The kynurenine pathway (KP) is a major route for L-tryptophan (L-TRP) metabolism, yielding a variety of bioactive compounds including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC). These tryptophan catabolites are involved in the pathogenesis of many neuropsychiatric disorders, particularly when the KP becomes dysregulated. Accordingly, the enzymes that regulate the KP such as indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase, kynurenine aminotransferases (KATs), and kynurenine 3-monooxygenase (KMO) represent potential drug targets as enzymatic inhibition can favorably rebalance KP metabolite concentrations. In addition, the galantamine-memantine combination, through its modulatory effects at the alpha7 nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors, may counteract the effects of KYNA. The aim of this review is to highlight the effectiveness of IDO-1, KAT II, and KMO inhibitors, as well as the galantamine-memantine combination in the modulation of different KP metabolites. KAT II inhibitors are capable of decreasing the KYNA levels in the rat brain by a maximum of 80%. KMO inhibitors effectively reduce the central nervous system (CNS) levels of 3-HK, while markedly boosting the brain concentration of KYNA. Emerging data suggest that the galantamine-memantine combination also lowers L-TRP, kynurenine, KYNA, and PIC levels in humans. Presently, there are only 2 pathophysiological mechanisms (cholinergic and glutamatergic) that are FDA approved for the treatment of cognitive dysfunction for which purpose the galantamine-memantine combination has been designed for clinical use against Alzheimer’s disease. The alpha7 nicotinic-NMDA hypothesis targeted by the galantamine-memantine combination has been implicated in the pathophysiology of various CNS diseases. Similarly, KYNA is well capable of modulating the neuropathophysiology of these disorders. This is known as the KYNA-centric hypothesis, which may be implicated in the management of certain neuropsychiatric conditions. In line with this hypothesis, KYNA may be considered as the “conductor of the orchestra” for the major pathophysiological mechanisms underlying CNS disorders. Therefore, there is great opportunity to further explore and compare the biological effects of these therapeutic modalities in animal models with a special focus on their effects on KP metabolites in the CNS and with the ultimate goal of progressing to clinical trials for many neuropsychiatric diseases.

L-Tryptophan (L-TRP), an essential amino acid, can be transported into the central nervous system (CNS) across the blood-brain barrier (BBB) via L-amino acid transporter 1 (LAT-1). Once it gains entry into the brain, L-TRP can be utilized in the biosynthesis of serotonin, but a major proportion of the amino acid is incorporated into the kynurenine pathway (KP) [1-3], thereby producing a number of bioactive metabolites, including kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) [4]. Although KYNA has been described as neuroprotective [5, 6], there is growing evidence that the majority of KP metabolites play a substantial role in the pathogenesis of a number of neuropsychiatric diseases [7, 8], including schizophrenia [9-11], depression [12-14], Parkinson’s disease (PD) [15, 16], bipolar disorder [11, 17], Huntington’s disease (HD) [18], multiple sclerosis [19], and Alzheimer’s disease (AD) [18, 20], particularly when the KP becomes dysregulated.

A number of enzymes have been associated with the KP, as shown in Fig. 1. Indoleamine/tryptophan 2,3-dioxygenase (IDO-1/TDO) catalyzes the first step, followed by the other major enzymes: kynurenine aminotransferases (KATs) and kynurenine monooxygenase (KMO) [21]. Animal studies indicate that the inhibition of these KP enzymes can have a beneficial therapeutic effect in neurological diseases through reduction of the levels of neurotoxic KP metabolites within the brain [22, 23]. As evidence suggests, the FDA-approved medications galantamine (acetylcholinesterase inhibitor and positive allosteric modulator of α7nACh receptors) and memantine (although classified as an antagonist, acts as an NMDA receptor modulator/glutamate receptor agonist, paradoxically [20, 24-26]) are well known for their effectiveness in various neuropsychiatric disorders [27]. However, recent clinical evidence [28] also hints at the possible role of these medications in decreasing KYNA levels, which can be particularly beneficial for patients with schizophrenia. These early data have set the stage for increasing recognition of their potential role in the therapeutic modulation of the KP (Fig. 1). To better target and reduce KYNA levels, KAT II and KMO inhibitors with the galantamine-memantine combination have been proposed as a potential new therapeutic tool to alleviate cognitive impairments in various neuropsychiatric diseases [21, 29].

Fig. 1.

Four major enzymes acting in the KP. KYN, kynurenine; KP, kynurenine pathway; 3-HK, 3-hydroxykynurenine; L-TRP, L-tryptophanl; KAT, kynurenine aminotransferase; PIC, picolinic acid; KMO, kynurenine monooxygenase; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase.

Fig. 1.

Four major enzymes acting in the KP. KYN, kynurenine; KP, kynurenine pathway; 3-HK, 3-hydroxykynurenine; L-TRP, L-tryptophanl; KAT, kynurenine aminotransferase; PIC, picolinic acid; KMO, kynurenine monooxygenase; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase.

Close modal

The aim of this review is to evaluate the current and future prospects with regard to the potential of this novel drug combination to favorably modulate KP.

Role of KP Metabolites in the Pathogenesis of Neuropsychiatric Disorders

The potential role of KYNA in the pathogenesis of schizophrenia [30-33] has been widely studied. Excess KYNA is associated with schizophrenia through 2 different signaling pathways. First, KYNA is a known NMDA antagonist, and decreased glutamatergic activity at the NMDA receptors is at the center of schizophrenia pathogenesis [34]. The glutamatergic nervous system for a possible therapeutic strategy in mood disorders has been discussed recently [35]. In addition, Erhardt et al. [36] also found a positive correlation between elevated brain KYNA levels and an increase in CNS dopaminergic activity. Hence, KYNA potentiates dopaminergic neurons, which provides a possible mechanistic link between KYNA and the development of schizophrenia [37]. There is, however, some contraindication to this belief [38, 39] as some researchers have indicated that KYNA leads to a drop in CNS dopamine levels, which is possibly mediated by its inhibitory effect on the responses to α7nACh receptor activation. Another important aspect of schizophrenia is a decline in the CNS GABAergic activity [40] where KYNA has been found to negatively influence the overall GABA-mediated neurotransmission within the brain [41].

Nicotinic receptor activity in the CNS (α7nAChR) has also been found to be downregulated due to increased KYNA levels [42, 43]. However, this theory still remains highly controversial as to whether any interaction is direct or indirect [44, 45]. Irrespective of its negative role in neuropsychiatric disorders, KYNA has been shown to play a neuroprotective role in HD, AD, PD, and other neurodegenerative disorders through its NMDA-antagonist activity [46-48]. On the contrary, elevated QUIN levels lead to excitotoxic stimulation of NMDA receptors in the glutamatergic pathway in HD [49]. Moreover, a substantially reduced KYNA/QUIN ratio has been found in patients with AD [50].

KYNA has been reported to possess an antioxidant activity [51], and as an agonist at aryl hydrocarbon receptors [52], it plays a key role in the regulation of neuroinflammation by altering the balance between proinflammatory and anti-inflammatory immune mediators [53]. Therefore, KYNA levels bidirectionally modulate the concentrations of glutamate [54], dopamine [55], and GABA [56, 57] as well as the redox and neuroinflammatory systems [51, 57-60]. KYNA is the conductor of the orchestra of the major pathophysiological mechanisms (Fig. 2). This is known as the KYNA-centric pathophysiology [24], as shown in Fig. 2. The KYNA-centric hypothesis has only been published recently [61]. Additionally, KYNA as well as other KP catabolites have been extensively identified as tolerogenic molecules in the milieu of cancer pathogenesis [62-65].

Fig. 2.

KYNA bidirectionally modulates the levels of dopamine, acetylcholine, glutamate, and GABA as well as the redox and neuroinflammatory systems. This is known as the KYNA-centric hypothesis. KYNA is the conductor of the orchestra of the major pathophysiological mechanisms of many CNS disorders. KYNA, kynurenic acid; CNS, central nervous system.

Fig. 2.

KYNA bidirectionally modulates the levels of dopamine, acetylcholine, glutamate, and GABA as well as the redox and neuroinflammatory systems. This is known as the KYNA-centric hypothesis. KYNA is the conductor of the orchestra of the major pathophysiological mechanisms of many CNS disorders. KYNA, kynurenic acid; CNS, central nervous system.

Close modal

Involvement of KP Metabolites in Neurocognitive Impairment

The pathological implications of KP metabolites in the impairment of cognitive function have become increasingly evident in recent years. Animal models have demonstrated that increased brain KYNA concentrations can significantly impair major cognitive skills [66], such as short-term working memory, conditioned reflexes, and other learning capabilities of the animal subjects [67, 68]. The commonly proposed underlying mechanisms involve the inhibitory impact of KYNA on the excitatory NMDA receptors and probably indirectly on α7nAChR [55]. Apart from animal studies, data derived from human populations have also revealed a significant correlation between elevated serum KYN/L-TRP ratio (indicative of inflammation-driven KP induction) and a progressively poor cognitive function [69, 70]. A possible association between aging and raised KYN/L-TRP ratio, accompanied by a poor mental capacity, was first hinted by Ramos-Chávez et al. [71]. Besides KYN/L-TRP, a progressively rising KYNA/QUIN ratio has also been strongly linked with a poor cognitive performance in cases of schizophrenia. Interestingly, some contrasting findings have been reported regarding this matter [72] wherein a few authors propose that a higher KYNA/QUIN ratio arises due to elevated CSF KYNA levels [9], while others opine that it may be due to a lower QUIN concentration [73].

IDO/TDO Inhibitors

IDO/TDO enzymes initiate the KP by catalyzing the synthesis of KYN from L-TRP. TDO is mostly associated with the formation of KYN (in the liver, reproductive system, and brain) [74] except under conditions that involve extensive immune activation wherein IDO becomes relatively more active. TDO activity is largely boosted by means of adrenal glucocorticoids along with L-TRP [75]. On the contrary, IDO-1 activity is usually induced at the site of an inflammation by means of cytokines including interferon-γ [76], the end result of which is an overall suppression of the body’s defense system [77]. This immunomodulatory action of IDO-1 has been shown to be utilized by certain body neoplasms and helps tumor cells evade the immune response [78]. Another isoform of IDO, IDO-2, is found in the hepatorenal tissues and the reproductive tract [79]. Similar to IDO-1, its expression is believed to be controlled via cytokines such as interferon-γ [80].

In terms of KYN metabolites, a targeted inhibition of IDO-1 by 1-MT or 1-methyl tryptophan [81] plays a major role in increasing the levels of brain KYNA (Table 1), while simultaneously decreasing the concentrations of the neurotoxic 3-hydroxykynurenine (3-HK) and QUIN metabolites [22]. Among the 2 isomeric forms of 1-MT, 1-methyl-L-TRP and 1-methyl-D-TRP, the former has a significantly higher affinity for IDO-1 [82]. Due to a structural and functional similarity between the 2 IDO isozymes, IDO-2 activity is also downregulated by 1-MT [82]. In addition, limited evidence suggests that deletion of the TDO gene is associated with significantly increased levels of brain L-TRP as well as KYN, while 3-HK and KYNA levels increase only moderately [83].

Table 1.

Effects of enzymatic inhibitors and the galantamine-memantine combination on KP metabolites

Effects of enzymatic inhibitors and the galantamine-memantine combination on KP metabolites
Effects of enzymatic inhibitors and the galantamine-memantine combination on KP metabolites

KAT II Inhibitors

KAT regulates the conversion of KYN into KYNA. Although a number of isozymes (I-IV) have been isolated [21], the CNS mostly comprises KAT I and KAT II isoforms, with the latter being more active in KYNA formation [84]. KAT III and KAT IV along with the other 2 isoforms are capable of influencing the metabolism of a large number of amino acids, including different aromatic, neutral, and sulfur-containing amino acids [84, 85], which highlights the potentially overlapping biological role of KAT enzymes.

Among the candidates for KAT inhibition, only KAT II inhibitors have been studied in detail with the aid of animal models (Table 1). Quantitative data from these studies have shown an efficacious role of several KAT II inhibitors in decreasing the levels of KYNA in the rat brain. The KAT I inhibitor BFF-122 [86] has been shown to decrease de novo synthesis of KYNA by 66%. It has been reported that (S)-4-(ethylsulfonyl) benzoylalanine [87] may decrease KYNA by 31% of baseline levels, while the drug PF-04859989 [88-90] may lower KYNA by 20–80%. It is worthwhile to note that a lack of BBB permeability represents a major clinical hurdle when targeting this metabolic pathway. Until the advent of PF-04859989, the first known KAT II inhibitor to cross the BBB, efforts to develop KAT II inhibitors for human use were hindered because none of the other drugs could penetrate the BBB and thus had to be administered directly into the rat brain [89].

Another pharmacological agent, BFF-816, can reduce KYNA by 12–32% of initial concentrations [91-93]. Moreover, PF-05579960 and PF-06253133 can also decrease KYNA by 80% [88]. Interestingly, the glutathione precursor N-acetylcysteine has also been effective in reducing KYNA by 50% of its baseline levels in the rat brain [94]. In addition, angiotensin II receptor blockers have also been demonstrated to block KAT II activity (Table 1), inducing a decrease in brain KYNA as high as 66% [95].

KMO Inhibitors

KMO is responsible for catalyzing the formation of 3-HK. It is produced mainly by infiltrating macrophages and microglial cells [21]. KMO has also been studied as a potential target of several novel therapeutic agents. Animal data show that KMO inhibitors effectively reduce levels of the neurotoxic KP metabolite 3-HK and to a lesser extent QUIN, while also partially increasing KYNA concentration in the brain. As shown in Table 1, UPF-648 [86] has been associated with a decrease in brain 3-HK by 64%. However, the QUIN and KYNA levels were not significantly altered in this particular study. Contrary to these findings, KYNA levels were remarkably elevated in another experimental study of UPF-648 [96], in which rat brain analysis showed an approximately 14-fold increase in brain KYNA concentration.

Another novel pharmacological agent, CHDI-340246, has proven its efficacy in increasing KYNA levels in the rat brain by as much as 60-fold. In addition, this KMO inhibitor also managed to increase 3-HK and QUIN levels in the rat striatum moderately [97]. Ro61-8048 is another experimental inhibitor of KMO that has been shown to substantially increase KYNA levels in the brain by more than 10-fold [98-100]. Another KMO inhibitor, meta-nitrobenzoyl alanine, has been studied widely [101, 102] and is associated with markedly elevated levels of KYNA in the rat brain (nearly 5 times more than the baseline). Similarly, meta-nitrobenzoyl alanine also leads to a reduction in brain levels of 3-HK by approximately 86%. A novel pharmacological agent, prodrug 1b, is capable of lowering the brain 3-HK concentration by 70% [103].

Only 2 pathophysiological mechanisms (cholinergic/nicotinic-cholinergic and glutamatergic/NMDA) have been approved by the FDA for the treatment of cognitive dysfunction, and the galantamine-memantine combination is currently being used in AD for this purpose [104, 105]. Memantine is known to antagonize glutamate activity at NMDA receptors [20, 26], a role also accomplished by KYNA [106-109], thereby attenuating the excitotoxic effects of QUIN [49]. KYNA is also known for its actions on cholinergic transmission in the brain [110-113], which can lead to the pathogenesis of AD [114], as shown in Fig. 2. It seems that KYNA does not act directly at α7nACh receptors [44, 45] or antagonizes the action of acetylcholine [115], as further indicated in Fig. 3, 4. Galantamine acts by stimulating α7nAChR [116] and other nicotinic receptors, including α4β2 receptors, which are the most abundant nicotinic receptors in the brain [117, 118]. Stimulation of α4β2-nAchR is capable of inducing positive changes in both memory and attention as well as ameliorating deficits in motivation and reward processing, which are associated with a multitude of neurodegenerative diseases [119, 120]. An interactive effect of the galantamine-memantine combination in reducing oxidative stress and KP metabolites has also been documented extensively [121]. Moreover, these pharmacological agents may also enhance mismatch negativity [122], brain-derived neurotrophic factor [123], and synaptic density [124, 125]. The α7 nicotinic-NMDA hypothesis has been recently published [61].

Fig. 3.

KYNA may not be an inhibitor of nicotinic receptors [44]. But, since KYNA blocks the glutamate-mediated effects of α7nACh receptors, it is possible that it may indirectly block the effects of α7nAChR. There are several ongoing studies that may shed light on this controversy. Meanwhile, galantamine and memantine can cross the BBB and target α7 nicotinic and NMDA receptors, respectively, thereby counteracting the effects of KYNA. KYNA, kynurenic acid; BBB, blood-brain barrier.

Fig. 3.

KYNA may not be an inhibitor of nicotinic receptors [44]. But, since KYNA blocks the glutamate-mediated effects of α7nACh receptors, it is possible that it may indirectly block the effects of α7nAChR. There are several ongoing studies that may shed light on this controversy. Meanwhile, galantamine and memantine can cross the BBB and target α7 nicotinic and NMDA receptors, respectively, thereby counteracting the effects of KYNA. KYNA, kynurenic acid; BBB, blood-brain barrier.

Close modal
Fig. 4.

Diagrammatic representation of a cholinergically modulated glutamatergic synapse to illustrate the usual site and mode of action of nicotinic receptors. ACh is released from cholinergic synaptic terminals or from cholinergic varicosities into an extracellular space with access to glutamatergic axon terminals. The normal action of ACh is to promote or facilitate the evoked release of glutamate onto its receptors, which will include pre- and postsynaptic receptors sensitive to NMDA, as well as receptors for AMPA and kainic acid. The dominant action of KYNA is to block all the glutamate receptors although with greatest potency at NMDA receptors since it blocks both the glutamate binding site and the co-agonist glycine binding site (not shown). This means that any facilitation of cholinergic activity, either by increasing ACh release or by allosteric modulators such as galantamine-enhancing Ach-receptor sensitivity, will indirectly promote glutamate release. They will therefore appear to overcome the blocking activity of KYNA even though they are acting through a different site from KYNA. Ach, acetylcholine; KYNA, kynurenic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Fig. 4.

Diagrammatic representation of a cholinergically modulated glutamatergic synapse to illustrate the usual site and mode of action of nicotinic receptors. ACh is released from cholinergic synaptic terminals or from cholinergic varicosities into an extracellular space with access to glutamatergic axon terminals. The normal action of ACh is to promote or facilitate the evoked release of glutamate onto its receptors, which will include pre- and postsynaptic receptors sensitive to NMDA, as well as receptors for AMPA and kainic acid. The dominant action of KYNA is to block all the glutamate receptors although with greatest potency at NMDA receptors since it blocks both the glutamate binding site and the co-agonist glycine binding site (not shown). This means that any facilitation of cholinergic activity, either by increasing ACh release or by allosteric modulators such as galantamine-enhancing Ach-receptor sensitivity, will indirectly promote glutamate release. They will therefore appear to overcome the blocking activity of KYNA even though they are acting through a different site from KYNA. Ach, acetylcholine; KYNA, kynurenic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Close modal

The potential of the galantamine-memantine combination was further demonstrated in a relatively small study (Table 1) that successfully estimated the effects of the 2 medications on the overall concentrations of various KP metabolites in plasma [28]. This is the only study of its kind involving human subjects. In this study, 2 participants with schizophrenia/schizoaffective disorder were treated with the galantamine-memantine combination, and plasma levels of L-TRP, KYNA, KYN, and PIC considerably improved as a result. At 6-week follow-up, the mean reduction of L-TRP, KYNA, KYN, and PIC was found to be 7.6, 21.2, 1.6, and 27.5%, respectively. Both subjects experienced some improvement in cognitive deficits as well as negative symptoms (suggestive of primary negative symptoms because at baseline psychosis, depression and extrapyramidal symptoms [factors associated with secondary negative symptoms] were none to minimal).

Increasing evidence confirms the therapeutic efficacy of KP enzyme inhibitors and the galantamine-memantine combination in the alteration of concentrations of various KP metabolites. These significant findings may prove to be highly relevant to the efficacious management of schizophrenia [28, 126], AD [127-129], HD [130, 131], PD [132, 133], amyotrophic lateral sclerosis [134-136], bipolar disorder [137, 138], depression [139-141], autism spectrum disorder [142, 143], epilepsy [144-146], cognitive impairments secondary to traumatic brain injury [147, 148], electroconvulsive therapy [149], aging [150], chronic pain disorders [151], and other neuropsychiatric disorders [149, 152, 153].

KAT II inhibition and its impact on KYNA levels have been documented by several studies. An in-vivo animal study found that the KAT II inhibitor, PF-04859989, significantly reduced KYN-induced KYNA levels in the rat brain [154]. Another study with KAT II gene knockout mice showed markedly reduced hippocampal KYNA levels (∼71%; p < 0.001) and an increased performance in cognitive tasks [155]. In another similar study, Yu et al. [156] reported a decrease in KYNA levels ranging from 48 to 60% following the deletion of KAT II gene in mice. Although no human trials have established the efficacy and safety profile of KAT II inhibitors, there is growing evidence that these pharmacological agents might play a decisive role in the management of neurocognitive disorders [157].

Targeted inhibition of IDO-1/TDO enzymes has been shown to reverse behavioral changes secondary to schizophrenia in rat models [158]. Coptisine, an essential component of traditional Chinese medicine, has proved to be an even more potent pharmacological inhibitor of IDO-1 compared to 1-MT and has been found to be useful in rat models of AD [159, 160]. It is noteworthy that TDO inhibitors have received less attention than IDO-1 inhibitors, particularly in the context of neurological disorders, reflecting that while TDO is found in the brain, it is primarily expressed in the liver. Recently, evidence regarding the experimental inhibition of IDO/TDO enzymes for immunomodulation in cancer therapy [161-163] has been increasing extensively. Still, there is a scarcity of clinical data of IDO/TDO inhibitors in relation to neurodegenerative disorders. KMO inhibitors have been thoroughly evaluated in animal studies. The systemic administration of JM-6 (a KMO inhibitor) has been associated with a significant elevation in KYNA levels in the rat brain [164]. Moreover, this was accompanied by improved memory and cognitive function in the rats. Studies involving mice with a knockout KMO gene (KMO−/−) have resulted in not only significantly increased KYNA [165, 166] but also grossly reduced 3-HK levels in the mutant mice brain, along with declining cognitive and psychosocial functions [167]. However, brain QUIN concentrations did not decrease substantially in these cases [166]. Pellicciari and colleagues [168] also reported that although KMO inhibitors can potentially increase KYNA and KYN levels within the brain, there is no conclusive evidence to suggest that they also alter QUIN.

The efficacy of galantamine and memantine has been broadly elaborated by means of clinical studies. In a randomized controlled trial involving aged individuals with cognitive impairment, this drug combination was associated with a remarkable improvement in cognitive function compared to galantamine alone [169]. The galantamine-memantine combination has also proved to be more effective in AD than the donepezil-memantine combination [170]. Galantamine and memantine have proved to be efficacious in the management of AD due to their combined actions on α7nAChR and NMDA receptors [149]. However, the synergistic activity of these 2 agents can also help avert the neurotoxic actions of QUIN by modulating KYNA. Keeping in mind their efficacy in the modulation of KP metabolites, it is possible to predict a therapeutic role of the galantamine-memantine combination in schizophrenia [28] and other neuropsychiatric diseases [149, 171]. Recent studies have indicated that galantamine and memantine can individually lead to significantly improved cognitive outcome in participants with schizophrenia [172, 173]. The 2 pharmacological agents may be substantially beneficial in treating the cognitive impairments [174] as well as the negative symptoms observed in schizophrenia [175].

Based on current evidence, it can be concluded that KAT II inhibitors have the best efficacy in reducing the levels of brain KYNA in rats. Used in adequate doses, KYNA can be expected to decline by 80% of basal levels. In contrast, brain KYNA levels can be drastically elevated in rats treated with KMO inhibitors. However, galantamine-memantine treatment in human subjects can lead to a decrease in serum KYNA levels by approximately 30%. This decline in plasma KYNA has been observed over a short duration of 6 weeks, which raises the possibility that much lower KYNA concentrations might be expected in patients over longer periods of time. Therefore, galantamine-memantine combined with KAT II inhibitors may have a potentially synergistic action in reducing KYNA levels in the brain [176].

Among KAT II inhibitors, KMO inhibitors, and the galantamine-memantine combination, only the latter is FDA approved and available for clinical use. A much broader clinical study comparing the relative efficacy of these drugs in the treatment of various neuropsychiatric disorders is thus warranted. The effects of these medications on modulating brain KYNA concentrations must be monitored precisely, which is possible through the careful utilization of PET tracers in subjects [177].

The KP enzyme inhibitors as well as galantamine-memantine combination, through their ability to modulate KP derivatives, are potentially suitable for neutralizing various impairments in neuropsychiatric disorders. In particular, the galantamine-memantine combination and KAT II inhibitors may exert a potent therapeutic effect by synergistically decreasing the KYNA concentrations in the CNS. Since KYNA is the “conductor of the orchestra” of the major pathophysiological mechanisms in CNS disorders, a possible future study comparing the effects of these 2 therapeutic options on the neosynthesis of KYNA [92] is essential to determine the most efficacious treatment for schizophrenia and other neuropsychiatric diseases.

The authors declare no conflicts of interest.

This work was not funded.

Bai prepared the first draft. All authors edited with intellectual contribution and approved the final version of the manuscript.

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