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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:Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol-water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans.

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.

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

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

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