Recommendations on the measurement and use of the alcohol consumption biomarker CDT. A position paper from the IFCC Working Group on CDT standardisation.

BACKGROUND: Carbohydrate deficient transferrin (CDT) is a biomarker for excessive alcohol consumption utilized in clinical and forensic medicine and workplace testing. Previously, many different analytical methods for CDT were used and the measurand varied considerably, making direct comparison of test results difficult. To end this confusion, the IFCC established a working group on CDT standardisation (WG-CDT) which completed its tasks in 2017. METHODS: This IFCC position paper by the WG-CDT summarizes state of the art information about the measurand and the analytical methods and gives concise recommendations for its utilization. RESULTS: The results achieved by the CDT standardisation process led to accuracy improvements in national external quality assessment schemes over the years. A brief review of ROC based comparison studies with the traditional biomarkers (GGT, MCV, ALT and AST) discusses the bias resulting from inadequate study populations. In large groups of the general population the superior diagnostic performance of CDT is confirmed. CONCLUSION: The relationship between alcohol intake versus resulting CDT is discussed as well as the cutoff and measurement uncertainty. Concerning the application in practice, potential pitfalls are considered and recommendations handling both analytical and preanalytical caveats are given. Finally, some examples of serious misunderstandings in publications about CDT are addressed.

Unique prefrontal GABA and glutamate disturbances in co-occurring bipolar disorder and alcohol dependence.

Bipolar disorder (BD) and alcohol dependence (AD) frequently co-occur, and co-occurring BD and AD are associated with devastating public health costs. Minimal neurobiological research exists to guide the development of effective treatments for this treatment-resistant population. We believe the present study represents the first investigation of prefrontal gamma-aminobutyric acid (GABA) and glutamate levels in co-occurring BD and current AD. The participants were 78 individuals who met DSM-IV criteria for BD I/II and current AD (n=20), BD I/II alone (n=19), current AD alone (n=20) or no diagnosis (n=19). The participants completed a baseline diagnostic visit, then returned approximately 4 days later for a two-dimensional J-resolved proton magnetic resonance spectroscopy (1H-MRS) acquisition in dorsal anterior cingulate cortex (dACC). All participants were required to demonstrate ⩾1 week of abstinence from alcohol/drugs via serial biomarker testing before 1H-MRS. A 2 × 2 factorial analysis of variance of cerebrospinal fluid (CSF)-corrected GABA/water concentrations demonstrated a significant BD × AD interaction (F=2.91, P<0.05), signifying uniquely low levels of GABA in BD+AD; this effect doubled when the sample was restricted to individuals who consumed alcohol within 2 weeks of 1H-MRS. There were no overall effects of BD/AD on CSF-corrected glutamate/water levels. However, the BD × AD interaction, signifying uniquely low levels of glutamate in BD+AD, approached statistical significance (F=3.83, P=0.06) in individuals who consumed alcohol within 2 weeks of 1H-MRS. The dACC GABA levels were significantly, negatively associated with Barratt Impulsiveness Scale (r=-0.28, P=0.02) and Obsessive Compulsive Drinking Scale (r=-0.35, P<0.01) scores. If replicated, these results may suggest that future treatment studies should preferentially evaluate therapeutics in BD+AD known to increase prefrontal GABA and glutamate levels.

Naltrexone and cognitive behavioral therapy for the treatment of alcohol dependence: do sex differences exist?

BACKGROUND: Sex differences in regards to pharmacotherapy for alcoholism is a topic of concern following publications suggesting naltrexone, one of the longest approved treatments of alcoholism, is not as effective in women as in men. This study was conducted by combining 2 randomized placebo controlled clinical trials utilizing similar methodologies and personnel in which the data was amalgamated to evaluate sex effects in a reasonable sized sample. METHODS: A total of 211 alcoholics (57 female and 154 male) were randomized to the naltrexone/cognitive behavorial thearpy (CBT) or placebo/CBT arm of the 2 clinical trials analyzed. Baseline variables were examined for differences between sex and treatment groups via ANOVA for continuous variable or chi-squared test for categorical variables. All initial outcome analysis was conducted under an intent-to-treat analysis plan. Effect sizes for naltrexone over placebo were determined by Cohen's D (d). RESULTS: The effect size of naltrexone over placebo for the following outcome variables was similar in men and women [% days abstinent (PDA) d = 0.36, % heavy drinking days (PHDD) d = 0.36, and total standard drinks (TSD) d = 0.36]. Only for men were the differences significant secondary to the larger sample size (PDA p = 0.03; PHDD p = 0.03; TSD p = 0.04). There were a few variables (GGT at week-12 change from baseline to week-12: men d = 0.36, p = 0.05; women d = 0.20, p = 0.45 and drinks per drinking day: men d = 0.36, p = 0.05; women d = 0.28, p = 0.34) where the naltrexone effect size for men was greater than women. In women, naltrexone tended to increase continuous abstinent days before a first drink (women d = 0.46, p = 0.09 and men d = 0.00, p = 0.44). CONCLUSIONS: The effect size of naltrexone over placebo appeared similar in women and men in our hands suggesting the findings of sex differences in naltrexone response might have to do with sample size and/or endpoint drinking variables rather than any inherent pharmacological or biological differences in response.

Alcohol consumption, %CDT, GGT and blood pressure change during alcohol treatment.

AIMS: Blood pressure (BP) changes in alcohol-dependent individuals during a 12-week alcohol relapse prevention study were examined in light of drinking status and biomarkers of alcohol consumption [carbohydrate-deficient transferrin (%CDT) and gamma-glutamyl transpeptidase (GGT)]. METHODS: Of 160 randomized alcoholic individuals, 120 who had hypertension and in whom daily drinking data was available, at 6 and 12 weeks of treatment were included. The impact of alcohol consumption on change in systolic BP (SBP) and diastolic BP (DBP) was examined. Further analysis determined the relationship between BP and alcohol-use biomarkers. RESULTS: A significant effect of complete abstinence on both SBP (-10 mmHg; P = 0.003) and DBP (-7 mmHg; P = 0.001) when compared to any drinking (SBP and DBP = -1 mmHg) was observed. At week 12, participants with a positive %CDT (> or =2.6) had 7 mmHg greater SBP (P = 0.01) and DBP (P < 0.001) than those with negative %CDT. Participants with positive GGT (> or =50 IU) had 10 mmHg greater SBP (P = 0.12) and 9 mmHg greater DBP (P = 0.03) than those with negative GGT. The percent change in SBP was correlated with percent change in %CDT (P = 0.003) but not GGT (P = ns). The percent change in DBP was correlated with both percent change in %CDT (P < 0.0001) and GGT (P = 0.03). CONCLUSIONS: Abstinence from alcohol significantly decreased the BP and a positive relationship between BP and both alcohol-use biomarkers was illustrated. Since %CDT is more specific than GGT for heavy alcohol consumption, clinicians may monitor the role of alcohol in hypertension using %CDT as a supplemental aid, providing an objective assessment of drinking to influence BP treatment decisions.

Superior vena cava syndrome with central venous catheter for chemotherapy treated successfully with fibrinolysis.

Recently, there has been an increase in the number of cases of superior vena cava (SVC) syndrome associated with chronic indwelling central venous catheters. Fibrinolytic therapy and endovascular treatment are currently achieving good results. We present a case history of a patient with SVC with a catheter used for chemotherapy, which was successfully treated with catheter-directed (intraclot) infusion thrombolytic therapy with urokinase.

Superior vena cava syndrome with central venous catheter for chemotherapy treated successfully with fibrinolysis

Recently, there has been an increase in the number of cases of superior vena cava (SVC) syndrome associated with chronic indwelling central venous catheters. Fibrinolytic therapy and endovascular treatment are currently achieving good results. We present a case history of a patient with SVC with a catheter used for chemotherapy, which was successfully treated with catheter-directed (intraclot) infusion thrombolytic therapy with urokinase (AU)

The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial.

OBJECTIVE: Benzodiazepines are the mainstay of treatment for mild-to-moderate alcohol withdrawal in outpatient settings, but they can interact with alcohol, cause motor incoordination, or be abused. This study compared the therapeutic responses of the benzodiazepine lorazepam and the anticonvulsant carbamazepine for the outpatient treatment of acute alcohol withdrawal in terms of patients' previous detoxification histories, and compared the effects of these 2 medications on drinking behaviors in the immediate postdetoxification period. DESIGN: This was a randomized double-blind trial comparing patient responses to carbamazepine and lorazepam across 2 levels of detoxification histories (0-1 or >or=2 previous medicated detoxifications). SETTING: A university medical center substance abuse clinic in Charleston, SC. PATIENTS: One hundred thirty-six patients in moderate alcohol withdrawal were randomized. Major exclusions were significant hepatic or hematologic abnormalities and use of medications that could alter withdrawal symptoms. INTERVENTIONS: Patients received 600-800 mg of carbamazepine or 6-8 mg of lorazepam in divided doses on day 1 tapering to 200 mg of carbamazepine or 2 mg of lorazepam. MAIN OUTCOME MEASURES: The Clinical Institute Withdrawal Assessment for Alcohol-Revised was used to assess alcohol withdrawal symptoms on days 1 through 5 and postmedication at days 7 and 12. Daily drinking was measured by patient report using a daily drinking log and a breath alcohol level with each visit. Side effects were recorded daily. RESULTS: Carbamazepine and lorazepam were equally effective at decreasing the symptoms of alcohol withdrawal. In the post-treatment period, 89 patients drank on at least 1 day; on average, carbamazepine patients drank less than 1 drink per drinking day and lorazepam patients drank almost 3 drinks per drinking day (P =.003). Among those with multiple past detoxifications, the carbamazepine group drank less than 1 drink per day on average and the lorazepam group drank about 5 drinks per day on average (P =.033). Lorazepam-treated patients had a significant rebound of alcohol withdrawal symptoms post-treatment (P =.007) and the risk of having a first drink was 3 times greater (P =.04) than for carbamazepine-treated patients. Twenty percent of lorazepam-treated patients had dizziness, motor incoordination, or ataxia and did not recognize their impairment. Twenty percent of carbamazepine-treated patients reported pruritus but no rash. CONCLUSIONS: Carbamazepine and lorazepam were both effective in decreasing the symptoms of alcohol withdrawal in relatively healthy, middle-aged outpatients. Carbamazepine, however, was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially for those with a history of multiple treated withdrawals.

Utility of a new assay for carbohydrate-deficient transferrin (Biorad %CDT TIA) to monitor abstinence during a treatment outcome study.

BACKGROUND: The ability to reliably detect heavy alcohol use is important in both clinical and research populations. The current study evaluates the utility of the newest method of measuring carbohydrate deficient transferrin (CDT) in monitoring the abstinence during a treatment outcome study. METHODS: Blood from 40 alcohol dependent individuals was obtained at baseline and at weeks 4, 8, and 12 of treatment. Differences in percent of baseline GGT and %CDT levels were analyzed in people who remained abstinent throughout treatment (abstainers) and in those who consumed alcohol during treatment (drinkers). RESULTS: There was a significant decrease in the percent of baseline %CDT levels in the subjects who abstained at week 4 and a trend at weeks 8 and 12. Conversely, there were no significant differences in percent of baseline GGT levels between drinkers and abstainers at any time point. CONCLUSIONS: Although small in nature, this study provides preliminary evidence for the use of the relatively new Biorad %CDT assay to monitor drinking status during treatment outcome studies. This study is also consistent with previously reported findings that GGT appears to be less sensitive than %CDT in detecting the consumption of alcohol. A larger trial focusing on sex differences in the utility of % CDT to monitor outcome would be of interest.

Pharmacologic approaches to the management of alcoholism.

Our understanding of alcohol craving, both as a cause for chronic abuse and relapse and as a target for intervention, has been refined significantly in recent years. For example, craving experienced during alcohol withdrawal may be mediated by gamma-aminobutyric acid (GABA) and glutamate receptor mechanisms, whereas the memory of the rewarding aspects of alcohol may be mediated by dopamine, opiate, and glutamate systems. Therefore, pharmacologic treatments for alcohol dependence may be targeted to numerous pathways. This article will discuss animal and clinical studies of the opioid antagonists (primarily naltrexone), acamprosate, and disulfiram. The side effects and treatment recommendations for each drug will also be reviewed.

Comparison of Bio-Rad %CDT TIA and CDTect as laboratory markers of heavy alcohol use and their relationships with gamma-glutamyltransferase.

BACKGROUND: Carbohydrate-deficient transferrin (CDT) is used as a serum marker for heavy drinking. We compared a new Bio-Rad %CDT TIA assay with the CDTect assay; we also compared both to gamma-glutamyltransferase (GGT) as markers of heavy drinking. METHODS: Serum samples of well-defined alcoholics (n = 404) and matched (age, race, and gender) social drinkers (204) from 10 clinical centers were assayed with both CDT assays. Both assays use microcolumn separation after iron saturation, followed by enzyme immunoassay (CDTect) or turbidimetric immunoassay (Bio-Rad %CDT). In the latter, CDT is expressed as a percentage of total transferrin. RESULTS: The slope and intercept [95% confidence intervals (CIs)] for linear regression of results obtained by the %CDT-TIA (as percentage) and CDTect (units/L) assays were 0.091 (0.088-0.097) and 0.70% (0.54-0.86%), respectively (S(y/x) =1.30%; r = 0.848). The areas under the ROC curves (95% CIs) for CDTect and Bio-Rad %CDT TIA were 0.89 (0.86-0.92) and 0.88 (0.85-0.91), respectively, for men (P, not significant) and 0.76 (0.72-0.80) and 0.72 (0.68-0.76) for women (P, not significant). When CDT (CDTect or Bio-Rad %CDT) was combined with GGT (either one positive), the clinical sensitivity in men was 90% for both assays, and specificities were 81% and 84%, respectively; sensitivities in women were 75% and 76%, respectively, and specificities were 87% and 91%. CONCLUSION: The new Bio-Rad %CDT TIA assay compares favorably to the widely studied CDTect assay in the detection of alcohol-use disorders.

Alcohol biomarkers: clinical significance and biochemical basis.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Raj Lakshman and Mikihiro Tsutsumi. The presentations were (1) Sialic acid index of apolipoprotein J: A new marker for chronic alcohol consumption, by P. Ghosh and M. R. Lakshman; (2) Microheterogeneity of serum glycoproteins in alcoholics, by M. Tsutsumi and S. Takase; (3) Probing protein-ethanol adducts with combinatorial peptide libraries displayed by filamentous phage, by H. Anni, O. Nikolaeva, and Y. Israel Y; (4) Carbohydrate-deficient transferrin as a marker for heavy alcohol use: What have we learned; Where do we go from here, by R. F. Anton; (5) Sensitivity and specificity of carbohydrate-deficient transferrin in drinking experiments and different patient groups, by O. M. Lesch; (6), Transferrin variants interfere with the measurement of carbohydrate-deficient transferrin, by A. Helender, G. Eriksson, and J-O. Jeppson; and (7) Chronic ethanol on protein trafficking in liver, by P. Marmillot, M. N. Rao, and M. R. Lakshman.

Neuroimaging in alcoholism: ethanol and brain damage.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues.

BACKGROUND: Functional imaging studies have recently demonstrated that specific brain regions become active in cocaine addicts when they are exposed to cocaine stimuli. To test whether there are regional brain activity differences during alcohol cue exposure between alcoholic subjects and social drinkers, we designed a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific cues. METHODS: Ten non-treatment-seeking adult alcoholic subjects (2 women) (mean [SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited, screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects were serially rated for alcohol craving before and after a sip of alcohol, and after a 9-minute randomized presentation of pictures of alcoholic beverages, control nonalcoholic beverages, and 2 different visual control tasks. During picture presentation, changes in regional brain activity were measured with the blood oxygen level-dependent technique. RESULTS: Alcoholic subjects, compared with the social drinking subjects, reported higher overall craving ratings for alcohol. After a sip of alcohol, while viewing alcohol cues compared with viewing other beverage cues, only the alcoholic subjects had increased activity in the left dorsolateral prefrontal cortex and the anterior thalamus. The social drinkers exhibited specific activation only while viewing the control beverage pictures. CONCLUSIONS: When exposed to alcohol cues, alcoholic subjects have increased brain activity in the prefrontal cortex and anterior thalamus-brain regions associated with emotion regulation, attention, and appetitive behavior.

The role of craving in alcohol use, dependence, and treatment.

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer and chair was Barbara A. Flannery, and the co-chairs were Barbara A. Flannery and Helen Pettinati. The presentations were (1) Animal models of alcohol craving and relapse, by Amanda Roberts; (2) Real-time field assessment of alcohol craving, by Ned Cooney; (3) Medications and alcohol craving, by Robert Swift; (4) The assessment of craving: Insights from the clinic and clinical laboratory studies, by Raymond Anton; (5) A comparison of three alcohol craving questionnaires, by Barbara Flannery; (6) and Assessing posttreatment urge to drink, by Damaris Rohsenow.

Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism.

Naltrexone, an opiate antagonist medication, has been reported to be efficacious in the treatment of alcohol dependence when added to psychosocial treatments. Although the within-treatment efficacy of naltrexone has received primary attention, there has been little published on the outcome of individuals once the medication is discontinued. Animal studies have led to concern regarding a quick rebound to heavy drinking. This report extends the data previously reported by evaluating the outcome in alcoholic subjects during the 14 weeks after a 12-week treatment with naltrexone or placebo in conjunction with cognitive behavioral therapy. Of the 131 subjects evaluated during the treatment phase, 124 (95%) had up to 14 weeks of posttreatment drinking data available for analysis. Measures of craving and blood markers of heavy drinking were also evaluated. By the end of treatment, naltrexone demonstrated significantly greater efficacy than placebo. However, once the medication was discontinued, there was a gradual increase in relapse rates, heavy drinking days, and drinks per drinking day, and fewer days of abstinence were reported. By the end of the 14-week follow-up period, although naltrexone-treated subjects were, on average, still doing better than control subjects, the effectiveness of naltrexone was no longer statistically significant. There was no evidence that naltrexone subjects had an immediate return to heavy alcohol use as suggested in animals. These data suggest that, for a number of alcoholic subjects, continued treatment with naltrexone, or perhaps psychosocial intervention, for longer than 3 months is indicated. Future research should identify which alcohol-dependent individuals may need prolonged treatment to improve treatment success in the long term.

Neuropsychological performance deficits in adults with attention deficit/hyperactivity disorder.

Neuropsychological deficits in children diagnosed with attention deficit/hyperactivity disorder (ADHD) have been well documented utilizing various neuropsychological tests. Only recently has research begun to examine if similar deficits are present in adults with ADHD. A neuropsychological testing battery was constructed that assessed verbal learning and memory, psychomotor speed, and sustained attention--all demonstrated to be deficient in individuals with ADHD. Fifty-six self-referred nonmedicated adults with a DSM-IV diagnosis of ADHD and 38 normal comparison adults participated. ADHD adults demonstrated verbal and nonverbal memory deficits and decreased psychomotor speed compared to normal controls. Differences between ADHD and normal adults were not documented on traditional measures of executive functioning. A pattern of results emerged whereby ADHD adults' performance, particularly with regard to psychomotor speed, became more impaired as task complexity increased. This study's results largely corroborate similar neuropsychological testing results in ADHD children and recent ADHD adult findings, and support a frontal lobe dysfunction hypothesis of ADHD.

Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy drinking. What have we learned? Where do we go from here?

Carbohydrate-deficient transferrin (CDT) has been widely investigated as a biological marker of heavy alcohol consumption. In general, it has been found to be at least as sensitive and probably more specific than gamma-glutamyltransferase (GGT). Because the two analytes are not highly correlated, their use in parallel enhances the sensitivity of detection of heavy alcohol consumption, especially in clinical populations. Women as a group produce more CDT under natural conditions and may produce less CDT in response to heavy drinking. Carbohydrate-deficient transferrin has found a place in the monitoring of alcoholics during treatment. Changes in CDT levels from individualized baseline values seem to be more sensitive to lower level relapse drinking than is the use of raw cut-off values. There are some conditions such as severe liver disease in which higher than normal levels of CDT are produced, thereby reducing the specificity of this marker for detecting heavy drinking under certain conditions. Future directions for the use of CDT include standardization and automation of measurement technology, evaluation of how to use it wisely in myriad medical and institutional settings, understanding more thoroughly the gender issues in its production, and greater evaluation of its performance as a monitoring tool during treatment and follow-up situations. How to combine CDT with both verbal tools of alcohol assessment and newer biological markers will also need more extensive evaluation.

Obsessive-compulsive aspects of craving: development of the Obsessive Compulsive Drinking Scale.

"Craving" for alcohol needs improved definition and measurement. This review provides a rationale for considering at least certain aspects of craving as having obsessive and compulsive features. As such, there may be phenomenological, but not necessarily etiological, overlap with obsessive-compulsive disorder. There are increasing data that suggest a neuroanatomical overlap between addiction/craving and obsessive-compulsive symptoms. The self-rated Obsessive Compulsive Drinking Scale (OCDS), based on the Yale-Brown Obsessive Compulsive Scale for heavy drinking interview (YBOCS-hd), was developed to assist in the examination of certain aspects of "craving" in alcoholics. The development, reliability, face validity, congruent validity and predictive validity of the OCDS are presented and discussed in this paper. The utility of the OCDS as a measurement tool in cognitive-behavioral and pharmacological alcoholism treatment research is highlighted. The potential of this instrument as a research and clinical tool for the understanding and evaluation of alcohol dependence needs further evaluation.