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REVIEW ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 6-15  

Oxidative stress biomarkers in bipolar disorder with suicidal behavior: A systematic review


1 Departments of Psychiatry, Universiti Kebangsaan Malaysia Medical Center, Cheras, Kuala Lumpur, Malaysia
2 Department of Psychiatry, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
3 Department of Biochemistry, Universiti Kebangsaan Malaysia Medical Center, Cheras, Kuala Lumpur, Malaysia
4 Department of Opthalmology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Cheras, Kuala Lumpur, Malaysia

Date of Web Publication22-Aug-2019

Correspondence Address:
Lai Fong Chan
Department of Psychiatry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Cheras, Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpnr.JPNR_3_19

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   Abstract 


Oxidative stress has been implicated in suicidal behavior and bipolar disorder (BD), respectively. However, the role of oxidative stress as a biomarker of suicidal behavior in BD remains inconclusive. This systematic review aims to determine the association between oxidative stress biomarkers and suicidal behavior among BD patients. All human studies from Scopus and Ovid Medline up until August 2017 on suicidal behavior, BD, and oxidative stress biomarkers were included according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of five studies met the eligibility criteria, of which 4 were case–control studies. Three studies identified at least one biomarker with significant association between suicidal acts and oxidative stress biomarkers (i.e., increased lipid peroxidation and NOS3 rs 1799983 TT genotype) in previous suicide attempt and increased deoxyribonucleic acid damage in suicide among sample populations with BD patients. No study reported conclusive associations between Ala-9 Val manganese superoxide dismutase or Pro 197 Leu glutathione peroxidase gene polymorphisms; or levels of nitric oxide metabolites, plasma total antioxidant potential, and malondialdehyde with suicidal acts among BD patients. Based on this systematic review, there is limited evidence of any association of the association between oxidative stress biomarkers and suicidal acts in BD patients. Definitive conclusions could not be ascertained due to lack of homogenous properly controlled and adequately powered studies. Future systematically well-designed and larger, prospective studies are warranted to clarify the role of oxidative stress pathways in the pathophysiology of suicidal behavior in BD.

Keywords: Antioxidant, bipolar disorder, deoxyribonucleic acid damage, oxidative stress, suicidal behavior


How to cite this article:
Mohamad Kamal NA, Loo JL, Goon JA, Damanhuri HA, Sharip S, Saini SM, Hamzah JC, Chan LF. Oxidative stress biomarkers in bipolar disorder with suicidal behavior: A systematic review. J Pharm Negative Results 2019;10:6-15

How to cite this URL:
Mohamad Kamal NA, Loo JL, Goon JA, Damanhuri HA, Sharip S, Saini SM, Hamzah JC, Chan LF. Oxidative stress biomarkers in bipolar disorder with suicidal behavior: A systematic review. J Pharm Negative Results [serial online] 2019 [cited 2019 Sep 23];10:6-15. Available from: http://www.pnrjournal.com/text.asp?2019/10/1/6/265150




   Introduction Top


One of the leading causes of injury and death worldwide is suicidal behavior. Bipolar disorder (BD) patients are a high-risk group for suicidal behavior with 30%–40% having attempted suicide in their lifetime, which is approximately 20–30 times greater than the general population.[1],[2]

Suicide refers to an intentional act of ending one's own life with death as an outcome.[3],[4],[5],[6] Nock et al. further classified suicidal behaviors into three other nonfatal categories: suicide ideation (thoughts of engaging in behavior with the intention to end one's life), suicide plan (preparation of a specific method through which one intends to die), and suicide attempt (engagement in self-injurious behavior with the intention to die).

Clinical features in BD patients with suicidal risks have been extensively studied for their ability to evaluate the risks for suicidal behavior. The stress–diathesis model of suicidal behavior incorporates factors such as history of multiple suicide attempts, increased levels of aggression as well as impulsivity, presence of cluster B personality disorders, and presence of suicidal behavior in the family which may signify genetic susceptibility.[7],[8] There is also an emerging body of evidence implying the role of oxidative stress underlying the pathophysiology of suicidal behavior.[9]

The Biomarkers Definitions Working Group (2001) defined a biomarker as ”a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”[10] The utility of biomarkers include defining the risk of developing a particular disease, predicting the prognosis as well as establishing novel therapeutic targets along with clarifying neurobiological processes.[11] At the molecular level, potential biomarkers may be in the form of genes such as genetic polymorphisms that increase one's vulnerability to BD or alelle variations such as in GSTM1*0/0, CAT-262C, superoxide dismutase 2 (SOD2), and Pro197 Leu GPx1 that have been associated with altered antioxidant levels in human brain, which may contribute to neurodegeneration and cognitive decline.[12],[13] In addition, products of gene expression such as proteins and enzymes can also be used as biomarkers.[11],[14]

An imbalance between the antioxidant capacity and the oxygen-free radicals could lead to production of oxidative stress. Both the capacity of internal antioxidant (i.e., ascorbic acid and glutathione) and antioxidant enzymes (i.e., peroxidase, SOD, and catalase) would be overwhelmed when the concentration of oxygen-free radicals is in excess. Proteins, lipids, and deoxyribonucleic acid (DNA) would be damaged leading to cytotoxicity, genotoxicity, and even carcinogenesis.[15] Many oxidative stress biomarkers have been postulated to be involved in the mechanisms underlying the pathophysiology of BD. Majority of studies identified oxidative damage to DNA, ribonucleic acid (RNA), proteins, and lipids. Altered levels of antioxidant enzymes have also been reported.[16] A recent meta-analysis by Brown et al. showed increased lipid peroxidation (LP) and nitric oxide (NO) levels, as well as DNA/RNA damage in BD.[17] These biomarkers are hypothesized to play a significant role in the pathophysiology of BD. Nevertheless, larger prospective studies are warranted to determine the utility of oxidative stress markers in predicting disease expression, course of illness, and treatment response in BD.[18] In a postmortem study by Kokacya et al., a significantly increased level of NO and LP and lowered total radical-trapping antioxidant parameter (TRAP) were found in 35 cases of death by suicide.[19] However, the validity of psychiatric diagnosis in that study was unclear, and it did not include cases with BD.

Evaluation of the reliability and validity of any particular biomarker of oxidative stress requires careful consideration of the relevant methodologies and protocols involved. Ng et al.'s review has highlighted that the majority of findings from literature on oxidative disturbances in psychiatric disorders have investigated oxidative status through indirect methods (i.e., using brain and peripheral measurements of oxidative products and enzymes as well as antioxidant levels).[20] For instance, metabolites of nitrite and nitrate have been investigated as a proxy of peripheral levels of NO-free radical concentrations. Nitrosative damage to lipids, DNA, and proteins have also been hypothesized to be a consequence of increased levels of NO in BD.[21] In view of the complexity of the interpretation of NO analysis, variability of results may arise under different study conditions, especially when different techniques such as the electrochemical sensors, Griess assay, and chemiluminescence analyzers are employed.[20],[22] Therefore, these authors have recommended that interpretation of oxidative stress analysis requires careful consideration of variables such as differing types of tissue samples including sample size and their respective metabolic features. This in turn should guide the selection of the most appropriate technique for any given sample to optimize the integrity of results obtained.

Numerous factors can influence the production of oxidative stress. Adaptive responses such as epigenetic systems, immune cell selection, and other mechanisms allow one to adapt with the changes of oxidative stress level.[23] Findings from Michels et al's study suggested that the CACNA1C risk gene for mood disorders may be involved in the mitochondrial oxidative stress pathways of mouse neuronal cells.[24] Twin heritability estimates for oxidative stress, specifically LP and nucleic acid damage have been reported as 22% and 17%, respectively. In that same Danish twin study, Broedbaek et al. showed that external modifiable environmental factors contributed significantly to the variation of oxidative stress level.[25]

Despite the aforementioned associations, a significant knowledge gap in the literatures still exists with regard to the role of oxidative stress markers as potential “biosignatures” of suicidal behavior, specifically in a high-risk population such as patients with BD.[26] Therefore, the objective of this systematic review is to determine the association between oxidative stress biomarkers and suicidal behavior (i.e., suicidal ideation, suicidal plan, suicidal attempt, and suicide) among patients with BD.


   Methods Top


This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.[27] It has been registered to and approved by the Secretariat for Medical Research and Innovation, National University of Malaysia.

Criteria for inclusion in this systematic review were (a) any human observational study (cohort, case–control, cross-sectional), randomized clinical trial or nonrandomized clinical trial, (b) published in English, (c) samples must include BD patients of any age with suicidal behavior, (d) at least one oxidative stress biomarker and one suicidal behavior, (e) articles published from 1965 to August 2017. The included study must analyze the association between oxidative stress biomarkers and suicidal behavior in samples that include patients with BD. Reviews, meta-analyses, editorials letters, conference abstracts, and proceedings were excluded.

A sensitive search strategy with both controlled subject headings and text terms relating to suicidal behavior (i.e., suicid*, parasuicid*), bipolar disorder (i.e., bipolar*, depress*, manic*), and oxidative stress biomarkers (i.e., oxidative stress biomarker*, superoxide dismustase*, SOD-1*, SOD-2*, catalase*, DNA damage*, RNA damage*, lipid peroxidation*, 8-Oxo-2'-deoxyguanosine*, 8-Ohdg*, reactive oxygen species*, antioxidant*, glutathione*, reduced glutathione*, oxidized glutathione*, glutathione peroxidase*, 4-HNE*, 4-Hydroxynenal*, protein damage*, protein carbonyl*, nitric oxide*, advanced glycosylated end product*, deoxyguanosine*, malondialdehyde*) was designed. The electronic databases Scopus and Medline were used, and all relevant studies published since the inception of these databases up until August 2017 were included.

The records identified from search strategy and additional studies from scanning reference lists of relevant articles were entered into the EndNote X7 reference manager software (Clarivate Analytics, Philadelphia, United States). Two authors (LFC and NA) conducted the assessment for selection of studies based on the inclusion and exclusion criteria independently. The first screening process was done based on the study title and abstract. Subsequently, 52 were retrieved for eligibility assessment using a Data Extraction Form (DEF). The DEF was pilot-tested on 10 random full texts derived from the initial screening and was refined accordingly. All discrepancies were resolved through discussion until consensus was reached. This process finally resulted in the final selection of five studies.

Two authors (LFC and NA) subsequently evaluated each study for its quality using the Standard Quality Assessment Criteria For Evaluating Primary Research Papers,[28] independently. This evaluation tool consists of 14 criteria, which is individually scored using a 3-point scale (0 = no, 1 = partially, 2 = yes). “Nonapplicable (N/A)” was marked if the criteria were not applicable to the study design. To get the summary score, the combined total score was divided into the numbers of criteria (excluding the ones marked with N/A) before converting it into a percentage. All discrepancies were again resolved through discussion until consensus was reached. A minimum score of 75% is required for a study to be included in this review.

Information was extracted from each included trial on: (1) characteristics of trial participants (diagnosis, method of diagnosis, method of eliciting suicidal behavior, and presence of controls); (2) characteristics of suicidal behavior; (3) type of outcome measures (level of oxidative stress biomarkers); and (4) other variables (sociodemographic characteristics, subtype of BD, severity of diagnosis, presence of other comorbidities, treatment received, obesity, smoking, alcohol use, and supplementation use).


   Results Top


The search of Ovid Medline and Scopus databases provided a total of 7799 citations after adjusting for duplicates. Of these, 7748 studies were excluded, as they did not meet the inclusion criteria. Two authors then screened 51 full texts independently and excluded 46 articles due to reasons detailed in [Figure 1]. The remaining 5 studies (4 case–control and 1 cross-sectional) that involved a total of 1500 participants aged between 18 and 60 years old met the quality score of more than 75% [Table 1] and [Table 2]. No unpublished relevant studies were obtained.
Figure 1: Flow chart of search strategy

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Table 1: Summary of included studies

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Table 2: Assessment of the quality of included studies

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In view of overall participants' characteristics and reported outcome measures that differed significantly, this review focused on describing the studies, methods, results, applicability, and limitations and performing a qualitative synthesis rather than a meta-analysis.

Methodology and protocols

One of the five studies interviewed the participants using the suicidal behavior section of Diagnostic Interview for Genetic Studies version 3.0 to determine the presence or absence of lifetime history of suicide attempt.[29] Two studies used self-reported questionnaire to elicit lifetime history of suicide attempt.[30],[31] Lee et al. reported obtaining the blood samples when a patient presented with a recent (exact time unspecified) suicide attempt at the emergency room (cases of suicide not included).[32] Mustak et al. obtained human postmortem brain tissue samples within an average of 6 h after the time of death by suicide. These authors reported that the average postmortem interval (PMI) between the time of death and freezing of the brain tissue samples at −80°C was not more than 6 h.[33] The level of DNA damage as a marker of oxidative stress was determined from the frontal cortex, pons, medulla, and thalamus. Their studies have shown that postmortem brain tissue is relatively well protected from DNA degradation.[34],[35] The postmortem stability of DNA allows for analysis up to years after death in the context of brain banks, especially after cryoprotection phase whereby postmortem brain samples are stored at −70°C to −80°C.[36],[37] Other studies have also outlined specific protocols and specialized systems of sample collection and storage of peripheral blood samples to improve the integrity and conservation of blood specimens for analysis purposes. Such procedures have been shown to reduce the possible variability from blood sampling to DNA purification such as collection tube, temperature fluctuation during transportation and RNA carryover, as well as measurement of NO metabolites (NOx) levels.[38],[39]

Apart from the timing of data collection and sample storage conditions, all five studies in this review reported standardized measurement and assessment techniques of oxidative stress biomarkers. Vargas et al. and Lee et al. measured the NOx using the Griess reagent, based on the reduction of nitrate to nitrite.[30],[32],[40] The measurement of LP was carried out using ferrous oxidation–xylenol orange assay, meanwhile MDA was measured using the modified thiobarbituric acid (TBA) assay.[30],[41],[42] TRAP was measured by chemiluminescence, which yields luminol when reacts with free radicals.[30],[43] DNA damage was assessed using the agarose gel electrophoresis.[30],[44] TaqMan assay was used to genotype NOS1, NOS2, and NOS3 gene variants.[29],[45] Real-time quantitative polymer chain reaction method was used by Cumurcu et al. for genotyping GSH-Px and manganese SOD (MnSOD).[31] Vargas et al. reported that the inter-assay coefficients of variability for all analytes in their study were <10%, which is within the acceptable range in terms of reliability.[30]

Free radicals

Nitrite and nitrate, the major oxidative metabolites of NO, are preeminent biomarkers for studies in both BD and suicidal behavior.[17] Two studies reported higher levels of NOx among patients who had attempted suicide.[30],[32]

In Vargas et al.'s study, based on univariate analyses, levels of NOx were significantly higher among suicide attempters compared with nonattempters (mean = 5.0, P = 0.001) in a combined group that consisted of healthy controls as well as unipolar and bipolar depression patients.[30] However, this association did not remain significant after controlling for potential confounders of oxidative stress such as gender, smoking behavior, mood disorder (unipolar and bipolar depression), other inflammatory (Creactive protein, fibrinogen, erythrocyte sedimentation rate, interleukin-6, and tumor necrosis factor-α), as well as metabolic parameters (body mass index [BMI] and waist circumference) (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 0.97–1.60, P = 0.083).[30] No separate analysis was performed exclusively among BD patients, therefore limiting further interpretation of that study's findings.

In Lee et al.'s study, the significant association of higher NO level in suicidal patients was between patients with major depressive disorder (MDD) and BD as a group, compared to patients with schizophrenia (P = 0.034). When BD per se was considered an independent psychiatric diagnosis, the higher level of NO found in suicidal patients was not statistically significant (P = 0.147).[32] The possibility of Type II error cannot be ruled out due to the very small sample of BD patients in this study that only represented 7% of the total psychiatric patients (n = 8).

Oxidative damage to lipid and deoxyribonucleic acid

Oxidative degradation of lipids is also known as LP with cell damage as end product. Levels of LP were found to be significantly higher among suicide attempters compared with nonattempters (mean = 1.3, P = 0.001) in Vargas et al.'s study.[30] However, levels of MDA, the end product of LP, showed no significant differences in both groups (mean = 15.9, P = 0.713). In the subsequent multivariate logistic regression analysis, higher levels of LP were associated with increased odds of suicide attempts by five folds (OR = 5.19, 95% CI = 1.6–15.98, P = 0.004). In addition, both unipolar and bipolar depression, female gender as well as smoking behavior were also significantly associated with a history of suicide attempt. In fact, these variables were independent of other established risk factors of suicidal behavior such as marital status, years of education, and alcohol abuse.[30]

Mustak et al. is the only study that assessed the oxidative stress biomarkers on the human postmortem brain tissue while the other remaining four studies used the human peripheral venous blood samples. Significantly higher levels of DNA damage specifically in the frontal cortex, pons, medulla, and thalamus were found among BD patients who died by suicide compared to healthy controls (P < 0.01).[33] The small sample size of this study (n = 18) is a major limitation, especially in postmortem studies whereby logistical and feasibility issues such as legal restrictions and low availability of samples have been recognized.[46] Cases of nonsuicide deaths among BD patients were not included in this study. Therefore, it is unclear from this study whether DNA damage was significantly associated with BD and/or suicide.

Antioxidant system

TRAP was significantly lower among suicide attempters compared with nonattempters (mean = 755.8, P = 0.005).[30] Similar to NOx levels, the association was not significant after controlling for other potential confounders (OR = 1.00, 95% CI = 0.99–1.00, P = 0.240). Again, no separate analysis was performed for each individual diagnosis. Thus, it is somewhat unclear whether the significant association was within the group of BD patients per se or not.

Genetic polymorphisms

Two studies analyzed the association of candidate oxidative stress genes with suicidal behavior.[29],[31] Three subtypes of BD (BD-I, BD-II, and BD nonotherwise specified) were investigated by Oliveira et al. whereby the authors did not find significant genetic associations between NOS1, NOS2, and NOS3 gene polymorphisms with BD per se.[29],[31] The NOS3 RS1799983 TT genotype was linked to violent suicide attempt (P = 0.002), and this significant association was restricted to the early-onset BD patients (OR = 5.05, 95% CI = 1.33–6.34, P = 0.0003).[29] Cumurcu et al. (2013) reported no significant association between Ala-9 Val MnSOD and Pro 197 Leu GSH-Px gene polymorphism in the patients with BD with prior history of suicide attempt.[30] In terms of ethnicity, Oliveira et al. mentioned about the homogeneity of study sample (exclusively French with minimum of three French grandparents) but Cumurcu et al. did not specify the ethnic composition of their study sample.[29],[31]

Control for confounding factors

Four studies clearly mentioned a case–control design under the methodology section except for Vargas et al.[30] Nevertheless, Vargas et al. did include BD patients with and without lifetime history of suicide attempt and excluded medical conditions with cell-mediated immune activation and peripheral inflammation, which are potential confounders of oxidative stress.[30] It is inferred from the Vargas et al.'s (2013) results that the normal controls mentioned under the discussion section were referring to study participants without the following conditions: unipolar or bipolar depression, suicidal behavior, or medical conditions with cell-mediated immune activation and peripheral inflammation. Oliveira et al. stated that the healthy controls were those without BD.[29] Meanwhile, the other three studies specified healthy controls as study participants without both BD and underlying medical disorders.[31],[32],[33] Three of five studies controlled for any substance or alcohol abuse by either excluding participants with these comorbidities from the study or including these dependent variables in the multivariate analysis.[30],[31],[33] Smoking increased the odds of suicide attempts (OR = 5.05, 95% CI = 1.33–6.34, P = 0.017) while BMI and waist circumference were also found to be significantly higher in those with history of suicide attempt/s.[30] Four of five studies matched the cases and controls in terms of age and gender.[29],[31],[32],[33]

Only one study stated the state of mood of BD patients at the time of recruitment whereby all BD patients in Oliveira et al.'s study were euthymic at inclusion.[29] Several lines of evidence from observational studies indicate that mood stabilizers potentially possess antioxidant properties.[47] The cases and controls in Mustak et al.'s study were not on any psychotropic medications before or at the time of suicide, whereas majority of participants in Lee et al.'s study had not taken any psychotropic medications for at least 2 weeks before study recruitment.[32],[33] Poisoning was also excluded as a method of suicide (only cases of suicide by hanging or burning were included). In addition, matching of cases and controls in terms of age, gender, PMI, tissue pH, and freezer storage time was employed by the authors to control for these potential confounding variables of oxidative stress.[33]


   Discussion Top


From a broad perspective, findings from this systematic review suggest that oxidative stress biomarkers may be associated with suicidal acts in BD. However, it is pertinent to highlight that the significant associations demonstrated in 3 of 5 studies were not replicated across the positive studies in terms of specific types of oxidative stress biomarkers, likely due to methodological heterogeneity [Table 1]. Nevertheless, the synthesis of this review's findings warrants further discussion.

Nitric oxide pathway in bipolar disorder and suicidal behaviors

Findings from this review seem to suggest a possible involvement of the NO pathway in suicidal acts among BD patients. However, this signal is weak in view of only one positive study by Oliveira et al.[29] Nevertheless, it is still noteworthy that BD patients (specifically those with an early onset of illness) with violent suicide attempts were significantly more likely to have the TT variant of NOS3 rs 1799983 compared to nonattempters with BD.[29] The authors did not find any significant association between BD per se and the NOS1, NOS2, and NOS3 genetic polymorphisms in that study. These findings allude to the possibility that the NOS3 rs 1799983 TT risk genotype may be a marker that potentially differentiates BD patients with more severe disease characterized by early-onset and violent suicide attempt from BD patients with lower severity and arguably better prognosis.

Based on the current level of evidence, premature conclusions cannot be drawn with regard to the role of the NOS3 genetic polymorphism as an oxidative stress biomarker of suicidal behavior in BD. Beyond this review, other studies that have investigated NOS genes in the context of suicidal behavior have shown inconsistent results albeit among patients with varied psychiatric diagnoses. Rujescu et al.'s study demonstrated that the NOS3 haplotype (haplotype CTA that included the NOS3 rs1799983 T allele) was protective rather than a risk for suicide.[48] Oliveira et al. (2015) explained that such differences in results could possibly be due to Rujescu et al.'s (2008) sample not being clinically or ethnically comparable in which Oliveira et al.'s (2015) sample consisted of homogeneous BD patients of French ancestry (at least 3 French grandparents) while Rujescu et al.'s (2008) sample was more ethnically heterogeneous whereby the study included samples of either Caucasian or German descent. In addition, patients in Rujescu et al.'s (2008) study did not state inclusion of BD patients among the study sample of borderline personality, affective, and schizophrenia spectrum disorder.

As highlighted in the results section, methodological and analytical limitations need to be considered when interpreting findings from this review. Beside Oliveira et al.'s (2015) study, this review identified two other studies that investigated the NO pathway and suicide attempt in BD.[29],[30],[32] Although both studies were considered negative with regard to the NO system, it is worthwhile noting that these studies demonstrated higher levels of NOx among suicide attempters compared to nonattempters. These findings did not remain significant after confounders of oxidative stress were controlled for and subanalysis of exclusively BD patients (n = 8) was performed.[30],[32] Oliveira et al.'s (2015) study of candidate NOS genetic polymorphisms did not report single-nucleotide polymorphism (SNP) heritability estimates, thus limiting the interpretation of the degree of heritability of the purported NOS3 rs 1799983 TT risk genotype. Moreover, the NOS3 rs 1799983 was neither identified among any of the genes identified at significant loci from Stahl et al.'s (2018) genome-wide association studies (GWAS) for BD nor among the tops SNPs for suicidal behavior from Galfalvy et al.'s GWAS for suicidal behavior.[49],[50] Therefore, the possibility of the reported significant association between this candidate gene polymorphism, NOS3 rs 1799983 with a history of violent suicide in BD being a false-positive result cannot be excluded.[51]

Despite Oliveira et al.'s (2015) speculation about the possibility of low NO levels as a consequence of the NOS3 rs 1799983 polymorphism, this was not confirmed by measurement of central or peripheral NO levels or the relationship with psychosocial stressors (adverse life events, etc.,) in that study. Thus, future prospective studies are needed to elucidate the pathway from the presence of a particular “risk” NOS genotype that leads to actual expression of altered levels NO and the manifestation of suicidal behavior phenotype in BD. Epigenetic processes and gene–environment interactions have to be accounted for in future studies. As highlighted by Kudlow et al.'s review, NOS genetic polymorphisms, in particular the NOS1 gene, which has also been associated with suicide, have been demonstrated to act as either a risk or protective factor for the development of MDD depending on the presence of low or high adversity.[52],[53],[54]

Deoxyribonucleic acid damage and lipid peroxidation

DNA damage and LP are markedly increased in BD patients.[16] In a normal physiological state, reactive oxygen species (ROS) are detoxified by the antioxidant enzymes. However, when the systems are overwhelmed by increased ROS, damage can occur to both DNA and lipids leading to apoptosis and cell membrane damage, respectively. This may then result in impairment of mood-stabilizing mechanisms.[21]

This review identified one small study by Mustak et al. that showed significant higher levels of DNA damage specifically in the frontal cortex, pons, medulla, and thalamus among BD patients who died by suicide compared to healthy controls.[33] As highlighted in the results section, the lack of inclusion of cases of nonsuicide deaths in BD limits the interpretation of that study's finding with regard to whether the association of oxidative stress is driven by BD and/or suicide. DNA damage has been shown to be significantly associated with the diagnosis as well as severity of BD.[55] DNA damage also seems to have a positive correlation with the severity of depression in BD patients.[56]

Individuals with higher levels of LP are five times more likely to have prior suicidal attempt/s.[30] A recent study by Sowa-Kućma et al. reported that higher levels of TBA reactive substance (TBARS), which is a byproduct of LP, were significantly associated with a more severe form of BD (presence of melancholic features, higher number of lifetime depressive episodes, history of suicide attempt/s, and current suicidal ideation).[57]

While there are many potential contributing pathways involved in the neuroprogression of BD, future research should include disease severity as a study variable to clarify the relationship between DNA damage, LP, and suicidal behavior specifically in BD.

Effect of comorbidities to oxidative stress biomarkers

Both exogenous factors (cigarette smoking, alcohol and substance abuse, dietary habits, physical activity, and supplement intake) and endogenous factors (medical conditions and presence of inflammation) can influence the level of the oxidative stress biomarkers.

It is well known that BD is associated with substantial morbidity and mortality, the most common being cardiovascular diseases.[58] This may be related to the increased prevalence of classical cardiovascular risk factors such as smoking and obesity in this population.[59] It has also become increasingly clear that oxidative stress is involved in several cardiovascular diseases. Hughes reported an association between smoking behavior, oxidative stress biomarkers, and suicidal behaviors.[60] In Vargas et al.'s study, female gender, smoking, and higher level of LP emerged as independent significant factors of previous suicide attempt among a population that included BD, after controlling for significant metabolic parameters such as BMI and waist circumference that were higher among suicide attempters.[30] Therefore, these potential confounding factors need to be considered in terms of interpreting the association between oxidative stress and suicidal behavior in BD.

Implications

Although there is some suggestion of a possible association between oxidative stress biomarkers and suicidal acts in BD, future larger and well-controlled prospective studies are warranted to elucidate the underlying mechanisms of specific oxidative stress pathways and suicidal behavior in patients with BD. There were also no studies identified from this review that examined oxidative stress and suicidal ideation on the distal, less severe spectrum of the suicidal behavior continuum compared to suicide attempt and suicide. Hence, future studies in this area should also include suicidal ideation as it is a common clinical presentation, accounting up to 59% of patients with BD that is amenable to early intervention with regard to suicide prevention.[61] In terms of methodology, protocols of oxidative stress biomarker measurement require improved standardization with regard to sample storage conditions, timing of data collection, and analysis to improve the reliability and validity of study results. Such study designs would be more ideal to clarify whether oxidative stress is a cause or effect of suicidal behavior in BD, which is currently unclear due to the retrospective designs of studies identified in this review.

Davis et al. classified biomarkers into six different types: risk, trait, state, stage, treatment response, and prognosis.[62] Oliveira et al.'s finding of a significant association between the genotype NOS3 rs1799983 TT identified during the euthymic period and the phenotype of previous violent suicide attempt in early-onset BD (defined as 28 age <22) is suggestive of the NOS3 gene polymorphism being a trait marker of past suicidal behavior.[29] Such a finding needs replication in more well-designed studies with epigenetic factors considered as described earlier before conclusions can be made with regard to the potential utility of this “risk” genotype in predicting future suicidal behavior. Savas et al.'s study showed that the number of manic episodes in BD was correlated with serum NO levels, suggesting that the more episodes one has, the higher the NO levels are.[63] This indicates that oxidative stress may also be a trait marker of more severe BD and that the chronic relapsing nature of the illness could lead to long-standing accumulation of oxidative stress. Studies have also found higher levels of oxidative stress biomarkers such as SOD and TBARS in manic and depressive BD episodes than in healthy controls and euthymic BD patients.[64],[65] These findings are congruent with Kapczinski et al.'s study whereby increased SOD activity was only found in depressive or manic states in BD but not in euthymic state.[66] This in turn suggests that a state type of such altered levels of oxidative stress may be markers of disease severity during the acute phases of BD activity.[67] Thus, clarity is also needed from further research to disentangle the individual and overlapping contribution of oxidative stress in the pathophysiology of BD per se and with suicidal behavior, respectively, while taking into consideration disease severity and potential confounders of oxidative stress.

In terms of clinical implications, once more definitive oxidative stress biomarkers have been identified as trait and/or state markers of suicidal behavior; other well-established sociodemographic and clinical predictors of suicidal behavior could be combined for more comprehensive risk stratification and prognostication models. Such models of suicidal behavior also need to account for the variance in the level of oxidative stress [68] that is influenced by factors such as genetics, smoking, and obesity. This would potentially improve the predictive value of such models for early identification of bipolar patients at risk for suicidal behavior as well monitoring of response to more “personalized” interventions.

To date, existing studies that have explored the combination of biological (not including oxidative stress makers) and clinical risk factors for suicidal behavior still have limitations in terms of the level of comprehensiveness with regard to inclusion of established risk factors.[69]

Beyond risk and prognostic predictions, there may also be other therapeutic implication in terms of the role of oxidative stress pathways and suicidal behavior in patients with BD. It has been suggested that antioxidants neutralize reactive oxidants and modulate gene expression that contribute to oxidative stress.[70] An example is lithium, the gold standard mood stabilizer in BD with antisuicidal properties.[71] Machado-Vieira et al. postulated that the usage of lithium in BD might exert antioxidant effects by lowering SOD/catalase ratio and NO levels, which warrants further study in terms of the possibility of NO pathway involvement as alluded to in our systematic review.[64]

Limitations

There are several limitations that need to be borne in mind to have a balanced perspective of interpretation of findings from this systematic review. The main limitations are the heterogeneity of methodology across all the five studies included in this review, especially in terms of the types of oxidative stress biomarkers being measured and adequacy of sample size. Another major limitation is the lack of consistency in terms of systematically controlling for significant confounders (i.e., BMI, substance use, and smoking) across all included studies. In addition, there is limited generalizability of this review's findings beyond the ethnic populations that were included in the 5 studies. Furthermore, there is a possibility of publication bias due to the exclusion of unpublished studies. Thus, we are unable to determine whether there were negative studies that were not identified in our review. Apart from that, we cannot ascertain whether the restriction of English-language publications could have contributed to any additional bias in our review.


   Conclusions Top


There appears to be limited evidence in terms of the association between oxidative stress biomarkers and suicidal acts in BD from the small number of studies (n = 5) identified in this review. The findings of increased LP and the NOS3 RS1799983 TT genotype in bipolar patients with a history of suicide attempt as well as increased DNA damage among bipolar patients who died by suicide were not replicated across the 3 positive studies. In view of the limitations with regard to study heterogeneity, small sample sizes, and lack of consistent control of confounding factors across included studies, definitive conclusions regarding the association between oxidative stress biomarkers and suicidal acts in BD cannot be drawn. Therefore, future larger, prospective studies that are systematically designed in terms of standardized protocols of oxidative stress biomarker assessment are warranted. In addition, comprehensive inclusion of potential confounders as well as the distal spectrum of suicidal behavior (i.e., suicidal ideation and plans) that may be arguably more amenable to early identification for suicide prevention need to be considered.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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