Dena Davidson

The Effect of Olanzapine on Craving and Alcohol Consumption

Previous studies have indicated that olanzapine decreases craving after a priming dose of alcohol, that craving after a priming dose of alcohol is greater among individuals with the seven-repeat allele of the DRD4 variable number of tandem repeats (VNTR) polymorphism, and that the effect of olanzapine (a D2/D4 antagonist) is more pronounced among individuals with this allele. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving and differentially effective as a treatment for alcohol dependence over the course of a 12-week, randomized, placebo-controlled trial among individuals with and without the seven-repeat allele. Participants who met DSM IV criteria for alcohol dependence were randomly assigned to receive olanzapine (5 mg) or a placebo over the course of the trial. After 2 weeks of treatment, participants completed a cue reactivity assessment. The results suggested that participants who were homozygous or heterozygous for the seven (or longer)-repeat allele of the DRD4 VNTR responded to olanzapine with reductions in cue-elicited craving as well as reductions in alcohol consumption over the course of the 12-week trial, whereas individuals with the shorter alleles did not respond favorably to olanzapine.

Role of the HPA Axis and the A118G Polymorphism of the μ-Opioid Receptor in Stress-Induced Drinking Behavior

AIMS The present study sought to investigate the relationship between the HPA axis reactivity to stress, the endogenous opioid system and stress-induced drinking behavior. METHODS In the present study, 74 non-treatment-seeking alcohol-dependent subjects were tested under two mood conditions, neutral and stress, in separate testing sessions. Salivary cortisol measurements were obtained following stress induction and during the neutral control condition. Multiple measurements of alcohol intake, latency to access the alcohol cue and craving for alcohol were obtained during cue-availability testing. In addition, 52 of the study subjects were genotyped for the mu-opioid receptor. RESULTS A blunted cortisol response to stress was significantly correlated with increased alcohol intake following stress exposure compared to alcohol intake during the neutral session. There was not a clear correlation between the change in cortisol in response to stress and the change in latency to access alcohol or alcohol craving in response to stress. Carriers of the Asp40 variant of the mu-opioid receptor exhibited a dampened cortisol response to stress, higher alcohol intake and greater craving in response to stress compared to Asn40 homozygotes, although these differences were not statistically significant. CONCLUSIONS The results of the present study indicate that a blunted biological stress response was correlated with increased drinking in response to stress. The Asp40 variant of the mu-opioid receptor may be associated with this HPA axis hyporeactivity although the small sample size used in the present study did not permit adequate evaluation of this association.

Influence of naltrexone on cue-elicited craving among hazardous drinkers: The moderational role of positive outcome expectancies.

This study was designed to elucidate mechanisms by which naltrexone (NTX) influences drinking among hazardous drinkers. Thirty-six hazardous drinkers received 50 mg NTX or placebo on 2 separate occasions before participation in a taste test procedure with low-alcohol beer. Urges to drink before consumption, beer volume consumed, and perceived stimulation and sedation after consumption were assessed. Although NTX did not influence beer consumption, hazardous drinkers who reported high positive reinforcement expectancies rated their urges to drink as significantly lower when they were on NTX compared with placebo. Positive outcome expectancies also moderated the effects of NTX on subjective reports of stimulation following drinking. These findings suggest that naltrexone may be particularly effective at reducing alcohol cue-elicited positive reinforcement for those with high positive alcohol outcome expectancies.

Using the cue-availability paradigm to assess cue reactivity.

BACKGROUND A recent meta-analysis on cue-reactivity research revealed that cue-specific craving for alcohol is substantially less robust than craving measured for other drugs of abuse. The small effect sizes for alcohol underscore the need for more powerful methods of assessing cue reactivity in humans. The cue-availability paradigm is a modification of the conventional cue-reactivity paradigm and is intended to increase the sensitivity of measuring cue-reactivity to alcohol in humans. METHODS Seventeen non-treatment-seeking alcoholics were tested individually on two different sessions (after priming with alcohol and after priming with placebo-alcohol). Subjects were presented with a total of 32 cue-availability trials. On each trial, subjects were presented with either a target cue (alcohol) or a neutral cue (water). Each cue was available for drinking on 50% of the trials (availability condition). Cue-reactivity measures were self-reports of craving and mood. RESULTS The alcohol prime had a robust effect on craving. Irrespective of the availability of the cue for consumption or the type of cue, craving was consistently higher when subjects were primed with alcohol than with placebo-alcohol. Negative mood was also higher when it was assessed after the alcohol prime. Negative mood decreased in alcohol-primed subjects when the alcohol cue was available for consumption. The alcohol cue also had a significant, although more modest effect on craving. The alcohol cue consistently elicited higher levels of craving relative to the water cue. CONCLUSIONS These data suggest that the priming effects of alcohol may be a significant factor contributing to the experience of craving and maintenance of drinking. The study also introduces the cue-availability as an additional new method for investigating manipulations of cue-reactivity in alcoholics.

Effect of ethanol drinking and naltrexone on subsequent drinking in rats

The effects of several days of oral ethanol drinking paired with naltrexone (NTX) on subsequent ethanol drinking were investigated in rats. We hypothesized that repeated pairings of NTX combined with forced oral ethanol intake would extinguish ethanol drinking so that when NTX injections were terminated, voluntary oral ethanol drinking would be suppressed. Thirty-two male. Long-Evans rats were provided with alternate days of either 8% ethanol solution or water as the sole source of fluid. Intraperitoneal injections of 0, 2.5, or 5.0 mg of NTX hydrochloride were administered on the ethanol days. Following the termination of injections, rats were returned to unrestricted access to water and ethanol and 24-h measurements of fluid intake were recorded. NTX decreased ethanol intake 4 h, but not 24 h, after NTX injections. Despite the consumption of significant amounts of ethanol during NTX treatment, there was no change in voluntary oral ethanol intake patterns after NTX injections were terminated (reinstatement of voluntary ethanol drinking). Thus, NTXs reduction in ethanol intake was limited in duration and did not result in long-term extinction of ethanol drinking behavior.

The Development of a Broad Spectrum Treatment for Patients with Alcohol Dependence in Early Recovery.

Estimates of the prevalence of alcohol dependence among Americans approach 14% (Read, Kahler, & Stevenson, 2001). Alcohol dependence was once considered among the most recalcitrant of problem behaviors, with only 20% to 30% attaining sustained abstinence (Hunt Barnett & Branch 1971). Although current definitions of treatment success now consider lapses and recycling (e.g., DiClemente, 2003), sustained abstinence remains the gold standard and is achieved in up to 60% of people in efficacy trials of current psychosocial treatments (e.g., Project MATCH). This article describes our efforts to develop the next-generation CBT treatment manuals for patients in early abstinence from alcohol, Broad Spectrum Treatment (BST). BST attempts to simultaneously address two seemingly incompatible treatment research goals. First, BST is a flexible but manual-guided treatment that can be standardized and used in the field with the broad spectrum of alcohol abusers. Second, BST seeks to maximize treatment effectiveness by tailoring the specific treatment package to the individual patients needs and capacities. Use of explicitly defined a priori decision trees is the vehicle through which these goals can be accomplished. This article describes the manual in its current form, and discusses the manner in which we are presently testing the efficacy of the manual as it stands.