Review
The promise of N-acetylcysteine in neuropsychiatry

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N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate.

Section snippets

Overview

NAC has been in use for over 30 years as an antidote in the treatment of paracetamol overdose, as a mucolytic for chronic obstructive pulmonary disease (COPD), as a renal protectant in contrast-induced nephropathy, and as therapeutic agent in the management of HIV [1]. A groundswell of recent evidence suggests that NAC may also have therapeutic benefits in multiple neuropsychiatric disorders.

The principal victories in biological psychiatry have arisen from the quest to reverse engineer

NAC biochemistry

NAC is the N-acetyl derivative of the amino acid l-cysteine and is rapidly absorbed following an oral dose [4]. l-Cysteine is rapidly oxidised to cystine in the prooxidant milieu of the brain. Cystine is the substrate of the cystine–glutamate antiporter, which shuttles glutamate out of the cell in exchange for cystine, thereby regulating extracellular glutamate levels and facilitating cysteine entry to the cell [5]. Inside the cell, cystine can be reduced to cysteine, which is the rate-limiting

Glutamate

NAC modulates several key neurotransmitter systems that are known to be involved in a range of psychopathology, including glutamate and dopamine [7]. Regulation of glutamate synthesis, release, synaptic levels, and recycling is tightly controlled, and dysfunction of this system is implicated in many neuropsychiatric disorders including schizophrenia [8] and addiction [9]. Excessive activation of the N-methyl-d-aspartate (NMDA) glutamate receptor is central to the excitotoxic damage associated

Role in oxidative homeostasis

The brain is acutely sensitive to changes in redox status. The high metabolic activity of this organ is a persistent source of oxidative species, as utilisation of O2 by energy-generating mitochondria constantly generates oxygen free radicals 24, 25. Neurotransmitter activity also generates free radicals, with autooxidation of dopamine and excitotoxicity related to glutamatergic signalling being important sources of oxidative stress 10, 20. Neurons rely on the integrity of extensive axonal

Interaction with inflammatory mediators

Another potential therapeutic avenue for NAC stems from its anti-inflammatory properties. Dysregulation of inflammatory pathways and cytokine levels in both the periphery and the central nervous system (CNS) are associated with psychiatric disorders, and in particular depression. Several meta-analyses have demonstrated dysregulated production of inflammatory cytokines in depressed patients 56, 57, 58. Patients treated with the cytokines interleukin-2 (IL-2) and interferon-α for other somatic

Use in psychiatry

There is a growing body of literature of potential benefit of NAC in a wide range of neuropsychiatric disorders. These are discussed briefly below and highlighted in Table 1.

Concluding remarks

Given the paucity of new drug development, NAC is a promising novel therapeutic option for a diverse range of neuropsychiatric disorders. Although there is only preliminary data of the efficacy of NAC in many of these disorders, this field is rapidly expanding with additional trials [e.g., investigating personality disorder (ClinicalTrials.gov: NCT01555970)]. Most notable is the sheer breadth of disorders that NAC appears to benefit and the lack of recognition within extant diagnostic systems

Disclaimer statement

G.S.M. has received research support from AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, and Wyeth; has been a speaker for AstraZeneca, Eli Lilly, Janssen–Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a consultant for AstraZeneca, Eli Lilly, Janssen–Cilag, Lundbeck, and Servier. M.B. has received research support from the Medical Benefits Fund of Australia, Bristol–Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier; has been a speaker

References (121)

  • A.C. Andreazza

    DNA damage in bipolar disorder

    Psychiatry Res.

    (2007)
  • M. Bilici

    Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments

    J. Affect. Disord.

    (2001)
  • M. Berk

    Glutamate cysteine ligase (GCL) and self reported depression: an association study from the HUNT

    J. Affect. Disord.

    (2011)
  • A. Kulak

    Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder

    Behav. Brain Res.

    (2012)
  • Y. Chen

    Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm−/− knockout mice

    Neurotoxicol. Teratol.

    (2012)
  • K.H. Choy

    Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats

    Eur. J. Pharmacol.

    (2010)
  • E.P. Zorrilla

    Leukocytes and organ-nonspecific autoantibodies in schizophrenics and their siblings: markers of vulnerability or disease?

    Biol. Psychiatry

    (1996)
  • Y. Dowlati

    A meta-analysis of cytokines in major depression

    Biol. Psychiatry

    (2010)
  • L. Capuron

    Neurobehavioral effects of interferon-α in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions

    Neuropsychopharmacology

    (2002)
  • A.H. Miller

    Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression

    Biol. Psychiatry

    (2009)
  • C. Csontos

    Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn

    Burns

    (2012)
  • K.A. Kigerl

    System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo

    Exp. Neurol.

    (2012)
  • P.W. Kalivas

    Glutamate transmission in addiction

    Neuropharmacology

    (2009)
  • R. Karler

    Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801

    Life Sci.

    (1989)
  • M. Alvaro-Bartolome

    Molecular adaptations of apoptotic pathways and signaling partners in the cerebral cortex of human cocaine addicts and cocaine-treated rats

    Neuroscience

    (2011)
  • O.S. El-Tawil

    d-Amphetamine-induced cytotoxicity and oxidative stress in isolated rat hepatocytes

    Pathophysiology

    (2011)
  • L.A. Knackstedt

    The role of cysteine–glutamate exchange in nicotine dependence in rats and humans

    Biol. Psychiatry

    (2009)
  • J.E. Grant

    A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence

    Eur. Neuropsychopharmacol.

    (2010)
  • P.N. Mardikian

    An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2007)
  • J.E. Grant

    N-Acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study

    Biol. Psychiatry

    (2007)
  • E. Ozdemir

    Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive–compulsive disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2009)
  • S. Ersan

    Examination of free radical metabolism and antioxidant defence system elements in patients with obsessive–compulsive disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2006)
  • D.A. Camfield

    Nutraceuticals in the treatment of obsessive compulsive disorder (OCD): a review of mechanistic and clinical evidence

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2011)
  • S. Dodd

    N-Acetylcysteine for antioxidant therapy: pharmacology and clinical utility

    Expert Opin. Biol. Ther.

    (2008)
  • O. Dean

    N-Acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

    J. Psychiatry Neurosci.

    (2011)
  • M. Arakawa et al.

    N-Acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology

    Cerebellum

    (2007)
  • V.I. Lushchak

    Glutathione homeostasis and functions: potential targets for medical interventions

    J. Amino Acids

    (2012)
  • M.M. Moran

    Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking

    J. Neurosci.

    (2005)
  • R. Sattler et al.

    Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death

    Mol. Neurobiol.

    (2001)
  • D.A. Baker

    The origin and neuronal function of in vivo nonsynaptic glutamate

    J. Neurosci.

    (2002)
  • D.A. Baker

    Contribution of cystine-glutamate antiporter to the psychotomimetic effects of phencyclidine

    Neuropsychopharmacology

    (2008)
  • D.A. Baker

    Neuroadaptations in cysteine–glutamate exchange underlie cocaine relapse

    Nat. Neurosci.

    (2003)
  • S.W. Leslie

    Stimulation of N-methyl-d-aspartate receptor-mediated calcium entry into dissociated neurons by reduced and oxidized glutathione

    Mol. Pharmacol.

    (1992)
  • V. Varga

    Glutathione is an endogenous ligand of rat brain N-methyl-d-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors

    Neurochem. Res.

    (1997)
  • R. Janaky

    Modulation of [3H]dopamine release by glutathione in mouse striatal slices

    Neurochem. Res.

    (2007)
  • E. Gere-Paszti et al.

    The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography

    Biomed. Chromatogr.

    (2009)
  • T.G. Hastings

    The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson's disease

    J. Bioenerg. Biomembr.

    (2009)
  • K. Hashimoto

    Protective effects of N-acetyl-l-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine

    Neuropsychopharmacology

    (2004)
  • N. Kaushal

    AC927, a sigma receptor ligand, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells

    Mol. Pharmacol.

    (2012)
  • J. Hirrlinger

    Glutathione release from cultured brain cells: multidrug resistance protein 1 mediates the release of GSH from rat astroglial cells

    J. Neurosci. Res.

    (2002)
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