PMID- 36055978
OWN - NLM
STAT- MEDLINE
DCOM- 20221021
LR  - 20231002
IS  - 1530-0277 (Electronic)
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 46
IP  - 10
DP  - 2022 Oct
TI  - A randomized, double-blind, placebo-controlled, pharmacogenetic study of 
      ondansetron for treating alcohol use disorder.
PG  - 1900-1912
LID - 10.1111/acer.14932 [doi]
AB  - BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT(3) 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-HT(3A) (HTR3A), and 5-HT(3B) (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.
CI  - (c) 2022 Research Society on Alcoholism.
FAU - Seneviratne, Chamindi
AU  - Seneviratne C
AUID- ORCID: 0000-0002-3135-2979
AD  - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Gorelick, David A
AU  - Gorelick DA
AD  - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Lynch, Kevin G
AU  - Lynch KG
AD  - Department of Psychiatry, University of Pennsylvania, Perelman School of 
      Medicine, Philadelphia, Pennsylvania, USA.
AD  - Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, 
      Philadelphia, Pennsylvania, USA.
FAU - Brown, Clayton
AU  - Brown C
AUID- ORCID: 0000-0002-0748-4509
AD  - Department of Epidemiology, University of Maryland School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Romer, Danielle
AU  - Romer D
AD  - Department of Psychiatry, University of Pennsylvania, Perelman School of 
      Medicine, Philadelphia, Pennsylvania, USA.
FAU - Pond, Timothy
AU  - Pond T
AD  - Department of Psychiatry, University of Pennsylvania, Perelman School of 
      Medicine, Philadelphia, Pennsylvania, USA.
FAU - Kampman, Kyle
AU  - Kampman K
AD  - Department of Psychiatry, University of Pennsylvania, Perelman School of 
      Medicine, Philadelphia, Pennsylvania, USA.
AD  - Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, 
      Philadelphia, Pennsylvania, USA.
FAU - Kranzler, Henry R
AU  - Kranzler HR
AUID- ORCID: 0000-0002-1018-0450
AD  - Department of Psychiatry, University of Pennsylvania, Perelman School of 
      Medicine, Philadelphia, Pennsylvania, USA.
AD  - Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, 
      Philadelphia, Pennsylvania, USA.
LA  - eng
GR  - R01 AA021163/AA/NIAAA NIH HHS/United States
GR  - R01 AA021164/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
DEP - 20220911
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 4AF302ESOS (Ondansetron)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 333DO1RDJY (Serotonin)
RN  - 0 (SLC6A4 protein, human)
SB  - IM
MH  - Adult
MH  - Humans
MH  - *Ondansetron/therapeutic use
MH  - *Alcoholism/drug therapy/genetics
MH  - Serotonin Plasma Membrane Transport Proteins/genetics
MH  - Serotonin
MH  - Pharmacogenomic Testing
MH  - Prospective Studies
MH  - Double-Blind Method
MH  - Treatment Outcome
PMC - PMC9901168
MID - NIHMS1869318
OTO - NOTNLM
OT  - alcohol use disorder
OT  - ondansetron
OT  - pharmacogenetics
OT  - randomized control trial
OT  - serotonin
EDAT- 2022/09/03 06:00
MHDA- 2022/10/22 06:00
PMCR- 2023/10/01
CRDT- 2022/09/02 22:42
PHST- 2022/08/04 00:00 [revised]
PHST- 2022/03/04 00:00 [received]
PHST- 2022/08/22 00:00 [accepted]
PHST- 2022/09/03 06:00 [pubmed]
PHST- 2022/10/22 06:00 [medline]
PHST- 2022/09/02 22:42 [entrez]
PHST- 2023/10/01 00:00 [pmc-release]
AID - 10.1111/acer.14932 [doi]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2022 Oct;46(10):1900-1912. doi: 10.1111/acer.14932. Epub 
      2022 Sep 11.