topiramate and Alcoholic-Intoxication

An intronic polymorphism in the delta-opioid receptor gene (OPRD1) was previously associated with cocaine dependence in African-Americans. However, it is not known if the polymorphism (rs678849) is associated with dependence-related phenotypes within the cocaine dependent population.. Cocaine and alcohol dependent subjects were randomized to either topiramate or placebo. Abstinence from cocaine use was confirmed by urine drug screens for benzoylecgonine three times per week. Cocaine withdrawal and craving were assessed at randomization using the Cocaine Selective Severity Assessment (CSSA) and Minnesota Cocaine Craving Scale (MCCS), respectively. Subjects were also interviewed using the Addiction Severity Index (ASI). Genotype at rs678849 was determined for 105 African-American subjects and compared to cocaine abstinence, as well as scores for CSSA, MCCS, and ASI.. African-American patients with the C/T or T/T genotypes (n=40) were more likely to be abstinent at the first urine drug screen and more likely to be abstinent for the week prior to randomization compared to patients with the C/C genotype (n=65). Subjects carrying the T allele were also more likely to have abstinent weeks over the course of the trial compared to those with the C/C genotype (RR=1.88, 95% CI=1.59-2.22, p=0.0035). No effects of rs678849 genotype on withdrawal, craving, or addiction severity were observed.. A polymorphism in OPRD1 appears to be associated with both cocaine dependence and cocaine use during treatment in African-Americans. Follow-up studies to confirm the effect on cocaine use are warranted.

Topics: Adult; Alcoholic Intoxication; Alleles; Black or African American; Cocaine-Related Disorders; Female; Follow-Up Studies; Fructose; Genetic Variation; Genotype; Humans; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Receptors, Opioid, delta; Temperance; Topiramate

Using retrospective reports obtained during treatment visits in 138 heavy drinkers, we found that topiramate's reduction of heavy drinking was moderated by a polymorphism (rs2832407) in GRIK1, which encodes the GluK1 kainate subunit (Kranzler et al., 2014a). A subsequent analysis of that 12-week topiramate treatment trial showed similar effects of medication and genotype on daily drinking reports obtained via interactive voice response technology (IVR; Kranzler et al., 2014b). Specifically, rs2832407*C-allele homozygotes treated with topiramate reported lower levels of drinking than those receiving placebo. This group also had the largest decreases in the expected positive effects of drinking (i.e., expectancies) and desire to drink. To extend that analysis, which focused on how mean levels of desire and expectancies changed over time with treatment, we used a within-person approach to examine whether daily variation in expectancies and desire to drink interact with topiramate treatment and genotype to predict nighttime drinking levels. In contrast to the previous analysis (Kranzler et al., 2014b), here we focus on whether alcohol expectancies and desire to drink moderate the effects of topiramate on drinking. Results showed a 3-way interaction of daily expectancies with genotype and medication, such that the protective effect of topiramate on nighttime drinking among rs2832407*C-allele homozygotes was decreased on days characterized by relatively high levels of anticipated positive effects of alcohol. There was no moderating effect of desire to drink or negative alcohol expectancies. Thus, there is specific moderation of the effects of topiramate by both genotype and cognitive process.

Topics: Activities of Daily Living; Adult; Alcohol Deterrents; Alcoholic Intoxication; Alcoholism; Alleles; Attitude to Health; Connecticut; Double-Blind Method; Drug Resistance; Female; Fructose; Genetic Association Studies; Humans; Male; Patient Education as Topic; Pennsylvania; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Students; Topiramate; Universities; Young Adult

The aim of this study was to determine the 12-week cognitive changes in topiramate-treated patients recently detoxified from alcohol.. Participants were inpatients with DSM-IV alcohol dependence. All of them were discharged within 14 days after the initiation of topiramate treatment. The topiramate dose range was 50-300 mg/day. The Montreal Cognitive Assessment (MoCA) was used on day 0, day 29, day 57, and day 85. Differences of the MoCA total and seven subtest scores among four time-points were compared.. Thirty-eight participants (36 men and two women) had a mean ± SD age of 43.1 ± 8.6 years old. At enrollment, they were abstinent for a mean ± SD of 11.5 ± 5.3 days. Five, one, and three patients dropped out of the study on day 29, day 57, and day 85, respectively. On day 85, the mean ± SD dose of topiramate was 253.1 ± 60.8 mg/day. Alcohol consumption decreased drastically during follow up. At each time-point, 75%-80% of the participants were continuous abstainers. The mean ± SD MoCA total, language subtest, and delayed recall subtest scores increased significantly from day 0 to day 85, from 22.0 ± 4.7 to 24.7 ± 3.4 (P < 0.01), from 1.1 ± 1.0 to 1.3 ± 1.0 (P = 0.03), and from 2.7 ± 1.7 to 4.1 ± 1.0 (P < 0.01), respectively.. Topiramate-treated patients recently detoxified from alcohol usually have an improvement of their cognitive function, especially in the language and delayed recall domains. This phenomenon may be caused by the greater influence of cognitive recovery associated with decreased drinking as compared with topiramate-induced cognitive impairment.

Topics: Adolescent; Adult; Alcoholic Intoxication; Alcoholism; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Patient Dropouts; Prospective Studies; Psychomotor Performance; Recovery of Function; Socioeconomic Factors; Topiramate; Treatment Outcome; Young Adult

Compounds with anti-glutamatergic properties currently in clinical use for various indications (eg Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, and topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (by comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (by chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, whereas oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiate ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J, or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with an NMDAR blocker, genetic background, or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.

Topics: Alcoholic Intoxication; Animals; Ataxia; Carbamazepine; Central Nervous System Depressants; Conscious Sedation; Dextromethorphan; Ethanol; Excitatory Amino Acid Agents; Fructose; Haloperidol; Hypothermia; Lamotrigine; Male; Memantine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Oxcarbazepine; Species Specificity; Stress, Psychological; Topiramate; Triazines