Darlene H. Moak

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

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

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

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

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

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

Sertraline treatment of co-occurring alcohol dependence and major depression.

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 ≥17 (group A) and 139 patients with Hamilton Depression Rating Scale scores ≤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.

Pharmacological Treatment of Alcohol Abuse/Dependence With Psychiatric Comorbidity

This article represents the proceedings of a symposium at the 2003 annual meeting RSA in Fort Lauderdale, FL. It was organized and cochaired by Charlene E. Le Fauve and Carrie L. Randall. The presentations were (1) Introduction, by Charlene E. Le Fauve and Raye Z. Litten; (2) Treatment of co-occurring alcohol use and anxiety disorders, by Carrie L. Randall and Sarah W. Book; (3) Pharmacological treatment of alcohol dependent patients with comorbid depression, by Darlene H. Moak; (4) Efficacy of valproate in bipolar alcoholics: a double blind, placebo-controlled study, by Ihsan M. Salloum, Jack R. Cornelius, Dennis C. Daley, Levent Kirisci, Johnathan Himmelhoch, and Michael E. Thase; (5) Alcoholism and schizophrenia: effects of antipsychotics, by Alan I. Green, Robert E. Drake, Suzannah V. Zimmet, Rael D. Strous, Melinda Salomon, and Mark Brenner; and (6) Conclusions, by Charlene E. Le Fauve; discussant, Raye Z. Litten. Alcohol-dependent individuals have exceptionally high rates of co-occurring psychiatric disorders. Although this population is more likely to seek alcoholism treatment than noncomorbid alcoholics, the prognosis for treatment is often poor, particularly among patients with more severe psychiatric illnesses. Development of effective interventions to treat this population is in the early stages of research. Although the interaction between the psychiatric condition and alcoholism is complex, progress has been made. The NIAAA has supported a number of state-of-the-art pharmacological and behavioral trials in a variety of comorbid psychiatric disorders. Some of these trials have been completed and are presented here. The symposium presented some new research findings from clinical studies with the aim of facilitating the development of treatments that improve alcohol and psychiatric outcomes among individuals with alcohol-use disorders and co-occurring psychiatric disorders. The panel focused on social anxiety disorder, depression, bipolar disorder, and schizophrenia.

Further Validation of the Obsessive-Compulsive Drinking Scale (OCDS): Relationship to Alcoholism Severity

The authors administered the Obsessive-Compulsive Drinking Scale (OCDS), a self-rated questionnaire that quantifies some cognitive and behavioral dimensions of “craving” for alcohol, to 124 alcohol-dependent subjects in three pharmacological treatment studies. The OCDS total scores had significant correlations with both the Alcohol Dependence Scale (r = 0.42; Plt;0.0001). and the alcohol subscale of the Addiction Severity Index (r = 0.44; P<0.0001). Previous alcoholism treatment was associated with higher OCDS Total and Obsessive subscale scores. These data support the congruent validity of the OCDS with previously well established measures of alcohol dependence severity and suggest that this measurement of craving may help in formulating appropriate treatment plans for alcoholic patients.

Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema.

Hypotheses about relationships between changes in membrane lipids and mental illness have focused primarily on three long‐chain polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Membrane deficiencies of these fatty acids have been reported in schizophrenia (AA, EPA, and DHA) and in depression (EPA and DHA). Long‐chain fatty acid‐CoA ligase type 4 (FACL4; MIM 300157) is a key enzyme involved in the metabolism of AA, EPA, and DHA. FACL4 selectively esterifies these fatty acids with co‐enzyme A, forming acyl‐co‐A, which can then be incorporated into membrane phospholipid. We used niacin‐induced dermal erythema as one index of AA metabolism to identify a common C to T single nucleotide polymorphism (SNP) in the first intron of the FACL4 gene (Xq22.3), which is associated with enhanced dermal erythema in both schizophrenia and control subjects. Male subjects with the T0 genotype showed greater dermal erythema following topical application of methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium with a functional polymorphism of the FACL4 gene that modulates re‐sequestration of agonist‐released free AA. We also examined the allele frequency of this polymorphism in 555 European–Americans (EA), including 229 control subjects, 198 subjects with major depression, 58 with schizophrenia or schizoaffective disorder, and 70 with alcohol dependence without co‐morbid psychiatric illness. We observed a significant excess of the T allele in subjects with major depression, as compared with controls (49% vs. 38%; P = 0.003) and a non‐significant excess of the T allele in schizophrenia (44%; P = 0.29). The allele frequency for subjects with alcohol dependence did not differ from controls.

Alleles of a functional serotonin transporter promoter polymorphism are associated With major depression in alcoholics

BACKGROUND Serotonergic neurotransmission has been implicated in the pathogenesis of both alcohol dependence and mood disorders and may therefore be important in understanding the pathophysiology of comorbid alcohol dependence and major depression. Studies of the association of these disorders with a functional polymorphism in the promoter region of the gene encoding the serotonin transporter protein (locus SLC6A4) have yielded inconsistent results. Because the convergence of these disorders may provide a refined phenotype, we examined the association of serotonin (5-HT) transporter linked polymorphic region (5-HTTLPR) alleles to comorbid alcohol dependence and major depression. METHODS A sample of 296 European American and 16 African American patients with comorbid alcohol dependence and major depression was recruited from treatment studies. The control group included 260 European Americans and 43 African Americans; all were screened to exclude the presence of a mood or substance use disorder. DNA isolated from whole blood was polymerase chain reaction-amplified, and genotypes were assigned on the basis of agarose gel size fractionation. RESULTS The frequency of the short allele in the patient group was in the range of those previously reported for samples with unipolar depression but was significantly more common than among controls (short allele frequency of cases, 45.8%; controls, 39.8%; chi(2)(1) = 4.02; p = 0.045). CONCLUSIONS With respect to the frequency of the short allele at the SLC6A4 locus (5-HTTLPR), major depression in alcoholics is similar to major depression in nonalcoholics. Further efforts to characterize depressed alcoholics and to examine genetic predictors of response to antidepressant treatment seem warranted.

A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal

Abstract Treatment of the alcohol withdrawal syndrome is best accomplished using pharmacologic agents that have minimal interaction with alcohol, have limited adverse effects, and are without abuse potential. The partial benzodiazepine receptor agonist beta-carboline compound, abecarnil, has been shown in animal and human studies to possess a number of these characteristics and to be useful in the reduction of alcohol withdrawal convulsions in mice. In this study, 49 alcohol-dependent inpatients who exhibited at least moderate symptoms of uncomplicated alcohol withdrawal were treated over a 5-day detoxification period with abecarnil or diazepam and rated daily for alcohol withdrawal symptoms and adverse events. Both the abecarnil and diazepam treatment groups exhibited a similar marked reduction in withdrawal symptoms over time. In addition, similar rates of successful treatment and improvement were observed after 1 day of treatment and at termination in alcoholics treated with either medication. Overall, rates of adverse events and changes in liver enzymes were similar in both treatment groups and were generally benign. Because of the unique pharmacologic profile of abecarnil in animal and in non-clinical human studies, including anticonvulsant action, low abuse liability, and a favorable side effect profile, further study of compounds of the partial benzodiazepine receptor agonist type in the treatment of alcohol withdrawal syndromes seems warranted.

Alcoholic Subjects with Anxiety Disorder: Characteristics of Completers and Noncompleters in a Pharmacologic Study

Data from a 6-month placebo-controlled, double-blind study of buspirone in alcohol-dependent subjects with generalized anxiety disorder were examined to determine if study completers and noncompleters differed on any identifiable characteristics. Twenty (299%) of 67 male veterans completed the 26-week protocol. An equal number (n = 10) of the completers were from each treatment condition. The completers had significantly fewer prior treatments and detoxifications and less heavy drinking in the month before the study than the noncompleters. Characteristics related to the severity of alcoholism may influence retention and medication compliance of alcohol-dependent subjects in pharmacologic treatment studies.