placebo-treated subjects., Conclusions: This gender-focused analysis found that alcohol-dependent women responded to naltrexone with COMBINE's Medical Management, similar to the alcohol-dependent men, on a wide range of outcome measures. These results suggest that clinicians can feel comfortable prescribing naltrexone for alcohol dependence in both men and women. In this study, it is also notable that fewer women than men reported receiving any alcohol treatment prior to entry into the COMBINE study. Of note, women tend to go to primary health care more frequently than to specialty substance abuse programs for treatment, and so the benefit we confirm for women of the naltrexone and MM combination has practical implications for treating alcohol-dependent women., (Copyright © 2010 by the Research Society on Alcoholism.)

Background: This study evaluated the efficacy of quetiapine versus placebo as an adjunct to lithium or divalproex in reducing alcohol consumption in patients with bipolar I disorder and coexisting alcohol dependence., Methods: Male and female outpatients (21 to 60 years) with a history of bipolar I disorder and alcohol dependence were included in this 12-week, placebo-controlled study. Patients treated with lithium or divalproex (ongoing or assigned at screening) were randomized to receive quetiapine (dosed up to 400 mg/d over 7 days, followed by 300 to 800 mg/d flexible dosing until study end) or placebo. The primary outcome measure was the change in the proportion of heavy drinking days from baseline to Week 12 (as derived from the Timeline Followback method). Secondary outcome measures included time to the first consecutive 2 weeks of abstinence, changes from baseline to Week 12 in the proportion of nondrinking days, mean number of standardized drinks per day, and Clinical Global Impressions-Severity of Illness score., Results: Of 362 enrolled patients (mean 38.6 years), 176 were randomized to receive quetiapine and 186 to placebo. The mean proportion of heavy drinking days at baseline was 0.66 in the quetiapine group and 0.67 in the placebo group. At Week 12, the mean change in the proportion of heavy drinking days was -0.36 with quetiapine and -0.36 with placebo (p = 0.93). No statistically significant differences in any of the secondary outcome measures were noted between the quetiapine and placebo groups. The incidence of adverse events was consistent with the previously known tolerability profile of quetiapine., Conclusions: The efficacy of quetiapine in the treatment of bipolar disorder is already well established. In this study, however, quetiapine added to lithium or divalproex did not result in significantly greater improvement compared with placebo in measures of alcohol use and dependence in patients with bipolar I disorder and alcohol dependence., (Copyright © 2010 by the Research Society on Alcoholism.)

Background: Extended-release naltrexone (XR-NTX) is a once-a-month injectable formulation for the treatment of alcohol dependence previously shown to reduce drinking and heavy drinking relative to placebo (Garbutt et al., 2005). A 24-week, randomized, double-blind, placebo-controlled study established the efficacy and safety of XR-NTX in this patient population. In this report, the effect of XR-NTX on quality of life (QOL) was examined., Methods: Alcohol-dependent patients were randomly assigned to receive XR-NTX 380 mg (N = 205), XR-NTX 190 mg (N = 210), or placebo (N = 209), combined with a standardized psychosocial intervention. QOL was assessed using the Medical Outcomes Study 36-item short-form health survey, administered at baseline and at 4-week intervals during 24 weeks of treatment., Results: Compared with U.S. population norms, patients showed initial impairment in the health-related QOL domains of mental health, social functioning, and problems with work or other daily activities due to emotional problems. Adherence to all 6 injections was 65% for XR-NTX 190 mg, 63% for XR-NTX 380 mg, and 64% for placebo. Generalized estimating equations analyses using an intention-to-treat sample revealed that XR-NTX 380 mg was associated with significantly greater improvements from baseline in mental health (p = 0.0496), social functioning (p = 0.010), general health (p = 0.048), and physical functioning (p = 0.028), compared with placebo. Linear regression analyses revealed that reductions from baseline in drinking (percentage of drinking days and percentage of heavy drinking days in the last 30 days) were significantly (p < 0.05) correlated with improvements in quality of life., Conclusion: Extended-release naltrexone 380 mg in combination with psychosocial intervention was associated with improvements in QOL, specifically in the domains of mental health, social functioning, general health, and physical functioning.

Background: This study investigated whether subgroups of alcohol-dependent patients responded differently to naltrexone versus placebo in the NIAAA COMBINE study. In particular, the A versus B and the Early Onset versus Late Onset typologies were examined. Relative to Type A alcoholics, Type B alcoholics are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders., Methods: COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI., Results: Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology., Conclusions: In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a MM model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment.

Background: Within the alcoholism field, there is mounting evidence supporting an important relationship between medication adherence and drinking outcomes. Little is known however, about the complex relationships between medication and treatment variables and drinking outcomes. The present paper reports on the differential impact of medication adherence and treatment factors on drinking outcomes. Data derived from the COMBINE Study was used to investigate the interrelationships between medication adherence, combination treatments and drinking outcomes., Methods: Twelve hundred and twenty-six patients were randomized to 1 of 8 different combination treatments involving 2 medications--naltrexone and acamprosate and placebo, and 2 behavioral treatments--medical management (MM) and combined behavioral intervention (CBI). Two primary drinking outcomes were percent days abstinent (PDA) and time to first heavy drinking day. Medication adherence was defined as a proportion that reflects the number of pills taken by the maximum number of pills expected to be taken over the course of the trial. A generalized linear mixed model was used to estimate the effects of adherence on PDA while proportional hazards model was used to examine similar co-variate effects on time to first heavy drinking day., Results: Concerning time to first heavy drinking day, a significant three-way interaction was found between medication adherence, CBI and naltrexone (p = 0.0160). Within the MM only plus placebo group (no CBI), significant differences were found in "recovery" (i.e., no heavy drinking days) rates between adherers and nonadherers (40% vs. 10%, p < 0.0001). Such differences became nonsignificant (p = 0.12) when CBI was introduced into the relationship. CBI did not add any such advantage to naltrexone-treated patients., Conclusions: CBI might serve a protective function for nonadherers in the placebo group; the median relapse time was reduced when these nonadherers were exposed to the alcohol specialty intervention. CBI offered little additional benefit to nonadherers in the naltrexone group. Among nonadherers in the naltrexone group, relapse rates appear to be more a function of inadequate exposure to the active medication and less influenced by CBI.

Background: Naltrexone is approved for the treatment of alcohol dependence when used in conjunction with a psychosocial intervention. This study was undertaken to examine the impact of 3 types of psychosocial treatment combined with either naltrexone or placebo treatment on alcohol dependency over 24 weeks of treatment: (1) Cognitive-Behavioral Therapy (CBT) + medication clinic, (2) BRENDA (an intervention promoting pharmacotherapy) + medication clinic, and (3) a medication clinic model with limited therapeutic content., Methods: Two hundred and forty alcohol-dependent subjects were enrolled in a 24-week double-blind placebo-controlled study of naltrexone (100 mg/d). Subjects were also randomly assigned to 1 of 3 psychosocial interventions. All patients were assessed for alcohol use, medication adherence, and adverse events at regularly scheduled research visits., Results: There was a modest main treatment effect for the psychosocial condition favoring those subjects randomized to CBT. Intent-to-treat analyses suggested that there was no overall efficacy of naltrexone and no medication by psychosocial intervention interaction. There was a relatively low level of medication adherence (50% adhered) across conditions, and this was associated with poor outcome., Conclusions: Results from this 24-week treatment study demonstrate the importance of the psychosocial component in the treatment of alcohol dependence. Moreover, results demonstrate a substantial association between medication adherence and treatment outcomes. The findings suggest that further research is needed to determine the appropriate use of pharmacotherapy in maximizing treatment response.

Background: Evidence supporting the use of serotonergic medications for the treatment of alcohol dependence is available from studies where pharmacotherapy targeted specific alcoholic subtypes. We previously established with Babor's alcohol typology that type A "lower risk/severity" alcoholics (n = 55) had better treatment response to 14 weeks of sertraline (200 mg/day) than placebo, and this was not found for type B "higher risk/severity" alcoholics (n = 45). The purpose of this study was to assess in this original study group whether treatment gains in the type A alcoholics were maintained or whether treatment outcomes changed for the type B alcoholics after discontinuing pharmacotherapy., Methods: After the end of a 3-month course of 200 mg/day sertraline, the subjects were interviewed at several time points about their alcohol drinking, if any, using the timeline follow-back method. For 90% of the original study group, mixed effects and generalized estimating equation models were used to compare monthly drinking amounts over a 6-month posttreatment period with drinking amounts in the last month of treatment., Results: We found that type A alcoholics who had been treated with sertraline, in contrast to placebo, maintained the good outcomes they had achieved during treatment for at least 6 months after pharmacotherapy. We found that type B alcoholics who had been treated with sertraline, in contrast to placebo, continued to show no advantage for pharmacotherapy in the 6 months after completing treatment. In addition, heavy drinking in type B alcoholics increased over the 6 months postpharmacotherapy in those initially treated with sertraline compared with placebo., Conclusions: These data support the importance of considering alcohol subtype when pharmacologically treating alcohol dependence.

Background: Carbohydrate-deficient transferrin (CDT) is a biochemical marker that has been shown to be sensitive in detecting heavy drinking in men, but studies examining CDT in women have been inconsistent because of small sample sizes and failure to consider hormonal status. In healthy female subjects, CDT levels are significantly higher in premenopausal women with higher estradiol (E2) levels (>30 pg/ml) and those taking exogenous estrogens (oral contraceptives, hormone replacement therapy) compared with men and postmenopausal women. This study examined the relationship between drinking behavior and CDT levels in a large sample of alcohol-dependent women and contrasted findings in a comparison group of alcohol-dependent men. The study also examined the extent that E2 levels mediated the relationship between CDT levels and heavy drinking in the alcohol-dependent women., Methods: This study examined the association between CDT level at treatment entry and alcohol consumption the month before initiating treatment in 96 women with a DSM-III-R diagnosis of alcohol dependence, as compared with similar data in 123 male alcoholics. To explore the relationship between E2 and CDT, E2 was measured in women at the time of CDT sampling. Linear regression was used to examine whether patterns of alcohol consumption in the 28 days before the CDT blood sampling predicted the CDT level in women and men presenting for treatment for alcohol dependence., Results: CDT levels were higher in women than men and were related to quantitative alcohol consumption (total standard drinks, percentage of days drinking, percentage of days of heavy drinking) in the month before initiating treatment, irrespective of E2 levels in women., Conclusions: These results suggest that in a larger sample of female alcoholics, the amount of alcohol consumed predicted CDT, similar to what has been reported in male alcoholics. The E2 status did not seem to mediate these results.

Background: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline., Methods: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups., Results: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo., Conclusions: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Background: This study introduces the Penn Alcohol Craving Scale (PACS), which has been used in several clinical trials at the University of Pennsylvania's Treatment Research Center. The PACS is a five-item, self-report measure that includes questions about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of craving for alcohol for the previous week. Each question is scaled from 0 to 6., Methods: To examine the questionnaire's psychometric properties, we sampled responses from 147 individuals participating in a 9-month combined natrexone (100 mg/day)/psychotherapy trial. The psychotherapy consisted of weekly sessions of nurse-administered medication compliance and supportive treatment., Results: The PACS proved to have excellent internal consistency. Predictive validity was demonstrated via a logistic regression analysis of craving during the 2nd week of the study on alcohol relapse during weeks 3-12 of the trial. Construct validity of the PACS was demonstrated via its convergence with two commonly used measures for assessing craving, the Obsessive Compulsive Drinking Scale and the Alcohol Urge Questionnaire. Lack of correlation between PACS scores and several other noncraving, self-report measures indicates that the PACS also had good discriminant validity. Additional analyses revealed that there were significant differences in craving scores during the initial 3 weeks of the trial among those who did and those who did not relapse during weeks 3-12., Conclusion: The PACS is a reliable and valid measure of alcohol craving and can predict which individuals are at risk for subsequent relapse.

Carbohydrate-deficient transferrin (CDT) has received increasing attention as a potential biological marker for heavy drinking or as an objective marker of relapse in patients who are treated for alcohol dependence. Previous studies have demonstrated the utility of CDT among men, but there are fewer and inconsistent reports on the utility of CDT among women. This study reports in a sample of 40 alcohol-dependent women, the association between CDT levels, and several different types of measures of drinking intensity including frequency of heavy drinking. Although the majority of drinking indices correlated with CDT levels in men, among women, CDT levels were significantly correlated with the percentage of days of heavy drinking when heavy drinking day was defined as drinking 6 or more drinks per drinking day. The results also support an association between current menstrual function, CDT levels, and drinking indices. These findings suggest that the pattern of drinking (combining high frequency and high intensity) may be an important determinant of CDT levels in women with alcohol dependence, compared with men.

Unlabelled: Clinical profiles of alcohol-dependent male and female outpatients were evaluated at treatment entry to compare the level of clinical severity in alcoholics with a coexistent comorbid depressive disorder to alcoholics who have never been depressed. Due to a higher proportion of females than males in the depressed alcoholic population, selected patient groups were oversampled to create a study group with equivalent number of males and females with and without comorbid depression. Clinical severity was assessed by examining both the extent of alcohol problems, and depressive symptomatology at treatment entry with respect to gender differences (unrelated to depression), effects of comorbid depression (unrelated to gender), and effects from the interaction of gender and depression. There were 93 DSM-III-R alcohol-dependent outpatients (50 males, 43 females), half of whom had a current or lifetime DSM-III-R depressive disorder. The amount of drinking in the 90 days before treatment entry, the degree of alcohol severity, and the number of lifetime drinking-related consequences were collected in the first week after detoxification. Diagnoses of lifetime and current depression were determined via the Structured Clinical Interview for DSM-III-R, and depressive symptoms were evaluated with rating scales 1 week after detoxification. In most cases, a depressive disorder was diagnosed only if sometime in the patient's history depressive symptoms had either predated problem drinking or been present during a 6-month abstinent period., Results: depressed males had a more severe clinical profile with respect to their alcoholism (i.e., more drinking, drinking-related problems, and alcohol severity than depressed females and never-depressed males). Surprisingly, females who had never been depressed (also no family history of depression) reported drinking the same quantities of alcohol in the 90 days before treatment and had comparable alcohol severity and number of consequences as males who had never been depressed. Depressed females, however, were more severely depressed (i.e., reported more intensive depressive symptoms than depressed male alcoholics). Thus, determining the type and extent of clinical severity at treatment entry in comorbidly depressed alcoholics depends on the gender of the patient The significant interaction between gender and the presence of comorbid depression that was found in this study may have important implications for predicting success in treatment.

This study presents a review of existing human studies that examine the role of serotonin [5-hydroxytryptamine (5-HT)] selective agents in the treatment of alcohol dependence. Findings of abnormally low 5-HT levels in many alcohol-dependent patients led investigators to explore the use of 5-HT selective pharmacotherapy in the treatment of alcoholism. Several studies reported that the administration of 5-HT selective pharmacological agents to alcohol-dependent patients effectively reduced alcohol intake, although results have been relatively modest. The most recent study by Kranzler et al. (Am. J. Psychiatry 152:391-397, 1995) found no added benefit over cognitive-behavioral treatment. However, the original relationship between the presence of alcohol dependence and low 5-HT levels in the brains of patients with alcoholism was predicated on subtypes of alcohol dependence. Research has suggested that 5-HT plays an important role in some forms of alcoholism that may be genetically or developmentally mediated. Thus, additional studies are needed to determine if treatment with 5-HT selective agents is viable therapeutic option for alcoholism, specifically in types of alcohol-dependent patients who are most likely to benefit from treatment with 5-HT selective pharmacotherapy.

Managed healthcare has had a major impact on the delivery of alcohol and drug abuse treatment services in the private setting, primarily by shifting patient enrollment from inpatient to outpatient treatment programs. The purpose of this study was to investigate the natural history of outpatient alcohol and drug abuse treatment in a private, nonprofit healthcare setting. Patient profiles at pretreatment, their attendance record in a 6-week outpatient program, and their outcome in the year after treatment were evaluated in 120 patients with a DSM-III-R diagnosis of alcohol and/or cocaine dependence. There were 70 outpatients who successfully completed the program, and 50 who did not. Two subtypes of outpatient treatment failures were identified: S5 who prematurely left treatment against medical advice (n = 23), and S8 who attended treatment but continued heavy use of substances (Treatment Resistant, n = 27). A logistic regression revealed that younger age, multiple prior treatments, and employment problems were related to outpatient treatment failure. Outpatient failures did not immediately seek alternative treatment, and most of them continued heavy substance use in the year post-treatment: i.e., 82% vs. 43% successful completers (chi 2 = 13.8, df = 1, p < 0.01). Thus, there were a clinically relevant number of outpatient failures (42%), either because of lack of program attendance or continued substance use throughout treatment. These behaviors were related to continued heavy use of substances in the year after treatment.

Alcoholic patients completed the Minnesota Multiphasic Personality Inventory (MMPI) while hospitalized for treatment and again after 4 years of follow-up. Those who remained abstinent and functioned well in the community for the 4-yr period were characterized during treatment by a significant elevation on the Depression (D) scale which decreased to normal ranges at follow-up. Those who continued to drink periodically over the 4-yr period had initial peaks on Psychopathy (Pd) and Hypomania (Ma) which were still elevated at follow-up. An intermediate group who were usually abstinent during the 4-yr period but had occasional relapses showed elevations on D and Pd during treatment with return to normal levels at follow-up.

Retrospective and outcome data were examined for 48 homemaking and 24 working women who came for treatment for alcoholism to an Addiction Recovery Unit at an inpatient psychiatric hospital. Outcome was assessed at the end of each of 4 years following treatment via personal interview by an experienced social worker and was corroborated by at least one source. At admission, the homemakers had been drinking for significantly more years (p less than 0.05) than working women. Occupation at admission did not directly relate to outcome. However, for a small subgroup comprised of both homemaking and working women, a change in occupation following treatment was associated with improvement.