Introduction

Major psychiatric disorders are heterogeneous disorders in which abnormalities occur in both the body and the brain through gene–environment interaction. These psychiatric disorders are neither just a state of mind nor disorders only of the brain. There are several biological systems involved in the pathophysiological mechanisms of the disorders. The crosstalk between (a) different biological systems in the body, (b) those biological systems and the environment and (c) the peripheral immune, endocrine, metabolic systems and the brain neurochemicals of the central nervous system together play as an orchestra in the pathophysiology of major psychiatric disorders.

Mood disorders, the major depressive disorders or major depression (MDD) and bipolar disorder are the most common of the psychiatric disorders. In Europe, MDD accounts for approximately 13% of the lifetime incidence with 4% being diagnosed with major depression within the past 12 months [1]. The lifetime prevalence of bipolar disorders is 2% and they are characterized by pathological disturbances in mood ranging from extreme elation (mania) to severe depression. Depression in general has a major detrimental impact on the quality of life of patients regardless of geographical, educational, socioeconomic and racial backgrounds. According to the 1990 Global Burden of Disease of the World Health Organization, depression has a greater negative impact on quality of life than cardiovascular disease and has been projected to be the second most important cause of disability, as disability adjusted years, by 2030 [2]. The pattern of occurrence, increasing severity and the frequent resistance to treatment are some of the reasons for the high burden of depression. There are different hypotheses upon which antidepressants and mood stabilizers have been developed. However, the currently available antidepressants are not adequately effective to treat the disease. This may be due to the fact that major depression is a heterogeneous disorder in which gene–environment interaction has effects on several systems in the body, which results in some neurochemical and mood changes that cannot be easily treated by manipulating one molecule or one neurotransmitter system.

Schizophrenia, another major psychiatric disorder, is a devastating psychotic illness characterized by impaired thinking, emotions and behaviour. The key symptoms are auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Earliest manifestation of this disorder typically occurs in young adulthood and affects around 1–1.5% of the population worldwide. Schizophrenia belongs to the so-called ‘complex disorders’ in which both a genetic component and environmental risk factors contribute to the vulnerability to develop this disease. It is a major problem for schizophrenia research that the disease is so heterogeneous that several discrete syndromes with different patho-aetiological mechanisms may be categorized as schizophrenia. However, there is a general consensus that an alteration of distinct neurotransmitter systems is crucially involved in its pathophysiology.

During the second half of the last century, the body and brain crosstalk through the immune system became of interest in the pathophysiology of major psychiatric disorders. The role of tryptophan as a precursor of serotonin was also of interest especially in the pathophysiology of depression. The depletion of tryptophan, which is the precursor of serotonin, the neurotransmitter of normal mood state, could lead to depletion of serotonin, which in turn induces a depressed mood state. At the beginning of the 21st century, the connection between the immune system and tryptophan metabolism, especially catabolism through the kynurenine (KYN) pathway, was highlighted in the pathophysiology of psychiatric disorders based on the fact that a clearer body–brain crosstalk could be explained and observed through this pathway.

Tryptophan metabolism in health

Tryptophan is an essential amino acid which has an indole ring structure and is obtained from dietary sources, approximately 20 nmol·day⁻¹. The reference value of plasma tryptophan ranges from 45 to 60  μmol·L⁻¹ [3]. Of this, 50–85% is bound to albumin in an unstable manner [4]. Serotonin is synthesized from about 1% of the available tryptophan in the body. The main serotonin synthesis occurs in the enterochromaffin cells in the gut and 10–20% occurs in the brain after crossing the blood–brain barrier (BBB). The central availability of tryptophan mainly depends on competition by the large amino acids for transport across the BBB and partly depends on the cerebral demand [5]. About 99% of tryptophan is metabolized in the liver by the tryptophan 2,3-dioxygenase (TDO) [6]. TDO activity is mainly controlled by the tryptophan level itself and therefore its activity is generally stable.

After tryptophan is catabolized into KYN, it is further catabolized into 3-hydroxykynurenine (OHK) by the kynurenine-3-monooxygenase (KMO) enzyme. The activity of KMO needs both NADPH2 and flavin co-factors although an association between human riboflavin deficiency and decreased blood OHK level was never reported [7]. After OHK, further degradation continues to 3-hydroxyanthranilic acid (HAA) through the action of kynureninase. After that, the catabolism proceeds in the liver either into the complete oxidation pathway and forms ATP or into quinolinic acid (QUIN) which is finally degraded into NAD. Picolinic acid is also formed in small quantities from the complete oxidation pathway. Under physiological conditions, the catabolism goes mainly to ATP formation and only a minor portion goes to NAD formation [8]. KYN can also be catabolized by the kynurenine aminotransferases (KATs) into kynurenic acid (KYNA) (Fig. 1). This metabolism in the liver is more or less stable and age and gender has an influence on it [8]. Vitamin B6 plays an important role in the metabolism since pyridoxyl 5-phosphate, the co-enzyme in the KYN pathway, is derived from this vitamin. The effect of vitamin B6 could be observed not only in conditions associated with B6 deficiencies but also in healthy conditions, since vitamin B6 supplementation to healthy subjects can influence the enzyme activities and formation of metabolites [8,9]. In the case of impaired function of this co-enzyme, urinary excretion of KYN, OHK and xanthurenic acid (XAN) are increased because of the reduced activity of kynureninase which converts the OHK and XAN into HAA, the activity of which is sensitive to the activity of the co-enzyme [7,10]. The final formation of nicotinic acid and its derivatives through different conversion steps in the tryptophan breakdown pathway is important for our nervous system and there will be insufficient formation of these derivatives in the case of vitamin B6 deficiency. Moreover, since ATP formation in the cells is dependent on NAD, depletion of NAD is fatal to the cells especially if they are under stress. In the normal state, to get normal NAD requirements, QUIN synthesis occurs only transiently in the liver and QUIN does not accumulate in the hepatocytes [11].

Since KYN itself can be transported across the BBB, on top of the KYN formed in the brain by tryptophan breakdown, extra KYN is available from the periphery for further KYN metabolism in the brain. Sixty per cent of brain KYN is contributed from the periphery [12]. In the brain, tryptophan catabolism occurs mainly in the astrocytes and microglia [13–15]. Although some neurons also possess indoleamine 2,3-dioxygenase (IDO) and/or TDO2 [16], neurons are not the main sites of the KYN pathway in the brain. While astrocytes are shown to produce mainly KYNA because of lack of the KMO enzyme, microglia and macrophages produce mainly QUIN [17–19]. The astrocytes metabolize QUIN produced by the neighbouring microglia [18].

The KYN pathway also plays a role in glucose metabolism. While the ATP and HAA formed from this pathway activate glycolysis [20], through which glycogen is stored in the cells to be utilized in case of stress or glucose need, the QUIN inhibits gluconeogenesis [21]. The latter process may prevent the cells from getting glucose from sources of fat and protein. In the central nervous system, glycogen storage and glucose availability are indeed important for neuroprotection in the case of inflammation and microglia activation. It has been reported that inhibition of the enzyme glycogen synthetase kinase 3, which in turn enhances the activity of glycogen synthase, could reduce the toxic effects of microglia on neurons in the case of immune activation in the brain [22]. Under physiological conditions, in the brain, this KYN pathway serves mainly for glycogen storage and synthesis of small amounts of NAD required for the central nervous system.

Tryptophan metabolism in inflammation

Under physiological conditions, as mentioned above, tryptophan metabolism takes place mainly in the liver through TDO as the first rate limiting enzyme. In cases of inflammation, infection or oxidative stress, which activate the enzyme IDO in the extrahepatic tissues such as the lungs, placenta, kidneys, spleen, blood and brain [23,24], the extrahepatic tryptophan metabolism shifts the tryptophan metabolism away from the liver [25]. Tryptophan breakdown through the KYN pathway then occurs mainly in the blood and lymphoid tissues [26]. The IDO activity is enhanced by pro-inflammatory cytokines such as interferon-γ (IFN-γ) [27,28] and inhibited by the anti-inflammatory cytokine interleukin 4 (IL-4) [29]. In cases of stress or related conditions where cortisol secretion is enhanced, TDO activity is also further enhanced by glucocorticoids [30,31]. Under these circumstances, KYN formation becomes much higher than in physiological conditions. Since the liver cell uptake of KYN is not efficient for extrahepatic KYNs, the metabolism of these KYNs mainly occurs extrahepatically. The activity of KMO is also enhanced by pro-inflammatory cytokines [24]. Therefore, during inflammation, the formation of OHK becomes enhanced much more quickly than KYNA formation and the balance between the formation of OHK and KYNA is shifted to the OHK side (Fig. 2). When OHK formation is increased, formation of XAN, which is reported as diabetogenic [32], and formation of QUIN are enhanced. In the presence of inflammation, activated monocytes are found to be the robust producers of QUIN [33]. In the midst of inflammation, QUIN production persists until the inflammatory process is completed [34]. Since some of the KYN metabolites activate an inflammatory reaction this could further prolong QUIN synthesis [35], whereas some of the metabolites inhibit the proliferation of T cells and natural killer cells [36], inhibit the further inflammatory process and stop further QUIN formation. In this way, immune tolerance is achieved through tryptophan depletion and homeostasis in the KYN pathway is maintained.

In the brain, the enhanced tryptophan breakdown induces low availability of tryptophan for serotonin synthesis. Moreover, with inflammation and IDO activation, serotonin is degraded not only by monoamine oxidase into 5-hydroxyindole acetic acid, but also by IDO into formyl-5-hydroxykynuramine [37], and therefore less serotonin is available for optimal serotonergic neurotransmission. During inflammation and enhanced tryptophan breakdown, extra amounts of peripheral KYN become available for further KYN metabolism in the brain, since KYN can be transported across the BBB. When there is a pro-inflammatory state in the brain, the KYN metabolism in the astrocytes and microglia might also be enhanced. Therefore the KYN pathway is highly activated in the brain from its own central source of KYN and extra KYN from peripheral sources. The KYN metabolites contribute directly to the neuroprotective–neurodegenerative changes in the brain through direct effects on several neurotransmissions. QUIN is an N-methyl-d-aspartate receptor (NMDA-R) agonist [38] and accumulation of QUIN could result in excitotoxicity. OHK causes neuronal apoptosis [39] while QUIN causes excitotoxic neurodegenerative changes [40,41] (V. Pérez-De La Cruz & A. Santamaría, unpublished results). However, KYNA is an NMDA-R antagonist [43] and is protective against excitotoxicity of QUIN [44] (Fig. 2). In central nervous system inflammation due to Lyme disease, the cerebrospinal fluid QUIN is increased and this might contribute to neurological and cognitive deficits [45]. In human stable multiple sclerosis patients who are relapsing and remitting, the KYNA levels in the cerebrospinal fluid are lower than normal controls [46] although KYNA levels increase during relapse [47]. Alzheimer’s disease is known to be associated with pro-inflammatory status and amyloid formation in the brain. Amyloid peptide Aβ1–42 induces expression of IDO and increases QUIN production [48].

In the pro-inflammatory state, although the balance between OHK and KYNA might generally shift to the OHK side, because of the general increase of KYN the formation of KYNA may also be higher than in the normal state. Since it is an NMDA-R antagonist, a well balanced increase may counteract the negative effects of QUIN through NMDA-R and homeostasis will be maintained. Even though KYNA is generally considered as a protective metabolite against QUIN, since it is also an antagonist of all ionotropic excitatory amino acid receptor activities [43], its abnormal accumulation beyond physiological levels could induce glutamatergic hypo-functioning and might disturb cognitive function [49]. Moreover, while one of the tryptophan metabolites, 5-hydroxyindole (5HI), activates the α7-nicotinic acetylcholine receptor (α7nAchR) and induces glutamate release [50,51], KYNA is an antagonist of α7nAchR [52]. Since KYNA downregulates the permissive role of 5HI activation on α7nAchR, the accumulation of KYNA could suppress α7nAchR function and induce disruption of auditory sensory gating [53]. Moreover, 5HI inhibits the non-α7nAchR mediated release of noradrenaline, dopamine and acetylcholine [54] while KYNA regulates the activity and expression of non-α7nAchR based on dosage and time of exposure [52]. In addition, it was reported that KYNA inversely regulates the dopaminergic tone [55] (Fig. 2). In this context, 5HI and KYNA exert synergistic action on dopaminergic neurotransmission. These interactions of KYNA with other neurotransmitters such as 5HI could contribute to some behavioural or cognitive consequences such as psychosis and cognitive impairment other than neurodegenerative changes.

On the other hand, 5HI has antioxidant activity and protects mitochondrial integrity, which, in combination, is anti-apoptotic [56], whereas OHK enhances formation of reactive oxygen species [57] which would further enhance the activities of IDO and KMO and shift the pathway to the OHK and QUIN side. Therefore, the synergistic action of 5HI and KYNA may contribute to a neuroprotective effect since KYNA antagonizes the toxic effect of QUIN.

These interactions between different KYNs indicate the importance of a well balanced state of the KYN pathway through which neuroprotection could be achieved in the case of inflammatory challenges.

Tryptophan metabolism in major psychiatric disorders

Future perspectives and conclusion

The findings discussed above are clear evidence that tryptophan degradation or the KYN pathway is involved in the pathophysiology of major psychiatric disorders. There are some differences and similarities between different psychiatric disorders in terms of changes in tryptophan and KYN metabolites. The manipulation of this metabolism is of interest for future therapeutic development and several studies are focusing on this aspect. Some enzyme inhibitors are already developed. However, it is important to consider the possible occurrence of an imbalance between different metabolites when a particular enzyme is blocked or manipulated to enhance or reduce the particular metabolite. Therefore, such manipulation should be carried out with a clear indication such as the evidence of a change in metabolites or ratios between metabolites as biomarkers. Moreover, close monitoring of those changes during therapy would also be necessary. Since tryptophan metabolism is the metabolism in which there is crosstalk between different systems in the periphery and the central nervous system, use of peripheral biomarkers as indirect evidence of central changes for diagnostic and prognostic purposes is not unrealistic.

Future studies should be carried out not only on manipulation of the metabolism for therapeutic purposes [102] but also on use of the KYN pathway metabolites as biomarkers in evidence based management for early detection, choice of correct medication and monitoring. The normal values of those metabolites in different populations are not yet known. Clear association between central and peripheral markers should be investigated. The validation of the usefulness of these biomarkers should be carried out in multidisciplinary approaches. Since currently available technologies to detect these metabolites are expensive and sophisticated, studies on the development of user-friendly and cost-effective technologies for detection of the metabolites are also necessary.

The indirect manipulation of this pathway through anti-inflammatory medication could also be another strategy. Manipulation or prevention of inflammation and oxidative stress using either some medications such as omega-3 fatty acids which are harmless or lifestyle intervention through diet, exercise and mindfulness practices could also be an option. However, this type of treatment should start as early as possible and for this purpose KYNs could be the potential biomarkers as timely indicators of immune–metabolic–neurochemical imbalances.