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Tanaka, M.;  Tóth, F.;  Polyák, H.;  Szabó, �.;  Mándi, Y.;  Vécsei, L. Psychiatric Disorders in Clinical Human Studies. Encyclopedia. Available online: https://encyclopedia.pub/entry/29713 (accessed on 13 December 2025).
Tanaka M,  Tóth F,  Polyák H,  Szabó �,  Mándi Y,  Vécsei L. Psychiatric Disorders in Clinical Human Studies. Encyclopedia. Available at: https://encyclopedia.pub/entry/29713. Accessed December 13, 2025.
Tanaka, Masaru, Fanni Tóth, Helga Polyák, Ágnes Szabó, Yvette Mándi, László Vécsei. "Psychiatric Disorders in Clinical Human Studies" Encyclopedia, https://encyclopedia.pub/entry/29713 (accessed December 13, 2025).
Tanaka, M.,  Tóth, F.,  Polyák, H.,  Szabó, �.,  Mándi, Y., & Vécsei, L. (2022, October 17). Psychiatric Disorders in Clinical Human Studies. In Encyclopedia. https://encyclopedia.pub/entry/29713
Tanaka, Masaru, et al. "Psychiatric Disorders in Clinical Human Studies." Encyclopedia. Web. 17 October, 2022.
Psychiatric Disorders in Clinical Human Studies
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9070734

Depression, anxiety and cognitive impairment are the most common symptoms of psychiatric disorders that may concur and/or sway during progression and comorbidity frequently occurs in mental illnesses, which renders the exact diagnosis even more difficult. Scrupulous studies are underway to untangle the thread of pathophysiology of mental disorders and their comorbidities not only in clinical medicine, but also in animal studies. Psychological stress, especially depression has been found to be a risk factor for dementia, a prognostic biomarker for stokes and a therapeutic target for meaning-centered psychotherapy in depression, and animal-assisted and pet-robot interventions in dementia. Four main representative psychiatric symptoms including positive, negative and cognitive symptoms, and anxiety are reviewed. Psychiatric disorders present inflammatory signs in serum, CSF and/or the brain tissue samples in which pro-inflammatory and anti-inflammatory cytokine levels can be detected and measured. The simultaneous alternations of KYN metabolism take place under inflammation, disturbing a balance of toxic and protective KYN metabolites. 

chronic inflammation low-grade inflammation immune tolerance

1. Major Depressive Disorder

MDD is a mental disorder with at least two weeks of low mood, often accompanied by low self-esteem, loss of interest, low energy and pain without a cause. Less than one-fifth of MDD patients experiences positive psychotic symptoms such as either delusions, hallucinations or both [1]. The mean score of the Hamilton Rating Scale for Depression, Scale for the Assessment of Negative Symptoms (SANS) and negative symptom scale of Positive and Negative Symptom Scale of the patients with MDD were significantly higher than those of control subjects, validating the clinical significance of negative symptoms and depressive symptoms in MDD patients [2]. Cognitive impairment in patients with MDD is often overlooked and may precede after symptoms of MDD, such as sleep, appetite and affective symptoms [3]. Generalized anxiety disorder (GAD) often co-occur in MDD. Many symptoms overlap with MDD and GAD, such as irritability, restlessness, sleep problems and concentration difficulty [4] (Table 1).
Table 1. The enzymes of the tryptophan-kynurenine pathways and related disease.
  Major Depressive Disorder Bipolar Disorder Generalized Anxiety Disorder Substance Use Disorder Post-Traumatic Stress Disorder Schizophrenia Autism Spectrum Disorder
Symptoms Positive + ++ ++ ++ ++ ++ +
Negative ++ ++ ++ + ++ ++ +
Cognitive + + ++ ++ ++ - +
Anxiety ++ ++ ++ ++ ++ ++ ++
Inflammatory factors Proinflammatory ↑ ↑ ↑ ↑ ↑ ↑ ↑
Anti-inflammatory ↑ ↑ ↓ ↓ ↓,? ↑ ↑
Kynurenines Toxic ↑ ? ↑ ? ? ↑ ↑
Protective ↓ ? (serum), ↑ (CSF) ? ? ? ↑,? ↓
+: noticeable; ++: prominent; -: not typical;↑: increase; ↓: decrease; ?: questionable or unknown.
Regarding inflammatory cytokines, meta-analyses reported strong evidence of significantly increased levels of CRP, IL-1, IL-6, TNF-α and sIL-2R in serum of MDD patients [5][6][7][8][9][10]. Decreased levels of CRP and IL-6 were observed after antidepressant treatment [11]. Higher concentration of CCL2/MCP-1 was also reported in MDD patients. CSF levels of IL-6 and IL-8 were significantly increased in patients with MDD [12] (Table 1).
Regarding the KYN system, meta-analyses reported the decreased levels of plasma TRP, KYN and KYNA in patients with MDD, and the increased level of QUIN was observed in antidepressant-free patients. The increased QUIN immunoreactivity was detected in the prefrontal cortex and hippocampus of the postmortem brain tissues from patients with MDD [13][14]. Magnetic resonance spectroscopy showed a higher turnover of cells with KYN and the 3-HAA/KYN ratio in adolescent depression. The findings are in accordance with the activation of the TRP-KYN pathway by pro-inflammatory cytokines activating IDO, and KMO enzymes toward 3-HK and QUIN branches, leading to higher levels of toxic 3-HK and QUIN [15] (Table 1).

2. Bipolar Disorder

BD is a mental disorder that causes alternating periods of depression and mania. Positive symptoms regularly occur to BD with prevalence rates ranging from 20 to 50% in acute bipolar mania [16]. Cognitive impairment is present in the minority of BD patients. SANS, Brief Psychiatric Rating Scale and Social and Occupational Functioning Assessment Scale showed that negative symptoms were present in more than a quarter of the patients. The patients had more sever affective flattening, alogia, anhedonia-asociality and avolition-apathy [17]. Cognitive deficits of verbal and visual memory, and executive tasks have been demonstrated during depressive episodes, while executive dysfunction and attention deficits have been reported during manic episodes [18][19]. Many patients with BD experience at least one anxiety attack [20] (Table 1).
Regarding inflammatory cytokines, four meta-analyses of serum or plasma samples from BD patients invariably reported significantly increased levels of TNF-α and sIL-2R; IL-4, IL-6, IL-1RA, sIL-6R and TNFR1 levels were significantly increased in two meta-analyses; IL-10 levels were significantly increased in one meta-analysis [10][21][22][23]. A meta-analysis of CSF samples from BD patients reported increased IL-1β levels [12] (Table 1).
Regarding the KYN system a case-control study showed that KYNA levels were reduced and the 3-HK/KYN and 3-HK/KYNA ratio was increased in BD compared to healthy control [24]. However, a meta-analysis reported no significant difference of TRP and KYN levels, KYN/TRP and KYNA/QUIN ratios in serum from BD patients [25] KYNA was significantly increased in CSF of BD patients [11] (Table 1).

3. Generalized Anxiety Disorder

GAD is a mental disorder characterized by excessive, uncontrollable and irrational anxiety. GAD is associated with the severity of positive symptoms such as delusions and hallucinations [26]. More than quarter of GAD patients showed negative symptoms [27]. Patients with GAD have an impaired cognitive function, particularly in attention and working memory [28] (Table 1).
On the status of inflammatory cytokines, CRP of blood, serum or plasma samples was significantly raised in GAD by meta-analysis, and IFN-γ and TNF-α levels were significantly increased in GAD in at least two or more studies [29]. Lower levels of IL-10 and higher ratios of TNF-α/IL10, TNF-α/IL4, IFN-γ/IL10 and IFN-γ/IL4 were observed in the serum of GAD patients, showing significantly increased pro- to anti-inflammatory cytokine ratios, which suggests a distinct cytokine imbalance [30] (Table 1).
On the KYN system, the plasma KYN levels were decreased in endogenous anxiety and normalized after treatment [31]. Metabolomic studies reported decreased KYN levels in patients diagnosed with Type D personality that is characterized by negative affectivity and social inhibition [32]. Stress and inflammation appear to activate the TRP-KYN pathway, depleting 5-HT and melatonin and thus making more susceptible to anxiety (Table 1).

4. Substance Use Disorder

Substance use disorder (SUD) affects a person’s brain and behavior leading to an inability to control the use of a drug or medication. In addition to an impaired control, patients show social impairment, risky use and pharmacological indicators including tolerance and withdrawal. Common substances are alcohol, sedatives, caffeine, hallucinogens, inhalants, stimulants and tabaco, among others [33]. SUD is frequently comorbid with other mental illnesses. Positive symptoms are more prominent among substance abusing SCZ patients [34]. The onset of positive symptoms occurs in nearly three-fourths of cannabis users after cannabis abuse [35]. Serious hallucinations and delusions are frequent in alcohol addicted SCZ patients [36]. Negative symptoms are less common in patients with substance use disorder probably because patients with social withdrawal have more difficulties to obtain abused substance [37]. Increased rates of criminal activity and violent behavior are more common in SCZ patients with SUD [38]. Cognitive impairments are prevalent among patients with SUD. Alcohol affects total and memory domain scores more than cannabis, while opioids affect visuospatial domain more than cannabis or stimulants [39]. SUD occurs at an increasing rate in patients with GAD. Substance use and anxiety are considered to occur in a vicious cycle [40] (Table 1).
Few studies regarding inflammatory cytokines were reported. Cocaine increased the mRNA expression of IL-1ß receptor in the ventral tegmental area, reducing cocaine seeking. It may suggest that chronic cocaine use induces proinflammatory signaling contributing to cocaine seeking [41]. A single nucleotide polymorphism in the IL-10 gene is associated with decrease expression of IL-10 and is linked to alcoholism. It was suggested that increased proinflammatory and reduced anti-inflammatory signals are predisposing factors for alcoholism [42] (Table 1).
No clinical study was found regarding the serum or CSF level of KYNs in patients with SUD. The TRP-KYN metabolic pathway is considered to play an important role in SUD and was discussed as a potential target for SUD therapy [43]. Patients with cocaine use disorder (CUD) frequently develop MDD. The plasma 5-hydroxytryptamine (5-HT) concentration was significantly higher and the KYN/5-HT ratio was significantly lower in patients with CUD-induced MDD than those with MDD, while there were no differences between CUD-primary MDD and MDD. It suggests that the TRP-KYN pathway participates less in CUD-induced MDD and the presence of other mechanisms of the development of depression [44] (Table 1).

5. Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) develops after a terrifying experience in individuals who suffer from flashbacks, nightmares, severe anxiety and uncontrollable thoughts regarding the event. Substantial evidence supports that PTSD is caused by insufficient integration of a trauma memory into the hippocampal-cortical memory networks, forming fragmented, incomplete and disorganized intrusive memories [45]. Most patients with PTSD complained of chronic sleep disturbances characterized by significantly reduced slow wave sleep (SWS), light sleep stages, awakenings, arousals and increased rapid eye movement (EEG). SWS drives memory consolidation by repeated reactivation of newly encoded memory. Thus, lowered sleep quality facilitates the formation of intrusive memories [46]. PTSD is frequently comorbid with SCZ. More than a half of patients with PTSD experienced psychotic positive symptoms, but emerging evidence suggests that PTSD with secondary psychosis might be different from PTSD without psychosis [47]. Patients with PTSD activate the fight-flight-freeze response and reduce overall brain functioning, leading to several negative symptoms [48]. PTSD causes long-term cognitive dysfunction such as memory, attention, planning and problem solving [49]. PTSD frequently cooccur with GAD and their symptoms overlap [50] (Table 1).
Inflammation has been linked to PTSD. Increased proinflammatory cytokines IL-1β, IL-6, IFN-γ and TNF-α were found elevated in the serum of patients with PTSD and partly correlated with the severity of PTSD [51]. Decreased levels of anti-inflammatory cytokine IL-4 were reported in patients with PTSD. The alteration of the serum anti-inflammatory cytokines IL-4 and IL-10 remains inconclusive in PTSD [52]. Higher levels of serum anti-inflammatory cytokine TGF-β were found to be predicative indicators for the development of PTSD one month after accidents [53] (Table 1).
No clinical study was reported regarding the peripheral or CSF samples of KYNs in patients with PTSD. KYN metabolites are monitored in clinical settings as evidence of inflammatory responses contributing to sleep deprivation and the formation of intrusive memories [52].

6. Schizophrenia

SCZ is a mental disorder in which patients abnormally interpret reality and suffer from hallucinations, delusions and extremely disordered thinking and behavior. Patients with SCZ usually experience positive symptoms such as hallucinations, delusions, flight of ideas, negative symptoms such as apathy, emotionless, lack of social functioning and cognitive symptoms including difficulty in concentration and attention, and memory impairments. However, cognitive symptoms are subtle and are often detected only when neuropsychological tests are performed [54]. The prevalence of GAD was significantly higher in patients with SCZ and the prevalence of panic disorder, social anxiety disorder and obsessive-compulsive disorder was significantly higher in SCZ patients [55] (Table 1).
The peripheral activation of the immune system was observed in SCZ. Three meta-analyses on serum cytokines of SCZ patients were reported accordingly. (1) IL-1β, IL-6 and TGF-β were increased in acutely relapsed and first-episode psychosis and the cytokine levels were normalized with antipsychotic treatment. Soluble IL-2 receptor (sIL-2R) stayed high in acute psychosis and after antipsychotic treatment [56]. (2) IL-6, TNF-α, sIL-2R and IL-1 receptor antagonist were significantly increased in acutely exacerbating and IL-6 levels significantly decreased following treatment. IL-1β and sIL-2R were significantly increased in chronic SCZ [10]. (3) MCP-1 (CCL2), MIP-1β (CCL4), eotaxin-1 (CCL11) and IL-8 were elevated in pooled analysis of all SCZ patients, while MCP-1 was elevated in first-episode psychosis (FEP) and IL-8, eotaxin-1 and MIP-1β were elevated in multiple-episode psychosis [57] (Table 1).
The activation of the central immune system was also observed. Three meta-analysis on CSF cytokines of SCZ were reported accordingly. (1) IL-1β was decreased significantly decreased in SCZ, but there was no significant difference in CSF levels of IL-1α, IL-2 or IL-6 between SCZ and healthy controls [56]. (2) IL-1β, IL-6 and IL-8 were significantly increased IL-2R were significantly decreased in SCZ [12]. (3) IL-6 and IL-8 were significantly elevated in SCZ and IL-6 levels were higher in early-stage SCZ than chronic SCZ [58] (Table 1). CRP, IL-6 and TNF-α are overlapping biomarkers in SCZ and cardiovascular diseases and anti-inflammatory drugs were proposed for the treatment of SCZ [59].
Regarding the KYN system, the serum KYN and KYN/TRP ratio was higher in SCZ [60]. A meta-analysis of CSF samples showed increased KYN and KYNA levels and another meta-analysis of plasma, CSF, brain tissue or saliva showed increased levels of KYNA in SCZ [12][61] (Table 1). Thus, the KYN system is activated in SCZ and elevated KYNA levels are considered to contribute to the cognitive impairments of SCZ. Recently, another meta-analysis reported that KYNA levels and the KYNA/3-HK ratio were not altered and the KYNA/KYN ratio was decreased in SCZ, suggesting the presence of differential pattern between SCZ and mood disorders [62]. The combination of acetylcholine inhibitor galantamine and N-methyl-D-aspartate receptor memantine was proposed as antioxidant treatment SCZ and for the treatment of SCZ cognitive impairments [63][64].

7. Autism Spectrum Disorder

Autism Spectrum Disorder (ASD), defined by the Diagnostic and Treatment Manual for Mental Disorders, Fifth Edition (DSM-5), is characterized by persistent deficits in social communication interaction and restricted-repetitive patterns of behavior, interests or activities. A specific subtype of ASD is linked to comorbid psychosis, showing positive symptoms of delusion, hallucination, thought disorder, mania and depression and negative symptoms of psychosis appear to share many features with ASD [65]. Cognitive deficits including mental deterioration, are associated with social and communication difficulties that involve components of cognition, communication and social understanding [66]. Meta-analyses reported that ASD children had higher anxiety levels than normally developing ones, that high-functioning ASD adolescents are at high risk of developing anxiety disorders, and that autism population showed higher prevalence of anxiety disorders, the highest being attention-deficit hyperactivity disorders, in decreasing orders, sleep-wake disorders, disruptive, impulse-control and conduct disorders depressive disorders, obsessive-compulsive disorder BD and SCZ spectrum disorders [67][68] (Table 1).
Regarding inflammatory cytokines, two Meta-analyses showed increases of IL-1β, IL-6, IL-8, IFN-γ, TNF-α, eotaxin and monocyte chemotactic protein-1, while TGF-β1 were significantly lower in ASD [69][70]. However, a case-control study reported that significantly higher levels of IL-4, IL-5 and IL-13, with Th-2 predominance in plasma and peripheral blood mononuclear cells of ASD children [71] (Table 1).
The alteration of the KYN system was also observed. The mean serum level of KYNA was significantly lower, while the KYN/KYNA ratio was significantly higher in children with ASD. The same relative values were found when comparing the childhood autism subgroup with the controls [72]. Significantly higher KYN/TRP ratio and KYN and QUIN levels were observed in blood samples of ASD patients, while no significant difference of KYNA and significantly lower picolinic acid level were detected in ASD [73] (Table 1).
All psychiatric disorders presented an evidence of the innate inflammatory activation by increased pro-inflammatory cytokines. MDD, BD, SCZ and ASD witnessed the activation of the secondary adaptive immune response by increased anti-inflammatory cytokines, while GAD, and SUD showed reduced levels of anti-inflammatory cytokines. PTSD showed no changes or mixed results depending on the cause of stress. Regardless of the activation of the secondary adaptive immune response, the inflammatory profiles of all psychiatric disorders described in this research, have shifted away from healthy state (Table 1).
Either causative or resultant of acute and chronic inflammation, the altered balance of toxic and protective KYN metabolites was observed. Toxic KYN metabolites are increased in MDD, GAD, SCZ, ASD and the CSF samples of BD. Modulatory KYN metabolites were increased in SCZ; decreased in MDD and ASD; unchanged in the serum of BP; unknown in GAD and SUD.

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Subjects: Medicine, Research & Experimental
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Masaru Tanaka , Fanni Tóth , Helga Polyák , Ágnes Szabó ,
Yvette Mándi
, László Vécsei
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Update Date: 18 Oct 2022
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