Oxidative Stress Implications in the Affective [602553]

ReviewArticle
Oxidative Stress Implications in the Affective
Disorders: Main Biomarkers, Animal Models Relevance,Genetic Perspectives, and Antioxidant Approaches
Ioana Miruna Balmus,1Alin Ciobica,2,3Iulia Antioch,1
Romeo Dobrin,3and Daniel Timofte3
1DepartmentofMolecularandExperimentalBiology,“AlexandruIoanCuza”University,11CarolI,700506Ias ¸i, Romania
2RomanianAcademy,IasiBranch,8CarolI,700505Ias ¸i, Romania
3“GrigoreT.Popa”UniversityofMedicineandPharmacy,16UniversitatiiStreet,700115Iasi,Romania
CorrespondenceshouldbeaddressedtoAlinCiobica;[anonimizat]
Received20April2016;Revised30June2016;Accepted5July2016
AcademicEditor:FelipeDalPizzolCopyright © 2016 IoanaMirunaBalmusetal. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
The correlation between the affective disorders and the almost ubiquitous pathological oxidative stress can be described in a
multifactorialway,asanimportantmechanismofcentralnervoussystemimpairment.Whethertheobviouschangeswhichoccurin
oxidativebalanceoftheaffectivedisordersareapartoftheconstitutivemechanismoracollateraleffectyetremainsasaninterestingquestion.Howeveritisnowclearthatoxidativestressisacomponentofthesedisorders,beingcharacterizedbydifferentaspectsin
adisease-dependentmanner.Still,therearealotofcontroversiesregardingtherelevanceoftheoxidativestressstatusinmostofthe
affectivedisordersanddespitethefactthatmostofthestudiesareshowingthattheaffectivedisordersdevelopmentcanbecorrelatedtoincreasedoxidativelevels,therearevariousstudiesstatingthatoxidativestressisnotlinkedwiththemoodchangingtendencies.
Thus,inthisminireviewwedecidedtodescribethewayinwhichoxidativestressisinvolvedintheaffectivedisordersdevelopment,
byfocusing onthemainoxidative stressmarkersthatcouldbeusedmechanistically andtherapeutically inthesedeficiencies, thegeneticperspectives,someantioxidantapproaches,andtherelevanceofsomeanimalmodelsstudiesinthiscontext.
1. Introduction
Inthepastfewdecades,astronglinkbetweentheinflamma-
tory, oxidant, mitochondrial, and apoptotic markers versus
the cognitive decline has been developed and theorized [1].
It seems that all these pathological background features aresomehow molecularly linked, leading to a complex inter-
action between the cellular/molecular control and causes-
effectsconditioning.Thisiswhy,generallyspeaking,mostof
the neuropsychiatric disorders causes that are leading to theknown and seen symptoms are a rather problematic matter
todetermineandtosuccessfullydiscriminatefromothercol-
lateralfeatures.Inthisway,theneuropsychiatricdiseasesstill
remain partly unknown due to a multifactorial background.
Thismaybethereasonwhynoefficientspecifictreatmenthasbeenyetdeveloped,thetherapyrelyingonlyonsymptomatic
alleviation[2–4].
This is also the case for the affective disorders or mood
disorders, which are a group of well-studied related psychi-atric disorders which have common socioaffective featuresand can accompany unipolar, bipolar, or schizoaffectivesyndromes [5]. The main spectrum is constituted of severalpsychiatric pathological conditions which occur in differ-ent combinations determining variable social or affectivebehaviour classified as mood impairments. The mainlyknownaffectivedisordersaredepressivedisorder(DD),anx-iety disorder (ANX), obsessive-compulsive disease (OCD),panic disorder (PD), and posttraumatic stress disorder(PTSD). Obviously, these pathological behaviours can gaindifferent shades (Figure 1) in developing other affectiveHindawi Publishing Corporation
Oxidative Medicine and Cellular Longevity
Volume 2016, Article ID 3975101, 25 pages
http://dx.doi.org/10.1155/2016/3975101

2 OxidativeMedicineandCellularLongevity
Depression
disorder
PTSDAnxiety disorderOCD
Panic disorderBipolar disorder
Dysthymia
Bulimia nervosa
ADHD
Impulse-control
disorder
Self-control impairmentsDystrophic
disorder
Cataplexy
Migraine
Irritable bowel
disease
Chronic pain
Hypnolepsy
Physiological control impairmentsSocial anxiety
disorderHypersexuality
Kleptomania
Oppositional-defiant
disorder
Personality
disorder
Social impairments
Figure1:Affectivedisordersverticalclassification(ADHD:attentiondeficitandhyperactivitydisorder;PTSD:posttraumaticstressdisorder;
OCD: obsessive-compulsive disorder). Some of the symptoms for the affective disorders are quite distinct between the affective variantsgroups,whilethemainaffectivedisorders(ANX,DD,PTSD,OSD,andPD)aremorelikelysymptomcombinationsofthegroups.Therefore,
ANX, MDD, and PTSD exhibit both self-control discrepancies, as observed in bulimia, impulse-control impairment, or attention deficits,
andphysiologicalcontrolalterations,suchasirritableboweldisease,frequentmigraines,orchronicpain.Furthermore,ontheoppositesidestandOCDandPD,whichexhibitmainlysocialimpairments,suchasoppositional-defiantbehaviour,socialanxiety,anddifferentpersonality
discrepancies,aswellasphysiologicalimpairments.Inthisway,itseemsthatthemajoraffectivesyndromescanbeclassifiedgiventhegeneral
symptomatology tendencies in two groups: self-control-associated syndromes (DD, ANX, and PTSD) and social-hurdle syndromes (OCD,PD)(basedon[6]).
variantssuchasself-controlimpairments,physiologicalcon-
trolimpairments,andsocialimpairments[6].
Also,itseemsthatseveralcellularandmolecularfeatures
of the affective disorders are quite similar, disregarding thespecific clinical symptomatology. In this way, one of theseaspectsisoxidativestressstatus,whichseemstobeimplicatedin most of the different affective disorders, since it has beenshown that increased oxidative damage occurs quite oftenin depression [7–9], anxiety [9, 10], bipolar disorder (BD)[10–14], panic disorder (PD) [15, 16], and also in obsessive-compulsivedisorder[17].
Oxidative stress can be easily defined as the condition
arising from the imbalance between toxic reactive oxygen
species (ROS) and the antioxidant systems [1]. Shortly, the
most studied ROS are the superoxide anion (O
2−), hydroxyl
radical(HO−),hydrogenperoxide(H2O2),nitricoxide(NO),
peroxyl (ROO−), and reactive aldehyde (ROCH), while on
theothersidethesereactivespeciesaredealtwithbythebodyin several ways, including the usage of the antioxidantenzymes(e.g.,superoxidedismutase,SOD,thatcatalyzestheconversion of superoxide radicals to hydrogen peroxide,which is then converted into water by glutathione perox-idase, GPX, and catalase, CAT), as our group previouslydemonstrated on different occasions through most of theneuropsychiatricdisorders[18–25].
Moreover, various tissues have different susceptibilities
to oxidative stress. In fact, the correlation between theoxidative stress status and affective disorders developmentcould arise from the vulnerability of central nervous system(CNS)tooxidativedamage.Oxygenrelatedfreeradicalsandreactive species are both produced by the body, primarily
as the result of the aerobic metabolism [26]. In the intra-and extraneuronal environment, these molecules have alsoimportantfunctions,suchassynapticplasticityandmemoryr e g u l a t i o n[ 2 7 ] .M o r et h a nt h a t ,t h eC N St i s s u e sa r er i c hin lipid molecules which are an easy target for oxidationreactionsofthepathwaysinwhichtheyareinvolved[28].Inaddition, the metabolism of some neurotransmitters is alsobasedonredoxpotentialtransmission[29].
Inthisway,ithasbeenshown,forexample,thatneuroin-
flammatorypathwaysactivationtogetherwithCNSoxidativeandnitrosativestresscouldplayanimportantroleintheDD’s
pathophysiological background [30]. Interestingly, it seems
that ROS and RNS can cause immune response aberrationsalongsidemolecularmembranesstructuralalterationleadingto immunogenic properties that could alert the immunesysteminthepresenceofoxidizedfattyacids.ThiswouldbepathwaythroughwhichDNA,proteins,lipids,andmitochon-dria damages can lead to the dysfunctions observed in DD[31].
Broad mitochondrial dysfunctions have also been
reported in the context of ROS and RNS overproductiondescribed in BD. As mitochondria are the most activeorganelles in ROS/RNS production, it seems that they alsocontributetoaffectivedisorderspathologicalmechanisms.Ithasbeenshownthat,inBD,theoccurrenceofmitochondrialDNA mutations and the occurrence of other mitochondrialdiseases are rather high [32]. This could be the reason whymitochondrial metabolism correction could actually resultinsomealleviationofBDsymptomatology[33].

OxidativeMedicineandCellularLongevity 3
In addition, a strong link between oxidative stress and
anxiety-related phenotypes has been observed [34]. In thisway, using genetically ANX-predisposed mice strains, thecorrelation between several antioxidant enzymes such asglutathione reductase-1 or glyoxalase-1 hyperactivity andintense anxiety behaviour has been described. Since then,
many of the studies showed that ANX is a GABAergic and
serotonergic modulated condition (as reviewed by [35]).Thus, it seems that both GABA and 5-HT are involved inthe modulation of anxiety responses in the brain. Regardingthe GABA release modulation, it seems that in anxiety themost important aspect is the 5-HT capacity to modulatethe excitability of GABAergic interneurons. Several detailedstudies on hippocampal response to serotonin stimulationvia dorsal raphe fibers showed that serotonin specificallytargets a subset of hippocampal interneurons involved inGABA B-mediated feed forward inhibition [36]. Moreover,GABA-Areceptoragonistswereshowedtoinhibituntrainedanxietyreactions.Inthisway,intrahippocampalinfusionsofglutamatergic, serotonergic, and cholinergic compounds arethoughttoproducereliableantianxietyeffects[37].
Also, GABA release modulation has been observed in
other brain areas involved in anxiety behaviour regulation,such as dentate gyrus, which plays importantroles in gener-ating contextual memories of fear; entorhinal cortex, whichmodulates contextual fear memory extinction;piriformcor-texwhichconsistsinamygdala,thefearcenter,frontalcortexinvolved in subcortical fear response, and anterior cingulatecortex-remotecontextualfearmemory[38].
Furthermore, a clear connection between fear response
and oxidative damage was established being given that
glyoxalase 1 cytotoxic substrate, methylglyoxal, is one of thewell-known GABA agonists and also a potent modulator inoxidative stress and apoptosis [39]. In this way, Hassanet al. [40] demonstrated a close interaction between brainantioxidant system genes expression (glutathione reductase1andglyoxalase1)andanxiety-likebehaviour.Furthermore,thelinkbetweenoxidativestressandemotionalstress,suchasfearandphobia,isbasedontheoxidativeimpairmentcausedin the brain by the imperfect gene expression that leads tooxidativeandenzymaticunbalance.Howeverthemodulationproperties of ROS on glutathione reductase 1 and glyoxalase1genesexpressionareyetunclear,asHassanetal.[40]basedtheir conclusions on lentiviral-modulated gene expression.Thefactthatantioxidantenzymes’genesoverexpressionwasobserved in fear-controlling brain areas in the absence ofoxidative stimuli leads to the conclusion that there mightbe other stress-controlled mechanisms that are involved inanxiety-likebehaviouroccurrence.
Moreover, Hassan et al. [40] showed that oxidative stress
m a ya c t u a l l yb et h el e a d i n gc a u s eo fA N X ,w h i l eM a s o o dgroup [41] found that glutathione synthesis inhibition mayinduce hippocampal and amygdala oxidative stress, leadingto the assumption that hippocampal oxidative stress and
ANXcouldbeindeedconnected.
In PD context, the latest studies also describe a strong
connection between antioxidant enzymes activity and panicsymptomatology [42, 43]. For instance, a certain phenotypicformulainantioxidantdefensemaybeassociatedwithgenders p e c i fi cP Dd e v e l o p m e n t .Th u s ,t h eP r o 1 9 8 L e up o l y m o r –
phism of the glutathione peroxidase 1 gene seems to partic-ipate in the development of anxiety-like behavioural pheno-types. Also, PD was newly characterized as an anxiety spec-trum disorder due to the similarities between the oxidativemechanisms[44].
Inthesameway,itseemsthatmitochondrialdysfunction
couldbeanimportantmechanismforthepathologyofOCD[45]. Moreover, a correlation between mitochondrial disor-dersandoxidativestressinOCDwasrevealedduetoageneticvariability of manganese-dependent superoxide dismutaseand a small mitochondrial protein [46]. More than that,an oxidative imbalance has been reported in OCD patients,but unfortunately the exact pathway in which oxidativestressisimplicatedinOCDisstillpartiallyunclear[17].
TheexactcorrelationbetweenMDDandoxidativestress
is also a major concern, since a close connection betweenglutamatergic hyperactivity and depression has been postu-lated [47]. Glutamate is the predominant excitatory neuro-transmitterbeingresponsibleforsynapticplasticity,learning,memory,andlocomotion.Theglutamatergicsystemnaturallyregulates the glutamate concentrations in the synaptic shaftviabothneuronalandglialreceptors.Severalstressfulstimulilead to excessive release of glutamate into the synapse thatcancauseglutamatergichyperactivity,neurotoxicity,andcelldeathwhenneuronalreceptorsextendedlyactivated.Follow-ing excessive glutamate release, a decrease in brain GABAis observed since glutamate is being used by the brain tosynthetizeGABA[48].Standingseveralbrainimagingstud-ies are also supporting this hypothesis, which showed that
acutedepressionisassociatedwithlowprefrontalandoccip-
italcortexGABAconcentrations[49].
Thus,alongsidepresynapticdownregulationofGABAer-
gicsystem,andthereforeGABAergicneuronsactivityreduc-tion, GABA-A receptor functionmay be impaired [50]. Fur-thermore, GABA(A) mediated neuronal inhibition inducedbypre-andpostsynapticsitesinteractionwithROSmayalsocontributetothedevelopmentofneuronaldamageleadingtoneurotransmission impairments [51]. Also, several studiessuggestthattheglutamatergicsystemdysfunctionisobviousdue to the exceptional efficiency of ketamine in MDD treat-ment.
Morespecificstudiesonthisaspectshowedthatincreased
NMDA receptor activity and glutamatergic synapse impair-ment are leading to depressive behaviour when localized intheprefrontalcortex.Inthisway,severalstudiesmanagedtodemonstrateequallyhyperactiveNMDAreceptorsandgluta-matergic synapses both in depressive patients and in animalmodelsofdepressivebehaviour[52,53].Thus,increasedglu-tamatelevelscouldleadtofreeradicalformationbyxanthineoxidase,forexample,andfurtherproductionofoxygenrad-icals and oxidative neurological damage. Also, nitric oxide-relatedtoxicitycausedbyperoxynitriteformationinNOandsuperoxide anions reaction results in microfilament tyrosine
residues nitration [54]. At the same time, Mg-SOD activity,
which is positively modulated by ROS accumulation, couldinhibitthemitochondrialrespiratorychainandtheglutamatetransporter and therefore lead to glutamate-induced neuro-toxicity[55].

4 OxidativeMedicineandCellularLongevity
However, MDD has been characterized as a progres-
sive stage-related process of neurodegeneration caused byapoptosis, reduced neurogenesis or neuronal plasticity, andincreased autoimmune responses. Thus, increased oxidativestressmarkersandneuroinflammationhavebeenreportedinthebloodofdepressedpatients[56],butthemolecularpath-
ways through which impaired redox homeostasis interacts
with the immune-inflammatory system in relation to MDDarestillnotclear.
O fc o u r s e ,t h e r ea r es t i l lal o to fc o n t r o v e r s i e sr e g a r d i n g
the relevance of the oxidative stress status in most of theaffectivedisordersanddespitethefactthatmostofthestudiesare showing that the affective disorders development can becorrelated to increased oxidative levels (as we showed formost of the shortly described studies above), there are alsosomedistinctstudies reportingthatoxidativestress maynotbelinkedinanyway,forexample,withPTSD[57,58].
Thus, in this minireview we decided to describe the way
inwhichoxidativestressisinvolvedintheaffectivedisordersdevelopment,byfocusingonthemainoxidativestressmark-ers that could be used mechanistically and therapeuticallyin these deficiencies, genetic perspectives, and antioxidanta p p r o a c h e s ,a sw e l la st h er e l e v a n c eo fs o m ea n i m a lm o d e l sstudiesinthiscontext.
2. Methodology
The information gathered for this review was searched int h em a i na v a i l a b l ed a t a b a s e s( e . g . ,S c i e n c e D i r e c t ,P u b M e d /Medline, Embase, and Google Scholar) taking into consid-erationjustthearticlesintheEnglishlanguage.Theselectionprocess was conducted regardless of the articles publicationdate and included articles up to March 2016. Firstly, thepublicationswerescreenedbytitle,thenbyabstractcontent,andthenbyfullcontent.Thisinquirywasconductedbythreeseparate researchers (Ioana Miruna Balmus, Alin Ciobica,andIuliaAntioch).Anydifferencesofopinionsweresolutionbycommonconsent.
3. The Relevance of Some Oxidative
Stress Markers and Their Mechanisms in
the Affective Disorders
Currently, many hypotheses are describing the affective
impairments. Depression development, for example, relies
onpsychological,psychosocial,hereditary,evolutionary,and
biologicalcombinedfactors.Inthisway,mostofthetheoriesrely on the monoamine hypothesis which states that sero-tonin, norepinephrine, and dopamine can assist the devel-opmentofdepressioninaconcentration-dependentmanner.Thus,serotoninisthoughttomodulateotherneurotransmit-ter systems and therefore any changes in its concentrationmay lead to unusual or aberrant neurotransmission [58].Low serotonin levels are promoting low norepinephrinelevels which could lead to DD [111]. Correlated to this, aw i d e l yk n o w nh y p o t h e s i ss t a t e dt h a tc e r t a i nm o n o a m i n eneurotransmitters can lead to affective impairments: nore-pinephrinedeficitsmayberelatedtoalertnessandenergylossleading to anxiety, attention deficits, and loss of interest in
life, while serotonin deficits is related to anxiety, obsessions,compulsions,anddopaminesystemimpairmenttoattentionand motivation loss [112]. Still, many limitations of themonoamine hypothesis led to the conclusion that DD mayberathercomplexalmostcertainlymultifactorial[113,114].In
thiswayoxidativestressanditsmainmarkerscouldrepresent
some viable solution for the understanding and for a bettermanagementofsomeaffectivedisorders.
Infact,clinicaltrialsweretheprimarysourceofevidence
that oxidative stress could be implicated in the pathogenesisof the affective disorders. In this way, it was shown that themood stabilizers and antidepressant therapies possess highantioxidant potential [115]. Also, other studies showed thatsomeoxidativestressmarkersarenormalizingduringorafterthespecifictherapyappliedfortheaffectiveepisodes,suggest-ingthatantidepressantscouldactuallyreduceoxidativestresslevels [116]. In this way, it was actually shown that severalantidepressants such as tianeptine [117], escitalopram [118],venlafaxine [119], or mirtazapine [120] could exert antioxi-danteffects.
However, there are still a lot of controversies about this
subject, since some authors such as Bilici et al. showedthattheadministrationofsomeselectiveserotoninreuptakeinhibitors(SSRIs)for3monthsisgeneratinganormalizationin levels for some oxidative stress markers such as someantioxidative enzyme activities and lipid markers [121] ortheGałeckigroup,whichdemonstratedthatfluoxetinegiventogether with acetylsalicylic acid is decreasing the oxidativestress levels in patients with major depression disorder
(MDD) [122], while on the other side the group of Sarandol
stated no significant modifications in the oxidative stresslevels after venlafaxine and sertraline administration for 6weeksand/orthesameGałeckiresearchgroup,whichshowedno modifications at all in the levels of some oxidative stressm a r k e r ss u c ha st h eg l u t a t h i o n ep e r o x i d a s ea ft e r3m o n t h sof fluoxetine treatment [123, 124]. In this way, one possibleexplanation for this lack of homogenous results could berepresented also by the dosage of antidepressantused, since,forexample,40mgoffluoxetinecouldexertsomeantioxidanteffects[125],whicharenotvisibleinotherstudiesthatused10or 20mg, as in the aforementioned Gałecki et al. study [126](asalsodescribedin[19]).
Infact,inMDD,whilemostoftheauthorshavegenerally
described decreased levels of GPX and increased levels ofmalondialdehyde (MDA), as a lipid peroxidation marker[123, 126], there are also controversies regarding the specificactivityofsomeantioxidantenzymessuchasSOD,whichwasreportedtobedecreasedinpatientswithMDD[56],showingnosignificantmodificationswhencomparedtocontrols[127]o ras i g n i fi c a n ti n c r e a s ei nm o s to ft h es t u d i e s[ 1 2 3 ,1 2 4 ,1 2 8 ,129].
As we also mentioned before when we described the
levels of SOD in some neuropsychiatric disorders [19, 130]
this could be perhaps explained by the fact that SOD
represents the first enzyme to get in contact with the freeradicals and its increase may suggest some compensatoryactions. However, when the specific activity of both SODand GPX us decreasing, this will lead to an accumulation of

OxidativeMedicineandCellularLongevity 5
hydrogenperoxidethatwillstimulateinacascadeofthelipid
peroxidation processes and protein oxidation, which couldexplain some pathological manifestations observed in thesedisorders.
In this way, it seems that lipid peroxidation is an impor-
tant component of the oxidative stress status observed in
depression[131].Infact,ourgroupshowedthatsubclassifying
depressionintodifferentstages,basedonchronicity(e.g.,firstepisode versus recurrent depression), can actually predictsignificantdifferencesinthelevelsofsomelipidperoxidationm a r k e r ss u c ha sM D Aa n da l s oi nt h es p e c i fi ca c t i v i t yo ft h em a i na n t i o x i d a n te n z y m e ss u c ha sS O Da n dG P X[ 1 9 ] .Thus, perhaps an increased production of oxygen and nitro-gen reactive species in these patients could generate a rapidconsumption of the plasmatic antioxidants. Thus, in a so-called vicious cycle in the various staging of these affectivepathologies, we could face an inadequate antioxidant enzy-matic activity incapable of counteracting increased concen-trations of free radicals and inflammatory processes, as wewill show immediately. Moreover, similar facts were showedby our group in the case of the mild cognitive impairmentand AD patients [18], so the aforementioned aspects couldrepresentperhapsanimportantpathwayinthedevelopmentoftheseneuropsychiatricdisorders.
Coming back to MDD, Dimopoulos et al. group [132]
showedthatplasmalevelsofisoprostane-8-epi-prostaglandinF2alphagetsunusuallyhighinelderpatientswithdepressivesymptoms. Moreover, M ¨u l l e re ta l .[ 1 3 3 ]p r o p o s ean e w
m a r k e ro fo x i d a t i v es t r e s s ,b a s e do nt h ef a c tt h a tt h eb r a i nmembrane lipids are very important in depressive and anx-
iety disorders progression. In this way, it seems that low
polyunsaturated fatty acids (PUFA) levels can be correlatedwith low antioxidant protection and an increased n-3 PUFAsupply mayreducemood-relatedbehaviours[133].In fact,itseems that omega-3 fatty acids may actually alleviate somedepression-related effects [134]. In this way, as we will insiston the last chapter of this review, dedicated to the possibleantioxidant therapeutic approaches in most of the affectivedisorders treatment, several recent studies also showed thateicosapentaenoic acid supplementation was actually quiteeffective against primary depression [135]. Moreover, it hasbeen also observed that GPX homologues could exert someantidepressant effects [136, 137], while Brown et al. [138]demonstrated that lipid peroxidation, DNA/RNA damage,andnitricoxidelevelscouldberelevantmarkersintheMDDpathology.
As mentioned, several recent studies such as the one
of Black et al. in 2015 [8] revealed that both 8-hydroxy-2-deoxyguanosine (8-OHdG) and F2-isoprostanes areincreased in depression, suggesting a strong implicationof inflammation and oxidative stress in its pathologicalmechanisms. Moreover, this recent finding supports thehypothesis that increased metabolic stress is present indepression contributing to its high somatic morbidity and
mortality. In fact, there are opinions in the literature that
MDD could be considered an inflammatory disorder, asjudgedmainlybytheincreasedlevelsoftheproinflammatorycytokines, such as interleukin-1b, interleukin-6, or tumornecrosis factor-alpha [139]. There is also a “vicious cycle”of pathogenic manifestations in this case, considering that
depression could be correlated to an increased productionof proinflammatory cytokines that, in turn, would lead toincreased oxidative stress [140, 141], while also decreasedlevels of antioxidants/antioxidant enzymes could generateincreasedinflammatoryresponse[142].
Brain antioxidant deficiencies also contribute to an
o x i d a t i v ed a m a g ew h i c hw a so b s e r v e di nB D .I nt h i sw a y ,glutathione was found in low concentrations in the pre-frontal regions of bipolar patients [143], while downregula-tions of important antioxidant enzymes (such as superoxidedismutase 1, glutathione peroxidase 4, and glutathione S-transferase) were observed in hippocampus [144]. More-over, considering that the thiobarbituric reactive substances(peroxidized species of lipids or lipid complexes) can easilychange protein conformations and therefore disturbing lipidmessengerssignallingsystems[145,146],someauthorsfoundt h a t ,i nB D ,t h eo x i d a t i v es t r e s st ol i p i ds t r u c t u r e sc o u l dactually increase in a stage-dependent manner, disregardingthemoodepisode[147,148].Ontheotherhand,asthenitrico x i d ei si n v o l v e di nt h ee x c e s s i v er e l e a s eo fg l u t a m a t ea n dabnormalreactionstothiolproteicgroups[26],itseemsthattheroleofglutamate-inducedoxidativestressvianitricoxidecouldbealsoextremelyrelevantinBD[148].
In addition, groups such as the one lead by Grande et al.
[149] or Vieta et al. [150] suggested that alongside theprogressionoftheBD,severalmarkerssuchasneurotrophinsand inflammatory cytokines (tumor necrosis factor-alpha(TNFa)) could be well correlated to the pathological evolu-tion of the disorder. Moreover, Kapczinski et al. [151] stated
even from 2009 that TNFa levels could represent an impor-
tantmarkerinthebipolardisorderstaging.
Also, it was stated that the lipid peroxidation processes
could represent an important biomarker in BD progression,togetherwith8-OHdG,whichcancauseimpropertranslationand protein aggregation [152] and with 5-hydroxymethyl-cytosine(5-HmC)[153].
Moreover, it seems that oxidative stress can alter brain
activity through similar mechanisms, but with differentvisible behavioural manifestations. In this way, glyoxalase 1isanenzymewhichprotectsagainstcarbonylstress,reactioncontrolledbyglutathioneasacofactorforthisenzyme[154].On the ground that glutathione reductase 1 and glyoxalase 1are antioxidant factors which are highly correlated to ANXbehaviour, many studies have been conducted in order tofind the nature of this correlation. Thus, Hovatta et al. [33]showed that overexpression of the glutathione reductase1 and glyoxalase 1 gene leads to anxiety-like behaviours,while inhibition of glyoxalase 1 expression produces onlylowintensityanxiety-likebehaviours.Also,basedonthefactthat excessive ROS accumulation induces overexpression ofthese genes and therefore intense activity of the enzymes, itc a nb es p e c u l a t e dt h a tt h e yc o u l dr e g u l a t eA N X .H o w e v e r ,there are also controversial results in this area of research,
sincethesefindingswerediscordantwithotherstudieswhich
showedthatglyoxalase1maybeamarkerforthetraitanxiety[155,156].
Also,mechanisticallyspeakinganxietycouldberelatedto
lo wlev e lso fga mma-a mino b u tyricacid(GAB A)occurr ence

6 OxidativeMedicineandCellularLongevity
Lipid
peroxidation
evaluation
Sucrose
preference
test
Intracranial
self-stimulation
Attention-set
shiftingTreadmill
running Forced
swim test
Tail
suspension
test
Dexamethasone
suppression
testConditioned
place
preference
Predator
simulation
test
Female
urine
sniffingSocial
interaction
testNovelty-induced
hypophagiaMorris
water maze
Home cage
behaviour
assessmentElevated
plus maze
Elevated
zero maze
Elevated
alley maze
Suok rope
walking
Place
aversion test
Open field
test Light-dark
box testModified
hole board
Defensive
marble test
Shock
burying test
Fear-potentiated
startleV ogel
conflict test
Depressive behaviour evaluation techniques Anxious behaviour evaluation techniques
Figure2:Behaviouraltestsbatteryusedindepression/anxietyassessment[165].Duetothefactthatdepressiveandanxiousbehavioursare
interconnected,andinsomecasesinterdependent,itisveryimportantforthedifferenceofanxietyasatraitorasasymptom,forexample,tobeclearlydefined.Thus,severalevaluationtechniquescanonlyevaluatedepressivebehaviour(thetestsshownintheleftsideofthepicture),
beingusefulindeterminingcleardepressivetraits.Ontheoppositesidethetypicalanxiousbehaviourtechniquesstandwhicharemeantto
evaluate general and conditioned anxiety, while in the middle the depressive-related anxiety techniques stand, which can be used in bothdepressionandanxietyevaluation.Thisaspectcanbecrucialwhenelaboratingcomplexhypothesisregardingcommonsymptomatologyand
behaviourwhichleadstoelucidatinginformationinaffectivesyndromesetiology.
whichisreducingbrainactivity[157].Inthisway,eitherover-
activation or underinhibition can lead to cortical and limbicglutamateneurotransmissionthroughN-methyl-D-aspartate( N M D A )r e c e p t o r st h a ti sl i n k e dt oa ne x c e s so fs t i m u -latory glutamate, calcium influx, or insufficient GABA orGABA receptor function deficits. Additionally, the researchon the GABAergic system has been performed on PD andOCD animal models and patients [158, 159], demonstratingalso that oxidative metabolism can affect the regulation ofANX behaviour. In this way, it has been shown that inoxidant conditions and due to the lipid-rich constitution ofbrain, lipid peroxidation increases which causes membranefluidity impairment and probably impairments in receptors,enzymes, and ion channels functions [160]. Therefore, it isquite possible that oxidative stress could alter neurotrans-
mission, cell signalling, and therefore brain activity in these
pathologies[161].
4. Oxidative Stress Implications in Some
Animal Models of Affective Disorders
To this date, the generation of various animal models is
considered an extremely valuable tool in understandingthe mechanisms behind a variety of specific diseases. Also,animalmodelsarewidelyandefficientlyusedintheaffective
disorders research area, considering the obvious ethicalconstraintsinusinghumansubjectsandtheimpossibilitytocontrolthehumanindividualvariability[144].
Of course, the animal models are not the perfect repre-
sentation of the complex human diseases, especially consid-
ering the fact that psychiatric concepts such as self-esteem,
recurrent thoughts of death [162], or fear of losing control[163] are not reproducible in this case. Instead, they arecreated to mimic certain characteristics of the disease or abehaviouraldimensionspecifictothatpsychiatricpathology(e.g.,affectivediseaseinthiscase)[164].
Due to this fact, it is extremely important to correctly
assess the specific affective spectrum behaviour. In order tod ot h i s ,t h e r ea r em a n yb e h a v i o u r a lt e s t sw h i c hc a nb es u c -cessfully used. A more comprehensive example is presentedin Figure 2, in regard to the various tests which can assessdepressiveandanxiousbehaviour.
Also, these animal models must fulfill several criteria to
bevalidated.Forthisreason,theymustbecomparabletothehuman dysfunction in the aspects of symptomatology (facevalidity), treatment manners (predictive validity), similarcausative neurobiological factors (construct validity), andcommon etiology (etiological validity) [59]. Another aspect

OxidativeMedicineandCellularLongevity 7
that must be met is repeatability between laboratories and
variousstudies[60].
Constantly,newmodelsaredesignedortheexistingones
are improved due to the need of a higher accuracy. It isalsothecaseofaffectivedisordersmodellinginanimalscon-sidering ethological aspects, genetics, surgical procedures,
chemical induction, or their combination resulting in a
multitudeofanimalmodels(Table1).
Inthisway,itseemsthatoxidativeimpairmentsobserved
in the animal models of affective disorders are somehowsimilar to the disparities found in humans. Thus, Brocardo’steam, for example, demonstrated the presence of increasedl e v e l so fo x i d a t i v ed a m a g ei nar a tm o d e lo ff e t a la l c o h o lexposure, in which they created the conditions of anxiety-and depression-like behaviour. They recorded significantlyhigher levels of lipid peroxidation and protein oxidationmeasuredinthehippocampusandcerebellum,whilephysicalexercising displayed protective effects in this matter andincreasedtheratesofglutathione[104].
Also, it was showed that in BD animal models there are
variousalterationsfortheproteinoxidationmarkers,withthespecific activity of SOD and CAT being increased and GPXactivitydecreased.Also,thelevelsoflipidperoxidationmark-erswerefoundtobeincreased,whichcorrelatedtolowratesof glutathione and vitamin C. Moreover, the administrationoflithiumandvalproateinthesecaseswasassociatedwithasignificant reduction for the lipid peroxidation processes inthehippocampusandtheprefrontalcortex[90–93].
In other several models of depression in rats it was
showedthattheseanimalsexhibitalterationsofsomeoxida-
tive mechanisms in the form of glutathione levels depletion,
decrease in GPX specific activity, lower levels of vitamin C,or increased rates of lipid peroxidation and nitric oxides[166, 167]. Another study also showed that lamotrigine,aripiprazole,andescitalopramexertedsomeprotectiveeffectsagainst depression linked GPX, glutathione, and vitaminC deficiency and also decreased lipid peroxidation levels.Moreover, from the aforementioned three drugs, it seemsthatlamotriginewasassociatedwiththestrongestantioxidantprotectiveabilities[168].
Also, we can mention here the study of Kumar group,
whichusedanimmobilizationstressanimalmodelofanxietyand proved that the six-hour time spent in restraint couldconsiderably increase the brain concentrations of lipid per-oxidation markers and nitrite in the animals. Furthermore,the same anxiety model had important effects on brain glu-tathioneandcatalaserateswhichweresignificantlydecreasedcomparedtothecontrolgroup[105].
Another animal model of affective disorder induced
by ouabain (African plant derived toxic substance) singleintracerebroventricularinjectionwhichactuallycouldmimicthe conditions of mania and that is course characteristic tothebipolardisorderresultedinincreasedthiobarbituricacidreactive substances (TBARS) and carbonyl levels especially
i nt h ef r o n t a lc o r t e xa n dh i p p o c a m p u sa r e a ,w h i l ee l e v a t e d
SOD activity and reduced CAT specific activity were alsoreportedintheaforementionedcentralareas[95].Moreover,the same group showed that sodium butyrate (e.g., with theinhibition of Na
+/K+-ATPase produced by ouabain) couldcounteracttheoxidativealterationsinducedbyspecifictoxin
administration, through the reversal of the protein and lipiddisturbancesfoundinthehippocampusandprefrontalcortexofinjectedratsandbyincreasingCATspecificactivity[169].
In addition phenelzine, which is a monoamine oxidase
inhibitordrug,showedgreatantioxidativedefensepotential,being capable of reducing the reactive oxygen species for-mationandthescavengingproprietiesofhydrogenperoxide[170]. Also venlafaxine, a drug from the selective serotoninreuptake inhibitors group, was able to reverse the deficits inglutathione (GSH) rates and also to decrease the levels ofhippocampal MDA and nitric oxide (NO) induced by thespecific stress depression tests such as forced swim test andtailsuspension[171].
In addition, the well-known antioxidant ascorbic acid
[172]wasreportedtoreverseoxidativedamageinaninducedmodel of depressive disorder, as compared to fluoxetine-treated controls, by mainly increasing the specific activity ofCATandglutathionereductase[108].
Oxidative unbalance was also demonstrated in anxiety
models by mainly pointing out the presence of increasedlipid peroxidation, protein carboxylation, and protein thioloxidationanddecreasedvitaminElevels[109,173].
Furthermore, other evidences of oxidative stress in an
anxiety rat model of social stress were demonstrated by animportant increase of plasma 8-isoprostane and hippocam-pus protein carbonylation, but interestingly without anychangesinprefrontalcortexandamygdalaregions[107].
Also,decreasedantioxidantenzymeratesofMnSODand
Cu/Zn SOD in the hippocampus were found in a modifiedmodelofresident-intruderparadigmtohighlightsocialstress
(e.g.,socialdefeatmodel)[110].
In addition, employing a model of PTSD induced by a
single prolonged stress, it was noticed that the decreasedlevelsofglutathionereductasefoundintheamygdalasignif-icantly elevated when grape powder treatment was applied.Also, when grape powder was given before the inducing ofPTSDmodel,itwasobservedthatraisesinoxidativeratesand
inflammationwereprevented,asproven,forexample,bythe
analysisofplasma8-isoprostanelevels[174].
In addition, by using a chronic social isolation model
which is designed to induce depressive and anxiety-likebehaviour in rats, some other authors studied the effect onthehepaticoxidativestressandinflammationlevelsforolan-zapine,anatypicalantipsychoticthatisalsousedsometimesas an adjuvant in anxiety or depressive states of bipolardisorder [175]. In this way, they saw that although the drugwas able to reverse decreased hepatic glutathione levels, itdidnotaltertheelevatedhepaticproinflammatorycytokines,possiblyindicatingthatitmighthavefavourableantioxidativeproprieties, but no effect on inflammation [176]. In fact, ithas been observed after studying the effects of treatmentswith typical and atypical antipsychotics that while the firstonespresentedmainlyprooxidanteffects[177–179],thelatterh a sp r o v e nt oh a v ea ni m p o r t a n ta n t i o x i d a n tc a p a c i t y[ 1 8 0 ,181]. Also, our group previously showed some importantantioxidant modifications for some atypical antipsychoticssuchasquetiapine,olanzapine,andrisperidone[130].

8 OxidativeMedicineandCellularLongevityTable1:Mainanimalmodelsfortheaffectivedisorders(adaptedfrom[59–63]).
InductionmethodModelledaffective
disordersfeatureExperimentdesign Description
NaturalbehaviourRepetitive/stereotypic
behaviour[64]RepetitivebehaviourinanxietyassessmenttestsObsessive-compulsive-likebehaviourincommon
anxiety
DrugadministrationBipolardisorder-associated
hyperactivity [65]Locomotoractivityevaluationinpsychostimulants
administrationPsychostimulantscancausehyperactivity
Drug-inducedanxiety[66]Pentylenetetrazol,sodiumlactate,
m-chlorophenylpiperazine,cholecystok inin
administrationSeveraldrugscanbeusedtogenerateanxiogenic
responses
Withdrawal-induced
depression[67]AddictivesubstancesadministrationDepressioncanalsooccurasaspecificsymptomof
drugwithdrawal
PhysiologicalstressManic-likebehaviour[68]Locomotoractivity,aggressivity,changesinsexual
activityduringsleepdeprivationSleepdeprivation(>72h)causesmanic-likebehaviour
Hyperthermiainduced
anxiety[69]Anxietyassessmentinhighenvironmental
temperaturesAnxiety-likebehaviourcanbeinducedbyhigh
environmenttemperatures
Helplessness-induced
depression[70]IterativephysiologicalstressAnimalslearnthatnoescapeconditionsareprovided;
thereforetheyfailtoexhibitescapebehaviouralsointheabsenceofthestimuli
PsychologicalstressResident-intruder
paradigm-basedaggressivity[71]Locomotoractivity,aggressivity,changesinsexual
activityduringsocialstressAggressivebehaviourcanbeacollateraleffectin
resident-intruderparadigm
Ultrasonic
vocalizations-inducedanxiety[72,73]Ultrasonicdistressinmousepupsseparatedfromtheir
mothersThedecreaseinthenumberofcalls,anxiolyticeffect
Hyponeophagia-induced
anxiety[74]Feedingbehaviourduring/afteranxiogenicstimulusof
noveltyNoveltyinfoodorenvironmentsuppressedfeeding
Maternaldeprivation
[75,76]MaternaldeprivationduringearlypostnatalphasesAlthoughcontroverted,maternaldeprivationduring
infancycancausedepressivedisordersoccurrencein
earlyadulthood
Resident-intruder
paradigmandsocial
defeat-baseddepression[77]Depressionassessmentinmalesduringconsecutive
cohabituationMalescanbeexposedtopsychologicalstressasaresult
ofconsecutivehabitationincages
Social
hierarchization-based
depression[78]Depressivebehaviourintreeshrewssocialhierarchy
andsubordinationNaturaldepressivebehaviourcanoccurindifferent
speciesasaresulttosocialhierarchy

OxidativeMedicineandCellularLongevity 9Table 1: Continued.
InductionmethodModelledaffective
disordersfeatureExperimentdesign Description
ConflictualstimuliVogel-punisheddrinking
[79]HydrationhabitsinanxietyDrinkingbehaviourisalteredwhenanxiogenicstimuli
areapplied
Geller-Seiftertask[80] FeedingbehaviourinanxiogenicstimulationFeedingbehaviourisalteredwhenanxiogenicstimuli
areapplied
CognitivePavlovian[81] BehaviouralchangesinPavlovianconditionsWhendisagreeablestimuliareappliedanxiety
behaviouroccurs
Neurosurgicalmodel Olfactorybulbectomy[82] BehaviouralassessmentafterolfactorybulbectomySpecificdepressivebehaviouroccursafterolfactory
bulbremoval
NeurodevelopmentalmodelClomipramine
administration[83]Anxietybehaviourinneonatalclomipramine
administrationBabyratsexposedtorepeatedinjectionsof
clomipraminedevelopanxiety-likefeaturesin
adulthood
GeneticengineeringSelectivebreeding[84] Manicbehaviourassessmentindifferentstrains Particularstrain-specificbehaviouralfeatures
Selectivebreeding[85] AnxiousbehaviourduringselectivebreedingInordertomaximizeanxiousbehaviour,theanimals
areeitherinbredoroutbred
Singlegenemanipulation[86]AnxiousphenotypingandsinglegenemanipulationKnock-outandtransgenicmicebasedonanxietygenes
manipulation
Selectivebreeding[87,88] DepressivebehaviourduringselectivebreedingAstronggeneticpredispositiontodepressioncanbe
obtainedthroughhighdepressivebehaviourstrainsbreeding
Geneticandontogenetic
modelling[89]GeneticandontogeneticmodellingofdepressivetraitsForwardorreversegenetictechniquesfacilitate
blockadeorstimulationofneuronalactivity

10 OxidativeMedicineandCellularLongevity
Table2:Shortoverviewfortheoxidativestressmodificationsinsomeaffectivedisordersinanimalmodels.
Followeddisease Animalmodel/test Oxidativedisturbances
BipolardisorderManicphase,inducedwithamphetamineBrain:↑SODproduction;↑TBARS[90]
↑proteinandlipidoxidativedamage[91]
↓SOD:↓CATspecificactivity[92]
↑lipidperoxidation[93]
↑proteinaggregationof4-HNE(amajorproductof
lipidperoxidation)[94]
Manicphase,chronicamphetamine
administrationSubmitochondrialfragmentsofprefrontalcortexand
hippocampus:↑superoxideproduction[91]
↓GSH-Px;↓glutathione;↓vitaminC[93]
Manicphase,inducedwithouabain↑TBARS;↑superoxideproduction;↑carbonylcontent
[95–98]
↑SOD;↓CAT[95]
DepressionChronicmildstress↑superoxideinhippocampus;↑TBARSincortex[99]
↓antioxidantGSTgeneexpression[100]
Olfactorybulbectomymodel ↓CATinbloodstream;↓GSH;↓GSH-Px;↑SOD[101]
Chronicunpredictablemildstress
(CUMS)↑liverMDA;↓TAC(totalantioxidantcapability); ↓
GSH;↓SOD;↓CAT[102]
Swimmingrestraint ↓plasmaGSH;↓plasmaTBARS[103]
AnxietyFetalalcoholexposureHippocampus,cerebellum:↑lipidperoxidation;↑
proteinoxidation;↓GSH[104]
Immobilizationstress ↑lipidperoxidation;↑nitrite;↓GSH;↓CAT[105]
ChronicsocialisolationHepatic levels:↓GSH;↓glutathionereductase;↑CAT;
↑glutathioneS-transferase[106]
Ovariectomy-inducedPlasma:↑8-isoprostane;hippocampus:↑protein
carbonylation[107]
PLTPknock-outmodel↓vitaminE;↑oxidativestressmarkersinphospholipid
transferproteinknock-outmice[108]
Vit.Asubacutesupplementation↑lipidperoxidation;↑proteincarbonylation;↑protein
thioloxidation;SODandCA T ,altered,inducedby
vitaminA[109]
Posttraumaticstressdisorder(PTSD)
modelSingleprolongedstressAmygdala:↓glutathionereductase;plasma: ↑
8-isoprostaneslevels[110]
Note: SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive sub stances; CAT: catalase; 4-HNE: 4-hydroxynonenal; MDA: malondialdehyde ;4 –
HDA:4-hydroxyalkenals;GSH:glutathione;GHS-Px:glutathioneperoxidase;TAC:totalantioxidantcapacity;GST:glutathione-S-transferase.
In fact, we also demonstrated the relevance of some
animalstudiesaffectivemanifestations,especiallyonanxiety-r e l a t e db e h a v i o u ri nt h ee l e v a t e dp l u sm a z es p e c i fi ct e s ta n d
the correlation of its factors (e.g., time in open arms, head-
dipping, and stretching behaviour) with the main markersof the oxidative stress from the amygdala (e.g., SOD, GPX,
or MDA), as a result of angiotensin (1–7) or angiotensin II
blockers administration, which resulted in anxiolytic effects
[22,182,183].
In addition, a restoration for the lipid peroxidation
processesandnitriteconcentrationwasobtainedaftercoad-ministrationofmelatoninandbuspironeinaspecificimmo-bilizationstress test known to induce anxiety-like behaviour[105].Also,otherantioxidantandanxiolyticagentshavebeenprovento be effective against theoxidative stress status suchas epigallocatechin gallate (EGCG), green tea polyphenol[184], and chlorogenic acid, a dietary polyphenol [185], aswewillinsistinthelastchapterofthisminireviewdedicatedto the relevance of the antioxidant administration in the
affectivedisorders.
Therefore, oxidative stress metabolism appears to have
importantimplicationsintheevolutionofreplicatedaffectivedisorders aspects in animal models [94], as synthesized inTable 2, but there is not yet a clear explanation to whythese processes occur. Consequently, the need to furtherdevelop animal models and strategies is highlighted thatwill eventually lead to an elucidation of the oxidative stressmechanismintheaffectivedisorders.
5. Genetic Aspects in the
Understanding of Oxidative Stress
Implications in Affective Disorders
Theimplicationsofthegeneticstatusintothemostcommon
diseases have been lately intensely argued. Thus, in orderto find an explanation for the high prevalence of several

OxidativeMedicineandCellularLongevity 11
diseases, the paradigm of genetic inheritance has been dis-
cussed. In this way, it seems that several classical diseasessuchashighbloodpressure,diabetes,andalsosomeneurode-generativedisordersmaybeabletopassbetweengenerations[186].Infact,itisnowwellacceptedthatastronginheritablegeneticcomponentmightbeinvolvedinthepathogenesisof
theaffectivedisorders[187].
In this way, many genes have been described to be
involvedinaffectivedisorders’pathology.Theymaybeasso-ciatedwithbraingrowthfactors,signalmolecules,receptors,chelation, and transport factors, while some of them areactually genes which encode several enzymes and factorsimplicatedinbrainoxidativestatus[187].
Although the way in which the genetic component
a c t u a l l yi n c r e a s e st h er i s kf o ra ff e c t i v ed i s o r d e r si sn o tf u l l yu n d e r s t o o d ,i ti sb e l i e v e dt h a tt h eg e n e t i cc o m p o n e n t so faffectivedisordersmaybearesultofmultiplegenemodifica-tions that lead to a specific environmental factor-dependentliability. In this way, the bipolar disorder was found to bet h em o s tl i k e l yt ob ei n h e r i t e d( u pt o8 0 %p r o b a b i l i t yb yadditivegeneticfactors)[188],whilemajordepression(40%–70%)[189]andanxiety(40–50%)[190]arelessprobabletobeinheritedbythedescendants.
Therefore, a contradiction between theoretical heritabil-
ity and susceptibility premises and the actual clinical statusmay occur. A good example in this way is the geneticcomponent of PTSD, which seems to occur in particulargenetic context and under particular environmental factors[191].Moreover,asignificantinteractionbetweenthreepoly-morphisms in the GABA receptor gene was reported to be
involved in PTSD prediction in correlation to childhood
traumaseverity[192].Besidestheneurotransmissionregula-toryfunctionofGABAreceptors,itseemsthatGABAalpha-2receptor is also implicated in stress modulation via chloridecotransportersdomains,whicharealsoactivatedbyoxidativestress responsive kinases [193]. In this way, since oxidativestressmaybeamolecularresponsetopsychologicalstress,itmightactuallymodulatetheregulatorofG-proteinsignalling2 (RGS2) [194], which is a part of the adrenergic receptorsduring conditioned fear response. Also, recently several sin-glenucleotidepolymorphismsoftheFK506bindingprotein5 (FKBP5) were found to interact with childhood trauma inordertocreatePTSDsusceptibility[195].
Similarly, oxidative stress may be involved in FKBP5
functionality due to the interaction between FOXO1 (atranscription factor involved in cell survival and modulatedby oxidative stress), glucocorticoid receptors, and increasedlevelsofpsychologicalstress[196].
In addition, the female predisposition to PTSD may
be modulated by a recently found single nucleotidepolymorphism of estrogen response element, found onpituitaryadenylate-cyclase1receptorgene[197].Itseemsthatpituitary adenylate-cyclase activating peptide/pituitaryadenylate-cyclase 1 pathway exhibits a role in psychological
stressresponse,whichisdependentonanestrogenresponse
element that conveys sex specific-modulation of fearresponse. Moreover, this pathway seems to be involved alsoinanoxidativestressprotectivesystemagainstROS-inducedmitochondrialdysfunctionsandapoptosis[198].Also, dopamine and serotonin receptors polymorphisms
may also be involved in PTSD predisposition due to thelimbic-frontal neurocircuitry complexity. In this way,dopamine transporter SLC6A3 and promoter region of theserotonin transporter genes polymorphisms seem to givehigh risk of PTSD, especially in increased risk environment
factors [192]. Dopamine receptor D2 association with
oxidative stress is rather controversial, considering, forexample, that one recent study correlated a dopamine D2receptor antagonist and anti-Parkinson medication withreduced excitotoxicity and therefore reduced neuronalapoptosisinoxidativestressconditions[199].
Another previous study also associated D2 and D3
dopamine receptor agonists with glutamate oxidative stressinhibition in oxygen/glucose deprivation models [200]. Inaddition, other groups correlated organophosphates expo-sure with oxidative stress and alterations in brain dopamineand serotonin receptors of young rats, but still no actualcorrelation between oxidative stress and these receptors hasbeenproposed[201].
In fact, although a clear correlation between genetic
componentsandPTSDhasbeenmadeandallofthesegenesmay be directly or indirectly implicated in oxidative stressmodulationordevelopment,nopreviouscorrelationbetweenallofthemisavailable.Therefore,sincethepredispositiontoP TS Dth r o u ghth e seg e n e spo l y m o rp h i s m sh a sbee ns h o w n ,the oxidative stress pathways in which they may be involvedarealmostunknowninPTSDconditions.
In this way, it can be stated that the genetic component,
the environmental risk factors, and their interaction in the
affective disorders development context are rather variable.
Basedonthisobservation,thelateststudiesinPTSDgeneticsactuallyrevealedthatidentifyingthespecificgenesorneuro-biological pathways involved in PTSD development and thespecific modifiable environments associated with PTSD risk( a sw e l la st h em e c h a n i s mo fi n t e r a c t i o nb e t w e e nt h et w o )couldbroadenposttraumainterventionapproachesinPTSDtherapyorevenresultinsomepreventionmechanism[191].
Modern molecular biology and developmental biology
rely on a crucial paradigm. As all living organisms arethe result of a complex interaction between genome andenvironment,thementaldisordersseemnottodeviatefromthispattern.Inthisway,interestingquestionscouldarise:inwhatwaythegeneticcomponentwouldformulateasufficientbackgroundforaffectivedisorderspathologicaldevelopmentand, on the other way around, how complex would theenvironmental interaction be in order to provide sufficientriskforpathologiestooccurviaoxidativestressdevelopment?Thereforeitseemsthatbothquestionseventuallygotanswersin the way that it has been shown by familial studies[202, 203] that several genetic modifications (mutations orpolymorphisms) in key genes could give rise to a sufficientmoodimbalancebackground.
Unfortunately, as the familial cases are thought to be
e a s i e rt os c r e e na n dt op r e v e n t ,t h e s ea r eo n l y5t o1 0 %
of all cases. On the other hand, twin and adoption studies[204, 205] revealed that a close interaction exists betweenthegeneticbackgroundandtheenvironment,raisingseveralenvironmental risk factors which could play an important

12 OxidativeMedicineandCellularLongevity
role in building up the risk for affective disorders develop-
ment.
There are plenty of studies that revealed the genetic
componentimplicationsintheaffectivedisordersoccurrenceandrarelythesamesusceptibilitylocusshowsuprepeatedly.Th i si st h er e a s o nw h yag e n e t i cs c r e e n i n gi na ff e c t i v e
disordersishardtoproduceanypreventiveactions.
In this way, a variety of genes have been shown to be
involved in affective disorders development (reviewed by[187]). Association analyses of PD genetics showed severalclassicalcandidatessuchasmonoamineoxidaseA(MAOA),catechol-O-methyl transferase (COMT), adenosine A2Areceptor (ADORA2A), and cholecystokinin B receptor(CCK-BR)genes[205].COMTgene,forexample,codesforacatecholaminecatabolicbreakdownenzyme,whichisknowntobeinvolvedinanxietydevelopmentashighlevelsofCOMThavebeenobservedinpatient’sserum[206].Theimplicationof the most common COMT polymorphism in PD is alsorather controversial due to extremely different study results(reviewed by [205]). In this way, although there are studieswhichnegativelycorrelateCOMTwithPD,itseemsthatthispolymorphismremainsasoneofthemostconsistentfindingsinPDgenetics.
Furthermore,thecorrelationbetweenCOMTandoxida-
tive stress has not been studied much. Still there are severalstudieswhichreporthighCOMTactivityandhighoxidativestress levels in vitiligo patients [207, 208]; a more relevantcorrelationbetweengeneticimplicationsinPDandoxidativestressmaybemaderegardingthemitochondrialmonoamineoxidase.
Also, MAO has been correlated with PD due to several
polymorphisms which modulate MAO gene transcriptionalactivity[209].Furthermore,agenderspecificmodulationhasbeen demonstrated and was associated with PD in severalpopulations[210].Theassociationremainscontroversialdueto the fact that in other populations this correlation failed tobeshown[211].
Also, the cholecystokinin (CCK) neuropeptide has been
associatedwithPDdevelopment.ItseemsthataninteractionbetweenCCKanddopaminemaybeinvolvedinpanicattacksmodulation [212]. In fact, ambiguous results have beenobtained through time in several studies and therefore theexact correlation between CCK and PD is not known,although it seems that CCK A receptor and dopamine D5genes are closely situated on the short arm of the fourthchromosome[212].
Anotherinterestingassociationisreferringtoconnection
between the serotonin transporter gene and both PD [213]andOCD[214]pathologies.Thisgeneiscodingforaproteinaffected by selective serotonin reuptake inhibitor (SSRI)medications, which are of course frequently used in anxietydisorders treatment [215]. Interestingly enough, discrimina-tionwasmadebyshowingthatthemodificationsthatleadtoPD or OCD are different and a question arises: why the way
inwhichamoleculeismodifiedcanchangethepathological
features?Maybetheanswerreliesonthegeneticcomponentsinvolved in these two diseases development. In this way, thesamegenemaypossessdifferentpolymorphicallelesofwhichdifferentoropposedinteractionsleadtodifferentresults.Forexample,theserotoninreceptor2Awasassociatedwithboth
PTSDandPD[216].
RegardingtheBDgeneticcomponent,itseemsthatmost
of the genetic studies on this matter focused on the neuro-transmittersystems,whichcanbeinfluencedbymedication,andparticularlydopamine,serotonin,andnoradrenalinsys-tems. In this way, direct implications were demonstrated forthemonoamineoxidaseA,5-hydroxytryptaminetransporter,andcatechol-O-methyltransferasegenes[217–220].Also,theimplicationsofthesemoleculesinoxidativestressstatushavebeen partially explained, but no direct correlative study hasbeencarriedout.Moreover,Menazzaetal.[221]showedthatMAOAactivitymayincreasemitochondrialROSproduction,which will lead to increased oxidative stress and myofiberdamage.Inthisway,increasedMAOAactivityinbraintissuem a ya l s ol e a dt oi n c r e a s e do x i d a t i v es t r e s s ,k n o w i n gt h a tthe neurons are mitochondria-rich high energy consumers.In the same way, COMT activity is thought to be oxidativestress promoter in association with high catalase activity inmelanocytesandmelaninbiosynthesis[208].
Also, while COMT plays an important role in the brain
catechol amines degradation, it also degrades dopamine in
the prefrontal cortex area which leads to working memory
correlated tasks resolving. Since impaired working memoryhasalsobeencorrelatedtooxidativestressanddamage[222],
it might be possible that high COMT activity is associated
withbothagitation/disorientationandoxidativestress.Later,
D-amino acid oxidase activator gene and brain derived
neurotrophic factor gene became also of great interest, but
it seems that no actual evidence was found in this matter
[223, 224], mainly due to the fact that most of these genes
are reported as schizophrenia susceptibility genes too. Sur-prisingly,itcanbeobservedthatbothD-aminoacidoxidaseactivator and brain derived neurotrophic factor are involvedin several oxidative stress pathways [14, 225], but a directcorrelationbetweenthesetwoandoxidativestressinBDhasnotbeenyetshowed.
In the same way, several susceptibility genes were
s h o w ni nD Da n dA N Xd e v e l o p m e n t .I na d d i t i o n ,t h e
brain derived neurotrophic factor (BDNF) polymorphism
V a l 6 6 M e tt h o u g h tt ob ei m p l i c a t e di nB Dw a sa l s oi n v e s t i -gatedinDD.Justasinothergenes’case,theresultswerequitecontroversial. In this way, no significant association withBDNFpolymorphismorinconsistentevidencewasreported[226, 227]. In spite of these reports, other variations in theBDNF gene may be influencing the susceptibility to DD
[228]. Thus, recently a link between BDNF and oxidative
stress has been confirmed in schizophrenia [229]. It seems
that the patients exhibit a significant decrease in BDNF
levels and also in the activities of SOD and GPX. Moreover,Numakawa et al. [230] showed that significant correlations
canbemaderegardingBDNFandSODspecificactivity.Also,they suggested that an interaction between BDNF and CATcouldbeassocia tedwiththepositiveandnega tivesyndrome
scale (PANSS) as a cognitive factor. Furthermore, a similar
PANSS factor (PANSS depressive factor) can be correlatedwith the interaction between BDNF and GPX. In this way,a possible association between BDNF and inflammatory

OxidativeMedicineandCellularLongevity 13
cytokines and also hypothalamic-pituitary-adrenal (HPA)
axiscouldemerge.
Another gene thought to be implicated in DD is trypto-
phanhydroxylasegene,whichencodesforanimportantrate-limiting enzyme of brain serotonin synthesis [231]. It seemsalso that a specific brain isoform of tryptophan hydroxylase
(TPH2)maybetheconnectionbetweenserotonergicsystems
anddepressionandBD[232].Inthisway,bothZilletal.[232]andZhangetal.[233]groupsreportedgeneticmodificationsthat could link TPH2 gene to DD susceptibility. Further-more, Kuhn et al. [234] reported a possible implication ofthe oxidative stress status in TPH2 activity, whereas THP2oxidationleadstolowTPH2enzymaticactivity.Inaddition,it seems that 5-hydroxytryptamine (5HT) synthesis by missfolding and aggregation due to the cysteine-rich structurecould also be highly susceptible to oxidative damage [235].Furthermore,averyrecentreportshowedincreasedsystemico x i d a t i v es t r e s si nT P H 2k n o c k – o u tm i c ea n da l s oi n c r e a s e dlipidmetabolismimpairmentswhichmightbeimplicatedinserotonindeficiency[235].
Other genes were similarly correlated to the DD devel-
opment, especially considering the wide implication in theo x i d a t i v es t r e s ss t a t u sa n dt h ea s s o c i a t i o nb e t w e e nh i g hoxidativestressanddepressivesymptoms.Inthisway,itwasreported that a polymorphic variant glutamic acid decar-boxylase 2 (GAD2) that is described as an enzyme involvedinGABAsynthesisandwhichseemstobeseverelyimpairedi nA N Xd i s o r d e r s[ 2 3 6 ]m a yb ea l s oi n v o l v e di nD D[ 2 3 7 ] .It also seems that GAD2 enzyme is involved in an extensiveantioxidant system yielded by the astrocytes. In this way,
several reports showed that enhanced GAD2 activity may
contribute to neuronal protection from oxidative stress invitroneuronaltissuecultures[238,239].
Also, controversial results were obtained in the case of
t h ep o l y m o rp h i s m sf o rt h er e g u l a t o ro fG – p r o t e i ns i g n a l l i n g2 (RGS2) gene, which could be implicated in anxiety-likebehaviours [240], but also in PTSD, emotional distress, andPD[241,242].Infact,acorrelationbetweenRGS2andoxida-tive stress was made in a report regarding the postischemicRGS2 upregulation, which leads to enhanced apoptosis inastrocytes via oxygen-glucose deprivation [243]. Similarly,anotherRGSfamilyprotein,calledRGS4,hasbeencorrelatedwith oxidative stress in postischemic and neurodegenerativedisorders.Inthisway,itseemsthatacommonlipidperoxida-tionproductsuchas4-hydroxy-2-nonenalcaninhibitRGS4,whichfurtherimpairstheGTPaseactivity[244].
Several single nucleotide polymorphisms (SNPs) within
the transcriptional coactivator PPARGC1A were also associ-ated with the anxiety phenotypes. PPARGC1A was actuallydiscovered in the muscle cells and brown fat and thought tostimulate mitochondrial biogenesis by increasing oxidativephosphorylation and by enhancing oxidative respiration[245], but it has been shortly connected to the nuclearrespiratory factors 1 (NRF1) and 2 (NRF2), which are linked
to oxidative stress and also well correlated to ANX both in
humanandrodentmodels[23,38].
However, we have to mention that a strong correlation
between genetics, oxidative stress, and affective disordershas not been made quite clear due to the extreme geneticvariability of the individuals. Interestingly enough, many
correlations were observed between these susceptibility loci
and oxidative stress status observed in affective disorders.
A l s o ,a sm e n t i o n e db e f o r e ,s o m eo ft h eg e n e sc o d ef o r
proteins which are important enzymes involved in oxidative
or phosphorylation reactions which commonly use ROS.
In this way, at least hypothetically and theoretically, a link
between the neuroprogression biomarkers and the decline
observed in affective disorders can be made. Also, due to
thecomplexmechanismsunderlyingthepathophysiologyof
these diseases, the way in which inflammatory processes,
oxidative stress, mitochondrial dysfunctions, and apoptosis
areinteractingisratherproblematicandcontroversial.
6. Antioxidant Approaches for the Affective
Disorders Treatment
Of course, the reason behind studying the connection
betweentheaffectivedisordersandtheoxidativestressstatus
is represented by the need of exploring new approaches
towardsthemanagementoftheseimportantpsychiatricdis-
orders. This acute need of finding new therapeutic methods
issustainedbythepositionthesedisordersareoccupyingon
a worldwide scale. In this way, according to an estimativeperspectivegivenbytheWorldHealthOrganization(WHO),
majordepressivedisorderwillbethesecondhealthproblem
worldwidebytheyearof2020[246].Evenmore,itseemsthat
inEuropeandUSAanxietydisordersarethemostprevalent
psychiatricconditions[247–249].
In this way, by knowing that oxidative stress is an
important component in many diseases, the idea of coun-teracting its effects emerged lately in the literature. Thus,
several approaches were designed, such as oxidant potential
inhibitionandantioxidantsystempotentiationapproaches.
Therefore several studies showed that oxidative stress in
theaffectivedisorderscanalsobeinhibitedbypsychiatricdis-
easetherapyitself,asthiswasdemonstratedtobeacausative
component [11,250,251]. For instance, lithium can exhibitmood stabilizing properties, but also antioxidant potential,as some early phase studies regarding the oxidative stress
status in BD showed [252]. Thus, a six-week lithium therapy
can successfully decrease lipid peroxidation markers andrestoreSODplasmalevels[253].Moreover,theseresultswerecomparable to prior studies on BD patients after manic andeuthymic episodes [124,254]. Furthermore, Banerjee et al.[254]groupshowedthatlithiumantioxidantactivityislinkedtoNa
+-K+-ATPase activity.
Also, when the modification of oxidative stress markers
was followed in patients with depressive disorder after flu-oxetine administration for three months, it was found thatthelevelsofsomeantioxidantenzymeslikeCu/Zn-SODandCATaresignificantlyhigherinthepatientsgroupversusthecontrols [124]. Moreover, it seems that also MDA levels aresignificantlylowerduringMDDmedication[255].
Additionally, it seems that oxidative unbalance in social
phobia patients can be corrected after eight weeks of citalo-pramadministration[256].

14 OxidativeMedicineandCellularLongevity
Moreover, the normalization of these parameters over
t h ec o u r s eo ft h e r a p yh a sb e e nd e m o n s t r a t e db yac l a s s i c a lcase report of twin brothers diagnosed with mania. Infact, this was presented as a situation where one brotheraccepted therapy and the TBARS or SOD levels came backto normal parameters after medication, whereas the other
brother refused the medication and these markers remained
unchanged,aswellasthemanicsymptomatology[257].
Also, it was noticed that the aforementioned lithium
therapy can affect SOD activity in the BD patients, but alsoin healthy volunteers exposed to this medication [258]. Inaddition,consistentevidencesareshowingthattheinhibitionof oxidative damaging processes provoked by injuries to ratcerebral cortical cells by the chronic treatment with lithiumis remarkably efficient [259]. It also appears that lithiumcan boost GSH rates and also the expression of glutamate-cysteine ligase [31], while also helping antioxidant defensemechanisms through the management of GST [260]. More-over,additionalreportsindicatedthatlithiumtherapyinratscan increase the specific activity of SOD and GPX in thebrain[261].AlsoseveralhumansubjectstreatedwithlithiumshowedthatdecreasedNOlevelsandincreasedSODactivitycan occur, as compared to first and the 30th day of hospitaladmission [262]. In addition, in a 3-month clinical trial itwas showed that increased GPX activity can be observedafter lithium treatment, as compared to before treatmentdeterminationsandcontrolsubjects[126].
Anti-inflammatory and antioxidant properties were also
showed for the antidepressants such as clomipramine andimipramine, which resulted in decreased NO levels [263].
In addition, antioxidant properties and decreased NO levels
werereportedforseveralSSRIssuchasfluoxetine,citalopram,fluvoxamine, or sertraline, together with reduced xanthineoxidaseactivity[264]andlipidperoxidationprocesses[265].
However, there are still a lot of controversies regarding
the effects for the specific medication used for the affectivedisorders on the oxidative stress status, since some otherstudiessuggestedthatantidepressanttherapiescouldactuallybe a facilitator factor for the oxidative stress generation. Inthis way fluoxetine (as a fluorinated product) can inducehepatotoxicity,asaresulttoincreasedoxidativestressactivity[266].Also,amitriptylinecanexhibitprooxidantactivityasaresult to coenzyme Q10 life shortage and lipid peroxidationpotentiation [267, 268]. More than that, oxidative stressevaluation through F2-isoprostanes quantification [269] indepressed patients treated with sertraline or bupropion foreight months revealed high rates of oxidation, despite somepsychiatricimprovements[139].Inthisway,althoughseveralmethodological issues were proposed, a clear argument of apossible oxidative stress potentiation due to antidepressantmedicationwasnotyetveryclearlytheorized[270].
Infact,inaspecificreview,Micheletal.groupsuggested
that antidepressant therapy and modulation of oxidativestressarelinkedandarecontributinginaspecificwaytothe
oxidativebalance[7,127].Although,inthecontextofdepres-
sion, various studies highlighted that GPX activity becomesnormalsubsequentlytosubchronictherapywithantidepres-sants [56] and NO levels substantially diminish [262], it canbe noted that, in the treatment course with fluoxetine, thespecifications of oxidative and antioxidant context did not
modify flagrantly, while including acetylsalicylic acid in thetreatment scheme resulted in a significant improvement forthe oxidative stress status [124]. One important argumentfor this could be represented by the fact that the depressiveepisodesinhumanindividualsaredefinedbythepresenceof
inflammatorycomponents,whicharerepresentingofcourse
anoriginatingsiteforthereactiveoxygenspecies[7,270,271].
Consequently the inclusion of a nonsteroidal anti-
inflammatory drug could counteract inflammation andtherefore could exert antioxidant actions. Several data areadding up to the fundaments of this hypothesis which areemphasising on the intensified features for the associationof antidepressant therapy with antioxidants such as omega-3acid[271]andN-acetylcysteine[272]indepressedpersonsandalsoanxietySSRIresistantadolescents,alloftheseresult-ing in a better outcome for the treatment course [11]. Again,this enhancement of antidepressant power phenomenontested in anxiety SSRI resistant adolescent patients provedthat the treatment association with N-acetylcysteine (NAC)resultedinanxiolyticeffects[273].
As in the present paper we referred to the main antiox-
idant markers as being mainly enzymes, it must be stated ofcoursethatantioxidantdefenseisalsoconstitutedinanonen-zymatic component (e.g., ascorbic acid, 𝛽-carotene, mela-
tonin,coenzymeQ10,vitaminE,zinc,andglutathione)[274].In this way, for example, in MDD it is important to observethe nonenzymatic antioxidant defense dynamics in orderto evaluate the psychiatric treatment yielding and to deter-mine future mood attacks [275]. Furthermore, it seems that
many biological active molecules are implicated in oxidative
stress such as folic acid (vitamin B9) [276]. In fact, it has
been proven that vitamin B9 supplementation can induce
several important changes in the biochemical context of themonopolarandbipolardepression[277].
ComingbacktoNAC,whichisaprecursorofglutathione,
it has been shown that it can significantly improve the
standard therapy, as a double-blind randomized placebo-
controlled clinical study performed by Ng et al. in 2008
demonstrated [13]. In fact, NAC is considered a product
whichcanmodulateglutathionelevels[149]anditisalready
c i t e da sa na d j u v a n ti nB Dt h e r a p y[ 2 7 8 ] .I na d d i t i o n ,
some studies showed that NAC could improve OCD-related
trichotillomania (pathological nail-biting and skin-picking)[279].Still,therearealsocontroversiesregardingtheusageof
itintheaffectivedisorders,sincethesameauthorconductedanother study in order to evaluate the NAC potential toa l l e v i a t eD Do u t b r e a k s ,w i t hn os i g n i fi c a n tr e s u l t so b t a i n e dinregardtoitsantidepressantpotential[280].
Also,melatoninseemstobeimplicatedintheantioxidant
defence,beinginfactrecognisedasaROSscavenger[281].In
fact,severalstudiescorrelatedthesleepdeprivationtomooddisorders via melatonin secretion impairments [282]. In
addition,melatoninmodulatorsarebeingsuggestedaspotent
mood regulators in BD, when used as adjuvant therapy to
valproate or lithium administration [283]. Moreover, con-
sidering the well-known implications of melatonin in regu-
lation of the circadian rhythm, melatonergic products have

OxidativeMedicineandCellularLongevity 15
been noticed to have antidepressant capacity in depression
encounteredinshiftworkers[282,284].
In addition, copper is another essential element for
the normal functioning of the antioxidant system, which
also plays an important role in immune system modula-
tion, myelin formation, erythropoiesis, and the synthesis of
hormones [155, 156]. Also, changes in copper level werenoted in depressed patients [285]. In this way, knowing that
alterations in copper levels could lead to deficiencies related
toanaemia,neuronaldegeneration,andcardiacandimmunedysfunctionsorthattheexcidinglevelsofcoppercouldcause
cellular instability [286, 287] there is an obvious need to
control its homeostasis [288]. Moreover, although the proofofitsimplicationsintheoxidativemechanismsisprettysolid,
someanimalmodelsstudiescontradictedtheclinicalfindings
[285]andtherefore,thereisstillaneedforthedeterminationof the real benefits for the copper therapy in patients withdepression[288].
Also in the case of zinc, there are reports demonstrating
that it could exert some antioxidant effects, with proveneffectiveness in clinical and preclinical studies, through the
potentiation of the classical antidepressant treatment [289,
290]. In this way, it was showed, for example, that there
is a positive effect generated by adjacent zinc therapy to
imipramine medication in the case of treatment resistant
depression[291].Inaddition,ananxiolyticeffectofzincwas
recorded in anxiety disorder preclinical [292, 293] and clin-
ical [294] discoveries backing up this hypothesis that could
raise hope for the appearance of a new therapeutic avenue
for patients fighting with anxiety, comorbid depression, ordepression[295].
Moreover, the influence of the ascorbic acid, an element
of the antioxidant defense [296], given to an animal model
withinduceddepressivesymptoms,pointedouttoafastand
serious reverse effect for the behavioural and biochemicaldeficiencies associated with it [108], therefore proving its
potentialpositiveeffectintherapy.
Also, lately some studies suggested that omega-3-fatty
acids, initially given as adjuvant in psychotropic treatment
of depressive disorder [297–299], can be extremely useful in
MDD therapy [300]. In this way, new studies regarding the
potentialofomega-3-fattyacidsinwalnutsandfishoilswere
designedinordertoovertakethesedrawbacksandtofurther
investigate this potential therapy direction (as reviewed by[301]).
Otherstudiesshowedthatlycopene(acarotenoidantiox-
idant found in tomatoes and other fruits and vegetables
[302]) may be an important antioxidant compound, which
exhibits no toxic reactions in the animal body [303]. In this
way,FrancisandStevensonfoundthatatomato-richdietcan
prevent depressive manifestations and revealed an indepen-
dent link to lower prevalence rates of depressive behavioursin an elderly community population aged 70 years and over,without any interconnection with intake of other vegetablesanddepressivesymptomatology[304].
In addition, it seems that individual diet and nutrition
are highly important to the brain mechanisms involved inmoodandaffectivedisorders.Inthisway,itwasshowedthat
a diet saturated in fats and carbohydrates can cause several
mood-related brain mechanisms damage [305]. In this way,
increased oxidative stress due to unbalanced alimentation
w a so b s e r v e di nc o m m o na ff e c t i v ea n i m a lm o d e l sa si n fl u –
encing ROS levels, ROS production, and lipid peroxidation
inbraintissues[306].Inaddition,acorrelationbetweenhigh
carbohydratedietandcognitiveimpairmentswaspreviously
demonstrated [307]. Thus, by adopting a healthy diet, the
oxidative stress levels may decrease resulting in a lower
mood disorder development and even decreased predispo-
sition. Therefore, further research on this approach may beextremelyuseful.
Several other studies [308, 309] showed that physical
exercises can also be an important component in MDD and
ANX treatments. From here an assumption could be made
thattheymightalsopreventaffectivedisordersdevelopment.
Even though the mechanisms underlying the relationship
between the effects of exercising and the affective disordersare unknown, some suspect also the possible involvementof oxidative stress [310–313]. However, there are also some
controversiesaboutthismatter,sincesomestudiessupported
the protective role of exercise against oxidative stress, while
othersdemonstratedincreasedoxidativestressmarkersafter
acute aerobic [310, 311] and anaerobic exercise [313, 314]. In
fact, it seems that ROS produced during exercise sessions
provoke specific adaptation and increased regulation inantioxidantendogenousdefenses,whileantioxidantenzymesactivityisleadingtohigherresistancetooxidativestress[315,316]. Also, our group previously showed that preadministra-tionofvitaminC,forexample,couldpreventsomeoxidativestressmanifestations,generatedasaresultof40-minutebouto fb i c y c l ee x e r c i s ei ny o u n gu n t r a i n e ds u b j e c t s[ 3 1 6 ] .Th u sit seems that the correlation between physical exercise inaffective disorders patients and oxidative stress levels maylead to the possibility of employing physical exercise as apotentialpreventivetherapy.
7. Conclusions
D u et ot h eh i g ho x y g e nu s ea n dm a n ym o d u l a t o r ys y s t e m swhichrelyonredoxpotentialexchange,itseemsthattheCNScanbeexcessivelyexposedtooxidativestress.Thecorrelationbetween the affective disorders which are a group of well-studiedpsychiatricdisorderssharingcommonsocioaffective
features and the almost ubiquitous pathological oxidative
stress can be described in a multifactorial background as animportantmechanismofcentralnervoussystemimpairment.Whether the obvious changes which occur in oxidativebalance of the mood disorder patients are a part of theconstitutive mechanism or a collateral effect yet remains aninteresting question. However it is now clear that oxidativestressisacomponentofthesediseasesbeingcharacterizedbydifferentaspectsinadiseasedependentmanner.Therefore,asignificantpatternofoxidativestressinvolvementinaffectivedisordersdevelopmentcanbetheorizedbyfurtherproposingseveralbiologicalmarkersthatcouldbeassessedinindicatingtheoxidativestatusorantioxidanttherapyefficiency.

16 OxidativeMedicineandCellularLongevity
Competing Interests
Ioana Miruna Balmus, Alin Ciobica, Iulia Antioch, and
Romeo Dobrin are supported by a PN II Research Grantno. PN-II-RU-TE-2014-4-1886, called “A Complex StudyregardingtheRelevanceofOxytocinAdministrationinSomeAnimal Models of Neuropsychiatric Disorders.” The otherauthorhasnocompetingintereststodisclose.
Acknowledgments
Ioana Miruna Balmus, Alin Ciobica, Iulia Antioch, andRomeo Dobrin were supported by a research grant offeredthrough CNCS-UEFISCDI, Project no. PN-II-RU-TE-2014-
4-1886.
References
[1] B. Halliwell, “Free radicals and antioxidants: updating a per-
sonalview,” NutritionReviews ,vol.70,no .5,pp .257 –265,2012.
[2] F. Hirth, “ Drosophila melanogaster in the study of human
neurodegeneration,” CNS and Neurological Disorders—Drug
Targets,vol.9 ,no .4,pp .504–523,2011.
[3] T. A. Rouault, “Iron metabolism in the CNS: implications for
neurodegenerative diseases,” Nature Reviews Neuroscience ,v o l .
14,no .8,pp .551 –564,2013.
[4] S. Ghavami, S. Shojaei, B. Yeganeh et al., “Autophagy and
apoptosisdysfunctioninneurodegenerativedisorders,” Progress
inNeurobiology ,vol.112,pp .24–49 ,2014.
[ 5 ]J .I .H u d s o na n dH .G .P o p eJ r . ,“ A ff e c t i v es p e c t r u md i s o r d e r :
does antidepressant response identify a family of disorders
with a common pathophysiology?” The American Journal of
Psychiatry ,vol.147 ,no .5,pp .552–564,1990.
[ 6 ]J .I .H u d s o n ,B .M a n g w e t h ,H .G .P o p ee ta l . ,“ F a m i l ys t u d yo f
affectivespectrumdisorder,” ArchivesofGeneralPsychiatry ,vol.
60,no.2,pp.170–177,2003.
[7] T.M.Michel,D.P ¨ulschen,andJ.Thome,“Theroleofoxidative
stress in depressive disorders,” Current Pharmaceutical Design ,
vol.18,no .36,pp .5890–5899 ,2012.
[ 8 ]C .N .B l a c k ,M .B o t ,P .G .S c h e ff e r ,P .C u i j p e r s ,a n dB .W .J .
H. Penninx, “Is depression associated with increased oxidative
stress?Asystematicreviewandmeta-analysis,” Psychoneuroen-
docrinology ,vol.51,pp .164–175,2015.
[9] M. Vav ´akov´a, Z.ˇDuraˇckov´a, and J. Trebatick ´a, “Markers of
oxidative stress and neuroprogression in depression disorder,”
Oxidative Medicine and Cell Longevity ,v o l .2 0 1 5 ,A r t i c l eI D
898393,12pages,2015.
[10] J. Bouayed, H. Rammal, and R. Soulimani, “Oxidative stress
and anxiety. Relationship and cellular pathways,” Oxidative
Medicine and Cellular Longevity ,vol.2,no .2,pp .63–67 ,2009 .
[11] I. Smaga, E. Niedzielska, M. Gawlik et al., “Oxidative stress
as an etiological factor and a potential treatment target of
psychiatricdisorders.Part2.Depression,anxiety,schizophrenia
and autism,” Pharmacological Reports ,v o l .6 7 ,n o .3 ,p p .5 6 9 –
580,2015.
[12] A. C. Andreazza, M. Kauer-Sant’Anna, B. N. Frey et al.,
“Oxidativestressmarkersinbipolardisorder:ameta-analysis,”JournalofAffectiveDisorders ,vol.111,no.2-3,pp.135–144,2008.
[13] F .Ng,M.Berk,O.Dean,andA.I.Bush,“Oxidativestressinpsy-
chiatricdisorders:evidencebaseandtherapeuticimplications,”International Journal of Neuropsychopharmacology , vol. 11, no.
6,pp.851–876,2008.
[14] M. Berk, F. Kapczinski, A. C. Andreazza et al., “Pathways
underlying neuroprogression in bipolar disorder: focus on
inflammation, oxidative stress and neurotrophic factors,” Neu-
roscienceandBiobehavioralReviews ,vol.35,no .3,pp .804–817 ,
2011.
[ 1 5 ]M .A .E r s o y ,S .S e l e k ,H .C e l i ke ta l . ,“ R o l eo fo x i d a t i v ea n d
antioxidative parameters in etiopathogenesis and prognosis ofpanic disorder,” International Journal of Neuroscience ,v o l .1 1 8 ,
no .7 ,pp .1025–1037 ,2008.
[16] I. G. Gul, R. Karlidag, B. E. Cumurcu et al., “The effect of
agoraphobia on oxidative stress in panic disorder,” Psychiatry
Investigation ,vol.10,no .4,pp .317 –325,2013.
[17]H.Kandemir ,M.A buhandan,N.Akso y ,E.Sa vik,andC.Ka ya,
“Oxidative imbalance in child and adolescent patients with
obsessive compulsive disorder,” J o u rn a lo fP s y c h i a t ri cR e se a r c h ,
vol.47 ,no .11,pp .1831 –1834,2013.
[18] M. Padurariu, A. Ciobica, L. Hritcu, B. Stoica, W. Bild, and
C. Stefanescu, “Changes of some oxidative stress markers inthe serum of patients with mild cognitive impairment andAlzheimer’sdisease,” NeuroscienceLetters ,vol.469,no.1,pp.6–
10,2010.
[19] C.StefanescuandA.Ciobica,“Therelevanceofoxidativestress
status in first episode and recurrent depression,” Journal of
Affective Disorders ,vol.143,no .1 –3,pp .34–38,2012.
[20] A. Ciobica, M. Padurariu, I. Dobrin, C. Stefanescu, and R.
Dobrin, “Oxidative stress in schizophrenia—focusing on the
mainmarkers,” PsychiatriaDanubina ,vol.23,no.3,pp.237–245,
2011.
[21] M.Padurariu,A.Ciobica,R.Lefter,I.L.Serban,C.Stefanescu,
and R. Chirita, “The oxidative stress hypothesis in Alzheimer’sdisease,”PsychiatriaDanubina ,vol.25,no.4,pp.401 –409,2013.
[22] W.BildandA.Ciobica,“Angiotensin-(1–7)centraladministra-
tion induces anxiolytic-like effects in elevated plus maze anddecreasedoxidativestressintheamygdala,” Journal of Affective
Disorders,vol.145,no .2,pp .165–171,2013.
[ 2 3 ]A .C i o b i c a ,L .H r i t c u ,M .P a d u r a r i u ,R .D o b r i n ,a n dV .B i l d ,
“Effects of serotonin depletion on behavior and neuronal
oxidativestressstatusinrat:relevanceforanxietyandaffective
disorders,” AdvancesinMedicalSciences ,vol.55,no.2,pp.289–
296,2010.
[24] L. Hritcu and A. Ciobica, “Intranigral lipopolysaccharide
administrationinducedbehavioraldeficitsandoxidativestressdamage in laboratory rats: relevance for Parkinson’s disease,”
BehaviouralBrainResearch ,vol.253,pp .25–31,2013.
[25] L.Hritcu,A.Ciobica,M.Stefan,M.Mihasan,L.Palamiuc,and
T. Nabeshima, “Spatial memory deficits and oxidative stress
damage following exposure to lipopolysaccharide in a rodentmodelofParkinson’sdisease,” NeuroscienceResearch ,vol.71,no.
1,pp.35–43,2011.
[26] W.Bild,A.Ciobica,M.Padurariu,andV.Bild,“Theinterdepen-
dence of the reactive species of oxygen, nitrogen, and carbon,”
Journal of Physiology and Biochemistry ,v o l .6 9 ,n o .1 ,p p .1 4 7 –
154,2013.
[27] C. A. Massaad and E. Klann, “Reactive oxygen species in the
regulationofsynapticplasticityandmemory,” Antioxidantsand
RedoxSignaling ,vol.14,no .10,pp .2013–2054,2011.
[28] B. Halliwell, “Free radicals and antioxidants—quo vadis?”
Trends in Pharmacological Sciences ,v o l .3 2 ,n o .3 ,p p .1 2 5 – 1 3 0 ,
2011.

OxidativeMedicineandCellularLongevity 17
[29] M.K.LehtinenandA.Bonni,“Modelingoxidativestressinthe
centralnervoussystem,” CurrentMolecularMedicine ,vol.6,no.
8,pp.871–881,2006.
[ 3 0 ]M .M a e s ,R .Y i r m y i a ,J .N o r a b e r ge ta l . ,“ Th ei n fl a m m a t o r y
& neurodegenerative (I&ND) hypothesis of depression: leads
forfutureresearchandnewdrugdevelopmentsindepression,”
Metabolic Brain Disease ,vol.24,no .1,pp .27 –53,2009 .
[31] L. Shao, M. V. Martin, S. J. Watson et al., “Mitochondrial
involvement in psychiatric disorders,” Annals of Medicine ,v o l .
40,no.4,pp.281–295,2008.
[32] H. B. Clay, S. Sillivan, and C. Konradi, “Mitochondrial dys-
functionandpathologyinbipolardisorderandschizophrenia,”InternationalJournalofDevelopmentalNeuroscience ,vol.29,no.
3,pp.311–324,2011.
[33] I. Hovatta, J. Juhila, and J.Donner, “Oxidative stressin anxiety
and comorbid disorders,” Neuroscience Research ,v o l .68 ,n o .4 ,
pp .261 –275,2010.
[34] K.Kumar,S.Sharma,P .Kumar,andR.Deshmukh,“Therapeutic
potentialofGABA
𝐵receptorligandsindrugaddiction,anxiety,
depression and other CNS disorders,” Pharmacology Biochem-
istryandBehavior ,vol.110,pp .17 4–184,2013.
[35] L. Ciranna, “Serotonin as a modulator of glutamate- and
GABA-mediatedneurotransmission:implicationsinphysiolog-
ical functions and in pathology,” Current Neuropharmacology ,
vol.4,no.2,pp.101–114,2006.
[36] E. Engin and D. Treit, “The role of hippocampus in anxiety:
intracerebral infusion studies,” Behavioural Pharmacology ,v o l .
18,no.5-6,pp.365–374,2007.
[37] T.Steimer,“Thebiologyoffear-andanxiety-relatedbehaviors,”
Dialogues in Clinical Neuroscience ,v o l .4 ,n o .3 ,p p .2 3 1 – 2 4 9 ,
2002.
[38] M. G. Distler and A. A. Palmer, “Role of glyoxalase 1 (Glo1)
and methylglyoxal (MG) in behavior: recent advances andmechanisticinsights,” FrontiersinGenetics ,vol.3,p .250,2012.
[39] I. Hovatta, R. S. Tennant, R. Helton et al., “Glyoxalase 1 and
glutathione reductase 1 regulate anxiety in mice,” Nature,v o l .
438,no .7068,pp .662–666,2005.
[40]W .Hassan,C.E.B.Silva,I.U .Mohammadzai,J .B.T .daRocha,
and J. Landeira-Fernandez, “Association of oxidative stress to
the genesis of anxiety: implications for possible therapeutic
interventions,” Current Neuropharmacology ,v o l .1 2 ,n o .2 ,p p .
120–139,2014.
[41] A. Masood, A. Nadeem, S. J. Mustafa, and J. M. O’Donnell,
“Reversal of oxidative stress-induced anxiety by inhibition of
phosphodiesterase-2 in mice,” Journal of Pharmacology and
ExperimentalTherapeutics ,vol.326,no .2,pp .369–379 ,2008.
[42] S.Salim,“Oxidativestressandpsychologicaldisorders,” Current
Neuropharmacology ,vol.12,no.2,pp.140–147,2014.
[43] M.Cengiz,B.Bayoglu,N.O.Alansal,S.Cengiz,A.Dirican,and
N. Kocabasoglu, “Pro198Leu polymorphism in the oxidativestress gene, glutathione peroxidase-1, is associated with agender-specificriskforpanicdisorder,” InternationalJournalof
PsychiatryinClinicalPractice ,vol.19,no.3,pp.201–207,2015.
[44] F.Liu,J.Havens,Q.Yuetal.,“ThelinkbetweenangiotensinII-
mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress,” International Journal of Physiology,
PathophysiologyandPharmacology ,vol.4,no.1,pp.28–35,2014.
[45] N. Orhan, C. I. Kucukali, U. Cakir, N. Seker, and M. Aydin,
“Genetic variants in nuclear-encoded mitochondrial proteinsare associated with oxidative stress in obsessive compulsive
disorders,” JournalofPsychiatricResearch ,vol.46,no.2,pp.212–
218,2012.[ 4 6 ]G .P a g a n o ,A .A .T a l a m a n c a ,G .C a s t e l l oe ta l . ,“ O x i d a t i v e
stress and mitochondrial dysfunction across broad-ranging
pathologies: toward mitochondria-targeted clinical strategies,”OxidativeMedicineandCellularLongevity ,vol.2014,ArticleID
541230,27pages,2014.
[47] A.Deschwanden,B.Karolewicz,A.M.Feyissaetal.,“Reduced
metabotropicglutamatereceptor5densityinmajordepression
determined by [
11C]ABP688 PET and postmortem study,” The
AmericanJournalofPsychiatry ,vol.168,no.7 ,pp.727 –734,2011.
[48] O.A.C.Petroff,“GABAandglutamateinthehumanbrain,” The
Neuroscientist ,vol.8,no .6,pp .562–573,2002.
[ 4 9 ]G .H a s l e r ,J .W .v a nd e rV e e n ,T .T u m o n i s ,N .M e y e r s ,J .S h e n ,
and W. C. Drevets, “Reduced prefrontal glutamate/glutamineand𝛾-aminobutyricacidlevelsinmajordepressiondetermined
using proton magnetic resonance spectroscopy,” Archives of
GeneralPsychiatry ,vol.64,no.2,pp.193–200,2007.
[50] D. Eser, C. Sch ¨u l e ,T .C .B a g h a i ,E .R o m e o ,a n dR .R u p p r e c h t ,
“Neuroactive steroids in depression and anxiety disorders:clinicalstudies,” Neuroendocrinology ,vol.84,no.4,pp.244–254,
2007.
[ 5 1 ]R .S a h ,F .G a l e ffi ,R .A h r e n s ,G .J o r d a n ,a n dR .D .S c h w a r t z –
Bloom, “Modulation of the GABA
𝐴-gated chloride channel by
reactiveoxygenspecies,” J ournalofN eurochemistry ,vol.80,no .
3,pp .383–391,2002.
[52] M. Wang, Z. Perova, B. R. Arenkiel, and B. Li, “Synaptic
modifications in the medial prefrontal cortex in susceptibilityandresiliencetostress,” TheJournalofNeuroscience ,vol.34,no.
22,pp.7485–7492,2014.
[ 5 3 ]B .L i ,J .P i r i z ,M .M i r r i o n ee ta l . ,“ S y n a p t i cp o t e n t i a t i o no n t o
habenulaneuronsinthelearnedhelplessnessmodelofdepres-sion,”Nature,vol.470,no .7335,pp .535–539 ,2011.
[54] Y. M. Sin, W. F. Teh, M. K. Wong, and P. K. Reddy, “Effect
of mercury on glutathione and thyroid hormones,” Bulletin of
EnvironmentalContaminationandToxicology ,vol.44,no.4,pp.
616–622,1990.
[55] K. Aoyama, K. Matsubara, Y. Fujikawa et al., “Nitration of
manganese superoxide dismutase in cerebrospinal fluids is a
markerforperoxynitrite-mediatedoxidativestressinneurode-
generativediseases,” AnnalsofNeurology ,vol.47 ,no.4,pp.524–
527,2000.
[56] H.Herken,A.Gurel,andS.Selek,“Adenosinedeaminase,nitric
oxide, superoxide dismutase, and xanthine oxidase in patients
with major depression: impact of antidepressant treatment,”ArchivesofMedicalResearch ,vol.38,pp .247 –252,2007 .
[57] P. G. Ozdemir, I. Kaplan, C. Uysal et al., “Serum total oxidant
and antioxidant status in earthquake survivors with post-
traumatic stress disorder,” Acta Neuropsychiatrica ,v o l .2 7 ,n o .
3,pp .153–158,2015.
[58] U. E. Lang and S. Borgwardt, “Molecular mechanisms of
depression: perspectives on new treatment strategies,” Cellular
PhysiologyandBiochemistry ,vol.31,no .6,pp .7 61 –777 ,2013.
[59] B. Cz ´e h ,E .F u c h s ,O .W i b o r g,a n dM .S i m o n ,“ A n i m a lm o d e l s
ofmajordepressionandtheirclinicalimplications,” Progressin
Neuro-Psychopharmacology and Biological Psychiatry ,v o l .6 4 ,
pp .293–310,2016.
[60] J.C.Crabbe,D.Wahlsten,andB.C.Dudek,“Geneticsofmouse
behavior: interactions with laboratory environment,” Science,
vol.284,no.5420,pp.1670–1672,1999.
[61] D. A. Slattery and J. F. Cryan, “Animal models of depression—
where are we going?” in Depression: From Psychopathology to
Pharmacotherapy ,J .F .C r y a na n dB .E .L e o n a r d ,E d s . ,K a r g e r ,
Basel,Switzerland,2011.

18 OxidativeMedicineandCellularLongevity
[62] J. F. Cryan and D. A. Slattery, “Animal models of mood
disorders:recentdevelopments,” CurrentOpinioninPsychiatry ,
vol.20,no .1,pp .1 –7 ,2007 .
[63]D.A.SlatteryandJ.F .Cryan,“Theupsanddownsofmodelling
mooddisordersinrodents,” ILARJournal ,vol.55,no.2,pp.297–
309,2014.
[64] J. T. Winslow and T. R. Insel, “Social status in pairs of male
squirrelmonkeysdeterminesthebehavioralresponsetocentral
oxytocinadministration,” JournalofNeuroscience ,vol.11,no.7,
pp.2032–2038,1991.
[65] L. Herman, T. Hougland, and R. S. El-Mallakh, “Mimicking
human bipolar ion dysregulation models mania in rats,” Neu-
roscienceandBiobehavioralReviews ,vol.3 1,no .6,p p .87 4–881,
2007.
[66] A.Shekhar,S.R.Keim,J.R.Simon,andW.J.McBride,“Dorso-
medial hypothalamic GABA dysfunction produces physiolog-
ical arousal following sodium lactate infusions,” Pharmacology
BiochemistryandBehavior ,vol.55,no .2,pp .249–256,1996.
[67]A.M.Ba rr ,A.M a r k o u ,a n dA.G.P hilli ps,“ A‘cra s h ’co ur seo n
psychostimulant withdrawal as a model of depression,” Trends
inPharmacologicalSciences ,vol.23,no .10,pp .475–482,2002.
[68] S. T. Szabo, R. Machado-Vieira, P. Yuan et al., “Glutamate
receptors astargetsofproteinkinaseCinthepathophysiologyandtreatmentofanimalmodelsofMania,” Neuropharmacology ,
vol.56,no .1,pp .47 –55,2009 .
[69] M. J. V. van Bogaert, L. Groenink, R. S. Oosting, K. G. C.
Westphal, J. Van Der Gugten, and B. Olivier, “Mouse straindifferencesinautonomicresponsestostress,” Genes, Brain and
Behavior,vol.5,no .2,pp .139–149 ,2006.
[70] S.F.MaierandM.E.P.Seligman,“Learnedhelplessness:theory
andevidence,” JournalofExperimentalPsychology:General ,vol.
105,no .1,pp .3–46,197 6.
[71] H. Einat, “Establishment of a battery of simple models for
facets of bipolar disorder: a practical approach to achieve
increased validity, better screening and possible insights into
endophenotypesofdisease,” BehaviorGenetics ,vol.37 ,no.1,pp.
244–255,2007.
[ 7 2 ]K .N a s t i t i ,D .B e n t o n ,P .F .B r a i n ,a n dM .H a u g ,“ Th ee ff e c t s
of 5-HT receptor ligands on ultrasonic calling in mouse pups,”
NeuroscienceandBiobehavioralReviews ,vol.15,no .4,pp .483–
487,1991.
[73] K. Nastiti, D. Benton, and P. Brain, “The effects of compounds
actingatthebenzodiazepinereceptorcomplexontheultrasonic
calling of mouse pups,” Behavioural Pharmacology ,v o l .2 ,p p .
121–128,1991.
[74] S.R.Bodnoff,B.Suranyi-Cadotte,D.H.Aitken,R.Quirion,and
M. J. Meaney, “The effects of chronic antidepressant treatment
inananimalmodelofanxiety,” Psychopharmacology ,vol.95,no.
3,pp.298–302,1988.
[75] C. R. Pryce, D. R ¨uedi-Bettschen, A. C. Dettling, and J. Feldon,
“Earlylifestress:long-termphysiologicalimpactinrodentsand
primates,” NewsinPhysiologicalSciences ,vol.17 ,no .4,pp .150–
155,2002.
[76] C. R. Pryce, D. R ¨uedi-Bettschen, A. C. Dettling et al., “Long-
term effects of early-life environmental manipulations in
rodents and primates: potential animal models in depression
research,” Neuroscience and Biobehavioral Reviews ,v o l .2 9 ,n o .
4-5,pp.649–674,2005.
[77] N.N.Kudryavtseva,I.V.Bakshtanovskaya,andL.A.Koryakina,
“Social model of depression in mice of C57BL/6J strain,”
Pharmacology,BiochemistryandBehavior ,vol.38,no.2,pp.315–
320,1991.[78] E. Fuchs, “Social stress in tree shrews as an animal model
of depression: an example of a behavioral model of a CNS
disorder,” CNSSpectrums ,vol.10,no.3,pp.182–190,2005.
[79] J. R. Vogel, B. Beer, and D. E. Clody, “A simple and reliable
conflict procedure for testing anti-anxiety agents,”
Psychophar-
macologia ,vol.21,no .1,pp .1 –7 ,1971.
[80] I. Geller and J. Seifter, “The effects of meprobamate, bar-
biturates, d-amphetamine and promazine on experimentally
induced conflict in the rat,” Psychopharmacologia ,v o l .1 ,n o .6 ,
pp.482–492,1960.
[81] G.N.ErvinandB.R.Cooper,“Useofconditionedtasteaversion
as a conflict model: effects of anxiolytic drugs,” Journal of
PharmacologyandExperimentalTherapeutics ,vol.245,no.1,pp.
137–146,1988.
[82] J. P. Kelly, A. S. Wrynn, and B. E. Leonard, “The olfactory
bulbectomized rat as a model of depression: an update,” Phar-
macologyandTherapeutics ,vol.74,no.3,pp.299–316,1997.
[83] S. L. Andersen, E. A. Greene-Colozzi, and K. C. Sonntag, “A
novel, multiple symptom model of obsessive-compulsive-like
behaviors in animals,” Biological Psychiatry ,v o l .6 8 ,n o .8 ,p p .
741–747, 2010.
[84] H. Einat, “Different behaviors and different strains: potential
n e ww a y st om o d e lb i p o l a rd i s o r d e r , ” Neuroscience and Biobe-
havioralReviews ,vol.31,no .6,pp .850–857 ,2007 .
[85] J. N. Crawley and L. G. Davis, “Baseline exploratory activity
predicts anxiolytic responsiveness to diazepam in five mousestrains,”BrainResearchBulletin ,vol.8,no.6,pp.609–612,1982.
[86] S. C. Heinrichs, H. Min, S. Tamraz, M. Carmouch ´e, S. A.
Boehme, and W. W. Vale, “Anti-sexual and anxiogenic behav-ioral consequences of corticotropin-releasing factor overex-
pression are centrally mediated,” Psychoneuroendocrinology ,
vol.22,no.4,pp.215–224,1997.
[87] S. A. Brunelli and M. A. Hofer, “Selective breeding for infant
ratseparation-inducedultrasonicvocalizations:developmental
precursors of passive and active coping styles,” Behavioural
BrainResearch ,vol.182,no .2,pp .193–207 ,2007 .
[88] A.Sartorius,M.M.Mahlstedt,B.Vollmayr,F.A.Henn,andG.
Ende, “Elevated spectroscopic glutamate/ 𝛾-amino butyric acid
in rats bred for learned helplessness,” NeuroReport ,v o l .1 8 ,n o .
14,pp.1469–1473,2007.
[89] C. S. Branda and S. M. Dymecki, “Talking about a revolution:
the impact of site-specific recombinases on genetic analyses in
mice,”DevelopmentalCell ,vol.6,no .1,pp .7 –28,2004.
[ 9 0 ]B .N .F r e y ,M .R .M a r t i n s ,F .C .P e t r o n i l h o ,F .D a l – P i z z o l ,J .
Quevedo, and F. Kapczinski, “Increased oxidative stress after
repeatedamphetamineexposure:possiblerelevanceasamodel
ofmania,” BipolarDisorders ,vol.8,no .3,pp .275–280,2006.
[91] B. N. Frey, S. S. Valvassori, G. Z. R ´e u se ta l . ,“ C h a n g e si n
antioxidant defense enzymes after d-amphetamine exposure:
implications as an animal model of mania,” Neurochemical
Research,vol.31,no .5,pp .699–703,2006.
[ 9 2 ]B .N .F r e y ,S .S .V a l v a s s o r i ,K .M .G o m e se ta l . ,“ I n c r e a s e d
oxidative stress in submitochondrial particles after chronicamphetamine exposure,” Brain Research ,v o l .1 0 9 7 ,n o .1 ,p p .
224–229,2006.
[93] A.C.Andreazza,M.Kauer-Sant’Anna,B.N.Freyetal.,“Effects
of mood stabilizers on DNA damage in an animal model of
mania,”Journal of Psychiatry and Neuroscience ,v o l .3 3 ,n o .6 ,
pp .516–524,2008.

OxidativeMedicineandCellularLongevity 19
[94] H.Tan,L.T .Y oung,L.Shao,Y .Che,W .G.Honer,andJ.-F .W ang,
“Mood stabilizer lithium inhibits amphetamine-increased 4-
hydroxynonenal-proteinadductsinratfrontalcortex,” Interna-
tional Journal of Neuropsychopharmacology ,v o l .1 5 ,n o .9 ,p p .
1275–1285,2012.
[95] S. S. Valvassori, G. C. Dal-Pont, A. V. Steckert et al., “Sodium
butyrate has an antimanic effect and protects the brain againstoxidative stress in an animal model of mania induced by
ouabain,” PsychiatryResearch ,vol.235,pp.154–159,2015.
[96] L.K.Jornada,S.S.Valvassori,A.V.Steckertetal.,“Lithiumand
valproatemodulateantioxidantenzymesandpreventouabain-
induced oxidative damage in an animal model of mania,”
JournalofPsychiatricResearch ,vol.45,no .2,pp .162–168,2011.
[97] R. E. Riegel, S. S. Valvassori, G. Elias et al., “Animal model
of mania induced by ouabain: evidence of oxidative stress in
submitochondrial particles of the rat brain,” Neurochemistry
International ,vol.55,no .7 ,pp .491 –495,2009 .
[98] R.E.Riegel,S.S.Valvassori,M.Morettietal.,“Intracerebroven-
tricular ouabain administration induces oxidative stress in the
ratbrain,” InternationalJournalofDevelopmentalNeuroscience ,
vol.28,no.3,pp.233–237,2010.
[99] T. F. Ejchel-Cohen, G. E. Wood, J.-F. Wang et al., “Chronic
restraint stress decreases the expression of glutathione S-transferasepi2inthemousehippocampus,” BrainResearch ,vol.
1090,no .1,pp .156–162,2006.
[100]C.Song,A.A.Killeen,andB.E.Leonard,“Catalase,superoxide
dismutase and glutathione peroxidase activity in neutrophils
of sham-operated and olfactory-bulbectomised rats following
chronic treatment with desipramine and lithium chloride,”Neuropsychobiology ,vol.30,no .1,pp .24–28,1994.
[101] D.Zhang,X.-S.Wen,X.-Y.Wang,M.Shi,andY.Zhao,“Antide-
pressanteffectofShudihuangonmiceexposedtounpredictable
chronicmildstress,” JournalofEthnopharmacology ,vol.123,no.
1,pp .55–60,2009 .
[10 2]F .G.deSouza,M.D .B .Rodrigues,S.T ufik,J .N.N obrega,and
V.D’Almeida,“Acutestressor-selectiveeffectsonhomocysteinemetabolism and oxidative stress parameters in female rats,”
Pharmacology Biochemistry and Behavior ,v o l .8 5 ,n o .2 ,p p .
400–407,2006.
[103] N. Todorovi ´c, N. Tomanovi ´c, P. Gass, and D. Filipovi ´c, “Olan-
zapinemodulationofhepaticoxidativestressandinflammation
in socially isolated rats,” European Journal of Pharmaceutical
Sciences, vol. 81, article no. 3382, pp. 94–102, 2016.
[104] P. S. Brocardo, F. Boehme, A. Patten, A. Cox, J. Gil-Mohapel,
andB.R.Christie,“Anxiety-anddepression-likebehaviorsare
accompaniedbyanincreaseinoxidativestressinaratmodeloffetalalcoholspectrumdisorders:protectiveeffectsofvoluntary
physicalexercise,” Neuropharmacology ,vol.6 2,no .4,pp .1607 –
1618,2012.
[105]A.K umar ,G.K a ur ,andP .Rin wa,“ Busp ir o nealo ngwi thmela-
toninattenuatesoxidativedamageandanxiety-likebehaviorin
a mouse model of immobilization stress,” Chinese Journal of
Natural Medicines ,vol.12,no.8,pp.582–589,2014.
[106] C. F. Zorumski and E. H. Rubin, Demystifying Psychiatry: A
ResourceforPatientsandFamilies ,OxfordUniversityPress,New
York, NY, USA, 2010.
[ 1 0 7 ]G .P a t k i ,F .H .A l l a m ,F .A t r o o ze ta l . ,“ G r a p ep o w d e ri n t a k e
prevents ovariectomy-induced anxiety-like behavior, memory
impairmentandhighbloodpressureinfemalewistarrats,” PLoS
ONE,vol.8,no .9 ,ArticleIDe7 4522,2013.
[108] C. Desrumaux, P.-Y. Risold, H. Schroeder et al., “Phospholipid
transfer protein (PLTP) deficiency reduces brain vitamin Econtentandincreasesanxietyinmice,” TheFASEBJournal ,vol.
19,no.2,pp.296–297,2005.
[109] M. R. de Oliveira, R. B. Silvestrin, T. Mello e Souza, and J. C.
F. Moreira, “Oxidative stress in the hippocampus, anxiety-like
behavioranddecreasedlocomotoryandexploratoryactivityof
adult rats: effects of sub acute vitamin A supplementation attherapeuticdoses,” NeuroToxicology ,vol.28,no.6,pp.1191–1199,
2007.
[110] N. Solanki, I. Alkadhi, F. Atrooz, G. Patki, and S. Salim,
“Grapepowderpreventscognitive,behavioral,andbiochemical
impairments in a rat model of posttraumatic stress disorder,”Nutrition Research ,vol.35,no .1,pp .65–75,2015.
[111] D. H. Barlow, Abnormal Psychology: An Integrative Approach ,
ThomsonWadsworth,Belmont,Calif,USA,5thedition,2005.
[112] N. Shah, T. Eisner, M. Farrell, and C. Raeder, “An overview
of SSRIs for the treatment of depression,” Th eJ o u r n a lo ft h e
PharmacySocietyofWisconsin ,pp.33–49,1999.
[113] D.J.Nutt,“Relationshipofneurotransmitterstothesymptoms
ofmajordepressivedisorder,” TheJournalofClinicalPsychiatry ,
vol. 69, no. 2, p. e04, 2008.
[114] V. Krishnan and E. J. Nestler, “The molecular neurobiology of
depression,” Nature,vol.455,no .7215,pp .894–902,2008.
[115] G. A. Behr, J. C. F. Moreira, and B. N. Frey, “Preclinical and
clinicalevidenceofantioxidanteffectsofantidepressantagents:
implications for the pathophysiology of major depressive dis-
order,”Oxidative Medicine and Cellular Longevity ,v o l .2 0 1 2 ,
ArticleID609421,13pages,2012.
[116] J. Sarris, D. Mischoulon, and I. Schweitzer, “Adjunctive
nutraceuticalswithstandardpharmacotherapiesinbipolardis-order: a systematic review of clinical trials,” Bipolar Disorders ,
vol.13,no .5-6,pp .454–465,2011.
[117] J. Quevedo, G. Reus, H. Abelaira et al., “Tianeptine treatment
reverses increase on oxidative damage and decrease of antiox-
idant defense enzymes into the brain of rats submitted to the
chronic mild stress model,” in Proceedings of the 28th CINP
WorldCongressofNeuropsychopharmacology ,2012.
[118] A. Shalaby and S. Kamal, “Effect of Escitalopram on GABA
levelandanti-oxidantmarkersinprefrontalcortexandnucleusaccumbensofchronicmildstressexposedalbinorats,” Interna-
tionalJournalofPhysiology,PathophysiologyandPharmacology ,
vol.1,pp.154–161,2009.
[119] I. Eren, M. Naziroglu, A. Demirdas et al., “Venlafaxine modu-
lates depression-induced oxidative stress in brain and medullaofrat,”NeurochemicalResearch ,vol.32,no.3,pp.497 –505,2007 .
[120] A. Tok, E. Sener, A. Albayrak et al., “Effect of mirtazapine on
oxidativestresscreatedinratkidneysbyischemia-reperfusion,”RenalFailure ,vol.34,no .1,pp .103–110,2012.
[121] M. Bilici, H. Efe, M. A. Koroglu, H. A. Uydu, M. Bekaroglu,
and O. Deger, “Antioxidative enzyme activities and lipid per-oxidation in major depression: alterations by antidepressant
treatments,” JournalofAffectiveDisorders ,vol.64,no.1,pp.43–
51,2001.
[122] P. Gałecki, J. Szemraj, M. Bie ´nkiewicz, K. Zboralski, and E.
Gałecka, “Oxidative stress parameters after combined fluox-
etine and acetylsalicylic acid therapy in depressive patients,”HumanPsychopharmacology ,vol.24,no .4,pp .277 –286,2009 .
[123] A.Sarandol,E.Sarandol,S.S.Eker,S.Erdinc,E.V atansever,and
S.Kirli,“Majordepressivedisorderisaccompaniedwithoxida-tive stress: short-term antidepressant treatment does not alter
oxidative-antioxidative systems,” Human Psychopharmacology ,
vol.22,no .2,pp .67 –73,2007 .

20 OxidativeMedicineandCellularLongevity
[124] P. Gałecki, J. Szemraj, M. Bie ´nkiewicz, A. Florkowski, and E.
Gałecka, “Lipid peroxidation and antioxidant protection in
patientsduringacutedepressiveepisodesandinremissionafterfluoxetinetreatment,” PharmacologicalReports ,vol.61,no.3,pp.
436–447,2009.
[125]D .H.Kim,H.Li,K.-Y .Y oo ,B .-H.Lee,I.K.H wang,andM.H.
Won,“EffectsoffluoxetineonischemiccellsandexpressionsinBDNF and some antioxidants in the gerbil hippocampal CA1
regioninducedbytransientischemia,” ExperimentalNeurology ,
vol.204,no.2,pp.748–758,2007.
[ 1 2 6 ]M .E .O z c a n ,M .G u l e c ,E .O z e r o l ,R .P o l a t ,a n dO .A k y o l ,
“Antioxidant enzyme activities and oxidative stress in affective
disorders,” International Clinical Psychopharmacology ,v o l .1 9 ,
no.2,pp.89–95,2004.
[127] N. Srivastava, M. K. Barthwal, P. K. Dalal et al., “A study
on nitric oxide,𝛽-adrenergic receptors and antioxidant status
in the polymorphonuclear leukocytes from the patients ofdepression,” JournalofAffectiveDisorders ,vol.72,no.1,pp.45–
52,2002.
[128] S. D. Khanzode, G. N. Dakhale, S. S. Khanzode, A. Saoji, and
R. Palasodkar, “Oxidative damage and major depression: the
potential antioxidant action of selective serotonin-re-uptake
inhibitors,” RedoxReport ,vol.8,no .6,pp .365–370,2003.
[129] J. Kodydkov ´a, L. V´avrov´a, M. Zeman et al., “Antioxidative
enzymes and increased oxidative stress in depressive women,”
ClinicalBiochemistry ,vol.42,no.13-14,pp.1368–1374,2009.
[130] M.Padurariu,A.Ciobica,I.Dobrin,andC.Stefanescu,“Evalu-
ation of antioxidant enzymes activities and lipid peroxidation
in schizophrenic patients treated with typical and atypical
antipsychotics,” NeuroscienceLetters ,vol.479,no.3,pp.317–320,
2010.
[131] P. Palta, L. J. Samuel, E. R. Miller III, and S. L. Szanton,
“Depression and oxidative stress: results from a meta-analysisofobservationalstudies,” PsychosomaticMedicine ,vol.76,no.1,
pp.12–19,2014.
[ 1 3 2 ]N .D i m o p o u l o s ,C .P i p e r i ,V .P s a r r a ,R .W .L e a ,a n dA .
Kalofoutis, “Increased plasma levels of 8-iso-PGF2 𝛼and IL-6
in an elderly population with depression,” Psychiatry Research ,
vol.161,no .1,pp .59–66,2008.
[133] C. P. M ¨uller, M. Reichel, C. M ¨uhle, C. Rhein, E. Gulbins, and
J. Kornhuber, “Brain membrane lipids in major depression
and anxiety disorders,” Biochimica et Biophysica Acta (BBA)—
Molecular and Cell Biology of Lipids ,v o l .1 8 5 1 ,n o .8 ,p p .1 0 5 2 –
1065,2015.
[134] A. Wilczy ´nska, “Fatty acids in treatment and prevention of
depression,” PsychiatriaPolska ,vol.47 ,no.4,pp.657 –666,2013.
[ 1 3 5 ]M .E .S u b l e t t e ,S .P .E l l i s ,A .L .G e a n t ,a n dJ .J .M a n n ,“ M e t a –
analysisoftheeffectsofEicosapentaenoicAcid(EPA)inclinical
trialsindepression,” JournalofClinicalPsychiatry ,vol.72,no.12,
pp.1577–1584,2011.
[136] Z. Zhao, W. Wang, H. Guo, and D. Zhou, “Antidepressant-
like effect of liquiritin from Glycyrrhiza uralensis in chronic
variable stress induced depression model rats,” Behavioural
BrainResearch ,vol.194,no.1,pp.108–113,2008.
[ 1 3 7 ]T .P o s s e r ,M .P .K a s t e r ,S .C .B a r a ´una, J. B. T. Rocha, A. L.
S. Rodrigues, and R. B. Leal, “Antidepressant-like effect of theorganoselenium compound ebselen in mice: evidence for the
involvement of the monoaminergic system,” European Journal
ofPharmacology ,vol.602,no .1,pp .85–91,2009 .
[138] A.D.H.Brown,D.A.Barton,andG.W.Lambert,“Cardiovas-
cularabnormalitiesinpatientswithmajordepressivedisorder:
autonomic mechanisms and implications for treatment,” CNS
Drugs,vol.23,no .7 ,pp .583–602,2009 .[139] M. Maes, Z. Fi ˇsar, M. Medina, G. Scapagnini, G. Nowak,
and M. Berk, “New drug targets in depression: inflammatory,
cell-mediate immune, oxidative and nitrosative stress, mito-chondrial, antioxidant, and neuroprogressive pathways. andnew drug candidates-Nrf2 activators and GSK-3 inhibitors,”
Inflammopharmacology ,vol.20,no .3,pp .127 –150,2012.
[140] M. Maes, “The cytokine hypothesis of depression: inflamma-
tion, oxidative & nitrosative stress (IO&NS) and leaky gut asnew targets for adjunctive treatments in depression,” Neuroen-
docrinologyLetters ,vol.29 ,no .3,pp .287 –291,2008.
[141] M. Catena-Dell’Osso, C. Bellantuono, G. Consoli, S. Baroni, F.
Rotella, and D. Marazziti, “Inflammatory and neurodegenera-tive pathways in depression: a new avenue for antidepressant
development?” Current Medicinal Chemistry ,v o l .1 8 ,n o .2 ,p p .
245–255,2011.
[142] R. Kobrosly and E. van Wijngaarden, “Associations between
immunologic,inflammatory,andoxidativestressmarkerswith
severity of depressive symptoms: an analysis of the 2005-
2006 National Health and Nutrition Examination Survey,”NeuroToxicology ,vol.31,no .1,pp .126–133,2010.
[ 1 4 3 ]F .M .B e n e s ,D .M a t z i l e v i c h ,R .E .B u r k e ,a n dJ .W a l s h ,“ Th e
expression of proapoptosis genes is increased in bipolar disor-
der,butnotinschizophrenia,” MolecularPsychiatry ,vol.11,no .
3,pp .241 –251,2006.
[144] K.L.Hoffman, ModelingNeuropsychiatricDisordersinLabora-
toryAnimals ,Elsevier,NewYork,NY,USA,2016.
[145] H. F. Poon, V. Calabrese, G. Scapagnini, and D. A. Butterfield,
“Free radicals and brain aging,” Clinics in Geriatric Medicine ,
vol.20,no.2,pp.329–359,2004.
[146] N. G. Bazan, V. L. Marcheselli, and K. Cole-Edwards, “Brain
response to injury and neurodegeneration: endogenous neu-
roprotective signaling,” Annals of the New York Academy of
Sciences,vol.1053,pp.137–147,2005.
[147] W. Dr ¨oge and H. M. Schipper, “Oxidative stress and aberrant
signalinginagingandcognitivedecline,” Aging Cell ,v o l .6,n o .
3,pp .361 –370,2007 .
[148] M. Berk, S. Dodd, M. Kauer-Sant’anna et al., “Dopamine dys-
regulation syndrome: implications for a dopamine hypothesis
ofbipolardisorder,” ActaPsychiatricaScandinavica.Supplemen-
tum,vol.116,supplement434,pp .41 –49 ,2007 .
[149] I.Grande,P.V.Magalh ˜aes,M.Kunz,E.Vieta,andF .Kapczinski,
“Mediators of allostasis and systemic toxicity in bipolar disor-
der,”Physiology&Behavior ,vol.106,no .1,pp .46–50,2012.
[150] E.Vieta,D.Popovic,A.R.Rosaetal.,“Theclinicalimplications
ofcognitiveimpairmentandallostaticloadinbipolardisorder,”EuropeanPsychiatry ,vol.28,no .1,pp .21 –29 ,2013.
[151] F. Kapczinski, V. V. Dias, M. Kauer-Sant’Anna et al., “Clinical
implications of a staging model for bipolar disorders,” Expert
ReviewofNeurotherapeutics ,vol.9 ,no .7 ,pp .957 –966,2009 .
[152] X. Shan, H. Tashiro, and C.-L. Lin, “The identification and
characterization of oxidized RNAs in Alzheimer’s disease,”
JournalofNeuroscience ,vol.23,no.12,pp.4913–4921,2003.
[ 1 5 3 ]F .M a t a r e s e ,E .C a r r i l l o – d eS a n t aP a u ,a n dH .G .S t u n n e n b e r g ,
“5-Hydroxymethylcytosine:anewkidontheepigeneticblock?”MolecularSystemsBiology ,vol.7 ,no .1,article562,2011.
[154] P. J. Thornalley, “Protecting the genome: defence against
nucleotide glycation and emerging role of glyoxalase I over-
expression in multidrug resistance in cancer chemotherapy,”Biochemical Society Transactions ,v o l .3 1 ,n o .6 ,p p .1 3 7 2 – 1 3 7 7 ,
2003.
[155] S. A. Kr ¨omer, M. S. Keßler, D. Milfay et al., “Identification of
glyoxalase-Iasaproteinmarkerinamousemodelofextremes

OxidativeMedicineandCellularLongevity 21
in trait anxiety,” The Journal of Neuroscience ,v o l .25 ,n o .1 7 ,p p .
4375–4384,2005.
[156] C.Ditzen,A.M.Jastorff,M.S.Kessleretal.,“Proteinbiomarkers
in a mouse model extremes in trait anxiety,” Molecular and
CellularProteomics ,vol.5,no .10,pp .1914–1920,2006.
[ 1 5 7 ]B .W .D u n l o pa n dP .G .D a v i s ,“ C o m b i n a t i o nt r e a t m e n tw i t h
benzodiazepines and SSRIs for comorbid anxiety and depres-sion: a review,” Primary Care Companion to the Journal of
ClinicalPsychiatry ,vol.10,no .3,pp .222–228,2008.
[158] M. Kuloglu, M. Atmaca, E. Tezcan, B. Ustundag, and S. Bulut,
“Antioxidant enzyme and malondialdehyde levels in patients
withpanicdisorder,” Neuropsychobiology ,vol.46,no.4,pp.186–
189,2002.
[159] M. Kuloglu, M. Atmaca, E. Tezcan, ¨O. Gecici, H. Tunckol,
andB.Ustundag,“Antioxidantenzymeactivitiesandmalondi-
aldehydelevelsinpatientswithobsessive-compulsivedisorder,”Neuropsychobiology ,vol.46,no .1,pp .27 –32,2002.
[160] M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur,
and J. Telser, “Free radicals and antioxidants in normal physi-ologicalfunctionsandhumandisease,” InternationalJournalof
BiochemistryandCellBiology ,vol.39 ,no .1,pp .44–84,2007 .
[161] J. Delattre, J. L. Beaudeux, and D. Bonnefont-Rousselot,
Radicaux Libres et Stress Oxydant. Aspects Biologiques et
Pathologiques ,Tec&DocLavoisier,2005.
[162] S. Rotzinger, D. A. Lovejoy, and L. A. Tan, “Behavioral effects
of neuropeptides in rodent models of depression and anxiety,”
Peptides,vol.31,no .4,pp .736–756,2010.
[163] J.F.CryanandF.F.Sweeney,“Theageofanxiety:roleofanimal
modelsofanxiolyticactionindrugdiscovery,” BritishJournalof
Pharmacology ,vol.164,no .4,pp .1129–1161,2011.
[164] R.Lefter,D.Cojocaru,A.Ciobica,I.M.Paulet,I.L.Serban,and
E.Anton,“Aspectsofanimalmodelsformajorneuropsychiatricdisorders,” ArchivesofBiologicalSciences ,vol.66,no.3,pp.1105–
1115,2014.
[165] N. Dedic, S. M. Walser, and J. M. Deussing, “Mouse models
of depression,” in Psychiatric Disorders—Trends and Develop-
ments,T .U e h a r a ,E d . ,c h a p t e r8 ,p p .1 8 5 – 2 2 2 ,I n T e c h ,R i j e k a ,
Croatia,2011.
[166] I. Eren, M. Nazıro ˘glu, A. Demirdas ¸ et al., “Venlafaxine modu-
lates depression-induced oxidative stress in brain and medulla
ofrat,”NeurochemicalResearch ,vol.32,no.3,pp.497 –505,2007 .
[167] S.N.PalandP.C.Dandiya,“Glutathioneasacerebralsubstrate
indepressivebehavior,” Pharmacology,BiochemistryandBehav-
ior,vol.48,no .4,pp .845–851,1994.
[168] I. Eren, M. Naziroglu, and A. Demirdas, “Protective effects
of lamotrigine, aripiprazole and escitalopram on depression-
induced oxidative stress in rat brain,” Neurochemical Research ,
vol.32,no .7 ,pp .1188–1195,2007 .
[ 1 6 9 ]C .S .L e e ,E .S .H a n ,a n dW .B .L e e ,“ A n t i o x i d a n te ff e c to f
phenelzineonMPP
+-inducedcellviabilitylossindifferentiated
PC12 cells,” Neurochemical Research ,v o l .2 8 ,n o .1 2 ,p p .1 8 3 3 –
1841,2003.
[ 1 7 0 ]B .A .A b d e l – W a h a ba n dR .H .S a l a m a ,“ V e n l a f a x i n ep r o t e c t s
againststress-inducedoxidativeDNAdamageinhippocampusduringantidepressanttestinginmice,” PharmacologyBiochem-
istryandBehavior ,vol.100,no .1,pp .59–65,2011.
[171] S. J. Padayatty, A. Katz, Y. Wang et al., “Vitamin C as an
antioxidant:evaluationofitsroleindiseaseprevention,” Journal
of the American College of Nutrition ,v o l .2 2 ,n o .1 ,p p .1 8 – 3 5 ,
2003.[ 1 7 2 ]M .M o r e t t i ,A .C o l l a ,G .d eO l i v e i r aB a l e ne ta l . ,“ A s c o r b i c
acid treatment, similarly to fluoxetine, reverses depressive-
like behavior and brain oxidative damage induced by chronicunpredictablestress,” JournalofPsychiatricResearch ,vol.46,no.
3,pp .331 –340,2012.
[ 1 7 3 ]G .P a t k i ,N .S o l a n k i ,F .A t r o o z ,F .A l l a m ,a n dS .S a l i m ,
“Depression, anxiety-like behavior and memory impairmentareassociatedwithincreasedoxidativestressandinflammation
inaratmodelofsocialstress,” BrainResearch ,vol.1539 ,pp.73–
86,2013.
[ 1 7 4 ]L .G h i o ,W .N a t t a ,P .R o s s ie ta l . ,“ C o m b i n e dv e n l a f a x i n e
and olanzapine prescription in women with psychotic major
depression: a case series,” Case Reports in Medicine , vol. 2011,
ArticleID856903,4pages,2011.
[175] N. Todorovi ´c, N. Tomanovi ´c, P. Gass, and D. Filipovi ´c, “Olan-
zapinemodulationofhepaticoxidativestressandinflammationin socially isolated rats,” European Journal of Pharmaceutical
Sciences,vol.81,pp .94–102,2016.
[176] I. Jeding, P. J. Evans, D. Akanmu et al., “Characterization
of the potential antioxidant and pro-oxidant actions of some
neurolepticdrugs,” BiochemicalPharmacology ,vol.49,no.3,pp.
359–365,1995.
[177] V. Parikh, M. M. Khan, and S. P. Mahadik, “Differential effects
of antipsychotics on expression of antioxidant enzymes and
membranelipidperoxidationinratbrain,” JournalofPsychiatric
Research,vol.37 ,no .1,pp .43–51,2003.
[ 1 7 8 ]A .P i l l a i ,V .P a r i k h ,A .V .T e r r yJ r . ,a n dS .P .M a h a d i k ,“ L o n g –
termantipsychotictreatmentsandcrossoverstudiesinrats:dif-
ferentialeffectsoftypicalandatypicalagentsontheexpressionofantioxidantenzymesandmembranelipidperoxidationinrat
brain,”JournalofPsychiatricResearch ,vol.41,no.5,pp.372–386,
2007.
[179] H. Wang, H. Xu, L. E. Dyck, and X.-M. Li, “Olanzapine and
quetiapine protect PC12 cells from 𝛽-amyloid peptide 25–35-
induced oxidative stress and the ensuing apoptosis,” Journal of
Neuroscience Research ,vol.81,no .4,pp .572–580,2005.
[ 1 8 0 ]H .X u ,H .W a n g ,L .Z h u a n ge ta l . ,“ D e m o n s t r a t i o no fa na n t i –
oxidative stress mechanism of quetiapine: implications for thetreatment of Alzheimer’s disease,” The FEBS Journal ,v o l .2 7 5 ,
no.14,pp.3718–3728,2008.
[181] A.Ciobica,V .Bild,L.Hritcu,M.Padurariu,andW .Bild,“Effects
of angiotensin II receptor antagonists on anxiety and someoxidative stress markers in rat,” Central European Journal of
Medicine,vol.6,no .3,pp .331 –340,2011.
[ 1 8 2 ]A .C i o b i c a ,L .H r i t c u ,V .N a s t a s a ,M .P a d u r a r i u ,a n dW .B i l d ,
“Inhibition of central angiotensin converting enzyme exerts
anxiolytic effects by decreasing brain oxidative stress,” Journal
ofMedicalBiochemistry ,vol.30,no .2,pp .109–114,2011.
[183] M. Vignes, T. Maurice, F. Lant ´ee ta l . ,“ A n x i o l y t i cp r o p e r t i e s
of green tea polyphenol (−)-epigallocatechin gallate (EGCG),”
BrainResearch ,vol.1110,no.1,pp.102–115,2006.
[184] N.G.Kolosova,N.A.Trofimova,andA.Z.Fursova,“Opposite
effects of antioxidants on anxiety in Wistar and OXYS rats,”
Bulletin of Experimental Biology and Medicine ,v o l .1 4 1 ,n o .6 ,
pp.734–737,2006.
[185] R. M. Post, “Heading off depressive illness evolution and
progressiontotreatmentresistance,” DialoguesinClinicalNeu-
roscience,vol.17 ,no .2,pp .105–109 ,2015.
[ 1 8 6 ]N .C r a d d o c ka n dL .F o r t y ,“ G e n e t i c so fa ff e c t i v e( m o o d )
disorders,” European Journal of Human Genetics ,v o l .1 4 ,n o .6 ,
pp .660–668,2006.

22 OxidativeMedicineandCellularLongevity
[187] P. McGuffin, F. Rijsdijk, M. Andrew, P. Sham, R. Katz, and A.
Cardno, “The heritability of bipolar affective disorder and the
geneticrelationshiptounipolardepression,” ArchivesofGeneral
Psychiatry ,vol.60,no .5,pp .497 –502,2003.
[188] K. S. Kendler, M. C. Neale, R. C. Kessler, A. C. Heath, and L.
J. Eaves, “The lifetime history of major depression in women:reliability of diagnosis and heritability,” Archives of General
Psychiatry ,vol.50,no .11,pp .863–870,1993.
[189] T. C. Eley, D. Collier, and P. McGuffin, “Anxiety and eating
disorders,” in Psychiatric Genetics and Genomics , P. McGuffin,
M. J. Owen, and I. I. Gottesman, Eds., pp. 303–340, Oxford
UniversityPress,Oxford,UK,2002.
[190] S. D. Norrholm and K. J. Ressler, “Genetics of anxiety and
trauma-relateddisorders,” Neuroscience ,vol.164,no.1,pp.272–
287,2009.
[ 1 9 1 ]K .S k e l t o n ,K .J .R e s s l e r ,S .D .N o r r h o l m ,T .J o v a n o v i c ,a n dB .
Bradley-Davino, “PTSD and gene variants: new pathways and
new thinking,” Neuropharmacology ,v o l .6 2 ,n o .2 ,p p .6 28 – 6 3 7 ,
2012.
[192] A. S. Galanopoulou, “GABA A receptors in normal develop-
ment and seizures: friends or foes?” Current Neuropharmacol-
ogy,vol.6,no .1,pp .1 –20,2008.
[193] J.W .Zmijewski,L.Song,L.Harkins,C.S.Cobbs,andR.S.Jope,
“Oxidative stress and heat shock stimulate RGS2 expression
in 1321N1 astrocytoma cells,” Archives of Biochemistry and
Biophysics ,vol.392,no .2,pp .192–196,2001.
[194] C. Nunn, M.-X. Zou, A. J. Sobiesiak, A. A. Roy, L. A. Kirshen-
baum, and P. Chidiac, “RGS2 inhibits 𝛽-adrenergic receptor-
induced cardiomyocyte hypertrophy,” Cellular Signalling ,v o l .
22,no.8,pp.1231–1239,2010.
[195] E.B.Binder,R.G.Bradley,W.Liuetal.,“AssociationofFKBP5
polymorphismsandchildhoodabusewithriskofposttraumaticstressdisordersymptomsinadults,” JAMA,vol.299,no.11,pp.
1291–1305,2008.
[196] G. Guidotti, F. Calabrese, C. Anacker, G. Racagni, C. M.
Pariante, and M. A. Riva, “Glucocorticoid receptor and fkbp5
expression is altered following exposure to chronic stress:
modulationbyantidepressanttreatment,” Neuropsychopharma-
cology,vol.38,no .4,pp .616–627 ,2013.
[197] K. J. Ressler, K. B. Mercer, B. Bradley et al., “Post-traumatic
stress disorder is associated with PACAP and the PAC1 recep-tor,”Nature,vol.470,no .7335,pp .492–497 ,2011.
[198] O. Masmoudi-Kouki, S. Douiri, Y. Hamdi et al., “Pituitary
adenylatecyclase-activatingpolypeptideprotectsastroglialcellsagainst oxidative stress-induced apoptosis,” Journal of Neuro-
chemistry ,vol.117,no.3,pp.403–411,2011.
[199] H. Odaka, T. Numakawa, N. Adachi et al., “Cabergoline,
dopamine D2 receptor agonist, prevents neuronal cell death
under oxidative stress via reducing excitotoxicity,” PLoS ONE ,
vol.9 ,no .6,ArticleIDe99271,2014.
[200] C.Rosin,S.Colombo,A.A.Calver,T.E.Bates,andS.D.Skaper,
“DopamineD2andD3receptoragonistslimitoligodendrocyteinjurycausedbyglutamateoxidativestressandoxygen/glucose
deprivation,” GLIA,vol.52,no .4,pp .336–343,2005.
[201] M.L.Sankhwar,R.S.Y adav,R.K.Shuklaetal.,“Monocrotophos
inducedoxidativestressandalterationsinbraindopamineand
serotonin receptors in young rats,” Toxicology and Industrial
Health,vol.32,no .3,pp .422–436,2016.
[ 2 0 2 ]N .C .P .L o w ,L .C u i ,a n dK .R .M e r i k a n g a s ,“ S p e c i fi c i t y
of familial transmission of anxiety and comorbid disorders,”
JournalofPsychiatricResearch ,vol.42,no.7 ,pp.596–604,2008.[203] K. R. Merikangas, J. J. Li, B. Stipelman et al., “The familial
aggregation of cannabis use disorders,” Addiction ,v o l .1 0 4 ,n o .
4,pp.622–629,2009.
[204] J.W.SmollerandC.T.Finn,“Family,twin,andadoptionstudies
ofbipolardisorder,” AmericanJournalofMedicalGeneticsPartC
(SeminariesofMedicalGenetics) ,vol.123,no.1,pp.48–58,2003.
[205] H.-R.Na,E.-H.Kang,J.-H.Lee,andB.-H.Yu,“Thegeneticbasis
ofpanicdisorder,”
JournalofKoreanMedicalScience ,vol.26,no.
6,pp.701–710,2011.
[ 2 0 6 ]C .L .L e h m a n ,T .A .B r o w n ,T .P a l f a i ,a n dD .H .B a r l o w ,“ Th e
effects of alcohol outcome expectancy on a carbon-dioxide
challenge in patients with panic disorder,” Behavior Therapy ,
vol.33,no .3,pp .447 –463,2002.
[ 2 0 7 ] D .A .M e h a n e y ,H .A .D a r w i s h ,R .A .H e g a z ye ta l . ,
“Analysis of oxidative stress status, catalase and catechol-O-
methyltransferasepolymorphismsinEgyptianvitiligopatients,”PLoSONE ,vol.9 ,no .6,ArticleIDe99286,2014.
[ 2 0 8 ]R .C o l u c c i ,F .D r a g o n i ,a n dS .M o r e t t i ,“ O x i d a t i v es t r e s sa n d
immune system in vitiligo and thyroid diseases,” Oxidative
Medicine and Cellular Longevity ,v o l .2 0 1 5 ,A rt i c l eI D6 3 1 9 27 ,7
pages,2015.
[209] E. G. J ¨onsson, N. Norton, K. Forslund et al., “Association
betweenapromotervariantinthemonoamineoxidaseAgene
andschizophrenia,” SchizophreniaResearch ,vol.61,no.1,pp.31–
37,2003.
[ 2 1 0 ]J .D e c k e r t ,M .C a t a l a n o ,Y .V .S y a g a i l oe ta l . ,“ E x c e s so fh i g h
activity monoamine oxidase A gene promoter alleles in female
patientswithpanicdisorder,” HumanMolecularGenetics ,vol.8,
no.4,pp.621–624,1999.
[211] S. P. Hamilton, S. L. Slager, G. A. Heiman et al., “No genetic
linkageorassociationbetweenafunctionalpromoterpolymor-
phism in the monoamine oxidase-A gene and panic disorder,”
MolecularPsychiatry ,vol.5,no .5,pp .465–466,2000.
[212] J.J.Vanderhaeghen,J.C.Signeau,andW.Gepts,“Newpeptide
in the vertebrate CNS reacting with antigastrin antibodies,”
Nature,vol.257 ,no .5527 ,pp .604–605,1975.
[213] K. Huppi, D. Siwarski, J. R. Pisegna, and S. Wank, “Chro-
mosomal localization of the gastric and brain receptors forcholecystokinin(CCKARandCCKBR)inhumanandmouse,”
Genomics ,vol.25,no .3,pp .727 –729 ,1995.
[214] L. J. Strug, R. Suresh, A. J. Fyer et al., “Panic disorder is
associated with the serotonin transporter gene (SLC6A4) butnot the promoter region (5-HTTLPR),” Molecular Psychiatry ,
vol.15,no .2,pp .166–17 6,2010.
[ 2 1 5 ]J .R .W e n d l a n d ,P .R .M o y a ,M .R .K r u s ee ta l . ,“ An o v e l ,
putativegain-of-functionhaplotypeatSLC6A4associateswithobsessive-compulsive disorder,” Human Molecular Genetics ,
vol.17 ,no .5,pp .717 –723,2008.
[216] L. N. Ravindran and M. B. Stein, “Anxiety disorders: somatic
treatment,” in Kaplan and Sadock Comprehensive Textbook of
Psychiatry ,B.J.Sadock,V.A.Sadock,andP.Ruiz,Eds.,pp.1906–
1914,LippincottWilliams&Wilkins,Philadelphia,Pa,USA,9th
edition,2009.
[217] E.Maron,T .Nikopensius,S.K ˜oksetal.,“Associationstudyof90
candidate gene polymorphisms in panic disorder,” Psychiatric
Genetics,vol.15,no .1,pp .17 –24,2005.
[218] M.Preisig,F.Bellivier,B.T.Fentonetal.,“Associationbetween
bipolar disorder and monoarnine oxidase a gene polymor-phisms: results of a multicenter study,” American Journal of
Psychiatry ,vol.157 ,no .6,pp .948–955,2000.
[219] I. Jones and N. Craddock, “Candidate gene studies of bipolar
disorder,” AnnalsofMedicine ,vol.33,no .4,pp .248–256,2001.

OxidativeMedicineandCellularLongevity 23
[220] M. Anguelova, C. Benkelfat, and G. Turecki, “A systematic
review of association studies investigating genes coding for
serotonin receptors and the serotonin transporter: I. Affectivedisorders,” MolecularPsychiatry ,vol.8,no.6,pp.574–591,2003.
[221] S. Menazza, B. Blaauw, T. Tiepolo et al., “Oxidative stress by
monoamine oxidases is causally involved in myofiber damageinmusculardystrophy,” Human Molecular Genetics ,vol.19 ,no .
21,pp.4207–4215,2010.
[222]W .Bild,L.Hritcu,C.Stefanescu,andA.Ciobica,“Inhibitionof
central angiotensin II enhances memory function and reducesoxidative stress status in rat hippocampus,” Progress in Neuro-
Psychopharmacology and Biological Psychiatry ,v o l .4 3 ,p p .7 9 –
88,2013.
[223] E.GreenandN.Craddock,“Brain-derivedneurotrophicfactor
as a potential risk locus for bipolar disorder: evidence, limi-
taions,andimplications,” CurrentPsychiatryReports ,vol.5,no.
6,pp.469–476,2003.
[ 2 2 4 ]E .H a t t o r i ,C .L i u ,J .A .B a d n e re ta l . ,“ P o l y m o r p h i s m sa tt h e
G72/G30 gene locus, on 13q33, are associated with bipolardisorderintwoindependentpedigreeseries,” AmericanJournal
ofHumanGenetics ,vol.72,no.5,pp.1131–1140,2003.
[225] J.-H. Cabungcal, P. Steullet, H. Morishita et al., “Perineuronal
nets protect fast-spiking interneurons against oxidative stress,”Proceedings of the National Academy of Sciences of the United
StatesofAmerica ,vol.110,no .22,pp .9130–9135,2013.
[226] J. Schumacher, R. A. Jamra, T. Becker et al., “Evidence for
a relationship between genetic variants at the brain-derived
neurotrophic factor (BDNF) locus and major depression,”
BiologicalPsychiatry ,vol.58,no.4,pp.307–314,2005.
[ 2 2 7 ]P .G .S u r t e e s ,N .W .J .W a i n w r i g h t ,S .A .G .W i l l i s – O w e ne ta l . ,
“No association between the BDNF Val66Met polymorphism
and mood status in a non-clinical community sample of 7389older adults,” Journal of Psychiatric Research ,v o l .4 1 ,n o .5 ,p p .
404–409,2007.
[228] K. Hashimoto, “Brain-derived neurotrophic factor as a
biomarker for mood disorders: an historical overview and
future directions,” Psychiatry and Clinical Neurosciences ,v o l .
64,no.4,pp.341–357,2010.
[ 2 2 9 ]X .Y .Z h a n g ,D . – C .C h e n ,Y . – L .T a ne ta l . ,“ Th ei n t e r p l a y
between BDNF and oxidative stress in chronic schizophrenia,”
Psychoneuroendocrinology ,vol.51,pp .201 –208,2015.
[230] T. Numakawa, M. Richards, S. Nakajima et al., “The role of
brain-derivedneurotrophicfactorincomorbiddepression:pos-
sible linkage with steroid hormones, cytokines, and nutrition,”
FrontiersinPsychiatry ,vol.5,article136,2014.
[231] F. W. Lohoff, “Overview of the genetics of major depressive
disorder,” CurrentPsychiatryReports ,vol.12,no.6,pp.539–546,
2010.
[ 2 3 2 ]P .Z i l l ,T .C .B a g h a i ,P .Z w a n z g e re ta l . ,“ S N Pa n dh a p l o t y p e
analysis of a novel tryptophan hydroxylase isoform (TPH2)
gene provide evidence for association with major depression,”MolecularPsychiatry ,vol.9 ,no .11,pp .1030–1036,2004.
[233] X. Zhang, R. R. Gainetdinov, J.-M. Beaulieu et al., “Loss-of-
function mutation in tryptophan hydroxylase-2 identified inunipolar major depression,” Neuron,v o l .4 5 ,n o .1 ,p p .1 1 – 1 6 ,
2005.
[234] D. M. Kuhn, C. E. Sykes, T. J. Geddes, K. L. E. Jaunarajs,
and C. Bishop, “Tryptophan hydroxylase 2 aggregates throughdisulfide cross-linking upon oxidation: Possible link to sero-
tonindeficitsandnon-motorsymptomsinParkinson’sdisease,”
JournalofNeurochemistry ,vol.116,no .3,pp .426–437 ,2011.[235] R. Weng, S. Shen, C. Burton et al., “Lipidomic profiling of
tryptophan hydroxylase 2 knockout mice reveals novel lipid
biomarkers associated with serotonin deficiency,” Analytical
and Bioanalytical Chemistry ,v o l .4 0 8 ,n o .1 1 ,p p .2 9 6 3 – 2 9 7 3 ,
2016.
[236]R.B.L ydiard,“TheroleofGAB Ainanxietydisorders, ” Journal
ofClinicalPsychiatry ,vol.64,supplement3,pp.21–27,2003.
[237] P. G. Unschuld, M. Ising, M. Specht et al., “Polymorphisms
in the GAD2 gene-region are associated with susceptibility for
unipolardepressionandwithariskfactorforanxietydisorders,”American Journal of Medical Genetics Part B: Neuropsychiatric
Genetics,vol.150,no .8,pp .1100–1109 ,2009 .
[238] C. Lamigeon, C. Prod’Hon, V. De Frias, C. Michoudet, and
B. Jacquemont, “Enhancement of neuronal protection from
oxidative stressby glutamic acid decarboxylase delivery with a
defectiveherpessimplexvirusvector,” ExperimentalNeurology ,
vol.184,no .1,pp .381 –392,2003.
[239] C. Lamigeon, J. P. Bellier, S. Sacchettoni, M. Rujano, and B.
Jacquemont, “Enhanced neuronal protection from oxidative
stressbycoculturewithglutamicaciddecarboxylase-expressing
astrocytes,” Journal of Neurochemistry ,v o l .7 7 ,n o .2 ,p p .5 9 8 –
606,2001.
[240] A. Leygraf, C. Hohoff, C. Freitag et al., “Rgs 2 gene polymor-
phismsasmodulatorsofanxietyinhumans?” JournalofNeural
Transmission ,vol.113,no .12,pp .1921 –1925,2006.
[241] J. W. Smoller, M. P. Paulus, J. A. Fagerness et al., “Influence of
RGS2 on anxiety-related temperament, personality, and brain
function,” ArchivesofGeneralPsychiatry ,vol.65,no.3,pp.298–
308,2008.
[242] K. C. Koenen, A. B. Amstadter, K. J. Ruggiero et al., “ RGS2
andgeneralizedanxietydisorderinanepidemiologicsampleof
hurricane-exposedadults,” Depression&Anxiety ,vol.26,no.4,
pp .309–315,2009 .
[243] M. Endale, S. D. Kim, W. M. Lee et al., “Ischemia induces
regulatorofGproteinsignaling2(RGS2)proteinupregulation
and enhances apoptosis in astrocytes,” American Journal of
Physiology-CellPhysiology ,vol.298,no .3,pp .C611 –C623,2010.
[244] C.A.Monroy,D.I.Mackie,andD.L.Roman,“Ahighthrough-
put screen for RGS proteins using steady state monitoring offree phosphate formation,” PLoS ONE ,v o l .8 ,n o .4 ,A r t i c l eI D
e62247,2013.
[ 2 4 5 ]Z .W u ,P .P u i g s e r v e r ,U .A n d e r s s o ne ta l . ,“ M e c h a n i s m sc o n –
trolling mitochondrial biogenesis and respiration through thethermogeniccoactivatorPGC-1,” TheCell,vol.98,no.1,pp.115–
124,1999.
[246] World Health Organization, The Global Burden of Disease:
2004Update ,WorldHealthOrganization,Geneva,Switzerland,
2008.
[247] D. J. Nutt, R. C. Kessler, J. Alonso et al., “Consensus statement
on the benefit to the community of ESEMeD (European study
of the epidemiology of mental disorders) survey data on
depression and anxiety,” Journal of Clinical Psychiatry ,v o l .6 8 ,
Supplement2,pp.42–48,2007.
[248] R. C. Kessler, “The global burden of anxiety and mood dis-
orders: putting the European Study of the Epidemiology ofMentalDisorders(ESEMeD)findingsintoperspective,” Journal
ofClinicalPsychiatry ,vol.68,supplement2,pp.10–19,2007.
[ 2 4 9 ]R .C .K e s s l e r ,W .T .C h i u ,O .D e m l e r ,K .R .M e r i k a n g a s ,a n d
E. E. Walters, “Prevalence, severity, and comorbidity of 12-monthDSM-IVdisordersintheNationalComorbiditySurvey
Replication,” Archives of General Psychiatry ,v o l .6 2 ,n o .6 ,p p .
617–627,2005.

24 OxidativeMedicineandCellularLongevity
[250] N. Bakunina, C. M. Pariante, and P. A. Zunszain, “Immune
mechanisms linked to depression via oxidative stress and
neuroprogression,” Immunology ,v o l .1 4 4 ,n o .3 ,p p .3 6 5 – 3 7 3 ,
2015.
[251] R.T .deSousa,C.A.Zarate,M.V .Zanettietal.,“Oxidativestress
inearlystagebipolardisorderandtheassociationwithresponse
tolithium,” JournalofPsychiatricResearch ,vol.50,no.1,pp.36–
41,2014.
[252] M.Kiełczykowska,K.Pasternak,I.Musik,J.W ro ´nska-Tyra,and
A. Hordyjewska, “The influence of different doses of lithium
administered in drinking water on lipid peroxidation andthe activity of antioxidant enzymes in rats,” Polish Journal of
EnvironmentalStudies ,vol.15,no .5,pp .7 47 –751,2006.
[253] R.Machado-Vieira,A.C.Andreazza,C.I.Vialeetal.,“Oxidative
stress parameters in unmedicated and treated bipolar subjectsduringinitialmanicepisode:apossibleroleforlithiumantioxi-danteffects,” NeuroscienceLetters ,vol.421,no.1,pp.33–36,2007 .
[254]U .Banerjee,A.Dasgupta,J.K.Rout,andO.P .Singh,“Effectsof
lithiumtherapyonNa+-K+-ATPaseactivityandlipidperoxida-
tioninbipolardisorder,” ProgressinNeuro-Psychopharmacology
andBiologicalPsychiatry ,vol.37 ,no .1,pp .56–61,2012.
[255] M. Atmaca, E. Tezcan, M. Kuloglu, B. Ustundag, and H.
Tunckol, “Antioxidant enzyme and malondialdehyde values in
socialphob iabefo r ea nda fterci talo p ra mtr ea tmen t, ” European
Archives of Psychiatry and Clinical Neuroscience ,vol.254,no .4,
pp .231 –235,2004.
[256] B.N.Frey,A.C.Andreazza,M.Kunzetal.,“Increasedoxidative
stress and DNA damage in bipolar disorder: a twin-casereport,”Progress in Neuro-Psychopharmacology and Biological
Psychiatry ,vol.31,no .1,pp .283–285,2007 .
[257] R. Khairova, R. Pawar, G. Salvadore et al., “Effects of lithium
on oxidative stress parameters in healthy subjects,” Molecular
Medicine Reports ,vol.5,no .3,pp .680–682,2012.
[ 2 5 8 ]P .S .W a n g ,A .M .W a l k e r ,M .T .T s u a n ge ta l . ,“ D o p a m i n e
antagonists and the development of breast cancer,” Archives of
GeneralPsychiatry ,vol.59 ,no .12,pp .1147 –1154,2002.
[259] J.Cui,L.Shao,L.T.Young,andJ.-F.Wang,“Roleofglutathione
inneuroprotectiveeffectsofmoodstabilizingdrugslithiumand
valproate,” Neuroscience ,vol.144,no .4,pp .1447 –1453,2007 .
[ 2 6 0 ]G .S .S h u k l a ,T .H u s s a i n ,a n dS .V .C h a n d r a ,“ P o s s i b l er o l e
of regional superoxide dismutase activity and lipid peroxidelevelsincadmiumneurotoxicity:invivoandinvitrostudiesin
growingrats,” Life Sciences ,vol.41,no .19 ,pp .2215–2221,1987 .
[261] S.Selek,H.A.Savas,H.S.Gergerlioglu,F .Bulbul,E.Uz,andM.
Yumru, “The course of nitric oxide and superoxide dismutaseduring treatment of bipolar depressive episode,” Journal of
Affective Disorders ,vol.107,no.1–3,pp.89–94,2008.
[262] J.Hwang,L.T .Zheng,J.Ocketal.,“Inhibitionofglialinflamma-
tory activation and neurotoxicity by tricyclic antidepressants,”Neuropharmacology ,vol.55,no .5,pp .826–834,2008.
[263] J. W. Hadden and A. Szentivanyi, Immunopharmacology
Reviews,vol.1,Plenum,N ewY ork,NY ,USA,1990.
[264] M. Bilici, H. Efe, M. A. K ¨oro˘g l u ,H .A .U y d u ,M .B e k a r o ˘glu,
and O. De ˘ger, “Antioxidative enzyme activities and lipid per-
oxidation in major depression: alterations by antidepressant
treatments,” JournalofAffectiveDisorders ,vol.64,no.1,pp.43–
51,2001.
[265] I. Inkielewicz-St ˆepniak, “Impact of fluoxetine on liver damage
in rats,”Pharmacological Reports ,v o l .6 3 ,n o .2 ,p p .4 4 1 – 4 4 7 ,
2011.
[266] A. M. Moreno-Fern ´andez, M. D. Cordero, J. Garrido-Maraver
et al., “Oral treatment with amitriptyline induces coenzyme Qdeficiency and oxidative stress in psychiatric patients,”
Journal
ofPsychiatricResearch ,vol.46,no .3,pp .341 –345,2012.
[267] M.R.Bautista-Ferrufino,M.D.Cordero,J.A.S ´anchez-Alc ´azar
et al., “Amitriptyline induces coenzyme Q deficiency andoxidative damage in mouse lung and liver,” Toxicology Letters ,
vol.204,no.1,pp.32–37,2011.
[ 2 6 8 ]G .L .M i l n e ,S .C .S a n c h e z ,E .S .M u s i e k ,a n dJ .D .M o r r o w ,
“Quantification of F
2- i s o p r o s t a n e sa sab i o m a r k e ro fo x i d a t i v e
stress,”Nature Protocols ,vol.2,no .1,pp .221 –226,2007 .
[269] C. P. Chung, D. Schmidt, C. M. Stein, J. D. Morrow, and R. M.
Salomon,“Increasedoxidativestressinpatientswithdepression
anditsrelationshiptotreatment,” PsychiatryResearch ,vol.206,
no.2-3,pp.213–216,2013.
[270] M. Maes, “The cytokine hypothesis of depression: inflamma-
tion, oxidative & nitrosative stress (IO&NS) and leaky gut as
new targets for adjunctive treatments in depression,” Neuroen-
docrinologyLetters ,vol.29 ,no .3,pp .287 –291,2008.
[271] M.PeetandD.F.Horrobin,“Adose-rangingstudyoftheeffects
ofethyl-eicosapentaenoateinpatientswithongoingdepressiondespite apparently adequate treatment with standard drugs,”
ArchivesofGeneralPsychiatry ,vol.59 ,no.10,pp.913–919 ,2002.
[272] A.F .Carvalho,D.S.Mac ˆedo,P.Goulia,andT.N.Hyphantis,“N-
Acetylcysteineaugmentationtotranylcypromineintreatment-
resistant major depression,” Journal of Clinical Psychopharma-
cology,vol.33,no .5,pp .719–720,2013.
[273] J. R. Strawn and S. N. Salda ˜na, “Treatment with adjunctive N-
acetylcysteine in an adolescent with selective serotonin reup-takeinhibitor-resistantanxiety,” JournalofChildandAdolescent
Psychopharmacology ,vol.22,no.6,pp.472–473,2012.
[ 2 7 4 ]M .M a e s ,P .G a l e c k i ,Y .S .C h a n g ,a n dM .B e r k ,“ Ar e v i e w
on the oxidative and nitrosative stress (O&NS) pathwaysin major depression and their possible contribution to the(neuro)degenerative processes in that illness,” Progress in
Neuro-Psychopharmacology and Biological Psychiatry ,v o l .3 5 ,
no .3,pp .67 6–692,2011.
[275] W. Ibrahim, E. Tousson, T. El-Masry, N. Arafa, and M. Akela,
“The effect of folic acid as an antioxidant on the hypothalamic
monoaminesinexperimentallyinducedhypothyroidrat,” Tox-
icologyandIndustrialHealth ,vol.28,no .3,pp .253–261,2012.
[ 2 7 6 ]M .J .T a y l o r ,S .M .C a r n e y ,G .M .G o o d w i n ,a n dJ .R .G e d d e s ,
“Folate for depressive disorders: systematic review and meta-
analysisofrandomizedcontrolledtrials,” JournalofPsychophar-
macology,vol.18,no .2,pp .251 –256,2004.
[277] K. R. Atkuri, J. J. Mantovani, L. A. Herzenberg, and L.
A. Herzenberg, “N-Acetylcysteine-a safe antidote for cys-teine/glutathionedeficiency,” CurrentOpinioninPharmacology ,
vol.7,no.4,pp.355–359,2007.
[278] B.L.OdlaugandJ.E.Grant,“N-acetylcysteineinthetreatment
ofgroomingdisorders,” JournalofClinicalPsychopharmacology ,
vol.27 ,no .2,pp .227 –229 ,2007 .
[ 2 7 9 ]M .B e r k ,O .M .D e a n ,S .M .C o t t o ne ta l . ,“ Th ee ffi c a c yo f
adjunctive N-acetylcysteine in major depressive disorder: a
double-blind,randomized,placebo-controlledtrial,” Journal of
ClinicalPsychiatry ,vol.75,no .6,pp .628–636,2014.
[280] K.-A. Marshall, R. J. Reiter, B. Poeggeler, O. I. Aruoma, and B.
Halliwell, “Evaluation of the antioxidant activity of melatonin
in vitro,” Free Radical Biology and Medicine ,v o l .2 1 ,n o .3 ,p p .
307–315,1996.
[281] M. A. Quera Salva, S. Hartley, F. Barbot, J. C. Alvarez, F.
Lofaso, and C. Guilleminault, “Circadian rhythms, melatonin
and depression,” CurrentPharmaceuticalDesign ,v o l .1 7 ,n o .1 5 ,
pp .1459–1470,2011.

OxidativeMedicineandCellularLongevity 25
[ 2 8 2 ]M .F o r n a r o ,M .J .M c C a r t h y ,D .D eBe r a r d i se ta l . ,“ A d j u n c t i v e
agomelatinetherapyinthetreatmentofacutebipolarIIdepres-
sion: a preliminary open label study,” Neuropsychiatric Disease
andTreatment ,vol.9,pp.243–251,2013.
[283] D. Sap `ede and E. Cau, “The pineal gland from development to
function,” CurrentTopicsinDevelopmentalBiology ,vol.106,pp.
171–215,2013.
[284] M. Maes, E. Vandoolaeghe, H. Neels et al., “Lower serum zinc
inmajordepressionisasensitivemarkeroftreatmentresistance
and of the immune/ inflammatory response in that illness,”BiologicalPsychiatry ,vol.42,no.5,pp.349–358,1997.
[ 28 5 ]J .F .Co ll i n sa n dL .M .Kl ev a y ,“ Co p pe r , ” Advances in Nutrition ,
vol.2,no .6,pp .520–522,2011.
[286] H.Kodama,C.Fujisawa,andW.Bhadhprasit,“Inheritedcopper
transport disorders: biochemical mechanisms, diagnosis, and
treatment,” CurrentDrugMetabolism ,vol.13,no.3,pp.237–250,
2012.
[287] K. Młyniec, M. Gaweł, U. Doboszewska et al., “Essential
elements in depression and anxiety. Part II,” Pharmacological
Reports,vol.67 ,no .2,pp .187 –194,2015.
[288] W. Swardfager, N. Herrmann, R. S. McIntyre et al., “Potential
roles of zinc in the pathophysiology and treatment of major
depressivedisorder,” Neuroscience&BiobehavioralReviews ,vol.
37,no.5,pp.911–929,2013.
[ 2 8 9 ]J .L a i ,A .M o x e y ,G .N o w a k ,K .V a s h u m ,K .B a i l e y ,a n dM .
McEvoy, “The efficacy of zinc supplementation in depression:systematic review of randomised controlled trials,” Journal of
Affective Disorders ,vol.136,no .1 -2,pp .e31 –e39 ,2012.
[290] M. Siwek, D. Dudek, I. A. Paul et al., “Zinc supplementation
augmentsefficacyofimipramineintreatmentresistantpatients:a double blind, placebo-controlled study,” Journal of Affective
Disorders,vol.118,no .1 –3,pp .187 –195,2009 .
[291] B. Szewczyk, “Zinc homeostasis and neurodegenerative disor-
ders,”FrontiersinAgingNeuroscience ,vol.5,article33,2013.
[292] B. Szewczyk, M. Kubera, and G. Nowak, “The role of zinc
in neurodegenerative inflammatory pathways in depression,”Progress in Neuro-Psychopharmacology & Biological Psychiatry ,
vol.35,no .3,pp .693–701,2011.
[293] M. Sayyah, A. Olapour, Y. S. Saeedabad, R. Yazdan Parast, and
A.Malayeri,“Evaluationoforalzincsulfateeffectonobsessive-
compulsivedisorder:arandomizedplacebo-controlledclinical
trial,”Nutrition,vol.28,no .9 ,pp .892–895,2012.
[294] G. Nowak, “Zinc, future mono/adjunctive therapy for depres-
sion: mechanisms of antidepressant action,” Pharmacological
Reports,vol.67 ,no .3,pp .659–662,2015.
[295] S. J. Padayatty, A. Katz, Y. Wang et al., “Vitamin C as an
antioxidant: evaluation of its role in disease prevention,” The
J o u r n a lo ft h eA m e r i c a nC o l l e g eo fN u t r i t i o n ,v o l .2 2 ,n o .1 ,p p .
18–35,2003.
[ 2 9 6 ]N .V .K r a g u l j a c ,V .M .M o n t o r i ,M .P a v u l u r i ,H .S .C h a i ,B .
S. Wilson, and S. S. Unal, “Efficacy of omega-3 fatty acids
in mood disorders—a systematic review and metaanalysis,”PsychopharmacologyBulletin ,vol.42,no .3,pp .39–54,2009 .
[297] P. Montgomery and A. J. Richardson, “Omega-3 fatty acids for
bipolardisorder,” CochraneDatabaseofSystematicReviews ,no.
2,ArticleIDCD005169,2008.
[298] J. Sarris, D. Mischoulon, and I. Schweitzer, “Omega-3 for
bipolar disorder: meta-analyses of use in mania and bipolar
depression,” Journal of Clinical Psychiatry ,vol.7 3,no .1,p p .81 –
86,2012.
[299]P .Y .Lina n dK.P .S u ,“ Am eta-a n al yticr eviewo fdo u b le-b lin d ,
placebo-controlled trials of antidepressant efficacy of omega-3fattyacids,” JournalofClinicalPsychiatry ,vol.68,pp.1056–1061,
2007.
[300] K. Lane, E. Derbyshire, W. Li, and C. Brennan, “Bioavailability
andpotentialusesofvegetariansourcesofomega-3fattyacids:ar e v i e wo ft h el i t e r a t u r e , ” Critical Reviews in Food Science and
Nutrition,vol.54,no .5,pp .572–579 ,2014.
[ 3 0 1 ]J .P .I s l a m i a na n dH .M e h r a l i ,“ L y c o p e n ea sac a r o t e n o i d
provides radioprotectant and antioxidant effects by quenching
radiation-inducedfreeradicalsingletoxygen:anoverview,” Cell
Journal,vol.16,no .4,pp .386–391,2015.
[302] D. Heber and Q.-Y. Lu, “Overview of mechanisms of action of
lycopene,” Experimental Biology and Medicine ,v o l .2 2 7 ,n o .1 0 ,
pp.920–923,2002.
[303] K.Niu,H.Guo,M.Kakizakietal.,“Atomato-richdietisrelated
to depressive symptoms among an elderly population aged 70
years and over: a population-based, cross-sectional analysis,”JournalofAffectiveDisorders ,vol.144,no.1-2,pp.165–170,2013.
[304] H. Francis and R. Stevenson, “The longer-term impacts of
Westerndietonhumancognitionandthebrain,” Appetite,vol.
63,pp.119–128,2013.
[305] T. Nishikawa, D. Edelstein, X. L. Du et al., “Normalizing
mitochondrialsuperoxideproductionblocksthreepathwaysof
hyperglycaemic damage,” Nature,v o l .4 0 4 ,n o .6 7 7 9 ,p p .7 8 7 –
790,2000.
[ 3 0 6 ]C .L .W h i t e ,P .J .P i s t e l l ,M .N .P u r p e r ae ta l . ,“ E ff e c t so f
high fat diet on Morris maze performance, oxidative stress,and inflammation in rats: contributions of maternal diet,”
Neurobiology of Disease ,vol.35,no .1,pp .3–13,2009 .
[307] A. Str ¨ohle, “Physical activity, exercise, depression and anxiety
disorders,” J o u r n a lo fN e u r a lT r a n s m i s s i o n ,v o l .1 1 6 ,n o .6 ,p p .
777–784,2009.
[308] F.Ng,S.Dodd,andM.Berk,“Theeffectsofphysicalactivityin
theacutetreatmentofbipolardisorder:apilotstudy,” Journalof
Affective Disorders ,vol.101,no .1 –3,pp .259–262,2007 .
[309] J. D. Benitez-Sillero, J. L. Perez-Navero, I. Tasset, M. Guillen-
Del Castillo, M. Gil-Campos, and I. Tunez, “Cardiorespiratoryfitness and oxidative stress: effect of acute maximal aerobic
exerciseinchildrenandadolescents,” JournalofSportsMedicine
andPhysicalFitness ,vol.51,no .2,pp .204–210,2011.
[310] R.J.Bloomer,“Effectofexerciseonoxidativestressbiomarkers, ”
AdvancesinClinicalChemistry ,vol.46,pp .1 –50,2008.
[311] M.Pittaluga,P.Parisi,S.Sabatinietal.,“Cellularandbiochemi-
calparametersofexercise-inducedoxidativestress:relationshipwith training levels,” Free Radical Research ,v o l .4 0 ,n o .6 ,p p .
607–614,2006.
[312] H. Eyre and B. T. Baune, “Neuroimmunological effects of
physicalexerciseindepression,” Brain,Behavior,andImmunity ,
vol.26,no.2,pp.251–266,2012.
[313] R. J. Bloomer and A. H. Goldfarb, “Anaerobic exercise and
oxidative stress: a review,” Canadian Journal of Applied Physi-
ology,vol.29,no.3,pp.245–263,2004.
[ 3 1 4 ]Z .R a d a k ,H .Y .C h u n g ,a n dS .G o t o ,“ S y s t e m i ca d a p t a t i o nt o
oxidative challenge induced by regular exercise,” Free Radical
BiologyandMedicine ,vol.44,no .2,pp .153–159 ,2008.
[ 3 1 5 ]A .L .L o p r e s t i ,S .D .H o o d ,a n dP .D .D r u m m o n d ,“ Ar e v i e wo f
lifestyle factors that contribute to important pathways associ-atedwithmajordepression:diet,sleepandexercise,” Journal of
Affective Disorders ,vol.148,no .1,pp .12–27 ,2013.
[316] F.-P.Trofin,M.Chirazi,C.Honceriuetal.,“Pre-administration
of vitamin C reduces exercise-induced oxidative stress in
untrained subjects,” Archives of Biological Sciences ,v o l .6 6 ,n o .
3,pp.1179–1185,2014.