cJ.

tralVic

ria,f Syoya

Review

TIPS-1023; No. of Pages 11treatment of paracetamol overdose, as a mucolytic forchronic obstructive pulmonary disease (COPD), as a renalprotectant in contrast-induced nephropathy, and as thera-peutic agent in the management of HIV [1]. A groundswellof recent evidence suggests that NAC may also have ther-apeutic benefits in multiple neuropsychiatric disorders.

The principal victories in biological psychiatry havearisen from the quest to reverse engineer serendipitousclinical findings. Exploring the biological effects of tricyc-lics, antipsychotics, and lithium have, respectively, led toelucidating the role of monoamines in depression, dopa-mine in schizophrenia, and second messenger systems inbipolar disorder [2]. In a similar vein, NAC provides a dualopportunity, first as a novel therapy, and second as a key tounlocking the pathophysiology of targeted disorders. It isnoteworthy that the mechanisms of action of NAC overlap

ty and biosynthesis of GSH is key to its therapeutic efficacy(Figure 1).

Effects on neurotransmissionGlutamateNAC modulates several key neurotransmitter systemsthat are known to be involved in a range of psychopatholo-gy, including glutamate and dopamine [7]. Regulation ofglutamate synthesis, release, synaptic levels, and recyclingis tightly controlled, and dysfunction of this system isimplicated in many neuropsychiatric disorders includingschizophrenia [8] and addiction [9]. Excessive activation ofthe N-methyl-D-aspartate (NMDA) glutamate receptor iscentral to the excitotoxic damage associated with manyforms of neuronal damage and degeneration [10]. Thecystine/glutamate antiporter, or x(c)-system, is a key ele-ment in the control of extracellular glutamate and feed-back regulation of glutamate release [11]. Predominantlyexpressed in astrocytes in the brain, activity of this trans-porter is the primary determinant of non-vesicular release

Corresponding author: Berk, M. (mikebe@barwonhealth.org.au).Keywords: neurodegeneration; glutathione; glutamate; schizophrenia; bipolar dis-order; Alzheimers; Parkinsons; mania; psychosis; anxiety; addiction; obsessivecompulsive disorder; depression; autism; cannabis; trichotillomania.The promise of N-aneuropsychiatryMichael Berk1,2,3,4, Gin S. Malhi5,6, Laura 1School of Medicine, Deakin University, Geelong, Victoria, Aus2Department of Psychiatry, University of Melbourne, Parkville, 3Orygen Research Centre, Parkville, Victoria, Australia4The Florey Institute of Neuroscience and Mental Health, Victo5Discipline of Psychiatry, Sydney Medical School, University o6CADE Clinic, Department of Psychiatry, Level 5 Building 36, R

N-Acetylcysteine (NAC) targets a diverse array of factorsgermane to the pathophysiology of multiple neuropsy-chiatric disorders including glutamatergic transmission,the antioxidant glutathione, neurotrophins, apoptosis,mitochondrial function, and inflammatory pathways.This review summarises the areas where the mecha-nisms of action of NAC overlap with known pathophysi-ological elements, and offers a precis of current literatureregarding the use of NAC in disorders including cocaine,cannabis, and smoking addictions, Alzheimers and Par-kinsons diseases, autism, compulsive and groomingdisorders, schizophrenia, depression, and bipolar disor-der. There are positive trials of NAC in all these disorders,and although many of these require replication and aremethodologically preliminary, this makes it one of themost promising drug candidates in neuropsychiatricdisorders. The efficacy pattern of NAC interestinglyshows little respect for the current diagnostic systems.Its benign tolerability profile, its action on multiple op-erative pathways, and the emergence of positive trialdata make it an important target to investigate.

OverviewNAC has been in use for over 30 years as an antidote in the0165-6147/$ see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.101etylcysteine in

Gray1, and Olivia M. Dean1,2,4

iatoria, Australia

Australiadney, Sydney, Australial North Shore Hospital, St Leonards, 2065, Australia

with the pathophysiology of a diverse range of neuropsy-chiatric disorders, including autism, addiction, depression,schizophrenia, bipolar disorder, and Alzheimers and Par-kinsons diseases [3]. Determining precisely how NACworks is crucial both to understanding the core biologyof these illnesses, and to opening the door to other adjunc-tive therapies operating on these pathways. The currentarticle will initially review the possible mechanisms ofaction of NAC, and then critically appraise the evidencethat suggests it has efficacy in the treatment of neuropsy-chiatric disorders.

NAC biochemistryNAC is the N-acetyl derivative of the amino acid L-cysteineand is rapidly absorbed following an oral dose [4]. L-Cyste-ine is rapidly oxidised to cystine in the prooxidant milieu ofthe brain. Cystine is the substrate of the cystinegluta-mate antiporter, which shuttles glutamate out of the cell inexchange for cystine, thereby regulating extracellular glu-tamate levels and facilitating cysteine entry to the cell [5].Inside the cell, cystine can be reduced to cysteine, which isthe rate-limiting component of the key endogenous antiox-idant molecule glutathione (GSH) [6]. The capacity forNAC to regulate both cystineglutamate antiporter activi-6/j.tips.2013.01.001 Trends in Pharmacological Sciences xx (2013) 111 1

TIPS-1023; No. of Pages 11Processes Presynapc neurons

Reviewof glutamate. The extracellular glutamate activates meta-botropic glutamate receptors (mGluR2/3) on presynapticneurons and regulates vesicular glutamate neurotrans-mission [11]. NAC administration can activate the cys-tine/glutamate antiporter through provision of additionalcystine, thus modulating glutamatergic neurotransmis-sion. Through regulation of this system NAC has been

Glu

Glu

ROS

ROS

Na+

Oxidave stress

Mitochondrial dysfuncon

Altered Ca2+ dynamics

Altered DA/Glu system

Cytokines

Mitochondrial toxicity

Cell damage

DAm

etab

olism

Ca2+

DA

GSH

NAC

NAC

DA

Glu

DAreceptor

AMPAreceptor

NMrec

NMDAreceptor

Mitochondrialdysfuncon

TNF- IL-6

Oxidave stress

Figure 1. Pathophysiological targets of N-acetylcysteine (NAC). Transmitter effects: glu

and glycine (Gly). Oral administration of NAC increases availability of Cys, which in turn

cells. Heightened activity of the CysGlu antiporter also leads to increased extracellular

(AMPA) and N-methyl-D-aspartate (NMDA) receptors. In addition, NAC facilitates the rele

and scavenges reactive oxygen species (ROS) and nitrous oxide (NO), both of wh

neurotransmission, respectively. Therefore, NAC induced increased GSH availability, le

damage. Neurogenesis: administration of NAC has been shown to promote neurogen

neurotrophic factor (BDNF), and indirectly by reducing apoptosis through an increa

dysfunction: NAC corrects mitochondrial dysfunction by modifying calcium (Ca+) dynam

mitochondrial toxicity which in turn decreases the ROS produced by dysfunctional mi

apoptotic pathways. Inflammatory response: alterations to neurotransmission activate i

dysfunction. NAC dampens the inflammatory response by decreasing the production o

2Target

GSH Glial c

Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xthought to show beneficial effects in psychotomimetic-in-duced models of schizophrenia, ameliorating behaviouraldeficits and reversing elevations of extracellular glutamate[12]. NAC also shows beneficial effects in animal models ofcocaine addiction, suggested to be through stimulation ofcystine/glutamate antiporter and presynaptic mGluR2/3signalling [8,13].

Glu

Glu

NO

Apoptosis

Neurotrophinse.g., BDNF

Neurogenesis

Neurogenesis

Nitrosave stress

Ca2+

CysNAC

NAC

Bcl-2

GlyCys

Transmiereects

Redoxmodulaon

ell

Mitochondrialdysfuncon

Inammatoryresponse

DAeptor

IL-6

Nitrosave stress

Cell damage

TRENDS in Pharmacological Sciences

tathione (GSH) is synthesized from three peptides: glutamate (Glu), cysteine (Cys),

facilitates the CysGlu antiporter and the production of glutathione (GSH) in glial

glutamate which then acts on 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate

ase of dopamine (DA). Redox modulation: GSH is the main antioxidant in the brain

ich are intracellular toxic byproducts of dysfunctional DA metabolism and Glu

ssens oxidative and nitrosative stressors in the brain, and this decreases cellular

esis both directly, by increasing neuroprotective proteins, such as brain derived

se of antiapoptotic proteins, such as B cell lymphoma 2 (Bcl-2). Mitochondrial

ics within the mitochondria, and by decreasing intracellular Ca+. NAC also reverses

tochondrial metabolism. Additionally, NAC scavenges ROS which overall inhibits

nflammatory pathways that can ultimately lead to cellular stress and mitochondrial

f cytokines such as tumour necrosis factor-a (TNF-a) and interleukin-6 (IL-6).

TIPS-1023; No. of Pages 11In addition to regulation of glutamate release, NAC, viaGSH or its derivatives, has the capacity to modulateNMDA activity [1416]. Earlier studies suggested thathis was through direct binding of the NMDA receptorbut more recent reports focus on modulation of redox stateby GSH. The NMDA receptor, along with many othercellular proteins, is regulated by subtoxic levels of oxidantspecies. Elevated levels of oxidising agents reduce theactivity of the NMDA receptor via binding to extracellularredox-sensitive sites and depletion of GSH has recapitu-lated this effect [17].

Taken together, these results provide clear evidencethat NAC modulates glutamatergic neurotransmissionboth directly and indirectly. Given the central role ofglutamate signalling in multiple neuropsychiatric disor-ders it is likely to be that this activity of NAC is a keycomponent of its therapeutic effect.

DopamineGiven that dopamine has historically played a lead role intheories underpinning the pathology of many neuropsychi-atric disorders (e.g., schizophrenia and Parkinsons dis-ease), the ability of NAC to modulate dopamine isnoteworthy. NAC regulation of the cystine/glutamate anti-porter and mGluR2/3 as described above can also regulatedopamine release from presynaptic terminals [11]. NACmay also regulate dopamine release via modulation of theredox status of the cell, via the antioxidant effects of GSHand L-cysteine [18,19] (Figure 1). Dopamine itself is strong-ly prooxidant, forming hydrogen peroxide (H2O2) and freeradicals through autooxidation and normal metabolism,and hence dysregulation of dopamine signalling is thoughtto be a major contributor to neurotoxicity [20]. Metham-phetamine evokes strong dopamine release and drivesneuronal apoptosis. NAC ameliorates the oxidative stressinduced by methamphetamine production and preventsthe downregulation of the dopamine transporter elicitedby excessive dopamine release [21,22]. These results notonly highlight the therapeutic effects of NAC but alsodemonstrate the importance of cystine/glutamate trans-port and GSH regulation of oxidative stress in dopaminer-gic signalling [23].

Role in oxidative homeostasisThe brain is acutely sensitive to changes in redox status.The high metabolic activity of this organ is a persistentsource of oxidative species, as utilisation of O2 by energy-generating mitochondria constantly generates oxygen freeradicals [24,25]. Neurotransmitter activity also generatesfree radicals, with autooxidation of dopamine and excito-toxicity related to glutamatergic signalling being impor-tant sources of oxidative stress [10,20]. Neurons rely on theintegrity of extensive axonal membranes for efficient in-formation signalling, and these membranes, high in poly-unsaturated fatty acids, are vulnerable to free radicaldamage. Compounding these factors, the levels of endoge-nous antioxidants in the brain are low relative to otherhighly metabolically active organs. At the far end of the

Reviewspectrum, excessive oxidative stress can lead to neurotox-icity and cell death, but redox systems also play an impor-tant regulatory role in the modulation of enzyme activity,intracellular signalling systems, and receptors (beyond thescope of this review, but discussed in [26]). One example ofthis is the redox regulation of the NMDA receptor, asdiscussed above. Thus, even moderate perturbations ofthe redox balance can alter neuronal function, even inthe absence of overt toxicity and neuronal damage.

Evidence for disrupted oxidative signalling in psychiat-ric disorders is compelling. Alterations in multiple bio-markers of oxidative stress, including enzymes involvedin the production or clearance of free radical species, havebeen observed in attention deficit hyperactivity, bipolardisorder, autism, depression, and schizophrenia [2729].Markers of oxidative damage to neurons have also beenobserved in postmortem samples in several psychiatricdiseases [3032]. Mitochondria are a major source of freeradicals in the brain as a byproduct of energy production,and dysfunction of mitochondrial function can significantlyelevate oxidative stress. Alterations in mitochondrial func-tion are observed in schizophrenia and bipolar disorder, inparticular [3335]. Interestingly, genetically mediated mi-tochondrial disorders are also associated with elevatedincidences of psychiatric disorders, particularly mood dis-orders and psychosis [36].

The major endogenous antioxidant molecule in thebrain is GSH, which is key to the mechanism of actionof NAC. GSH reduction is ironically one of the oldestbiomarkers in psychiatry, known for three-quarters of acentury, and noted in studies of depression, schizophrenia,and bipolar disorder [3746]. GSH is a very efficient redoxscavenger, carrying a free thiol group which can interactdirectly with reactive oxygen/nitrogen species and canmaintain the oxidative status of key cellular enzymes.The cycle of GSH and the reduced species glutathionedisulphide (GSSG) is a critical mechanism for regulationof cellular oxidative balance.

Mice deficient in the rate-limiting enzyme for GSHsynthesis show a range of behavioural symptoms reminis-cent of schizophrenia and bipolar disorder, including aheightened response to psychotomimetics. Treatment withNAC reverses some of these deficits [47,48]. Similarly,experimental GSH depletion in the brain induces spatialmemory deficits which are reversed by NAC [49]. GSHlevels are efficiently restored by NAC [50], which acts as adonor of cysteine, the rate-limiting component of GSHsynthesis. NAC is also effective in reversing the oxidativestress associated with mitochondrial dysfunction [51,52].

NAC also contributes to the maintenance of oxidativebalance through the actions of the cysteine/cystine cycle.Similarly to GSH and GSSG, cysteine and cystine arecoupled redox partners which help to prevent oxidativecellular dysfunction and injury [5355]. Hence, the actionsof NAC are multifold and inter-related, with the produc-tion of GSH, the cysteine/cystine cycle, and the action of theglutamate/cystine antiporter contributing to maintenanceof oxidative balance and cellular function.

Interaction with inflammatory mediatorsAnother potential therapeutic avenue for NAC stems from

Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xits anti-inflammatory properties. Dysregulation of inflam-matory pathways and cytokine levels in both the peripheryand the central nervous system (CNS) are associated with

3

TIPS-1023; No. of Pages 11psychiatric disorders, and in particular depression. Sever-al meta-analyses have demonstrated dysregulated produc-tion of inflammatory cytokines in depressed patients [5658]. Patients treated with the cytokines interleukin-2 (IL-2) and interferon-a for other somatic conditions report asignificantly higher incidence of depressive symptoms [5961]. Dysregulated inflammatory pathways are thought toalter the production of neurotransmitters and key neuro-trophic factors in the CNS and contribute to the patho-physiology of depression [62,63].

NAC has been shown to reduce IL-6 levels in haemo-dialysis patients [64] and tumour necrosis factor-a (TNF-a)and IL-1b in patients undergoing surgery [65]. NAC alsosuppresses production of multiple inflammatory cytokinesin burn patients [66]. In rat models of both traumatic braininjury and focal cerebral ischemia, increased TNF-a andIL-1b levels were reduced following NAC administration[67,68].

Administration of lipopolysaccharide (LPS), a bacterialendotoxin, induces widespread inflammation and depres-sive-like symptoms in animal models [69]. However, NACpretreatment prevents the upregulation of inflammatorycytokines in the brain in response to LPS [70]. Further-more, sensitisation to hypoxic brain injury by LPS andmarkers of cerebral inflammation are prevented by NACtreatment [71]. The capacity for NAC to reduce neuroin-flammation may be through inhibition of the brain inflam-matory cells, the microglia. Microglia are brainmacrophage-like cells which can be activated by cytokinesand in turn produce inflammatory mediators, induce oxi-dative stress, and promote neurotoxicity [72,73]. NAC caninhibit activation, cytokine production, and oxidative spe-cies production by macrophages and microglia [74]. Thiseffect is likely to be through both stimulation of GSHproduction and regulation of cystine/glutamate antipor-ters, regulating oxidative stress and glutamate excitotoxi-city [75].

Use in psychiatryThere is a growing body of literature of potential benefit ofNAC in a wide range of neuropsychiatric disorders. Theseare discussed briefly below and highlighted in Table 1.

AddictionThe majority of the clinical studies investigating addictionhave based their rationale for using NAC on the extantliterature implicating glutamatergic abnormalities in ad-diction [76]. Glutamatergic dysfunction has been consid-ered a central tenet of addictive disorders since thedemonstration that blockade of NMDA glutamatergicreceptors inhibits sensitisation [77], and glutamate isnow thought to additionally regulate dopaminergic activityin the ventral tegmental reward area. The ability of NAC toregulate glutamate availability via the activity of thecystine/glutamate antiporter highlights the potential ther-apeutic efficacy of this drug in treating addictive disorders.In an open-label crossover imaging study of cocaine-depen-dent patients NAC normalised elevated levels of gluta-

Reviewmate, as measured by brain imaging [78].However, there is now data from both clinical studies

and animal models suggesting a role of oxidative stress in

4addiction [7984], suggesting a further pathway wherebyNAC may offer an alternate rational approach via promo-tion of GSH synthesis. In addition to the disorders listedbelow, NAC is also being investigated as an adjunctivetreatment for alcohol dependence (ClinicalTrials.gov:NCT01214083), and a pilot randomised controlled trial(RCT) of NAC in combination with naltrexone has beenconducted for the treatment of methamphetamine depen-dence, with a negative outcome [85].

Cannabis dependence. An open-label study of NAC(1200 mg BD) was conducted in 24 dependent cannabisusers [86]. After NAC treatment, users reported reductionsin days per week of use, number of hits, and compulsivity,emotionality, and purposefulness with cannabis use. Inter-estingly, objective urine cannabinoid measures did not sig-nificantly change with treatment and remained higher thanthe tests detection range [86]. However, a recent 8-weekdouble-blind RCT (n = 116) investigated treatment withNAC (1200 mg BD) versus placebo for cannabis cessationin adolescents and found that during treatment, thosereceiving NAC had more than twice the odds of havingnegative urine cannabinoid test results than placebo, sup-porting its efficacy as a primary cessation therapy althoughin an intent-to-treat analysis [87]. Studies are continuing toexplore the potential of NAC in cannabis dependence (Clin-icalTrials.gov: NCT01005810, NCT01439828).

Nicotine addiction. NAC has also been studied in nicotineaddiction because of its potential to restore glutamatehomeostasis and modulate redox balance. In a placebo-controlled study of NAC (2400 mg/day) for tobacco cessa-tion (n = 29), there was no significant difference in thenumber of cigarettes smoked or carbon monoxide levelsbetween NAC and placebo groups. However, post hocanalysis revealed trends towards decreased number ofcigarettes smoked in the NAC group after the removal oftwo outliers based on alcohol consumption, but this too didnot correspond with decreased carbon monoxide levels [84].In another small-scale 6-month placebo-controlled study ofNAC (1200 mg/day), the detrimental biophysical aspects ofsmoking were examined (participants were instructed tocontinue their cigarette use). In the NAC group, there weredecreases between baseline and endpoint in markers ofDNA damage, compared with the placebo group, indicatinga decrease in oxidative stress processes associated withaddiction [88].

A recent pilot double-blind study investigated theeffects of a larger daily dose of NAC (3600 mg) on short-term abstinence in heavy smokers. Participants receivedNAC (n = 10) or placebo (n = 12) over 3.5 days. Thoseparticipants receiving NAC rated the first cigarette afterabstinence as significantly less rewarding than those onplacebo; however, there was no significant effect of NAC oncraving [78]. There are small active-placebo gaps in thisgenre of research, and because a relatively small numberof individuals stop smoking in these cessation trials, sam-ple sizes in the hundreds are usually needed to demon-

Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xstrate efficacy. Further studies that address theselimitations (see ClinicalTrials.gov: NCT00967005) arebeing conducted.

Table 1. Clinical trials of NAC in neuropsychiatric disorders

Disorder Trial type Dose of NAC Duration of trial Number of participants Clinical outcome Biomarkers Refs

Methamphetamine

dependence

Placebo-controlledRCT (NAC +naltrexone)

6002400 mg/day(NAC) + 50200 mg/day (naltrexone)

8 weeks NAC + naltrexone = 14Placebo = 17

No effect on cravingsor drug use

[85]

Cannabis

dependence

Open-label 1200 mg BD 4 weeks 24 Reduced use andcraving

No change in urinecannabinoid levels

[86]

Double-blindRCT

1200 mg BD 8 weeks NAC = 58Placebo = 58

Twofold increase inlikelihood of a negativeurine cannabinoid test

[87]

Nicotine

addiction

Placebo-controlledRCT

2400 mg/day 4 weeks NAC = 15Placebo = 14

No change in numberof cigarettes smoked

No change in carbonmonoxide levels

[84]

Placebo-controlledRCT

1200 mg/day 6 months NAC = 20Placebo = 21

Decrease in somemarkers of oxidativedamage

[88]

Pilot double-blindRCT

3600 mg/day 3 days NAC = 10Placebo = 12

Reduced rewardingstimulus after short-term abstinence,no effect on craving

[78]

Cocaine

addiction

Placebo-controlledcrossover study

2400 mg 2 days 13 Reduced withdrawalsymptoms and craving

[89]

Double-blindplacebo-controlledcrossover study

2400 mg 3 days 13 Reduced cue reactivityto cocaine-related stimuli

[90]

Open-label trial 1200, 1800, or3600 mg/day

4 weeks 23 Nonsignificant reductionsin use

[91]

Open-labelcrossover trial

Single dose 10 Normalised glutamatelevels

[78]

Pathological

gambling

Open-label studyfollowed by placebo-controlled RCT

1800 mg 8 weeks, 6 weeks 27, 16 responders Reduced gamblingsymptoms

[92]

Obsessive

compulsivedisorder

Case report intreatment-resistantpatient

300 mg daily 6 weeks 1 Reduced symptoms [98]

Trichotillomania,

skin picking

Two case reports 1800 mg 2 Reduced symptoms [101]

Double-blindplacebo-controlled

1200 mg for 6 weeks,followed by 2400 mgfor 6 weeks

12 weeks 50 Reduced symptoms [102]

Case report 1800 mg/day 1 Reduced symptoms [101]

Schizophrenia Double-blindplacebo-controlled trial

1000 mg BIDadjunctive

6 months 140 Reduced negativesymptoms

[45]

Case report intreatment resistance

600 mg/day Improved symptoms [108]

Bipolar disorder Double-blind placebo-controlled RCT

1000 mg BID 6 months 75 Decreased depressionrating scores andimprovements onglobal functioning scale

[109]

Open-label trial 1000 mg BID 8 weeks 149 Decreased depressionrating scores andimprovements on globalfunctioning scale

[121]

Review

Trends

in Pharm

acological

Sciences

xxx

xxxx,

Vol.

xxx,

No.

x

TIPS-1023;

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Pag

es 11

5

Table

1(Continued)

Disorder

Trialtype

Dose

ofNAC

Durationoftrial

Numberofparticipants

Clinicaloutcome

Biomarkers

Refs

Autism

Do

ub

le-b

lin

dp

lace

bo

-co

ntr

oll

ed

RC

T900

mg

up

to2700

mg

dail

y12

weeks

Imp

rovem

en

tsin

irri

tab

ilit

y,

rep

eti

tive

beh

avio

urs

,an

dm

an

neri

sms

[113]

Alzheim

ers

disease

Do

ub

le-b

lin

dp

lace

bo

-co

ntr

oll

ed

RC

T50

mg

/kg

/day

6m

on

ths

NA

C=

23

Pla

ceb

o=

20

Imp

roved

cog

nit

ive

perf

orm

an

ceN

och

an

ge

inp

eri

ph

era

lm

easu

res

of

oxid

ati

ve

stre

ss

[115]

Op

en

-lab

el

tria

lN

AC

inco

mb

inati

on

wit

ho

ther

neu

trace

uti

cals

1year

14

Imp

roved

cog

nit

ive

perf

orm

an

ce[6

0]

Pla

ceb

o-c

on

tro

lled

tria

lN

AC

inco

mb

inati

on

wit

ho

ther

neu

trace

uti

cals

9m

on

ths

12

Imp

roved

cog

nit

ive

perf

orm

an

ce[1

17]

Review

TIPS-1023; No. of Pages 11

6Cocaine addiction. Perhaps the most active area of studyin addiction using NAC is cocaine addiction. In a 2-daycrossover study (n = 13), participants who were abstainingfrom cocaine were given 2400 mg NAC or placebo. Fourdays later, participants were crossed over to alternativetreatment arms. Although there was no between-groupdifference, the NAC within-group comparison identifieda significant reduction in cravings, withdrawal symptoms,and self-reported use compared with baseline, a patternnot mirrored by the placebo group [89]. In a subsequentstudy, a similar sample was treated with 2400 mg of NAC.Using cue-reactivity slides (a paradigm assessing the pro-pensity for people with addictions to have significantphysiological and subjective reactions to drug-related sti-muli), NAC decreased the amount of time spent looking atthe cocaine-related slides, indicating a reduced interestand desire for cocaine [90]. In a subsequent larger open-label trial of NAC over 4 weeks, eight participants weregiven 1200 mg/day of NAC, a further nine participantswere treated with 1800 mg/day, and six participants re-ceived 3600 mg/day [91]. Nonsignificant reductions in thenumber of days of use, the amount spent on cocaine, andimprovements on the Cocaine Selective Severity Assess-ment were noted. In an open-label crossover study of tencocaine dependant individuals, after a single administra-tion of NAC, magnetic resonance spectroscopy was con-ducted. In the cocaine-dependent group, glutamate levelswere discernibly reduced, and there was a trend towardsdecreased self-reported cocaine use and glutamate/crea-tine ratios in the dorsal anterior cingulate cortex [78].

Pathological gambling. In an 8-week, open-label study of20 confirmed pathological gamblers, Grant et al. utilised1800 mg (titrated dose) of NAC and found 16 completershad significant reductions in gambling behaviour [92]. Arandomised trial of 13 responders was conducted over thesubsequent 6 weeks using a fixed dose of 1800 mg/kg NACor placebo. At the end of the treatment phase, only 28% ofthe placebo group were still considered responders, com-pared with 83% of the NAC group [92]. Further studiesare currently being conducted to explore the potential ofNAC as a therapy for gambling (ClinicalTrials.gov:NCT00967005).

Obsessivecompulsive disorder (OCD) and othercompulsive disordersThe biochemical pathways and brain regions implicated inaddiction and the OCD spectrum of disorders overlapconsiderably [93,94]. Oxidative stress has been reportedin OCD and is reflected by decreased antioxidant levels[95], increased lipid peroxidation [96], and overall alteredoxidative status [27] that are associated with the severityof symptoms [95]. In addition, there is evidence of gluta-matergic abnormalities in OCD [97].

With respect to treatment however, there is currently asingle case report of the use of adjunctive NAC 3000 mgdaily in a person with partial response to selective seroto-nin reuptake inhibitor (SSRI) treatment for refractory

Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xOCD, a disorder known to have low placebo response rates.Scores on both the YaleBrown Obsessive CompulsiveScale and the Hamilton Depression Rating Scale improved,

TIPS-1023; No. of Pages 11and were associated with improvements in compulsivewashing and obsessional triggers [98]. Randomisedcontrolled trials are underway (ClinicalTrials.gov:NCT01555970, NCT01172275).

Trichotillomania (obsessive pulling of ones hair; TTM)is thought to exist on a continuum with OCD [99]. There isalso a hypothesised overlap between TTM and addictivedisorders, given the shared role of impulsivity and dys-functional reward pathways [100]. There are two reportedcase studies that have suggested benefits of NAC in TTM[101], where a titrated dose of 1800 mg of NAC reducedhair pulling.

There has been one double-blind, placebo-controlledtrial of adjunctive NAC for the treatment of TTM, inwhich 50 individuals were treated with 1200 mg ofNAC for 6 weeks, followed by 6 weeks of treatment with2400 mg of NAC (or placebo). There was a greater im-provement in the NAC group than the placebo group,separating at week 9 and persisting throughout the study[102]. There is a case report of cessation of nail biting withNAC in a person with both TTM and nail biting beha-viours, in which symptoms recurred upon discontinuationbut remitted once again on recommencement of NAC[101]. Further evidence for this action comes from a 6-month study primarily investigating NAC (2000 mg/day)in the treatment of mood disorders, which reported anincidental treatment concomitant finding of reduced nailbiting in three participants [103]. Lastly, there is a casereport of utility in skin picking with 1800 mg/day of NAC,in which both the urge to pick, and skin picking beha-viours remitted [101] and therefore NAC for skin pickingis currently being investigated in a RCT (ClinicalTrials.-gov: NCT01063348).

SchizophreniaIn the pathophysiology of schizophrenia, glutamate isthought to play a key role, evidenced by decreased gluta-mate levels in the prefrontal cortex and dysfunction inglutamate metabolism [104]. Oxidative stress is also ex-tensively documented in schizophrenia, and there areemerging links between symptom severity, diagnostic sub-type, and oxidative stress [105].

A large-scale (n = 140) randomised double-blind place-bo-controlled trial of adjunctive NAC 1000 mg BID inschizophrenia conducted over 6 months [106] found sig-nificant improvements in negative symptoms (includingblunted affect, lack of volition, and social withdrawal),assessed by the Positive and Negative Symptoms Scale(PANSS). Specifically, there were improvements inPANSS total and general subscales and significantimprovements also occurred in abnormal movements,particularly akathisia, as well as global functioning. In-terestingly, benefits were lost 1 month after treatmentdiscontinuation. Of note, in a study subsample, auditorysensory processing was assessed using mismatch negativ-ity (MMN), as it is a marker of glutamatergic function anda potential endophenotype of psychosis. As anticipated,individuals with schizophrenia had reduced MMN at

Reviewbaseline compared with healthy controls, but after 8weeks of treatment MMN normalised significantly inthose on NAC [45].In a blinded qualitative analysis of clinician observa-tions and participant reports in this trial, participantstreated with NAC showed more improvements in insight,social interaction, motivation, self-care, psychomotor sta-bility, volition, and stabilisation of mood [107]. Finally,there is a case report of the use of NAC 600 mg/day in ayoung female with treatment-resistant schizophrenia,which suggested significant improvements in symptoms[108]. Other studies of NAC in schizophrenia are underway(ClinicalTrials.gov: NCT01354132, NCT01339858).

Bipolar disorder and unipolar depressionAlterations in pro- and anti-inflammatory cytokines, oxi-dative biology, mitochondrial function, glutamate, inflam-mation, and neurotrophins have been described in bipolardisorder, dovetailing the known pharmacokinetic proper-ties of NAC [3]. A 6-month double-blind, RCT of NAC1000 mg BID in addition to treatment as usual was con-ducted in 75 participants with bipolar disorder [109].Scores on both the MontgomeryAsberg Depression RatingScale (MADRS) and the Bipolar Depression Rating Scale(BDRS) evidenced large decreases in symptoms of depres-sion between NAC and placebo groups at endpoint. Com-parable improvements were seen on global improvement,severity, and functioning scales. A secondary analysisincluding those participants meeting criteria for a majordepressive episode showed large effect sizes in favour ofNAC for depressive symptoms and functional outcomes atendpoint [110]. Another secondary analysis of the trialexamined individuals with bipolar II disorder. In theNAC group, six out of seven people attained remission ofboth depressive and manic symptoms, whereas only twoout of seven people in the placebo group reached remission[111].

In a recent maintenance design RCT of 1000 g BID ofNAC for bipolar disorder, the effect of NAC amongst 149individuals with moderate depression was studied. MeanBDRS scores significantly reduced at the end of the 8-weekopen-label treatment phase. Comparable and significantimprovements in functioning and quality of life were seen.Studies involving NAC for the treatment of bipolar depres-sion are continuing [Australian and New Zealand ClinicalTrials Registry (ANZCTR): ACTRN12612000830897] andthe first trial of NAC in unipolar depression is nearingcompletion (ANZCTR: ACTRN12607000134426).

AutismIn autism, analogous to schizophrenia, dysregulation ofredox biology, inflammation, and glutamate transmissionhave been noted [112]. Recent tantalising data on theefficacy of NAC in autism has been published [113]. Inthis 12-week, double-blind, randomised, placebo-controlledstudy of NAC, participants were initiated on 900 mg dailyfor 4 weeks and titrated to 2700 mg daily over 8 weeks. Ofnote, significant improvements on the Aberrant BehaviourChecklist irritability subscale in the NAC group have beenreported, as well as on the Repetitive Behaviour Scale-Revised stereotypies measure and Social Responsiveness

Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. xScale mannerisms scores [113]. Further studies areunderway (ClinicalTrials.gov: NCT00889538; ANZCTR:ACTRN12610000635066).

7

TIPS-1023; No. of Pages 11Alzheimers disease and other neurodegenerativedisordersNAC impacts multiple pathways implicated in a variety ofneurodegenerative disorders. In Parkinsons disease, forexample, in addition to the overt impacts of altered dopa-mine metabolism on oxidative events, mitochondrial com-plex I dysfunction and dysregulated phosphorylation arereported [114], and may be potentially targeted by NACtreatment. Furthermore, there is preclinical evidence,particularly in Alzheimers disease (AD) and Parkinsonsdisease models, suggesting potential benefits of NAC.Hence, a few clinical investigations of NAC as a treatmentoption in neurodegenerative disorders have been con-ducted.

Late-stage AD patients treated with 50 mg/kg/day ofNAC for 6 months showed significant improvements inperformance on the Letter Fluency Task and the WechslerMemory Scale Immediate Number Recall; however, pe-ripheral measures of oxidative stress did not change[115]. In a 12-month, small (n = 14) open-label trial ofindividuals with early-stage AD, the efficacy of a vita-min/nutraceutical formulation (NAC, folate, vitamin B6,a-tocopherol, S-adenosyl methionine, and acetyl-L-carni-tine) was examined. Improvements were noted in theDementia Rating Scale and Clock-drawing tests, as wellas in reports from family caregivers [116]. In a similarstudy (n = 12), the same nutraceutical formulation showedmore favourable cognitive endpoints compared with place-bo [117]. However, given the small number of studies, andtheir exploratory nature, definitive conclusions are prema-ture. Research into the potential benefits of NAC in neuro-degenerative disorders is continuing (ClinicalTrials.gov:NCT01470027; NCT01427517, NCT01370954).

Concluding remarksGiven the paucity of new drug development, NAC is apromising novel therapeutic option for a diverse range ofneuropsychiatric disorders. Although there is only prelim-inary data of the efficacy of NAC in many of these dis-orders, this field is rapidly expanding with additional trials[e.g., investigating personality disorder (ClinicalTrials.-gov: NCT01555970)]. Most notable is the sheer breadthof disorders that NAC appears to benefit and the lack ofrecognition within extant diagnostic systems commensu-rate with its efficacy profile. Indeed, the seeming univer-sality of NAC action is intriguing and implies that itperhaps targets downstream pathways that are commonacross disorders. Oxidative stress and associated mito-chondrial dysfunction are plausible candidates as theytoo appear to lack specificity across psychopathologies.Equally, however, dysregulation of neurotrophins, inflam-matory pathways, and neurotransmitters such as gluta-mate and dopamine have been similarly widely reported ina multitude of disorders. This is emphasised by the factthat there is extensive overlap of other treatments andbiomarkers across disorders.

There are several caveats that need to be borne in mind.As the database increases, it is likely to be that the profile

Reviewof efficacy of NAC will be greater in some disorders thanothers. The optimal dose of NAC is not clear; dose-findingstudies may show equal efficacy at lower doses or greater

8efficacy at higher doses. Although the tolerability profile ofNAC seems benign, there is as yet an insufficient evidencebase for longer term use. Idiosyncratic events, such asasthma, have been shown in some studies, but not repli-cated, and pulmonary hypertension at very high dose hasbeen reported in a few animal studies, but, as yet, has notbeen found in human studies [118]. At low dose NACappears to be anti-epileptic [119], but at high doses sei-zures have been reported [120]. Hence, ongoing data col-lection regarding safety is necessary, concomitant withcorroborating efficacy data.

Lastly, it is interesting that historically, the richestdiscoveries in psychopharmacology have been derived byreverse engineering the beneficial mechanisms of action ofdrugs discovered serendipitously. Notable examples in-clude the monoamine oxidase (MAO) inhibitors, tricyclics,lithium, and phenothiazines. To date, two divergent hypo-thetical paths have converged on NAC as a potentialtreatment. Firstly, oxidative stress and GSH deficiencyhas driven the focus on NAC in schizophrenia, bipolardisorder, and depression. Superadded to this, and in par-allel, addiction research has hypothesised NAC to be activevia the modulation of glutamate and the cystinegluta-mate antiporter [76]. However, knowing that NAC also haseffects on inflammatory pathways, neurotrophins, mito-chondrial function, and oxidative stress, its true efficacyprofile may turn out to be due to preferential effects on anyof these, or a summative interaction of influences on avariety of pathways. Unravelling these complexities hasthe potential to open up new avenues for the developmentof novel psychotropic agents.

Disclaimer statementG.S.M. has received research support from AstraZeneca, Eli Lilly, Orga-non, Pfizer, Servier, and Wyeth; has been a speaker for AstraZeneca, EliLilly, JanssenCilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth;and has been a consultant for AstraZeneca, Eli Lilly, JanssenCilag,Lundbeck, and Servier. M.B. has received research support from theMedical Benefits Fund of Australia, BristolMyers Squibb, Eli Lilly,GlaxoSmithKline, Organon, Novartis, Mayne Pharma, and Servier;has been a speaker for AstraZeneca, BristolMyers Squibb, Eli Lilly,GlaxoSmithKline, JanssenCilag, Lundbeck, Merck, Pfizer, SanofiSynthelabo, Servier, Solvay, and Wyeth; and has served as a consultantto AstraZeneca, BristolMyers Squibb, Eli Lilly, GlaxoSmithKline, Jans-senCilag, Lundbeck, and Servier. M.B. is a co-inventor on two provi-sional patents regarding the use of NAC and related compounds forpsychiatric indications, assigned to the Mental Health Research Insti-tute. L.J.G. has received grant support from the Rebecca L. CooperMedical Research Foundation. O.M.D. has received grant support fromthe Brain and Behaviour Foundation, the Simons Autism Foundation,the Stanley Medical Research Institute, Lilly, National Health andMedical Research Council (NHMRC), and an Society for Bipolar andDepressive Disorders (ASBDD)/Servier grant.

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Review Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. x

TIPS-1023; No. of Pages 1111

The promise of N-acetylcysteine in neuropsychiatryOverviewNAC biochemistryEffects on neurotransmissionGlutamateDopamine

Role in oxidative homeostasisInteraction with inflammatory mediatorsUse in psychiatryAddictionCannabis dependenceNicotine addictionCocaine addictionPathological gamblingObsessivecompulsive disorder (OCD) and other compulsive disorders

SchizophreniaBipolar disorder and unipolar depressionAutismAlzheimer's disease and other neurodegenerative disordersConcluding remarks

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