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In the field of clinical alcohol disorders treatment in North America, abstinence continues to be largely viewed as the optimal treatment goal; however, there is a growing awareness of limitations when abstinence is considered the only successful outcome. Although this issue has been discussed in research settings, new studies on the public health significance of heavy drinking (defined as five or more standard drinks per drinking day in men, and four or more standard drinks per drinking day in women) in the past 10 years suggest that clinical providers should consider the value of alternative outcomes besides abstinence. A focus on abstinence as the primary outcome fails to capture the impact of treatment on reduction in the pattern and in the frequency of alcohol consumption. In addition, evaluating reduction in drinking as "positive" has value for patients as an indicator of clinical progress. Measurement of continuous variables, such as the quantity and the frequency of alcohol consumption, has provided a clearer understanding of the scope of alcohol-related morbidity and mortality at the societal level, and of the relationship between individual patient characteristics and the naturalistic course of alcohol use, abuse, and dependence. A review of these characteristics suggests that there are clinical benefits associated with reducing heavy drinking in alcohol-dependent patients. Given the significant public health consequences associated with heavy drinking and the benefits associated with its reduction, it is proposed that researchers, public health professionals, and clinicians consider using reduction in heavy drinking as a meaningful clinical indicator of treatment response, and that outcomes be individualized to patients' goals and readiness to change.

Background: In almost 2 decades of naltrexone research for treating alcoholism, there have been 29 published randomized placebo-controlled trials of opioid antagonists, primarily naltrexone, for the treatment of alcohol dependence. The present review builds on prior systematic reviews while maximizing the number of included studies to date, for the purpose of resolving inconsistencies in naltrexone's reported efficacy across trials. Clinical trial results in this article are evaluated by the type of outcome measure used to determine naltrexone's treatment advantage, that is, measures related to reducing heavy drinking versus those related to increasing abstinence., Methods: We conducted a Medline search to identify double-blind studies from 1990 to the present (2006) that evaluated the use of anopiate antagonist for the treatment of alcohol dependence. There were 29 studies identified, representing 5997 alcohol-dependent patients, which met our study inclusion criteria for this review. Studies were evaluated in this review on 4 prespecified drinking outcomes-2 related to "any drinking" and 2 related to "heavy or excessive drinking.", Results: In the treatment of alcohol dependence, we found that 19 (70%) of 27 clinical trials that measured reductions in "heavy or excessive drinking" demonstrated an advantage for prescribing naltrexone over placebo, whereas only 9 (36%) of 25 clinical trials that measured abstinence or "any drinking" found an advantage for medication over placebo., Conclusion: The majority of double-blind clinical trials in the literature favored prescribing naltrexone for alcohol dependence to reduce heavy drinking. This finding is consistent with our understanding of naltrexone's mechanism of action of decreasing excessive drinking by reducing the reward associated with drinking alcohol. Thus, we conclude that outcome measures related to heavy or excessive drinking are most relevant to defining naltrexone's therapeutic effects. Factors influencing naltrexone response (treatment adherence and distinct patient subgroups) are also discussed.

In the past decade, scientists have made important progress toward understanding the neurobiology underlying an alcohol disorder. This knowledge has led to the development of promising pharmacotherapies that target the neural pathways involved in the brain's reward center in such a way that the usual treatment response (via counseling) is substantially improved upon. There are now four US Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of alcohol dependence: disulfiram (Antabuse; Odyssey Pharmaceuticals, East Hanover, NJ), oral naltrexone (ReVia; Barr Pharmaceuticals, Inc., Pomona, NY), acamprosate (Campral; Forest Laboratories, Inc., New York, NY), and, as of April 2006, an extended-release (30-day) injectable suspension formulation of naltrexone (Vivitrol; Alkermes, Inc., Cambridge, MA). Other types of medications (eg, topiramate and quetiapine) are currently under investigation for the treatment of alcohol dependence. Research also has provided insights into best practices for prescribing the available medications. This report reviews the latest innovations in pharmacotherapy for the treatment of alcohol dependence, focusing on FDA-approved medications presently available to the treatment community.

For more than 55 years, disulfiram has been approved by the Food and Drug Administration for the treatment of alcohol dependence. It is a unique medication that relies on "psychological threat" to avoid disulfiram-ethanol reactions. This paper reviews the history of disulfiram treatment, the current status of disulfiram treatment, the ensuing developments in disulfiram use in treating various addictions, and future directions. Clinical trials using disulfiram for the treatment of alcohol, cocaine, or co-occurring alcohol + cocaine dependence were included in this review. Disulfiram efficacy studies focusing on supervised, implant, and combination pharmacotherapies were also examined. In clinical trials, disulfiram has demonstrated inconsistent results in helping patients to abstain from alcohol, and patients poorly adhere to a disulfiram-treatment regimen. This has raised questions about disulfiram's practicality in the treatment of alcohol dependence. Recently, however, disulfiram has gained attention as a complementary agent to newer pharmacological medications, such as an opiate antagonist that specifically reduces alcohol craving. One hypothesis is that disulfiram would assist patients in gaining psychological control over drinking when given in conjunction with an opiate antagonist that would act directly on reducing alcohol craving. Preliminary evidence also suggests that disulfiram treatment could be a viable treatment for cocaine dependence because it was shown to reduce cocaine use among nonalcoholic, cocaine-dependent patients.

Background: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders., Method: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores > or =17 (group A) and 139 patients with Hamilton Depression Rating Scale scores < or =16 (group B)., Results: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients., Conclusion: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.

Objective: Given the national trend toward integrating substance abuse treatment into medical practice, experts in the field of alcoholism designed a psychosocial, medically based intervention to be used with pharmacotherapy in the COMBINE multisite national study, supported by the National Institute on Alcohol Abuse and Alcoholism. A main purpose of the COMBINE Study is to investigate optimal treatment for patients with alcohol dependence by combining pharmacotherapy and psychosocial interventions., Method: The medically based intervention, called Medical Management (MM), was specifically constructed to be implemented by medically trained practitioners in nonspecialty settings. Each visit includes evaluations of medication safety and adherence, monitoring of alcohol use and direct advice to the patient for achieving full recovery., Results: There are several themes implicit in MM. Patient education about the disorder and about the treatment being provided are both essential. The clinician also educates the patient about how he or she has been affected by alcohol dependence. Information is given on how to take the medication(s) as prescribed, what the patient should expect from the medication(s) and what kinds of events the clinician will need to know about during treatment. Finally, the clinician and patient discuss strategies for ensuring medication safety and adherence to the prescribed regimen., Conclusions: MM was easily implemented in the COMBINE Study with the aid of the MM Treatment Manual.

Objective: This article describes the process by whichthe COMBINE investigators evaluated and chose the two pharmacotherapies to be studied in COMBINE., Method: The pharmacotherapies were chosen through a consensus process that involved the evaluation of neuropharmacological agents known to modify alcohol consumption or other alcohol-related behaviors in animals and humans. Medications were classified according to the published evidence, with the highest ranking given to those with evidence of efficacy in human clinical trials. The investigators also considered evidence for safety, potential drug-drug interactions, management of side effects, optimal dose, treatment duration, availability of the medication and integration with the psychosocial therapies. The full evaluation required conducting two pilot studies and the development of an instrument to monitor safety, the COMBINE Systematic Assessment for Treatment Emergent Events., Results: Naltrexone, at a dose of 100 mg per day, and acamprosate, at a dose of 3,000 mg per day, were chosen for the study. The medications were administered for a period of 4 months, concurrent with the COMBINE psychosocial therapies, Conclusions: The results of the decision making with respect to medications and safety monitoring resulted in a well-planned and well-executed study that minimized risks to the participants.

Context: Alcohol dependence is a common disorder associated with significant morbidity and mortality. Naltrexone, an opioid antagonist, has been shown to be effective for treatment of alcohol dependence. However, adherence to daily oral pharmacotherapy can be problematic, and clinical acceptance and utility of oral naltrexone have been limited., Objective: To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients., Design, Setting, and Participants: A 6-month, randomized, double-blind, placebo-controlled trial conducted between February 2002 and September 2003 at 24 US public hospitals, private and Veterans Administration clinics, and tertiary care medical centers. Of the 899 individuals screened, 627 who were diagnosed as being actively drinking alcohol-dependent adults were randomized to receive treatment and 624 received at least 1 injection., Intervention: An intramuscular injection of 380 mg of long-acting naltrexone (n = 205) or 190 mg of long-acting naltrexone (n = 210) or a matching volume of placebo (n = 209) each administered monthly and combined with 12 sessions of low-intensity psychosocial intervention., Main Outcome Measure: The event rate of heavy drinking days in the intent-to-treat population., Results: Compared with placebo, 380 mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days (P = .02) [corrected] and 190 mg of naltrexone resulted in a 17% decrease (P = .07). Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome, with men and those with lead-in abstinence both exhibiting greater treatment effects. Discontinuation due to adverse events occurred in 14.1% in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group. Overall, rate and time to treatment discontinuation were similar among treatment groups., Conclusions: Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during 6 months of therapy. These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence.

Aims: To determine whether substance use severity, psychiatric severity, social support, self-help attendance or motivation moderated substance use outcomes in a telephone-based continuing care intervention., Design: A randomized study comparing three 12-week continuing care interventions: weekly telephone monitoring and counseling combined with a support group in the first 4 weeks (TEL), twice-weekly individualized relapse prevention (RP) and twice-weekly standard group counseling (STND)., Methods: Following completion of 4-week intensive out-patient programs (IOP), 359 patients with alcohol and/or cocaine dependence were assigned randomly to a continuing care condition and followed quarterly for 12 months. Ten potential moderator variables were examined in separate analyses. Two of these variables reflected pretreatment status, whereas the other variables were focused on performance while in the IOP. A composite risk measure was also constructed from dichotomized versions of seven of these variables, with higher scores indicating greater potential for relapse. The dependent measures were total abstinence and percentage of days abstinent from alcohol and cocaine in each quarter., Findings: Of 40 interaction contrasts that were examined with individual risk indicator measures, only one reached the 0.05 level of significance. Patients with any alcohol use in IOP had a higher percentage of days abstinence in STND than in TEL. In addition, high scores on the composite risk indicator predicted higher total abstinence rates in STND than in TEL, whereas low to moderate scores predicted higher abstinence rates in TEL than in STND., Conclusion: For most graduates of IOPs, the combination of brief weekly telephone therapeutic contacts and a support group in the first month produced outcomes that are as good as those obtained in more intensive face-to-face continuing care interventions. However, patients with current dependence on both alcohol and cocaine who make little progress towards achieving the central goals of IOP may have better outcomes if they receive twice-weekly group counseling following IOP.

Context: Telephone-based disease management protocols have shown promise in improving outcomes in a number of medical and psychiatric disorders, but this approach to continuing care has received little study in alcohol- and drug-dependent individuals., Objective: To compare telephone-based continuing care with 2 more intensive face-to-face continuing care interventions., Design: A randomized 3-group clinical trial with a 2-year follow-up., Setting: Two outpatient substance abuse treatment programs, one community-based and the other at a Veterans Affairs medical center facility., Patients: Alcohol- and/or cocaine-dependent patients (N = 359) who had completed 4-week intensive outpatient programs., Interventions: Three 12-week continuing care treatments: weekly telephone-based monitoring and brief counseling contacts combined with weekly supportive group sessions in the first 4 weeks (TEL), twice-weekly cognitive-behavioral relapse prevention (RP), and twice-weekly standard group counseling (STND)., Main Outcome Measures: Percentage of days abstinent from alcohol and cocaine, total abstinence from alcohol and cocaine, negative consequences of substance use, cocaine urine toxicological results, and gamma-glutamyltransferase., Results: Participants in TEL had higher rates of total abstinence over the follow-up than those in STND (P<.05). In alcohol-dependent participants, 24-month gamma-glutamyltransferase levels were lower in TEL than in RP (P = .005). In cocaine-dependent participants, there was a significant group x time interaction (P = .03) in which the rate of cocaine-positive urine samples increased more rapidly in RP as compared with TEL. On percentage of days abstinent or negative consequences of substance use, TEL did not differ from RP or STND. Participants with high scores on a composite risk indicator, based on co-occurring alcohol and cocaine dependence and poor progress toward achieving intensive outpatient program goals, had better total abstinence outcomes up to 21 months if they received STND rather than TEL, whereas those with lower scores had higher abstinence rates in TEL than in STND (P = .04)., Conclusions: Telephone-based continuing care appears to be an effective form of step-down treatment for most patients with alcohol and cocaine dependence who complete an initial stabilization treatment, compared with more intensive face-to-face interventions. However, high-risk patients may have better outcomes if they first receive group counseling continuing care after completing intensive outpatient programs.

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25-63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (> or =3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence.

This study of continuing care for substance dependent patients compared a telephone-based monitoring and brief counseling intervention (TEL) with 2 face-to-face interventions, relapse prevention (RP) and standard 12-step group counseling (STND). The participants were graduates of intensive outpatient programs who had current dependence on alcohol and/or cocaine. Self-report, collateral, and biological measures of alcohol and cocaine use were obtained over a 12-month follow-up. The treatment groups did not differ on abstinence-related outcomes in the complete sample (N = 359) or on cocaine use outcomes in participants with cocaine dependence (n = 268). However, in participants with alcohol dependence only (n = 91), TEL produced better alcohol use outcomes than STND on all measures examined and better outcomes than RP on some of the measures., (Copyright 2004 APA.)

The use of antidepressant pharmacotherapy to treat patients with co-occurring depression and alcohol dependence is controversial. There is a stigma attached to giving medications to alcohol-dependent persons. Also, empirical evidence is sparse and inconsistent, which discourages the use of antidepressants in these patients. Historically, it has been a challenge to accurately diagnose a depressive disorder in the presence of alcohol dependence. In addition, early clinical studies were fraught with methodological problems; however, improved diagnostic assessments are now available, and in the last decade, results from well-controlled trials appear to support the use of antidepressants in this patient population in the specific role of relieving depressive symptoms. The majority of these trials also demonstrate that antidepressants have relatively little impact on reducing heavy drinking in this patient population, even though the medications reduce depressive symptoms. Newer approaches to treating patients with co-occurring depression and alcohol dependence suggest adding to the antidepressant a pharmacotherapy that directly impacts drinking. The findings from this review better define the action of antidepressants in patients with co-occurring depression and alcohol dependence as specific to reducing depressive symptoms, and these medications and their action on mood have little impact on treating the co-occurring alcohol dependence.

We previously established that Babor Type A "lower-risk/severity" alcoholics (n = 55) had better treatment response to fourteen weeks of sertraline (200 mg/day) than placebo, a finding not present for Type B "higher-risk/severity" alcoholics (n = 45). This exploratory study extended these results by examining the original sample for gender differences in response to sertraline pharmacotherapy. Type A alcoholic men, but not Type A alcoholic women, had consistently better outcomes with sertraline compared to placebo on several common drinking measures: time to relapse, days drinking, days drinking heavily, drinks per drinking day, and number of those continually abstinent. There were no significant differences in drinking with sertraline compared to placebo in Type B alcoholic men or women.

This study compared the effects of alcohol and cocaine dependence severity on the outcome of outpatient detoxification from alcohol and cocaine. Subjects included 84 subjects with both alcohol and cocaine dependence admitted for outpatient detoxification. Fifty-three of the 84 subjects (63%) completed detoxification. Baseline cocaine use, cocaine craving, and cocaine withdrawal symptoms predicted detoxification outcome, whereas alcohol use, alcohol craving, and alcohol withdrawal symptoms did not. Among cocaine- and alcohol-dependent subjects, cocaine dependence severity appears to be a more important predictor of detoxification success than alcohol dependence severity.

This study evaluated for 152 patients the relationship between their attitudes toward treatment and session attendance in pharmacotherapy research trials aimed at treating alcohol dependence. The study included a new, 50-item, patient-administered measure of attitudes, Treatment Research Experiences and Attitudes Task (TREAT), which is comprised of ten items from each of five attitudinal dimensions typically associated with treatment adherence: treatment setting, taking medication, social support, medical professional, and intrinsic patient factors. Patients attending 80% or more clinical sessions scored higher, i.e., were more favorable on four of five of attitudinal dimensions. Thus, patient attitudes toward treatment may be useful in identifying areas that limit or improve treatment attendance.

Research performed during the past 20 years has shown that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission is related to alcohol dependence. Both theoretical and empirical research have supported the idea that alcohol dependence is a chronic disease and that, in addition, biological vulnerabilities contribute to the pathogenesis of alcohol dependence. Preclinical studies have consistently demonstrated that there is a relationship between 5-HT function and alcohol consumption. Furthermore, there is evidence building that lends support for the existence of distinct alcoholic subtypes that may be differentiated by the type or complexity of their 5-HT dysfunction. Beyond excessive drinking, behaviors that are indicators of 5-HT dysregulation are depression, anxiety, impulsiveness, and early-onset problem drinking. This chapter will discuss the usefulness of 5-HT-selective pharmacotherapy in treating alcohol dependence and will provide both historical and current perspectives on its use.

This study examined the relation between depression diagnoses and outcomes in 132 cocaine-dependent patients who were randomized to relapse prevention (RP) or standard 12-step focused group continuing care and followed for 2 years. Depressed patients attended more treatment sessions and had more cocaine-free urines during treatment than participants without depression, but they drank alcohol more frequently before treatment and during the 18-month posttreatment follow-up. Cocaine outcomes in depressed patients deteriorated to a greater degree after treatment than did cocaine outcomes in patients without depression, particularly in patients in RP who had a current depressive disorder at baseline. The best alcohol outcomes were obtained in nondepressed patients who received RP. The results suggest that extended continuing care treatment may be warranted for cocaine-dependent patients with co-occurring depressive disorders.

Naltrexone has repeatedly been shown to reduce drinking in alcohol-dependent patients. Previous clinical research suggests that naltrexone may be more effective at reducing drinking among patients with high levels of alcohol craving at the beginning of treatment. In addition, laboratory studies suggest that naltrexone may be more efficacious among patients with a high familial loading of alcohol problems. We explored both of these possibilities in the context of the first 12-week phase of a double blind, placebo-controlled naltrexone trial. A total of 121 patients were randomized to receive 100 mg/day naltrexone and 62 patients were randomized to receive placebo. Both naltrexone and placebo were given in conjunction with a psychosocial intervention designed to be integrated with the use of pharmacotherapy. This intervention was administered by nurse practitioners. Overall, patients randomized to naltrexone reported drinking five or more drinks on fewer days than did placebo controls (p = .04). Interactions were observed between medication group assignment and both craving level prior to randomization (p = .02) and family loading of alcohol problems (p = .05). In both cases, the interaction was in the predicted direction. These data suggest that patients with high levels of alcohol craving or a strong family history of alcoholism are more likely to benefit from naltrexone treatment.

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.

The usefulness of selective serotonin reuptake inhibitors (SSRIs) to treat alcohol dependence continues to be a subject of debate. Most recently, investigations have tried to predict whether a given patient will respond to SSRIs in terms of reducing excessive alcohol drinking. The subtyping of alcohol-dependent individuals has ranged from relatively simple classifications (e.g., presence of comorbid depression) to more complex classifications (e.g., potential to have abnormalities in serotonin [5-HT] neurotransmission). Although only a few studies have been completed, results thus far indicate that alcoholic subgroups are differentially responsive to 5-HT pharmacotherapy with respect to drinking-related outcomes. In addition, there are preliminary results encouraging the use of SSRIs in combination with other medications for treating alcohol dependence in patients with and without comorbid psychiatric disorders. Information from these studies is promising, suggesting the need for further investigation.

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.

We examined differences in clinical presentation for outpatient alcohol treatment in: 1) males and females, considering comorbidity; and 2) three comorbid groups, considering gender. Drinking indices and emotional, physical, and sexual abuse reports were compared in 127 male and 69 female alcohol-dependent patients who have a current (36.2%) or lifetime (20.4%) psychiatric disorder or who never had a psychiatric disorder (43.4%). Females reported more emotional and physical abuse than males. Females reported drinking smaller volumes of alcohol but on more days than males. All with current comorbidity, irrespective of gender, reported more days of heavy drinking than other groups. When evaluating drinking status, gender and comorbidity should be considered.

The majority of studies that have examined the usefulness of pharmacotherapies selective for serotonin (5-hydroxytryptamine; 5-HT) as a treatment for alcohol dependence have been standard, double-blind clinical trials that include patients with a variety of clinical presentations. Almost all of the early studies evaluated heavy social drinkers and found only a modest advantage for 5-HT pharmacotherapies in reducing the number of drinks per day. Also, the advantage of these pharmacotherapies was observed primarily when these agents were given at higher daily dosages than suggested prescribing practices for use as an antidepressant. The few studies that evaluated treatment-seeking patients found that 5-HT pharmacotherapies were not instrumental in reducing drinking rates compared with placebo. These results led to a dampening of enthusiasm for use of these agents in treating alcohol dependence. However, more recent investigations have begun to target subgroups with potential abnormalities in 5-HT neurotransmission. The thinking is that these medications should be most useful in alcohol-dependent individuals who have more clearly delineated suggestive signs of 5-HT dysfunction, such as concomitant depression or anxiety. Although few results are available to date, there is growing evidence to suggest that alcohol-dependent subgroups are differentially responsive to 5-HT pharmacotherapies with respect to drinking-related outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic effects that were reported in the earlier studies, which included large heterogeneous patient groups. Further investigations are needed to confirm these initial optimistic results.

The effectiveness of naltrexone, a FDA-approved medication for alcohol dependence, can be improved if we support and help patients to consistently take their medication. We illustrate how patient noncompliance with treatment negatively affects outcome, and, we describe a new intervention to enhance medication compliance. Outcome was evaluated for 196 alcohol dependent outpatients who were treated with 50 mg/day naltrexone or placebo for 12 weeks. For patients who adhered to the prescribed treatment, relapse rates were lower with naltrexone than placebo (10% vs. 38.6%, p < 0.001). For noncompliant patients, relapse rates were high and comparable between naltrexone- and placebo-treated patients (42.9% vs. 40%). In a second study of 100 alcohol dependent outpatients, we introduced an intervention that resulted in better medication compliance rates compared to a previous naltrexone study of patients who did not receive the intervention (77.0% vs. 60.8%, p < 0.01). This provided some support for the use of an intervention that targets medication compliance when prescribing naltrexone.

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.

This study investigated whether selected patients have better outcomes with inpatient than outpatient treatment. There were 93 inpatients and 80 outpatients with alcohol dependence who were evaluated at treatment entry to a private healthcare setting. Patients with multiple drinking-related consequences were less likely to return to significant drinking in the first 3 months after treatment ended if they had attended inpatient compared to outpatient treatment. Thus, inpatient appeared to have some advantage over outpatient treatment in the early recovery period for patients with multiple drinking-related consequences. The gap between inpatient and outpatient costs was also reduced when computed as a cost-effectiveness ratio, although treatment costs continued to remain proportionally higher with inpatient than outpatient treatment.

Concurrent dependence on cocaine and alcohol is common among patients seeking addiction treatment. This study was undertaken to explore the effectiveness of naltrexone (150 mg) as a potential treatment for patients who are alcohol and cocaine dependent. Of 15 subjects enrolled in the 12-week, open medication trial, 7 subjects did not complete the study. Relapse to clinically significant drinking occurred in 7 subjects (47%). There was a reduction in the average daily amount of alcohol consumed from pretreatment to treatment (p < .001) and the percentage of days engaged in drinking behavior (p < .001). Similarly, there was a reduction in the average weekly amount spent on cocaine from pretreatment to treatment (p = .001) and the percentage of days using cocaine (p < .001). This preliminary study suggests that naltrexone (150 mg) may be tolerable in patients dependent upon alcohol and cocaine and may be effective in reducing both cocaine and alcohol use. The results of this study provide a rationale for a double-blind placebo-controlled study of the efficacy of naltrexone in this difficult to treat but prevalent population.

This study evaluated the prevalence of Axis II disorders in substance abuse patients and the relationship between Axis II psychopathology and two other known predictors of adverse addiction treatment outcomes, i.e., Axis I psychiatric comorbidity and illegal drug use, specifically cocaine. 232 patients with cocaine and/or alcohol dependence were admitted to either inpatient or outpatient addiction recovery programs at Carrier Foundation, a nonprofit, private-pay hospital in New Jersey. Axis II disorders were more prevalent in cocaine than alcohol dependence and in patients with Axis I psychiatric comorbidity. When all three predictors were evaluated in one prediction model, the combination of Axis I and II psychopathology was the best predictor of a return to substance use at one year post-treatment, compared to the three factors alone. These findings highlighted the importance of the interrelationship of the relative prognostic value of three known predictors of addiction treatment.

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.

The authors evaluated the reliability of two pretreatment assessments (screening and intake) of cigarettes smoked per day (CPD) by the commonly used aggregate method. The validity of the aggregate method was also determined by comparison with results of the timeline followback (TLFB) method for the identical periods. The study participants were 49 outpatients undergoing nicotine patch treatment. The reliability of the two aggregate method evaluations of CPD was quite high by Pearson product-moment correlation (r) and good when based on the intraclass correlation. Correspondence between the CPD assessments based on the aggregate and TLFB methods for the two time-points ranged from fair (screening) to good (intake). Overall, the study findings indicate that the aggregate method provides reasonably consistent data.

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.

Objective: The adequacy of pharmacologic treatment received by patients with psychotic major depression was evaluated., Method: The authors systematically assessed the pharmacotherapy received by 187 depressed patients before initiation of ECT and compared the medication trials of those with psychotic (N = 53) and nonpsychotic (N = 134) depression., Results: Despite a median of four medication trials and median index episode duration of 20 weeks, only two (4%) of the patients with psychotic depression received at least one adequate pharmacotherapy trial. In contrast, 70 (52%) of the patients with nonpsychotic depression received at least one adequate trial. Twenty-five (47%) of the patients with psychotic depression received either no neuroleptic treatment (N = 11) or treatment for less than 3 weeks (N = 14). Only eight (15%) received a daily neuroleptic dose higher than 200 mg of chlorpromazine equivalents., Conclusions: These findings suggest that many patients with psychotic major depression referred for ECT receive inadequate pharmacotherapy because of either the absence or the inadequate use of neuroleptic medication.

Carbohydrate-deficient transferrin (CDT) has been identified as a potential biochemical marker of heavy alcohol consumption. Published studies to date primarily have focused on the ability of CDT levels to distinguish individuals with heavy alcohol drinking from nondrinking populations. In contrast, this study examines the utility of CDT levels in distinguishing alcohol-dependent patients who drink heavily from those who drink smaller amounts. This study also evaluates the potential relationship of CDT to severity of alcohol dependence and its gender differences. Serum was collected in 38 DSM-III-R alcohol-dependent outpatients at treatment entry (22 males, 16 females). CDT levels correlated with the extent of alcohol drinking in the month before treatment in males (r = 0.56, df = 20, p < .01), but not in females (r = 0.08, df = 14, NS). CDT levels also correlated with alcohol severity at pre-treatment in males (r = 0.53, df = 20, p < .05), but not in females (r = 0.27, df = 14, NS). Thus, elevated CDT levels may be mediated by alcohol severity, distinguishing CDT not only as a marker of heavy drinking, but also as an indicator of the severity of drinking-related biological and psychosocial dysfunction that may require further intervention.

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects' QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

There is a great deal of interest in the use of naltrexone as a treatment for alcohol (ethanol) dependence since there is a rapidly expanding body of evidence to support its efficacy and tolerability in this indication. Naltrexone, a long-acting, nonselective opioid receptor antagonist has been shown to reduce alcohol intake when combined with behavioural treatment. Naltrexone may prevent the return to clinically significant drinking by blocking the pleasurable effects or "high' associated with alcohol drinking. Results from controlled studies showed that in alcohol dependent patients taking naltrexone 50 mg/day in combination with behavioural treatment, relapse rates were reduced by 50% compared with placebo treated patients. Historically, several factors have limited the use of effective pharmacological adjuncts in the treatment of alcohol dependence. These include safety considerations in this vulnerable population, and the fact that some treatment programmes discourage alcohol-dependent patients from taking medications. The most common adverse effects reported with the use of naltrexone at a dosage of 50 mg/day include nausea and vomiting. Naltrexone does not appear to be hepatotoxic in dosages recommended in the treatment of alcohol dependence, i.e. 50 mg/day. Thus, naltrexone appears to offer significant therapeutic benefits at a relatively low risk, when used judiciously and with behavioural treatment for alcohol dependent patients.

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.

Objective: Traditionally, it has been widely assumed that the likelihood of response to ECT is independent of the adequacy of previous treatment with antidepressant medications. However, recent research has raised the possibility that medication-resistant patients with depression have a poorer clinical ECT outcome than patients who have not failed previous adequate medication trials., Method: Medication resistance of 100 patients with primary, unipolar, nonpsychotic major depression was evaluated during the index episode with the Antidepressant Treatment History Form. Patients were recruited and treated with ECT at three sites; standardized ECT and clinical assessment procedures were used. Clinical outcome was assessed immediately and 1 week after completion of the ECT course., Results: Patients who previously had failed one or more adequate antidepressant medication trials were less likely to respond to subsequent ECT than patients not known to be medication resistant. This finding held within each study site, whether clinical response was assessed categorically or in terms of the magnitude of symptomatic improvement and after the authors accounted for other potential predictors of clinical outcome. Resistance to heterocyclic antidepressants predicted poorer outcome after ECT, while resistance to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors did not show significant predictive relations., Conclusions: While a substantial percentage of medication-resistant patients respond to ECT, clinical outcome in this group is inferior to that of patients without established medication resistance. The predictive power of medication resistance is generalizable across diverse clinical settings, particularly for heterocyclic antidepressants, which perhaps suggests an overlap in the mechanisms of actions of ECT and this medication class.

The Comprehensive Addiction Severity Index for Adolescents (CASI-A) is a 45 to 90-minute comprehensive, semi-structured clinical interview for evaluating adolescents who present for treatment at various provider agencies. CASI-A modules and their individual items were selected and revised based on theory, clinical wisdom, and adolescent experiences obtained during pilot interviews and focus groups. The CASI-A assesses known risk factors, concomitant symptomatology, and consequences of adolescent alcohol/drug use within seven primary areas of functioning: education status, alcohol/drug use, family relationships, peer relationships, legal status, psychiatric distress, and use of free time. The CASI-A is not a diagnostic or screening instrument, but rather a clinical assessment tool that obtains clinically pertinent information designed to guide treatment planning and to evaluate treatment outcome. The CASI-A's design makes it suitable for administration in a variety of settings, for repeat administration at posttreatment follow-up evaluations, and for assessment of virtually all adolescents in treatment regardless of their admission problem. Overall, the CASI-A has encouraging but preliminary evidence of validity and internal consistency. Information collected soon after admission during administration of the CASI-A by nonclinical interviewers corresponded quite well with that obtained over the course of the adolescent's treatment stay by the entire treatment team. Revisions to the instrument are being made in those areas where correspondence between information on the CASI-A and that extracted from clinical records dropped below 75%, or in those early subscales, where alpha coefficients dropped below .6. As a result of the encouraging results reported in this paper, we are beginning additional psychometric testing, refining the proposed scoring system, and developing a computerized data entry, scoring, and report system.

Electroconvulsive therapy (ECT), a safe and effective treatment for major depression, has been more harshly criticized than any other psychiatric treatment. Despite widespread negative public opinion, clinical impressions that are supported by limited empirical data suggest that patients who benefit from ECT do not share these negative sentiments. This study surveyed attitudes toward ECT in 78 depressed inpatients, twice during hospitalization and at 6 months after discharge, using a semi-structured interview. Significantly more ECT-treated patients (n = 56) were favorable about ECT, compared to depressed patients (n = 22) never treated with ECT, both at pretreatment (chi square = 8.4, df = 1, p < .01) and at post-treatment (chi square = 12.5, df = 1, p < .01). Favorable attitudes were maintained after 6 months. ECT-treated patients, initially uncertain or negative about ECT, changed to a favorable attitude after completing treatment. Ninety-eight percent of ECT-treated patients said they would agree to ECT if they became depressed again.

Miller and Hester's 1986 review of inpatient versus outpatient alcohol treatment studies concluded with no "justification" for inpatient treatment. Further examination of these studies revealed shortcomings such as the use of random assignment designs which excluded psychiatrically-complicated patients. Carrier Foundation's inpatient/outpatient study of private psychiatric patients with alcohol and/or cocaine dependence includes a patient-treatment matching design to address weaknesses in the existing literature. Patients with high psychiatric severity and/or a poor social support system are predicted to have a better outcome in inpatient treatment, while patients with low psychiatric severity and/or a good social support system may do well as outpatients without incurring the higher costs of inpatient treatment. Preliminary results from 183 inpatients and 120 outpatients indicated outpatients, regardless of level of psychiatric severity, were 4 times more likely to be early treatment failures (chi-square = 41.2, df = 1, p < .01). While the determination of long-term follow-up status of early treatment failures is currently underway, this finding underscores the potential risk of early treatment failure in outpatient compared to inpatient substance abuse treatment programs and the importance of addressing the issue of early attrition in conducting outcome analyses.

Benzodiazepines (BZD) possess anticonvulsant properties that may potentially elevate seizure threshold, inhibit seizure propagation, and alter some of the neurobehavioral effects of electroconvulsive shock (ECS) in animal models. Nevertheless, considerable controversy exists regarding the clinical impact of oral BZD use during electroconvulsive therapy (ECT). The existing literature is contradictory, and all studies attempting to address this topic suffer from important design flaws. Most studies are retrospective and some address only seizure duration. Also, studies examining treatment outcome are difficult to compare because of differing types and dosages of BZD, varied electrode placement and stimulus energy, and lack of information about the relationship of the stimulus energy to the patients' seizure thresholds. While firm conclusions must await further studies, limited data suggest that BZD have the potential to shorten seizure duration and decrease treatment efficacy, particularly with unilateral ECT.

The selection of an electroconvulsive therapy (ECT) device from the more than 10 American-made models can be a difficult endeavor. This article is meant to be a single source of basic descriptions of these ECT devices. The information provided will allow the ECT clinician to be aware of the important issues involved in the selection of an ECT device and to become familiar with the basic features of each model.

Vasopressin may be involved in normal memory functions and may alleviate certain memory impairments. In this study, the usefulness of vasopressin to relieve electroconvulsive therapy (ECT)-induced memory impairment was evaluated using a placebo-controlled, random assignment, double-blind design. Patients were 33 depressives receiving bilateral ECT. Vasopressin, in a nasal spray, was administered q.i.d. from the first through the fifth ECT. Extensive memory testing evaluated both retrograde and anterograde amnesia; ratings of depression and patient ratings of subjective memory complaints were also obtained. Results did not show statistically significant evidence of benefit from vasopressin, though a number of comparisons were in the predicted direction. The role of vasopressin in reducing memory impairment of various types remains to be elucidated.