Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial.

BACKGROUND: The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS). METHODS: Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4-day periods (experiments), separated by minimum 7-day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LA LA ) versus 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SERT mRNA (the primary outcome measure) using qRT-PCR and (2) plasma EtG and EtS levels using tandem mass-spectrometry. RESULTS: The association between administered beverage dose and SERT mRNA from completers of at least one 4-day experiment (N = 18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (ß = 5.8, SE = 1.2, p < 0.0001; ß = 1.3, SE = 0.6, p = 0.023; and ß = 3.0, SE = 0.7, p < 0.0001, respectively; the C-statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures. CONCLUSION: The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking.

Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence.

On the basis of the converging evidence showing regulation of drinking behavior by 5-HT3AB receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 (P = 0.004) and 0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10(-6) for prediction accuracy of the two models based on 10(6) permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P < 0.001) in carriers of genotype combinations 5'-HTTLPR:LL/LS(SLC6A4)-rs1042173:TT/TG(SLC6A4)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B) and 5'-HTTLPR:LL/LS(SLC6A4)-rs10160548:GT/TT(HTR3A)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B). Combining all five genotypes resulted in an OR of 3.095 (P = 2.0 × 10(-4)) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS (N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 × 10(-5); Z = 3.155, P = 1.6 × 10(-3); and Z = 3.389, P = 7.0 × 10(-4), respectively), but also protective effects for rs33940208:T (χ (2) = 3.316, P = 0.0686) and rs2276305:A (χ (2) = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4-HTR3A-HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects.

Penalized likelihood estimation for semiparametric mixed models, with application to alcohol treatment research.

In this article, we implement a practical computational method for various semiparametric mixed effects models, estimating nonlinear functions by penalized splines. We approximate the integration of the penalized likelihood with respect to random effects with the use of adaptive Gaussian quadrature, which we can conveniently implement in SAS procedure NLMIXED. We carry out the selection of smoothing parameters through approximated generalized cross-validation scores. Our method has two advantages: (1) the estimation is more accurate than the current available quasi-likelihood method for sparse data, for example, binary data; and (2) it can be used in fitting more sophisticated models. We show the performance of our approach in simulation studies with longitudinal outcomes from three settings: binary, normal data after Box-Cox transformation, and count data with log-Gamma random effects. We also develop an estimation method for a longitudinal two-part nonparametric random effects model and apply it to analyze repeated measures of semicontinuous daily drinking records in a randomized controlled trial of topiramate.

Topiramate's effects on cocaine-induced subjective mood, craving and preference for money over drug taking.

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects.

Trajectory analyses in alcohol treatment research.

BACKGROUND: Various statistical methods have been used for data analysis in alcohol treatment studies. Trajectory analyses can better capture differences in treatment effects and may provide insight on the optimal duration of future clinical trials and grace periods. This improves on the limitation of commonly used parametric (e.g., linear) methods that cannot capture nonlinear temporal trends in the data. METHODS: We propose an exploratory approach, using more flexible smoothing mixed effects models, more accurately to characterize the temporal patterns of the drinking data. We estimated the trajectories of the treatment arms for data sets from 2 sources: a multisite topiramate study, and the Combined Pharmacotherapies (acamprosate and naltrexone) and Behavioral Interventions study. RESULTS: Our methods illustrate that drinking outcomes of both the topiramate and placebo arms declined over the entire course of the trial but with a greater rate of decline for the topiramate arm. By the point-wise confidence intervals, the heavy drinking probabilities for the topiramate arm might differ from those of the placebo arm as early as week 2. Furthermore, the heavy drinking probabilities of both arms seemed to stabilize at the end of the study. Overall, naltrexone was better than placebo in reducing drinking over time yet was not different from placebo for subjects receiving the combination of a brief medical management and an intensive combined behavioral intervention. CONCLUSIONS: The estimated trajectory plots clearly showed nonlinear temporal trends of the treatment with different medications on drinking outcomes and offered more detailed interpretation of the results. This trajectory analysis approach is proposed as a valid exploratory method for evaluating efficacy in pharmacotherapy trials in alcoholism.

Changes in Affect and Drinking Outcomes in a Pharmacobehavioral Trial for Alcohol Dependence.

OBJECTIVE: Despite extensive research exploring affect in alcohol dependent individuals in recovery, empirical research on affective changes over the course of psychosocial treatment and their role on drinking outcomes has been minimal. The present study examined the relationship between changes in positive affect (PA), negative affect (NA), and drinking outcomes during a pharmacobehavioral trial. METHOD: Data for these post-hoc exploratory analyses were derived from a clinical trial of 321 alcohol dependent male and female individuals. The study design had four treatment arms for medication: three levels of dose of ondansetron as well as a control condition (placebo). All participants received weekly cognitive behavioral therapy for twelve weeks. We conducted an exploratory evaluation of changes in negative and positive affect and drinking behavior over time during the treatment phase of the trial using multilevel modeling. RESULTS: Participants experienced substantial reductions in drinking, decreases in NA, and increases in PA over the course of treatment. Individuals who experienced increases in PA over the course of treatment significantly reduced their drinking in subsequent weeks, while those who had reductions in NA only experienced reductions in drinking later in treatment if they also reported increases in PA. These results support the role of affect regulation in treatment. CONCLUSIONS: These results suggest that affective change during the course of treatment may serve as one potential mechanism of action for changes in drinking behavior. The interaction between reductions in NA and increases in PA may be particularly important in promoting new coping skills and reducing drinking.

Impact of motivational changes on drinking outcomes in pharmacobehavioral treatment for alcohol dependence.

BACKGROUND: Psychological factors such as motivation to change and self-efficacy influence drinking outcomes in alcohol-dependent individuals who are enrolled in pharmacobehavioral studies. Previous results from our research clinic indicated that initial stage of change of heavy drinkers enrolled in a pharmacobehavioral trial was significantly associated with alcohol consumption. However, overall empirical findings regarding the consistency and extent of the connection between motivational factors and behavior are mixed. This may be in part because of the impact of changes in motivation over the course of treatment and/or characteristics of the individuals receiving the intervention. Our goal in the present study was to examine the extent to which levels of motivation and self-efficacy changed during the treatment phase of a pharmacobehavioral treatment trial, and the extent to which these variables affected drinking behavior in subsets of alcohol-dependent individuals. METHODS: We conducted an exploratory evaluation of changes in motivation, temptation to drink, confidence to abstain, and drinking behavior over time during the treatment phase of a pharmacobehavioral study involving 321 alcohol-dependent individuals. We also examined the extent to which individual variables such as initial drinking severity, onset of alcohol dependence, and medication status influenced changes in motivation, self-efficacy, and drinking behavior. RESULTS: Participants reported improvements in motivation to change, self-efficacy for change, and drinking behaviors over the course of treatment. As hypothesized, motivation to change and self-efficacy for change were related to specific dimensions of posttreatment drinking. Heavy drinkers reported more improvement in drinking behaviors than did nonheavy drinkers. Early-onset drinkers who were on medication reduced their drinking more than those on placebo, and these drinking changes appear to be partially mediated by reductions in temptation. CONCLUSIONS: Reductions in drinking occur and are predicted by increased motivation to change, reduced temptation to drink, and increased confidence to abstain in this population of alcoholic-dependent individuals. Early and late onset and heavy drinkers and those taking medications displayed differential changes in drinking behavior, some of which were explained by the mediating effects of self-efficacy. This is a first step in understanding more about which alcoholic individuals respond best to treatment and what mechanisms may be involved in the changes in drinking and drinking-specific changes in frequency and intensity of drinking.

Should the reorganization of addiction-related research across all the National Institutes of Health be structural?--The devil is truly in the details.

The recent proposal to dissolve the National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse and create a new institute for substance use, abuse, and addiction will require significant effort by the staff of both institutes, the Advisory Councils, and outside experts to overcome complex challenges that could threaten its success. Although integration of the grants portfolios can be achieved, harmonization of goals and policies related to legal use of alcohol versus illegal consumption of drugs will present serious challenges. Consolidating the infrastructure of the 2 existing institutes would entail avoiding encroachment on grant funding. A new institute for substance use, abuse, and addiction would require an enormous amount of cooperation from other institutes as the portfolios of research on alcohol, tobacco, and other drug abuse should logically be transferred to the new institute. In the near term, a structural reorganization would be less efficient and more costly than the individual institutes are currently. Increasing efficiency and reducing costs over time will necessitate careful strategic planning. Success in this difficult task would be made easier and less costly by first implementing carefully placed building blocks of increasing functional reorganization. The newly created institute should increase opportunities for specialization within disorders of addiction, attract new leadership, and build a novel strategic plan that will energize scientists and staff and incorporate ideas of stakeholders to advance the public good in preventing and treating alcohol, tobacco, and all addictions. Attention must be paid to the devil in the details.

A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis.

BACKGROUND: Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD. METHODS: One-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses. RESULTS: Participants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029). CONCLUSIONS: Ondansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

Characterization of a functional polymorphism in the 3' UTR of SLC6A4 and its association with drinking intensity.

BACKGROUND: The propensity for severe drinking is hypothesized to be regulated by differential expression of serotonin transporter gene (SLC6A4) in the human brain. The SLC6A4 promoter region 5-HTTLPR has been examined previously as a candidate polymorphic variant associated with severe drinking. In this study, we investigated whether other SLC6A4 single nucleotide polymorphisms (SNPs) are associated with drinking intensity among treatment-seeking alcoholics and whether these polymorphic variants result in differential SLC6A4 expression levels. METHODS: We analyzed associations of drinking intensity in 275 (78.5% male) treatment-seeking alcoholics of Caucasian and Hispanic origin, with 6 SLC6A4 polymorphisms. Next, to examine the functionality of the SNP that showed a significant association with drinking intensity, we transfected the 2 alleles of rs1042173 into HeLa cell cultures and measured serotonin transporter mRNA and protein expression levels by using qRT-PCR and western blotting techniques. RESULTS: One of the 6 polymorphisms we examined, rs1042173 in the 3' untranslated region (3'-UTR) of SLC6A4, showed a significant association with drinking intensity. The G allele carriers for rs1042173 were associated with significantly lower drinking intensity (p = 0.0034) compared to T-allele homozygotes. In HeLa cell cultures, the cells transfected with G allele showed a significantly higher mRNA and protein levels than the T allele-transfected cells. CONCLUSION: These findings suggest that the allelic variations of rs1042173 affect drinking intensity in alcoholics possibly by altering serotonin transporter expression levels. This provides additional support to the hypothesis that SLC6A4 polymorphisms play an important role in regulating propensity for severe drinking.

Can serotonin transporter genotype predict craving in alcoholism?

BACKGROUND: We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT) transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral depletion of tryptophan (5-HT's precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT neurotransmission transiently and lowering alcohol craving. METHODS: We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability. RESULTS: On subjective "urge to drink" and "crave for a drink," we found a significant (p < 0.05) main effect of genotype and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking, the opposite effect was seen in those with the SS genotype. CONCLUSION: These results not only provide support for the hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol.

Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking?

Serotonin transporter (5-HTT) activity is greater in carriers of the long (L) vs. short (S) alleles of the 5-HTT-linked polymorphic region (5'-HTTLPR) among healthy control subjects but not alcohol-dependent adults. In 198 alcoholics, we determined the relationship between current or lifetime drinking and platelet 5-HTT function and density among allelic variants of the 5'-HTTLPR. SS subjects were younger than L-carriers (LL and LS) (p<0.0085) and had fewer years of lifetime drinking. For L-carriers, the mean of Bmax for paroxetine binding, but not Vmax for serotonin (5-HT) uptake, was lower than that for SS subjects (p<0.05). More L-carriers than their SS counterparts had Vmax for 5-HT uptake below 200 nmol/10(7) platelets-min (p<0.05) and Bmax for paroxetine binding below 600 nmol/mg protein (p<0.06). Current drinking (drinks per day during the past 14 days) correlated positively with Km and Vmax of platelet 5-HT uptake (p<0.05) and negatively with Bmax, but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Years of lifetime drinking correlated negatively with Km and Vmax of platelet 5-HT uptake (p<0.05) and B(max), but not Kd, of paroxetine binding (p<0.05) for L-carriers alone. Among L-carriers alone, there were higher levels of platelet 5-HT uptake and lower levels of platelet paroxetine binding with increased drinking, and more lifetime drinking was associated with modestly lower levels of 5-HT uptake and paroxetine binding. Thus, 5-HTT expression varies with current and lifetime drinking in L-carriers alone.

Prediction of serotonergic treatment efficacy using age of onset and Type A/B typologies of alcoholism.

BACKGROUND: Previously, we reported that ondansetron was efficacious at treating early-onset (< or =25-years old) but not late-onset (> or =26-years old) alcoholics in a double-blind, randomized, placebo-controlled clinical trial (n = 321 enrolled patients, 271 of them randomized). Randomized participants underwent 11 weeks of treatment with ondansetron (1, 4, or 16 microg/kg twice daily; n = 67, 77, and 71, respectively) or identical placebo (n = 56), plus weekly standardized group cognitive behavioral therapy. METHODS: For this study, we reanalyzed the original sample to determine whether the Type A/B typological classification predicts ondansetron treatment response. In this comparative analysis, k-means clustering was applied to 19 baseline measures of drinking behavior, psychopathology, and social functioning, similar to those used by Babor in the original typological derivation. A 2-factor solution described robustly 2 groups phenomenologically consistent with Type A/B classification. Subjects were subdivided into early- and late-onset alcoholics. RESULTS: Seventy-two percent of Type B subjects had early-onset alcoholism (EOA); 67% of Type A subjects had late-onset alcoholism (LOA). The A/B typology better discriminated 2 clusters based upon baseline severity of alcoholism. There was a significant effect (p < 0.05) for Type B alcoholics to respond to ondansetron (4 microg/kg); however, Type A alcoholics receiving ondansetron showed no beneficial effect. Early-onset vs. late-onset classification predicted ondansetron response substantially better than Type A/B classification, which did not add to the prediction of treatment outcome. Further analyses showed that ondansetron was effective in the 33% of Type A alcoholics with EOA but ineffective in the 28% of Type B alcoholics with LOA. CONCLUSIONS: Type A/B classification best discriminates alcoholic subtypes based upon baseline severity. Early- vs. late-onset classification is, however, a better predictor of response to ondansetron treatment because it might be more closely related to fundamental neurobiological processes associated with the underlying pathophysiology of alcoholism.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Substance Use and Related Disorders, Part 1: Alcoholism.

These practice guidelines for the biological treatment of substance use disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal during the development of these guidelines was to review systematically all available evidence pertaining to the treatment of substance use disorders, and to reach a consensus on a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by physicians evaluating and treating people with substance use disorders and are primarily concerned with the biological treatment of adults suffering from substance use disorders. The data used to develop these guidelines were extracted primarily from various national treatment guidelines for substance use disorders, as well as from meta-analyses, reviews and randomized clinical trials on the efficacy of pharmacological and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorized into four levels of evidence (A-D). This first part of the guidelines covers the treatment of alcohol dependence; Part 2 will be devoted to the treatment of drug dependence.

Effects of topiramate on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent individuals.

Methamphetamine-dependent individuals often cite the need to maintain enhanced cognitive performance and attention as a reason for continuing or relapsing to drug-taking. Further, methamphetamine addicts might not comply with taking a potentially therapeutic medication if it had a profound effect on these cognitive processes. Topiramate, a sulfamate-substituted fructopyranose derivative, has been suggested as a putative therapeutic medication for treating methamphetamine dependence. Examination of topiramate's effects on cognitive performance and attention is a clinically and scientifically important component of understanding its potential therapeutic profile. In 10 male and female individuals who met DSM-IV criteria for methamphetamine dependence, we examined the effects of low (50 mg b.i.d.)- and high (100 mg b.i.d.)-dose topiramate - in both the presence and absence of low (15 mg)- and high (30 mg)-dose intravenous methamphetamine--on cognitive performance, attention, and concentration on the rapid visual information processing task and the digit symbol substitution test. Intravenous methamphetamine enhanced cognitive performance, attention, and concentration among recently withdrawn methamphetamine addicts--an effect that hitherto had not been well characterized. Topiramate's cognitive effects were mixed and rather paradoxical, with a tendency to improve attention and concentration both alone and in the presence of methamphetamine while worsening psychomotor retardation. No deleterious interaction occurred between topiramate and methamphetamine on any of these cognitive processes. While clinical studies with topiramate should prepare participants for possible psychomotor retardation, the cognitive effects profile observed would not likely present an important obstacle to compliance in motivated patients. Topiramate's complicated cognitive effects among methamphetamine addicts need more comprehensive examination.

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals.

Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study, 10 methamphetamine-dependent individuals participated in a double-blind, placebo-controlled, cross-over design, with oral doses of topiramate (0, 100, and 200 mg) administered as a pretreatment before intravenous doses of methamphetamine (0, 15, and 30 mg). The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. Methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.

Topiramate for treating alcohol dependence: a randomized controlled trial.

CONTEXT: Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system. OBJECTIVE: To determine if topiramate is a safe and efficacious treatment for alcohol dependence. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites. INTERVENTIONS: Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention. MAIN OUTCOME MEASURES: Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma gamma-glutamyltransferase). RESULTS: Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%). CONCLUSION: Topiramate is a promising treatment for alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00210925.