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Antioxidants as Antidepressants

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 CNS Drugs 2012; 26 (6): 477-490
LEADING ARTICLE 1172-7047/12/0006-0477/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Antioxidants as Antidepressants
Fact or Fiction?
Giovanni Scapagnini,1 Sergio Davinelli,1 Filippo Drago,2 Antonino De Lorenzo3
and Giovannangelo Oriani1

This material is
1 Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
2 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry,
University of Catania, Catania, Italy
3 Department of Neuroscience, Division of Human Nutrition, University of Rome Tor Vergata, Rome, Italy

the copyright of the

Abstract Depression is a medical condition with a complex biological pattern of
aetiology, involving genetic and epigenetic factors, along with different en-

original publisher. vironmental stressors. Recent evidence suggests that oxidative stress pro-
cesses might play a relevant role in the pathogenic mechanism(s) underlying
many major psychiatric disorders, including depression.
Reactive oxygen and nitrogen species have been shown to modulate levels
and activity of noradrenaline (norepinephrine), serotonin, dopamine and

Unauthorised copying
glutamate, the principal neurotransmitters involved in the neurobiology of
depression. Major depression has been associated with lowered concentra-
tions of several endogenous antioxidant compounds, such as vitamin E, zinc
and coenzyme Q10, or enzymes, such as glutathione peroxidase, and with an
impairment of the total antioxidant status. These observations introduce new

and distribution
potential targets for the development of therapeutic interventions based on
antioxidant compounds.
The present review focuses on the possible role of oxidative stress pro-
cesses in the pathogenesis of depression. The therapeutic potential of anti-
oxidant compounds as a co-adjuvant treatment to conventional antidepressants

is prohibited.
is discussed. For instance, N-acetyl-cysteine has been shown to have a signif-
icant benefit on depressive symptoms in a randomized placebo-controlled
trial. Additionally, curcumin, the yellow pigment of curry, has been shown to
strongly interfere with neuronal redox homeostasis in the CNS and to possess
antidepressant activity in various animal models of depression, also thanks to
its ability to inhibit monoamine oxidases. There is an urgent need to develop
better tolerated and more effective treatments for depressive disorders and
several antioxidant treatments appear promising and deserve further study.

1. Introduction pected to become the second most prevalent dis-

ease after ischaemic heart disease by 2020.[1]
Major depressive disorder (MDD) is a highly MDD is also one of the most costly dis-
debilitating disease, which represents the fourth orders in Western countries, and antidepressants
leading cause of disability worldwide and is ex- account for 20% of the total CNS drug sales.[2]
478
Antidepressants constitute a heterogeneous group
of compounds characterized by different mecha-
nisms of action, including serotonin-noradrenaline
(norepinephrine) reuptake inhibitors (SNRIs),
serotonin antagonist and reuptake inhibitors,
selective serotonin reuptake inhibitors (SSRIs),
noradrenaline reuptake inhibitors (NRIs), nor-
adrenaline-dopamine reuptake inhibitors (NDRIs),
noradrenaline-dopamine releasing agents (NDRAs),
This material is
tricyclic antidepressants (TCAs) and monoamine
oxidase inhibitors (MAOIs).
Despite the widespread use of antidepressants,
approximately 30% of depressed patients do not
respond to the existing drug therapies and the
the copyright of the
remaining 70% fails to achieve complete remis-
sion.[3] Moreover, antidepressants are associated
with a plethora of side effects and a propensity
for abuse.
For many psychiatric disorders, including MDD,
original publisher.
a number of neurotransmitter systems were in-
itially suspected of playing a role in the disease
mechanism. A causal relationship was suggested
between disturbances in monoamine metabolism
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and MDD.[4,5] Serotonin and noradrenaline be-
came a target because of their involvement in the
mechanism of action of antidepressants.[6]
Data showing immune activation in MDD were
reported for the first time more than 20 years ago
and distribution
by Maes et al.[7] Since then, the presence of an
inflammatory response in MDD has been de-
scribed several times. Transcriptome studies have
recently emphasized the potential role of the im-
mune system in the pathogenesis and progress
is prohibited.
of MDD, as well as several other psychiatric
disorders such as bipolar disorder (BPD) and
schizophrenia.[8] The role of pro-inflammatory
cytokines in MDD is supported by the observa-
tion that they can induce various clinical aspects
of MDD, including disturbed serotonin metabo-
lism and neurovegetative symptoms.[9]
Meta-analysis studies have revealed that in-
creased peripheral blood levels of cytokines,
interleukin (IL)-6, tumour necrosis factor (TNF)-a,
the acute-phase reactant and C-reactive protein
(CRP) are some of the most reliable biomarkers of
increased inflammation in depressed patients.[10,11]
Importantly, depressed patients and controls have
showed major differences in inflammatory mark-
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Scapagnini et al.
ers and significant associations have been found
between blood concentrations of inflammatory
factors and the severity of depressive symptoms,
including impaired sleep, cognitive dysfunction
and fatigue.[12-14]
Inflammatory cytokines also interact with mito-
chondria to increase the reactive oxygen species
(ROS) production, which in turn increases cyto-
kine expression.[15] Free radicals are atoms with
an odd (unpaired) number of electrons, and free
radicals involving oxygen are referred to as ROS.
Free radicals are produced from a number of
sources, among which there are enzymatic, mi-
tochondrial and redox metal ion-derived.[16] ROS
include inorganic molecules, such as the super-
oxide radical anion, hydrogen peroxide (H2O2)
and hydroxyl radicals, as well as organic mole-
cules such as alkoxyl and peroxyl radicals. ROS
at low concentrations may function as signalling
molecules and participate in the regulation of cell
activities, such as cell growth. In contrast, ROS at
high concentrations may cause cellular injury and
death. An altered redox status in the CNS of
patients with MDD was hypothesized more than
a decade ago when oxidative damage to the red
blood cell membranes and serum phospholipids
was described.[17,18]
The present review aims to discuss the recent
discoveries on the relationship between oxidative
status and depression. In particular, we will focus
on the latest advances in the treatment of major
depression describing the most promising anti-
oxidant compounds suitable for the management
of this disease.
2. Oxidative Disturbances in Psychiatric
Disorders and Major Depression
There is an increasing body of evidence to
suggest that both oxidative stress and inflamma-
tory mechanisms within the CNS can contribute
to cognitive impairment and degenerative pro-
cesses. Recent studies have documented oxidative
disturbances in psychiatric patients and signif-
icant increases in oxidative and inflammatory
stress biomarkers have been described in MDD.
Interestingly, the brain appears to be more sus-
ceptible than other organs to the generation and
CNS Drugs 2012; 26 (6)
Antioxidants as Antidepressants
detoxification of ROS, potential explanations for
this include: (i) the high content of peroxidizable
unsaturated fatty acids; (ii) the high oxygen con-
sumption per unit weight; (iii) the high content
of lipid peroxidation key ingredients (iron and
ascorbic acid); and (iv) the scarcity of antioxidant
defense systems.[19]
The activity of monoamine oxidase (MAO),
which catalyses the oxidative deamination of mono-
This material is
amine neurotransmitters, has also been implicated
as a potential cause of brain redox imbalance.[20]
Byproducts of MAO reactions, such as H2O2,
can trigger overproduction of ROS and induce
mitochondrial damage and neuronal apoptosis.
the copyright of the
2.1 Role of Oxidative Stress in Major Depressive
Disorder (MDD) Pathology
The involvement of catecholamine metabo-
original publisher.
lism in the production of free radicals also sup-
ports the putative link between oxidative stress,
neurodegeneration and MDD. Further evidence
to support this link can be found in the fact that
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MDD has been associated with neurodegener-
ation and reduced neurogenesis,[21] and magnetic
resonance morphometry[22-24] has shown that pa-
tients affected by MDD have decreased volumes
of various brain regions, including the hippo-
and distribution
campus. Cognitive impairment in the domains of
executive functioning, attention, memory, visuo-
spatial processing and psychomotor function is
a typical feature of MDD. Permanent cognitive
impairment in immediate memory and atten-
is prohibited.
tion has been reported in subjects with previous
MDD.[25] Finally, MDD is relatively common
among patients with a diagnosis of dementia and
may represent a risk factor for development of
dementia.[26]
It is evident that oxidative stress may con-
tribute to depression through a variety of pro-
posed mechanisms; it could also function in part
towards the pathogenesis of MDD.
Psychological stress, which accompanies MDD,
has been associated with increased lipid perox-
idation.[27] Although the reason for increased
lipid peroxidation in MDD has not been clearly
explained, it has been related to several mechan-
isms including enhancement of immune activa-
Adis ª 2012 Springer International Publishing AG. All rights reserved.
479
tion and increased production of proinflammatory
cytokines. These proinflammatory cytokines may
in turn increase lipid peroxidation by inducing
free radical production or increased monoamine
metabolism (figure 1).
Recent research has shown that individuals
with increased chronic courses of MDD had sig-
nificantly shorter leukocyte telomeres than healthy
controls. This research demonstrated significant
inverse correlations between telomere length and
oxidative (F2-isoprostane/ascorbic acid ratio) or
inflammatory (IL-6) stress biomarkers in MDD
patients.[28] The average telomere length of sub-
jects suffering from MDD for longer than the
lifetime median exposure (‡9.2 years cumulative
duration) was 281 base pairs shorter than in con-
trols; this corresponds to approximately 7 years
of ‘accelerated cell aging’. Wolkowitz et al.[28]
suggested that chronic inflammation and oxida-
tion may be the mechanisms by which chronic
MDD can result in such shortened telomeres.
Human and animal studies have reported an
association between MDD produced by chronic
mild stress and elevated lipid peroxidation lev-
els.[29,30] A study conducted on 96 MDD patients
has shown that plasma levels of malondialdehyde
(MDA) [an end-product of lipid peroxidation]
were significantly higher in the impaired group
than in 54 healthy controls.[31] Increased plasma
MDA levels observed in this study are in line with
previous reports.[30,32] A further study[33] with 25
MDD patients and 25 healthy control subjects
showed increased 4-hydroxy-2-nonenal (4-HNE)
levels, another major indicator of lipid perox-
idation. Furthermore, MDA exerts an inhibitory
effect on the ligand binding areas of the serotonin
receptor[34] (figure 1), which suggests the ex-
istence of a relationship between serotonin me-
tabolism and oxidative stress. Overproduction of
ROS may also cause the destruction of neuronal
membrane phospholipids and consequently af-
fect serotonergic and catecholaminergic receptor
functions (figure 1).[35] Membrane lipid perox-
idation also modifies neurotransmitter release
and uptake, ion-channel activity, adenosine tri-
phosphatase function and glucose transporters,
affecting the coupling of cell-surface receptors to
guanosine triphosphate-binding proteins, leading
CNS Drugs 2012; 26 (6)
480 Scapagnini et al.

Unpredictable chronic mild stress

Proinflammatory
Nitric oxide
cytokines

ROS production

This material is Depletion of membrane

omega-3 polyunsaturated fatty
Depletion of endogenous
Increased lipid peroxidation
antioxidants
acids

the copyright of the Destruction of membrane phospholipids

Oxidative-nitrosative stress

original publisher. Depression

Decrease of serotonergic and

Inhibition of
serotonin
catecholaminergic receptor functions
binding to receptor

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Fig. 1. Schematic diagram showing the effects of stress on the generation of reactive oxygen species (ROS) and the involvement of ROS in
the development of depression.

to impaired mitochondrial function; a cascade of (NO) in the cortex and medulla of the brain has

and distribution
events that culminates in apoptotic cell death.[36]
Recently, Maes and co-workers have shown
that oxidative and nitrosative stress damages
to membrane lipids and functional proteins are
been shown to induce behavioural depression in
male Wistar rats.[29] Bilici and co-workers found
significant correlations between superoxide dis-
mutase (SOD) levels and the severity of MDD,
accompanied by increased autoimmune reactions suggesting that antioxidant enzymes may be state

is prohibited.
against neoepitopes. This is evidenced by increased
plasma concentrations of IgG autoantibodies
against oxidized low-density lipoproteins (LDL),
IgM-mediated immune responses directed against
anchorage molecules and autoimmune activity
directed against 5-hydroxytyrptophan. It is in-
teresting to note that these effects have been
linked to depression pathology onset.[37,38]
Increasing evidence points to the notion that
reduced cellular expression and activity of anti-
oxidant proteins are fundamental causes for brain
redox disturbances, neurodegeneration and de-
pressive disorders. Glutathione depletion, glu-
tathione peroxidase (GSH-Px) level reduction,
and the rise in lipid peroxidation and nitric oxide
markers of MDD.[30] Specifically, this study re-
ported that depressed patients had higher anti-
oxidative enzyme activities and lipid peroxidation
levels than healthy controls. It showed that after
treatment with SSRIs the antioxidant enzymes
and MDA were significantly decreased. Altera-
tions and increased susceptibility to oxidation in
peripheral blood system have been clearly de-
scribed in MDD. Patients have been reported to
overproduce superoxide anion, which is directly
correlated with the level of polymorphonuclear
cell apoptosis.[39] Moreover, Herken et al. dem-
onstrated statistically significant lower activity of
SOD in the erythrocytes of patients with depres-
sion.[40] These findings also explain why the total

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (6)
Antioxidants as Antidepressants
antioxidant capacity is significantly decreased in
patients with depression.[41]
2.2 Mitochondrial Impairment and Oxidative
Stress in MDD Associated Disorders
Mitochondrial dysfunction and related redox
dyshomeostasis seems to play a relevant role
in the pathophysiology of depressive disorders.
This material is
Mitochondrial structure and function have been
measured by a variety of different techniques,
and have proven to be abnormal in patients with
mood disorders including MDD, in addition to
other affective spectrum disorders. Mitochon-
the copyright of the
drial diseases are frequently co-morbid with psy-
chotic symptoms and frequently misdiagnosed as
BPD or schizophrenia.[42]
Patients exhibiting classical mitochondrial dis-
ease symptoms in muscle tissue, such as ragged
original publisher.
red fibres and electron transport chain deficiency,
also commonly present with psychosis or depres-
sion.[43] Decreased gene expression for 6 of 13
mitochondrial DNA (mtDNA) encoded tran-
Unauthorised copying
scripts in frontal cortex tissue (Brodmann areas 9
and 46) have been reported in MDD. The results of
this study also showed significant alterations in the
expression of 10 out of 13 mitochondrial transcripts
in patients with schizophrenia, and a significantly
and distribution
increased mtDNA common deletion in patients
with BPD (and non-significant increases in those
with schizophrenia and MDD).[44]
Messenger RNA (mRNA) and protein levels
of mitochondrial complex I subunits (NDUFV1,
is prohibited.
NDUFV2 and NADUFS1) in the cerebellum
showed significant reductions in depressed patients.
Moreover, schizophrenia-specific reductions in
mitochondrial complex I subunits were observed
in the prefrontal cortex and in the striatum, while
in the same study the BPD group showed reduc-
tions in the cerebellum and increased expression
in the parieto-occipital cortex, similar to those
observed in schizophrenia. These brain areas may
constitute part of several complex neuronal cir-
cuits implicated in all three mental disorders.[45]
Several reports have recently documented a
substantial relationship between oxidative stress
and other psychiatric disorders. Numerous lines
of evidence have suggested alterations in diverse
Adis ª 2012 Springer International Publishing AG. All rights reserved.
481
oxidative stress parameters in the course of
BPD.[46] Studies conducted with peripheral blood
cells showed that BPD is associated with altera-
tions in antioxidant enzymes,[47] increased lipid
peroxidation,[48] increased levels of NO and in-
creased DNA fragmentation.[49] Together, these
findings are consistent with the above-mentioned
MDD results, suggesting a possible relationship
between a disturbed cellular redox balance and
psychotic features.
A recent study on post-mortem brain samples
has shown increased levels of 4-HNE in anterior
cingulate brain sections of patients with BPD.[50]
Interestingly, the levels of 4-HNE were signif-
icantly increased in BPD subjects and in schizo-
phrenia subjects, but not in MDD subjects when
compared with controls.
Recent findings have suggested that mitochon-
drial dysfunction[51] and the nitration process[52]
may be associated with the pathophysiology of
BPD and schizophrenia. Moreover, gene expres-
sion studies have shown abnormal patterns of
mitochondrial genes in BPD. Expression profiles
in BPD and schizophrenia show a level reduction
of mRNA and proteins involved in mitochondrial
functions, such as oxidative phosphorylation.[53]
Similar molecular signatures have been observed
in BPD, schizophrenia and MDD and several
data suggest significant overlap across these dis-
orders.[54] It is interesting to consider the fact that
oxidative stress may be an important factor
associated with their pathophysiology.
In particular, Gawryluk and colleagues have
shown that levels of reduced, oxidized and total
glutathione were significantly decreased in the
post-mortem prefrontal cortex from MDD, BPD
and schizophrenia patients compared with con-
trols.[55] However, they found a significant reduc-
tion of GSH-Px levels in MDD and schizophrenia
patients, but not in BPD and more recently a re-
duction of glutathione S-transferase Mu isoform
level in MDD, schizophrenia and untreated BPD
patients, while BPD subjects treated with a mood
stabilizer showed no differences with respect to
controls.[56]
In a recent work it has been shown that during
acute mania increased oxidative stress correlates
with decreased levels of brain-derived neurotrophic
CNS Drugs 2012; 26 (6)
482
factor (BDNF).[57] Thus, changes in the oxidative
balance may affect the expression/folding and/or
secretion of neurotrophic factors. Activation of
pro-apoptotic pathways has been reported in BPD,
and the data described provides a new framework
for the investigation of changes in neuroplasti-
city, as well as cell endangerment related to mood
episodes. There have been reports of oxidative
stress in populations with obsessive-compulsive
This material is
disorder (OCD), including increased lipid perox-
idation,[58-61] decreased vitamin E, catalase, GSH-Px
and selenium, increased SOD, and changes in over-
all oxidative status.[62] Some of these alterations
have been linked to symptom severity.
the copyright of the
3. Antioxidants for the Treatment
of Depression
Since processes that cause oxidative stress are
original publisher.
involved in the pathogenesis of MDD, anti-
oxidant compounds have recently been evaluated
as co-adjuvants or as supportive care in combi-
nation with other therapeutic approaches. In-
Unauthorised copying
deed, considering that the conventional antide-
pressants have limited effectiveness and are often
inadequate for many individuals, especially for their
side effects, the discovery of new strategies and
compounds able to improve current therapies and
and distribution
the management of depression are needed.
Usually, the term ‘antioxidant’ refers to any
compound able to block or delay the reaction
of a substrate with molecular oxygen or reactive
oxygen or nitrogen species. A critical aspect re-
is prohibited.
lates to the concentration ratio between the oxi-
dizable substrate and the antioxidant compound.
By definition, a substance could be considered an
antioxidant only if it is able to significantly re-
duce or prevent oxidation of a substance[63] at
very low concentrations compared with those of
an oxidizable substrate. Recently, it was reported
that a compound is an effective antioxidant when
the concentration ratio of free radical : antioxidant
is at least 100 : 1, as a molar ratio.[64] In this way,
it is possible to detect effective compounds with
antioxidant activity able to efficiently quench re-
active species. Moreover, this definition has a
certain validity also in a biological context; how-
ever, the mechanisms by which a compound acts
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Scapagnini et al.
as an antioxidant are multiple and there is not a
universal system able to provide information
about the ‘true’ antioxidant power because the
validity of the term ‘antioxidant’ depends on the
environment of its action. In addition, there are
still gaps in our knowledge on these molecules
and their antioxidant activity and the results of
clinical trials are not totally convincing yet.
Moreover, it should be emphasized that oxidants
are not only harmful but they also play essential
roles in a range of physiological processes and not
all the compounds show a high scavenger effect
or good antioxidant properties. Furthermore, a
poor correlation between in vitro and in vivo an-
tioxidant properties of natural compounds has
been observed.[65]
Many dietary compounds with antioxidant
activity (e.g. ascorbic acid, vitamin E, carotenoids,
polyphenolics) are capable of counteracting the
negative effects of ROS. Moreover, several exam-
ples of phytochemicals with significant antioxidant
capacities and benefits are found in whole foods and
beverages (e.g. acai berry, gogi berry, green tea), as
well as in isolated substances sold primarily as
dietary supplements (e.g. ascorbic acid, lycopene,
selenium) or added to foods (e.g. vitamin E).
In a biological context, antioxidant compounds
protect against oxidative damage using four main
mechanisms: (i) preventing ROS formation by
sequestering transition metal ions into com-
plexes; (ii) scavenging or quenching free radicals
and other reactive species; (iii) breaking chain
reactions initiated by free radicals; and (iv) in-
ducing antioxidants and repair systems.
There are two general classes of antioxidants:
endogenous and exogenous. Among the endoge-
nous there are the tripeptide glutathione, various
vitamins, proteins and products of reactions catal-
ysed by a huge variety of enzymes that are upre-
gulated in response to oxidative stress (e.g. bilirubin
from heme oxygenase). Among the exogenous an-
tioxidants we can include elements such as selenium
or zinc, amino acids, vitamins, polyphenols and
other phytochemicals characterized by moieties
that increase endogenous levels of glutathione or
have reactive sulfhydryl group functionalities.
Significantly, antioxidants such as ascorbic
acid, a-tocopherol and b-carotene have been in-
CNS Drugs 2012; 26 (6)
Antioxidants as Antidepressants 483

vestigated in animal experiments as radical scav-
engers for the prevention of oxidative damage to
the cellular membrane or to the DNA in the CNS.
In addition, vitamin E and ascorbic acid can en-
hance learning and memory and prevent memory
deficits in pathological conditions such as Alz-
heimer’s disease, aging and aminoacidopathies.
3.1 Trace Elements
Beck Depression Inventory of healthy young
adults,[74] an indication of mood improvement.
Other parameters reduced by ascorbic acid were
blood pressure, subjective stress and state of
anxiety response to an acute interpersonal psy-
chological stressor. Finally, the vitamin was also
associated with a faster recovery in the produc-
tion of salivary cortisol after the stressor.[75] Re-
cently, the behavioural activity of ascorbic acid

This material is
Zinc and selenium are not real antioxidants,
but from a nutritional perspective they are often
considered essentials for redox homeostasis. Many
has been evaluated in an animal model of depres-
sion. Ascorbic acid given systemically or centrally
has been shown to produce an antidepressant-
like effect in the tail suspension test (TST). In
epidemiological studies have examined the asso-
addition, in the same report the authors showed

the copyright of the

ciation of low zinc status with depression.[66] In
animal models, dietary zinc deficiency has been
proven to elicit cognitive dysfunction, neuropsycho-
logical symptoms and depressive-like behaviours,[67]
that ascorbic acid was able to potentiate the ac-
tion of conventional antidepressants in the pre-
dictive test of antidepressant action, reinforcing
the idea that this vitamin has antidepressant prop-
and pre-clinical studies suggest a potential role
erties.[76] Ascorbic acid and vitamin E have also

original publisher.
of zinc in reducing or preventing depressive
symptoms.[68]
Selenium is a potent protective agent for neu-
rons through the expression of selenoproteins.
been evaluated on the effects elicited by chronic
variable stress in the Morris water maze test in
rats, a proposed animal model of depression.
Treatment with vitamin E (40 mg/kg) and ascorbic
Several studies suggest that low selenium status

Unauthorised copying
acid (100 mg/kg) during the period of stress was able
is associated with depressed mood, anxiety and
to prevent the impairment observed in the acquisi-
cognitive decline, and high dietary or supplemen-
tion phase of the task, but did not have any effect in
tary selenium seems to improve mood.[69] How-
the impairment observed in the retention test.[77]
ever, clinical trials on the effect of zinc and selenium
a-Tocopherol, the most active and abundant
supplementation in MDD are limited and do not

and distribution
provide conclusive evidence.[70]

3.2 Vitamins
form of vitamin E in human plasma, has been
recently evaluated in an animal model of depres-
sion. Acute oral treatment with a-tocopherol (30
and 100 mg/kg), or with a-tocopheryl phosphate,
Ascorbic acid is highly concentrated in the a water-soluble analogue of vitamin E, was able

is prohibited.
CNS and despite its fine regulation at brain level
the physiological role of this compound in the
CNS is not well established even if some neuro-
modulatory properties have been proposed.[71]
A role for ascorbic acid in mood disorders was
initially suggested by the evidence that its plasma
levels were decreased in depressed patients and by
other studies that have shown that depressive
symptoms are present in scurvy disease.[72] Pre-
vious clinical findings noticed that treatment with
this vitamin (50 mg/kg/day intravenously) for
2 weeks was able to relieve depressive symptoms
in depressed patients.[73] Furthermore, it was re-
ported that the administration of ascorbic acid
for 14 days (3000 mg/day) decreased scores in a
to significantly reduce the immobility time in the
forced swimming test (FST) and in the TST.[78]
Additionally, long-term treatment (28 days) with
a-tocopherol (10 mg/kg) increased glutathione
levels, GSH-Px and glutathione reductase ac-
tivity in the hippocampus and in the prefrontal
cortex, reduced the immobility time in the FST
and potentiated the effect of fluoxetine (10 mg/kg)
in the same model.[78]
3.3 Carotenoids
The six major dietary carotenoids (a-carotene,
b-carotene, b-cryptoxanthin, lutein, zeaxanthin
and lycopene) comprise an important component

Adis ª 2012 Springer International Publishing AG. All rights reserved. CNS Drugs 2012; 26 (6)
484
of the antioxidant defence system in humans, and
are considered a good indicator of fruit and veg-
etable intake. The antioxidant activity of carot-
enoids is largely due to the extended system of
conjugated double bonds. Carotenoids can be
efficient quenchers of singlet oxygen species and
can directly scavenge free radicals.
The cross-sectional and longitudinal relation-
ship between plasma carotenoids and depressive
This material is
symptoms has been recently assessed over a 6-year
follow-up in 661 older persons, part of the In-
CHIANTI (Invecchiare in Chianti, aging in the
Chianti area) study, a prospective, population-
based study of older persons in Tuscany, Italy.[79]
the copyright of the
Depressive behaviour was evaluated using the
Center for Epidemiological Studies-Depression
scale (CES-D).[80] Higher total plasma carotenoid
(per standard deviation increase) concentrations
were associated with a lower probability (odds
original publisher.
ratios [OR] = 0.82; 95% CI 0.68, 0.99; p = 0.04)
of depressed mood at baseline after adjustment
for age, sex, antidepressants use, body mass
index (BMI), physical activity, number of chronic
Unauthorised copying
diseases, disability and inflammatory markers.
Estimated ORs for participants in the lowest
carotenoid quartile, compared with those in the
highest quartile, were 1.72 (95% CI 1.05, 2.83;
p = 0.03) after full adjustment for confounders.
and distribution
After the exclusion of participants with baseline
depressed mood and use of antidepressants, higher
total carotenoid level was associated with lower
risk of incident depressed mood (OR = 0.72; 95%
CI 0.52, 0.99; p = 0.04) at 6-year follow-up, after
is prohibited.
adjustment for confounders plus baseline CES-
D. The study did not measure any biomarker of
oxidative damage, but has found evidence that
inflammatory markers, in particular blood levels
of IL-1 receptor antagonist, partially mediated
the relationship between carotenoid concentra-
tions and development of depressed mood after
6 years.[79]
3.4 N-Acetyl-Cysteine
N-Acetyl-cysteine (NAC) is a thiol compound
that, by providing sulfhydryl groups, can act as
a direct ROS scavenger, particularly effective for
the reduction of the hydroxyl radical, OH and
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Scapagnini et al.
hypochlorous acid.[81] In clinical practice, besides
its well known and efficient mucolytic action, it
has been used as a precursor to glutathione in the
treatment of paracetamol (acetaminophen) over-
dose for more than 30 years. Glutathione is a
water soluble tripeptide (g-L glutamylcysteinylgly-
cine) mainly present inside cells and is the primary
endogenous antioxidant in the brain. NAC pro-
vides cysteine for glutathione production and its
oral administration results in increased plasma
cysteine levels, ultimately leading to increases in
plasma glutathione.[82] NAC crosses the blood
brain barrier, and efficiently replenishes brain
glutathione in rats that received 2-cyclohexene-1-
one (75 mg/kg), a compound that induces a sig-
nificant depletion of glutathione levels in the
striatum and frontal cortex.[83] Previous works
have shown the ability of NAC to protect the brain
against markers of oxidative stress in rat models
of neurodegeneration.[84] Proteomics analyses
have recently shown that in an Alzheimer’s dis-
ease mouse model, treatment with NAC (2 mg/kg
bodyweight) for a period of 5 months, was ben-
eficial for influencing the levels of energy- and
mitochondria-related proteins.[85] NAC additionally
promotes neuronal differentiation of mouse em-
bryonic stem cells, and has been shown to enhance
the extension of neuritogenesis.[86] NAC has been
also shown to modulate, through cystine-glutamate
antiporter, both glutamate levels and release of
dopamine.[87] NAC is also endowed with anti-
inflammatory properties that are linked to oxi-
dative pathways, being able to reduce IL-1b, IL-6
and TNFa in different rat brain injury models.[88]
There is a growing body of literature exploring
the use of NAC in the treatment of psychiatric
illness. NAC shows antidepressant effects in the
FST, the benchmark screening test for antide-
pressant properties.[89] Provisional evidence of
the potential benefit of NAC in a wide range of
disorders has been reported, including a large
clinical trial of schizophrenia[90] and small-scale
clinical studies in OCD[91] and compulsive and
grooming disorders,[92] pathological gambling[93]
and cocaine dependence.[94] A double-blind, ran-
domized, placebo-controlled trial with NAC
2000 mg/day was conducted for 6 months on 75

participants with either bipolar I or II disorder.
CNS Drugs 2012; 26 (6)
Antioxidants as Antidepressants
Rating scores on the Montgomery-Åsberg De-
pression Rating Scale (MADRS) and the Bipolar
Depression Rating Scale showed large decreases
in depressive symptoms (about 9 points on the
MADRS between NAC and placebo groups at
the endpoint).[95] A subsequent report evaluated
from the same trial a subset of patients with bi-
polar II disorder, a condition where depressive
symptoms are the major hallmark, reinforcing the
This material is
significant effects of NAC on MDD.[96] A more
recent study investigated the efficacy of ad-
junctive NAC (1 g twice daily) as a maintenance
treatment for depression episodes in BPD in the
initial open-label phase of a randomized, double-
the copyright of the
blind, placebo-controlled, maintenance trial (149
patients). Open-label data demonstrate a robust
decrement in depression scores and improve-
ments in functioning and quality of life with NAC
treatment.[97]
original publisher.
3.5 Polyphenols
In recent years, there has been a growing interest,
Unauthorised copying
supported by a large number of experimental and
epidemiological studies, in the beneficial effects
of some commonly used food-derived products in
preventing various age-related pathological con-
ditions, including depression. Spices and herbs
and distribution
often contain active phenolic substances endowed
with potent antioxidative and chemopreventive
properties and a series of works focused on spe-
cific neuroprotective effects of some of those
polyphenols[98] and their potential roles against
is prohibited.
depressive symptoms.
Polyphenols are secondary metabolites pro-
duced by plants in order to interact with their en-
vironment. It is generally assumed that the phenol
moiety is responsible for the antioxidant proper-
ties of any plant phenolic compound because it is
able to scavenge free radicals or bind pro-oxidant
metal ions by means of their OH groups. More-
over, some of these compounds have been re-
ported to specifically activate cellular antioxidant
pathways, such as phase II enzymes, and to have
anti-inflammatory activities.[99]
Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-
1,6-heptadiene-3,5-dione) from the rhizome of
Curcuma longa is a colouring agent and a food
Adis ª 2012 Springer International Publishing AG. All rights reserved.
485
additive commonly used in Indian culinary
and traditional medical preparations from time
immemorial.[99]
It is a polyphenolic substance that has the
potential to inhibit lipid peroxidation and to ef-
fectively intercept and neutralize ROS[100] and
NO-based free radicals.[101] In this regard, cur-
cumin has been demonstrated to be more potent
than vitamin E. The free radical chemistry of
curcumin is focused on the redox peculiarities
of its phenol ring, and the possible involvement of
the b-diketone moiety in the antioxidant action of
curcumin has been considered.[102,103]
Beyond its ROS quencher activity, curcumin
effects have been mostly associated with its abil-
ity to interfere at a molecular level with numerous
cellular pathways. Its anti-inflammatory properties
and cancer-preventive activities have been con-
sistently reported using in vitro and in vivo models
of tumour initiation and promotion.[104] Of par-
ticular interest is the ability of curcumin to in-
hibit cyclo-oxygenase (COX)-1 and COX-2[105]
enzymes and to reduce the activation of nucleus
transcription factor-kb (NF-kb).[106] Curcumin
has been demonstrated to stimulate the mitogen-
activated protein kinase pathway (MAPK) and
to activate heterodimers of NF-E2-related fac-
tors 2 (Nrf2), leading to induction of the antioxi-
dant responsive element (ARE) activated reporter
genes.[107] Nrf2, a member of the Cap ‘n’ Collar
family of transcription factors, is sequestered in
the cytoplasm by binding to protein Keap1 in
nonstimulated conditions.[99] However, several
stimuli, including oxidative stress, lead to the dis-
ruption of this complex, freeing Nrf2 for translo-
cation to the nucleus and dimerization with basic
leucine zipper transcription factors such as Maf
and Jun family members.[99] In this pathway
(ARE/Nrf2), curcumin and other similar poly-
phenols strongly induce the expression of cellular
stress response genes (phase II detoxification en-
zymes and heme oxygenase-1), resulting in cell
protection and enhancing cell survival.[99]
The involvement of curcumin in restoring cel-
lular homeostasis and rebalancing redox equili-
brium by the activation of defensive genes, and its
ability to establish an effective neuroprotection
suggests that it might be a useful adjunct also in
CNS Drugs 2012; 26 (6)
486
MDD treatment. Interestingly, curcumin possesses
both MAO-A- and MAO-B-inhibiting proper-
ties and was shown to modulate the levels of nor-
adrenaline, dopamine and serotonin in the brain.[108]
The antidepressant effects of curcumin have
been explored in various animal models of be-
havioural despair. Curcumin has been found to
attenuate various behavioural and biochemical
alterations induced by chronic fatigue, which rep-
This material is
resents one of the core symptoms of MDD. In one
of the studies, animals exposed to chronic fa-
tigue demonstrated an increase in the immobility
period in the FST, which was reversed by daily
administration of curcumin (5–60 mg/kg).[109]
the copyright of the
Furthermore, curcumin attenuated various pa-
rameters of oxidative stress, such as enhanced
lipid peroxidation, nitrite and TNFa, and reduced
glutathione levels in chronic fatigue models,[104]
thus showing the antioxidant property.
original publisher.
Curcumin has the ability to regulate the levels
of BDNF.[110] At a dose range of 10–20 mg/kg
curcumin enhanced hippocampal neurogenesis in
stressed animals in a manner comparable with
Unauthorised copying
the tricyclic antidepressant imipramine.[110] The
exact mechanism of curcumin’s neuroregenerative
ability is not clear, but it has been hypothesized
that curcumin prevents stress-induced decrease in
serotonin 5-HT1A, mRNA and BDNF protein
and distribution
levels in the hippocampus.[110] Furthermore, curcu-
min reversed chronic stress-induced reduction in
BDNF protein levels.[111] Chronically stressed
rats exhibited a significant increase in the im-
mobility period compared with control animals
is prohibited.
in a forced swim test. This immobility period was
reversed by daily administration of curcumin (20
and 40 mg/kg).[112] Finally, piperine potentiated
the antidepressant-like effect of curcumin in this
test model. Also, chronic stress for 21 days increased
the activity of MAO enzymes, resulting in the
depletion of the neurotransmitter levels. Inter-
estingly, this enhanced MAO activity was brought
back to normal by curcumin treatment.[112] Lastly, it
was tested that chronic unpredictable stress depleted
the levels of noradrenaline, serotonin and dopa-
mine in the whole brain. Chronic administra-
tion of curcumin normalized the depleted levels
of serotonin and dopamine without affecting
noradrenaline.[112]
Adis ª 2012 Springer International Publishing AG. All rights reserved.
Scapagnini et al.
Taking into account that the serotonergic sys-
tem in the pathogenesis of MDD is an important
target for the conventional pharmacotherapy, a
recent study with ferulic acid, a phenolic com-
pound close to curcumin, showed in a widely ac-
cepted predictive mouse model of depression that
this phytochemical exerts antidepressant-like ef-
fects through an interaction with NMDA receptors,
influencing serotonergic neurotransmission.[113]
Epigallocatechin-3-gallate, the major constituent
of green tea, has been shown to ameliorate be-
havioural deficits in a rat model of chronic fa-
tigue syndrome, by the attenuation of oxidative
stress and TNFa production.[114] Recent research
has also shown that green tea polyphenols exert
antidepressant-like effects in a mouse behavioural
model of depression, by reducing serum cortico-
sterone and adrenocorticotropic hormone (ACTH)
levels in mice exposed to FST.[115]
Rojas and co-workers demonstrated the anti-
depressant-like effect of EGb761, a mixture of
antioxidant phytochemicals from Ginkgo biloba
leaves, in an animal model. The mechanism of
this effect was proposed to be activation of the
serotonergic and dopaminergic systems in the
cortex.[116]
4. Conclusion
Antioxidant treatment may provide synergis-
tic antidepressant-like effects when administered
with conventional antidepressants. Although such
strategies have been tested in the hope of leading
to new therapeutic options, further investigation
of the efficacy of antioxidant treatment in de-
pression is needed, especially using double-blind,
randomized, placebo-controlled studies.
Oxidative stress in MDD subjects raises the
possibility that these individuals are more sensi-
tive to cytotoxic stimuli or have a compromised
ability to recover from oxidative damage. How-
ever, many questions remain to be answered,
especially as the studies investigating the oxida-
tive and antioxidative systems in MDD are lim-
ited and have provided little evidence about the
effects of antidepressants on these systems. We
need a better understanding of the role played by
antioxidant substances in the CNS, specifically
CNS Drugs 2012; 26 (6)
Antioxidants as Antidepressants
their functions as neuromodulators and their
antidepressant properties.
There are multiple pathways that are involved
in the pathogenesis of MDD. The antioxidant
compounds represent an attractive strategy for
MDD management. However, it is crucial to
point out that numerous antioxidant compounds
are involved in different pathways that have
an effect on mood control and mental state. Ac-
This material is
cordingly, even though these substances could
be effective on the treatment of MDD, further
investigations are needed to establish their sec-
ondary effect and their precise mechanism of
action.
the copyright of the
In summary, even though antioxidant treatment
for MDD is still in its infancy, current evidence
suggests some beneficial value of various anti-
oxidants in MDD. Moreover, the main categories
of drugs used to treat MDD have been demon-
original publisher.
strated to exert effects on energy and monoamine
metabolism, as well as on inflammation. It is
therefore possible to be optimistic that the use of
antioxidant substances, which are able to affect
Unauthorised copying
these pathways, might be a useful co-adjuvant treat-
ment in MDD, providing a novel clinical angle to
augment the effectiveness of conventional treat-
ments. However, the therapeutic potential of
such compounds to treat MDD requires further
and distribution
investigation.
Acknowledgements
No sources of funding were received for the preparation of
is prohibited.
this manuscript. The authors have no conflicts of interest that
are directly relevant to the content of this article.
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Correspondence: Dr Giovanni Scapagnini, Department of
Health Sciences, University of Molise, Campobasso, Via De
Sanctis s.n.c., Italy.
E-mail: g.scapagnini@gmail.com
CNS Drugs 2012; 26 (6)