Pharmacogenetics of Dopamine β‐Hydroxylase in cocaine dependence therapy with doxazosin

Abstract

The α -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine β-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DβH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DβH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DβH levels from the DBH CC genotype and 27 with lower DβH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DβH and NE levels, as compared with no net reduction in the CC genotype group with normal DβH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

Molecular genetics of cocaine use disorders in humans

“…Early CUD pharmacogenetic studies focused on mouse models (reviewed by [131]). Now, some double-blind randomized placebo-control trials in humans have been performed to analyze cocaine drug treatment response based on the genotypes of specific functional variants on ten genes (ADRA1A, ADRA1D, ANKK1, DRD2, DBH, MTHFR, OPRK1, THP2, SLC6A4, and SLC6A3) related with cocaine physiological mechanisms [132][133][134][135][136][137][138][139][140][141][142][143]. The medications assessed include doxazosin, an α1A adrenergic antagonist that decreases noradrenergic activity; levodopa, a dopamine precursor; cocaine vaccine, succinylnorcocaine covalently linked to cholera B [137]; and disulfiram, a cooper chelator that inhibits noradrenergic synthesis.…”

“…Interestingly, the SNP rs161115 (-1021C>T) in the dopamine βhydroxylase gene (DBH), responsible for up to 50% of plasma activity variation of the enzyme, has been analyzed in multiple studies. Different clinical responses for each allele (C/T) were observed when distinct treatments were used [134][135][136][137][138], suggesting that the individual's genotype could help to make treatment choices. For instance, individuals with the CC genotype, associated with normal DBH levels, presented significant cocaine-positive urine reduction rates on disulfiram treatment in one study [136], although the results were not supported by another study [135].…”

“… [ 137 ] DBH rs1611115 C>T -1021 5′UTR T: lowest DBH levels circulating 12 weeks 8 mg/day n = 76 (47 + 29) 33CC, 14CT/TT; 16CC, 13CT/TT C only Doxazosin + CBT CT/TT: reduced positive-cocaine urine rate with greater efficacy vs CC. [ 134 ] DBH rs1611115 C>T -1021 5′UTR T: lowest DBH levels circulating 12 weeks n = 71 (38 + 33) 26CT/TT, 12CC; 20CC, 13CT/TT C only Levodopa-carbidopa CT/TT reduced cocaine-positive urine rate on levodopa/carbidopa pharmacotherapy. CC no effect.…”

Doxazosin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in military veterans

“…Both family history and BP are being measured in the current study. Future research in this area should include measurements of pre-treatment BP, family history of AUD, as well as genetic data [75]. …”

Pharmacotherapeutic strategies for treating cocaine use disorder—what do we have to offer?

“…In a recent trial, doxazosin‐treated (8 mg/day) individuals exhibited a greater reduction in cocaine use relative to those treated with placebo [45]. Genetic subgroup analysis further indicated that the percentage of cocaine‐positive urine toxicology screens for doxazosin‐treated individuals was lower in the group with lower DA beta‐hydroxylase (DβH) levels from T‐allele carriers (CT or TT) than the group with higher DβH levels from the DβH CC genotype.…”