Patrick K. Randall

Prospective Relations Between Social Support and Depression: Differential Direction of Effects for Parent and Peer Support?

The authors tested whether deficits in perceived social support predicted subsequent increases in depression and whether depression predicted subsequent decreases in social support with longitudinal data from adolescent girls (N = 496). Deficits in parental support but not peer support predicted future increases in depressive symptoms and onset of major depression. In contrast, initial depressive symptoms and major depression predicted future decreases in peer support but not parental support. Results are consistent with the theory that support decreases the risk for depression but suggest that this effect may be specific to parental support during early adolescence. Results are also consonant with the claim that depression promotes support erosion but imply that this effect may only occur with peer support during this period.

EFFECT OF NALTREXONE AND ONDANSETRON ON ALCOHOL CUE-INDUCED ACTIVATION OF THE VENTRAL STRIATUM IN ALCOHOL-DEPENDENT PEOPLE

CONTEXT Medication for the treatment of alcoholism is currently not particularly robust. Neuroimaging techniques might predict which medications could be useful in the treatment of alcohol dependence. OBJECTIVE To explore the effect of naltrexone, ondansetron hydrochloride, or the combination of these medications on cue-induced craving and ventral striatum activation. DESIGN Functional brain imaging was conducted during alcohol cue presentation. SETTING Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the magnetic resonance imaging suite of a major training hospital and medical research institute. PATIENTS Ninety non-treatment-seeking alcohol-dependent (by DSM-IV criteria) and 17 social drinking (< 14 drinks per week) paid volunteers recruited through advertisements at an academic center. INTERVENTIONS A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone (n = 23), 0.50 mg of ondansetron hydrochloride (n = 23), the combination of the 2 medications (n = 20), or matching placebos (n = 24). MAIN OUTCOME MEASURES Difference in brain blood oxygen level-dependent magnetic resonance when viewing alcohol pictures vs neutral beverage pictures with a particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving. RESULTS The combination treatment decreased craving for alcohol. Naltrexone with (P = .02) or without (P = .049) ondansetron decreased alcohol cue-induced activation of the ventral striatum. Ondansetron by itself was similar to naltrexone and the combination in the overall analysis but intermediate in a region-specific analysis. CONCLUSIONS Consistent with animal data that suggest that both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination, could decrease alcohol cue-induced activation of the ventral striatum, consistent with their putative treatment efficacy.

Patterns of gene expression in the frontal cortex discriminate alcoholic from nonalcoholic individuals.

Alcohol dependence is characterized by tolerance, physical dependence, and craving. The neuroadaptations underlying these effects of chronic alcohol abuse are likely due to altered gene expression. Previous gene expression studies using human post-mortem brain demonstrated that several gene families were altered by alcohol abuse. However, most of these changes in gene expression were small. It is not clear if gene expression profiles have sufficient power to discriminate control from alcoholic individuals and how consistent gene expression changes are when a relatively large sample size is examined. In the present study, microarray analysis (∼47 000 elements) was performed on the superior frontal cortex of 27 individual human cases (14 well characterized alcoholics and 13 matched controls). A partial least squares statistical procedure was applied to identify genes with altered expression levels in alcoholics. We found that genes involved in myelination, ubiquitination, apoptosis, cell adhesion, neurogenesis, and neural disease showed altered expression levels. Importantly, genes involved in neurodegenerative diseases such as Alzheimers disease were significantly altered suggesting a link between alcoholism and other neurodegenerative conditions. A total of 27 genes identified in this study were previously shown to be changed by alcohol abuse in previous studies of human post-mortem brain. These results revealed a consistent re-programming of gene expression in alcohol abusers that reliably discriminates alcoholic from non-alcoholic individuals.

Gene expression profiling of individual cases reveals consistent transcriptional changes in alcoholic human brain

Chronic alcohol exposure induces lasting behavioral changes, tolerance, and dependence. This results, at least partially, from neural adaptations at a cellular level. Previous genome‐wide gene expression studies using pooled human brain samples showed that alcohol abuse causes widespread changes in the pattern of gene expression in the frontal and motor cortices of human brain. Because these studies used pooled samples, they could not determine variability between different individuals. In the present study, we profiled gene expression levels of 14 postmortem human brains (seven controls and seven alcoholic cases) using cDNA microarrays (46 448 clones per array). Both frontal cortex and motor cortex brain regions were studied. The list of genes differentially expressed confirms and extends previous studies of alcohol responsive genes. Genes identified as differentially expressed in two brain regions fell generally into similar functional groups, including metabolism, immune response, cell survival, cell communication, signal transduction and energy production. Importantly, hierarchical clustering of differentially expressed genes accurately distinguished between control and alcoholic cases, particularly in the frontal cortex.

A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal.

INTRODUCTION Some anticonvulsants ameliorate signs and symptoms of alcohol withdrawal, but have an unacceptable side effect burden. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol that could increase psychomotor deficits, increase cognitive impairment, or increase intoxication. The aim of this study was to evaluate alcohol use and symptom reduction of gabapentin when compared with lorazepam in the treatment of alcohol withdrawal in a double-blinded randomized clinical trial. METHODS One hundred individuals seeking outpatient treatment of alcohol withdrawal with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) ratings > or =10 were randomized to double-blind treatment with 2 doses of gabapentin (900 mg tapering to 600 mg or 1200 tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg) for 4 days. Severity of alcohol withdrawal was measured by the CIWA-Ar on days 1 to 4 of treatment and on days 5, 7, and 12 post-treatment and alcohol use monitored by verbal report and breath alcohol levels. RESULTS CIWA-Ar scores decreased over time in all groups; high-dose gabapentin was statistically superior but clinically similar to lorazepam (p = 0.009). During treatment, lorazepam-treated participants had higher probabilities of drinking on the first day of dose decrease (day 2) and the second day off medication (day 6) compared to gabapentin-treated participants (p = 0.0002). Post-treatment, gabapentin-treated participants had less probability of drinking during the follow-up post-treatment period (p = 0.2 for 900 mg and p = 0.3 for 1200 mg) compared to the lorazepam-treated participants (p = 0.55). The gabapentin groups also had less craving, anxiety, and sedation compared to lorazepam. CONCLUSIONS Gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal in our population especially at the higher target dose (1200 mg) used in this study. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the immediate postwithdrawal week compared to lorazepam.

Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence

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

Phosphatidylethanol and alcohol consumption in reproductive age women.

BACKGROUND Fetal alcohol disorders are preventable, but self-reported alcohol consumption can be misleading and impede effective treatment. Biomarkers represent an alternative method for assessing alcohol use, and this study evaluated the relationship between blood phosphatidylethanol (PEth) and alcohol use in a sample of reproductive age women. METHODS Alcohol use was estimated by validated self-report methods in 80 nonpregnant women ages 18 to 35. PEth was measured by a contracted laboratory using a liquid chromatography-tandem mass spectrometry assay. Regression methods appropriate for the distribution of PEth were used to define its relationship to alcohol consumption during the prior 2 weeks and explore the effects of drinking patterns on this association. Receiver operating characteristic analysis was used to estimate the sensitivity of PEth for various drinking levels at 95% specific cutoffs. RESULTS PEth had a positive linear association with grams of alcohol consumed (p < 0.001), and was detectable in 93% of subjects consuming an average of 2 or more drinks per day. The relationship between total alcohol consumption and PEth may be stronger in women with recent heavy drinking days. The relationship between drinking and PEth varied considerably between individuals, and sensitivity for a certain amount of drinking was low at a highly specific cutoff concentration. CONCLUSIONS PEth is a highly sensitive indicator of moderate and heavy alcohol consumption in reproductive age women and may complement the use of self-report alcohol screens when additional objective markers of alcohol use are desirable. However, choosing a highly valid cutoff concentration for PEth to differentiate various levels of alcohol consumption may not be feasible.

A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence.

BACKGROUND There remains no FDA approved medication for the treatment of cocaine dependence. Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in the treatment of the disorder. OBJECTIVE The present report assessed the efficacy of NAC in the treatment of cocaine dependence. METHODS Cocaine-dependent volunteers (n = 111) were randomized to receive daily doses of 1,200 mg of NAC, 2,400 mg of NAC, or placebo. Participants were followed for 8 weeks (up to three visits weekly). At each of these visits, urine samples were collected, along with self-reports of cocaine use. Urine samples were assessed for quantitative levels of benzoylecognine (ie, cocaine metabolite). RESULTS Overall, the primary results for the clinical trial were negative. However, when considering only subjects who entered the trial having already achieved abstinence, results favored the 2,400 mg NAC group relative to placebo, with the 2,400 mg group having longer times to relapse and lower craving ratings. CONCLUSION While the present trial failed to demonstrate that NAC reduces cocaine use in cocaine-dependent individuals actively using, there was some evidence it prevented return to cocaine use in individuals who had already achieved abstinence from cocaine. SCIENTIFIC SIGNIFICANCE N-acetylcysteine may be useful as a relapse prevention agent in abstinent cocaine-dependent individuals.

Childhood Gender Nonconformity and Body Dissatisfaction in Gay and Heterosexual Men

Although researchers have long hypothesized a relation between gender role orientation (i.e., masculinity and femininity) and body dissatisfaction, findings have been inconsistent. The current study employed a measure of recalled childhood gender nonconformity to examine gender role behaviors in association with body dissatisfaction among an ethnically diverse (76% Caucasian, 2% African American, 8% Asian, and 16.4% Hispanic American) group of predominantly college-aged males of both homosexual (n = 129) and heterosexual (n = 52) orientation. Consistent with past research, gay males reported more body dissatisfaction and recalled more childhood gender atypical behaviors (e.g., disliking athletics, playing with dolls). Group differences in body dissatisfaction, however, disappeared when childhood gender nonconformity was statistically controlled, suggesting childhood atypical gender role behavior may place males at greater risk for adult body dissatisfaction. A within-group analysis also found that a “high feminine” subtype of gay males had greater body dissatisfaction than “less feminine” subtypes had. Results support the assertion that gender role behaviors may contribute to body dissatisfaction among gay males.

Preliminary evaluation of phosphatidylethanol and alcohol consumption in patients with liver disease and hypertension.

AIMS The goal of this preliminary study was to evaluate the relationship between blood phosphatidylethanol (PEth) and recent drinking in patients with liver disease and hypertension. METHODS Twenty-one patients with liver disease and 21 patients with essential hypertension were recruited at an academic medical center. Alcohol consumption was estimated using validated self-report methods, and blood PEth was measured by HPLC-MS/MS at a contracted laboratory. Nonparametric comparisons were made between abstainers/light drinkers, moderate drinkers consuming between 1 and 3 drinks per day, and those drinking above this level. Regression methods were used to estimate the effects of liver disease, gender, and age on the relationship between PEth and alcohol use, and to estimate the strength of the linear relationship between PEth and drinking. RESULTS PEth differed significantly between the three drinking groups (P < 0.001). The relationship between PEth and alcohol did not differ between hypertension and liver disease patients (P = 0.696), nor by gender and age. While there was substantial variability between subjects in the PEth concentration given a similar level of reported drinking, the amount of ethanol consumed was strongly associated with the PEth concentration (P < 0.001). CONCLUSION Results support PEth measurement by HPLC-MS/MS as a promising marker of past 1- to 2-week moderate to heavy alcohol consumption in patients with and without liver disease. PEth appears useful for differentiating abstinence or light drinking from moderate to heavy consumption, but may have limited utility for differentiating moderate from heavy alcohol use.