RESUMO
BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.
Assuntos
Alcoolismo , Ondansetron , Adulto , Humanos , Ondansetron/uso terapêutico , Alcoolismo/tratamento farmacológico , Alcoolismo/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina , Testes Farmacogenômicos , Estudos Prospectivos , Método Duplo-Cego , Resultado do TratamentoRESUMO
Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward-the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate's attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug's neurobiological mechanism of action in reducing heavy drinking.