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Oxidative Stress in Depression 103
Piotr Gałecki
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2370
Mechanisms of O & NS in MDR and Disturbances in Pro- and
Antioxidant Equilibrium . . . .................................................................... 2371
Neurotransmitter System Abnormalities/Neurotransmitter System Abnormalities and
Free Radical Generation . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2371
Immune Cells- and Inflammatory Molecules-Related O & NS/Immune Cells and
Inflammatory Molecules as a Source of Free Radicals ................................... 2373
Mitochondrial Dysfunction and Oxidant Overproduction ................................ 2374
Markers of O & NS in Depression . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2375
Lipid Peroxidation/Lipids Damage as a Sign of Oxidants . . .............................. 2375
Antioxidant System Imbalance . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2376
Antidepressants, O & NS, and Pro- and Antioxidant Equilibrium . . . . ....................... 2377
Selective Serotonin Reuptake Inhibitors and Free Radicals and Antioxidant ........... 2377
Pro- and Antioxidant Equilibrium and Antidepressants Other than SSRI ............... 2379
Antidepressants and Anti-Inflammatory Drugs in Depressive Treatment and Reduction
of O & NS ...................................................................................... 2380
Mechanism of Antidepressants . . . . . . . . . . . . . . . . .. . . ........................................ 2380
Efficiency of Anti-Inflammatory Molecules . . . ........................................... 2382
Molecules of Antioxidant Properties in Depression Treatment .............................. 2384
Biological and Natural Antioxidants . . . ................................................... 2384
Polyunsaturated Fatty Acids . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 2385
Data to Discuss . . . .......................................................................... 2386
Conclusion . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2387
References ...................................................................................... 2388
P. Gałecki
Department of Adult Psychiatry, Medical University of Ło
´dz
´,Ło
´dz
´, Poland
e-mail: galeckipiotr@wp.pl;piotr.galecki@umed.lodz.pl
I. Laher (ed.), Systems Biology of Free Radicals and Antioxidants,
DOI 10.1007/978-3-642-30018-9_190, #Springer-Verlag Berlin Heidelberg 2014
2369
Abstract
Depressive disorders, especially major recurrent depression (MRD), are among
the most common psychiatric diseases and are expected to become the second
most common form of psychiatric illness by the year 2020. The mechanisms
responsible for the development of depression have been discussed widely, and
evidence suggests heterogenic and mixed etiologies for the disease.
Depressive disorder is characterized by inflammatory processes, oxidative
and nitrosative stress (O&NS), and disturbances in the pro- and antioxidant
equilibrium. Patients diagnosed with major depressive disorder (MDD) using
DSM-IV criteria and patients diagnosed with recurrent depressive disorder
according to the ICD-10 criteria as well as individuals who suffer with major
depression meeting other scale display a decrease in the levels of total glutathi-
one, uric acid, and ascorbic acid, a decrease in the levels of glutathione perox-
idase (GPX), an increase in malondialdehyde (MDA) levels, high free radical
generation, an increase in 8-hydroxy-deoxyguanosine, and an increase in nitrite
and nitrate levels. Antidepressants affect pro- and antioxidant equilibrium and
are able to reduce O&NS and inflammation. The involvement of inflammation
and O&NS in depression, as well as a 70 % effectiveness in the treatment of
MRD with antidepressants, and the anti-inflammatory activity of antidepressants
all suggest the coadministration of antidepressants and anti-inflammatory drugs.
Clinically, novel approaches to reduce free radical production are needed to
improve the therapeutic strategies that target O&NS.
Keywords
Antioxidant • Inflammation • Major recurrent depression • Oxidative and
nitrosative stress
Introduction
Depressive disorders, especially major recurrent depression (MRD), are among the
most common psychiatric diseases and are expected to become the second most
common form of psychiatric illness by the year 2020 (Gelenberg 2010). The
mechanisms responsible for the development of depression have been discussed
widely, and evidence suggests heterogenic and mixed etiologies for the disease.
A large number of different studies have proposed hypotheses for the develop-
ment of depression. These hypotheses include the following:
– The monoamine theory of depression, with its modifications (Farvolden et al. 2003).
– The hypothesis of disturbed neuroplasticity (Christoffel et al. 2011).
– The inflammatory, oxidative, and nitrosative stress (O&NS) theory of depression
(Leonard and Maes 2012). Data suggest that depression is associated with
possible increases in the numbers and activity of macrophages/monocytes and
with immunocompetent phagocytic cells in the brain (McNally et al. 2008; Maes
2011), producing free radicals (Maes 2011).
2370 P. Gałecki
In addition, depression may be associated with disturbances in melatonin
levels, thyroid hormone levels, and many others (Beck-Friis et al. 1985;
Fountoulakis et al. 2006).
Low physiological levels of free radicals and their derivatives play a role in
various processes. Nevertheless, overproduction of free radicals and disturbances in
the pro- and antioxidant equilibrium result in harmful processes involved in many
diseases (Valko et al. 2007). One of the processes widely known for underlying
many diseases is known as O&NS. The overproduction of free radicals has been
widely investigated in depressive disorders, including MRD. Changes and distur-
bances in pro- and antioxidant equilibrium influence the development, course, and
management of depression.
Evidence suggesting and confirming a role for O&NS and for abnormalities in
pro- and antioxidant equilibrium in depression includes a decrease in the levels of
total glutathione, uric acid, and ascorbic acid, a decrease in the levels of glutathione
peroxidase (GPX), an increase in malondialdehyde (MDA) levels, high free radical
generation, an increase in 8-hydroxy-deoxyguanosine, and an increase in nitrite and
nitrate levels (Suzuki et al. 2001; Khanzode et al. 2003; Pedreanez et al. 2006; Maes
et al. 2009; Galecki et al. 2009a; Gawryluk et al. 2011).
Mechanisms of O & NS in MDR and Disturbances in Pro- and
Antioxidant Equilibrium
Reactive oxygen species (ROS), reactive nitrogen species (RNS), other free radi-
cals, and their related molecules are produced during many physiological and
pathological processes taking place in different brain regions and in the periphery
(Valko et al. 2007).
Neurotransmitter System Abnormalities/Neurotransmitter System
Abnormalities and Free Radical Generation
The monoamine theory of depression is widely known. In addition to their
physiological role in brain function, monoamines are also important free radical
scavengers, and a lack of monoamines might result in an increase in O&NS (Liu
and Mori 1993). Serotonin (5HT), the most important of the monoamines/
neurotransmitters involved in depression pathology, is decreased in
depression-related brain regions during depressive episodes and is one of the
important free radical scavengers. The molecule is easily oxidized in the pres-
ence of peroxidase and hydrogen peroxide (H
2
O
2
) and during respiratory burst.
Studies in animal models have found that 5HT is able to scavenge free radicals
produced by microglia cells during oxygen burst (Huertha et al. 1997). It should
also be emphasized that the product of oxidized 5HT is not cytotoxic and that it
may participate in the protection of central nervous system (CNS) cells (Huertha
et al. 1997). A lack of 5HT in the brain may increase oxidative stress.
103 Oxidative Stress in Depression 2371
Tryptophan, the precursor of 5HT synthesis, is also an essential substrate for the
synthesis of melatonin, one of the important antioxidants. Studies suggest that
“low melatonin syndrome,” namely, a low overall melatonin level, may consti-
tute a biological marker for depression (Beck-Friis et al. 1985). Low levels of
melatonin may also be one of the sources of oxidative stress in depression, as the
molecule possesses antioxidant and anti-inflammatory properties (Tan et al.
2007;Maurizetal.2012).
Monoamine oxidase A and B (MAO-A,B) might also be involved in pro- and
antioxidant equilibrium disturbances, as neuronal and glia mitochondrial mem-
brane levels of these enzymes are increased in depression (To et al. 2005). The
by-products of MAO-mediated reactions include several chemical species with
neurotoxic potential, such as H
2
O
2
, ammonia, and aldehydes. As a consequence,
it is widely speculated that prolonged excess activity of these enzymes may be
conducive to oxidative stress, as well as mitochondrial and cell damage (Halliwell
2006; Bortolato et al. 2008).
One of the most typical biological changes in neurotransmitter function observed
in depressive disorders is the increased activity of the glutamate system, which is
now widely investigated in depression (Hashimoto 2009). The CNS consists of two
major cells types: neurons and glial cells. Glial cells include astrocytes and
microglia. Higher glutamate system activity is related to inflammatory pathways
characteristic to the course of depression and to lesser-known tryptophan metabo-
lism pathways via the kynurenine pathway. Activated microglia and astrocytes
convert the metabolism of tryptophan into kynurenic acid, picolinic acid, and
quinolic acid, which are all important N-methyl-D-aspartate (NMDA) receptor
agonists that are able to directly induce glutamate release. In addition, during the
formation of picolinic and quinolic acid free radicals, 3-hydroksykynurenine and 3-
hydroxyanthraline are also produced. The aforementioned acids induce inducible
nitric oxide synthase (iNOS) to produce nitric oxide. Moreover, interaction between
these acids and 3-hydroksykynurenine and 3-hydroxyanthraline results in increased
lipid peroxidation and affects activation of the arachidonic acid pathway by the
induction of cyclooxygenase (COX) and 5-lopoxygenase (5-LOX) pro-influx
inflammatory enzymes (McNally et al. 2009; Oxenkrug et al. 2010).
Excessive activation of the glutamate system is known as excitotoxicity. One of
the typical features of excitotoxicity is the induction of O&NS. Classic studies
confirming the involvement of glutamate system were conducted by Sengpiel et al.
(1998) and described by Hashimoto (2009). The mechanism of glutamate-related
increases in free radicals is associated with an increased activity of the glutamate
system that is followed by the influx of calcium ions into cells. An overproduction
of free radicals observed as a consequence of glutamate activity is named “gluta-
mate neurotoxicity.” In general, the mechanisms of glutamate neurotoxicity are
related to an overload of calcium ions and a massive influx from extracellular
compartments as well as a release from intracellular stores (Atlante et al. 2001).
Mechanisms leading to the overproduction of free radicals include also reactions
catalyzed by xanthine oxidase (XOD). Calcium ions induce the conversion of
xanthine dehydrogenase (XDH) into XOD, thus allowing for the production of
2372 P. Gałecki
H
2
O
2
and superoxide radical (O
2
). The possible involvement of XOD in free
radical formation in brain areas is suggested by the presence of XOD activity in
nerve cells (Atlante et al. 2001). A second mechanism influencing free radical
production involves the activation of nitric oxide synthase (NOS) and phospholi-
pase A2 (PLA2) by calcium ion influx (Ciani et al. 1996).
Immune Cells- and Inflammatory Molecules-Related O & NS/Immune
Cells and Inflammatory Molecules as a Source of Free Radicals
Multiple lines of evidence suggest that the activity of brain inflammatory cells, as
well as the infiltration of peripheral cells into CNS, is related to depression, at least
in some groups of patients (Leonard et al. 2006; McNally et al. 2009). Both types of
aforementioned cells are important sources of free radicals. Activation of these
cells enhances the release of O
2
, NO, products of NADPH oxidase during
phagocytic burst, and inducible nitric oxide synthase (iNOS) (Guzik et al. 2003;
Wilkinson and Landreth 2006).
In immune cells and neurons, iNOS is an inducible form expressed after stim-
ulation with proinflammatory cytokines or lipopolysaccharide (LPS) (Aktan 2004).
Evidence suggests this enzyme is linked in depression etiology with the following:
increased levels of iNOS-derived NO in patients (Suzuki et al. 2001), increased
iNOS expression in the hippocampus and cortex following stress (Olivenza et al.
2000), increased expression of genes encoding iNOS in the peripheral blood cells of
depressed patients (Gałecki et al. 2012), and reduction of depressive-like behavior
after inhibition of iNOS (Wang et al. 2008).
Activated cells of the immune system express enzymes that catalyze the
production of free radical derivatives. One such enzyme is myeloperoxidase
(MPO) (Nauseef 2001; Yap et al. 2007). Activation of this enzyme results in the
production of hypochlorous acid and other toxic oxidants (Winterbourn 2002).
Following an increase in gene expression coding for encoding MPO, increased
protein levels are observed in the peripheral cells of depressive patients
(Vaccarino et al. 2008;Gałeckietal.2012). Cyclooxygenase -2 (COX-2),
which produces prostaglandin from arachidonic acid and produces O
2
as
a by-product of the reaction, stimulates glutamate release and has been found
to be highly expressed in depression (Dubois et al. 1998; Balboa and Balsinde
2006; Vesce et al. 2007). Similarly to MPO, higher gene expression for COX-2
in peripheral cells (Gałecki et al. 2012) leads to increased concentrations of
prostaglandin E
2
in the cerebrospinal fluid and saliva of patients (M€
uller and
Schwarz 2007). As the by-product of this reaction, O
2
is increased, and the
generation of free radicals is possible. The role of COX-2 in depression has been
demonstrated in animal studies which estimate high levels of cortical and
hippocampal expression (M€
uller et al. 2006; Guo et al. 2009).
Recent evidence also suggests that there is increased expression of the secretory
phospholipase A2 type II in depressed patients (Gałecki et al. 2012). This enzyme
103 Oxidative Stress in Depression 2373
belongs to a molecular group that is another important source of free radicals
(Adibhatla and Hatcher 2008). Figure 103.1 demonstrates possible inflammatory –
related mechanism leading to increase in O&NS in depression.
Mitochondrial Dysfunction and Oxidant Overproduction
Several investigators have proposed that mitochondrial dysfunction is related to the
pathophysiology of MRD (Rezin et al. 2009). The main role of mitochondria,
cytoplasmic organelle, is as a producer of energy, a process that generates high
levels of reactive oxygen species. An important site where oxidants may be
produced is the mitochondrial electron transport chain, where O
2
is reduced to
H
2
O. Nevertheless, the mitochondrial electron transport chain does not work
perfectly and results in the production of O
2
. Recently, mitochondria were
identified as a source of the NO
.
synthesized by mitochondrial nitric oxide synthase
(mtNOS) (Altante et al. 2001; Sas et al. 2007). Studies have examined if there is an
association between depressive disorder and an increase in the production of
oxidants by mitochondria. An experiment by Lucca et al. (2009) found an increase
Bacterial and viral
infection
Chronic psychological / biological
stress
Activation peripheral
and brain immune cells
HPA axis -
disequilibrium
DEPRESSIVE DISORDER
↑COX-2; ↑iNOS; ↑MPO;
↑NAD(P)H oxidase
↑ROS; ↑RNS; ↑other oxidants
and
proinflammatory cytokines
Lipids; protein; DNA and cell
damage / death
Lower antioxidant capacity
and antioxidant protection
Kynurenine pathway =
↑TRYCATS and ↓5HT;
↓DA;↓NA; ↓MT
Glutamate / glutaminergic
excitotoxicity
Fig. 103.1 Outline of possible immune-related mechanism leading to O&NS in depressive
disorder. COX-2 cyclooxygenase2, iNOS inducible nitric oxide synthase, MPO mieloperoxidase,
NAD(P)H reduced nicotinamide adenine dinucleotide phosphate, ROS reactive oxygen species,
RNS reactive nitric species, TRYCATS trypophan catabolites, 5HT serotonine, DA dopamine, NA
noradrenaline, MT melatonine, "# denominator that are increased/decreased in depressive disorder
2374 P. Gałecki
in the production of O
2
in the hippocampus and prefrontal cortices of rats
undergoing unpredictable chronic mild stress (UCMS), an animal model of depres-
sion. As mitochondria are an important source of O
2
, it should be emphasized that
one of the causes of these high levels of O
2
may be that patients suffering from
depressive disorders are characterized by a mutant variant of the gene coding for
manganese superoxide dismutase (MnSOD), resulting in the lower activity of the
enzyme (Galecki et al. 2009a).
As previously mentioned, an important marker for depression is the increased
number and activity of immune phagocytic cells observed in the periphery and in
CNS. It is widely known that phagocytic cells are major sources of different
oxidants, including O
2
, NO, H
2
O
2
, and HOCl. Depressive disorder is character-
ized by increased activity and levels of immune cells, including the following:
monocytes, macrophages, and lymphocytes. These cells are an important source of
free radicals in the periphery. Higher activity of these cells may explain the
appearance of O&NS in depressed patients. A link between O&NS pathways has
been found in anxiety, which is often a hallmark of depression and a prodromal
factor for disease diagnosis. Animal models suggest that anxiety is accompanied by
significantly high levels of intracellular free radicals in immune cells in peripheral
blood (Bouayed et al. 2009).
Markers of O & NS in Depression
Oxidants are harmful to lipids, proteins, and nucleic acids and may result in cell
death. One of the signs of an overproduction of free radicals is an abundance of lipid
peroxidation, a marker for oxidant activity.
Lipid Peroxidation/Lipids Damage as a Sign of Oxidants
Many studies have investigated lipid peroxidation in depression, observing high
levels of the process, as measured by MDA and 4-hydroxy-2-nonenal in the plasma
of depressed patients (Selley et al. 2004; Galecki et al. 2009a). Tsuboi et al. (2006)
determined that increased plasma levels of MDA correlated with depressive symp-
toms in job-stressed patients. The results extending knowledge about depression
and oxidative damage to lipids and to increases in lipid peroxidation were
conducted by Yager et al. (2010). The authors measured serum level of F-(2a)-
isoprostanes (8-iso-PGF(2a)), a new biological marker of lipid damage. Depressed
patients had significantly higher levels of 8-iso-PGF(2a) compared with matched
healthy controls. Nevertheless, there was no significant relationship between clin-
ical data measured with the Hamilton Depression Rating Scale (HDRS) and the
investigated molecules. Higher plasma concentrations of 8-iso-PGF(2a) were
found in patients with geriatric depression, and the levels of prostaglandins were
correlated with interleukin-6 (IL-6) concentrations (Dimopoulos et al. 2008). Such
103 Oxidative Stress in Depression 2375
results confirmed the involvement of inflammation in the induction of oxidative
stress in depression, as the activity of immune system results in an increase in free
radical production.
High levels of lipid peroxidation, high NO levels, and low levels of TAS
correlate with different depressive symptoms, for example, with declarative and
working memory in depressive patients (Talarowska et al. 2012a,b,c).
Antioxidant System Imbalance
Disturbances in pro- and antioxidant equilibrium may include differences not only
in the gross levels of oxidative damage but also in the measured levels and activity
of entire antioxidant systems.
Q10 (CoQ10) is a strong antioxidant. Concentrations of CoQ10 in the plasma of
depressed patients are significantly lower than in the healthy controls. The lowest
plasma levels are found in patients suffering from treatment-resistant depression
and those with chronic fatigue syndrome (Maes et al. 2009a). Signs of O&NS,
measured as damage to DNA, are also found in the urine of patients with major
depression, especially in depressed patients with accompanying myalgic encepha-
lomyelitis and chronic fatigue syndrome. Levels of 8-hydroxy-deoguanosine sig-
nificantly correlated with the Fibromyalgia and CSF Rating (FF) scales (Maes et al.
2009b), and serum levels of 8-OHdG were higher in the depressed group. Subjects
with major depression had significantly higher levels of 8-OHdG and marginally
higher levels than those with less severe depression. Patients with recurrent depres-
sion were characterized by more oxidative damage than patients with single
episodes (Forlenza and Miller 2006). Women with depressive disorders may be
particularly vulnerable to the activity of the main oxidants. Women with depressive
disorders show decreased peripheral activity of GPX, decreased concentrations of
GSH, and increased concentrations of conjugated dienes (Kodydkova et al. 2009).
Increases in XO levels were found also in depressed patients (Herken et al. 2007).
Cancer patients are also particularly vulnerable to depressive disorders, which may
arise as oxidative damage inherent in the etiology of various cancers and result in
the development of depression in these patients. Nevertheless, there may not be
a causal relationship between cancer and depression. Wei et al. (2009a) measured
markers of pro- and antioxidant equilibrium in two groups of patients with colo-
rectal carcinoma. Their cutoff for the HDRS score was 20. The depressed group
consisted of 52 depressed patients. A second group did not meet the HDRS criteria
for depression. Serum total antioxidant capacity, catalase (CAT) activity, and
superoxide dismutase (SOD) activity were all lower in depressed patients, whereas
NO and MDA, and 8-hydroksy-deoguanosine levels were higher. Moreover, the
study observed a similar increase in the expression of genes involved in DNA-
damage signalling pathways. Increased gene expression was also observed for
oxoguanine glycosylase-1 in depressed patients with gastric (Wei et al. 2009b)
adenocarcinoma. Significant decreases in serum total antioxidant capacity SOD
concentration and increased concentrations of the reactive oxygen species NO and
2376 P. Gałecki
MDA, as well as increased expression of mRNA for hOGG1 encoding for
8-hydroksyguanine glycosylase 1, were all found in depressed leukemic patients
(Zhou et al. 2007). Based on this evidence, it seems that, whether the antioxidant
system is impaired in leukemic patients, oxidative stress seems to affect depression
development. Oxidative damage to nucleic acid RNA, as measured by the level of
8-hydroxy guanosine, was also observed in depression (Che et al. 2010) in the CA1,
CA3, and dentate gyrus of postmortem hippocampi. Depressed patients had lower
levels of GSH, GSH reductase glutamyl-cysteine ligase (GCL), and GPX in their
prefrontal cortices (Gawryluk et al. 2011). Evidence for oxidative stress and for
abnormalities in pro- and antioxidant equilibrium was also found by Michel et al.
(2007). Their postmortem study showed a significant increase in the concentration
of copper/zinc (Cu/Zn) SOD in the frontal cortex in patients with recurrent depres-
sive disorder. Animal models of depression detecting antidepressant drug efficacy
have also found increased generation of O
2
in the cerebrum and cerebellum of
forced-swim test (FST) rats (Pedreanez et al. 2006).
To obtain additional information about antioxidant defense in depressed
patients, some investigators examined the total antioxidant status. Gałecki et al.
(2009a) found that levels of TAS are characteristically low in depression. Reduc-
tions in the level of TAS are in agreement with the results of Lesgard et al. (2002),
who observed such decreases in patients undergoing stress, a typical predictor of
future depression. Depleted TAS was also correlated with other symptoms that are
themselves correlated with depression, such a chronic fatigue (Manuely Keenoy
et al. 2000). There have been several reports describing lower levels of single
antioxidants in depression. Maes et al. (2000) reported lower levels of vitamin E in
the serum of patients suffering from depression. Khanzode et al. (2003) showed
a decrease in vitamin C concentration in plasma in depression.
Antidepressants, O & NS, and Pro- and Antioxidant Equilibrium
The relationship between O&NS and depression provides background for recent
investigations into whether and to what extend antidepressants affect pro- and
antioxidant equilibrium. Studies have used animal models, in vitro imaging, post-
mortem materials, and clinical data.
Selective Serotonin Reuptake Inhibitors and Free Radicals and
Antioxidant
Selective serotonin reuptake inhibitors (SSRIs) appear to be the most widely
investigated group of antidepressants. Recently, a pilot investigation examined
the effects of sertraline on circulating markers of oxidative stress in depressed
patients with chronic heart failure. All depressed patients had significantly higher
levels of MDA compared with the healthy controls. Baseline levels of MDA and
other oxidative stress markers, such as protein carbonyls (PC), were the same in all
103 Oxidative Stress in Depression 2377
patients meeting criteria for depression. One group of depressed patients was
treated with 3 months of sertraline therapy. After therapy, a significant reduction
in MDA was observed, while depressed patients refusing treatment showed no
changes in MDA levels (Michalakeas et al. 2011). A protective role for sertraline
against 3-nitropropionic acid-impaired antioxidants was observed in the cortex and
hippocampus of the rat brain. Biochemical analyses revealed that sertraline treat-
ment for as little as 14 days significantly improved glutathione levels. This study
also suggests that the mechanism of the antioxidant action of sertraline is indepen-
dent of its known action on the serotonin system. Combinations of antagonists of
serotonin receptors with sertraline did not affect antioxidant effects of sertraline.
Sertraline was used in the treatment of patients diagnosed with fibromyalgia. These
patients were also characterized by higher serum levels of MDA (Kumar and
Kumar 2009).
Fluoxetine is regarded as the one of the most popular and widely used SSRIs.
Various biochemical studies, including those related to O&NS, have investigated
the effects of fluoxetine on markers of O&NS. One recent study using the UCSM
model of depression observed that fluoxetine influences and reduces oxidative
damage in the cerebral cortex and hippocampus of mice (Morreti et al. 2012).
Investigations of the oxidative status of peripheral blood leucocytes of mice that
underwent restraint stress, inducing disorders such as depression, showed that in
stress mice overproduce reactive species in peripheral defense cells. Fluoxetine
pharmacotherapy reverses the adverse effects of reactive species by improving
cellular oxidative status and by normalizing SOD and CAT activities (Novio
et al. 2011). Attenuation of oxidative stress following fluoxetine treatment was
observed in another animal model of depression and chronic restraint stress.
Chronic fluoxetine administration to stressed animals for 21 days prevented
restraint stress-induced oxidative damage, as evidenced by significant enhance-
ments of key endogenous antioxidant defense components, comprising the free
radical scavenging enzymes, SOD, CAT, glutathione S-transferase (GST), and GR,
as well as nonenzymatic antioxidants, GSH, glucose, and uric acid, which were
severely depleted by restraint stress in animals receiving no treatment. Oxidative
stress markers, (S)-lactate:NAD(+) oxidoreductase activity, MDA, and PC were
also significantly decreased following fluoxetine treatment (Zafir and Banu 2007).
FST was used to identify the antioxidant potential of antidepressants, including
fluoxetine in the brains of rodents. Significant recovery in the activities of SOD,
CAT, GST, GR, and GSH levels was observed with fluoxetine treatment.
In addition, MDA and PC contents were normalized by fluoxetine (Zafir et al.
2009). Another important role of fluoxetine as an inhibitor of oxidant production
was suggested when the drug was found to inhibit the activation of microglial cells,
one known source of free radicals (Chung et al. 2011). Fluoxetine-mediated sup-
pression of microglial activations was related to fluoxetine-mediated reductions in
NADPH oxidase activation and iNOS upregulation (Chung et al., 2010). Effects of
fluoxetine on antioxidant status were studied in vivo using a melanoma experimen-
tal model. Fluoxetine dose-dependently reduces the production of free radicals,
especially hydroxyl radicals OH
and O
2
. A dose-dependent protection of
2378 P. Gałecki
fluoxetine on oxidative stress in rat PC12 cells was demonstrated by Kolla et al.
(2005). Fluoxetine attenuates the decrease in cell viability induced by oxidants and
significantly increases SOD activity. The results confirming the antioxidant properties
of fluoxetine have been observed in the blood of patients suffering from depressive
disorder. Depressed patients show a decrease in serum SOD and serum MDA and an
increase in plasma ascorbic acid levels in patients of major depression when compared
with the control subjects after fluoxetine treatment (Khanzode et al. 2003). Gałecki
et al. (2009b) found significant changes in MDA and TAS levels after fluoxetine
treatment. Decreased MDA concentrations can be associated with partially reduced
production of or amount of free radicals. Increases in TAS after pharmacotherapy
probably lead to the inhibition of free radical production. Evidence for an increase in
the concentration of uric acid after treatment with fluoxetine is one of the important
nonenzymatic antioxidant effects that have also been observed (Zafir and Banu 2007).
A strong, but dose-dependent, protective effect of fluoxetine against 3-nitropropionic
acid-induced oxidative damage has also been demonstrated (Zhu et al. 2012).
Pro- and Antioxidant Equilibrium and Antidepressants Other
than SSRI
Protective effects against O&NS were also examined when other SSRIs were used.
The antioxidant activity of escitalopram was observed by Lee et al. (2011), who
found a decrease in 4-hydroxy-nonenal levels after escitalopram treatment.
Escitalopram is also able to reduce CuZnSOD activity, which might suggest that
lowering the levels of O
2
generation could significantly decrease glutathione
peroxidase (GPX) activity (Lee et al 2011). Reduced GSH and vitamin C in the
cortex of rats undergoing chronic mild stress (CMS) were restored by escitalopram
treatment (Eren et al. 2007). Neuroprotective effects against free radicals are also
characteristic of citalopram. This antidepressant restores depleted GSH and CAT
activity and attenuates raised lipid peroxidation and raised nitrite level compared
with the control animals (Garg and Kumar 2008). Subchronic treatment with
citalopram decreases antioxidant enzyme activities and MDA concentrations and
increases levels of ascorbic acid. Biochemical markers return to normal values with
treatment (Khanzode et al. 2003; Atmaca et al. 2004).
The effects of other classes of antidepressants on O&NS have also been inves-
tigated. Venlafaxine and imipramine affect the antioxidant status of animals
subjected to the FST. Treatment with imipramine and venlafaxine recovers the
activity of SOD, CAT, GST, GR, and levels of GSH. Moreover, normalization of
MDA and PC is also characteristic after the above-mentioned treatments (Zafir
et al. 2009). Long-term therapy with venlafaxine reduces oxidative DNA and cell
damage (Abdel-Wahab and Salama 2011). In vitro studies have observed that
fluvoxamine and reboxetine reduce the activation of microglia in a dose-related
manner, as measured by the level of NO production (Hashioka et al. 2007).
Protection of cultured neurons against glutamate-related oxidative stress was
observed for doxepin by suppressing the accumulation of intracellular calcium
103 Oxidative Stress in Depression 2379
ions, decreasing lipid peroxide generation, and stimulating antioxidant enzymes
(Ji and Liu 2004). A relationship between O&NS and pro- and antioxidant distur-
bances has been studied with imipramine. Reduction in activated microglia-related
NO levels (Hashioka et al. 2007) increases in SOD and CAT activity and decreases
in lipid and protein damage have all been observed (Reus et al. 2010). The results
demonstrate a relationship between antidepressants and pro- and antioxidant equi-
librium in a group of patients treated with different antidepressants. For example, in
their study, Bilici et al. (2001) included 32 patients characterized by increased
activity of SOD and GPx and increased levels of MDA. The group consisted of
seven patients treated with fluoxetine, 13 with sertraline, five with fluvoxamine, and
five with citalopram. After all types of pharmacotherapy, antioxidant enzyme
activity and MDA levels were comparable to those of normal controls. The dosage
of drugs was in the typical therapeutic range.
Similar effects in TAS, total oxidative stress (TOS), and oxidative stress index
(OSI) have been observed after 3 months of treatment with different antidepres-
sants. TOS and OSI decreased after treatment with escitalopram, paroxetine, and
sertraline, while TAS increased (Cumurcu et al. 2009). Reductions in free radical
overproduction were also found after treatment with other antidepressants, such as
milnacipran, tianeptine, and moclobemide. Increased plasma MDA concentrations,
serum oxidized LDL, and SOD activity were all lower after treatment (Kotan et al.
2011). All of the aforementioned studies were longitude and lasted 12 weeks,
3 months, and 24 weeks, respectively. By contrast, only 6 weeks of therapy did
not seem to influence pro- and antioxidant equilibrium abnormalities (Sarandol
et al. 2007).
O & NS and disturbances in pro- and antioxidant equilibrium both play an
important role in the etiology of depression and are worth investigating. Increasing
lines of evidence also indicate that one of the mechanisms of action of antidepres-
sants includes a reduction in O&NS and a restoration of pro- and antioxidant
equilibrium. Nevertheless, the exact mechanism of the antioxidant actions of
antidepressants is not fully known or understood. The previously reviewed back-
ground should be linked with mechanisms that are unique sources of O&NS and are
also characteristic specifically of depressive disorders. Evidence suggests that
inflammatory and immune components are involved in depressive disorders. It is
widely known that inflammation and the activity of immune cells are sources of free
radicals and their derivatives.
Antidepressants and Anti-Inflammatory Drugs in Depressive
Treatment and Reduction of O & NS
Mechanism of Antidepressants
One possible explanation why antidepressants are so effective and why they reduce
O&NS is that many of them have anti-inflammatory effects. The antioxidant
efficiency of antidepressants may be partially attributable to the suppression of
2380 P. Gałecki
inflammation (Tynan et al. 2012). Multiple types of antidepressants are able to
inhibit the production of proinflammatory cytokines, which are inducers of many
processes and mechanisms leading to the overproduction of free radicals (Hendriks
et al. 2005; Mathy-Hartert et al. 2008). Proinflammatory cytokines can induce
expression of the important inflammatory enzymes, such as iNOS and COX-2
(Dubois et al. 1998; Aktan 2004). Elevated systemic levels of interleukin-1 beta,
interleukin-6, tumor necrosis factor alpha, and interferon gamma all were normal-
ized with antidepressant treatment (Hayley 2011). An increasing data set informs
about the mechanism reducing inflammation and inflammation-related O&NS.
These effects may be reduced with fluoxetine treatment by the suppression of
microglial NADPH oxidase activation and iNOS upregulation (Chung et al.
2010). A significant correlation was found between kynurenine metabolites,
known to possess pro-oxidant activity. After fluoxetine treatment, kynurenine
metabolism was lower (Mackay et al. 2009). Anti-inflammatory properties of
fluoxetine were observed in a septic shock model. In vitro fluoxetine inhibits the
release of tumor necrosis factor alpha (TNF-alpha) from LPS-treated monocytes in
a dose-dependent manner. Fluoxetine is also able to reduce the number of macro-
phages, lymphocytes, and neutrophils (Roumestan et al. 2007). Inhibition of NO
and prostaglandin E2 release is a mechanism by which fluoxetine, as well as
amitriptyline, affect inflammation and O&NS (Yaron et al. 1999). This
cytoprotective effect against O&NS was also observed for paroxetine. The protec-
tive activities of paroxetine are associated with the suppression of astroglial MPO
expression and/or NADPH oxidase-derived radical production, as well as with
a reduction in expression of IL-1beta, TNF-alpha, and iNOS by activated microglial
(Chung et al. 2010). The antioxidant effects of some classes of antidepressants
result from their ability to inhibit and attenuate the overload of intracellular calcium
ions. Such effects are observed in the case of desimipramine and fluoxetine (Li et al.
2003). The inhibition of calcium influx is also exhibited by paroxetine via inhibition
P2X4 receptors, which explains the analgesic effects of paroxetine and possibility
of neuropathic pain, which is sometimes associated with depressive disorder
(Nagata et al. 2009). Fluoxetine was found to suppress kainic acid—NMDA
receptor agonist-induced pathogenesis in the brain (Jin et al. 2009). Recently,
studies have revealed that SSRIs inhibit microglial TNF-alpha and NO production
after inflammatory stimuli, such as an LPS (Tynan et al. 2012). Considering that
antidepressants are able to reduce O&NS via multiple mechanisms and to restore
pro- and antioxidant equilibrium, it is logical that pharmacotherapy with antide-
pressants should be used to supplement with other drugs that can also reduce O&NS
by different mechanisms. Recently, attention has been paid to the use of anti-
inflammatory drugs in depression. These studies have examined the effectiveness
of anti-inflammatory drugs with animal models as well as clinical trials. Protective
effects against oxidative damage by both selective and nonselective cyclooxygen-
ase inhibitors have been observed in FST mice. Chronic treatment with naproxen,
rofecoxib, meloxicam, nimesulide, and valdecoxib significantly attenuated oxida-
tive damage in chronic stressed mice (Kumar et al. 2010). Similar effects were
observed after treatment with rofecoxib, which significantly attenuated quinolinic
103 Oxidative Stress in Depression 2381
acid-induced biochemical changes, including increased MDA and nitrite concen-
trations and depleted SOD and CAT levels in rats (Kalonia et al. 2010).
Chronic treatment with celecoxib reverses UCMS-induced depressive, such as
behavior via reducing COX-2 in the brain. In addition, it reduces COX-2 expression
and PGE2 concentrations in stressed rats and correlates with improvement of
emotional state (Guo et al. 2009).
Efficiency of Anti-Inflammatory Molecules
The involvement of inflammation and O&NS in depression, as well as 70 %
effectiveness in the treatment MRD with antidepressants, and the anti-inflammatory
activity of antidepressants all suggest the coadministration of antidepressants and
anti-inflammatory drugs. Combined treatment of fluoxetine and acetylsalicylic acid
(ASA) completely reverted the condition of escape within 7 days in a chronic
escape deficit model of depression, while fluoxetine alone was effective after
administration for at least 3 weeks; ASA alone was not effective (Brunello et al.
2006). Fluoxetine co-administered with anti-inflammatory and antioxidant mole-
cules, such as melatonin, may be beneficial in the inflammatory pain condition
(Abdel-Salam et al. 2004). Rats subjected to FST were used to investigate the anti-
inflammatory and subsequent antioxidant effects of fluoxetine co-administrated
with amantadine, an NMDA antagonist. Coadministration of amantadine with
fluoxetine decreases the proinflammatory properties of macrophages and causes
a reduction of immune response towards anti-inflammatory activity (Roman et al.
2009). Considering the fact that inflammation and the proinflammatory abilities of
immune cells are followed by O&NS, one may suggest that a reduction in free
radical production occurs during the inhibition of inflammation and immune
activity.
Preclinical data from animal models underlies clinical trials of anti-
inflammatory drugs in depression. The first such study was conducted by
Mendlewicz et al. (2006) in which they examined the effect of ASA augmentation
therapy on SSRI in 21 depressed nonresponder patients. Patients were treated with
daily dosage of 160 mg of ASA added to antidepressant treatment for 4 weeks. The
combination of SSRI-ASA resulted in a response rate of 52.4 %. In the responder
group, the mean HDRS 21-item score decreased from 29.3 4.5 to 8.4 4.1;
a significant improvement was observed within 1 week, and sustained improvement
was observed until day 28.
Administration of ASA may potentially be effective in depression treatment due
to its obvious anti-inflammatory effects. For example, ASA inhibits the interleukin-
1-beta-stimulated increase in iNOS, NO, and PGE2 production (Carnovale et al.
2001). In addition, the ability of ASA to increase anti-inflammatory lipoxin A4 and
15-epi-LXA4 and to reduce proinflammatory PGE2 and thromboxane B2 (TXB2)
(Basselin et al. 2011) suggests that ASA should be considered for the treatment of
depression characterized by (neuro) inflammation. It is believed that the anti-
inflammatory effects of ASA are achieved with 300 mg in a single dosage, while
2382 P. Gałecki
the dosage in the aforementioned clinical trial was only 160 mg of ASA. Moreover,
in animal models, fluoxetine alone was effective. These results suggest the impor-
tant of determining a therapeutic dosage and a possible mechanism of any
co-therapy. One possible explanation is that the two drugs work synergistically.
Considering the anti-inflammatory effects of antidepressants, improvements in
clinical effects after ASA may have resulted not only from its anti-inflammatory
effects but also from antioxidant activity. The results obtained with combined
therapy, consisting of fluoxetine and ASA, indicate a reduction in MDA concen-
tration and an increase in TAS. This study was performed in a group of 77 patients
with MDD, subdivided into two groups. The first group consisted of 52 patients
treated with 20 mg of fluoxetine, and the second group received 150 mg of ASA in
addition to 20 mg of fluoxetine. Such results favor a role for ASA as an antioxidant
in supplementation treatment for major depression. A large group of reports
demonstrate a reduction in lipid peroxidation and in free radical generation induced
by various factors, such as NMDA receptor agonists, proinflammatory cytokines, or
LPS by ASA, on both the periphery and in the CNS (Kirkova et al. 1995; Daya et al.
2000; De Cristobal et al. 2001; De La Cruz et al. 2004; Maharaj et al. 2006).
Preclinical and animals studies have also observed that nonsteroidal anti-
inflammatory drugs, other than ASA, have antidepressant properties. In
a prospective, double-blind, add-on study, 40 patients diagnosed with depression
meeting the DSM-IV criteria received reboxetine in a dosage of 4–10 mg plus
placebo, and the second group also received reboxetine plus 400 mg of celecoxib
for 42 days. After 6 weeks of treatment, both groups achieved significant remission,
while the celecoxib group was found to have significantly greater improvement
(M€
uller et al. 2006). Another clinical trial regarding the supplementation of major
depression treatment with celecoxib was performed in a group of 40 patients
meeting DSM-IV criteria and treated with fluoxetine. The results were similar to
the aforementioned. Both groups were characterized by significant improvement.
Treatment with 40 mg of fluoxetine plus 400 mg of celecoxib was superior
(Akhondzadeh et al. 2009). The effective therapy with celecoxib possibly results
from its reduction of inflammatory markers and immune activity characteristic of
depression and favoring free radical generation. In the subsequent, randomized
double-blind placebo-controlled study, it was found that the group treated with
200 mg of sertraline and celecoxib in a dosage of 200 mg had a significant reduction
in serum IL-6 concentration as well as HDRS scores. The patients from the
celecoxib group showed a greater response and higher rates of remission. Baseline
serum IL-6 levels were significantly correlated with baseline HDRS (Abbasi et al.
2012). Case study also showed a therapeutic effect of celecoxib alone for major
depression comorbid with neurocognitive dysfunction in a 75-year-old woman. In
initial treatment, three different antidepressants were used successively but only for
4–6 weeks each. The woman responded poorly to all three drugs. After
discontinuing the antidepressants, the woman was treated with 200 mg of celecoxib
to reduce somatic symptoms. The depressive symptoms improved within 2 weeks.
In addition, no recurrence of depression was observed with continuous therapy
(Chen et al. 2010).
103 Oxidative Stress in Depression 2383
The anti-inflammatory mechanisms of nonsteroidal anti-inflammatory drugs are
widely known and can potentially explain the effectiveness of such treatments in
depression. Effective therapy with anti-inflammatory drugs may also result from the
influence of anti-inflammatory drugs on O&NS and on pro-and antioxidant equi-
librium. Nonsteroid anti-inflammatory drugs can reduce O
2
and peroxide pro-
duction and reduce GSH depletion (Petersen et al. 2008). Inhibition of COX-2 by
anti-inflammatory drugs also results in inhibition of kynurenic acid synthesis,
a known source of oxidants (Andrade et al. 2008). In vitro studies have investigated
the antioxidant activity of the selective COX-2 inhibitor celecoxib. Celecoxib
decreases the spontaneous and Fe/ascorbic acid-induced lipid peroxidation.
Because the brain has large amounts of iron (Fe) that participate in Fenton reac-
tions, one of the mechanisms of celecoxib may also be its antioxidant properties, as
celecoxib possesses antioxidant and metal-chelating abilities. Antioxidant effects
of celecoxib against H
2
O
2
-treated DNA were also observed (Matthias et al. 2006;
Halliwel 2006; Kirkova et al. 2007).
Increasing evidence suggests that MRD is characterized by O&NS. Such results
suggest that finding new components that might be effective in depressive treatment
via direct or indirect antioxidative mechanisms would be beneficial. The presence
of O&NS steers a discussion of the potential role of antioxidants in the treatment
of depression.
Molecules of Antioxidant Properties in Depression Treatment
Biological and Natural Antioxidants
5HT and its precursors possess antioxidant properties. Exogenous administration of
5-hydroxytryptophan reduces generation of lipid peroxide and improves antioxi-
dant status in the brain (Munoz Castaneda et al. 2006). Serotonin and its precursors
could supplement as antioxidants in depressive disorder treatment. Another
molecule having antioxidant effects involved in tryptophan metabolism is
N-acetylserotonin (NAS)—a precursor of melatonin. Antioxidant effects of NAS
might underpin its antidepressant effect and suggest the use of NAS in protection
against free radical damage in major depression (Oxenkrug 2005). This antioxidant
effect was observed with treatment restraint-stressed rats with tautomeric com-
pounds, such as Curcuma longa. Oxidative markers, such as MDA and CP, were
significantly decreased following Curcuma longa treatment. Molecules affecting
antioxidants are a promising way to treat oxidation stress in depression (Zafir and
Banu 2007). Depressive-like behavior and brain oxidative damage in UCMS rats
were reversed by vitamin C. Depressive-like behavior was accompanied by lipid
peroxidation, decreases in CAT and GR activity, and reduced levels of GSH in the
area of cerebral cortex and hippocampus after ascorbic acid treatment (Moretti et al.
2012). Reductions in lipid peroxidation and in the generation of O
2
were
observed after Ginko biloba extract in FST mice. In addition, reductions in oxida-
tive stress correlated with antidepressant-like effects of the Ginko biloba extract.
2384 P. Gałecki
These results suggest that the extract possesses antidepressant properties via anti-
oxidant mechanisms (Rojas et al. 2011). A remarkable protective effect against
oxidative damage in PC-12 cells was observed after treating the cells with an
extract of Apocynum venetum (Shirai et al. 2005). In UCMS models, increased
lipid peroxidation and nitrite levels and decreased SOD and CAT activity in mice
were significantly reversed by chronic treatment with sesamol (Kumar et al. 2011).
An experimentally induced form of depression, chronic mild stress (CMS), was
used to investigate the antioxidant effects in the cerebral cortex of rats of absolute
rose oil, which contains flavonoids, such as rutin and quercetin. After treatment
with rose oil for 28 days, lipid peroxidation levels were restored to normal levels.
Levels of vitamins A, C, and E and beta-carotene in the cerebral cortex were higher
in the rose-oil-treated group (Nazırog
˘lu et al. 2012).
Researchers suggest that adjunct therapy with probiotics has the potential to
decrease systemic inflammation and to decrease oxidative stress in depression
(Logan and Katzman 2005).
Polyunsaturated Fatty Acids
Free radicals are a critical cause of damage in various diseases, including MRD.
Useful antioxidant treatments have been investigated and discussed. Biochemi-
cal and clinical studies suggest that treatment with omega-3 polyunsaturated
fatty acids (PUFAs) is beneficial in mood disorders, including depression.
A meta-analytic review of 14 studies comparing the levels of PUFAs between
depressed patients and healthy subjects showed that depression is characterized
by lower levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA),
andtotalomega-3polyunsaturatedfatty acids and suggests rational use of
omega-3 polyunsaturated fatty acids as an adjunct or alternative treatment in
depressive disorder (Lin et al. 2010). An olfactory bulbectomized (OB) rat
model of depression was used to investigate the effectiveness of ethyl-
eicosapentaenoate, one of the omega (n)-3 fatty acids, known to have
antidepressant effects. Ethyl-eicosapentaenoate treatments reduce serum con-
centrations of IL-1-beta and PGE
2,
the inflammatory and immune molecules
that contribute to the induction of O&NS (Song et al. 2009). A double-blind,
placebo-controlled study evaluating DHA in the treatment of major depressive
disorder found significant decreases in scores on the 21-item HDRS after 8 weeks
(Su et al. 2003). Ethyl ester of eicosapentaenoic acid appeared to be beneficial
after 3 week as an adjunct therapy in patients with MRD (Nemets et al. 2002).
A50%reductiononHDRSwasachievedinpatients with persistent depression
after12weeksoftreatmentwith1gofethyl-eicosapentaenoate(Peetetal.
2002).Treatmentwith20mgoffluoxetinewas equally as effective treatment
with 1,000 mg of EPA after 8 weeks in those diagnosed with major. Treatment
had a significant effect on HDRS. Nevertheless, EPA and fluoxetine when given
together had better effect (Jazayeri et al. 2008). Scores on depressive scales, such
as the 20-item Hopkins Symptoms Checklist Depression Scale (HSCL-D-20) and
103 Oxidative Stress in Depression 2385
the 21-item HDRS, improve significantly after ethyl ester of eicosapentaenoic
acid treatment given in a dosage of 500 mg three times daily (Lucas et al. 2009).
The enhancement in mood in depression after treatment with omega-3 polyun-
saturated fatty acids may be partially explained by the antioxidant abilities of
omega-3 polyunsaturated fatty acids. Antioxidant mechanisms of PUFAs are
reviewed by Pascoe et al. (2011). The possible pathways by which PUFAs reduce
O&NS are as follows: a reduction in intracellular influx of calcium ions after
glutamate-related excitotoxicity. Regulation of calcium ion influx resulted from
limiting the sodium/calcium channels. EPA and DHA have an ability to increase
SOD, GPX, and levels of vitamin E. These acids were found to reduce O
2
generation by human polymorphonuclear leukocytes and monocytes, possibly
via reducing COX-2. Administration of DHA and EPA decreases iNOS in the
hippocampal neurons of rats.
Data to Discuss
Investigating O&NS in depression, one should be objective (impartial) that in some
results regarding O&NS in depression, levels of antioxidants are opposite to those
that have found increased free radical generation and protective effects of antide-
pressants and other molecules used, while treating MRD.
A group of studies has suggested increased activity of antioxidant enzymes in
MRD. But, for example, Herken et al. (2007) have demonstrated statistically lower
activity of CuZnSOD in the blood of patients with depression. Srivastava et al.
(2002) have observed similar changes in the activity of CuZnSOD in the polymor-
phonuclear leukocytes from depressed patients and healthy controls. Nonenzymatic
antioxidant system has been widely stated as lowered, while Sarandol et al. (2007)
has demonstrated an increase in vitamin E concentration in the serum of patients
with depression.
Significant augmentation of antioxidant defense and recovery in the activities of
antioxidant enzymes including CAT are in conflict with the data that have observed
CAT as the molecule potentiating IL-1-induced expression of iNOS (Guikema et al.
2005). Significant upregulation of COX-2 induced by CAT have also been observed
(Litvinov and Turpaev 2004).
Above-mentioned studies were performed with the use of rats’ vascular smooth
muscle cells and primary human chondrocytes. Nevertheless, the mechanism is
possible in other cells. The strong relation between the increased expression of
COX-2, the gene encoding the molecule, depression, and pharmacotherapy are in
contrast with data presented by Cassano et al. (2006), who have found differential
expression of the gene and protein in rat hippocampus after injection with
clomipramine.
A large amount of results have observed antioxidant properties of different
antidepressants. However, some results argue against such data. Tricyclic antidepres-
sants have been found to induce free radical generation and O&NS. For example,
2386 P. Gałecki
clomipramine significantly increases levels of lipid peroxidases and decreases levels
of GSH, GPx, and SOD activities, while the toxic effects are reduced by free radical
scavengers (El-Demerdash and Mohamadin 2004). In patients with depressive epi-
sodes following amitriptyline treatment, the reduction in levels of coenzyme Q and
increased lipid peroxidation have been characteristically seen when compared to
healthy control (Moreno-Fernandez et al. 2012). These results suggest that O&NS
may be a consequence of some variant of treatment. In vitro study in isolated rat liver
cells has found that exposure to trazodone imposed oxidative stress measured via
glutathione depletion (Dykens et al. 2008). Rat liver damage has been also observed
after fluoxetine treatment that increased the levels of carbonyl groups and
thiobarbituric acid in rat liver (Inkielewicz-Ste˛pniak 2011). Anti-inflammatory
effects of fluoxetine are denied by the results that have found fluoxetine-stimulated
NO overproduction and increase in mRNA expression of pro -inflammatory mole-
cules including IL-6 and TNF-ain microglial cells (Ha et al. 2006).
Toxic and not antioxidant properties were also observed regarding molecules
that are found to reduce O&NS and suggested to be used in depression treatment.
PUFA may participate in cytotoxic effects as the molecules enhance oxidative
stress (Kello et al. 2010). Pro-oxidant features have been found for tryptophan.
Administration of the molecule induces oxidative stress in brain cortex of rats
measured by increases in thiobarbituric acid-reactive substances, reduced glutathi-
one, and reduced CAT activity (Feksa et al. 2008).
Discussion is also made on treating depression with COX-2 inhibitors as it was
stated by Maes et al. (2012) that the drugs may increase lipid peroxidation, lower
antioxidant enzyme activities, and cause mitochondrial dysfunction. COX-2 inhib-
itors are widely described as anti-inflammatory molecules with antioxidant prop-
erties. Nevertheless, there are data that have found the pro-oxidant properties of
celecoxib. Study performed by Sozer et al. (2011) with the use of rat material has
observed that plasma MDA levels were increased by treatment with celecoxib.
CAT activity was higher while GPx activity was lower. COX-2-selective inhibitor
and nonselective NSAID have also been observed to induce oxidative stress by
upregulating vascular NADPH oxidases (Li et al. 2008).
Conclusion
There are many results suggesting that MRD is characterized by an increase in the
generation and levels of free radicals and their derivatives. Different studies have also
observed disturbances in pro- and antioxidant equilibrium. It should be emphasized
that reviewed studies include animal models; in vitro studies; investigations of patients’
blood, cerebrospinal fluid, urine, and saliva; and postmortem brain studies. It is known
that O&NS is followed by abnormalities in various mechanisms and by cell damage.
Considering the important role of O&NS, alternative procedures for assessing
biological parameters involved in O&NS induction and direct markers of free
radical generation should be considered for patients diagnosed with MRD.
103 Oxidative Stress in Depression 2387
The results could be related to depression scores, and eventually, modification and/
or adjunct therapy should be included in the course of treatment, with the effects of
the above-mentioned parameters from depression scores adequately controlled.
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