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Oxidative stress and anxiety

oxidative stress and anxiety

Yao JK Leonard Oixdative Reddy RD Oxidative stress and anxiety XY Zhou DF Zhang PY Wu GY Su JM Cao LY b. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice.

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Most data demonstrating oxidative disturbances have examined indirect measures of oxidative status, such as peripheral and brain levels of antioxidants, oxidative enzymes and products. The direct measurement of free radicals is hindered by their short half-lives and low titres.

Some studies have examined peripheral concentrations of the free radical nitric oxide NO in patients with schizophrenia by measuring its metabolites, nitrites and nitrates, but have yielded inconsistent results. Whilst some have found elevated plasma NO Akyol et al. Comparatively lower concentrations of the NO metabolites were found in the cerebrospinal fluid CSF of schizophrenia patients Ramirez et al.

The disparate sample sizes, patient characteristics, tissue specimen types and substances measured in these studies, and the many inherent metabolic variables in any given individual, make direct comparison of these results difficult, although they support the presence of abnormal NO metabolism in schizophrenia.

Similarly, studies involving blood assays of intrinsic antioxidants have collectively demonstrated significantly altered antioxidant activities. Deficiency of glutathione, the major intracellular antioxidant, in its reduced form GSH , has been observed and suggested to be of pathophysiological significance in schizophrenia as early as Looney and Childs, , although differences did not reach statistical significance in that study.

Significant GSH deficiency has subsequently been reported Altuntas et al. Reduced levels of the major antioxidant enzymes, superoxide dismutase SOD , catalase CAT and glutathione peroxidase GSH-Px , have also been found in patients with schizophrenia compared with controls Ben Othmen et al.

Others have reported unchanged levels for these three enzymes Srivastava et al. A strong negative correlation between blood GSH-Px and structural measures of brain atrophy was also reported by an early study Buckman et al.

Furthermore, some studies have differentiated enzymatic changes among the schizophrenia subtypes Herken et al. The antioxidants uric acid Yao et al. Albumin, bilirubin and uric acid were shown to be significantly lower in neuroleptic-naive patients with first-episode schizophrenia, results that were independent of smoking status Reddy et al.

Interestingly, the same study found no impairment of antioxidative defence as determined using the same indices, in those with first-episode affective psychosis Reddy et al. In tandem with the peripheral antioxidant abnormalities found in patients with schizophrenia, post-mortem brain tissue studies have reported significantly lower levels of glutathione in both its reduced GSH and oxidized forms GSSG , and the two enzymes responsible for conversions between these two forms GSH-Px, and glutathione reductase or GR , in the caudate region from donors with schizophrenia compared with those with other psychiatric conditions and without psychiatric conditions.

A concomitant reduction in GSH:GSSG ratio, inverse correlations between age and GSSG and between age and GR, as well as the loss of normal correlations that exist in dynamic equilibrium, were also identified in the schizophrenia group Yao et al.

Another post-mortem study examined a number of cortical and subcortical areas from donors with schizophrenia and controls, and found elevated levels of two SOD isoenzymes in the frontal cortex and substantia innominata of those with schizophrenia, thereby suggesting neuroanatomical specificity of redox disturbances in schizophrenia Michel et al.

The low CSF glutathione appears to be consistent with previous findings of decreased levels of its metabolite, γ-glutamylglutamine, in the CSF of schizophrenia patients Do et al.

Estimating levels of oxidative reactive products provide another useful strategy to determine the impact of oxidative stress. Published studies have predominantly examined products of lipid peroxidation and DNA oxidation as markers of oxidative damage.

A widely used method of measuring lipid peroxidation is the performance of thiobarbituric acid reactive substances TBARS assays. TBARS are low-molecular-weight substances, consisting largely of malondialdehyde MDA , which are formed from the decomposition of unstable lipid peroxidation products and react with thiobarbituric acid to form fluorescent adducts Fukunaga et al.

TBARS have been reported to be elevated in the plasma Akyol et al. Data on CSF levels of TBARS in schizophrenia are limited, but one small study has been published, reporting reduced levels in a group of actively psychotic patients compared with controls Skinner et al.

This unexpected finding raises questions about the origins of the elevated blood TBARS that has been broadly reported in the literature, although the CSF results may have been confounded by diminished neuronal membrane substrates in the patient cohort Skinner et al.

The F 2 isoprostanes, products of the free radical-induced oxidation of arachidonic acid, have been suggested to be superior to TBARS as markers of lipid peroxidation, and a marked increase of urinary 8-isoprostaglandin F 2α has recently been reported in a sample of schizophrenia patients compared with healthy controls Dietrich-Muszalska and Olas, A smaller collection of studies has been published in relation to markers of DNA damage in schizophrenia.

One study reported a trend increase in lymphocyte DNA damage in schizophrenia patients compared with control subjects Young et al.

Evidence from molecular and genetic studies support fundamental redox disturbances in the aetiopathogenesis of schizophrenia. In an integrative study of post-mortem prefrontal cortex, using a parallel transcriptomics, proteomics and metabolomics approach, a large proportion of alterations on the transcript, protein and metabolite levels were demonstrated to be associated with mitochondrial function, energy metabolism and oxidative stress responses.

This provides persuasive evidence that mitochondrial function and oxidative stress pathways are intrinsically involved in the pathogenesis of the disorder, although the exact nature of their roles, in particular whether they are primary or secondary changes, are yet to be clarified.

Other studies have identified links between schizophrenia and specific genes, such as those for the key glutathione-synthesizing enzyme, glutamate cysteine ligase modifier GCLM subunit Tosic et al.

The glutamate cysteine ligase GCL connection seems particularly promising, in view of recent data indicating reduced GCL activity, decreased expression of its catalytic subunit GCLC , and GCLC polymorphism in those with schizophrenia Gysin et al. A mitochondrial DNA sequence variation affecting a subunit of NADH-ubiquinone reductase Complex I , a component of the electron transport chain responsible for generating superoxide, has also been associated with schizophrenia patients and with increased superoxide levels in post-mortem brain samples Marchbanks et al.

On a related subject, polymorphism of the glutathione S-transferase pi gene GSTP1 has been reported to be associated with vulnerability to develop psychosis in the setting of methamphetamine abuse Hashimoto et al.

Antioxidant effects of established antipsychotic agents provide indirect evidence for oxidative pathophysiological mechanisms in schizophrenia. Abnormalities in levels of antioxidants and oxidative products have been reported to reverse over the course of treatment with atypical antipsychotics, coinciding with symptomatic improvement Dakhale et al.

In two published studies, baseline serum SOD Dakhale et al. Within the patient groups, their baseline levels significantly shifted towards normality after treatment with atypical antipsychotics over the study durations of 8 wk Dakhale et al.

Another study with a smaller sample size conducted over 6 months likewise showed normalization of the antioxidative enzymes SOD, CAT and GSH-Px with treatment Evans et al. These oxidative marker changes correlated with symptomatic improvements as measured by validated scales, further substantiating an intrinsic link between oxidative stress status and psychotic symptomatology.

In contrast, others did not find significant changes in a number of oxidative-antioxidative parameters Sarandol et al. Membrane essential polyunsaturated fatty acids EPUFAs depletion has been reported in schizophrenia, with one proposed mechanism being oxidative peroxidation Evans et al.

Data showing repletion of EPUFAs with treatment Evans et al. A differential impact on oxidative stress status may exist between typical and atypical antipsychotic medications. Higher levels of lipid peroxidation products have been reported in patients treated with typical than atypical drugs Kropp et al.

The differing pro-oxidant potentials of the antipsychotics have been postulated as a mediating factor in the more common development of tardive dyskinesia with typical agents Andreassen and Jorgensen, Animal data have demonstrated elevated oxidative stress markers with d and d administration of haloperidol, but not atypicals Parikh et al.

In extending this study in rats to d, haloperidol was again associated with the greatest level of oxidative stress, but oxidative stress as gauged by significant reductions in enzymatic activities were also seen with chlorpromazine and the atypical agents ziprasidone, risperidone and olanzapine.

Both typical and atypical agents were associated with increased lipid peroxidation after d, except for olanzapine.

In addition, clozapine, olanzapine, and to a lesser extent risperidone, were able to reverse the changes induced by haloperidol Pillai et al.

Haloperidol-induced oxidative stress parameters in rats have also been shown to be ameliorated by the antioxidant drug, N -acetylcysteine NAC Harvey et al.

In-vitro cell studies have demonstrated a protective effect of atypicals, such as olanzapine and quetiapine, on PC12 cells exposed to oxidative stress Wang et al. Clinical trials investigating adjunctive antioxidants in the treatment of schizophrenia have utilized vitamins C and E, Ginkgo biloba extract EGb , and NAC.

The vast majority of vitamin E studies in schizophrenia has focused on its preventive and therapeutic roles in tardive dyskinesia. Conflicting results have been found for dyskinetic symptoms Adler et al. Symptomatic outcome, as measured with the Brief Psychiatric Rating Scale BPRS , was also significantly better for the vitamin C group Dakhale et al.

Other studies reported positive treatment outcomes, in terms of symptoms, functioning and extrapyramidal side-effects, with the supplementation of a combination of omegafatty acids and vitamins C and E Arvindakshan et al.

A small body of literature has suggested efficacy of supplementary EGb in schizophrenia. Scores on these scales did not significantly vary in the placebo group, although both groups improved on BPRS scores. Furthermore, treatment-emergent behavioural and neurological side-effects were significantly lower in the EGb group Zhang et al.

These authors additionally reported elevated pre-treatment SOD levels among patients with treatment-resistant schizophrenia, correlating with positive symptomatic severity, which was selectively reduced in patients receiving EGb but not placebo Zhang et al.

A confounder in this group of studies is the use of haloperidol as treatment base, which through its potential in inducing oxidative stress and cognitive blunting, may have added iatrogenic complexities to the disease and treatment process, such that it is difficult to determine whether the superior outcomes were due to lessened adverse effects, underlying psychopathology, or both.

NAC is a cysteine prodrug with high bioavailability, which is thought to exert antioxidative effects primarily through enhancing stores of the major intracellular antioxidant, glutathione, by stimulating its formation from cysteine Atkuri et al.

A series of experiments using an animal model has demonstrated that the pharmacodynamic actions of NAC involve the cystine-glutamate antiporter and extrasynaptic group II metabotropic glutamate receptors mGluR Baker et al. This may have particular relevance in schizophrenia, as glutamatergic dysfunction has been implicated as a pathophysiological pathway Goff and Coyle, Similar types of studies, albeit more limited in scope, have provided evidence for oxidative dysfunction in bipolar disorder Table 2.

The majority is derived from biochemical and pharmacological data. BDRS, Bipolar Depression Rating Scale; CAT, catalase; ECT, electroconvulsive therapy; GCL, glutamate cysteine ligase; GSH, reduced glutathione; GSH-Px, glutathione peroxidase; MADRS, Montgomery—Åsberg Depression Rating Scale; MDA, malondialdehyde; NAC, N -acetylcysteine; NOS1, nitric oxide synthase; ROS, reactive oxygen species; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances.

Oxidative disturbances have been demonstrated in both animal models and human studies. In animal models of mania, where amphetamine was administered to rats, raised levels of protein oxidation markers were detected in brain tissues following both single and repeated dosing, with the additional induction of lipid peroxidation markers on repeated exposure Frey et al.

Exposure to amphetamine has also been linked to SOD and CAT alterations Frey et al. In these studies, the striatum, hippocampus and prefrontal cortex have shown differential vulnerability and adaptivity Frey et al.

Human data of oxidative markers in bipolar disorder are often derived from studies with patient samples that include other psychiatric disorders.

In two such studies, increased SOD activities as compared with healthy controls were associated with both bipolar disorder and schizophrenia Abdalla et al. However, GSH-Px changes were reported for schizophrenia only Kuloglu et al. An increase in the lipid peroxidation product, TBARS, was also reported for both bipolar disorder and schizophrenia Kuloglu et al.

In a study involving patients with bipolar disorder, major depressive disorder and schizoaffective disorder, the pooled data showed reduced NO, CAT and GSH-Px levels, unchanged SOD and elevated MDA levels compared with controls, but the results were not analysed according to diagnosis Ozcan et al.

A comparatively large study was conducted solely on bipolar disorder patients, who were at various phases of the illness, thus allowing the exploration of phase-specific changes in oxidative stress status.

Interestingly, raised TBARS levels were observed regardless of illness phase, whereas GSH-Px activity was only elevated in euthymia but not in depressed or manic phases. Increased SOD activity was associated with manic and depressive episodes but not euthymia, and CAT reduction with mania and euthymia but not depression Andreazza et al.

An oxidative profile consistent with these findings were reported in a twin case report of mania Frey et al. However, another study reported lowered SOD levels in bipolar depression, in conjunction with elevated NO levels Selek et al. In a study comparing both unmedicated and lithium-treated patients in manic episodes with healthy controls, TBARS, SOD and CAT levels were significantly higher in manic patients compared with controls, with the lithium-treated group showing lower levels of TBARS and SOD than unmedicated patients, suggesting possible corrective effects of lithium on oxidative parameters Machado-Vieira et al.

Elevated NO and nitrite levels have been reported in bipolar disorder patients Gergerlioglu et al. Genetic studies have identified certain polymorphisms in bipolar disorder patients that play a role in oxidative homeostasis.

A single-nucleotide polymorphism of the TRPM2 gene, which encodes for a calcium channel receptor, has been strongly associated with bipolar disorder and is understood to cause cellular calcium dysregulation in response to oxidative stress McQuillin et al.

Dysregulation of second-messenger calcium has been described in bipolar disorder, and the modulation of this is thought to be a therapeutic mediating mechanism of lithium Berk et al. Innate dysregulation of the apoptosis and oxidative processes has been suggested by a recent study, in which the hippocampal expression of genes encoding DNA repair and antioxidant enzymes were found to be down-regulated in bipolar disorder, while many apoptosis genes were up-regulated Benes et al.

A related theoretical framework for the pathophysiology of bipolar disorder has centred on impaired mitochondrial metabolism as the primary defect in bipolar disorder Kato, ; Young, This concept is supported by data from a number of sources, including magnetic resonance spectroscopy evidence of decreased brain energy metabolism, maternal hereditary patterns, comorbid mitochondrial diseases, mitochondrial mechanisms of mood stabilisers, and mitochondrial DNA deletions, mutations and polymorphisms Kato, Indirect support for the pathophysiological role of oxidative stress in bipolar disorder comes from clinical studies that demonstrate normalisation of oxidative parameters over the course of treatment Frey et al.

This has been elegantly illustrated by a case report of twins presenting with mania, where increased TBARS, SOD and DNA damage, and decreased CAT were observed in both patients prior to treatment.

Whilst the twin who was successfully treated showed normalization of TBARS and SOD, the oxidative parameters remained unchanged for the other twin who refused treatment and continued to be manic Frey et al. In addition, the evidence behind the antioxidant properties of antipsychotics is also relevant for bipolar disorder, considering their efficacy in its treatment, particularly of mania.

An early study of psychiatric patients, including those with bipolar disorder, also bears some relevance to the current discussion through demonstrating a rise in blood glutathione 2—4 h following electroconvulsive therapy Henneman and Altschule, The antioxidant properties of mood stabilisers have been further strengthened by findings from animal and cell studies.

In a rat model of mania using amphetamine, both lithium and valproate were able to prevent and reverse amphetamine-induced hyperactivity, prevent lipid peroxidation in the hippocampus and reverse lipid peroxidation in the prefrontal cortex.

No alterations were seen for protein carbonyl formation in this model, and changes in antioxidant enzymes were variable Frey et al. Others have supported the antioxidant effects of lithium, but have not found it able to prevent stress-induced oxidative damage in rats de Vasconcellos et al.

Treatment with valproate has been shown to inhibit lipid peroxidation and protein oxidation in primary cultured rat cerebrocortical cells exposed to an oxidant Wang et al. Using similar cell cultures, treatment with lithium or valproate was also shown to inhibit the glutamate-induced intracellular calcium release, lipid peroxidation, protein oxidation, DNA fragmentation and cell death Shao et al.

Other cell culture studies have associated lithium and valproate with increased expression of the endoplasmic reticulum stress proteins GRP78, GRP94 and calreticulin Chen et al. However, increased glutathione levels and glutamate-cysteine ligase gene expression found with other mood stabilizers such as carbamazepine and lamotrigine suggest that glutathione may be a common neuroprotective target among mood stabilizers Cui et al.

Furthermore, evidence from human cell studies have found neuroprotective effects from lithium and valproate in neural but not glial cells Lai et al. The primary findings were improvement in depressive symptomatology, on both the Bipolar Depression Rating Scale BDRS and the Montgomery—Åsberg Depression Rating Scale MADRS , with significant benefits on functioning and quality of life also documented Berk, In the rat model of mania, pre-treatment with NAC significantly attenuated the methamphetamine-induced hyperlocomotion, behavioural sensitization, and striatal dopamine depletion in a dose-dependent fashion Fukami et al.

There is evidence for oxidative disturbances in major depression, as demonstrated by oxidative marker studies and those examining the antioxidant effects of antidepressants Table 3.

There is no data of antioxidants as therapeutic agents for this condition. Data from animal models have demonstrated the depletion of glutathione Pal and Dandiya, , reduction of GSH-Px and vitamin C, and rise in lipid peroxidation and NO Eren et al.

Human studies have reported a number of oxidative disturbances in patients with major depression, including oxidative damage in erythrocytic membranes as suggested by the depletion of omega-3 fatty acids Peet et al.

Albumin, which has antioxidant activity, has also been reported to be compromised in major depression Van Hunsel et al. Findings of altered antioxidant enzyme levels have been mixed, with reports of elevated SOD Bilici et al.

In one study of major depressive disorder patients who had been medication-free for at least 2 months, the plasma total antioxidant potential and uric acid were reduced in patients compared with controls, whereas their total plasma peroxide levels and oxidative stress index were both higher Yanik et al.

Moreover, a significant positive correlation was found between oxidative stress index and the Hamilton Depression Rating Scale HAMD Yanik et al. Similarly, other studies have also reported correlations between depressive severity and the magnitude of disturbances in their respective oxidative indices Bilici et al.

As oxidation of lipoproteins and low paraoxonase activity have been implicated in atherogenesis and coronary artery disease, these results may be relevant in understanding the link between major depression and cardiovascular disease Sarandol et al.

Others have also suggested oxidative changes, such as cumulative oxidative DNA damage, to be a common pathophysiological mechanism underlying major depression and medical comorbidities Forlenza and Miller, A small group of studies, by demonstrating reversals of antioxidant and oxidative disturbances after antidepressant treatments, has provided evidence for the antioxidant effects of these drugs Bilici et al.

Relating to this observation, oxidative parameters have been nominated by some authors to be candidate markers of antidepressant efficacy Bilici et al. However, studies have not been unanimous in associating normalization of oxidative parameters with antidepressant treatment. One comparatively larger study found that 6 wk of antidepressant treatment did not affect oxidative-antioxidative systems, regardless of the response or remission status of the patients Sarandol et al.

For drugs other than antidepressants, the antioxidant effects of lithium may also lend support for oxidative stress mechanisms behind major depression, as it has an established role as adjunctive treatment.

In animal studies, antidepressants of different classes have been shown to replenish, to varying degrees, the glutathione depletion seen in the inescapable shock behavioural paradigm of depression Pal and Dandiya, Venlafaxine was associated with the correction of several depression-specific oxidative markers in the rat cortex Eren et al.

A proteomic study using rats has found multiple protein modulations in the hippocampus after venlafaxine or fluoxetine administration. Antioxidant and anti-apoptotic proteins were among those identified Khawaja et al. In another animal study, lamotrigine, aripiprazole and escitalopram were all shown to improve depression-related GSH-Px, glutathione and Vitamin C depletion, and lipid peroxidation increase.

Of the three drugs, lamotrigine was associated with the greatest antioxidative protective effects Eren et al. An in-vitro study of rat cerebrocortex neuronal and astroglial cultures showed that moclobemide could attenuate cell death induced by anoxia and glutamate, a process involving oxidative stress pathways Verleye et al.

The monoamine oxidase inhibitor phenelzine was able to attenuate the loss of differentiated rat PC12 cells exposed to chemical oxidative stress, and demonstrated antioxidant effects including the reduction of ROS formation and the scavenging of the pro-oxidant hydrogen peroxide Lee et al.

As no clinical trials of antioxidant therapies have been published for major depressive disorder, the primary evidence for antioxidant efficacy at present is derived from the previously cited animal study, which demonstrated the prevention and reversal of shock-induced behavioural depression with glutathione Pal and Dandiya, The beneficial effects of NAC on mood in a non-clinically depressed population have been reported from a double-blind, placebo-controlled study of NAC in patients with mild chronic bronchitis.

NAC recipients showed significantly superior outcomes on the General Health Questionnaire GHQ , which predominantly measures mood, compared with the placebo group Hansen et al.

The limitations to generalizing these indirect results to depression are apparent. The notion of oxidative stress mechanisms underlying anxiety disorder has been in existence for some years, with the earlier suggestion that NO and peroxynitrite might play a major role in setting up a vicious aetiological cycle involving free radicals and inflammatory cytokines in post-traumatic stress disorder Miller, ; Pall and Satterlee, However, oxidation biology research in anxiety disorders is still at its infancy, and the bulk of the limited literature originates from animal studies, which have nevertheless generated intriguing findings.

An interesting set of animal experiments have linked glyoxalase 1 Glo1 and glutathione reductase 1 GR genes, both of which protect against oxidative stress, with anxiety in mice Hovatta et al. By using behavioural analysis of six inbred mouse strains to determine anxiety phenotypes and quantitative gene expression profiling of seven pertinent brain regions, 17 candidate genes were identified, of which both Glo1 and GR showed positive correlations between their expressed activity levels and phenotypic anxiety status.

The causal role that these genes may play in anxiety were supported by a series of experiments, which confirmed a highly significant positive correlation between the expressed activities of these genes and anxiety in cross-bred mice, and demonstrated that over-expression of Glo1 and GR in the cingulate cortex increased anxiety behaviours, while inhibition of Glo1 gene expression reduced such behaviours Hovatta et al.

The over-expression of Glo1 in innately anxious mice has also been reported by others Landgraf et al. Further evidence for oxidative pathways being involved in mouse models of anxiety can be derived from the association of vitamin E depletion and increased oxidative stress markers and anxiety behaviours in phospholipid transfer protein PLTP knock-out mice Desrumaux et al.

The pro-oxidative vitamin A has been demonstrated to induce oxidative stress in the rat hippocampus, as measured by increased lipid peroxidation, protein carbonylation, protein thiol oxidation, and altered SOD and CAT levels, as well as causing anxiety behaviours in the animal model de Oliveira et al.

In addition, green tea polyphenol — -epigallocatechin gallate EGCG , a potent antioxidant, showed anxiolytic effects on mice with a dose-dependent relationship Vignes et al. Anxiolytic effects have also been reported in mice with chlorogenic acid, a dietary polyphenol and antioxidant Bouayed et al.

Inconsistent results have been reported for whortleberry extracts in rats, and vitamin E was found to increase anxiety in the same study Kolosova et al. In humans, only a handful of relevant studies have been published.

These have reported elevated lipid peroxidation products and antioxidant changes in obsessive—compulsive disorder Ersan et al. The study on social phobia also found a reversal of these disturbances following 8 wk of citalopram treatment Atmaca et al.

A study of anxious women found reduced total antioxidant capacity among this group compared with non-anxious controls, in conjunction with several parameters of impaired immune functioning Arranz et al.

A case series has reported improvement in trichotillomania, pathological nail-biting and skin-picking, conditions that have similarities with obsessive—compulsive disorder, using NAC Odlaug and Grant, Substance abuse and dependence are important to consider in psychiatric disorders, given the substantial overlap between the two in terms of syndromal manifestations and causality.

A solid body of literature exists in support of the association between oxidative stress and common drugs of abuse, including nicotine Petruzzelli et al. Although their precise roles are yet to be fully understood, oxidative mechanisms have been proposed to mediate both the processes of drug addiction and toxicity Kovacic, ; Kovacic and Cooksy, , and antioxidants may thus have therapeutic potential in the management of these conditions.

Preclinical evidence has indicated antioxidants to be promising in alcohol Amanvermez and Agara, , heroin Zhou and Kalivas, and cocaine dependence Baker et al. Pilot clinical trial data of NAC in cocaine dependence have been promising, suggesting that craving and withdrawal symptoms LaRowe et al.

A growing literature has been published that cites evidence for oxidative disturbances in autism, including genetic polymorphisms affecting oxidative metabolic pathways James et al. Currently, the most robust and multi-dimensional evidence for the pathophysiological involvement of oxidative stress is for schizophrenia, followed by bipolar disorder, with both having support from preclinical and clinical research.

The data is less extensive for the other psychiatric disorders, but there is accumulating evidence indicating a role of oxidative stress in their aetiopathogenesis. In summary, there is evidence for glutathione depletion in schizophrenia; increased lipid peroxidation in schizophrenia, bipolar and major depressive disorders; and reduction in antioxidants such as albumin and bilirubin in schizophrenia and major depressive disorder.

Findings in relation to NO and antioxidative enzymes in these disorders have been less consistent. Data from molecular and genetic studies have implicated oxidative metabolic pathways in the aetiopathogenesis of schizophrenia, bipolar disorder and possibly anxiety disorders.

Antipsychotics, mood stabilizers and antidepressants have all been demonstrated to have antioxidative effects, and some antioxidants have been reported to be of therapeutic benefit, including vitamins C and E and EGb for schizophrenia, and NAC for schizophrenia and bipolar disorder.

In the interpretation of mass data, the context and limitations of each investigation must be borne in mind. In view of the complexities of psychiatric conditions and biological systems, and the diversity of research areas, the collective significance of study findings would be expected to have greater strength than individual results.

For instance, a substantial portion of the existing evidence base is derived from the comparison of oxidative biochemical status of patients with controls, and such studies have yielded apparently inconsistent results, with varying presence, directions or combinations of disturbances in markers of oxidant and antioxidant activities.

Moreover, psychiatric syndromes are aetiologically heterogeneous, commonly chronic and multiphasic, and often overlapping, thus further complicating the specificity of individual marker changes.

Alternatively, it is possible that the mixed findings may signify an indirect pathophysiological role of the relevant oxidative markers in the disorders. However, on balance, the literature as a whole seems to provide sufficient consistent evidence that oxidative stress balance is significantly altered in patient groups.

In particular, findings of elevated oxidative products across disorders supply fairly direct evidence of increased oxidative stress, while its aetiological significance is supported by genetic and molecular studies that link specific oxidative pathway polymorphisms or gene expression to specific disorders.

Genetic manipulation experiments demonstrating positive correlations between the expression of specific oxidative genes and anxiety behaviours in animal models further validate this aetiopathogenic hypothesis. However, it is difficult to distinguish from current data whether oxidative stress results from primary excessive mitochondrial energy generation, primary dysfunction within oxidative homeostatic mechanisms, or both.

Impaired mitochondrial energy metabolism has also been suggested to be a fundamental defect in bipolar disorder Kato, ; Young, , with hypometabolism, energy imbalance and oxidative stress assuming secondary roles, and may present an alternative hypothesis.

In practical terms, pharmacological and clinical studies have established the antioxidant properties of efficacious pharmacotherapies, and antioxidant treatment data, although limited in quantity, have reported promising therapeutic potentials.

The implications of the expanding data on oxidative stress mechanisms in psychiatric disorders are twofold, having salience in both furthering their aetiopathogenic understanding and treatment options.

In relation to the former, the aetiopathogenic mechanisms for psychiatric disorders remain largely elusive, despite the growth of hypotheses on multiple conceptual levels that include sociocultural systems, personality, cognitive schemata, behavioural learning, neuroanatomy, psychoneuroendoimmunology, biomolecules and genetics.

Given the complexities of human psychobehavioural systems and the infinite deterministic variability behind their manifestations, basic biopathway pathologies may present tangible and widely applicable pathophysiological models, as all psychobehavioural manifestations must have fundamental biological underpinnings.

There is gathering evidence for oxidative stress to be one such biopathway, as oxidative damage is believed to be a major mechanism underlying cell dysfunction and death in both ageing and disease processes, although its temporal role in and relative contribution to these processes is likely to vary.

Theoretically, oxidative stress may result from the overproduction of free radicals, defective oxidative homeostasis, or a combination of both.

Each of these situations, in turn, is likely to stem from different causes, which may include overactive oxidative metabolism driven by physiological stress, pathogens or the inflammatory response, genetic polymorphisms and physiological factors that undermine the oxidative defence capacity of the individual, and differential expression of mitochondrial and metabolic enzymes.

Once established, secondary amplifications or self-perpetuating oxidative cascades may also play a role in the pathogenesis of illnesses, the continuation of symptoms and vulnerability to future illness relapses. Evidence for the interdependent relationships between oxidative pathways and those involving neurotransmitters, hormones and inflammatory mediators further enhance the plausibility of the oxidative stress hypothesis, and provide a unifying framework for the various conceptual theories of causality.

Dopaminergic, noradrenergic and glutamatergic overactivity have been demonstrated to induce cytotoxicity via oxidative stress among other mechanisms Chan et al. These connections provide a basis for explaining phenomena such as drug-induced and organic psychiatric syndromes, as well as comorbid somatic and psychiatric disorders.

The association of particular neurochemical pathways with oxidative stress induction, combined with the differing vulnerabilities of neuronal and glial cells to oxidative damage according to their types and anatomical positions, may help to explain the involvement of specific neurological sites in psychiatric syndromes.

This specificity of site can be observed in neuroimaging studies Ettinger et al. The involvement of similar sites across conditions may also account for their symptomatic overlap and diagnostic mutability. Apart from conceptual utility, a theory of value should also demonstrate practical applicability.

An appealing aspect of the oxidative stress theory is that regardless of the precise defect s , this state of disequilibrium can theoretically be corrected by bolstering the total antioxidant capacity, providing that the supplementary antioxidants are bioactive and able to access the brain.

The practical utility of this theory has already garnered support from the existing literature, which has found benefits from the use of vitamins C and E, EGb, NAC and other antioxidants in psychiatric disorders. NAC, in particular, seems to hold the most promising evidence for efficacy across diagnoses, with benefits recently reported for schizophrenia, bipolar disorder, cocaine dependence, and impulsive control disorders.

This may relate to its bioavailability and putative mechanisms of replenishing and enhancing glutathione stores Dean et al. Further clinical evidence is required to consolidate the efficacies of antioxidants for the various conditions, but their potential in acute and maintenance treatment settings are clearly implied on theoretical grounds.

Furthermore, these treatments may be useful in the prevention of long-term sequelae by minimizing cell damage and cell death, as well as primary prevention in vulnerable individuals. These treatments are generally associated with low occurrence of side-effects, which is an attractive feature conducive to long-term treatment adherence.

The investigation of antioxidants in psychiatric disorders has perhaps been hampered by several unfavourable factors, the main ones probably relating to the conventional aetiopathophysiological understanding of psychiatric disorders and to misconceptions about antioxidants.

Traditionally, psychiatric teachings and research have focused on neurotransmitter aetiological theories, such as the dopamine theory for schizophrenia and the monoamine hypothesis for depression, and these have provided a basis for therapeutic manipulations.

The unfamiliar mechanisms of action of antioxidants to clinical psychiatry may thus have contributed to their peripheral therapeutic status.

Furthermore, the heterogeneity within antioxidants as a class is not widely appreciated. Differences exist among the antioxidants in their targets of action, as well as in their pharmacokinetic properties. Vitamin E, for example, has a principal antioxidant action of scavenging peroxyl radicals in biological lipid phases Traber and Atkinson, , in addition to multiple non-antioxidant properties that include modulation of signal transduction, transcriptional and translational processes Zingg and Azzi, , yet its antioxidant efficacy in pathological redox states has not been established Azzi, Vitamin C, on the other hand, is a scavenger of free radicals in water phases Rodrigo et al.

The specific antioxidant actions of these agents, when applied to neuropsychiatric conditions where the precise oxidative defects are not yet clear, may account for some inefficacious trial findings Boothby and Doering, In this respect, glutathione may be the most generic of cellular antioxidants in terms of its molecular actions, which may explain the promising findings with NAC.

Besides pharmacological treatments, lifestyle and dietary manipulations are relevant in optimizing oxidative balance. A diet rich in natural antioxidants and the avoidance of oxidative stress-inducing habits such as cigarette smoking and substance abuse are prudent measures.

Diets high in saturated fats may increase oxidative stress Shih et al. Physical exercise, specifically endurance training, has also been suggested to have a beneficial impact on oxidative stress status, possibly mediated by increasing total antioxidant capacity and GSH-Px activity Fatouros et al.

Although the current state of evidence is not yet mature enough to adopt this in clinical practice, findings of syndrome- Reddy et al. Genetic polymorphisms of antioxidant enzymes, associated with psychiatric disorders Akyol et al.

In research, broad areas remain to be explored on both preclinical and clinical levels, especially for mood and anxiety disorders which have an early evidence base. The use of antioxidants in their treatment is both substantiated and promising, in view of the internally consistent theoretical framework, convincing early evidence, wide-ranging potential therapeutic benefits, the high population prevalence and overall disease burden associated with these disorders, and the limited efficacies of existing pharmacotherapies.

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However, a close relation between oxidative stress and carbonyl stress was established. Curiously, other findings from another laboratory Krömer et al.

Contradictory, they have proposed that the level of expression of glyoxalase 1 could be used as a physiological marker of trait anxiety level, with high protein expression indicating low trait anxiety level and low expression for high trait anxiety. Indeed, comparing two Swiss CD1 mouse lines with extremes in trait anxiety, these authors found that glyoxalase 1 was more expressed in the line with low-anxiety-related behavioural phenotype than in the line with high-anxiety-related behavioural phenotype.

The expression of glyoxalase 1 has been assessed in several brain areas and also in red blood cells of mice. Differences in the genotype of this strain and those used by Hovatta et al. Thus, it would be interesting to compare in the same strain, anxiety-related behaviour of mice with their oxidative status rather than compare the redox status of strains differing in their anxiety-related phenotypes.

This approach takes into account the intra-variability between individuals of the same strain. Because of the large heterogeneity in their anxiety levels, Swiss albino male mice OF1 constitute an interesting behavioural model to study the link between oxidative status and anxiety-related behaviour.

Our results suggested a positive relationship between peripheral oxidative status and level of anxiety in mice. To confirm the relationship between OS and emotional stress, we comparatively evaluated the peripheral oxidative status of mice with contrasting levels of anxiety anxious and non-anxious.

Following strict selection criteria from a general population of mice Rammal et al. We found that high anxiety level was associated with a significant generation of ROS in the peripheral blood lymphocytes, granulocytes and monocytes in mice compared to low anxiety level Rammal et al.

Our results confirm that there is a relationship between the level of intracellular ROS in peripheral blood cells and anxiety-related behaviour in mice. These results prompted us to study the oxidative status of the brain in mice with distinct levels of anxiety. Using the same behavioural approach to distinguish between anxious and non-anxious mice, we found that anxiety levels were associated with the oxidative status in both neuronal and glial cells in the cerebellum and hippocampus, in neurons of the cerebral cortex and in peripheral leucocytes monocytes, granulocytes and lymphocytes Rammal et al.

Our results clearly indicated the presence of OS in the central and peripheral systems of anxious mice. OS in the brain and blood immune cells could predispose anxious mice to neuroinflammation and neurodegeneration as well as recurrent infections.

We considered that type of anxiety evaluated in mice with contrasting levels of anxiety is a trait-anxiety, for two reasons. First, we have verified that the level of anxiety of anxious and non-anxious mice was stable during time a period of 15 days.

We have also found that the general activity, both horizontal locomotion and vertical rears , of anxious mice was significantly lower than of non-anxious mice unpublished results , which was in keeping with the findings of do-Rego et al.

These authors also found that these groups of mice did not significantly differ with regard to their immobility time, marker of depressive behaviour, in the forced swimming test.

In agreement with these results, we have also found that the behaviour of anxious and non-anxious mice did not significantly vary in the tail suspension and forced swimming tests, the well-known predictive tests of depression-related behaviour unpublished results.

From the above, it could be suggested that high trait anxiety level in anxious mice from Swiss albino male mice OF1 was not associated with depressive symptoms.

The results of our studies are in good concordance with the initial findings of Hovatta et al. In keeping with the animal experiments, the link between OS and human trait anxiety was also determined. Indeed, Yasunari et al.

To study the causal relation between OS and anxiety, Masood et al. Surprisingly, BSO-treated mice developed anxious behaviour in several mouse models of anxiety including elevated plus maze, hole-board and open field tests.

The NADPH oxidase was suggested to be the principal oxidative pathway responsible for the anxiogenic behaviour following BSO treatment. Depletion of GSH was also reported to cause cognitive impairment short-term spatial memory disturbances in rodents as assessed in the Y-maze test Dean et al.

It is also suggested that GSH might play a role in psychiatric illnesses including schizophrenia and bipolar disorder Dean et al. However, despite that GSH is considered as a major antioxidant in aerobic cells functioning as an important cellular redox buffer, GSH depletion can cause other cellular stresses, including nitrosative and carbonyl stresses, as GSH is also an important determinant of the nitrogen and dicarbonyl metabolism.

Excessive production of ROS induces oxidative damage of cellular structures; production of reactive nitrogen species triggers nitrosylation reactions, which can alter the structure of proteins to inhibit their normal function; excessive accumulation of reactive dicarbonyl compounds leads to damage of protein and nucleotides by dicarbonyl glycation.

Additionally, GSH may also have an additional double role in the central nervous system by acting as a neurotransmitter and neuromodulator, e.

by regulating the release of other neurotransmitters such as dopamine and gamma-aminobutyric acid GABA , which is an important regulator of anxiety Oja et al. Therefore, the anxiogenic behaviour resulting from depletion of GSH in mice could be independent from oxidative metabolism disturbances generated by BSO treatment.

Thus, it is difficult to deduce, from this study, a direct causal relationship between oxidative stress and anxiety. Other studies have mentioned that OS state could cause anxiogenic behaviour, however the link is indirect. Desrumaux et al. Souza et al. Berry et al. In addition, Berry et al.

At physiologic conditions, antioxidants play a crucial role in maintaining redox homeostasis by maintaining the level of ROS at physiological doses necessary for optimal cellular functioning. Thus, the excess of ROS is neutralized by antioxidants avoiding the oxidation of cellular components and consequently their damage.

Exogenous antioxidants complete the antioxidative action of endogenous antioxidants by acting together, e. additively or synergistically. The principal source of exogenous antioxidants is our diet. However, diets relatively deficient in antioxidants may favour oxidative stress.

Vitamin E, vitamin C, carotenoids, zinc, selenium, and polyphenols e. phenolic acids and flavonoids constitute the principal dietary antioxidants existing in food. Of course, these antioxidants can be found naturally e. in plant foods or animal products such as eggs and honey , however, other sources can also exist e.

supplementation and fortification. Currently, there is increasing evidence that the advantageous effects of antioxidants on health are not only attributed to their antioxidant properties. This is due to the fact that antioxidants can also act e. The effect of dietary antioxidants on the central nervous system has gained interest in the last decades.

In this sense, it has been demonstrated that dietary antioxidants can also exhibit cognitive enhancing effect, psychostimulant activity, and antidepressant and anti-anxiety properties. For example, it has been shown that antioxidants e.

vitamin C, rutin, caffeic acid and rosmarinic acid possess antidepressant activity with relatively lower doses 0. The mechanism of action of antioxidants on the central nervous system is not well elucidated, however, it has been demonstrated that rutin exerts its antidepressant activity similarly to conventional antidepressants by increasing the availability of serotonin and noradrenalin in the synaptic cleft reviewed by Bouayed, Interestingly, antioxidant effects of conventional antidepressants have been reported in several studies Atmaca et al.

The antioxidant effects of anxiolytic treatments with citalopram also used as an antidepressant have been emphasized by Atmaca et al. Polyphenols have also shown their ability to reverse anxiety-related behaviour of rodents.

Some polyphenols have a pharmacological profile that suggests a partial agonistic action that may produce the anxiolytic-like effects, but without the side effects such as dependency, which are a feature of full agonists such as benzodiazepines. However, a fold increase in dosage of this flavonoid produced slight sedative effects.

Polyphenols may present a dose-effect response on the central nervous system. The ability of polyphenols to cross the blood-brain barrier might explain the difference in their active concentration. The intranasal administration of polyphenols in the form of liposomes could be an effective strategy both to facilitate the movement of these substances across the blood-brain barrier and to effectively reduce the active dose.

Therefore, the use of liposomes is a potentially novel strategy which can facilitate the delivery of polyphenols across the blood-brain barrier and also can effectively reduce the active dose reviewed by Bouayed, Although psychopharmacological studies present antioxidants as a potential new strategy for the treatment of anxiety and depression, the use of these substances has to be with caution.

Several studies are required to investigate the toxicity of antioxidants at non-nutritional doses. At high doses, it has been discussed that antioxidants could enact deleterious effects on health, acting e.

as prooxidants. Therefore, antioxidants from a normal diet could prevent from anxiety development. In this respect, it has been demonstrated that some specific foods prevent aging-accompanying anxiety. Viggiano et al. The decrease of anxiety was not associated with a change in general activity, however a reduction of OS was also found.

Indeed, these authors found that brain superoxide dismutase SOD activity of aged rats fed with an apples enriched diet was not different from young animals feed with the standard diet with or without apples, while SOD activity of aged rats fed with the standard diet was significantly elevated.

Pitozzi et al. Interestingly, the reduction of anxiety was associated with significant decreased glutathione reductase activity and expression in the brain. Chepulis et al. They found that anxiety of rats fed with the diet supplemented with honey was significantly lower than in the other groups.

No information was given on the oxidative status of different groups; however, the antioxidant power of honey has already been stressed in other reports.

It has been suggested that the anti-anxiety effect of long intake of apples, olive oil and honey may be attributed to the whole food matrix containing complex mixtures of nutrients and non-nutrients including vitamins, flavonoids, phenolic acids, several carotenoids, and many more acting on a synergistic or additive manner, rather than to specific compounds.

Anxiety has a multifactorial origin and can result e. from pharmacological treatment with some drugs e. methyl-β-carbolinecarboxylate , stressful situations e. immobilization stress or natural conditions e. aging process. Although the link between OS disturbances and anxiety is not disputed, whether oxidative stress is a side effect resulting from emotional stress, or inversely itself is the pathogenesis factor for this condition remains unclear.

Nevertheless, results of Masood et al. Nevertheless, diazepam can abolish e. restraint stress-induced anxiety, although immobilization stress being a prooxidant.

Interestingly, Masood et al. Salim et al. It has been discussed that moderate physic activity reduces the vulnerability of brain to oxidative stress by increasing the resistance of brain antioxidant system following an adaptation, while acute or intense exercise are prooxidants.

The vulnerability of brain to oxidative damages is in line with the theory that anxiety could be generated directly by OS. Antioxidants may constitute a potential treatment when OS is the causal factor in anxiety.

In addition, a mixture of antioxidants and anxiolytics could be also a useful treatment in patients with anxiety, since OS is associated with anxiety disorders. It has been demonstrated that vitamin C caused a synergistic antidepressant-like effect with conventional antidepressants administered at subeffective doses.

However, the use of antioxidants as a pharmacological approach to treat anxiety or as a co-adjuvant treatment with conventional anxiolytics should be employed with precaution.

Indeed, antioxidants at high doses could become toxic by behaving e. In this sense, supplementation of the human diet with high doses of antioxidants, e.

Therefore, several studies are necessary to determine the safety of antioxidants at high doses, and the duration of the treatment, when the pharmacological approach is envisaged.

However, antioxidants from natural foods rich in antioxidants could constitute a preventive therapy against anxiety, owing to their presence at physiological doses. Several animal studies have shown that long-term consumption of honey, apple or olive oil can prevent aging-accompanying anxiety.

Nevertheless, the efficiency of antioxidants from fruits and vegetables has been prospectively verified against human diseases related to oxidative stress including coronary heart disease and stroke but has shown to be effective in preventing diseases predominantly when consumed at least at 5 portions per day.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike Edited by Vladimir V. Open access Relationship Between Oxidative Stress and Anxiety: Emerging Role of Antioxidants Within Therapeutic or Preventive Approaches Written By Jaouad Bouayed.

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Impact of this chapter. Introduction Oxidative stress OS represents a loss of balance in oxidation-reduction reactions redox state. References 1. Atmaca M. Tezcan E. Kuloglu M. Ustundag B. Tunckol H. Eur Arch Psychiatry Clin Neurosci, 2. Bayani A. Kocheki A. Berry A. Capone F. Giorgio M.

Pelicci P. de Kloet E. Alleva E. Minghetti L. Cirulli F. Bilici M. Efe H. Koroglu M. Uydu H. Bekaroglu M. Deger O. J Affect Disord , 64 43 51 5.

Blanchard D. Sakai R. Mc Ewen B. Weiss S. Blanchard R. Behav Brain Res , 58 6. Bouayed J. Rammal H. Soulimani R.

Oxid Med Cell Longev , 2 2 , 63 EOF 7 EOF 7. Bohn T. Oxid Med Cell Longev, 3 4 9. Younos C. Chepulis L. Starkey N. Waas J. Molan P. Dean O. Bush A. Berk M. Copolov D. van den M. Buuse Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice Behav Brain Res, Desrumaux C.

Risold P. Schroeder H. Deckert V. Masson D. Athias A. Laplanche H. Le Guern N. Blache D. Jiang X. Tall A.

Desor D. Lagrost L. FASEB, J 19 Ditzen C. Jastorff A. Keßler M. Bunck M. Teplytska L. Erhardt A. Krömer S. Varadarajulu J. Targosz B.

Sayan-Ayata E. Holsboer F. Landgraf R. Turck C. Protein biomarkers in a mouse model of extremes in trait anxiety. Mol Cell Proteomics, 5, do-Rego J. Viana A.

Le Maître E. Deniel A. Rates M. Stela I. Leroux-Nicollet J. Costentin Comparisons between anxiety tests for selection of anxious and non anxious mice Behav Brain Res , 2 , EOF EOF Ferrari P.

Editor-in-Chief: Ferdinando Nicoletti Department of Pharmaceutical Sciences University Rome'da Sapienza' Rome Stgess. ISSN Print syress Oxidative stress and anxiety ISSN Online : DOI: Oxidative stress caused xoidative reactive species, including reactive oxygen species, reactive Ginseng for weight loss species, and unbound, adventitious metal Tart cherry juice for digestive health naxiety. These oxidative stress and anxiety species are an inevitable by-product of cellular respiration or other metabolic processes that may cause the oxidation of lipids, nucleic acids, and proteins. Oxidative stress has recently been implicated in depression and anxiety-related disorders. Furthermore, the manifestation of anxiety in numerous psychiatric disorders, such as generalized anxiety disorder, depressive disorder, panic disorder, phobia, obsessive-compulsive disorder, and posttraumatic stress disorder, highlights the importance of studying the underlying biology of these disorders to gain a better understanding of the disease and to identify common biomarkers for these disorders. oxidative stress and anxiety

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