Neurotransmitter and neuromodulator genes associated with a history of depressive symptoms in individuals with alcohol dependence

Background: Depressive symptoms are common among individuals with alcohol use disorders and impact treatment outcome. Substantial overlap exists among the neurobiological systems proposed in the pathophysiology of depressive and alcohol use disorders; however, specific genetic effects contributing to risk for depressive comorbidity remain poorly understood. Methods: This study examines the association of depressive symptom scores for lifetime depression (the sum of DSM‐IV major depression co‐endorsed criteria for lifetime depression) with markers in 120 candidate genes in 554 alcohol‐dependent individuals. The candidate genes code for molecules involved in dopamine, serotonin, glutamate, gamma‐aminobutyric acid (GABA), and opioid neurotransmission, cell signaling, pharmacokinetics, stress biology, and behavioral control. Analyses were conducted at the single marker level with experimentwise permutation to control for multiple testing. Results: Results revealed nominal associations for markers in 20 genes. Following experimentwise permutation, markers in the corticotropin‐releasing hormone‐binding protein (CRHBP) the μ‐opioid receptor (OPRM1) and the β1 subunit of GABA A (GABA_A) receptors (GABRB1) met or exceeded the significance threshold. None of the markers associated with depressive symptom scores were significantly associated with alcohol dependence symptom scores. Conclusion: These findings suggest potential risk genes for depressive symptoms in alcohol‐dependent individuals.     

Nefazodone treatment of comorbid alcohol dependence and major depression

BACKGROUND: Major depression is a common comorbid condition among individuals with alcohol dependence. This study examined the effects of nefazodone, a norepinephrine and serotonin reuptake blocker and 5-hydroxytryptamine-2 receptor antagonist, on mood and anxiety symptoms and drinking behavior in a sample of depressed alcoholics. METHODS: This study was a double-blind, placebo-controlled comparison of nefazodone (200-600 mg/day) or placebo in a sample of alcohol-dependent subjects (n = 41; 52% women) with current major depression. After a 1-week placebo lead-in period, subjects were randomly assigned to receive study medication and supportive psychotherapy for 10 weeks. RESULTS: Depressive and anxiety symptoms declined significantly over time. Although the nefazodone group showed greater reductions in these symptoms, the effects did not reach statistical significance. Nonetheless, nefazodone-treated subjects showed a significantly greater reduction in heavy drinking days and in total drinks compared with placebo-treated subjects. CONCLUSIONS: The lack of significant effects on depression and anxiety symptoms may reflect limited statistical power. Despite the small sample size, nefazodone significantly reduced some measures of alcohol consumption in this sample of depressed alcoholics.     

Impact of motivational changes on drinking outcomes in pharmacobehavioral treatment for alcohol dependence

Background: Psychological factors such as motivation to change and self‐efficacy influence drinking outcomes in alcohol‐dependent individuals who are enrolled in pharmacobehavioral studies. Previous results from our research clinic indicated that initial stage of change of heavy drinkers enrolled in a pharmacobehavioral trial was significantly associated with alcohol consumption. However, overall empirical findings regarding the consistency and extent of the connection between motivational factors and behavior are mixed. This may be in part because of the impact of changes in motivation over the course of treatment and/or characteristics of the individuals receiving the intervention. Our goal in the present study was to examine the extent to which levels of motivation and self‐efficacy changed during the treatment phase of a pharmacobehavioral treatment trial, and the extent to which these variables affected drinking behavior in subsets of alcohol‐dependent individuals. Methods: We conducted an exploratory evaluation of changes in motivation, temptation to drink, confidence to abstain, and drinking behavior over time during the treatment phase of a pharmacobehavioral study involving 321 alcohol‐dependent individuals. We also examined the extent to which individual variables such as initial drinking severity, onset of alcohol dependence, and medication status influenced changes in motivation, self‐efficacy, and drinking behavior. Results: Participants reported improvements in motivation to change, self‐efficacy for change, and drinking behaviors over the course of treatment. As hypothesized, motivation to change and self‐efficacy for change were related to specific dimensions of posttreatment drinking. Heavy drinkers reported more improvement in drinking behaviors than did nonheavy drinkers. Early‐onset drinkers who were on medication reduced their drinking more than those on placebo, and these drinking changes appear to be partially mediated by reductions in temptation. Conclusions: Reductions in drinking occur and are predicted by increased motivation to change, reduced temptation to drink, and increased confidence to abstain in this population of alcoholic‐dependent individuals. Early and late onset and heavy drinkers and those taking medications displayed differential changes in drinking behavior, some of which were explained by the mediating effects of self‐efficacy. This is a first step in understanding more about which alcoholic individuals respond best to treatment and what mechanisms may be involved in the changes in drinking and drinking‐specific changes in frequency and intensity of drinking.     

Energy drink consumption and increased risk for alcohol dependence

Background: Energy drinks are highly caffeinated beverages that are increasingly consumed by young adults. Prior research has established associations between energy drink use and heavier drinking and alcohol‐related problems among college students. This study investigated the extent to which energy drink use might pose additional risk for alcohol dependence over and above that from known risk factors. Methods: Data were collected via personal interview from 1,097 fourth‐year college students sampled from 1 large public university as part of an ongoing longitudinal study. Alcohol dependence was assessed according to DSM‐IV criteria. Results: After adjustment for the sampling design, 51.3%_wt of students were classified as “low‐frequency” energy drink users (1 to 51 days in the past year) and 10.1%_wt as “high‐frequency” users (≥52 days). Typical caffeine consumption varied widely depending on the brand consumed. Compared to the low‐frequency group, high‐frequency users drank alcohol more frequently (141.6 vs. 103.1 days) and in higher quantities (6.15 vs. 4.64 drinks/typical drinking day). High‐frequency users were at significantly greater risk for alcohol dependence relative to both nonusers (AOR = 2.40, 95% CI = 1.27 to 4.56, p = 0.007) and low‐frequency users (AOR = 1.86, 95% CI = 1.10, 3.14, p = 0.020), even after holding constant demographics, typical alcohol consumption, fraternity/sorority involvement, depressive symptoms, parental history of alcohol/drug problems, and childhood conduct problems. Low‐frequency energy drink users did not differ from nonusers on their risk for alcohol dependence. Conclusions: Weekly or daily energy drink consumption is strongly associated with alcohol dependence. Further research is warranted to understand the possible mechanisms underlying this association. College students who frequently consume energy drinks represent an important target population for alcohol prevention.     

Implications of depression on outcome from alcohol dependence: a 3-year prospective follow-up

The prognostic implications of comorbid depression for outcome from alcohol dependence are unclear. It has been suggested that drinking may represent self-medication of depressive disorders and, alternatively, that the pharmacological properties of alcohol induce episodes of depression. In the present study, these questions were investigated by following 84 alcohol-dependent individuals seeking treatment (34% women) for 3 years in a naturalistic, prospective design. During the follow-up period, depressive and drinking outcomes were significantly related. However, there was no evidence that drinking reliably preceded depressive episodes or that depressive episodes precipitated heavy drinking. Despite their high co-occurrence, this study did not find evidence of a strong, direct causal relationship between these phenomena.     

Impact of depressive symptoms on future alcohol use in patients with co-occurring bipolar disorder and alcohol dependence: a prospective analysis in an 8-week randomized controlled trial of acamprosate

Background: Bipolar disorders and alcohol use disorders commonly co‐occur, yet little is known about the proximal impact of bipolar symptoms on alcohol use in patients with this comorbidity. The present study examined the impact of depressive symptoms and alcohol craving on proximal alcohol use in patients with co‐occurring bipolar disorder and alcohol dependence. Methods: Data were collected during an 8‐week randomized controlled trial of acamprosate for individuals with co‐occurring bipolar disorder and alcohol dependence (n = 30). Depressive symptoms and alcohol craving were assessed biweekly using the Montgomery Asberg Depression Rating Scale (MADRS) and the Obsessive Compulsive Drinking Scale (OCDS), respectively. Daily alcohol use data were available via administration of the Time‐line Follow‐back interview at baseline and at subsequent weekly study visits. Correlational analyses and hidden Markov modeling were used to examine the prospective relationships between depressive symptoms, alcohol craving, and alcohol use. Results: Depressive symptoms and alcohol craving were significantly correlated with proximal (i.e., 1 week later) alcohol use across a variety of alcohol consumption summary measures. In hidden Markov models, depressive symptoms (OR = 1.3, 95% credible interval = [1.1, 1.5]) and alcohol craving (OR = 1.6, 95% credible interval = [1.4, 1.9]) significantly predicted transitioning from a light to a heavy drinking state, or remaining in a heavy drinking state. Conclusions: The results from the present study suggest that depressive symptoms and alcohol craving increase proximal risk for alcohol use in individuals with co‐occurring bipolar and alcohol use disorders.     

The genetics of alcohol intake and of alcohol dependence

BACKGROUND: Because alcohol has multiple dose-dependent consequences, it is important to understand the causes of individual variation in the amount of alcohol used. The aims of this study were to assess the long-term repeatability and genetic or environmental causes of variation in alcohol intake and to estimate the degree of overlap with causes of susceptibility to alcohol dependence. METHODS: Data were used from three studies conducted between 1980 and 1995 on volunteer adult male and female Australian twin subjects. In each study, alcohol intake was reported both as quantity x frequency and as past-week data. Repeatability was calculated as correlations between occasions and between measures, and the effects of genes and environment were estimated by multivariate model fitting to the twin pair repeated measures of alcohol use. Relationships between mean alcohol use and the lifetime history of DSM-III-R alcohol dependence were tested by bivariate model fitting. RESULTS: Repeatability of the alcohol intake measures was between 0.54 and 0.85, with the highest repeatability between measures within study and the lowest repeatability between the first and last studies. Reported alcohol consumption was mainly affected by genetic factors affecting all times of study and by nonshared environmental factors (including measurement error) unique to each time of study. Genes that affect alcohol intake do affect alcohol dependence, but genetic effects unique to dependence are also significant; environmental effects are largely unique to either intake and dependence. CONCLUSIONS: Nearly all the repeatable component of variation in alcohol intake is due to genetic effects. Genes affecting intake also affect dependence risk, but there are other genes that affect dependence alone. Studies aiming to identify genes that affect alcohol use disorders need to test loci and candidate genes against both phenotypes.     

Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy

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.     

Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome

OBJECTIVE: (1) To perform a 9-year study of abstinence, lapse, and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as an adjunct for maintenance of long-term abstinence. METHOD: This prospective open treatment study evaluates the long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993 to 2002. Subsamples are compared for (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, and (3) AD use for 13 to 20 versus >20 months. RESULTS: In this 9-year study, the cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26. Despite long-term use, disulfiram/calcium carbimide was well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S = 0.86 vs. S = 0.49, p = 0.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p < 0.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p < 0.001). The cumulative abstinence probability was S = 0.75 for patients with long-term intake compared with S = 0.50 for patients who stopped AD between months 13 and 20 (p < 0.001). CONCLUSIONS: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.     

Effects of chronic alcohol dependence and chronic cigarette smoking on cerebral perfusion: a preliminary magnetic resonance study

BACKGROUND: Although approximately 80% of individuals with alcohol use disorders are chronic smokers and despite reported associations between chronic cigarette smoking and lower cerebral perfusion in nonalcoholics, previous brain perfusion studies with alcoholics did not account for the potential effects of concurrent chronic cigarette smoking. METHODS: One-week-abstinent alcohol-dependent individuals in treatment (ALC) [19 smokers (sALC) and 10 nonsmokers (nsALC)] and 19 healthy light drinking, nonsmoking control participants (nsLD) were scanned with a pulsed arterial spin labeling method to measure cerebral perfusion without an exogenous contrast agent. Studies were performed with 2 different postlabeling delay times (time from labeling pulse to the excitation pulse; PLD=1,500 ms and PLD=1,200 ms) to assess the potential effect of arterial blood transit time on the perfusion. Average gray matter (GM) and white matter (WM) perfusion for the frontal and parietal lobes were calculated for each hemisphere from voxels containing at least 90% GM and 100% WM. RESULTS: At PLD=1,500 ms, multivariate analyses compared ALC (combined sALC and nsALC) with nsLD (p=0.04) and contrasted sALC, nsALC, and nsLD (p=0.006). ALC, as a group, showed 13% lower frontal GM perfusion (p=0.005) and 8% lower parietal GM perfusion than nsLD (p=0.03). With ALC separated into smokers and nonsmokers, sALC showed 19% lower frontal GM perfusion (p=0.001) and 12% lower parietal GM perfusion than nsLD (p=0.004). In sALC, a higher number of cigarettes smoked per day was associated with lower perfusion. Overall, regional perfusion did not differ significantly between nsALC and nsLD. Results obtained with PLD=1,200 ms generally confirmed the 1,500 ms findings. CONCLUSIONS: This study provides preliminary evidence that chronic cigarette smoking adversely affects cerebral perfusion in frontal and parietal GM of 1-week-abstinent alcohol-dependent individuals. These results are in line with our spectroscopic and structural magnetic resonance studies that suggest chronic cigarette smoking compounds the detrimental effects of alcohol dependence on brain neurobiology.     

A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder

Background: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? Methods: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short‐tandem‐repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. Results: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. Conclusions: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.     

Prolactin serum levels during alcohol withdrawal are associated with the severity of alcohol dependence and withdrawal symptoms

Background: Prolactin serum levels have been described to be elevated during alcohol withdrawal in alcohol‐dependent patients and normalize during abstinence. Alterations in prolactin levels may reflect disturbances of dopaminergic neurotransmission which is of crucial importance for alcohol‐seeking behavior. Methods: In this longitudinal observational study, we investigated prolactin serum levels in 99 male patients during the first 14 days of alcohol withdrawal and early abstinence and in 43 healthy controls. To assess the severity of alcohol dependence, the extent of withdrawal symptoms, craving, depressive symptoms, and anxiety, we employed a structured interview including psychologic measurements. Results: Prolactin serum levels were elevated during the whole study period in alcohol‐dependent patients compared to the healthy control group. Prolactin levels at admission (first day of alcohol withdrawal) were associated with the severity of alcohol withdrawal (CIWA‐Ar) and of alcohol dependence (SESA) but not with the other assessed psychologic parameters. Conclusions: The presented findings confirm that prolactin is significantly elevated in alcohol‐dependent patients during alcohol withdrawal and early abstinence, not showing a rapid decline after cessation of drinking. The association with the severity of withdrawal and dependence may reflect at least partially the individual alterations in the dopaminergic and glutamatergic pathways.     

Effects of variation at the ALDH2 locus on alcohol metabolism, sensitivity, consumption, and dependence in Europeans

BACKGROUND: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. METHODS: Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. RESULTS: The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. CONCLUSIONS: Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.     

Alcohol dependence symptoms and alcohol dehydrogenase 2 polymorphism: Israeli Ashkenazis,Sephardics, and recent Russian immigrants

BACKGROUND: Jews have lower rates of alcohol-related problems than other Caucasians. The ADH2*2 allele of the alcohol dehydrogenase 2 (ADH2 ) gene protects against alcoholism in Asians and is found in approximately 20% of Jews. We studied the relationship of ADH2*2 to DSM-IV dependence severity in a random community sample of Israeli Ashkenazis, recent Russian immigrants (also Ashkenazis), and Sephardics. METHODS: Subjects participated in a structured interview that included highly reliable questions on DSM-IV alcohol dependence symptoms. ADH2 genotype was determined for 68 subjects. RESULTS: Recent Russian immigrants had more past and lifetime DSM-IV dependence symptoms. Sephardics had a higher prevalence of ADH2*2 than Ashkenazis. Controlling for group and other potentially confounding factors, ADH2*2 was associated with a lower lifetime DSM-IV alcohol dependence severity, although this differed somewhat within groups. CONCLUSIONS: ADH2*2 protects against dependence severity in Jewish samples. Future work in larger samples should address genetic and environmental factors that affect the relationship of ADH2*2 to alcohol consumption and dependence.     

The five-year predictive validity of each of the seven DSM-IV items for alcohol dependence among alcoholics

BACKGROUND: Information about the prognostic implications of a DSM-IV diagnosis of alcohol dependence is important to both clinicians and researchers. In this regard, only limited data are available on the performance of specific diagnostic items. METHODS: This study reports data gathered with a structured, validated interview with 642 alcohol-dependent men and women from the Collaborative Study of the Genetics of Alcoholism (COGA). The goals were to evaluate the ability of each of the DSM-IV dependence items to predict the occurrence over the next 5 years of a broad pattern of 27 alcohol-related problems. For comparison, similar data are reported regarding the performance of abuse criteria for 516 additional subjects. RESULTS: The results revealed that dependence item 3 (use of alcohol in larger amounts) was the only criterion that did not relate significantly to outcome, and indicated that the dependence criteria related relatively similarly to different types of outcomes among alcoholics. No specific combination of diagnostic items stood out in predicting outcome but, rather, the span of items generally performed well. CONCLUSIONS: These data support the potential usefulness of the DSM-IV dependence criteria.