Biomedical subjects

H R Kranzler

Publications and source records attributed to H R Kranzler.

At least 19 recordsLinked to original sources

PubMed2004

Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus.

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains >30000000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125-126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P=0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P=0.01), D1S2804 (126.16 cM, P=0.04), and D1S2776 (126.16 cM, P=0.02), which are all located within a <350000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

Adult↗

PubMed2003

Pharmacotherapies to enhance smoking cessation during pregnancy.

Smoking during pregnancy is a significant public health concern. Maternal smoking increases the risk of spontaneous abortion, low birth weight, premature delivery, sudden infant death syndrome and learning and behavioral problems in the offspring. Unfortunately, the majority of pregnant women do not quit smoking during pregnancy. Although pharmacotherapy may improve smoking cessation rates in pregnancy, very few studies exist that have studied the safety and efficacy of medications to treat pregnant smokers. This article reviews the available safety and efficacy data for the use in pregnancy of the five first-line therapies and two second-line therapies that are recommended for smoking cessation in non-pregnant smokers. Other promising nicotine replacement therapies are also reviewed. Ultimately, the choice whether to use pharmacotherapy for smoking cessation should be made jointly by the pregnant smoker and her health care provider. This article reviews factors that may be considered when prescribing pharmacotherapy to pregnant smokers (i.e. the role of behavioral counseling, identification of appropriate patients, potential advantages and disadvantages of each of the pharmacotherapies, proposed monitoring strategies, dose and duration and goals of treatment). More research regarding the safety and efficacy of pharmacotherapy during pregnancy is needed to define the risk/benefit profile of each medication for use in smoking cessation in pregnant women.

Administration, Cutaneous↗

PubMed2001

Adverse effects of oral naltrexone: analysis of data from two clinical trials.

RATIONALE: Naltrexone treatment of alcohol dependence is associated with adverse events that may limit its effectiveness. Consequently, understanding the impact of adverse events on medication compliance and treatment retention may enhance naltrexone therapy of alcoholism. OBJECTIVES: To examine the relations among adverse events, drinking behavior, medication compliance and study retention in alcoholics receiving naltrexone for relapse prevention. METHODS: The current report is based on analysis of data from 92 subjects who participated in two previously published studies. Moderate or severe adverse effects were monitored weekly and categorized as either neuropsychiatric (NP) or gastrointestinal (GI). Medication compliance was determined by weekly urinary riboflavin testing. Study retention was determined by the proportion of study weeks completed by the subject. The causal relations among adverse events, medication compliance and study retention were analyzed separately for NP and GI adverse events using regression-based recursive path models. RESULTS: Both the NP and GI models fit the data well [NP model: chi 2(4) = 0.59, P = 0.96; GI model: chi 2(4) = 2.81, P = 0.59]. NP adverse events exerted little influence on medication compliance (beta = -0.17, P = 0.071), but directly decreased the length of study retention (beta = -0.35, P < 0.001). In contrast, there was a significant impact of GI adverse events on medication compliance (beta = -0.29, P = 0.002), but not directly on study retention (beta = -0.14, P = 0.081). CONCLUSION: Future studies aimed at enhancing the effectiveness of naltrexone should examine ways of reducing both NP and GI adverse events, in order to enhance both medication compliance and treatment retention.

Administration, Oral↗

PubMed2001

Reliability of personality disorder symptoms and personality traits in substance-dependent inpatients.

The authors compared the internal consistency, 1-year temporal stability, and self-informant agreement of ratings of personality trait (NEO Five-Factor Inventory; NEO-FFI; P. T. Costa & R. R. McCrae, 1992) and personality disorder symptom severity (Structured Clinical Interview for DSM-III-R Personality Disorders Questionnaire; SCID-II-Q; R. L. Spitzer, J. B. W. Williams, M. Gibbon, & M. First, 1990) in 131 substance-dependent inpatients. Internal consistency coefficients were acceptable to very good for most NEO-FFI and SCID-II-Q scales, and temporal stability correlations were significant for all measures. Agreement between patient and informant ratings was more modest. Substance abuse and depression symptom severity moderated the temporal stability and self-informant agreement of several personality trait and disorder ratings. The authors did not find that the five factors were more reliable than the Axis II symptoms. Issues related to the reliability of personality assessment in multiply diagnosed patients are discussed.

Adult↗

PubMed2001

Double-blind clinical trial of sertraline treatment for alcohol dependence.

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.

Adult↗

PubMed2001

Sweet taste preference as a risk factor for alcohol dependence.

OBJECTIVE: Previous research has found that alcoholics have a greater preference for sweet solutions than comparison subjects. This study tested the hypothesis that preference for sweet solutions is a marker for alcoholism risk. METHOD: A total of 122 nonalcoholic subjects (59 men) participated. Fifty-eight subjects had a paternal history of alcoholism, and 64 did not. Each subject rated a series of sucrose solutions for intensity of sweetness and degree of preference. RESULTS: Subjects were able to rate accurately the relative intensity of sweetness in the sucrose solutions. Both subjects with and those without a paternal history of alcoholism preferred a 0.42-M sucrose solution, irrespective of gender. CONCLUSIONS: This study failed to support the hypothesis that sweet preference is a marker of alcoholism risk. The sweet preference observed previously among alcoholics may be a consequence of chronic alcohol consumption or other factors associated with heavy drinking.

Adult↗

PubMed2001

Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis.

BACKGROUND: Renewed interest in medications to prevent relapse in alcoholics (i.e., antidipsotropics) resulted in approval by the Food and Drug Administration of naltrexone to treat alcohol dependence. Acamprosate, although not approved in the United States, is used in alcoholism treatment in many other parts of the world. In the absence of studies that compare the effects of these medications, we used a meta-analytic approach to the literature to compare their efficacy in alcoholism treatment. METHODS: All published placebo-controlled trials of naltrexone or acamprosate for alcohol dependence were examined, and, when suitable, data were extracted for calculation of a mean effect size. A sample of studies of selective serotonin reuptake inhibitors for treatment of major depression conducted over the last two decades served as a comparator for the antidipsotropics. RESULTS: Both antidipsotropics exerted significant, but modest, effects on treatment retention and/or drinking outcomes. There was significant variability among the studies for the measure on which the largest effect was exerted by each of these medications. Based on limited comparisons of the two medications, there appears to be no statistical difference in their efficacy in the treatment of alcohol dependence. In contrast, there was a consistent effect of selective serotonin reuptake inhibitors on depressive symptoms in major depression, which was significantly greater than the effects observed for the antidipsotropics. CONCLUSIONS: Both naltrexone and acamprosate are efficacious in reducing alcohol consumption in alcoholics. However, their specific role in alcoholism treatment remains to be more clearly defined. New approaches to the use of these medications and development of new medications are needed if pharmacotherapy is to play a substantial role in the treatment of alcoholism.

Acamprosate↗

PubMed2000

Family-based study of DRD2 alleles in alcohol and drug dependence.

Numerous case-control studies have addressed the hypothesis that variant alleles of the dopamine D2 receptor gene (DRD2) increase the liability for alcohol and/or drug dependence, and both positive and negative results have been reported. Because population frequencies of these alleles vary considerably, the conflicting results could be due to population stratification bias. Using the transmission disequilibrium test, the present study examined linkage disequilibrium of alcohol and drug (opioid and/or cocaine) dependence with three DRD2 polymorphic systems: (a) TaqI A, (b) TaqI D, and (c) the functional -141CIns/Del promoter systems. DNA samples were collected from small nuclear families (SNFs), where one or more offspring met DSM-III-R or DSM-IV criteria for alcohol and/or drug dependence. Because positive association between DRD2 alleles and alcohol and/or drug dependence has been reported only in populations of European ancestry, we limited the present study to European Americans (EAs). No evidence for linkage disequilibrium was found for any of the polymorphic systems when examined in relation to any substance dependence, alcohol dependence (with or without drug dependence), or drug dependence (with or without alcohol dependence). These results are consistent with those from a recent family-based study of alcohol dependence. Together, these studies suggest that the conflicting findings from case-control studies of the association between alleles of DRD2 and substance dependence may be attributable to population stratification in some samples.

Alcoholism↗

PubMed2000

Variant detection at the delta opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence.

The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.

Alleles↗

PubMed2000

Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial.

This study compared the effects of nefazodone, a serotonergic antidepressant, with the opioid antagonist naltrexone, and an inactive placebo in 183 alcohol-dependent subjects receiving weekly relapse prevention psychotherapy. Following a single-blind, placebo lead-in period, subjects were randomly assigned to receive study medication, which they took under double-blind conditions for 11 weeks. Naltrexone treatment was associated with significantly more adverse neuropsychiatric and gastrointestinal effects, poorer compliance, and a greater rate of treatment attrition. There were no reliable between-group differences in drinking behavior. These results indicate that nefazodone is not efficacious for treatment of alcohol dependence. Furthermore, the clinical utility of naltrexone seems to be limited by its adverse effects, a finding that has important implications for efforts to develop medications to treat alcohol dependence.

Adult↗

PubMed2000

Co-occurrence of Axis I and Axis II disorders in substance abusers.

OBJECTIVE: This study examined the co-occurrence of anxiety/mood and personality disorders (PDs) in substance abusers, the impact of anxiety/ mood disorders on the symptom profiles of PDs, and the impact of anxiety/mood disorders and PDs on pre-treatment status. METHOD: Current anxiety/mood disorders and PDs and pre-treatment status were assessed using semi-structured interviews in 370 treated substance abusers. RESULTS: Anxiety/mood disorders and PDs frequently co-occurred, with the overall pattern of associations being non-specific. The strongest associations were of social phobia with avoidant and schizotypal PD, and of major depression with borderline PD. However, symptom profiles of PDs were not associated with anxiety/mood disorders. Finally, anxiety/mood disorders and PDs were both independently and differentially associated with poor pre-treatment characteristics. CONCLUSION: The findings suggest the clinical importance of obtaining both Axis I and Axis II diagnoses in treated substance abusers, and highlight the distinctiveness of the Axis I and Axis II disorders.

Adult↗

PubMed2000

Give them prizes, and they will come: contingency management for treatment of alcohol dependence.

This study evaluated the efficacy of a contingency management (CM) procedure that provided opportunities to win prizes as reinforcers. At intake to outpatient treatment, 42 alcohol-dependent veterans were randomly assigned to receive standard treatment or standard treatment plus CM, in which they earned the chance to win prizes for submitting negative Breathalyzer samples and completing steps toward treatment goals. Eighty-four percent of the CM participants were retained in treatment for an 8-week period compared with 22% of the standard treatment participants (p < .001). By the end of the treatment period, 69% of those receiving CM were still abstinent, but 61% of those receiving standard treatment had used alcohol (p < .05). These results support the efficacy of this CM procedure. Participants earned an average of $200 in prizes. This CM procedure may be suitable for use in standard treatment settings because prizes can be solicited from the community.

Alcoholism↗

PubMed2000

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

Alleles↗

PubMed2000

Axis I and Axis II disorders in alcoholics and drug addicts: fact or artifact?

OBJECTIVE: It has been argued that Axis I and Axis II disorders diagnosed in substance users refer to substance-induced conditions rather than to independent psychiatric conditions; this argument will be referred to as the substance-related artifact hypothesis. Furthermore, Axis II symptoms co-occurring with Axis I disorders have been attributed to the contamination of personality assessment by mood and/or anxiety state effects (the trait-state artifact hypothesis). The present study is the first to prospectively examine the validity of these two hypothesized "artifacts" in substance users. METHOD: In 276 individuals (57.6% female) applying for substance use treatment, current substance use disorders, mood/anxiety disorders and Axis II disorders were diagnosed using semistructured interviews both at baseline and at 1-year follow-up. The substance-related artifact hypothesis is tested by examining the covariation between recovery from substance use disorders on the one hand and recovery from and/or improvement of mood/anxiety and Axis II disorders on the other hand. The trait-state artifact hypothesis is tested by examining the covariation between recovery from mood/anxiety disorders on the one hand and recovery from and/or improvement of Axis II disorders on the other hand. RESULTS: Recovery from substance use disorders covaried with recovery from and improvement of mood/anxiety disorders, but not with recovery from or improvement of Axis II pathology. Furthermore, recovery from mood/anxiety disorders covaried with recovery from and improvement of personality disorders, in particular Cluster C disorders. CONCLUSIONS: Results from this study suggest that mood/anxiety disorders, but not personality disorders, diagnosed among people with substance use disorder may partly reflect substance-related artifacts. Furthermore, this study provides evidence for the contention that semistructured interview assessment of Axis II, at least without inquiry on an item-by-item basis, is susceptible to contamination by mood/anxiety state effects.

Adult↗

PubMed2000

Does affect mediate the association between daily events and alcohol use?

OBJECTIVE: We examined the within-person associations among positive and negative daily events, positive and negative affect, desire to drink, and alcohol consumption in a sample of heavy drinkers. METHOD: Forty-six subjects (25 men; mean [SD] age = 47.0 [9.3] years) who were enrolled in an 8-week treatment program for heavy drinkers were studied using a daily diary methodology. RESULTS: Multilevel regression analyses indicated that individuals reported stronger desire to drink and greater consumption on days in which more positive and negative nonwork events occurred. Lower levels of desire to drink and number of drinks were reported on days with more positive work events. Negative work events had a marginal positive association with daily desire to drink. Daily positive and negative affect uniquely predicted greater daily consumption and desire to drink, but only weak evidence was found for their mediating role in the association between daily events and the criterion variables. Several of the within-person associations among affect and the criterion variables varied as a function of number of lifetime symptoms of alcohol dependence and treatment condition. CONCLUSIONS: These findings generally support the dual-process (i.e., tension-reduction and experience-enhancement) motivational model of alcohol consumption. However, the observed associations among events, affect and alcohol-related behavior suggests that these pathways are complex, with each being comprised of affective and cognitive subpathways.

Adolescent↗

PubMed2000

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype.

BACKGROUND: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. METHODS: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. RESULTS: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. CONCLUSIONS: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Adolescent↗

PubMed1999

Pharmacologic treatments for drug and alcohol dependence.

Pharmacotherapy remains a relatively underused strategy for the treatment of patients with psychoactive substance-use disorders. This is partly because of a widely held view among the public and the substance-abuse treatment community that substance-use disorders are non-medical and should be treated through nonpharmacologic means. Furthermore, the pharmaceutical industry has been slow in developing medications for the treatment of patients with these disorders because of skepticism over the potential profitability of such medications. These factors have limited research activity in this area, with much of the impetus for study of these medications coming from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, where the substantial public health implications of medications development for substance-use disorders have been recognized. Despite limitations, considerable advances in medication development for patients with substance-use disorders have occurred in recent years, and more can be expected in the near future. This is most evident in the treatment of patients with nicotine and opioid dependence, for whom several pharmacologic options exist. Recently renewed interest in the pharmacologic treatment of patients with alcohol dependence is likely to advance that therapeutic area substantially with time. Ongoing efforts should focus on identifying new compounds, systematically assessing them for activity in specific substance-use disorders, and educating the public and the treatment community about the substantial benefits that can accrue from medication development for patients with substance-use disorders.

Alcohol Deterrents↗

PubMed1999

The validity of self-reported cocaine use in two groups of cocaine abusers.

To evaluate the validity of 2 self-report methods for estimating cocaine use, Timeline Follow-Back (TLFB) and weekly calendar reports from 65 patients with a cocaine use disorder were compared with urine drug test results. The TLFB showed fair to moderate validity, and the weekly calendar showed moderate to high validity in measuring the frequency of cocaine use. Similar results were obtained when the self-report measures were used to time specific cocaine use episodes. In addition to evidence for superiority of the weekly calendar, the validity of self-reports was inversely related to the percentage of positive urine test results. Furthermore, there was some evidence that validity increased as the time window over which the comparisons were drawn increased. Given the central role of self-reports in the clinical and research evaluation of drug use, factors affecting their validity warrant further investigation.

Adult↗