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A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

ABSTRACT: For many years, research from around the world has suggested that the neuroactive steroid (3?,5?)-3-hydroxypregnan-20-one (allopregnanolone or 3?,5?-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs.

SUBMITTER: Morrow AL

PROVIDER: S-EPMC7018555 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

Morrow A Leslie AL Boero Giorgia G Porcu Patrizia P

Alcoholism, clinical and experimental research 20191217 2

For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone or 3α,5α-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatme ...[more]

PMID: 31782169

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Project description:ObjectiveThis paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy.Literature searchA literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website.Data synthesisOne phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache.Place in therapyAllopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed.ConclusionAllopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.

Project description:AIMS:To compare individuals with comorbid life-time post-traumatic stress disorder (PTSD) and alcohol use disorders [AUD; i.e. no drug use disorders (DUD)] with those with comorbid PTSD and DUD on past-year prevalence of these disorders, social functioning, life-time psychiatric comorbidities, and treatment receipt. The comorbid groups were also compared with their single diagnosis counterparts. DESIGN AND SETTING:Cross-sectional cohort study using data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC-III). PARTICIPANTS:The total sample size was 36?309. Six groups were established: PTSD/AUD, PTSD/DUD, AUD, DUD, PTSD, and neither PTSD nor AUD/DUD. Life-time prevalence of AUD among those with PTSD/DUD was 80.2% and among those with DUD was 73.8%. MEASUREMENTS:The Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-5 version assessed life-time and past-year psychiatric disorders and treatment receipt. Demographics and social stability indicators were queried. Group characteristics were summarized using weighted means. Prevalences and estimates for adjusted differences in means and adjusted odds ratios (aORs) were derived from multiple linear regression and logistic regression models, respectively. Analyses were conducted in R and accounted for the NESARC-III's complex survey design, clustering, and non-response. FINDINGS:Compared with those with life-time PTSD/AUD, those with life-time PTSD/DUD were significantly less likely to have neither disorder in the past year (PTSD/AUD = 16.1%; PTSD/DUD = 8.5%; aOR = 0.54), and were more likely to report worse social and psychiatric functioning, and to have received both addiction and mental health treatment (PTSD/AUD = 18.4%; PTSD/DUD = 43.2%; aOR = 3.88). Compared with their single disorder counterparts, those with PTSD/DUD reported greater impairment than both groups, whereas the comorbid PTSD/AUD group differed more from the AUD than the PTSD group. CONCLUSIONS:People with comorbid PTSD and drug use disorder have greater social and psychiatric impairment and may require different types and intensity of intervention than people with comorbid post-traumatic stress disorder and alcohol use disorder.

Dataset Information

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

Publications

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

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