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The relevance of some new biomarkers (e.g. oxidative stress) in psychiatry as evidenced by non -invasive methods in saliva, tears, urine or feaces.


Recent years of research have brought to the forefront a considerable number of biomarkers in areas such as psychiatry, which can help diagnose, treat and even prevent diseases in this sphere and beyond. Considering the need to be able to make testing easier, the idea of identifying biomarkers by less invasive methods has been of particular interest. Target patients, those with neuro-psychiatric disorders (focusing here on Alzheimer's, Parkinson's, schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, or autism) could be more difficult to address in terms of blood sampling, therefore, alternative methods targeting urine samples, saliva or even tears can help. The use of non-invasive methods is all the more desirable as they involve avoiding contamination or needle sticking after blood collection. Thus, contamination with infectious agents from chronic patients can be successfully avoided. We also mention here imaging methods like magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and positron-emission tomography (PET), which although more expensive, could provide essential morphological or functional information related to the brain as an aid to the diagnosis of disease in a timely manner. Thus, the purpose of this review is to synthesize the latest information about some biomarkers which can be found in some neuropsychiatric disorders and how they could vary in urine, tears, saliva etc.


biomarkers, psychiatry, non-invasive methods


Oxidative stress occurs when there is an imbalance between the reactive oxygen species (ROS) and the antioxidant system, an imbalance that comes to the detriment of the latter. The brain is the largest oxygen user being subjected to an oxidative stress that induces cellular destruction through free radicals and becomes more vulnerable due to high levels of polyunsaturated fatty acids and high metal content (1). Also, being rich in iron there is a strong catalytic reaction that generates highly reactive hydroxyl radicals via Fenton reaction (2).

The imbalance between the antioxidant system and the reactive oxygen species can lead to adverse consequences such as damage to the blood brain barrier, nervous tissue or even myelin destruction (3). The destructive process is aggravated by age due to the diminished antioxidant defense as well as the amplification of the mitocondrial dysfunctions (4). The devastating effect of oxidative stress is countered by antioxidant systems such as superoxide dismutase enzymes (SOD) or glutathione peroxidase (GPX) (5). Free radicals produce lipid peroxidation with alteration of cell membrane permeability, the most representative markers of lipid peroxidation being malondialdehyde (MDA) and 4hydroxynonenal (4-HNE) (6). Although biomarkers are used in many areas, unfortunately the one related to neuropsychiatry disorders are poorly represented (not a single biomarker until today!). However, recent years of research have made progress in identifying certain biomarkers related to some psychiatric disorders that can lead to diagnosis, treatment and perhaps even pre vention. It is preferred that a biomarker be cost-effective, reliable, and preferably noninvasive (7). Long has gone on the principle that the brain is the only organ that can be investigated related to some psychiatric illnesses, although it is far less accessible to studies. Recent studies have attempted to link biomarkers in the postmortem brain to those measured in the serum, yielding satisfactory results, namely comparable molecules from both sources, particularly those responsible for the inflammatory response (8). A specific marker example is peripheral inflammatory cytokines that can interfere with numerous psychiatric disorders, mediators in cellular communication, synaptic plasticity and mood-relevant neurocircuitry (9). Studies have gone on to try to highlight results obtained by non-invasive methods from other biological fluids such as urine, tears, saliva or even faeces.

Stress related cortisol levels can be dosed in urine, saliva or hair just as it can be dosed from blood. Cortisol can also vary in other neuropsychiatric disorders such as major depressive disorder (10), schizophrenia, where its level decreases (11) as it decreases during antipsychotic treatments (12) to grow back after treatment is discontinued (13). Some studies have contradictory results on cortisol levels in conditions such as PTSD (posttraumatic stress disorder), perhaps because cortisol is linked to exposure to trauma (14), depression or other psychiatric disorders (15), making it impossible to delineate the disease by the molecular factor that may increase the risk of developing the disease. Starting from these contradictions, Young and Breslau have delineated the levels of urine catecholamines in patients with PTSD, trauma patients without PTSD, and traumatized patients (16). Also, further studies have identified and delineated the urinary levels of dopamine and norepinephrine in patients with and without depression (17) or those undergoing treatment (18). Although easy to analyze, these biomarkers could not be relevant because were not able to differentiate between patients with affections and those who were healthy.

As it is very difficult for a single molecule to make a difference between diagnoses, symptoms, research focused on identifying a profile of multiple biological markers. This approach proved to be successful, given the fact that a recent study compared sera from controls and patients with schizophrenia, major depressive disorder (MDD), borderline personality disorder (BPD) and Asperger's Syndrome (19) and after examining a total of 52 analysts (20), patients with schizophrenia could be highlighted by other patients with various other psychiatric conditions or controls.

It has also been attempted to understand how proteins act in a particular stage of a disease using proteomic approaches that go beyond genetic and epigenetic ones. Thus, this method was able to differentiate patients with major depression disorder with or without psychotic symptoms. The good part of this aspect is that tests can be performed from all body fluids (21).

Fortunately, there are potential biomarkers that do not require the use of biological samples. For example, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and positron-emission tomography (PET) can provide essential morphological or functional information related to the brain as an aid to the diagnosis of disease in a timely manner. Unfortunately these techniques can not make a difference between groups and high costs can limit research (23).

If the biologically active molecule selected for PET is fludeoxyglucose (FDG), an analogue of glucose, the concentrations of tracer image will indicate tissue metabolic activity as it corresponds to regional glucose uptake. A recent study evaluating metastasis of glucose in the brain by this method revealed that patients with a low glucose metabolite in the island respond favorably to cognitive behavioral therapy and those with high glucose metabolism have favorable outcomes after treatment with escitalopram (22) which is used to treat depression and anxiety. It works by helping to restore the balance of a certain natural substance (serotonin) in the brain. Magnetoencephalography (MEG) can be applied in a clinical setting to locate abnormalities, as well as in an experimental framework for measuring brain activity. This technique has been successfully and accurately identified with patients with various conditions such as multiple sclerosis, Alzheimer's, schizophrenia, Sjogren's syndrome (24).

Alteration of brain-derived neurotrophic factor (BDNF) gene expression and the decrease in serum BDNF levels are associated with several neuropsychiatric disorders, including schizophrenia (in which serum levels are low and in correlation with positive and negative symptoms, making BDNF an unspecific marker), and major depression disorder (25). Making it an important biomarker is that it is expressed both in the central nervous system and the peripheral nervous system at the same levels (26). Although considered relevant in some studies, it is necessary to deepen the research in order to prove it to the utmost importance as a biomarker.


In general, urinary biomarkers are linked to kidney disease, given the connection between the urine and the kidneys (27). However, the importance of biomarkers in other affections such as psychiatric disorders should not be ignored, even if the brain and the urine do not have a direct link, and there is also a filtering effect of the blood-brain barrier and kidneys. Although a relatively low number of proteins in the urine were identified at the beginning, most of them from the bloodstream through filtration, from the urinary tract or the secretions of the urinary tract, the proteomic studies revealed the existence of 6000 proteins in the urine, which made the study of urinary biomarkers a little easier. Now, there are studies that link urinary biomarkers to sleep apnea (28), eclampsia (29), and cardiovascular diseases (30).

Metabolites in urine can also indicate a state of the body and can be relevant biomarkers. Currently, metabolomics is used in the study of many diseases such as chronic heart failure (31), liver cancer (32), breast cancer (33) and diabetic nephropathy (34).

A study done on 42 untreated patients with major depressive disorder (MDD) and 28 healthy patients using peptidomics methods revealed 5 peptides selected from 29 urinary peptides and established the candidate classification model which showed good diagnostic performance. Of the five peptides, 4 have a protein correspondence: serum albumin, alpha1-microglobulin, heparan sulfate proteoglycan and apolipoprotein A1, whose modified expressions have been associated with multiple mental illnesses (35). At the same time, metabolomics techniques have identified biomarkers so that 82 patients with untreated MDD and 82 healthy patients were tested and identified urinary metabolites associated with the tricarboxylic acid cycle, intestinal microflora metabolism and tryptophan-nicotinic acid pathway underwent changes in the urine of MDD patients. Subsequently, the same group of patients was tested, and 6 metabolites were identified in their urine: sorbitol, uric acid, azelaic acid, hippuric acid, quinolinic acid and tyrosine, which may be biomarkers of reference for MDD (36).

Bipolar disorder (BD), also known as manicdepressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-today tasks. Studies have reported that a biomarker panel that includes 5 metabolites: azelaic acid, 2,4-dihydroxypyrimidine, betaalanine, pseudouridine and alpha-hydroxybutyrate can be a candidate model model (37). Because the patients in the study were under the influence of antipsychotic treatment, the impact of this aspect on the study results can not be estimated.

A study led by Yap on children with autism and healthy children, have shown that the presence of metabolites associated with nicotinic acid and some amino acids in the urine, such as taurine, glutamate or N-acetyl glycoprotein fragments, are in low levels in children with autism (38). Also high levels of organic acids and sugars and low levels of fructose, 1,2,3-butanetriol and propylene glycol in children with autism compared to controls (39). Thus, changes in glucose meta bolism with the emphasis of glucose in urine, as evidenced by other studies (40), make these metabolites possible as biomarkers in the detection and treatment of the disease. A study of patients with schizophrenia and healthy patients whose urine was analyzed before and after a six-week treatment with antipsychotics (risperidone) (41) revealed the modification of neurotransmitter metabolites such as glucosamine, glutamic and mandelic acide along with urinary creatinine, citrate, valine and glycine in schizophrenic patients indicating imbalances in amino acid and energy metabolism.

There are two studies conducted on mice linking urinary biomarkers to Alzheimer's disease progression. The 3-hydroxykynurenine, homogentisate and tyrosine biomarkers were identified before dementia, and 1methylnicotinamide, 2-oxoglutarate, citrate, urea, dimethylamine, trigonelline and trimethylamine (42) could be identified in the advanced stages of the disease. A proof that oxidative stress is established before disease symptoms is the elevated level of proteins associated with it such as 3-hydroxykynurenine, homogentisate and allantoin in 4-month mice with Alzheimer's. The second study (43) indicated the presence of methionine, 5-hydroxyindolacetic acid, desaminotyrosine, taurine, which is the only biomarker present in both studies, indicating that different biomarkers of the same disease can be highlighted by different methods.

Research on 106 Parkinson's and 104 healthy patients indicates notable differences in urinary metabolites in the two categories (44). Notable differences are seen in the metabolism of phenylalanine, histidine, tryptophan, nucleotides and tyrosine in steroido genesis. Also, the fact that alterations have been observed in the kynurenine pathway in tyrosine metabolism in parkinsonian fly, it can be concluded that kynurenine pathway which is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD +) from the degradation of the essential amino tryptophan acid, may be associated with Parkinson's disease.

Concluding the above mentioned, is safe to say that specific biomarkers, different from the general ones, are needed to be effective in the diagnosis, treatment and eventual prevention of psychiatric illness.


Saliva test is a considerably simpler, more economical and less invasive diagnostic method compared to blood analysis. It consists in the sampling of saliva from the inside of the oral cavity. Scientists from the University of Health and Sciences in Oregon, USA, have found that saliva contains 1,166 proteins, more than one-third than they are found in the blood. And most of the saliva proteins are part of the central system of body reactions to disease. Recent studies have attempted to link diseases such as multiple sclerosis to certain biomarkers present not only in cerebrospinal fluid or plasma, but also in saliva, due to the easy way of taking samples, reduced testing time, reduced costs involved in testing, and non-invasive test mode, repeated sampling and longitudinal monitoring (45).

A number of 29 patients with multiple sclerosis and all sorts of matching age, sex and smoking controls were tested in blood and saliva. High concentrations of advanced oxidation protein products (AOPP), which were proposed as one of the possible markers of oxidative injury, originating under oxidative and carbonyl stress and increase global inflammatory activity, and thiobarbituric acid reacting substances (TBARS), which is probably the oldest and one of the most widely used assays for measuring lipid peroxidation end product malondialdehyde, and reactive aldehyde produced by lipid peroxidation of polyunsaturated fatty acids, have been found in patients with multiple sclerosis compared to controls. Similar results were obtained in saliva, making it a biomarker worthy of investigation in terms of neurological disorders (46).

Another study conducted on 19 healthy patients (9 females and 10 males with age between 20-30 years, during two consecutive days analyzed the level of thiobarbituric acid reacting substances (TBARS), advanced oxidation protein products (AOPP) and advanced glycation end products (AGEs), as well as antioxidant status by highlighting antioxidant power (FRAP) and total antioxidant capacity (TAC) in saliva and the results did not reveal differences in the oxidative stress between gender (47).

It is known that melatonin is the hormone that plays a crucial role in the health of the human body. At a normal circadian rhythm, melatonin is secreted by the pineal gland of the brain, with the darkness, and is considered an important antioxidant (48). This was measured both in blood and saliva, the results being comparable (49). The results of salivary testing can be dramatically influenced by circadian rhythm on the one hand, but also by diet, oral hygiene (50) and vitamin C administration. The free radical neutralization capacity is very high for vitamin C, which is considered to be one of the strongest antioxidants, as revealed in the tests that led to the conclusion that administration of this vitamin leads to a decrease in carbonyl stress and increased antioxidant status (51).


Studies on human tears have shown that can be sources for biomarkers, although they are not as tested as they should, not receiving the same attention as urine, serum or other bodily fluids.

In a study of 7 patients, 54 tear samples were analyzed and 300 proteins were identified, of which 59 were previously detected (52) and the rest were not reported in the literature until the study (53). Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. Elevated levels of PACAP from tears have been highlighted in post-traumatic stress disorder in women, but not in men (54).

Clusterin is also a metered protein from tears. There are studies that indicate that in patients with Alzheimer's disease, the level of serum clusterin is high and is all the more so as the cognitive decline is more advanced. However, it can not be determined whether high clusterin levels may indicate the onset of the disease (55). Cystatin has also been identified from the cystatin superfamily which encompasses proteins that contain multiple cystatin-like sequences and is considered to be a tumoral marker gastrointestinal esophageal squamous cell carcinoma (56), and colorectal cancer; (57) ankyrin-3 other protein found in tears, is an immunologically dis tinct gene product from ankyrins ANK1 and ANK2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. It plays an important role in neuronal activity and appears to be related to bipolar disorder and schizophrenia (58). Also our research group previously determined some oxidative stress makers in the serum and the tears! of some patients with keratoconus or some rat model of dry eyetress model (59-61).


With the deeper understanding of neuropsychiatric diseases, their methods of investigation may overcome certain barriers. There is no longer the premise that the brain is the only organ that can provide essential information on psychiatric illnesses. Studies have shown that some markers of oxidative stress, whose role in neuropsychiatric diseases is known, can also be found in biological fluids, the novelty coming from testing in urine, saliva or even tears. More effectively than that, it could be combining test methods with neuroimaging methods. Of course, some factors that may influence and modify results such as diet, certain medications and even lifestyle needs to be taken into account. It has been observed that certain biomarkers may be associated with different psychiatric disorders, such as for example low levels of N-methylnicotinamide have been found in both patients with major depressive disorder and those with borderline personality disorder compared to controls (62) just as uric acid in urine has elevated levels in both schizophrenic and depressive disorder patients (63). This makes it necessary to delimit the general biomarkers of those specific for the diagnosis and identification of therapeutic strategies. There are changes in the structure of saliva influenced by the diet, but besides the variations given by certain pathologies, saliva has a circadian rhythm that influences its production and composition (64). On the other hand, there are studies that indicate that patients with neuropsychiatric disorders have poor oral hygiene, so saliva testing can lead to inconclusive results (65). Further research will have to take these issues into consideration in order to make saliva testing more conclusive. Unfortunately, the progress in biomarkers related to psychiatric illnesses (not a single one existent until now!) is quite limited, which makes the need for further studies to be evident.


C.A. is supported by an UEFISCDI grant called "Complex study regarding the interactions between oxidative stress, inflammation and neurological manifestations in the pathophysiology of Irritable bowel syndrome (animal models and human patients)" code PNIII-P1-1.1-TE-2016-1210, no. 58 din 02/05/2018.


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Cojocariu Roxana Oana--Biochimist "Sf.Dimitrie" Hospital, Targu Neamt, Romania

Alin Ciobica--Researcher II Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, no 11, Iasi, Romania, Academy of Romanian Scientists, Splaiul Independentei nr. 54, sector 5, 050094 Bucuresti, Romania, Center of Biomedical Research, Romanian Academy, Iasi, B dul Carol I, no 8, Romania

Daniel Timofte--Associate Professor "Gr. T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania


Daniel Timofte, MD, PhD, "Gr.T.Popa" University of Medicine and Pharmacy,"Sf. Spiridon" University Hospital, Iasi, 700111, Iasi, ROMANIA, e-mail:, Tel. + 40 731 46 00 00

Submission: 28 mar 2018

Acceptance: 25 may 2018
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Author:Oana, Cojocariu Roxana; Ciobica, Alin; Timofte, Daniel
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Jun 1, 2018
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