Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption

Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption Joshua L. Gowin, Ph.D., Matthew E. Sloan, M.D., M.Sc., Bethany L. Stangl, Ph.D., Vatsalya Vatsalya, M.D., M.Sc., Vijay A. Ramchandani, Ph.D.

Objective: Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health out- comes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested thehypothesis that risk factors foralcoholusedisorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session.

Method: This cross-sectional study included 159 young so- cial drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional

hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure.

Results:Agreaterpercentageofrelativeswithalcoholism(hazard ratio: 1.04, 95% CI=1.02–1.07), male sex (hazard ratio: 1.74, 95% CI=1.03–2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participantswith all three risk factors had the highest rate of binging throughout the session compared with the lowest riskgroup(hazard ratio:5.27,95%CI=1.81–15.30).

Conclusions: Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.

AmJPsychiatry2017;174:1094–1101;doi:10.1176/appi.ajp.2017.16101180

Alcohol use disorder has a lifetime prevalence of nearly one in three individuals intheUnitedStates (1).An importantgoal is to identify at-risk individuals prior to the development of this disorder so that they canbe targeted for early intervention.One way to determine early phenotypic differences in those at risk is to examine behavior at the level of an individual drinking session. For example, the rate of drinking and total alcohol exposuremay differ between those at high and low risk. These parameters, however, are difficult to quantify in the field be- cause of the lack of instruments that can continuously and accurately monitor blood alcohol concentration. Furthermore, asking individuals to report details about their rate of con- sumption does not account for variability in absorption and metabolism (2) and would likely be inaccurate because in- toxication impairs recall (3). Despite these measurement difficulties, there is evidence that the rapid consumption of large quantities of alcohol leading to a blood alcohol con- centration of 80 mg%, defined as binge drinking (4), affects psychological and physical well-being. Binge drinking is associatedwith greater riskof negativehealth consequences

(e.g., myocardial infarction) and legal trouble (5, 6). Binge drinking may signify an innate preference for higher brain alcohol exposure and may begin before an individual meets criteria for an alcohol use disorder, but this hypothesis has never been empirically tested.

Onemethod to assess alcohol consumption that overcomes many of these measurement difficulties is intravenous alcohol self-administration (7). This method has shown good test- retest reliability and external validity (8, 9) and has been employed in pharmacological (10) and genetic studies (11). Intravenous alcohol self-administration has several advan- tages over oral self-administration. Whereas oral adminis- tration at fixed doses can result in up to threefold variability in alcohol exposure between individuals as a result of phar- macokinetic differences (12, 13), intravenous administration standardizes alcohol exposure by bypassing gastrointestinal absorption and first-pass metabolism. Interindividual differ- ences in alcohol distribution and elimination are accounted for by using an infusion algorithm that adjusts for age, sex, height, and weight (2). Accordingly, each infusion increases

See related features: Editorial by Dr. Petrakis (p. 1034), Clinical Guidance (Table of Contents), CME course (p. 1127), AJP Audio (online), and Video by Dr. Pine (online)

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ARTICLES

 

 

alcohol levels by a fixed quantity, allowing the infusion software to provide continuous esti- mates of blood alcohol levels that closely track brain alcohol exposure (14) and breathalyzer readouts(15).Theseestimatescanthenbeusedto measurean individual’s total alcohol exposure, as wellashowquicklytheindividualreachesabinge level of exposure. This paradigm also eliminates specific cues associated with oral alcoholic bev- erages, including taste, smell, and appearance.As a result, intravenous self-administration should be driven primarily by alcohol’s pharmacody- namic effects, such as dopamine release in the nucleus accumbens (16). This method is there- fore ideal to determine whether preference for higher alcohol exposure is evident prior to the development of alcohol use disorder among in- dividuals with biological risk factors.

The DSM-5 lists the following genetic and physiological risk factors for alcohol use dis- order (17): family history of alcoholism (18), male sex (1), impulsivity (19), absence of acute alcohol-related skin flush (20), pre-existing schizophrenia or bipolar disorder (21), and low level of response toalcohol (22).Although these factorsmarkedly increase the risk of developing alcohol use disorder, it remains unclear how they affect the likelihood of risky drinking patterns prior to disorder onset. In the present study, we examined the largest community sample to date of young adult social drinkers using intravenous alcohol self-administration. We investigated whetherthegeneticandphysiological riskfactors listed inDSM-5 (except for skinflush and comorbid psychiatric disorders, which were exclusion criteria) were associated with the rate of binge- level exposure during an individual drinking session. We hy- pothesized that individuals at higher risk for developing an al- cohol use disorder would exhibit a preference for higher brain alcohol exposure as demonstrated by higher rates of binging throughout thesessionandhigher levelsof totalalcoholexposure.

METHOD

Participant Characteristics A total of 162 social drinkers between the ages of 21 and 45 were recruited through newspaper advertisements and the National Institutes of Health (NIH) Normal Volunteer Office (for detailed demographic information, seeTable 1 and Tables S1–S3 in the data supplement accompanying the online version of this article). To be included, participants must have consumed at least five drinks on one occasion at one point in their life. Participants completed a telephone screen and sub- sequently completedan in-personassessment at theNIHClinical Center in Bethesda, Md. The study protocol was approved by theNIHAddictions Institutional ReviewBoard, and participants were enrolled after providing written, informed consent.

Participants were excluded if they met any of the fol- lowing 10 exclusion criteria: 1) nondrinker; 2) lifetimehistory

ofmood, anxiety, or psychotic disorder; 3) current or lifetime history of substance dependence (including alcohol and nicotine); 4) recent illicit use of psychoactive substances; 5) history of acute alcohol-related skin flush; 6) regular to- bacco use (.20 uses/week); 7) history of clinically significant alcohol withdrawal; 8) lifetime history of suicide attempts; 9) current or chronic medical conditions, including cardiovascular conditions, requiring inpatient treatment or frequent medical visits; or 10) use of medications that may interact with alcohol within 2weeks prior to the study. Femaleswere excluded if they were breastfeeding or pregnant or if they intended to become pregnant.

All participants were assessed for psychiatric diagnoses, history of acute alcohol-related skin flush, drinking history, andother risk factors foralcoholusedisorder.Diagnoseswere assessed by the StructuredClinical Interview forDSM-IVAxis I disorders (23). History of acute alcohol-related skin flush was assessedusingtheAlcoholFlushingQuestionnaire(24).Drinking history was assessed using the Alcohol Use Disorder Identifi- cation Test (25). Two participants were excluded from this analysisbecause theywereheavydrinkersbasedon theTimeline Followback Interview (.20drinks/week formales,.15 drinks/ week for females). One participant was excluded because software failure caused the session to be terminated prior to minute 20 of the alcohol self-administration session, resulting in a final sample size of 159 participants.

Alcohol Use Disorder Risk Factor Measures Family history. Participants completed the Family Tree Questionnaire (26) to identify first- and second-degree rel- atives who may have had alcohol-related problems. They subsequently completed the family history assessment plus

TABLE 1. Characteristics of the Sample by Sex

Characteristic Male (N=86) Female (N=73)

Mean SD Mean SD

Age (years) 26.4 5.2 25.8 5.0 Family history densitya,b 3.6 8.5 2.6 6.9 Delay discountinga,c –4.7 1.8 –4.5 1.7 Level of alcohol responsed,e 4.8 2.1 3.7 1.7 Alcohol Use Disorder Identification Test score 5.8 2.5 5.1 2.8

N % N %

Family history positive 17 19.8 11 15.1 Current alcohol abusea 2 2.4 2 2.7

a Dataweremissing for someparticipants (family history, N=158; delay discounting, N=134; current alcohol abuse, N=158).

b Family history density was obtained by dividing the number of first- and second-degree relatives withanalcoholusedisorderby the total numberoffirst- andsecond-degree relatives; it is reported as a percentage. The value displayed represents themean and SD for thewhole sample (see Table S1 in the online data supplement for family history density in the family history positive group).

c Delaydiscounting isabehavioralmeasureof impulsivity inwhichparticipantschoosebetweensmaller immediate or larger delayed rewards; values are reported as the natural logarithmof the discounting constant, k; lower values of ln(k) indicate lower degrees of delay discounting and less impulsivity.

d Level of alcohol response is derived from the Self-Rating of the Effects of Alcohol form, assessing response during the first five drinking occasions; the final score represents the mean of the number of drinks needed to achieve four possible intoxication-related outcomes, with a higher number indicating a lower level of response to alcohol.

e Male and female participants showed statistically different distributions for level of alcohol re- sponse using the Mann-Whitney test (Zu=3.7, p,0.01).

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individual assessment modules of the Semi-Structured As- sessment for Genetics of Alcoholism for all identified relatives (27). This assessment is widely used in family history-based studies, including large genetic studies, such as the Collabo- ration on the Genetics of Alcoholism (28). If no information was available about a relative, then that relativewas scoredas a 0. Relatives with a known history of alcohol-related problems werescoredasa1.Afamilyhistorydensityscorewascalculated by dividing the number of relatives with alcohol problems by the total number of first- and second-degree relatives. One participant did not complete this measure, and his value was imputedwith the samplemedian of 0 given that family history density was not normally distributed (Shapiro-Wilk test: p,0.001). We conducted all models with and without this participant and found that his exclusion did not alter our findings, and thus we report the results with this participant included.

Behavioral impulsivity. Participants completed a delay dis- counting task (29), which is a well-validated measure of behavioral impulsivity that has a robust association with alcohol use disorder (30, 31). During this task, participants chose between smaller immediate rewards or $100 re- ceived after a delay (e.g., $90 now or $100 in 7 days). Im- mediate rewards ranged in value from $0 to $100, and delay periods ranged from 7 to 30 days. The degree of discount- ing delayed rewards, k, can be calculated using the equation developed by Mazur et al. (32). Since k values were not normally distributed, they were normalized using a loga- rithmic transformation and reported as ln(k). Lower values of ln(k) suggest less impulsivity and lower degrees of dis- counting. A portion of the sample did not complete this task (N=25), and missing values of ln(k) were imputed with the sample mean.

Level of response to alcohol. Participants also completed the Self-Rating of the Effects of Alcohol form (33). This in- strument assesses response to alcohol during the first five drinking occasions of a person’s life, their heaviest drinking period, and their most recent drinking period. For each period, it asks how many drinks it took for them to feel different, to feel dizzy, to begin stumbling, and to pass out. The final score represents the mean of the number of drinks needed to achieve each outcome, with a higher number of drinks indicating a lower level of response to alcohol. We focused on the first five drinking occasions in the present analyses to reduce the potentially confounding impact of tolerance.

Intravenous Alcohol Self-Administration Participants were instructed not to drink alcohol in the 48 hours prior to study procedures. Upon arrival, they provided a breathalyzer reading to confirm abstinence. Participants also provided a urine sample that was tested for illicit drugs and, for females, pregnancy; bothhad to benegative to proceed with the study session. After the participant ate a

standardized (350 kcal) meal, an intravenous catheter was inserted into a vein in the forearm. Self-administration was conducted using the computer-assisted alcohol infusion systemsoftware,whichcontrolled the rateof infusionof 6.0% v/v alcohol in saline for each individual using a physiologi- cally based pharmacokinetic model for alcohol distribu- tion andmetabolism that accounts for sex, age, height, and weight (2).

The alcohol self-administration session consisted of a 25-minuteprimingphase anda 125-minute free-accessphase. During the first 10minutes of the priming phase, participants were required to push a button four times at 2.5-minute intervals. Each button press resulted in an alcohol infu- sion that raised blood alcohol concentration by 7.5 mg% in 2.5 minutes, such that participants achieved a peak con- centration of approximately 30mg%atminute 10. During the next 15 minutes, the button remained inactive while par- ticipants experienced the effects of the alcohol. Atminute 25, the free-access phasebegan, andparticipantswere instructed to “try to recreate a typical drinking session outwith friends.” Participants could self-administer ad libitum, but they had to wait until one infusion was completed before initiating another. Blood alcohol concentration was estimated con- tinuously by the software based on infusion rate and model- estimated metabolism, and a readout was provided at 30-second intervals. Breath alcohol concentration was also obtained via breathalyzer at 15-minute intervals to confirm the software-calculated estimates; these readings were en- tered into the software to provide the model feedback, and the infusion rate was automatically adjusted accordingly (2). Software estimates of blood alcohol concentration were used to determine whether a participant reached binge- level exposure, defined as achieving an estimated blood alcohol concentration greater than 80mg% (4). A limit was imposed such that estimated blood alcohol concentration could not exceed 100 mg% to prevent adverse events due to intoxication.

Statistical Analysis To examine whether risk factors for alcohol use disorder were predictors of rate of binging throughout the free- access phase of the intravenous alcohol self-administration session, we plotted Kaplan-Meier survival curves and conductedCoxproportional hazardsmodels.Wegenerated the following four Kaplan-Meier survival curves using binary variables (Figure 1): 1) male compared with female; 2) family-history positive compared with negative; 3) high compared with low impulsivity (median split); and 4) high compared with low level of response to alcohol (median split). For the Cox proportional hazards analyses, the outcome variable was time to binge (estimated blood al- cohol concentration of 80 mg%), and participants were censored when they reached a binge or ended the session early (one participant). For the initial Cox proportional hazards model, five independent variables were included: sex was coded as a binary variable (0 for females, 1 for

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males), and delay discounting, family history density, level of response to alcohol, and age were entered as continuous variables.

To determine whether faster rate of consumption translated into greater overall exposure to alcohol, we cal- culated the area under the curve for the estimated breath alcohol concentration by time plot during the free-access phase of the session. Three individuals ended the session early due to software malfunction or adverse events (at minutes 59, 88.5, and 99.5); thus, in order to generate the area under the curve for these participants, we imputed values for

the remainder of the session by carrying their last observed alcohol concentration forward. To confirm the validity of this approach, we applied the same imputation procedure for 20 random participants starting at minute 59 and found that the imputed values correlated highly with the actual values (Spearman’s rho.0.9).WeconductedMann-Whitney tests to compare area under the curve distributions for each risk factor, as area under the curve valueswere not normally distributed (Shapiro-Wilk test: p,0.05). For these analy- ses, we used the binary categorical risk factors described above.

FIGURE 1. Cumulative Probability of Achieving Binge-Level Exposure by Each Alcohol Use Disorder Risk Factora

Time (minutes)

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Delay Discounting Family History

Level of Response to Alcohol Sex

a Cumulative probability of achieving a binge-level exposure (estimated breath alcohol concentration of 80 mg%) was higher in males compared with females, in family-history positive compared with family-history negative individuals, in high compared with low delay discounters, and in low compared with high responders to alcohol.

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To assess the additive effects of significant variables from the aforementioned analyses, we coded individuals according to their number of risk factors for alcohol use disorder. For this analysis, we only used the binary risk factors described above, excluding level of response to al- cohol, which did not contribute to the aforementioned models. We thus created four groups: zero-, one-, two-, and three-risk factor groups. The zero-risk factor group served as the reference group. We plotted Kaplan-Meier survival curves to examine differences between groups and also to fit a Cox proportional hazards model additionally adjusted for age. We also tested whether there was evidence of additive effects of risk factors on overall alcohol exposure during the session by comparing the area under the curve values for different risk groups using a Jonckheere-Terpstra test (34, 35).

RESULTS

Effect of Risk Factors on Rate of Binging Overall, 60 participants achieved a binge-level exposure, and 99 participants had estimated blood alcohol concentrations beneath 80 mg% across the entire session. A higher per- centage of bingers was found in family-history positive compared with negative individuals (57.1% and 33.1%, respectively),males comparedwith females (43.0%and31.5%, respectively), high compared with low delay-discounting in- dividuals (49.3% and 29.9%, respectively), and those with a low compared with high level of response to alcohol (43.8% and 32.6%, respectively) (Figure 1).

We tested whether risk factors for alcohol use disorder predicted the rate of binging throughout the session using a Cox proportional hazards model with all four risk factors and age as independent variables (model 1). Family history density was a significant predictor (hazard ratio=1.04, 95% confidence interval [CI]=1.02–1.07, p=0.001), whereas male sex (hazard ratio=1.71, 95%CI=1.00–2.94, p=0.052) and delay discounting (hazard ratio=1.17, 95% CI=1.00–1.37, p=0.056) weremarginally significant. Level of response to alcohol was not a significant predictor of the rate of binging throughout the session (hazard ratio=1.01, 95% CI=0.89–1.15, p=0.840) (Table 2). Because the level of response was not contribut- ing to the model and was significantly correlated with sex (Spearman’s rho=0.29, see Table S4 in the online data supplement), we dropped it from themodel. In this second analysis (model 2), male sex (hazard ratio=1.74, 95% CI=1.03–2.93, p=0.038), delay discounting (hazard ratio=1.17, 95% CI=1.00–1.37, p=0.048), and family history density (hazard ratio=1.04, 95% CI=1.02–1.07, p=0.002) all signifi- cantly predicted binge rate throughout the session. The effects of these risk factors remained consistent when controlling for the Alcohol Use Disorder Identification Test score (model 3). As would be expected, participants with a higher Alcohol Use Disorder Identification Test score were more likely to binge (hazard ratio=1.14, 95% CI=1.04–1.24, p=0.004).

Effects of Individual Risk Factors on Total Alcohol Exposure We also tested whether each individual risk factor was as- sociated with total alcohol exposure as measured by the area under the estimated blood alcohol concentration versus time curve during the free-access phase.Median alcohol exposure was higher in family-history positive individuals, males, and participants with delay-discounting scores above themedian (see Figure S1 in the online data supplement), with sig- nificantly different distributions across sex and delay- discounting groups and marginal significance across family history groups (family history:U[28, 130]=2247, p=0.052; sex: U[86, 73]=3763, p=0.031; delay discounting: U[67, 67]=2839, p=0.008). There was no significant difference between those with high and low levels of alcohol response (U[73, 86]=2619, p=0.072).

Additive Effects of Risk Factors on Rate of Binging To investigate whether the significant risk factors from the prior analysis had additive effects, we divided participants basedontheirnumberof risk factors into fourgroups: zerorisk factors (N=26), one risk factor (N=65), two risk factors (N=36), and three risk factors (N=8), where zero risk factors indicates a family-history negative female with a delay-discounting score below the median (Figure 2) (see Table S5 in the online data supplement for characteristics of the sample by risk factor group). Cox proportional hazards regression controlling for age demonstrated that compared with the zero-risk factors group, individuals in the two-risk factors group (hazard ratio=2.54, 95%CI=1.05–6.12,p=0.038)and three-risk factors group (hazard ratio=5.27, CI=1.81–15.30, p=0.002) binged at higher rates throughout the session. The zero- risk factors group and the one-risk factor group did not differ (hazard ratio=1.29, 95% CI=0.55–3.04, p=0.562). These effects remained significant when controlling for the level of alcohol response as a continuous variable and the AlcoholUseDisorder IdentificationTest score (seeTableS6 in the online data supplement).

Additive Effects of Risk Factors on Total Alcohol Exposure Individuals with a greater number of risk factors achieved higher levels of alcohol exposure, with median area under the curve values of 2132.5 mg%*min, 3814.8 mg%*min, 4565.7 mg%*min, and 7208.5 mg%*min for individuals with the lowest to highest number of risk factors, respec- tively. The results of a Jonckheere-Terpstra test for ordered alternatives indicated that there was a significant effect of number of risk factors on the distribution of area under thecurvevalueswithasmall-to-mediumeffect size (TJT=3746.0, p=0.001, Kendall’s t=0.22) (Figure 3). Bonferroni-corrected pairwise comparisons indicated that the distribution of the areas under the curve for the two- and three-risk factors groups were significantly different than that of the zero-risk factors group, and the three-risk factors group distribution of area under the curve values also

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differed from that of the one-risk factor group (all p values ,0.05).

DISCUSSION

Young social drinkers at risk for an alcohol use disorder had consumption patterns that were markedly different from low-risk drinkers during a free-access intravenous alcohol self-administration session. Vulnerable drinkers had higher rates of binging throughout the session and greater overall exposure to alcohol. The effects of these risk factors were additive. This finding is especially remarkable given the similarity of Alcohol Use Disorder Identification Test scores between the higher- and lower-risk groups and given that these effects remained largely unchanged when control- ling for test scores. To our knowledge, this is the first large pharmacokinetically controlled study to show that the presence of risk factors for alcohol use disorder leads to different patterns of drinking at the level of an individual drinking session in young social drinkers who have not yet developed the disorder. These findings suggest an innate neurobiological preference for higher alcohol exposure that may contribute to alcohol use disorder risk.

Of the factors we examined, family history of alcoholism was most strongly associated with the rate of binging dur- ing the session, with a small-to-medium effect size. This finding is in accordance with epidemiologic studies showing that up to one-half of the risk of alcoholism is genetic and corroborates the results of a small intravenous alcohol self- administration study demonstrating that family-history positive individuals achieved higher alcohol exposures (36). Our study extends these intravenous alcohol self- administration results by showing that participants with a greater percentage of biological relatives with alcohol problems were at greater risk. Our study also found higher rates of alcohol consumption in males compared with fe- males,which is consistentwith a recent studyof intravenous alcohol self-administration in adolescents (9). Delay discount- ing has previously been observed as a predictor of labo- ratory alcohol consumption (8), and we confirmed that here. The level of response to alcohol was not related to the rate of binging or total alcohol exposure in our study. This may be

partially due to the surprising fact that participants with a low level of response to alcohol in our study actually had lower family history densities for alcoholism than partici- pants with a high level of response (see Table S3 in the online data supplement), which is the opposite of what has been found in most studies (37), although controlling for family history density did not change our results. Level of response to alcohol may have been influenced by recall bias and may have shown more predictive power if it had been assessed experimentally, as in the original studies by Schuckit (22). Despite some evidence that level of response may vary as a function of rate of change in blood alcohol concentration and drinking history (37, 38), we chose to use a simpler static measure of level of response here. More complex assess- ments of level of response may yield different results.

There were several limitations to this study, most notably the cross-sectional design. Longitudinal studies will be

TABLE 2. Hazard Ratios From Cox Proportional Hazards Models Examining the Effect of Alcohol Use Disorder Risk Factors on Rate of Binginga

Variable

Model 1 Model 2 Model 3

Hazard Ratio 95% CI Hazard Ratio 95% CI Hazard Ratio 95% CI

Family history density (%) 1.04 1.02–1.07 1.04 1.02–1.07 1.04 1.02–1.07 Male sex 1.71 1.00–2.94 1.74 1.03–2.93 1.67 0.99–2.82 Delay discounting 1.17 1.00–1.37 1.17 1.00–1.37 1.17 1.00–1.37 Level of alcohol response 1.01 0.89–1.15 — — — — Age (years) 0.90 0.83–0.97 0.90 0.83–0.96 0.91 0.85–0.98 Alcohol Use Disorder Identification Test score — — — — 1.14 1.04–1.24

a Model 1 examined alcohol use disorder risk factors and age; model 2 excluded level of alcohol response because it was significantly correlated with sex and did not contribute to model 1; model 3 also accounted for the Alcohol Use Disorder Identification Test score to control for the effect of alcohol consumption; for all three models, female sex is the reference group.

FIGURE 2. Cumulative Probability of Achieving Binge-Level Exposure by Alcohol Use Disorder Risk Factor Groupa

Risk Factors

0 (N=26)

1 (N=65)

2 (N=36)

3 (N=8)

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a Each participant was categorized as having zero, one, two, or three risk factors (0=female, family-history negative, low impulsivity; 3=male, family-history positive, high impulsivity). The cumulative probability of binging increased in participants with a greater number of risk factors.

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needed to confirm that differing patterns of consumption early on are predictive of the development of an alcohol use disorder. Intravenous alcohol self-administration also differs inmanyways fromreal-world alcohol consumption. However, recent results suggest that intravenous self- administration is reflective of external consumption pat- terns when comparing across drinkers of varying severity (9, 39). A few individuals in our sample were in their forties, and an even younger sample would have been ideal to assess the effects of these risk factors, although the vast majority of the individuals in our sample (86.1%) were at or below the age of

30. When we controlled for age in our analyses, the effects we observed remained significant. The additive risk factor analysis requires replication, especially given the low number of individuals in the three-risk factors group. Finally, we could not assess how acute alcohol-related skin flush, smoking, and preexisting psychiatric disorders contributed to the rate of binging in this sample because these were exclusion factors for our study. This limits the generalizability of our findings, especially because smoking and psychopathology are highly comorbid with alcoholism. Future studies should determine whether these factors affect rates of alcohol consumption in young adults.

Prior to the development of an alcohol use disorder, those at higher risk demonstrated differing patterns of alcohol consumption, including higher rates of binging and greater total alcohol exposure. Although most screening tools for alcoholism focus on quantity of consumption across many sessions, focusing on binging and total alcohol exposure during individual drinking sessions may be clinically rel- evant and may allow for earlier detection of high-risk in- dividuals. Assessing binging and total alcohol exposure in the laboratory, and eventually in the field when appropriate technology is available, may be a helpful way of selecting individuals who require early intervention. Clinical ques- tions regarding the time course of typical drinking sessions, in addition to standard questions about quantity of alcohol consumed, may help better characterize total alcohol ex- posure and stratify risk. There are likely neurobiological factors that contribute to the way each person drinks, and this may dispose some individuals to achieve blood alcohol concentrations that endanger them.

AUTHOR AND ARTICLE INFORMATION

Drs. Gowin and Sloan contributed equally to this study.

From the Section on Human Psychopharmacology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md., and the University of Louisville and Robley Rex Veterans Affairs Medical Center, Louisville, Ky.

Address correspondence to Dr. Ramchandani (vijayr@mail.nih.gov).

Supported by the NIAAA Division of Intramural Clinical and Biological Research (Z1A AA000466). Development of the software used for the intravenous alcohol self-administration session was supported by Sean O’Connor, M.D., at the Indiana Alcohol Research Center (NIH P60 AA007611).

The authors thank the late Dr. Daniel Hommer for his mentorship and clinical oversight,Dr.MaryLee,Dr.DavidT.George, andNursePractitioner LaToya Sewell for medical support and monitoring safety of the partici- pants, as well asMarkus Heilig, RezaMomenan, andMelanie Schwandt for their programmatic andoperational support. Theauthorsalso thankTasha Cornish and Monique Ernst for comments on earlier drafts of this study; Joel Stoddard and Ruth Pfeiffer for analytic suggestions; the staff of the 5-SW day hospital and 1-HALC alcohol clinic at the NIH Clinical Center; and, for their help with data collection, Julnar Issa, Megan Cooke, Marion Coe, Molly Zametkin, Kristin Corey, JonathanWestman, Lauren Blau, and Courtney Vaughan.

ClinicalTrials.gov identifier: NCT00713492

The authors report no financial relationships with commercial interests.

Received Oct. 26, 2016; revision received March 28, 2017; accepted May 4, 2017; published online Aug. 4, 2017.

FIGURE 3. Total Alcohol Exposure by Alcohol Use Disorder Risk Factor Groupa

Number of Risk Factors

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at io

n (m

g %

)

Time (minutes)

0-Risk Factors Group

1-Risk Factor Group

2-Risk Factors Group

3-Risk Factors Group

aGraph A shows the area under the curve for the estimated breath alcohol concentration by time plot (total alcohol exposure) examined in each alcohol use disorder risk factor group. Having a higher number of risk factors was significantly associated with total alcohol exposure during the session. The horizontal line in the middle of each box indicates the median, while the bottom and top borders of the box represent the 25th and 75th percentile values, respectively. In graph B, the lines represent the mean blood alcohol concentration for each group.

1100 ajp.psychiatryonline.org Am J Psychiatry 174:11, November 2017

VULNERABILITY FOR ALCOHOL USE DISORDER AND RATE OF CONSUMPTION

 

 

REFERENCES 1. Grant BF, Goldstein RB, Saha TD, et al: Epidemiology of DSM-5

alcoholusedisorder: results fromtheNationalEpidemiologicSurvey on Alcohol and Related Conditions III. JAMA Psychiatry 2015; 72: 757–766

2. Ramchandani VA, Bolane J, Li TK, et al: A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping. Alcohol Clin Exp Res 1999; 23:617–623

3. Goodwin DW, Powell B, Bremer D, et al: Alcohol and recall: state- dependent effects in man. Science 1969; 163:1358–1360

4. US Department of Health and Human Services; NIH; National In- stitute on Alcohol Abuse and Alcoholism: NIAAA Council Ap- proves Definition of Binge Drinking. https://www.researchgate.net/ publication/285020940_NIAAA_Council_Approves_Definition_of_ Binge_Drinking

5. Ruidavets J-B, Ducimetière P, Evans A, et al: Patterns of alcohol consumption and ischaemic heart disease in culturally divergent countries: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). BMJ 2010; 341:c6077

6. Wechsler H, Davenport A, Dowdall G, et al: Health and behavioral consequences of binge drinking in college: a national survey of students at 140 campuses. JAMA 1994; 272:1672–1677

7. Zimmermann US, O’Connor S, Ramchandani VA: Modeling alcohol self-administration in the human laboratory. Curr TopBehavNeurosci 2013; 13:315–353

8. Stangl BL, Vatsalya V, Zametkin MR, et al: Exposure-response rela- tionships during free-access intravenous alcohol self-administration in nondependent drinkers: influence of alcohol expectancies and impulsivity. Int J Neuropsychopharmacol 2016; pii: pyw090. doi: 10.1093/ijnp/pyw090

9. Jünger E, Gan G, Mick I, et al: Adolescent women induce lower blood alcohol levels than men in a laboratory alcohol self- administration experiment. Alcohol Clin Exp Res 2016; 40: 1769–1778

10. Vatsalya V, Gowin JL, Schwandt ML, et al: Effects of varenicline on neural correlates of alcohol salience in heavy drinkers. Int J Neuropsychopharmacol 2015; 18(12) pii: pyv068. doi: 10.1093/ijnp/ pyv068

11. Suchankova P, Yan J, Schwandt ML, et al: The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence. Transl Psychiatry 2015; 5:e583

12. Ramchandani VA, Plawecki M, Li T-K, et al: Intravenous ethanol infusions canmimic the timecourseofbreathalcohol concentrations following oral alcohol administration in healthy volunteers. Alcohol Clin Exp Res 2009; 33:938–944

13. Friel PN, Baer JS, Logan BK: Variability of ethanol absorption and breath concentrations during a large-scale alcohol administration study. Alcohol Clin Exp Res 1995; 19:1055–1060

14. Gomez R, Behar KL, Watzl J, et al: Intravenous ethanol infusion decreases human cortical g-aminobutyric acid and N-acetylaspartate asmeasuredwith protonmagnetic resonance spectroscopy at 4 Tesla. Biol Psychiatry 2012; 71:239–246

15. PlaweckiMH,ZimmermannUS,VitvitskiyV, et al: Alcohol exposure rate control through physiologically based pharmacokinetic mod- eling. Alcohol Clin Exp Res 2012; 36:1042–1049

16. RamchandaniVA,UmhauJ, PavonFJ, et al: Agenetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 2011; 16:809–817

17. AmericanPsychiatricAssociation: Diagnostic andStatisticalManual of Mental Disorders, 5th ed.Washington, DC, American Psychiatric Publishing, 2013

18. DawsonDA,GrantBF:Familyhistoryof alcoholismandgender: their combined effects on DSM-IV alcohol dependence and major de- pression. J Stud Alcohol 1998; 59:97–106

19. Caspi A, Moffitt TE, Newman DL, et al: Behavioral observations at age 3 years predict adult psychiatric disorders: longitudinal evidence from a birth cohort. Arch Gen Psychiatry 1996; 53:1033–1039

20. Li D, Zhao H, Gelernter J: Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet 2012; 131:725–737

21. Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental dis- orders with alcohol and other drug abuse: results from the Epide- miologic Catchment Area (ECA) Study. JAMA 1990; 264:2511–2518

22. SchuckitMA:Lowlevel of response to alcohol as apredictorof future alcoholism. Am J Psychiatry 1994; 151:184–189

23. FirstMB, Spitzer RL, GibbonM, et al: Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York, Biometrics Research, New York State Psy- chiatric Institute, 2002

24. Johnson RC, Nagoshi CT, Schwitters SY, et al: Further investigation of racial/ethnic differences and of familial resemblances in flushing in response to alcohol. Behav Genet 1984; 14:171–178

25. Saunders JB, Aasland OG, Babor TF, et al: Development of the Al- cohol Use Disorders Identification Test (AUDIT): WHO Collabo- rative Project on Early Detection of Persons with Harmful Alcohol Consumption, II. Addiction 1993; 88:791–804

26. Vogel-SprottM,ChipperfieldB,HartDM:Familyhistoryof problem drinking among young male social drinkers: reliability of the Family Tree Questionnaire. Drug Alcohol Depend 1985; 16:251–256

27. Bucholz KK, Cadoret R, Cloninger CR, et al: A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. J Stud Alcohol 1994; 55:149–158

28. Rice JP, Reich T, Bucholz KK, et al: Comparison of direct interview and family history diagnoses of alcohol dependence. Alcohol Clin Exp Res 1995; 19:1018–1023

29. Bickel WK, Odum AL, Madden GJ: Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers. Psychopharmacology (Berl) 1999; 146:447–454

30. MacKillopJ,AmlungMT,FewLR,et al:Delayedrewarddiscounting and addictive behavior: ameta-analysis. Psychopharmacology (Berl) 2011; 216:305–321

31. Amlung M, Vedelago L, Acker J, et al: Steep delay discounting and addictive behavior: a meta-analysis of continuous associations. Addiction 2017; 112:51–62

32. Mazur JE: An adjusting procedure for studying delayed re- inforcement, in The Effect of Delay and of Intervening Events on Reinforcement Value: Quantitative Analyses of Behavior, vol 5. Edited byCommonsML,Mazur JE,Nevin JA, et al, 1987, pp 55–73

33. Schuckit MA, Smith TL, Tipp JE: The Self-Rating of the Effects of Alcohol (SRE) form as a retrospective measure of the risk for al- coholism. Addiction 1997; 92:979–988

34. Terpstra TJ: The Asymptotic Normality and Consistency of Kendall’s TestAgainstTrend,WhenTiesarePresent inOneRanking.Amsterdam, Stichting Mathematisch Centrum, 1952

35. Jonckheere AR: A distribution-free k-sample test against ordered alternatives. Biometrika 1954; 41:133

36. Zimmermann US, Mick I, Laucht M, et al: Offspring of parents with analcohol usedisorderpreferhigher levels of brain alcohol exposure in experiments involving computer-assisted self-infusion of ethanol (CASE). Psychopharmacology (Berl) 2009; 202:689–697

37. Quinn PD, Fromme K: Subjective response to alcohol challenge: a quantitative review. Alcohol Clin Exp Res 2011; 35:1759–1770

38. Wetherill L, Morzorati SL, Foroud T, et al: Subjective perceptions associated with the ascending and descending slopes of breath al- cohol exposure vary with recent drinking history. Alcohol Clin Exp Res 2012; 36:1050–1057

39. Hendershot CS,Wardell JD,McPheeMD, et al: A prospective study of genetic factors, human laboratoryphenotypes, andheavydrinking in late adolescence. Addict Biol (Epub ahead of print, April 5, 2016)

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