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

Back, Sudie E.; Flanagan, Julianne C.; Jones, Jennifer; Augur, Isabel F; Peterson, Alan L.; Young‐McCaughan, Stacey; Shirley, David W.; Henschel, Aisling V.; Joseph, Jane E.; Litz, Brett T.; Hancock, Allison K; Roache, John D.; Mintz, Jim; Wachen, Jennifer Schuster; Keane, Terence M.; Brady, Kathleen T.

doi:10.1016/j.cct.2018.08.009

Cited by 11 publications

(7 citation statements)

References 68 publications

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“…Behavioral abnormalities, including cognitive dysfunction and anxious behaviors are widely expressed in individuals suffering from moderate to severe AUD (Back et al, 2018;Bradford et al, 2017;Koob, 2015;Silva-Peña et al, 2019), making AUD highly comorbid with conditions such as post-traumatic stress disorder and depression. Although treatable, very few medications are effective (Back et al, 2018;Bradford et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

Staples

Herman

Lockner

et al. 2021

J of Neuroscience Research

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Plasticity in the dentate gyrus (DG) is strongly influenced by ethanol, and ethanol experience alters long-term memory consolidation dependent on the DG. However, it is unclear if DG plasticity plays a role in dysregulation of long-term memory consolidation during abstinence from chronic ethanol experience. Outbred male Wistar rats experienced 7 weeks of chronic intermittent ethanol vapor exposure (CIE). Seventytwo hours after CIE cessation, CIE and age-matched ethanol-naïve Air controls experienced auditory trace fear conditioning (TFC). Rats were tested for cue-mediated retrieval in the fear context either twenty-four hours (24 hr), ten days (10 days), or twenty-one days (21 days) later. CIE rats showed enhanced freezing behavior during TFC acquisition compared to Air rats. Air rats showed significant fear retrieval, and this behavior did not differ at the three time points. In CIE rats, fear retrieval increased over time during abstinence, indicating an incubation in fear responses.Enhanced retrieval at 21 days was associated with reduced structural and functional plasticity of ventral granule cell neurons (GCNs) and reduced expression of synaptic proteins important for neuronal plasticity. Systemic treatment with the drug Isoxazole-9 (Isx-9; small molecule that stimulates DG plasticity) during the last week and a half of CIE blocked altered acquisition and retrieval of fear memories in CIE rats during abstinence. Concurrently, Isx-9 modulated the structural and functional plasticity of ventral GCNs and the expression of synaptic proteins in the ventral DG.These findings identify that abstinence-induced disruption of fear memory consolidation occurs via altered plasticity within the ventral DG, and that Isx-9 prevented these effects.

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Section: Discussionmentioning

confidence: 99%

Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

Staples

Herman

Lockner

et al. 2021

J of Neuroscience Research

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“…Several clinical trials are in progress to investigate the effect of molecules directly acting on adrenergic receptors to clarify their efficacy and tolerance: two of them concern the effect of guanfacine in tobacco and alcoholism [82,83], and an ongoing protocol is evaluating the effectiveness of doxazosin in the comorbidity of PTSD and alcoholism [84].…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of drugs acting on adrenergic receptors in the treatment for tobacco or alcohol use disorders: systematic review and meta‐analysis

et al. 2020

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Aim To assess the efficacy of drugs directly acting on alpha‐ and beta‐adrenergic receptors in the treatment of patients suffering from tobacco or alcohol use disorder. Methods Using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, studies were identified through PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and http://clinicaltrial.gov. We selected only randomized controlled trials with adult patients with tobacco or alcohol use disorders according to DSM‐5 criteria. Interventions included any molecule having a direct pharmacological action on alpha‐ or beta‐adrenergic receptors (agonist or antagonist). Comparators were placebo or other validated pharmacotherapies. The duration of the intervention was a minimum of 1 month, with 3 months of follow‐up. Measurements included smoking cessation for tobacco; for alcohol, we selected abstinence, alcohol consumption (drinks per day or week) and heavy drinking days (HDD). Ten studies with tobacco and six with alcohol use disorder were included in the qualitative synthesis and fifteen studies in the quantitative analysis. Results We found that clonidine, an alpha‐2 agonist, significantly increased smoking abstinence [relative risk = 1.39 with a 95% confidence interval (CI) = 1.04, 1.84]. Beta‐blockers had no significant effect on smoking abstinence. The alpha‐1 antagonists prazosin and doxazosin decreased alcohol consumption [SMD = −0.32 (−0.56, −0.07)] but had no effect on abstinence or HDD. Conclusions The noradrenaline system may represent a promising mechanism to target in tobacco and alcohol use disorders.

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“…We will have 80% power to detect treatment group differences of 4 units of improvement in DAS-7 scores. 79…”

Section: Powermentioning

confidence: 99%

Design of a randomized controlled trial examining the efficacy of oxytocin to enhance alcohol behavioral couple therapy

Flanagan

Joseph

Nietert

et al. 2019

Contemporary Clinical Trials

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Combining pharmacological interventions with evidence-based behavioral interventions may help optimize treatment outcomes for alcohol use disorder (AUD). While several effective behavioral interventions for AUD have been developed, the vast majority target individual patients, despite evidence that behavioral interventions for couples have the ability to outperform individual treatments for AUD. Alcohol Behavioral Couples Therapy (ABCT) is an evidence-based behavioral intervention for couples that has been shown to significantly reduce AUD severity as well as improve relationship functioning. Accumulating evidence suggests that the neuropeptide oxytocin has the ability to reduce alcohol craving and consumption, symptoms of tolerance and withdrawal, and ameliorate neurobiological deficits associated with AUD. Furthermore, oxytocin has demonstrated the ability to increase prosocial behavior and cognition, and restore sensitivity to natural rewards such as interpersonal relationships. No study to date has examined the ability of oxytocin to enhance ABCT. Thus, the primary objective of this Phase II study is to examine the effects of oxytocin versus placebo in combination with ABCT in reducing AUD severity and improving relationship functioning. We also will utilize neuroimaging techniques before and after treatment to investigate the underlying pathophysiology of AUD among couples and identify prognostic indicators of treatment outcome. The findings from this study might provide critical new information to help inform clinical practice and accelerate research on the pharmacological treatment of AUD.

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

Cited by 11 publications

References 68 publications

Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

Effectiveness of drugs acting on adrenergic receptors in the treatment for tobacco or alcohol use disorders: systematic review and meta‐analysis

Design of a randomized controlled trial examining the efficacy of oxytocin to enhance alcohol behavioral couple therapy

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