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1.
Neuropsychopharmacology ; 42(5): 1012-1023, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27658483

ABSTRACT

Alcohol use disorder has been linked to dysregulation of the brain stress systems, producing a negative emotional state leading to chronic relapsing behavior. Vasopressin receptors appear to have a regulatory role in stress, anxiety, and alcohol. This study evaluated the novel compound, ABT-436, a V1b receptor antagonist, in alcohol-dependent participants in a 12-week clinical trial. Men and women (n=150) who met criteria for DSM-IV alcohol dependence were recruited across four sites. Participants received double-blind ABT-436 or placebo, and a computerized behavioral intervention. ABT-436 was titrated to 800 mg/day during weeks 2-12. Although the primary outcome, percentage of heavy drinking days, was lower in participants receiving ABT-436 compared with placebo, this difference was not statistically significant (31.3 vs 37.6, respectively; p=0.172; d=0.20). However, participants receiving ABT-436 had significantly greater percentage of days abstinent than those receiving placebo (51.2 vs 41.6, respectively; p=0.037; d=0.31). No significant differences were found between treatment groups on any other measures of drinking, alcohol craving, or alcohol-related consequences. Smokers receiving ABT-436 smoked significantly fewer cigarettes per week than those receiving placebo (p=0.046). ABT-436 was well tolerated, with diarrhea (mild-to-moderate severity) being the most common side effect. In subgroup analyses, participants with relatively higher baseline levels of stress responded better to ABT-436 than placebo on select drinking outcomes, suggesting there may be value in testing medications targeting the vasopressin receptor in high stress, alcohol-dependent patients.


Subject(s)
Alcoholism/drug therapy , Antidiuretic Hormone Receptor Antagonists/administration & dosage , Antidiuretic Hormone Receptor Antagonists/therapeutic use , Receptors, Vasopressin/physiology , Adult , Alcohol Drinking , Anxiety , Double-Blind Method , Female , Humans , Male , Middle Aged , Treatment Outcome
2.
J Clin Psychopharmacol ; 35(1): 34-42, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25427171

ABSTRACT

The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing.


Subject(s)
Alcohol-Related Disorders/drug therapy , Cognition Disorders/chemically induced , Fructose/analogs & derivatives , Isoxazoles/therapeutic use , Neuropsychological Tests , Piracetam/analogs & derivatives , Adult , Aged , Alcohol Drinking/drug therapy , Alcohol Drinking/psychology , Alcohol-Related Disorders/diagnosis , Alcohol-Related Disorders/psychology , Anticonvulsants/adverse effects , Anticonvulsants/therapeutic use , Cognition Disorders/diagnosis , Cognition Disorders/psychology , Double-Blind Method , Female , Fructose/adverse effects , Fructose/therapeutic use , Humans , Isoxazoles/adverse effects , Levetiracetam , Male , Middle Aged , Piracetam/adverse effects , Piracetam/therapeutic use , Topiramate , Treatment Outcome , Young Adult , Zonisamide
3.
Am J Drug Alcohol Abuse ; 38(2): 181-6, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22221171

ABSTRACT

BACKGROUND: Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder. METHODS: Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively. RESULTS: Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use.


Subject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Cocaine-Related Disorders/drug therapy , Cocaine/administration & dosage , Depressive Disorder/drug therapy , Mianserin/analogs & derivatives , Adult , Cocaine-Related Disorders/complications , Depressive Disorder/complications , Double-Blind Method , Female , Humans , Male , Mianserin/therapeutic use , Middle Aged , Mirtazapine , Self Report , Treatment Outcome
4.
Am J Drug Alcohol Abuse ; 36(2): 102-5, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20337506

ABSTRACT

OBJECTIVES: The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant zonisamide in an open label trial of the treatment of alcohol dependence. METHODS: In this trial, zonisamide (400-mg daily) was administered to alcohol-dependent subjects (ADS) (n = 16) over 13 weeks. The mean daily consumption of standard alcoholic drinks and performance on a verbal fluency task, the COWAT, and on a measure of attention and visuomotor speed, the DSMT were assessed, and the occurrence of adverse events was monitored weekly. RESULTS: The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period. Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment. Overall, zonisamide was well tolerated by the study subjects. CONCLUSION: These results indicate that zonisamide administration may not impair verbal fluency in ADS, and are consistent with other studies that found zonisamide administration may reduce alcohol intake.


Subject(s)
Alcohol-Related Disorders/drug therapy , Isoxazoles/adverse effects , Adult , Analysis of Variance , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Drug Administration Schedule , Female , Humans , Intention to Treat Analysis , Isoxazoles/administration & dosage , Male , Middle Aged , Patient Selection , Psychiatric Status Rating Scales , Surveys and Questionnaires , Treatment Outcome , Zonisamide
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