Traumatic Brain Injury, Sleep Quality, and Suicidal Ideation in Iraq/Afghanistan Era Veterans.

The objective of this study was to test the hypothesis that sleep quality mediates the association between traumatic brain injury (TBI) history and current suicidal ideation. Measures of TBI history, sleep quality, and suicidal ideation were administered to 130 Iraq/Afghanistan veterans. As expected, sleep quality mediated the effect of TBI history on current suicidal ideation (indirect effect, 0.0082; 95% confidence interval, 0.0019-0.0196), such that history of TBI was associated with worse sleep quality, which was, in turn, associated with increased suicidal ideation. These findings highlight the importance of assessing TBI history and sleep quality during suicide risk assessments for veterans.

Effects of idazoxan on alcohol pharmacokinetics and intoxication: a preliminary human laboratory study.

BACKGROUND: Preliminary basic and human studies suggest that the α2 -adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects. METHODS: This was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40 mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition. RESULTS: There were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40 mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p < 0.01) and time to peak (p < 0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40 mg idazoxan with alcohol decreased alcohol-related stimulation (p < 0.05) and increased alcohol-related sedation (p < 0.05). CONCLUSIONS: This study supports the safety and tolerability of 40 mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients.

Family history of alcoholism mediates the frontal response to alcoholic drink odors and alcohol in at-risk drinkers.

Although a family history of alcoholism is the strongest risk factor for developing alcohol dependence, there are few studies of the association between familial alcoholism and the human brain's reward system activity. We used functional magnetic resonance imaging (fMRI) to determine how family history affects the brain's response to subjects' preferred alcoholic drink odors (AO) as compared to appetitive control odors (ApCO). Fourteen non-dependent heavy drinkers (HD) who were family history positive (FHP) participated, as did 12 HD who were family history negative (FHN). Subjects were imaged under both alcohol intoxication and placebo, using intravenous infusion and pharmacokinetic modeling to target a blood alcohol level of 50 mg%. Under placebo, HD-FHP had a larger medial frontal [AO>ApCO] effect than did HD-FHN. Alcohol intoxication dampened this response in the HD-FHP but potentiated it in the HD-FHN. This suggests that a family history of alcoholism and brain exposure to alcohol interact in heavy drinkers to differentially affect how the brain responds to alcohol cues.

Role of the HPA axis and the A118G polymorphism of the mu-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.

Alcohol sensitizes cerebral responses to the odors of alcoholic drinks: an fMRI study.

BACKGROUND: Small, priming doses of alcohol enhance desire to drink, and thus play a role in the loss of control of alcohol consumption. Using functional magnetic resonance imaging (fMRI), we previously showed that alcoholic drink odors (AO; subjects' drinks of choice) induce greater nucleus accumbens (NAc) activity than non-appetitive odors (NApO; grass, leather) in subjects at risk for alcoholism. Here we hypothesized that priming exposure to alcohol would enhance responses to AO in the NAc and orbitofrontal cortex in comparison to NApO (grass, leather) and to the appetitive control odors (ApCO) of chocolate and grape. METHODS: Ten hazardous drinkers (mean age = 22.7; SD = 2.9, average drinks per drinking day = 5.9, SD = 2.3; drinking days/90 days = 50.4, SD = 13.7) were scanned on a 1.5 T GE Signa MR scanner during intravenous infusion of lactated Ringer's or 6% ethanol in lactated Ringer's that was pharmacokinetically modeled to achieve a constant breath alcohol concentration (BrAC) of 50 mg% throughout imaging. During scanning, subjects sniffed AO, NApO, and ApCO. RESULTS: Alcohol infusion enhanced the contrast between AO and NApO in the NAc, and in orbitofrontal, medial frontal, and precuneus/posterior cingulate regions. The contrast between AO and appetitive control odors (ApCO; chocolate and grape) was similarly larger in the orbital, medial frontal, precuneus, and posterior cingulate/retrosplenial areas, with the most robust finding being a potentiated response in the posterior cingulate/retrosplenial area. The orbital region is similar to an area previously shown to manifest satiety-related decreases in activity induced by food cues. CONCLUSIONS: The results suggest that priming exposure to alcohol renders a limbic network more responsive to alcohol cues, potentially enhancing desire to drink.

Naltrexone's suppressant effects on drinking are limited to the first 3 months of treatment.

RATIONALE: Twelve weeks of naltrexone significantly improves drinking outcomes in alcoholics; however, the clinical benefits of naltrexone decline shortly after treatment is discontinued. OBJECTIVE: The present study investigated whether extended treatment with naltrexone significantly improved drinking outcomes. METHODS: One hundred forty-six alcohol-dependent patients received broad spectrum treatment or motivational enhancement therapy and either 12 or 24 weeks of naltrexone. The primary dependent variables were percent days abstinent and percent heavy drinking days. RESULTS: Using an intention-to-treat analysis, there were no significant differences in percent days abstinence or percent heavy drinking days at the end of phase 2 between patients who received 24 weeks of treatment with naltrexone (chi = 63.23) or patients who received 12 weeks of treatment with naltrexone followed by 12 weeks of treatment with placebo (chi = 65.82). Similarly, the average percent heavy drinking days was not significantly different at the end of phase 2 between the group that received 24 weeks of naltrexone (chi = 21.9) and the group that received 12 weeks of naltrexone followed by 12 weeks of placebo (chi = 22.14). Medication compliance was low in the second phase of the study. Drinking outcomes declined with declining compliance whether patients were taking naltrexone or placebo. CONCLUSIONS: The results of this study suggest that administering naltrexone beyond an initial 12 weeks of treatment may not be beneficial to all patients and should be administered along with close medical monitoring to insure compliance.

The Association Between Toxic Exposures and Chronic Multisymptom Illness in Veterans of the Wars of Iraq and Afghanistan.

OBJECTIVE: The purpose of this study was to determine if post-9/11 veterans deployed to the Iraq and Afghanistan conflicts experienced toxic exposures and whether they are related to symptoms of chronic multisymptom illness (CMI). METHODS: Data from 224 post-9/11 veterans who self-reported exposure to hazards in theater were analyzed using hierarchical regression. RESULTS: Of the sample, 97.2% endorsed experiencing one or more potentially toxic exposure. In a regression model, toxic exposures and CMI symptoms were significantly associated above and beyond covariates. Follow-up analyses revealed that pesticide exposures, but not smoke inhalation was associated with CMI symptoms. CONCLUSIONS: These findings suggest that toxic exposures were common among military personnel deployed to the most recent conflicts, and appear to be associated with CMI symptoms. Additional research on the impact of toxic exposures on returning Iraq and Afghanistan Veterans' health is needed.

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.

Predicting Suicide Risk in Trauma Exposed Veterans: The Role of Health Promoting Behaviors.

INTRODUCTION: Returning veterans of the wars in Iraq and Afghanistan experience high rates of post-traumatic stress disorder (PTSD) and suicidal behavior. Suicidal ideation is among the strongest risk factors for completed suicide. Some research suggests an association between PTSD and suicidal ideation, and that health-promoting behaviors-behaviors that sustain or increase well-being-play a role in this association. The current study examined whether health-promoting behaviors moderate the association between PTSD severity and suicidal ideation. METHODS: Veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF; N = 108) completed measures of PTSD symptoms, trauma exposure, suicidal ideation, and health-promoting behaviors. RESULTS: Moderated regression was used to test the hypothesis. Results indicated that health promoting behaviors, ß = -.06, p = .001, and PTSD symptoms, ß = .36, p < .001, were significantly related to suicidal ideation. Consistent with our main hypothesis, the health promoting behaviors x PTSD interaction term was significantly associated with suicidal ideation, ß = -.09, p = .001. The overall model accounted for 13% of the variance in suicidal ideation. Among individuals with high PTSD symptom severity, those who engaged in more health promoting behaviors reported less suicidal ideation than those who engaged in fewer health promoting behaviors. CONCLUSIONS: Health-promoting behaviors could be important for reducing suicidal ideation among veterans with high levels of PTSD symptoms. It is recommended that future research examine health promotion interventions as a means of reducing suicidal ideation.

Does participation in an alcohol administration study increase risk for excessive drinking?

It has long been thought that research protocols involving alcohol administration may exacerbate problem drinking in alcoholic subjects following their participation in such a study. However, recent studies suggest that involvement in an alcohol administration study does not, in fact, have a negative impact on subsequent drinking behavior. In the present study, 27 non-treatment-seeking alcohol-dependent subjects and 32 social drinkers participated in an alcohol administration study designed to investigate the effects of repeated doses of alcohol on craving, mood, and alcohol-seeking behavior. The volume of alcohol administered to the subjects was calculated in such a way that their blood alcohol concentration would reach a peak of 0.08 g/dl midway through testing. Before their release, alcohol-dependent subjects were given feedback regarding their level of alcohol consumption and provided with information about the potential harmful effects of their drinking behavior. Percentage of days abstinent (PDA), drinks per drinking day (D/DD), and percentage of heavy drinking days (PHDD, defined as >or=4 drinks per occasion for females and >or=5 drinks per occasion for males) were recorded for the 6 weeks preceding laboratory testing and for the 6 weeks following participation in the study. The alcohol-dependent subjects exhibited a significant increase of 24% in PDA during the poststudy period compared to the prestudy period. They also decreased their D/DD by 2.4 drinks per occasion, and decreased their PHDD by 21.6%. There were no differences in PDA or D/DD for the social drinkers between pre- and poststudy periods. There was, however, a small but significant increase of 3.5% in PHDD for the social drinkers following laboratory testing. These data suggest that participation in an alcohol administration study does not put alcoholic subjects at risk for increased alcohol consumption following study participation. In fact, participation in such studies may actually precipitate at least a temporary decrease in alcohol consumption, especially when paired with a brief intervention session. Thus, non-treatment-seeking alcoholics can be safely included in alcohol administration studies to provide results that are most relevant to the population of interest.

Assessing the stimulant effects of alcohol in humans.

The stimulant effects of alcohol were assessed in humans. Twenty social drinkers were tested in dyads in the laboratory on three separate occasions, held 7 days apart. For their first session, one-third of the group consumed a dose of alcohol that was calculated to reach a target peak blood alcohol concentration (BAC) of 0.05 g/dl, one-third of the group consumed placebo-alcohol, and one-third consumed diet Sprite. For alcohol and placebo-alcohol conditions, subjects were told that they may or may not be given alcohol. For the soda condition, subjects were told they were consuming soda. Subjective stimulation, activity levels, and speech production were assessed over a 15-min period after beverage consumption (posttreatment) and compared to measurements taken prior to beverage consumption (baseline). Scores on the stimulant subscale of the Biphasic Alcohol Effects Scale (BAES) were significantly greater for the alcohol condition relative to the soda condition. There was also a trend for stimulant scores to be greater for the alcohol condition relative to the placebo-alcohol condition. Activity levels were significantly greater for the alcohol condition compared to either the placebo-alcohol or soda conditions. There were no group differences found for speech production. Subjective stimulant score and activity levels were not correlated. Peak BAC obtained in subjects who consumed alcohol was not correlated with either subjective stimulant scores or activity levels. Activity levels may provide a useful behavioral assay for assessing the stimulant effects of alcohol in humans.

Naltrexone and brief counseling to reduce heavy drinking in hazardous drinkers.

The present study examined the utility of daily naltrexone for decreasing alcohol drinking in hazardous drinkers. Forty-one participants participated in a 10-week trial and received 30 min of brief counseling on the first and second week of treatment, as well as a daily dose of 50 mg of naltrexone throughout the trial. Overall, naltrexone-treated participants did not show the same degree of improvement on drinking outcomes as placebo-treated participants. The placebo group drank fewer drinks per drinking day and achieved more abstinence days than the naltrexone group. Craving was also lower for the placebo group. The groups were not balanced on gender or family history of alcoholism and this may explain the lack of effect of naltrexone on the drinking outcomes.

Effects of alcohol availability, access to alcohol, and naltrexone on self-reported craving and patterns of drinking in response to an alcohol-cue availability procedure.

OBJECTIVE: Craving has long been cited by patients and providers as a principal construct in alcohol use disorders and an essential target for treatment. The goal of the current study was to examine the effects of alcohol availability (20% vs. 80% availability), access to alcohol ("open" vs. "locked" trials), and medication (oral naltrexone [Revia] vs. placebo) on self-reported craving and two behavioral measures of drinking (latency of attempt to access alcohol, amount of alcohol consumed when access permitted) in response to an alcohol-cue availability procedure. METHOD: Non-treatment-seeking, alcohol-dependent men and women (N = 58) self-referred for an alcohol administration study and were administered a modified alcohol-cue availability procedure under two medication conditions (naltrexone, placebo) using a within-subjects, repeated-measures design. RESULTS: Analyses demonstrated that the experimental manipulations used in this study had differential effects on craving and patterns of drinking. Specifically, reduced availability of alcohol (i.e., when alcohol was available in only 20% as opposed to 80% of trials) resulted in greater amounts of alcohol consumed per open trial; the unanticipated blocking of access to alcohol (i.e., a "locked" trial during the 80% availability condition) triggered more rapid attempts to obtain alcohol on subsequent trials. Naltrexone, relative to placebo, was associated with significant reductions in cravings for alcohol. CONCLUSIONS: Taken together, these findings offer partial support for the cognitive processing model and reinforce the utility of evaluating both self-report and behavioral indicators of motivation to drink in studies designed to identify factors associated with the construct of craving.

Extended naltrexone and broad spectrum treatment or motivational enhancement therapy.

BACKGROUND: Randomized clinical trials on the effectiveness of naltrexone (NTX) in the treatment of alcohol dependence have produced conflicting results. One possible explanation for these discrepancies may lie in the various psychosocial treatments for which NTX is an adjunct. The goal of this study was to examine the interplay between psychosocial treatment and duration of NTX. METHODS: One hundred and seventy-four alcohol-dependent outpatients participated in a double-blind trial where they were randomly assigned to 12 vs. 24 weeks NTX duration and to one of two psychosocial treatments: motivational enhancement therapy (MET) and broad spectrum treatment (BST), a cognitive behavioral therapy tailored to the patient's specific needs. After an initial 12-week period of NTX and psychosocial treatment, half of each psychotherapy condition was assigned to continue NTX for an additional 12 weeks while the other half was assigned to placebo. Patient drinking outcomes were measured for the year following treatment completion. It was hypothesized that the combination of extended duration of NTX and the moderate intensity of BST would be predictive of longer time to a first heavy drinking day than any of the three alternative combinations: MET with short or extended NTX administration or BST with short NTX administration. RESULTS: The median time to first drink and time to first heavy drinking day were found to be significantly longer for patients who received BST and extended NTX than for patients in the other three groups. CONCLUSIONS: These results may suggest that the kind of psychosocial treatment delivered in combination with duration of NTX administration may partially explain the inconsistent findings regarding the efficacy of NTX in the treatment of alcohol dependence.

Building better cognitive-behavioral therapy: is broad-spectrum treatment more effective than motivational-enhancement therapy for alcohol-dependent patients treated with naltrexone?

OBJECTIVE: The current study investigated the treatment effectiveness, during treatment, of a second-generation cognitive-behavioral therapy for alcoholism--broad-spectrum treatment (BST)--compared with motivational-enhancement therapy (MET), when both were offered in conjunction with a therapeutic dose of naltrexone (Revia). METHOD: One hundred forty-nine alcohol-dependent patients completed a 3-month randomized, controlled trial of BST and naltrexone versus MET and naltrexone. RESULTS: Patients receiving BST had a significantly higher percentage of days abstinent than patients receiving MET. The superior effect of BST is particularly strong in interaction with support for drinking, suggesting that the advantage of BST is worth the additional cost for patients whose psychosocial networks are supportive of continued drinking. This effect remains significant when controlling for pretreatment percentage of days abstinent. CONCLUSIONS: In aggregate, these findings suggest that it is either the combination of naltrexone and BST or the unique properties of BST that account for BST's superiority to MET and naltrexone. The results of this initial phase of the trial suggest that a second-generation cognitive-behavioral therapy such as BST may have a meaningful clinical advantage over brief interventions such as MET, at least when combined with naltrexone.

Preclinical and clinical studies on naltrexone: what have they taught each other?

Proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California; organized and co-chaired by Janice C. Froehlich and Stephanie O'Malley. The presentations were (1) Introduction, by Janice C. Froehlich and Stephanie O'Malley; (2) Preclinical studies on naloxone: genetics and site of action, by Petri Hyytiä; (3) Clinical studies on naltrexone for treating hazardous drinkers, by Dena Davidson; (4) Clinical studies on naltrexone and sertraline in the treatment of alcohol dependence, by Conor Farren; and (5) Discussion by Janice D. Froehlich, Stephanie O'Malley, and Rainer Spanagel. Both preclinical and clinical studies are critical in the development of effective pharmacotherapeutic approaches for the treatment of alcoholism. Nowhere has this been more evident than in the development of naltrexone for the treatment of alcohol relapse. As research continues on the optimal use of naltrexone for modifying alcohol intake, a number of factors have emerged that are likely to determine the efficacy of naltrexone as a pharmacotherapeutic agent for the treatment of alcoholism. Some of these factors include dose, frequency and duration of treatment, pattern and severity of alcohol drinking prior to initiation of naltrexone treatment, genetic aspects of responsive subpopulations, degree of alcohol craving, and susceptibility to adverse effects of naltrexone. New, as well as established, animal models are being used to determine the parameters that optimize the ability of naltrexone to modify alcohol drinking in acute and chronic alcohol access paradigms, under conditions of intermittent versus continuous alcohol intake, and in populations that vary in genetic predisposition toward alcohol drinking. Current clinical studies are exploring the ability of naltrexone to alter alcohol drinking when delivered in combination with pharmacotherapeutic agents that act on nonopioid transmitter systems and the difference in efficacy of naltrexone when administered in populations that differ in drinking frequency and intensity, family history of alcoholism, and alcohol craving. This symposium presented new research findings from both preclinical and clinical studies with the aim of facilitating the development of treatment regimens that optimize the therapeutic potential of naltrexone in the treatment of alcoholism.

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.