Fig. 10.1
Effects of inflammation on related metabolisms. The lines in green colour = metabolic process, the lines in blue colour = transport across blood brain barrier, the lines in red colour (complete) = activation, the lines in red (interrupted) = inhibitory effect, IDO indoleamine 2,3 dioxygenase, TDO tryptophan 2,3 dioxygenase, KMO kynurenine-3 mono-oxygenase, KATs kynurenine aminotransferases, PAH phenylalanine 5-hydroxylase, TH tyrosine 5-hydroxylase, TPH tryptophan hydroxylase, KYNA kynurenic acid, 3HK 3-hydroxy-kynurenine, HAA 3-hydroxyanthranilic acid, QUIN quinolinic acid, NAD nicotinamide adenine dinucleotide, BBB blood–brain barrier
Tryptophan metabolism in psychiatric depression has been studied since 1960s, since tryptophan is the essential amino acid from which serotonin is synthesized. Increased degradation of tryptophan into kynurenine (KYN) could induce depressive mood (Lapin and Oxenkrug 1969). Normally, tryptophan is metabolized to kynurenine in the liver by the tryptophan 2,3-dioxygenase (TDO) (Watanabe et al. 1980). The activity is mainly controlled by the tryptophan level itself, resulting in a stable metabolism. The central availability of tryptophan mainly depends on the competition by the large amino acids at the transport across BBB and partially depends on the cerebral demand (Fernstrom 1977). KYN is further catabolized into 3-hydroxy-kynurenine (3HK) by the kynurenine-3-mono-oxygenase (KMO) enzyme, and then to 3-hydroxyanthranilic acid (HAA) through the action of kynureninase. After that, the catabolism continues either into the complete oxidation pathway and forms adenosine triphosphate (ATP) which occurs mainly in the liver or into quinolinic acid (QUIN) which is finally degraded into nicotinamide adenine dinucleotide (NAD). From the complete oxidation pathway, picolinic acid (PIC) is also formed in small quantity. In physiological condition, the catabolism goes mainly into ATP formation and only a minor portion goes into NAD formation (Leklem 1971). In normal state, to get a normal NAD requirement for the nervous system, QUIN synthesis occurs only transiently in the liver and it does not accumulate in the hepatocytes (Bender 1989). KYN can also be catabolized by the kynurenine aminotransferases (KATs) into kynurenic acid (KYNA). Tryptophan metabolism is generally influenced by age and gender (Leklem 1971). Since KYN itself could be transported across the blood–brain barrier, in addition to the kynurenine formed in the brain by tryptophan breakdown, extra KYN is available from the periphery for further kynurenine metabolism in the brain. Sixty percent of brain KYN was contributed from the periphery (Gal and Sherman 1980). In the brain, tryptophan catabolism occurs mainly in the astrocytes and microglia (Grant et al. 2000; Grant and Kapoor 1998; Heyes et al. 1996), although some neurons also possess indoleamine 2,3-dioxygenase (IDO) and/or TDO2 (Miller et al. 2004). The astrocytes are the main source of KYNA because of a lack of KMO enzymes, whereas microglia and macrophages are the main sources for QUIN (Guillemin et al. 2000, 2001, 2005a). The astrocytes metabolize QUIN produced by the neighbouring microglia (Guillemin et al. 2001).
In case of inflammation, the enzyme indoleamine 2,3-dioxygenase (IDO) degrades tryptophan in the extrahepatic tissues (Heyes et al. 1993; Mellor and Munn 1999). Enzyme activity is enhanced by pro-inflammatory cytokines such as interferon-γ (IFNγ) (Carlin et al. 1987; Yasui et al. 1986). Thus, the extrahepatic tryptophan metabolism is shifted away from the liver (Moffett et al. 1998). In this case, tryptophan breakdown through KYN pathway occurs mainly in the blood and lymphoid tissues (Moffett and Namboodiri 2003). The IDO activity is inhibited by the anti-inflammatory cytokine IL4 (Musso et al. 1994). In case of stress or related conditions where cortisol secretion is enhanced, TDO activity is also further enhanced by glucocorticoids (Knox 1951; Salter and Pogson 1985). In this case, the KYN formation becomes much higher than physiological condition. Since the liver-cell uptake of KYN is not efficient for extrahepatic KYN, the further KYN catabolism mainly occurs extrahepatically. The activity of KMO is also enhanced by pro-inflammatory cytokines (Mellor and Munn 1999). In case of inflammation, formation of 3HK therefore becomes enhanced much faster than KYNA formation and the balance between formation of 3HK and KYNA shifted to the arm of the metabolism with 3HK and QUIN. In the presence of inflammation, activated monocytes are also found to be the robust producers of QUIN (Chiarugi et al. 2001). The accumulation of 3HK could induce neuronal apoptosis (Okuda et al. 1998), while accumulation of QUIN, the endogenous NMDA-R agonist (Bender and McCreanor 1985), induces excitotoxic neurodegenerative changes (Schwarcz et al. 1983) and astrocytes apoptosis (Guillemin et al. 2005b). However, KYNA is the NMDA-R antagonist (Perkins and Stone 1982) and is protective against excitotoxicity of QUIN (Kim and Choi 1987), although accumulation of KYNA could induce glutamatergic hypo-functioning and might disturb cognitive function (Olney et al. 1991). Moreover, KYNA is an antagonist of α7-nicotinic acid acetylcholine receptor (α7nAchR) (Hilmas et al. 2001) and influences the expression of non-α7nAchR (Hilmas et al. 2001). This in turn disturbs the α7 and non-α7nAchR mediated release of noradrenaline (NA), dopamine (DA) and acetylcholine (Ach) (Myint 2012).
Non-depressed patients with hepatitis C who were treated with IFNα and who later developed depression showed an increase in IL-6 and a decrease in KYNA, which showed significant association with the development of depressive symptoms. Since IFNα could induce 15 kD protein, this would further increase IFNγ production and activate IDO and KMO (Wichers et al. 2005). Another study also showed increased KYN pathway with an increase in both KYNA and QUIN in the CSF of IFNα treated patients (Raison 2010). In the patients with major depression who are drug naïve or medication free for at least 4 months, an imbalance between those neuroprotective and neurotoxic pathways with lower protective metabolite has been observed (Myint et al. 2007a). The possible important role of KYNA in depression was supported by a recent genetic study which demonstrates that a single nucleotide polymorphism (SNP) from the KAT-III gene is associated with major depression and bipolar depression (Claes et al. 2011). A magnetic resonance (MR) spectroscopy study in melancholic depressed adolescents also reported that the choline levels in the brain, which indicated the turnover of cells, showed positive correlation with serum KYN and the HAA/KYN ratio (Gabbay 2010) and serum KYN and the HAA/KYN ratio were positively correlated with depression scores.
The plasma of bipolar mania patients shows reduced tryptophan levels (Myint et al. 2007b) and an increased KYN to tryptophan ratio (Reininghaus et al. 2014). A post-mortem study on TDO2 and KYN in the anterior cingulate cortex (ACC) showed increased TDO2 expression and KYN levels in the brains of bipolar patients (Miller et al. 2006). In a study on the in vitro fibroblast culture from patients with bipolar disorder and controls, an increase of both 3HK and KYNA was observed in the culture of the cells from the patients; when the culture was challenged immunologically, the cytokines IL1 and IL6 and the 3HK and 3HK/KYNA were significantly increased in the culture from the patients compared with controls (Johansson et al. 2013).
The findings in schizophrenia patients are quite controversial. A study in post-mortem brain tissue in different cortical regions revealed increased KYNA levels in schizophrenic samples compared to a control sample, particularly in the prefrontal cortex (PFC) (Schwarcz et al. 2001). Another investigation in the amygdala observed an insignificant increase of KYNA in medicated schizophrenics (Miller et al. 2006). Increased levels of KYNA were also observed in the CSF of drug-naive first-episode schizophrenic patients (Erhardt et al. 2001). It was hypothesized that accumulation of KYNA in the brain may lead to schizophrenic symptoms (Erhardt et al. 2003). However, not only the positive symptoms and cognitive impairment but also the negative symptoms and loss of brain volume (Takahashi et al. 2009) are components of the psychopathology of schizophrenia. Yao and group have reported on 3HK levels in schizophrenia (Yao 2010), demonstrating the positive association between OHK and the total symptoms score at the time of recruitment. Our recent finding in medication-naïve schizophrenia patients indicated increased plasma 3HK and decreased plasma KYNA compared to healthy controls (Myint et al. 2011a). Part of the same study mentioned above, which tested the in vitro fibroblast culture from patients with schizophrenia and controls, also observed the increase of both 3HK and KYNA in the culture of the cells from the schizophrenia patients; when the culture was challenged immunologically, the cytokines IL1 and IL6, and the 3HK and 3HK/KYNA were significantly increased in the culture from schizophrenia patients compared with controls (Johansson et al. 2013).
Another metabolic pathway that links the immune system and neurochemicals is the tyrosine metabolism, from which dopamine and catecholamines are synthesized. In this metabolism the tetrahydrobiopterin (BH4) is the cofactor of phenylalanine 4-hydroxylase (PAH), tyrosine 5-hydroxylase (TH), tryptophan 5-hydroxylase (TPH), nitric oxide synthases (NOS) (Werner-Felmayer et al. 2002) and alkylglycerol mono-oxygenase (Werner-Felmayer et al. 2002). PAH converts phenylalanine to tyrosine and subsequently TH initiates the production of DA, adrenaline and noradrenaline through the formation of l-3,4-dihydroxyphenylalanine (l-DOPA). The enzyme TPH is also important for synthesis of serotonin from tryptophan. Since BH4 is a labile molecule, the oxidation of BH4 by molecular oxygen is irreversible (Connor et al. 1979). Under conditions of oxidative stress, one can expect that metabolites such as BH4 are rapidly destroyed (Fuchs et al. 2001; Widner et al. 2001) and the enzymes dependent on this metabolite lose their activity. In this case, the activities of PAH and TH are reduced, leading to an increase in phenylalanine/tyrosine ratio and a decrease in dopamine synthesis from tyrosine. This mechanism was proposed as part of the pathophysiology of depression (Sperner-Unterweger et al. 2014), based on the finding in the study in an elderly population that increased tryptophan catabolism was associated with the depressive symptoms of lassitude, reduced motivation, anorexia and pessimistic thoughts, whereas phenylalanine/tyrosine alterations showed a more pronounced correlation to neurovegetative symptoms, including sleep disturbance, digestive symptoms, fatigue, sickness and motor symptoms (Capuron et al. 2011).
Oxidative Stress Related Biomarkers
The evidence of increased oxidative stress, which is also related to activation of IRS, is also well documented in psychiatric disorders. A recent post-mortem brain study has reported that the gene expression levels of oxidative defence enzymes superoxide dismutases, catalase and glutathione peroxidase in association with telomere length were significantly lower in white matter oligodendrocytes from patients with MDD as compared to controls (Szebeni et al. 2014). The increased levels of an early component of the peroxidation chain in the plasma samples of euthymic patients with bipolar disorder were also reported (Andreazza et al. 2015). The redox dysbalance, which is the imbalance between anti-oxidants and pro-oxidants (reactive oxygen species and reactive nitrogen species) was also well documented in schizophrenia (Steullet et al. 2014). However, there is no report from in-depth biomarker studies on oxidative stress markers in relation to clinical course and clinical symptoms or treatment response in adult psychiatric disorders.
Clinical Aspects of Cytokines and Related Metabolic Biomarkers
From the late twentieth century and the beginning of the twenty-first century to date, the field of research in immune changes and its related metabolic changes in psychiatric disorders developed significantly in terms of translational and clinical studies. Evidences of the associations of changes in cytokines and the metabolites with clinical features, response to treatment and choice of treatment in different adult psychiatric disorders were documented in clinical settings.
Association with Clinical Symptoms and Response to Psychotrophic Medication
Major Depressive Disorders
The role of high Th1 and Th2 cytokines in the blood of the patients with major depression has been well documented (Maes 1994; Musselman et al. 2001; Seidel et al. 1996). It has also been found that antidepressants can decrease the Th1/Th2 or pro-inflammatory/anti-inflammatory cytokine ratio (Kubera et al. 2001). A study on Th1, Th2 and Th3 balance has shown that there was an increase in Th1 cytokine IFNγ positivity in the depressed patients, and the Th3 cytokine TGFβ1, which regulates the balance between Th1 and Th2, was increased in depressed patients following effective antidepressant treatment (Myint et al. 2005). This study has shown that the Th1 and Th2 balance was dependent on age and gender. The concentrations of the blood inflammatory markers at baseline are also related to symptom severity and outcome of the treatment. In our recent study, increase in pro-inflammatory markers such as IFNγ, TNFα and CRP is associated with severity of the symptoms such as lack of interest and psychomotor retardation (Halaris et al. 2015). In a study on IFNα-treated hepatitis C patients, concentrations of the baseline soluble interleukin-2 receptor (sIL-2r), IL-6 and IL-10 were significantly increased in those who developed clinical depression during treatment compared with those who did not (Wichers et al. 2006). Altered plasma and CSF IL-6 (Lindqvist et al. 2009) and chemokines (Janelidze et al. 2013) are also reported to be associated with suicide attempts. Those findings indicated that the activation of IRS might be involved in the development of depressive symptoms. In addition, the activation of IRS can induce changes in the tryptophan degradation pathway.
A recent immunogenetic study on the IFNγ gene reported that the presence of IFNγ CA repeat allele 2 homozygous, which was associated with increased IFNγ secretion, had significant association with higher kynurenine concentrations in controls (F = 4.47, p = 0.038) as well as in patients (F = 3.79, p = 0.045), and also with an increase of tryptophan breakdown over time during the study period (F = 6.0, p = 0.019) (Myint et al. 2013). The imbalances in the tryptophan degradation pathway were also associated with symptom severity. In our recent study, the serum KYNA concentration showed significant inverse correlation with depressive symptom and paranoid symptom scores in depressed patients (Halaris et al. 2015). A recent study on the polymorphism of the genes of the enzymes involved in the tryptophan degradation pathway reported that KATIII enzyme polymorphism is associated with unipolar and bipolar depression and associated somatic anxiety symptoms (Claes et al. 2011). A study on people who have attempted suicide showed that they have significantly higher concentrations of QUIN in their plasma and CSF, regardless of the associated psychiatric disorders, including schizophrenia (Erhardt et al. 2013). The increase in QUIN immune-positive microglia cell density in the anterior mid cingulate cortex and subgenual anterior cingulate cortex areas of the ACC of post-mortem brain tissues was also reported in those patients with unipolar and bipolar depression who committed suicide compared with the control brain tissues from those who died from other causes (Steiner et al. 2011). These findings pointed out the fact that neuronal excitotoxicity during depression played an important role in suicide and raised a question as to whether the reduction of NMDA-mediated neurotoxicity using ketamine could be a preventive therapy for suicide in patients with high serum or plasma QUIN concentration. Unlike in the ACC, the QUIN immune-positive microglia cell density was reduced in the right CA1 region of the hippocampus area in both unipolar and bipolar depressed suicidal brains (Busse et al. 2014). The confounding effect of minor hippocampal degeneration could not be excluded, although there was no gross volume loss. These findings indicated that changes in the brain are area-specific and cannot be generalized as in the periphery.
Fortunately, currently available antidepressants could help to a certain degree in terms of biochemical changes. The 6-week treatment with SSRIs could increase the ratio of KYNA to KYN, indicating the rebalancing the shift of kynurenine pathway (Myint et al. 2007a). In another study, monotherapy with escitalopram could reduce inflammatory molecule CRP and the neurotoxic QUIN around the 8th week of therapy, although those rose again around the 12th week, whereas 3HK was significantly reduced in the 12th week (Halaris et al. 2015). In this study, it was reported that those patients who responded to the therapy had higher initial serum CRP, although those patients did not have a reduction in anti-inflammatory cytokines and imbalance in the kynurenines. In another study on the changes in kynurenines in the CSF, it was observed that the higher the protective metabolite KYNA in relation to the toxic 3HK, the better the response to antidepressants and mood stabilizers in patients with affective disorders (Schwarz et al. in press). Those findings together indicated that activated IRS is not always a negative indicator as long as it is not yet associated with imbalance in the whole immune-neurochemical network.
Bipolar Disorder
The studies in bipolar disorder reported a somewhat different but similar direction to that of major depression. In terms of cytokines changes, a meta-analysis on 18 studies with a total of 761 bipolar disorder patients and 919 healthy controls reported that concentrations of soluble IL-2 receptor (sIL2R), TNFα, soluble tumour necrosis factor receptor type 1 (sTNFR1) (p < 0.001 each), sIL6R (p = 0.01) and IL-4 (p = 0.04) were significantly higher in bipolar patients compared with healthy controls, whereas there was no significant difference in other cytokine (Munkholm and Brauner 2013). Another meta-analysis on 30 studies reported the difference between phases such as manic and euthymic for sIL2R, sIL6R, IL4 and TNFα (Modabbernia et al. 2013). In general, maniac phase showed more inflammatory changes compared with euthymic phase.
In a study on tryptophan metabolites in bipolar mania, it was reported that bipolar manic patients have a significantly lower tryptophan index than normal controls (F = 9.779, p = 0.004) (Myint et al. 2007b) and the mean tryptophan breakdown index was increased significantly after a 6-week treatment. The reduction in plasma tryptophan and reduction in tryptophan index showed significant negative correlation with reduction in YMRS score (r = −0.577, p = 0.019 and r = −0.520, p = 0.039, respectively). In another study, both blood kynurenine concentrations and the KYN-to-tryptophan ratio were significantly higher in the total sample of euthymic patients with bipolar disorder, with greater increases noted in both parameters in the subsample of overweight patients. When compared to controls, peripheral neopterin concentrations were significantly lower. Within the patient group, there were also significant between-group differences in neopterin concentrations, with higher levels in those who were overweight and in patients in the later stages of illness compared to earlier stages (Reininghaus et al. 2014).
Schizophrenia
The results of the studies in schizophrenia are still controversial. However, involvement of infection and immune changes in schizophrenia has been well accepted. Prenatal maternal infection of immune changes that programmed the brain changes in the foetus in the early neurodevelopmental stage which predisposes the development of schizophrenia in adulthood was a well-recognized hypothesis (Meyer et al. 2006).
The plasma and serum levels of tryptophan metabolites, which are related to immune activation, showed significant associations with clinical symptom scores. A study on serum 3HK in schizophrenia discussed that there is an association between initial 3HK concentrations and (1) total positive and negative symptoms score (PANSS) at the time of recruitment, and (2) delayed response of positive symptoms at 4-week neuroleptic treatment in first-episode neuroleptic-naïve schizophrenia patients (Condray et al. 2011). In another study, it was reported that the baseline plasma tryptophan levels in schizophrenia patients showed negative correlations with the PANSS positive symptoms scores (Kim et al. 2009). It was also reported that the initial plasma KYNA concentrations were associated with a reduced PANSS positive symptoms score and a reduced depressive symptoms score upon discharge. In contrast, the higher the KYNA/KYN ratio on admission, the higher the positive symptoms score on admission, although the higher the KYNA/KYN ratio on admission the better the reduction in depressive symptoms scores at discharge. Moreover, the increase in this ratio after 6-week medication was associated with better reduction in the positive symptoms, general symptoms and depressive symptoms scores. Initial plasma 3HK concentrations were negatively associated with the admission PANSS positive symptoms score. However, this study reported that, the higher the plasma 3HK on admission, the lower the reduction in general symptom scores at the time of discharge (Myint et al. 2011b). In another study on CSF kynurenines and response to treatment, it was observed that the higher the KYNA in the CSF in relation to 3HK, the better the response to treatment (Schwarz et al. in press). Taking those findings together could lead to the interpretation that an increase in KYNA concentration might induce positive symptoms and cognitive symptoms, although the lower concentration of KYNA could result in poor response to treatment.
A post-mortem brain study demonstrated the increase in KYNA levels in schizophrenic samples compared to those of controls, particularly in the PFC (Schwarcz et al. 2001). Another post-mortem brain study on the amygdale region also showed an insignificant increase of KYNA in medicated schizophrenics (Miller et al. 2006). A recent immunohistochemical study on a post-mortem brain showed reduction in QUIN positive microglia cell density in the CA1 region in schizophrenia patients compared with controls (Gos et al. 2014). Since a similar finding was reported in the study for major depression and bipolar depression (Busse et al. 2014) as well, it could be hypothesized that reduction in NMDA-R agonist QUIN in the hippocampus area might be related to impaired cognitive function in psychiatric disorders.
Cytokines and Related Metabolism in Immunomodulation Therapy
The proof of concept regarding the involvement of immune activation in the pathophysiology of psychiatric disorders is that the anti-inflammatory medications improved the symptoms of those disorders. Several medications which are neither antidepressants nor psychotropic drugs but which modulate the immune system directly and indirectly are reported to give positive outcomes in treatment of adult psychiatric disorders.
The most studied anti-inflammatory medication is the COX2 inhibitor, celecoxib. Celecoxib is used as an add-on to the currently used antidepressants or antipsychotics. Clinical studies have suggested that the COX2 inhibitor celecoxib has positive effects on cognitive function in depressed patients (Muller et al. 2006; Chen et al. 2010). In a double-blind controlled trial in which celecoxib was given as an add-on to an antidepressant, reboxetine, those depressed patients with higher KYN-to-tryptophan ratios responded to the add-on treatment better than those with lower KYN-to-tryptophan ratios (N. Müller, Biomarkers in celecoxib trial, personal communication). Since this ratio indicates the degradation of tryptophan to kynurenine, which indirectly indicates the activation of IRS, it could be interpreted that those with an inflammatory condition or an activated IRS in association with depression responded better to COX2 inhibitor add-on medication. In the same study, it was also observed in the placebo + reboxetine group that those who responded to reboxetine had a lower initial QUI/KYNA ratio. In addition, in overall combined group, the responders had a lower initial QUIN/KYN ratio. Those findings indicated that the general response to treatment might be better if the neurotoxic QUIN formation is lower, whereas a celecoxib add-on is necessary for those with activated IRS. To date, there is only one study of celecoxib in treatment-resistant bipolar disorder (Nery et al. 2008) and the significant reduction in Hamilton Depression Score was noted at the first week time-point but not afterward. No biomarker was measured in this study. In another study on celecoxib add-on therapy in treatment-resistant depression, no clinical data was reported; only a reduction in blood TNFα in the celecoxib group was mentioned (Kargar et al. 2014). The suppression of TNF, which is a pro-inflammatory cytokine, could be one of the mechanisms involved in better improvement of depressive symptoms in celecoxib add-on therapy. Treatment with an anti-TNF antibody, infliximab, did not show a clinical advantage in overall analyses, but a baseline hs-CRP > 5 mg/L was found to be the point at which infliximab-treated patients began to exhibit a greater decrease in HAM-D-17 scores than placebo-treated subjects (Raison et al. 2013). Further study continued with analyses of transcriptome for response to treatment with infliximab revealed that 148 transcripts were predictive of infliximab response and were associated with gluconeogenesis and cholesterol transport, and those were enriched in a network regulated by the hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis (Mehta et al. 2013). Interestingly, tryptophan metabolite QUIN, which is associated with response to treatment, is also associated with suppression of gluconeogenesis (Lardy 1971). Therefore, gluconeogenesis might be considered involved in the response to antidepressant treatment. Moreover, the cytokines and related metabolic biomarkers should be applied to the treatment with anti-inflammatory therapy since these medications will work if only IRS activation is involved. There was only one open-labelled trial of aspirin in depression (Galecki et al. 2009) and it did not show a satisfactory advantage over fluoxetine, although some population-based studies showed advantages over mood and cognitive function (Dinnerstein and Halm 1970; Lieberman et al. 1987; Kang et al. 2007).
In schizophrenia, unlike in affective disorders, the meta-analysis study on the randomized controlled trials with celecoxib and aspirin reported only a marginal effect on the PANSS total scores and that was mainly due to the effect of aspirin (Nitta et al. 2013). In the placebo-controlled trial with aspirin 100 mg/day as adjuvant to antipsychotics, total psychopathology was reduced significantly by aspirin in those patients who had the lowest initial value of Th1:Th2 ratio (Laan et al. 2010). It was reported that only those patients with early stage of schizophrenia responded to anti-inflammatory therapy (Nitta et al. 2013).
Another medication which is not an anti-inflammatory, although it induces anti-inflammatory-like action in the brain by suppression of microglia activation, is a second-generation tetracycline, minocycline. The earliest case report was by a Japanese group who reported the antipsychotic effect especially on negative symptoms in two patients with schizophrenia treated with minocycline as adjunct to haloparidol (Miyaoka et al. 2007). That report was followed by another double-blind randomized study on 54 schizophrenia patients who were treated with minocycline as an adjunct to atypical antipsychotics, which delivered a beneficial outcome in terms of negative symptoms, general symptoms and cognitive function, especially in the early stage patients (Levkovitz et al. 2010). Another case report in which minocycline was used as an adjunct therapy to clozapine in two patients with treatment-resistant schizophrenia also reported the beneficial effect on the negative symptoms (Kelly et al. 2011). Another three more randomized double-blind placebo-controlled trials in schizophrenia also reported the beneficial effect of minocycline on the negative symptoms (Fekadu et al. 2013; Khodaie-Ardakani et al. 2014; Liu et al. 2014). To date, only an open-label study of minocycline therapy in combination with SSRIs on patients with psychotic depression has reported that 6-week therapy could reduce HDRS, Brief Psychiatric Rating Scale and psychotic symptoms (Miyaoka et al. 2012). None of the studies have mentioned the role of cytokines and related metabolic biomarkers in terms of prediction of treatment response. Markers related to microglia activation, such as QUIN, or imaging of glia activity could be useful markers to predict the response to treatment. This area still needs to be investigated, since no medication will give 100 % response, and treatment-response indicators are important in future personalized psychiatry.
Another medication which indirectly suppresses the IRS activation is polyunsaturated fatty acid (PUFA) which is widely studied and has shown beneficial effects, especially in schizophrenia. Meta-analysis of 11 placebo-controlled trials conducted on patients with a DSM-defined diagnosis of MDD reported significant clinical benefits of omega-3 PUFA treatment compared to placebo (Grosso et al. 2014). Earlier, several placebo-controlled trials of omega-3 fatty acid as either mono- or add-on therapy in schizophrenia in the beginning of the twenty-first century showed advantage of PUFA over the placebo (Peet 2008; Müller 2013), although a meta-analysis showed no advantage (Fusar-Poli and Berger 2012). However, a recent study from Norway in which PUFA or vitamins C and E add on to antipsychotics in acute psychotic patients with schizophrenia showed that, in patients with low erythrocyte PUFA, both add-on medications worsen the psychotic symptoms, but not if PUFA was combined with vitamins (Bentsen et al. 2013). This negative effect could be due to drug interaction of those add-on medications with antipsychotics. Another possibility is that those patients with low erythrocyte PUFA might also have vitamin C and E deficiency, and that the positive effects of vitamin C and E will occur only if PUFA levels are normal and vice versa. Therefore, it was reported that it was safe to give those add-on medications in combination.
Those studies indicated the role of biomarkers in choosing an anti-inflammatory therapy to predict the outcome. In addition it should be noted that it is not that simple to conclude that low blood level of a biological compound indicates the need for that compound as an add-on therapy. Since biological compounds or metabolites or cytokines do not work simply as a single molecule but through the interaction with other chemicals, careful interpretation considering the possible interactions is essential.
Future Perspectives and Conclusion
Based on the above findings, there are several options open for future research studies related to clinical application. From the diagnostic aspects, studies for early diagnosis and for choice of therapy will be the promising approach in terms of prevention and personalized medicine. However, in terms of therapeutic research, there should be a cautious approach, since careless manipulation of the system can induce long-term deleterious effect that could not be easily detected in the short-term animal experiments.
Diagnostic Perspective
The studies on the role of cytokines and related biomarkers have clearly indicated that, in a certain percentage of patients with adult psychiatric disorders, there are an activated IRS and disturbances in the metabolism related to immune function. Based on those findings and also on findings from the studies of the anti-inflammatory treatment trials, it could be concluded that activated IRS and dysbalance in immune function and related metabolism are part of the aetiology of adult psychiatric disorders. Therefore, those disturbances are expected to take place before the disturbances in brain neurochemicals in some patients. In this case, those early changes could be considered as early detection of abnormal changes in the system. To detect those early disturbances, it is necessary to know the normal profile of those markers in each individual, since immune system related metabolic profile can be influenced by many individual factors. If those early disturbances persist for a longer period than regular infection or inflammation should, it is necessary to consider this as detection of early pathological changes and those changes should be corrected in time by using simple anti-inflammatory medications or vitamins. That would prevent the unnecessary use of psychotropic medications, which not only could induce untoward effects but also could increase the cost of treatment and socioeconomic burden.
In addition to the early diagnostic perspectives, some of the markers such as QUIN in the blood and CSF could be applied for a predictive marker for suicide. By giving medications that could block the NMDA-R and induce antidepressant effects such as ketamine to those with high QUIN in the blood, we might prevent untimely death of the patients and could improve the quality of life of the patients as well as of the family members.
Moreover, by stratifying the whole group of patients with mood disorders and psychoses, those markers might be able to predict the response to treatment of particular psychotropic medications. Future research should be carried out in this direction. In this way, we might be able to give the medication that better fits with the patient from the beginning of the illness. This might in turn prevent the development of treatment resistance and chronicity of the disorders which result in considerable socioeconomic burdens.
However, to reach this applicability, further innovation in terms of the development of a diagnostic test system which could be applied at the community health-care level is necessary. Since most of the molecules are small molecules, the development of a sensitive and specific test system is a challenge to the scientific community. In addition, standardization among the available methods is also important to establish a reference system for new developments.
Therapeutic Aspect
Regarding the therapeutic aspects use of simpler medications with low possible side effects or application of life-style intervention, such as exercise and mindfulness practice for prevention and as adjuvant therapy, should be encouraged. However, it is important to realize that life-style intervention studies do not always work as we expect. This could be due to genetics and sociocultural predisposition that would make a person get benefit from a particular way of intervention. One way of life-style change cannot be expected to produce a similar effect in the whole population. Future studies that cover this aspect should be considered to make possible providing personalized advice.
Regarding the development of new compounds, it should be considered with great care. The results from the previous studies have clearly indicated that the pathophysiology of the adult psychiatric disorders is not due to one gene or one molecule. Manipulation based on the change of a molecule without proper monitoring could cause severe untoward effect. For example, in the kynurenine pathway, shift to 3HK can induce toxic changes but use of KMO inhibitor to block the pathway can induce deficiency and energy metabolism and can induce some psychiatric symptoms which we may not easily be able to detect in the acute animal models. Another example is the inhibitor of the KAT II enzyme to reduce the formation of KYNA with the intention of treating the cognitive symptoms in schizophrenia. This could lead the metabolic pathway to increased formation of QUIN which can induce not only excitotoxicity but also suicidal symptoms which are impossible to detect in the acute animal models.
Related posts:
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The Role of Inflammation in Alzheimer’s Disease
Microglia Activation, Herpes Infection, and NMDA Receptor Inhibition: Common Pathways to Psychosis?
The Role of Infections and Autoimmune Diseases for Schizophrenia and Depression: Findings from Large-Scale Epidemiological Studies
Animal Models Based on Immune Challenge: The Link to Brain Changes and Schizophrenia
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