Trends in Pharmacological Sciences
ReviewThe promise of N-acetylcysteine in neuropsychiatry
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
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