INTRODUCTION
Bipolar disorder (BD), with a prevalence estimated to be as high as 2% [1] and having the highest suicide rate among mental disorders (about 20-30 times higher than that of the general population) [2], constitutes a serious public health problem. The potential number of lost years of life in patients with BD is, on average, approximately 13. The diagnosis of BD is still based on a clinical assessment on the basis of a patient’s history using the ICD-11 and DSM-5 diagnostic criteria, as there are still no reliable biomarkers [1].
BD is a multifactorial psychiatric disorder presenting different clinical phenotypes (of which the division into type I with fully-blown manic states and type II with states of hypomania most commonly considered), suggesting a diversity of potential metabolic biomarkers. Moreover, these differences may be related to factors such as co-morbidities like chronic inflammation, disruption of hormone secretion and diurnal rhythm, difference in gut microbiota and gastrointestinal mucosal permeability, and mitochondrial dysfunction. Notably, mitochondrial function appears to increase during manic episodes in BD and to diminish during depressive episodes [1].
The main aim of the study is a preliminary assessment of the current state of knowledge about deviations in the levels of amino acids (AAs), purines and pyrimidines in blood serum during the occurrence of bipolar disorder, taking into account attempts to modify the course of the disease using these substances.
METHODS
The study used the PubMed database, entering “Bipolar disorder” in combination with “Amino acid”, “Purines” and “Pyrimidines” as search terms, with compounds of these individual terms also being entered. There are many difficulties in finding differences in the levels of the above-mentioned molecules when it comes to distinguishing BD patients from healthy individuals, and within the different forms of BD itself. The difficulties experienced by sufferers have both psychiatric and biochemical causes. BD is not only associated with the aforementioned polymorphism of phenotypes, but also with the course of the disorder itself. Changes in an individual can potentially vary depending on the phase of the disorder [episode of (hypo)mania, depression, mixed, lucidum intervallum]. Moreover, treatment, diet and habits have a significant impact on the level of the substances tested. For this reason, the authors decided to present the results not according to clinical condition but according to biochemical data, grouping them on the basis of similar molecules. However, it must be remembered that difficulties then arise with the comparison of works. These are caused by the diversity of the assays made using high-performance liquid chromatography (HPLC), liquid chromatography combined with mass spectrometry (LC-MS), metabolomics and other methods.
Metabolomics deals, as a part of biochemistry, with the study of metabolites, i.e. small-molecule metabolic products in biological samples (e.g. blood, urine, tissues). It analyses entire sets of metabolites, or metabolome, at specific times and under specific conditions. Advanced methods are used to analyse the metabolome, such as HPLC, LC-MS, gas chromatography combined with mass spectrometry (GC-MS), nuclear magnetic resonance spectroscopy (NMR) and HPLC, which is an analytical technique used to separate, identify and determine chemical components in a sample, which is then dissolved in a liquid and passed through a column filled with stationary material. The individual components of the sample move at different speeds as a result of their interaction with a stationary phase and a mobile phase, which leads to their separation. Anyone who expects a simple answer to the simple question “what is the serum level of molecule ‘x’ that can confirm a BD diagnosis?” will be disappointed. But some clues suggesting future possibilities can be indicated [3].
POTENTIAL ROLE OF BRANCHED-CHAIN AMINO ACIDS IN THE PATHOGENESIS OF BIPOLAR DISORDER
The level of AAs found in plasma reflect the functional status not only of the brain, but also of other organs, such as the liver, heart, and kidneys [4]. It is noteworthy, however, that many metabolites are continuously exchanged between cerebrospinal fluid (CSF) and peripheral blood – 60% of the metabolites detected in cerebrospinal fluid have also been found to be present in plasma [5]. This gives hope for potential discoveries regarding the use of amino acids, purines, and pyrimidines as potential biochemical markers in this kind of research.
In particular, branched-chain amino acids (BCAAs), which include leucine, isoleucine, and valine, deserve special attention. The argument for considering BCAAs as potential correlates of BD is first of all supported by studies conducted on their supplementation and clinical use for the relief of symptoms [5-7] as well as their use as markers of the efficacy of the second-generation antipsychotic drugs (SGAs) used and the side effects of pharmacotherapy in BD [6].
Levels of BCAAs were found to be significantly lower in BD subjects compared to the control group. In terms of severity, negative correlations were noted between valine and symptoms of depression measured by the Hamilton scale, and valine and Beck scale [7]. BCAA supplements have also been studied in the treatment of the manic phase, and has been shown to alleviate manic symptoms. In addition, the intensive use of such supplements increases prolactin levels in the plasma and impairs performance on the spatial recognition task, which is consistent with impaired dopamine neurotransmission [8]. The supply of BCAAs to individuals with bipolar disorder during periods of mania is thought to reduce tyrosine uptake in the brain, which is thought to slow the synthesis of catecholamines – substances that likely have pathogenic effects in mania [9]. A daily BCAA dose of 60g was given for 7 days, leading to a significant decrease in manic symptoms, which aligns with that have shown an impact on brain catecholamines [9, 10]. Moreover, branched short-chain fatty acid, due to its structural similarity to valproic acid, plays a role in the metabolization of BCAAs. Individuals treated with valproic acid, one of the more common mood-stabilizing drugs in BD treatment, had increased BCAAs levels in the serum and urine [11].
Supplementation with a mixture of BCAAs reduces dopamine release for the first few hours after administration, although there is no data on the duration of this effect [8]. In addition, using positron emission tomography, Sarna et al. [8] found that a mixture of completely tyrosine-free BCAAs increased the binding in the striatum of the dopamine receptor [11C] ligand raclopride in healthy volunteers, which is a result of reduced presynaptic dopamine release. BCAAs induce the activation of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Furthermore, this activation appears to be critically involved in the development and progression of major depressive disorders. Research has shown that individuals with clinical depression have significantly lower levels of BCAAs compared to those in healthy control groups. This suggests that BCAAs may exert their effects on mood and depression primarily through the activation of mTOR pathways. Interestingly, the reduction in levels of BCAAs observed in depressed individuals may contribute to the underlying biological mechanisms of depression, highlighting the potential role of BCAAs in the etiology and treatment of depressive disorders [7].
Pharmacological data indicate that the metabolic side effects of SGAs, such as obesity and diabetes, impact the metabolization of BCAAs in the blood serum. Eight AAs (alanine, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine, aspartate/asparagine, and arginine) were significantly elevated in obese subjects compared to those who were not, while glycine levels were lower in subjects with obesity [6]. Newgard et al. [12] proposed that consuming a diet high in fat and protein not only promotes weight gain but also leads to increased levels of BCAAs in the blood. Their findings suggest a link between diet and metabolic changes, including the concentration of BCAAs.
In conclusion, our existing knowledge (mitigating effects on the course of the disorder through a high supply of BCAAs) suggests that there is some theoretical basis for their effects on neurotransmission (mainly dopaminergic) as well as – unfortunately – some elementary deficiencies in clinical trials as the determination of their levels in serum has been published in only one study. Therefore, we should not draw too far-reaching conclusions. In addition, some difficulty in coming to any conclusions may be caused by the fact that people with BD often have metabolic disorders that are reflected in various measurable indicators, such as BMI. BMI and BCAAs have been shown to be positively correlated, so it is not entirely clear what abnormal levels actually indicate [7].
POTENTIAL ROLE OF OTHER AMINO ACIDS IN THE PATHOGENESIS OF BIPOLAR DISORDER
We now expand on the results presented to include AAs described in the paragraphs to follow. At the present stage of research, this process is significantly advanced by metabolomic techniques. Metabolomics focuses primarily on small molecules with a molecular weight of less than 1000 Da. This analytical technique enables the simultaneous detection and quantification of thousands of metabolites, providing a detailed metabolic profile. This approach is crucial for understanding complex biochemical processes and uncovering metabolic changes associated with various physiological and pathological conditions [1].
Wei et al. [4] examined 91 patients with bipolar disorder and 92 healthy individuals in a control group using metabolomic techniques. They identified dysfunctions in nine metabolic pathways, four of which involve amino acids: glycine and serine, glutamate, arginine and proline, and tyrosine. Importantly, the metabolization of glutamate and tyrosine plays a role in the production of the neurotransmitters gamma-aminobutyric acid (GABA) and monoamines, respectively. No significant differences in metabolic profiles were observed according to disorder type (BP-I vs. BP-II), phase (manic vs. depressive), or the presence of psychotic symptoms. These findings indicate that metabolic profiling might be effective as a general biological marker for BD rather than being used to distinguish individual clinical subtypes.
This has been corroborated by other research. Blood analyses revealed alterations in the metabolism of phenylalanine, tryptophan, glycine, serine, and threonine. Additionally, urine analyses identified abnormalities in the metabolic pathways of tyrosine, glycine, serine, and threonine [1, 13]. The most important results of research into the functioning of AAs are presented below.
Glycine
A study by Xiang-Jie et al. [14] conducted on 31 untreated depressed bipolar patients found lower glycine levels in these patients compared to the people in the control group. After eight weeks of treatment, glycine levels continued to decline, despite effective treatment and improvement in mental state. Changes in glycine levels in BD patients are also similar to those found in their cerebrospinal fluid [15]. On the basis of this study, it may be suggested that glycine could serve as a potential marker of depression (including the post-treatment period) in individuals with BD.
Pålsson et al. [15] were the first to assess the glutamatergic system in patients with BD in euthymia compared to a healthy control group by measuring serum and cerebrospinal fluid levels of glutamine, glutamate, glycine, L-serine, and D-serine. They observed elevated glycine levels in patients with stable BD, and it is notable that this study included a large cohort of 215 patients and a 112-person control group [15]. Wan Nasru et al. [16] reported elevated concentrations of glutamate, glycine, and alanine in patients during remission and manic periods of BD. Previous studies by Zheng et al. [17] and Xu et al. [18] reported higher urinary glycine levels in BD patients compared to healthy controls. However, some studies contradict these findings. For instance, Kageyama et al. [19] conducted a study in which they were unable to identify any distinct metabolic biomarkers, including glycine, which differentiated patients with BD from control subjects. Their findings suggest that glycine and other metabolites may not be reliable indicators for distinguishing between these two groups.
Glutamate and serine
Glycine or serine, in combination with glutamate as a co-agonist, stimulate the activation of N-methyl- D-aspartate receptors (NMDAR). Dysregulation of NMDAR activity has been implicated in affective and cognitive dysfunctions – which are central features of mood disorders – due to its role in reducing neuroplasticity [3]. A decrease in serine levels impairs NMDAR-dependent processes in the hippocampus, prefrontal cortex, and amygdala – brain structures strongly associated with mood disorders [3].
The cited study by Pålsson et al. [15] showed increased levels of not only glycine but also glutamate and D-serine in the plasma (and decreased L-serine), as well as higher levels of glutamine and glutamate in the brains of individuals with BP compared to those in a healthy control group. Similar results are reported by Gigante et al. [20], who observed higher levels of glutamine and glutamate in the brains of individuals with BD compared to a healthy control group. In contrast, Hashimoto et al. [21] observed increased glutamate levels specifically in the frontal cortex of BD patients in a post-mortem study.
Glutamatergic conductance requires the presence of serine as a co-factor, making the findings of Pålsson et al. [15] particularly noteworthy, especially the increase in D-serine and decrease in L-serine they observed. These alterations indicate potential aberrations in serine metabolism in individuals with BD, potentially implicating the enzyme racemase. Racemase, a type of isomerase, is responsible for catalyzing the conversion of L-amino acids to their D-amino acid forms. Despite these findings, CSF examination did not reveal statistically significant differences between patients and members of the control group. Similarly, the postmortem brain samples analyzed by Hashimoto et al. [21] showed no significant differences in L-serine and D-serine levels when compared to control subjects. Additionally, a meta-analysis by Hawkins et al. [22] indicated that glycine and L-serine concentrations in the CSF are about 10% of their concentrations in the blood. For glutamate, this proportion is much lower, whereas glutamine concentrations are nearly equal in CSF and blood. This phenomenon can be attributed to the active transport of AAs from the CSF to the blood across the blood-brain barrier.
According to Chen et al. [23], individuals with BD exhibit elevated levels of glycine and β-alanine, alongside reduced levels of 2-4-dihydroxypyrimidine and phenylalanine. Additionally, a panel of six potential biomarkers – propionate, formate, 2,3-dihydroxybutanoic acid, phenylalanine, 2,4-dihydroxypyrimidine, and β-alanine – was identified, which can effectively differentiate BD patients from those with MDD. Notably, urinary concentrations of α-hydroxybutyrate and β-alanine, both linked to the propionate metabolic pathway, were significantly higher in BD patients compared to both healthy controls and MDD patients.
Homocysteine
Felger et al. [24] showed that in patients with depression in the course of bipolar disorder, homocysteine (Hcy) levels in the serum are elevated and positively correlated with clinical symptoms. In contrast, Tan et al. [25] noted that Hcy levels in the serum also significantly increase during manic episodes. This suggests that elevated Hcy levels in the serum may be a potential marker indicating the onset of a phase, regardless of its type.
The collected data on the amino acids most relevant to the pathogenesis of bipolar affective disorder are shown in the Table 1.
Table 1
Amino acid levels refer to their values in blood serum
| Amino acid | study (lead author) [Ref.] and sample size | Phase of disorder | study result | Analysis type |
|---|---|---|---|---|
| Glycine | Guo et al. [14] (31 patients, 47 controls) | Depression | Lower | Metabolomics |
| Guo et al. [14] (31 patients, 47 controls) | Remission | Lower | Metabolomics | |
| Pålsson et al. [15] (215 patients, 112 controls) | Remission | Higher | HPLC | |
| Wan Nasru et al. [16] (83 patients, 82 controls) | Remission and mania | Higher | Metabolomics | |
| Chen et al. [24] (43 patients, 126 controls) | No phase distinction | Higher | GC-MS/NMR | |
| Ren et al. [13] (120 patients, 120 controls)) | Depression | Lower | Metabolomics | |
| Glutamate | Wan Nasru et al. [16] (83 patients, 82 controls) | Remission and mania | Higher | Metabolomics |
| Pålsson et al. [15] (215 patients, 112 controls) | Remission | Higher | HPLC | |
| Alanine | Wan Nasru et al. [16] (83 patients, 82 controls) | Remission and mania | Higher | Metabolomics |
| Guo et al. [14] (15 patients, 15 controls) | Depression | Lower | Metabolomics/LC-MS | |
| D-serine | Pålsson et al. [15] (25 patients, 25 controls) | Remission | Higher | HPLC |
| L-serine | Pålsson et al. [15] (25 patients, 25 controls) | Remission | Lower | HPLC |
| Serine | Ribeiro et al. [quoted after [1] (30 patients, 30 controls) | No phase distinction | Lower | Metabolomics |
| Glutamine | Pålsson et al. [15] (25 patients, 25 controls) | Remission | Higher | HPLC |
| Beta-alanine | Chen et al. [24] (43 patients, 126 controls) | No phase distinction | Higher | GC-MS/NMR |
| Yoshimi [quoted after [1]] (30 patients, 30 controls) | No phase distinction | Lower | Metabolomics/LC-MS | |
| Homocysteine | Tan et al. [26] (no data shared) | Mania | Higher | Metabolomics |
| Felger et al. [25] (40 patients, 40 controls) | Depression | Higher | GC-MS/NMR | |
| Phenylalanine | Chen et al. [24] (43 patients, 126 controls) | No phase distinction | Lower | GC-MS/NMR |
| Valine | Guo et al. [quoted after [1]] (15 patients, 15 controls) | Depression | Higher | Metabolomics/LC-MS |
| Wei et al. [4] (91 patients, 92 controls) | Acute episode (mania/depression) | Lower | Metabolomics | |
| Arginine | Yoshimi [quoted after [1]] (30 patients, 30 controls) | No phase distinction | Higher | Metabolomics/LC-MS |
| Wei et al. [4] (91 patients, 92 controls) | Acute episode (mania/depression) | Higher | Metabolomics | |
| Tryptophan | Poletti et al. [???] (22 patients, 5 controls) | No phase distinction | Lower | HPLC |
| Steen et al. [???] (73 patients, 68 controls) | No phase distinction | Lower | LCECA |
In addition, while measuring AAs Wei et al. [4] noted higher concentrations of proline, arginine, and tyrosine and lower concentrations of valine, threonine, aspartate, aspartic acid, lysine, methionine, histidine, and tryptophan.
EXPLANATION OF RESULTS – AN ATTEMPT
The results of the studies of AAs presented here generally correspond with the current state of knowledge of transmitter system changes in BD, with a few exceptions (e.g., the increase in arginine in the BD group is difficult to explain). Phenylalanine and tyrosine are precursors for the synthesis of dopamine, norepinephrine, and epinephrine, which are essential for mood regulation and cognitive function [1, 3]. Thus, disruptions in the metabolism of phenylalanine and tyrosine could potentially result in imbalances in neurotransmission, contributing to the symptoms of BD [26]. Interestingly, a downregulation of phenylalanine and tyrosine levels has been observed exclusively in BD and schizophrenia [3]. Tryptophan, on the other hand, is involved in the biosynthesis of 5-hydroxytryptamine, or serotonin, affecting mood and behavioral regulation. In the case of these AAs, the relatively small number of reports of abnormalities in levels is noteworthy [1, 27]. Glutamate is a neurotransmitter the disturbed pathway of which is often associated with the pathophysiology of affective disorders. It is important to remember that concentrations of AAs in the plasma will not necessarily translate into biochemical processes in the brain, as mentioned in the introduction. Therefore, analyses of peripheral biomarkers are worth conducting in parallel with analyses of neurochemical substances in the CSF [15]. Threonine is an amino acid that the body cannot produce and must be acquired through diet. It is metabolized into glycine, which, along with serine and threonine, plays roles in neurotransmission as NMDA receptor agonists and in brain energy metabolism, particularly through glycine’s involvement in glutathione synthesis [1]. Impaired metabolization of these amino acids can lead to neurotransmission imbalances, potentially exacerbating symptoms of BD. Additionally, research indicates that serine may help reduce oxidative stress [28, 29]. Furthermore, no significant clinical correlations were observed between amino acid levels and scores on the Montgomery-Åsberg Depression Rating Scale [15].
Pharmacotherapy is a complicating factor in both conducting a test and interpreting the results. Antidopaminergic drugs, such as risperidone and quetiapine, are increasingly used in BD treatment. It is crucial to note that antipsychotic and antidepressant medications also impact the metabolization of AAs in individuals with BD.
BCAAs, mainly leucine, have been linked both to models of obesity and as being potential markers for predicting the development of diabetes [30]. This information may be important when looking at the possible development of metabolic syndrome and clinically observed obesity as a potential side effect of the use of SGAs. Amino acids that increase in volume in obese individuals in particular are alanine, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine, aspartate/aspartate, and arginine, some of which show correlations with BD in terms of levels or dietary interactions [12].
The potential disruptive effects of other drug groups – mood stabilizers – should also be considered. Valproate therapy has been found to elevate glutamine and serine levels in cerebrospinal fluid. In turn, treatment with lithium has also been associated with increased levels of glutamine, D-serine, and L-serine in the CSF [15]. The impact of medications on glutamate metabolism was further substantiated by pharmacological studies conducted by Malhi et al. [31]. Their research revealed that lithium, a commonly used treatment for BD, effectively reduces the levels of excitatory neurotransmitters, including dopamine and glutamate. Simultaneously, lithium increases the levels of inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA). These findings underscore the role of lithium in modulating neurotransmitter balance, which is crucial for its therapeutic effects in managing BD.
According to some randomized controlled trials (RCTs), baseline levels of AAs may have prognostic significance in predicting treatment response in BD. One example is augmentation with N-acetylcysteine (NAC), a precursor of glutathione that exhibits antioxidant properties and modulates glutamatergic neurotransmission. Studies suggest that patients with lower baseline levels of specific amino acids, such as cysteine, may respond better to NAC supplementation, potentially leading to a reduction in depressive symptoms and improved functioning. This is supported by the study by Berk et al. [32], which assessed the impact of NAC as an adjunct to standard treatment in patients with BD.
However, it should be noted that studies examining baseline levels of AAs as predictors of treatment response in BD are limited. The aforementioned study focuses on NAC but does not directly analyze baseline amino acid concentrations as prognostic markers for therapy response. Further research is needed to better understand the role of AA profiles in the personalization of BD treatment.
Hcy also can affect the metabolism of monoamine- like neurotransmitters, causing a downregulation of the receptors intended for them. It can also enhance the oxidative stress response, increase the expression of apoptotic proteins, and direct neuronal cells into the apoptotic pathway, making it an independent risk factor for depressive episodes. The clinical manifestation of this can also be cognitive dysfunction, such as in memory, concentration, attention, thinking, and language, as often observed during affective disorders, including BD [25].
Not all AAs were considered in the studies on BD presented here, probably due to the lack of a statistically significant difference in the results obtained or the lack of clinical relevance based on current medical knowledge in this field. Nevertheless, their involvement in the pathogenesis of BD cannot be definitively ruled out. This may serve as a potential subject for further research by other investigators.
ROLE OF PURINES AND PYRIMIDINES IN THE PATHOGENESIS OF BIPOLAR DISORDER
Purines are essential for neurotransmission and neuromodulation, influencing the activity of neurotransmitters. Adenosine agonists have sedative, anti-aggressive, anticonvulsant and antipsychotic effects, while antagonists like caffeine are stimulants. Uric acid, a purine metabolism product, contributes significantly to free radical scavenging in blood [33]. Elevated uric acid levels in serum may indicate increased purinergic turnover. Consequently, both adenosine and uric acid levels may correlate with mood and sleep dysregulation, which are prevalent in affective disorders [33].
Some publications have focused on 2,4-dihydroxypyrimidine, a metabolite identified by Xu et al. [34] using a GC-MS-based metabolomic approach. Their study found 37 metabolites showing altered levels in individuals with BD compared to those in good health. Interestingly, 2,4-dihydroxypyrimidine, found only in urine and not in blood serum, emerged as a valuable diagnostic biomarker for BD, with levels of it notably lower in BD patients relative to healthy individuals. This metabolite is also implicated in glutamine synthesis, with lower concentrations in BD patients correlating with decreased glutamine levels in this population [35].
In the examination of purine and pyrimidine metabolism, it is important to highlight the point that uric acid in the bloodstream serves as a final product of purine breakdown and is linked to the symptomatic expression of bipolar disorder [33]. This association may underlie the elevated occurrence of metabolic syndrome and hyperuricemia in bipolar disorder individuals when compared to those in good health [4]. Initial findings suggest that manic episodes, as opposed to depressive or stable mood states, may specifically correlate with heightened serum levels of uric acid [36].
The review of multiple studies has verified that BP individuals exhibit notably elevated uric acid concentrations in contrast to healthy counterparts, and moderately higher levels when compared to individuals experiencing depression. Furthermore, analysis across different phases of bipolar disorder revealed that patients in a manic or mixed state had even higher uric acid levels than those in a depressive phase [33]. Preliminary clinical investigations have suggested an indirect involvement of uric acid in the development of BD, indicating the potential of purinergic modulators as supplementary treatment for manic symptoms [37]. Additionally, a significant association has been observed between lower uric acid levels and improved outcomes for manic symptoms [38].
CONCLUSIONS
The study of biochemical markers in BD is one of the more challenging tasks in medical research. Considering the complex clinical problems involved, and the extremely simplistic juxtaposition two forms of disorder with three phases – (hypo)mania, lucidum intervallum, and depression – gives us a total of six variables, to say nothing of the mixed phases, or stages, of depression.
From the biochemical point of view the main problem is the comparison of all the results, based frequently as they are on different forms of biotechnology (e.g., HPLC, LC-MS, metabolomics). Metabolomics allows for a better understanding of diseases because changes in metabolism may be related to the pathophysiology of diseases. The identification of disease biomarkers and understanding of their molecular mechanisms may enable the implementation of personalized therapy. HPLC, in turn, is one of the most important techniques in chemical analysis, enabling the accurate examination of complex samples.
In BP patients the greatest differences in level are observed in AAs closely linked to the pathogenesis of the disorder. An example is phenylalanine, which is essential for the synthesis of tyrosine, and which next produces neurotransmitters like dopamine, norepinephrine, and epinephrine, impacting mood and cognitive function in BD patients. Another amino acid responsible for regulating mood as well as behavior is tryptophan, which plays a crucial role in the biosynthesis of serotonin (5-hydroxytryptamine). Glycine, serine, and threonine, as NMDA receptor agonists, are involved in the neurotransmission of glutamate, and glycine itself also affects brain energy metabolism by participating in glutathione synthesis.
In addition, reduced levels of BCAAs are observed in BD patients. Fellendorf reported that patients with BD and subjects in the control group did not differ in levels of valine and isoleucine, whereas the level of leucine was significantly lower in BD [7]. However, only a small number of studies have examined serum level per se, while there is an abundance of studies related to pharmacotherapy and diet, connected to relatively numerous attempts at clinical application. The result of studies about BCAAs was used to try to alleviate depressive as well as manic symptoms with BCAAs and perhaps to use them as markers of the effectiveness of the SGAs used.
Hyperuricemia, observed especially in manic phases, is a consequence of increased purinergic turnover, the end product of which is uric acid. Special mention should be made of 2,4-dihydroxypyrimidine in the metabolization of purines and pyrimidines, a typical candidate for a diagnostic marker, the low level of which in BD patients further correlates with reduced glutamine levels.
However, it is worth considering the results so far. Metabolomic and concentration analyses show changes in AAs, purines and pyrimidines levels, which may suggest an abnormal role and disturbance in the citric acid cycle, with the urea cycle as well as the metabolization of AAs itself involved in the pathogenesis of BD. There is potential for using peripheral AAs or purine concentrations as biomarkers of BD. To validate the conclusions, additional research with a larger sample size and extended duration is necessary.
