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Original Contribution |

Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients:  A Randomized Controlled Trial FREE

Bankole A. Johnson, MD, PhD; John D. Roache, PhD; Martin A. Javors, PhD; Carlo C. DiClemente, PhD; Claude Robert Cloninger, MD; Thomas J. Prihoda, PhD; Patrick S. Bordnick, PhD; Nassima Ait-Daoud, MD; Julie Hensler, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, University of Texas Health Science Center, San Antonio (Drs Johnson, Roache, Javors, Prihoda, Bordnick, Ait-Daoud, and Hensler); Department of Psychology, University of Maryland, Baltimore (Dr DiClemente); and School of Medicine, Washington University, St Louis, Mo (Dr Cloninger).


JAMA. 2000;284(8):963-971. doi:10.1001/jama.284.8.963.
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Published online

Context Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.

Objective To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT3 (serotonin) antagonist ondansetron.

Design Double-blind, randomized, placebo-controlled clinical trial.

Settings University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).

Participants A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.

Interventions After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 µg/kg (n = 67), 4 µg/kg (n = 77), or 16 µg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.

Main Outcome Measures Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.

Results Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 µg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P = .03, P = .01, and P = .02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P = .03, P = .004, and P = .03, respectively). Ondansetron, 4 µg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P = .02) and total days abstinent per study week (6.74 vs 5.92; P = .03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 µg/kg twice per day) compared with those who received the placebo (−0.17 and −0.19 vs 0.12; P = .03 and P = .01, respectively).

Conclusion Our results suggest that ondansetron (particularly the 4 µg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality.

Figures in this Article

Selective 5-HT3 (serotonin) receptors mediate alcohol's important brain effects.1 Molecular studies show that alcohol potentiates selective 5-HT3 receptor-mediated ion currents, an effect blocked by selective 5-HT3 receptor antagonists.2,3 Mesocorticolimbic dopamine pathways mediate alcohol's rewarding effects and that of other abused substances.48 Densely distributed 5-HT3 receptors in mesocorticolimbic neuronal terminals regulate dopamine release.9,10 Selective 5-HT3 receptor blockade, by attenuating dopamine release, reduces alcohol consumption in several animal models and across species.1119

We were the first, to our knowledge, to show that pretreatment with the selective 5-HT3 receptor antagonist ondansetron attenuates low-dose alcohol–induced positive, subjective effects and the "urge to drink" in humans.20,21 Swift et al,22 using higher alcohol and ondansetron dosages, found that ondansetron pretreatment decreased alcohol preference. However, a mixture of stimulant and sedative interactions between ondansetron and alcohol were also reported. In contrast, Doty et al23 found that ondansetron did not alter alcohol-induced mood, presumably because using intravenous rather than oral ondansetron and a group rather than an individual experimental setting reduced the sensitivity of their mood assessments.

In a preliminary 6-week, double-blind study of 71 patients not severely dependent on alcohol, 0.5 mg/d but not 4 mg/d of ondansetron was almost superior to placebo (P = .06) at reducing alcohol consumption.24 These results strengthened the rationale for testing ondansetron's efficacy in treating alcoholism within a larger-scale trial but raised also the possibility that ondansetron's dose-response curve was an inverted U-shape.

Psychopathological factors distinguish alcoholic subtypes based on course, prognosis,2527 and differential treatment response. Alcoholic patients with early onset compared with late onset develop problem drinking earlier, exhibit a broad range of antisocial behaviors, and have a higher predisposition toward alcoholism. High concordance between age of onset and other hypothetically-derived28,29 and empirically-driven typologies26,30 validated age of onset for a priori segregation of alcoholic subtypes in a recent trial.31

Solid evidence exists that an early compared with late alcoholism onset is associated with serotonergic dysfunction.3238 While this 5-HT dysfunction among patients with early-onset alcoholism has been hypothesized to be a deficient state,39,40 newer evidence implicates the interaction between chronic drinking and mechanistic processes regulating serotonergic function.

Our double-blind, randomized, placebo-controlled clinical trial tested the hypothesis that patients with early-onset alcoholism compared with late-onset alcoholism (classified a priori), would experience better drinking outcomes in response to ondansetron treatment due to the amelioration of serotonergic dysfunction. We examined ondansetron's dose-dependent effects by testing a 16-fold dose range (ie, 1, 4, and 16 µg/kg twice per day) encompassing those used in a previous clinical trial.24

Subjects

The 321 enrollees (70% male; 78.6% white) were diagnosed as having alcoholism by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.41 Enrollees were 25 to 65 years old; scored more than 5 on the Michigan Alcoholism Screening Test,42 which assessed the severity of alcohol-related problems; reported drinking 3 or more standard drinks per day during the telephone screening; and had a negative urine toxicological screen for narcotics, amphetamines, or sedative hypnotics at enrollment. Abstinence was not a study entry criterion; however, participants reported a desire to stop drinking and to participate in psychosocial treatment. Exclusion criteria were a current psychiatric diagnosis other than alcohol or nicotine dependence; alcohol withdrawal symptoms necessitating inpatient detoxification; clinically significant abnormalities (ie, on physical examination, electrocardiographic recording, hematological evaluation, or elevated bilirubin levels); pregnancy; lactation; taking medications with a potential effect on alcohol consumption; mandated incarceration or employment loss for not receiving alcoholism treatment; and receipt of alcoholism treatment 30 days prior to enrollment. Ethics approval was provided by the Committee for the Protection of Human Subjects, Health Science Center, University of Texas, Houston. Subjects were recruited by newspaper or radio advertisement.

General Procedures

All testing took place at the University of Texas Health Science Center in Houston between April 1995 and June 1998. Data was analyzed at the University of Texas Health Science Center in San Antonio between July 1998 and December 1999. At enrollment (visit 0), after providing written, informed consent, we assessed subjects on (1) physical health, which included a medical history and physical examination, vital signs (ie, blood pressure, pulse, and temperature), 12-lead electrocardiogram, and laboratory studies including a urine pregnancy test; (2) breath alcohol concentration (BAC); (3) urine drug and biochemical screens; (4) psychiatric diagnosis, which included a Structured Clinical Interview for DSM-III-R43,44; (5) age of onset, which was determined using item B 28 of the Comprehensive Drinking Profile45; (6) the Michigan Alcoholism Screening Test42; (7) addiction severity, which was assessed using the Addiction Severity Index46; (8) self-reported drinking based on a timeline follow-back (TLFB) over the past 90 days47; (9) objective quantification of alcohol consumption using the sensitive and specific marker, plasma carbohydrate deficient transferrin (CDT) level4851; and (10) an assessment of alcohol withdrawal symptoms assessed by the revised Clinical Institute Withdrawal Assessment (CIWA-Ar) scale.52 Eligible subjects were invited back to the clinic at visit 1, following a review of the hematological, biochemical, and urine tests, in which they received the single-blind placebo for 1 week and attended their first cognitive behavioral therapy (CBT) session.

At visit 2 (after 1 week of receiving single-blind placebo), we assessed subjects' vital signs, BAC, TLFB, and CIWA-Ar. Subjects were also assessed for adverse events, concomitant medication use, pill count (amount of study medication prescribed and amount returned), and psycho-social treatment attendance outside the study. Double-blind medication (ie, placebo or ondansetron 1, 4, or 16 µg/kg twice per day) was randomly dispensed across medication dosage and onset groups, and the subjects attended their second CBT session.

From visits 3 through 12, subject assessment included weekly vital signs, BAC, TLFB, CIWA-Ar, an adverse event profile, concomitant medications, pill count, percentage of urine riboflavin (an inert tracer for assessing medication compliance), and psycho-social treatment attendance outside the study. At visits 4, 8, and 12, subjects received a plasma CDT measurement; an electrocardiogram; a urine pregnancy test; hematological, biochemical, and urine drug screens. Subjects were expected to attend weekly CBT sessions throughout the study period. At visit 12 (study end), a physical examination and the hematological and biochemical checks were repeated to establish health status (Figure 1). Visits were interspersed by a period of 1 study week, which was a maximum of 11 days (from Monday of the previous week to Friday of the current week).

Figure 1. Trial Flow Diagram of Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Patients diagnosed as having early-onset and late-onset alcoholism were similar in number, age, sex, and drinking level at enrollment. Trial completers were those patients who completed all 11 double-blind visits or 10 double-blind visits plus the final physical health evaluation.
Supply, Dosages, Blinding, and Compliance for Medication

Ondansetron, obtained from Glaxo-Wellcome Inc as 8-mg tablets ($19.50/tablet), was compounded and dispensed using procedures approved by the Food and Drug Administration under investigational new drug No. 45,228. Crushed ondansetron tablets (1, 4, and 16 µg/kg twice per day) were packed into opaque size 1 gelatin capsules (Shinogi Qualicaps SA, Madrid, Spain) with cornstarch filler. Placebos were opaque gelatin capsules of the same size, shape, and color containing cornstarch. Body weight categories were used for the microgram per kilogram dosing procedure (mean [SD] ondansetron dosages taken vs those assigned were 0.99 [0.02] vs 1.00, 4.00 [0.05] vs 4.00, and 16.18 [0.38] vs 16.00 µg/kg twice per day, which is equivalent to 0.15, 0.63, and 2.56 mg/d, respectively based on mean body weight). Medication was packaged with the inert tracer (a 50-mg crushed riboflavin tablet),53,54 and dispensed in bottles labeled with identification, study and visit numbers, and the date. The returned medication bottle at each weekly visit was used to calculate the pill count.

Ultraviolet fluorescence of the subjects' urine samples were compared against a background control sample that contained 7 µmol of riboflavin per milliliter using an AMINCO-Bowman spectrofluorimeter (Spectronic Unicam, Rochester, NY) with an excitation wavelength of 464 nm and an emission wavelength of 530 nm. The relative optical density of the riboflavin control sample was set at a high cut-off point (70%) and the samples were read as a percentage of optical density (a percentage of urine riboflavin).

Cognitive Behavioral Therapy

Cognitive behavioral therapy, an integration of cognitive behavioral and social learning theory, enables alcoholic patients to achieve and maintain abstinence by enhancing their ability to manage high-risk situations, which can trigger alcohol-seeking behavior.55,56 All study patients received standardized CBT in groups of up to 8 individuals using the Cognitive Behavioral Coping Skills Therapy57 manual, and selected exercises from Treating Alcohol Dependence: A Coping Skills Therapy Guide.58

Statistical Analysis

Data quality was supervised by a database coordinator and statistician. Individual subject plots were checked for unusual values and completeness. Efficacy values were validated as correct against the case records. Data were analyzed using SAS statistical software.59

Efficacy variables were self-reported alcohol consumption from visit 3 through 12 using the TLFB (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent), and plasma CDT level, which is an objective measure of drinking, at visits 4, 8, and 12. Treatment compliance measures were study attendance rate and medication compliance (both pill count and percentage of urine riboflavin). Physical health and safety measures were BAC at clinic attendance; CIWA-Ar; vital signs; hematological, biochemical, and urine drug screens; use of concomitant medications; attendance at psycho-social treatments outside the study; and adverse events profile.

Subjects' data were analyzed as randomized using an urn60 procedure after the screening visit. Subjects did not receive their randomized, double-blind study medication (ie, ondansetron or placebo) until the end of the 1-week single-blind placebo period (at visit 2). The first recorded response to medication was, therefore, not measured until the end of the first week of double-blind treatment (visit 3). Response to the double-blind study medication treatment was, therefore, measured from visits 3 to 12 and all subjects randomized were included in the efficacy analyses,61 irrespective of whether they completed the study. Previous visit values of outcome measures (before visit 3) were used as covariates to control for study entrance and placebo pill taking effects.62

Alcoholic patients with early vs late onset developed alcoholism at 25 years or younger and older than 25 years, respectively. Subjects were randomly assigned to 1 of the 4 dosage groups (placebo, or ondansetron 1, 4, or 16 µg/kg twice per day) after balancing based on age of onset, sex, and the average intake drinking level (drinks per day). The 2 × 4 factorial study design examined age of onset (patients with early-onset vs late-onset alcoholism) and medication dosage (placebo, or ondansetron 1, 4, and 16 µg/kg twice per day), and their interaction. Treatment response was measured over visits 3 to 12 (10 double-blind visits using the TLFB technique) after adjusting for differences in study entrance, study enrollment effect (visit 1), and placebo pill taking effect (visit 2).

Counts and/or percentages for categorical items were compared among groups with the χ2 test for independence when measured at either 1 time or accumulated over multiple time points. Continuously distributed data were reported as mean (SE) for raw measures or as mean change (SE) from baseline (visit 2) for calculated outcome measures, and as 95% confidence intervals (CIs) for mean response from the primary efficacy analyses.

If a 2-way analysis of variance at visits 0, 1, or 2 was significant either for the age of onset or dosage main effects or their interaction, then the groups were unequal on that measure and the baseline values (study entry, visits 1 or 2) were included as a covariate in the efficacy analysis to adjust for these differences. Covariate values from other visits were excluded if they were not significantly related to outcome and did not reduce variability by controlling for individual study entrance and placebo pill taking effects. These covariates removed the study entrance and placebo pill taking effects from the double-blind efficacy response. Any covariate for inclusion in the final model was tested for its interaction with the age of onset, dosage groups, and their interaction. Additionally, covariates were plotted against the residuals to determine their random normal distribution. In all cases, these plots showed significant covariates to be linear and resulted in valid analyses.

As a data reduction technique, self-reported drinking response was calculated as the mean of visits 3 through 12. This average response analysis preserved sample size since all subjects with at least one outcome measure (ie, any of visits 3-12) were included in the efficacy analysis. Since these means have a variance inversely proportional to the number of visits attended,63 the outcome analysis was weighted by the number of visits. The residuals of this 2-way analysis of covariance, weighted for missing data effects, were checked for normality by computing their skewness, kurtosis, and homogeneity of variance by histogram plots and against the predicted outcome. When needed, standard transformations (eg, square root for percentages or the log when residual variability increased with response) were used to satisfy the assumptions of the analytic procedure. The objective drinking marker, plasma CDT, was analyzed using a similar statistical strategy to the self-reported measures except that enrollment was used as the baseline (CDT was only obtained monthly) and response was calculated over the monthly visits (ie, 4, 8, and 12) as an average log ratio with enrollment values. Type I errors were minimized by conducting only a priori pairwise dosage comparisons within the patient groups with early-onset or late-onset alcoholism when there was a main effect of ondansetron or an interaction between age of onset and treatment dosage.

Study Sample

Patients with early-onset and late-onset alcoholism were equally represented, and had similar levels of self-reported and objective drinking within the cohort. Alcoholic patients with early compared with late onset were younger, of lower social class, more severely addicted with a longer history of alcoholism, and had higher rates of antisocial personality disorder (Table 1). There was no significant interaction between age of onset and treatment dosage for any of the intake variables except for drinks per day, which was addressed by the analysis of covariance. By visit 2 (start of the double-blind period), all 8 groups had similar drinking levels.

Table Graphic Jump LocationTable. Demographic and Psychopathological Characteristics of Early-Onset and Late-Onset Alcoholic Patients at Intake*
Efficacy Measures

Among patients with early-onset alcoholism, ondansetron (1, 4, and 16 µg/kg twice per day) compared with placebo, significantly reduced self-reported drinking. For patients with early-onset alcoholism, significant improvements between the start of the double-blind response period (visit 3) and study end were seen on (1) all drinking measures for those who received 4 µg/kg of ondansetron twice per day and (2) percentage of days abstinent and total days abstinent for those who received 16 µg/kg of ondansetron twice per day. In contrast, only the placebo and 16 µg/kg ondansetron group patients with late-onset alcoholism had significantly improved drinking outcomes during double-blind treatment (Figure 2).

Figure 2. Mean (95% Confidence Interval) Drinking Outcomes During the Double-Blind Response Period of Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Data are responses observed at the start of double-blind (visit 2) and the mean outcome observed during study (mean of visits 3-12). Analyses refer to pairwise comparisons between the ondansetron treatment groups and placebo. The a* and a† represent significant differences between an ondansetron dosage and placebo groups at the 5% and 1% levels, respectively. The b* and b† denote significant differences within a given treatment group from the start of the double-blind response period to the outcome during study at the 5% and 1% levels, respectively.

There was a significant interaction between age of onset and treatment dosage on the self-reported drinking variables of drinks per day (F3,245 = 3.65; P = .01); drinks per drinking day (F3,174 = 3.17; P = .03); percentage of days abstinent (F3,237 = 2.9; P = .04), and total days abstinent (F3,237 = 2.9; P = .04). Patients with early-onset alcoholism who received dosages of ondansetron of 1, 4, or 16 µg/kg twice per day reported significantly lower numbers of drinks per day or drinks per drinking day compared with those who received placebo. Also, patients with early-onset alcoholism who received ondansetron 4 µg/kg twice per day, compared with placebo, had more percentage of days abstinent and total days abstinent. Effect sizes were as follows for drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent for (1) 1 µg/kg of ondansetron twice per day: 0.26, 0.25, 0.13, and 0.06; (2) 4 µg/kg of ondansetron twice per day: 0.37, 0.41, 0.26, and 0.24; and (3) 16 µg/kg of ondansetron twice per day: 0.22, 0.23, 0.17, and 0.18. Effect sizes of 0.2, 0.5, and 0.8 are small, medium, and large, respectively.64

On the objective drinking measure (plasma CDT), there was a main effect during the study on the mean log CDT ratio (F3,177 = 3.15; P = .03). Among patients with early-onset alcoholism, the mean log CDT ratio was significantly reduced when ondansetron dosages 1 and 4 µg/kg twice per day were compared with placebo (Figure 3). For patients with early-onset alcoholism, effect size on mean log CDT ratio for the ondansetron 1, 4, and 16 µg/kg twice per day dosages were 0.55, 0.58, and 0.21, respectively. While there was a decrease in mean log CDT ratio for groups of patients with late-onset alcoholism, none of the ondansetron dosage groups were superior to placebo.

Figure 3. Mean (95% Confidence Interval) Log Plasma Carbohydrate Deficient Transferrin (CDT) Ratio for Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Mean log CDT ratio was the mean log CDT at a given visit (ie, 4, 8, or 12) divided by the mean log CDT at enrollment. The dagger indicates P<.01 and the asterisk indicates P<.05.

Our results yielded a significant effect on 5 response variables related to actual drinking measures. The probability of making a type I error on any 1 to all 5 ranges from .05 to less than .001. A factor analysis of cases for all 5 ranges indicates 2 dimensions; so for any 2 independent comparisons, the type I error rate is less than .0025. Even when all baseline measures related to outcome were used in the model,62 rather than just the confounding61 baseline measures, the results were similar. For example, the interaction between patients with early-onset and late-onset alcoholism receiving ondansetron was significant for drinks per day (P = .006) with the patients with early-onset alcoholism in the ondansetron 4 µg/kg twice per day dosage group being superior to placebo (P<.001).

Compliance Measures

Patients with early-onset and late-onset alcoholism did not differ significantly in mean (SE) percentage of pills taken of 92.43 (3.29) vs 92.39 (2.98) and urine riboflavin of 93.68 (0.01) vs 94.73 (0.01), respectively. Generally, patients with early-onset alcoholism attended fewer study sessions than patients with late-onset alcoholism (mean [SE], 7.30 [0.36] vs 8.24 [0.37], respectively; F1,313 = 4.10; P = .04); however, differences between dosage groups were insignificant. Only 34% of alcoholic patients failed to attend the eighth or a later double-blind visit.

Physical Health and Safety Measures

No serious adverse events occurred. Adverse event rates were similar for the ondansetron and placebo groups, and required no supervised medical intervention. The most common adverse events by organ system for the ondansetron vs placebo dosages were central nervous system (headache), 3.4% vs 4.2%; gastrointestinal tract (constipation), 5.0% vs 1.4%; cardiovascular (tachycardia), 0.3% vs 0.0%; skin (rash/pruritis), 2.2% vs 2.8%; and others, 1.8% vs 1.0%. One fatality unrelated to the study medication occurred due to the subject falling down a flight of stairs at home.

Positive BACs were rare (mean, .01%) with no difference between patients with early-onset and late-onset alcoholism. Alcohol withdrawal symptoms were infrequent (mean [SE] for CIWA-Ar, 2.8 [0.25] and 2.5 [0.23]; patients with early-onset and late-onset alcoholism, respectively). Testing positive for 1 or more of 9 agents in the urine drug screen was similar for patients with early-onset (15.5%) and late-onset alcoholism (15.6%). Drug use frequencies for patients with early-onset vs late-onset alcoholism were 44% vs 29% for marijuana; 24% vs 19% for cocaine; 16% vs 26% for opiates; and 16% vs 26% for benzodiazepines. Rates of concomitant medication use and of psychosocial attendance outside the study were similar for patients with early-onset (13.6% and 4.9%) and late-onset alcoholism (14.4% and 4.3%).

Ondansetron significantly reduced alcohol consumption and increased abstinence among patients with early-onset but not late-onset alcoholism. A dosage of ondansetron of 4 µg/kg twice per day was most efficacious; however, its superiority over the other ondansetron dosages was statistically insignificant. We did not detect an inverted U-shaped dose-response curve for ondansetron among patients with early-onset alcoholism; however, increased efficacy at higher dosages appears unlikely. Limitations of a short treatment period and the inclusion of only white males in the Sellers et al24 study precluded direct comparison with this study. Nevertheless, finding ondansetron efficacious among patients with early-onset alcoholism is not inconsistent with their observation24 that excluding heavy drinkers (ie, >10 drinks per day) rendered ondansetron-related drinking reductions compared with placebo statistically significant as this procedure simply decreased variance in their smaller sample size study.

Abstinence at enrollment was not a study entry requirement but the treatment goal. Enrolling actively drinking alcoholic patients represented a more naturalistic point related to when help was sought. By not requiring an abstinence period at enrollment, the potential for postcessation rebound into drinking was reduced. Yet, abstinence rate for the 4 µg/kg of ondansetron twice per day group among patients with early-onset alcoholism was relatively high (about 70%). Exploratory analyses indicated that ondansetron's antidrinking effects did not differ between abstainers and active drinkers at the start of double-blind analysis (data not shown). Consistently, the visit 2 baseline covariate was not needed in our full analyses; thus, drinking status was not a determinant of ondansetron response. Ondansetron does not alter alcohol pharmacokinetics65; hence, its utility in actively drinking alcoholic patients was an additional therapeutic benefit.

Participants nearly halved their drinking between enrollment and the end of the lead-in, single-blind placebo period. Emphasis on drinking quantification probably evoked self-regulatory measures. The single-blind placebo, lead-in period enabled measurement of how the psychological effect of pill taking contributed to the overall treatment response. Promise or delivery of psychosocial treatment might also have improved drinking outcomes. Since all subjects received CBT, it was impossible to discern if, and by how much, psychotherapy type or intensity would interact with ondansetron treatment response, or whether psychotherapy alone is sufficient in treating patients with late-onset alcoholism due to their limited disease predisposition.

We discounted the remote possibility that ondansetron's effectiveness among ondansetron-receiving patients with early-onset alcoholism was due to a less pronounced placebo effect in those who received placebo. The placebo lead-in period should have controlled for any differential placebo effects. Extensive exploratory analyses of all data collected in this trial revealed no significant baseline outcome predictor that would selectively impair drinking behavior among patients with early-onset alcoholism who received placebo compared with the ondansetron recipients. Patients with early-onset alcoholism in treatment groups were similar on baseline drinking measures and psychosocial characteristics. Hence, among patients with early-onset alcoholism, the significant drinking reduction and cessation in ondansetron compared with placebo recipients was due to the efficacy of the pharmacological treatment.

Another study strength was the use of a dose-ranging paradigm, still a rarity in medications in development for alcoholism.66 Future studies can now focus on testing different treatment options using ondansetron's most efficacious dosage. Ondansetron was well tolerated and its adverse event profile was similar to that of placebo.

Pill-taking rates were high (>92%). Although the analyses of percentage urine riboflavin could have been confounded by dietary changes, including the intake of multivitamin supplements, its close agreement with the pill count data would argue that each measure provided validation of the other. Additionally, use of riboflavin dosages greater than 50 mg/d increases this measure's reliability since the dosage greatly exceeds that commonly found in over-the-counter multivitamin preparations.54

Patients with early-onset alcoholism had higher rates of antisocial personality disorder than patients with late-onset alcoholism. Also, baseline data from a cohort of the current sample, which are detailed elsewhere, showed that patients with early-onset compared with late-onset alcoholism have higher rates of childhood risk behaviors, hostility, impaired social functioning, and an increased number of male relatives with alcoholism.25 Further, age of onset in the current sample was significantly correlated with a family history of alcoholism in a male parent or grandparent; that is, the earlier the subjects' age of onset the greater was the likelihood that they had either a male parent or grandparent who was an alcoholic (data not shown). Hence, an early age of onset was associated with a range of variables that contribute to biological vulnerability toward alcoholism.

Mechanistically, it is intriguing that a selective 5-HT3 receptor antagonist was efficacious for treating patients with early-onset alcoholism whereas a selective serotonin reuptake inhibitor had failed67 because these classes of compounds have opposite effects on serotonergic function. Serotonergic function augmentation by a partial selective serotonin 1A agonist was also an ineffective treatment for patients with early-onset alcoholism.32 Patients with early-onset alcoholism do not have a simple selective 5-HT deficiency state. Instead, patients with early-onset alcoholism may be more likely to possess a high-functioning polymorphic variant of the serotonin transporter68,69 that is more readily damaged by chronic alcohol consumption.70 As these raphe transporters are somatodendritic rather than axonal, the net result is a reduced 5-HT firing rate due to increased self-inhibition.71 We hypothesize that reduced 5-HT neurotransmission in patients with early-onset compared with late-onset alcoholism, differentially upregulates postsynaptic 5-HT3 receptors, a blockade of which may account for ondansetron's differential treatment effectiveness.66,72

Efficacy of such small ondansetron dosages in treating patients with early-onset alcoholism is consistent with animal studies of its antirewarding effects on ethanol consumption,11,13,17 and strengthen the proposal that 5-HT3 receptors are an important site of alcohol's brain effects1 and that chronic 5-HT3 receptor blockade is not associated with neuroadaptation of mesocorticolimbic dopamine or 5-HT neurons.73

Scientific frustration had grown because promising animal studies66 showing that medications which alter serotonergic function could attenuate the urge to drink or drinking per se were not confirmed by clinical trials. Earlier clinical trials with serotonergic agents looked for their effects on drinking among heterogeneous alcoholic groups. We show that alcoholic subtypes varying in selective 5-HT function respond differently to treatment with a specific serotonergic agent. Medication trials specifically targeting treatment of underlying biological abnormalities in particular alcoholic subtypes heralds a new vista in the alcoholism field.

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Kilpatrick GJ, Hagan RM, Gale JD. 5-HT3 and 5-HT4 receptors in terminal regions of the mesolimbic system.  Behav Brain Res.1996;73:11-13.
Costall B, Domeney AM, Naylor RJ, Tyers MB. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.  Br J Pharmacol.1987;92:881-894.
Hodge CW, Samson HH, Lewis RS, Erickson HL. Specific decreases in ethanol but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930.  Alcohol.1993;10:191-196.
Fadda F, Garau B, Marchei F, Colombo G, Gessa GL. MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats.  Alcohol Alcohol.1991;26:107-110.
Rodd-Henricks ZA, McKinzie DL, Li TK, Crile RS, Murphy JM, McBride WJ. Intracranial Self-Administration of Ethanol Into the Posterior VTA of Wistar Rats is Mediated by 5-HT3 Receptors. Santa Barbara, Calif: Research Society on Alcoholism; 1999.
Meert TF. Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference.  Alcohol Alcohol.1993;28:157-170.
McBride WJ, Li TK. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents.  Crit Rev Neurobiol.1998;12:339-369.
Tomkins DM, Le AD, Sellers EM. Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure.  Psychopharmacology (Berl).1995;117:479-485.
Barnes N, Sharp T. A review of central 5-HT receptors and their function.  Neuropharmacology.1999;38:1083-1152.
Beardsley PM, Lopez OT, Gullikson G, Flynn D. Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats.  Alcohol.1994;11:389-395.
Johnson BA, Campling GM, Griffiths P, Cowen PJ. Attenuation of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers.  Psychopharmacology (Berl).1993;112:142-144.
Johnson BA, Cowen PJ. Alcohol-induced reinforcement: dopamine and 5-HT3 receptor interactions in animals and humans.  Drug Dev Res.1993;30:153-169.
Swift RM, Davidson D, Whelihan W, Kuznetsov O. Ondansetron alters human alcohol intoxication.  Biol Psychiatry.1996;40:514-521.
Doty P, Zacny J, deWit H. The effects of ondansetron pretreatment on acute responses to ethanol in social drinkers.  Behav Pharmacol.1994;5:461-469.
Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB. Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence.  Alcohol Clin Exp Res.1994;18:879-885.
Johnson BA, Cloninger CR, Roache JD, Bordnick PS, Ruiz P. Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population.  Am J Addict.2000;9:17-27.
Babor TF, Dolinsky ZS, Meyer RE, Hesselbrock M, Hofmann M, Tennen H. Types of alcoholics: concurrent and predictive validity of some common classifications schemes.  Br J Addict.1992;87:1415-1431.
Brown J, Barbor TF, Litt MD, Kranzler HR. The type A/type B distinction: subtyping alcoholics according to indicators of vulnerability and severity.  Ann N Y Acad Sci.1994;708:22.
Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism.  Science.1987;236:410-416.
Cloninger CR, Bohman M, Sigvardsson S. Inheritance of alcohol abuse: cross-fostering analysis of adopted men.  Arch Gen Psychiatry.1981;38:861-868.
Litt MD, Babor TF, DelBoca FK, Kadden RM, Cooney NL. Types of alcoholics, II: application of an empirically derived typology to treatment matching.  Arch Gen Psychiatry.1992;49:609-614.
George D, Sirocco K, Eckhardt M, Linnoila M. Age of onset for alcoholism and CSF homovanillic acid concentrations predict relapse.  Clin Pharmacol Ther.1998;63:203.
George D, Rawlings R, Eckardt M, Phillips M, Shoaf S, Linnoila M. Buspirone treatment of alcoholism: age of onset and cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid concentrations but not medication treatment predict return to drinking.  Alcohol Clin Exp Res.1999;23:272-277.
Buydens-Branchey L, Noumair D, Branchey MH. Age of alcoholism onset, I: relationship to psychopathology.  Arch Gen Psychiatry.1989;46:225-230.
Fils-Aime M-L, Eckardt MJ, George DT, Brown GL, Mefford I, Linnoila M. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics.  Arch Gen Psychiatry.1996;53:211-216.
Vikkunen M, Linnoila M. Serotonin in early-onset alcoholism. In: Galanter M, ed. Recent Developments in Alcoholism, Alcohol and Violence: Epidemiology, Neurobiology, Psychology, Family Issues. New York, NY: Plenum Press; 1997:173-189.
Virkkunen M, Linnoila M. Serotonin in early onset, male alcoholics with violent behaviour.  Ann Med.1990;22:327-331.
Swann AS, Johnson BA, Cloninger CR, Chen YR. Alcoholism and serotonin: relationships of plasma tryptophan availability to course of illness and clinical features.  Psychopharmacology (Berl).1999;143:380-384.
Ballenger J, Goodwin F, Major L, Brown G. Alcohol and central serotonin metabolism in man.  Arch Gen Psychiatry.1979;36:224-227.
LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: clinical evidence.  Biol Psychiatry.1994;36:326-337.
LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: findings of animal studies.  Biol Psychiatry.1994;36:395-421.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
Selzer ML. The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument.  Am J Psychiatry.1971;127:1653-1658.
Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID), I: history, rationale, and description.  Arch Gen Psychiatry.1992;49:624-629.
Williams JB, Gibbon M, First MB.  et al.  The Structured Clinical Interview for DSM-III-R (SCID), II: multisite test-retest reliability.  Arch Gen Psychiatry.1992;49:630-636.
Miller WR, Marlatt GA. Manual for the Comprehensive Drinker Profile. Odessa, Fla: Psychological Assessment Resources; 1984.
McLellan AT, Luborsky L, Cacciola J.  et al.  New data from the addiction severity index: reliability and validity scores from three centers.  J Nerv Ment Dis.1985;173:412-423.
Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten R, Allen J, eds. Measuring Alcohol Consumption. Totowa, NJ: Humana Press Inc; 1992:41-72.
Stibler H, Borg S, Joustra M. A modified method for the assay of carbohydrate-deficient transferrin (CDT) in serum.  Alcohol Alcohol Suppl.1991;1:451-454.
Stibler H. Carbohydrate-deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed.  Clin Chem.1991;37:2029-2037.
Huseby NE, Bjordal E, Nilssen O, Barth T. Utility of biological markers during outpatient treatment of alcohol dependent patients: carbohydrate deficient transferrin responds to moderate changes in alcohol consumption.  Alcohol Clin Exp Res.1997;21:1343-1346.
Niemela O, Sorvajarvi K, Blake JE, Israel Y. Carbohydrate-deficient transferrin as a marker of alcohol abuse: relationship to alcohol consumption, severity of liver disease, and fibrogenesis.  Alcohol Clin Exp Res.1995;19:1203-1208.
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment of alcohol scale (CIWA-Ar).  Br J Addict.1989;84:1353-1357.
Anton RF. New methodologies for pharmacological treatment trials for alcohol dependence.  Alcohol Clin Exp Res.1996;20:3A-9A.
Del Boca FK, Kranzler HR, Brown J, Korner PF. Assessment of medication compliance in alcoholics through UV light detection of a riboflavin tracer.  Alcohol Clin Exp Res.1996;20:1412-1417.
Marlatt GA, Gordon JR. Relapse Prevention. New York, NY: Guildford Press; 1985.
Bandura A. Self-efficacy: toward a unifying theory of behavioral change.  Psychol Rev.1977;84:191-215.
US Department of Health and Human Services.  Cognitive Behavioral Coping Skills Therapy: NIAAA Project Monograph Series. Rockville, Md: US Dept Health and Human Services; 1992.
Monti PM, Abrams DB, Kadden R, Cooney N. Treating Alcohol Dependence: A Coping Skills Therapy Guide. New York, NY: Guildford Press; 1989.
Statistical Analysis System II.  SAS User's Guide: Statistics, Version 6.12. 6th ed. Cary, NC: SAS Institute Inc; 1997.
Stout RL, Wirtz PW, Carbonari JP, Del Boca FK. Ensuring balanced distribution of prognostic factors in treatment outcome research.  J Stud Alcohol Suppl.1994;12:70-75.
Meinert CL. Clinical Trials: Design, Conduct, and Analysis. New York, NY: Oxford University Press; 1986.
Senn S. Testing for baseline balance in clinical trials.  Stat Med.1994;13:1715-1726.
Graybill FA. Chapter six: general linear model. In: Press D, ed. Theory and Application of the Linear Model. North Scituate, Mass: Wadsworth Publishing Co; 1970:207-212.
Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Mahwah, NJ: Lawrence Erlbaum Associates; 1988.
Johnson BA, Rue J, Cowen PJ. Ondansetron and alcohol pharmacokinetics.  Psychopharmacology (Berl).1993;112:145.
Johnson BA, Ait-Daoud N. Neuropharmacological treatments for alcoholism: scientific basis and clinical findings.  Psychopharmacology (Berl).2000;149:327-344.
Kranzler HR, Burleson JA, Brown J, Babor TF. Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics.  Alcohol Clin Exp Res.1996;20:1534-1541.
Schuckit MA, Mazzanti C, Smith TL.  et al.  Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study.  Biol Psychiatry.1999;45:647-651.
Ishiguro H, Saito T, Akazawa S.  et al.  Association between drinking-related antisocial behavior and a polymorphism in the serotonin transporter gene in a Japanese population.  Alcohol Clin Exp Res.1999;23:1281-1284.
Heinz A, Jones DW, Mazzanti C.  et al.  A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.  Biol Psychiatry.2000;47:643-649.
Little KY, McLaughlin DP, Zhang L.  et al.  Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels.  Am J Psychiatry.1998;155:207-213.
Johnson BA. Serotonergic agents and alcoholism treatment: rebirth of the subtype concept—an interactive psychosocial and bio-molecular hypothesis.  Alcohol Clin Exp Res.In press.
Koulu M, Lappalainen J, Hietala J.  et al.  Effects of chronic administration of ondansetron (GR 38032F), a selective 5-HT3 receptor antagonist, on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal D2-receptor binding.  Psychopharmacology (Berl).1990;101:168-171.
Hollingshead A, Redlich F. Social Class and Mental Illness: A Community Study. New York, NY: Wiley; 1958.

Figures

Figure 1. Trial Flow Diagram of Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Patients diagnosed as having early-onset and late-onset alcoholism were similar in number, age, sex, and drinking level at enrollment. Trial completers were those patients who completed all 11 double-blind visits or 10 double-blind visits plus the final physical health evaluation.
Figure 2. Mean (95% Confidence Interval) Drinking Outcomes During the Double-Blind Response Period of Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Data are responses observed at the start of double-blind (visit 2) and the mean outcome observed during study (mean of visits 3-12). Analyses refer to pairwise comparisons between the ondansetron treatment groups and placebo. The a* and a† represent significant differences between an ondansetron dosage and placebo groups at the 5% and 1% levels, respectively. The b* and b† denote significant differences within a given treatment group from the start of the double-blind response period to the outcome during study at the 5% and 1% levels, respectively.
Figure 3. Mean (95% Confidence Interval) Log Plasma Carbohydrate Deficient Transferrin (CDT) Ratio for Early-Onset and Late-Onset Alcoholic Patients
Graphic Jump Location
Mean log CDT ratio was the mean log CDT at a given visit (ie, 4, 8, or 12) divided by the mean log CDT at enrollment. The dagger indicates P<.01 and the asterisk indicates P<.05.

Tables

Table Graphic Jump LocationTable. Demographic and Psychopathological Characteristics of Early-Onset and Late-Onset Alcoholic Patients at Intake*

References

Lovinger D. 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic.  Neurochem Int.1999;35:125-130.
Lovinger DM. Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells.  J Neurophysiol.1991;66:1329-1337.
Zhou Q, Lovinger DM. Pharmacologic characteristics of potentiation of 5-HT3 receptors by alcohols and diethyl ether in NCB-20 neuroblastoma cells.  J Pharmacol Exp Ther.1996;278:732-740.
Di Chiara G, Imperato A. Drug abuse by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.  Proc Natl Acad Sci U S A.1988;85:5274-5278.
Koob GF. Neural mechanisms of drug reinforcement.  Ann N Y Acad Sci.1992;654:171-191.
Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction.  Psychol Rev.1987;94:469-492.
Hemby SE, Johnson BA, Dworkin SI. Neurobiological basis of drug reinforcement. In: Johnson B, Roache J, eds. Drug Addiction and Its Treatment: Nexus of Neuroscience and Behavior. Philadelphia, Pa: Lippincott-Raven; 1997:137-169.
Bloom FE, Morales M. The central 5-HT3 receptor in CNS disorders.  Neurochem Res.1998;23:653-659.
Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding.  Nature.1987;330:746-748.
Kilpatrick GJ, Hagan RM, Gale JD. 5-HT3 and 5-HT4 receptors in terminal regions of the mesolimbic system.  Behav Brain Res.1996;73:11-13.
Costall B, Domeney AM, Naylor RJ, Tyers MB. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.  Br J Pharmacol.1987;92:881-894.
Hodge CW, Samson HH, Lewis RS, Erickson HL. Specific decreases in ethanol but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930.  Alcohol.1993;10:191-196.
Fadda F, Garau B, Marchei F, Colombo G, Gessa GL. MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats.  Alcohol Alcohol.1991;26:107-110.
Rodd-Henricks ZA, McKinzie DL, Li TK, Crile RS, Murphy JM, McBride WJ. Intracranial Self-Administration of Ethanol Into the Posterior VTA of Wistar Rats is Mediated by 5-HT3 Receptors. Santa Barbara, Calif: Research Society on Alcoholism; 1999.
Meert TF. Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference.  Alcohol Alcohol.1993;28:157-170.
McBride WJ, Li TK. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents.  Crit Rev Neurobiol.1998;12:339-369.
Tomkins DM, Le AD, Sellers EM. Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure.  Psychopharmacology (Berl).1995;117:479-485.
Barnes N, Sharp T. A review of central 5-HT receptors and their function.  Neuropharmacology.1999;38:1083-1152.
Beardsley PM, Lopez OT, Gullikson G, Flynn D. Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats.  Alcohol.1994;11:389-395.
Johnson BA, Campling GM, Griffiths P, Cowen PJ. Attenuation of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers.  Psychopharmacology (Berl).1993;112:142-144.
Johnson BA, Cowen PJ. Alcohol-induced reinforcement: dopamine and 5-HT3 receptor interactions in animals and humans.  Drug Dev Res.1993;30:153-169.
Swift RM, Davidson D, Whelihan W, Kuznetsov O. Ondansetron alters human alcohol intoxication.  Biol Psychiatry.1996;40:514-521.
Doty P, Zacny J, deWit H. The effects of ondansetron pretreatment on acute responses to ethanol in social drinkers.  Behav Pharmacol.1994;5:461-469.
Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB. Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence.  Alcohol Clin Exp Res.1994;18:879-885.
Johnson BA, Cloninger CR, Roache JD, Bordnick PS, Ruiz P. Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population.  Am J Addict.2000;9:17-27.
Babor TF, Dolinsky ZS, Meyer RE, Hesselbrock M, Hofmann M, Tennen H. Types of alcoholics: concurrent and predictive validity of some common classifications schemes.  Br J Addict.1992;87:1415-1431.
Brown J, Barbor TF, Litt MD, Kranzler HR. The type A/type B distinction: subtyping alcoholics according to indicators of vulnerability and severity.  Ann N Y Acad Sci.1994;708:22.
Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism.  Science.1987;236:410-416.
Cloninger CR, Bohman M, Sigvardsson S. Inheritance of alcohol abuse: cross-fostering analysis of adopted men.  Arch Gen Psychiatry.1981;38:861-868.
Litt MD, Babor TF, DelBoca FK, Kadden RM, Cooney NL. Types of alcoholics, II: application of an empirically derived typology to treatment matching.  Arch Gen Psychiatry.1992;49:609-614.
George D, Sirocco K, Eckhardt M, Linnoila M. Age of onset for alcoholism and CSF homovanillic acid concentrations predict relapse.  Clin Pharmacol Ther.1998;63:203.
George D, Rawlings R, Eckardt M, Phillips M, Shoaf S, Linnoila M. Buspirone treatment of alcoholism: age of onset and cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid concentrations but not medication treatment predict return to drinking.  Alcohol Clin Exp Res.1999;23:272-277.
Buydens-Branchey L, Noumair D, Branchey MH. Age of alcoholism onset, I: relationship to psychopathology.  Arch Gen Psychiatry.1989;46:225-230.
Fils-Aime M-L, Eckardt MJ, George DT, Brown GL, Mefford I, Linnoila M. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics.  Arch Gen Psychiatry.1996;53:211-216.
Vikkunen M, Linnoila M. Serotonin in early-onset alcoholism. In: Galanter M, ed. Recent Developments in Alcoholism, Alcohol and Violence: Epidemiology, Neurobiology, Psychology, Family Issues. New York, NY: Plenum Press; 1997:173-189.
Virkkunen M, Linnoila M. Serotonin in early onset, male alcoholics with violent behaviour.  Ann Med.1990;22:327-331.
Swann AS, Johnson BA, Cloninger CR, Chen YR. Alcoholism and serotonin: relationships of plasma tryptophan availability to course of illness and clinical features.  Psychopharmacology (Berl).1999;143:380-384.
Ballenger J, Goodwin F, Major L, Brown G. Alcohol and central serotonin metabolism in man.  Arch Gen Psychiatry.1979;36:224-227.
LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: clinical evidence.  Biol Psychiatry.1994;36:326-337.
LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: findings of animal studies.  Biol Psychiatry.1994;36:395-421.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
Selzer ML. The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument.  Am J Psychiatry.1971;127:1653-1658.
Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID), I: history, rationale, and description.  Arch Gen Psychiatry.1992;49:624-629.
Williams JB, Gibbon M, First MB.  et al.  The Structured Clinical Interview for DSM-III-R (SCID), II: multisite test-retest reliability.  Arch Gen Psychiatry.1992;49:630-636.
Miller WR, Marlatt GA. Manual for the Comprehensive Drinker Profile. Odessa, Fla: Psychological Assessment Resources; 1984.
McLellan AT, Luborsky L, Cacciola J.  et al.  New data from the addiction severity index: reliability and validity scores from three centers.  J Nerv Ment Dis.1985;173:412-423.
Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten R, Allen J, eds. Measuring Alcohol Consumption. Totowa, NJ: Humana Press Inc; 1992:41-72.
Stibler H, Borg S, Joustra M. A modified method for the assay of carbohydrate-deficient transferrin (CDT) in serum.  Alcohol Alcohol Suppl.1991;1:451-454.
Stibler H. Carbohydrate-deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed.  Clin Chem.1991;37:2029-2037.
Huseby NE, Bjordal E, Nilssen O, Barth T. Utility of biological markers during outpatient treatment of alcohol dependent patients: carbohydrate deficient transferrin responds to moderate changes in alcohol consumption.  Alcohol Clin Exp Res.1997;21:1343-1346.
Niemela O, Sorvajarvi K, Blake JE, Israel Y. Carbohydrate-deficient transferrin as a marker of alcohol abuse: relationship to alcohol consumption, severity of liver disease, and fibrogenesis.  Alcohol Clin Exp Res.1995;19:1203-1208.
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment of alcohol scale (CIWA-Ar).  Br J Addict.1989;84:1353-1357.
Anton RF. New methodologies for pharmacological treatment trials for alcohol dependence.  Alcohol Clin Exp Res.1996;20:3A-9A.
Del Boca FK, Kranzler HR, Brown J, Korner PF. Assessment of medication compliance in alcoholics through UV light detection of a riboflavin tracer.  Alcohol Clin Exp Res.1996;20:1412-1417.
Marlatt GA, Gordon JR. Relapse Prevention. New York, NY: Guildford Press; 1985.
Bandura A. Self-efficacy: toward a unifying theory of behavioral change.  Psychol Rev.1977;84:191-215.
US Department of Health and Human Services.  Cognitive Behavioral Coping Skills Therapy: NIAAA Project Monograph Series. Rockville, Md: US Dept Health and Human Services; 1992.
Monti PM, Abrams DB, Kadden R, Cooney N. Treating Alcohol Dependence: A Coping Skills Therapy Guide. New York, NY: Guildford Press; 1989.
Statistical Analysis System II.  SAS User's Guide: Statistics, Version 6.12. 6th ed. Cary, NC: SAS Institute Inc; 1997.
Stout RL, Wirtz PW, Carbonari JP, Del Boca FK. Ensuring balanced distribution of prognostic factors in treatment outcome research.  J Stud Alcohol Suppl.1994;12:70-75.
Meinert CL. Clinical Trials: Design, Conduct, and Analysis. New York, NY: Oxford University Press; 1986.
Senn S. Testing for baseline balance in clinical trials.  Stat Med.1994;13:1715-1726.
Graybill FA. Chapter six: general linear model. In: Press D, ed. Theory and Application of the Linear Model. North Scituate, Mass: Wadsworth Publishing Co; 1970:207-212.
Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Mahwah, NJ: Lawrence Erlbaum Associates; 1988.
Johnson BA, Rue J, Cowen PJ. Ondansetron and alcohol pharmacokinetics.  Psychopharmacology (Berl).1993;112:145.
Johnson BA, Ait-Daoud N. Neuropharmacological treatments for alcoholism: scientific basis and clinical findings.  Psychopharmacology (Berl).2000;149:327-344.
Kranzler HR, Burleson JA, Brown J, Babor TF. Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics.  Alcohol Clin Exp Res.1996;20:1534-1541.
Schuckit MA, Mazzanti C, Smith TL.  et al.  Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study.  Biol Psychiatry.1999;45:647-651.
Ishiguro H, Saito T, Akazawa S.  et al.  Association between drinking-related antisocial behavior and a polymorphism in the serotonin transporter gene in a Japanese population.  Alcohol Clin Exp Res.1999;23:1281-1284.
Heinz A, Jones DW, Mazzanti C.  et al.  A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.  Biol Psychiatry.2000;47:643-649.
Little KY, McLaughlin DP, Zhang L.  et al.  Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels.  Am J Psychiatry.1998;155:207-213.
Johnson BA. Serotonergic agents and alcoholism treatment: rebirth of the subtype concept—an interactive psychosocial and bio-molecular hypothesis.  Alcohol Clin Exp Res.In press.
Koulu M, Lappalainen J, Hietala J.  et al.  Effects of chronic administration of ondansetron (GR 38032F), a selective 5-HT3 receptor antagonist, on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal D2-receptor binding.  Psychopharmacology (Berl).1990;101:168-171.
Hollingshead A, Redlich F. Social Class and Mental Illness: A Community Study. New York, NY: Wiley; 1958.
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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