Table 1.
Observational and experimental studies with human sample.
| AUTHOR, ANO | SAMPLE | DESIGN | ASSESSMENT | MAIN FINDINGS |
|---|---|---|---|---|
| ALTMAIER, 2013 | n=1502 community sample |
Cross-sectional Population-based study |
Depressive (PHQ-9) and anxious (GAD-7) symptoms | Lower levels of TRP and KYN were associated with type D personality, while no significant associations could be found for depressive and anxious symptoms |
| BAY-RICHTER, 2015 | n=66 (30 patients with suicide attempters and 36 HC) | Cross-sectional study | Cytokines and kynurenine metabolites in CSF; depressive symptoms (MADRS) and symptoms of suicidality over time (SUAS) | QUIN was increased and KA decreased over time in suicidal patients compared to HC Significant association between low KA and severe depressive symptoms, as well as between high OL-6 levels and more severe suicidal symptoms was found |
| BARANYI, 2013 | n=41 patients with chronic HCV |
Clinical study Interferon-α treatment |
TRP, KYN and QUIN were assessed before, during (at 1, 3, 6 and 9 months) and after the end of IFN-α treatment | 53.7% of patients fulfilled the criteria for treatment-related MDD TRP depletion and KYN and QUIN elevated levels in depressive patients |
| CAPURON, 2003 | n=26 patients with malignant melanoma |
Randomized clinical trial, double blind Interventions: placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment | TRP, KYN, Neopterin (a marker of immune activation) and depressive symptoms (HDRS) were assessed at baseline and at 2, 4, and 12 weeks of treatment | IFN-α therapy increased plasma KYN, Neopterin concentrations, and KYN/TRP ratio Antidepressant-free patients lower TRP was correlated with depressive symptoms |
| CLAES, 2011 | n=338 (266 MDD, 72 bipolar depression, and 310 population controls) | Case-control study | TPH2, KMO and KAT SNPs and haplotype association analysis | SNP in enzymes involved with KYN metabolism (TPH-2, KMO and KAT) were shown to be altered in patients with MDD and BD compared to population control |
| CUTLER, 2012 | n=1953 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study |
Clinical study | Genotypes corresponding to 94 SNPs in the genes IDO1 and IDO2 were extracted from a larger genome-wide set | SNP in the genes IDO1 and IDO2 exhibited association to citalopram treatment in depressive patients |
| ELOVAINIO, 2011 | n=986 young with cardiovascular risk |
Cohort study | IDO, KYN-TRP ratio and depressive symptoms (BDI) | Positive correlation between IDO activation with depressive symptoms and carotid atherosclerosis in women |
| ELOVAINIO, 2012 | n=986 young with cardiovascular risk |
Cohort study | IDO and depressive symptoms (BDI) | Positive correlation between IDO and depressive symptoms at baseline and follow-up |
| ERHARDT, 2013 | n=100 (64 medication-free suicide attempters and 36 HC) | Clinical study | QUIN and KYNA were assessed in CSF; suicidality (SIS) and severity of depressive symptoms (MADRS) | QUIN and IL-6, but not KYNA, was elevated in patients with suicide attempters. QUIN levels correlated with the total scores on Suicide Intent Scale They verified a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt |
| FITZGERALD, 2008 | n=74 females (41 IBS subjects and 33 controls) |
Case-control study | KYN, TRP and IFN-gamma; IDO (KYN/TRP); Depression and anxiety (PHQ) and IBS (IBS self-report ordinal scales) | Individuals with severe IBS exhibited higher levels of IDO, compared to less severe symptoms and controls, and were over twice when linked to depression and anxiety compared to less severe |
| GABBAY, 2010A | n=72 adolescents |
Cross-sectional study | KYN, TRP, KYN/TRP (estimating IDO activity), 3-HAA/KYN (reflecting neurotoxic load), and diagnosis groups by K-SADS | IDO activity were elevated and TRP concentrations were reduced in adolescents with M-MDD compared to non M-MDD and HC |
| GABBAY, 2010B | n=20 adolescents |
Cross-sectional study | KYN, 3-HAA, striatal total choline, and diagnosis groups by K-SADS | In M-MDD patients was found a positive correlation between KYN, 3-HAA, and striatal total choline in the right caudate and the left putamen brain areas |
| GABBAY, 2012 | n=56 adolescents |
Cross-sectional study | KYN, TRP, IDO, MDD (K-SADS) and anhedonia (BDI-II - item 4 and 12; CDRS-R - item 2; and K-SADS-PL - page 8) | IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD and in a combined group of MDD subjects and healthy controls |
| GALVÃO, 2011 | n=277 hepatitis C patients |
Cross-sectional study | IDO SNPs were genotyped (rs3824259; rs10089084 and rs35099072); Current depression and anxiety disorder (MINI) | Current major depression and/or current anxiety disorder was significantly associated with IFN-α-related depression In patients in IFN-α therapy depression and anxiety symptoms were not linked to variants in the IDO gene |
| HUGHES, 2012 | n=78 (39 patients with MDD and 39 HC) | Case-control study | Plasma IL-6, TNF-a, IL-1 b, IFN-c and CRP; TRP, KYN metabolites using HPLC; Depressive symptoms (HDRS) | IDO expression, plasma KYN levels and metabolites levels were not different between MDD patients, when compared to controls A reduction in circulating TRP concentrations was correlated with HDRS score |
| MACKAY, 2009 | n=63 (28 patients treated with fluoxetine 20 mg/day, 12 patients treated with fluoxetine 20 mg/day together with T3, and 23 patients received counselling with no antidepressant therapy) | Clinical study treatment for 18 weeks |
5-HT, 5-HIAA, tryptophan metabolites, BDNF, and IL-2, CRP were measured in peripheral blood, depressive symptoms (BDI, HDRS) | Showed a correlation between KYN metabolites concentration and psychiatric rating scores in depressive patients treated for 18 weeks with fluoxetine, an SSRI |
| MAES, 2011 | n=146 psychiatric inpatients (117 patients and 35 HC) |
Clinical study Inpatient treatment Center for Psychiatric and psychosomatic disorders |
TRP, KYN, KA, IDO (KYN/TRP ratio), KAT (KYN/KA ratio), somatization symptoms (SSI, SOMS), depression (BDI) | TRP is lower in patients than in HC and lower in somatization than in depression KA is lower in patients than in HC, and lower in somatization than in depression The severity of somatization was correlated with KY/TRP and KY/KA (positive) and TRP (negative) KYN and KA were correlated in controls, somatization + depression, and depression, but not in somatization |
| MARTINEZ, 2014 | n=504 HIV-infected |
Cross-sectional study nested a cohort study | TRP, KYN, dietary diversity, and severity of depressive symptom (HSCL-D) | The severity of depressive symptoms in HIV-infected patients was correlated with lower plasma levels of TRP and a higher plasma KYN/TRP ratio |
| MYINT, 2007 | n=247 (56 MDD patients hospitalized during 6-week and 189 HC) | Clinical study | QUIN, TRP, 3-HAA, and MDD (SCID) | Higher levels of TRP breakdown and protective KYN pathway metabolites were decreased in patients with depression compared to controls The neuroprotective ratio increased after treatment in those with first episodes |
| MYINT, 2013 | n=218 (125 MDD patients and 93 HC) | Case-control study with clinical sample | CA-repeat polymorphism in intron 1 of the interferon-γ gene, TRP, KYN, 5HIAA, depressive symptoms (HDRS) | IFN-α gene CA repeat polymorphisms was associated higher KYN concentrations, and increase in TRP breakdown in patients with depression compared to HC |
| PERTL, 2013 | n=61 breast cancer patients prior to chemotherapy |
Clinical study | IFN-γ, IL-6, TNF-α, CRP, KYN; | KYN levels predicted the trajectory of depression and were an important factor associated with depression and fatigue |
| RAISON, 2009 | n=27 HCV patients (16 in treatment group and 11 awaiting therapy) |
Clinical study Therapy with IFN-alpha/ribavirin for 12 weeks |
TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood; IL-6, sIL6R, sTNFR2, MCP-1, IFN; MDD (SCID) and depressive symptoms (MADRS) | Increased levels of KYN, QUIN and KYNA in CSF were correlated with increase of depressive symptoms after IFN-α treatment |
| SAVITZ, 2015B | n=128 unmedicated subjects (49 MDD, 21 remitted MDD, and 58 HC) |
Cross-sectional study | KYNA, QUIN, 3-hydroxykynurenine, and MDD (SCID) | Showed a reduction in KYNA/QUIN ratio among MDD and remitted MDD patients, compared to HC An inverse correlation between KYNA/QUIN and anhedonia in MDD patients was demonstrated, as well as a negative correlation between number of depressive episodes and KYNA/QUIN, and a positive correlation between the number of months in remission and KYNA/QUIN |
| SAVITZ, 2015C | n=49 unmedicated subjects (29 MDD and 20 HC) |
Cross-sectional study | KYNA, QUIN, KYN, TRP, IL-1, and MDD (SCID) | Interleukin-1 receptor antagonist, QUIN, and KYN were significantly elevated in MDD patients, compared to HC KYNA, TRP, and KYN were positively correlated with hippocampal and amygdala volume in MDD patients |
| SUBLETTE, 2011 | n=61 (14 MDD with history of suicide attempt, 16 MDD, and 31 HC) | Cross-sectional study | KYN, TRP, neopterin, MDD (SCID), depressive symptoms (BDI and HDRS) | Plasma kynurenine levels are elevated in MDD patients with history of suicide attempters, compared to MDD patients without history of suicide attempters and HC |
| SWARDFAGER, 2009 | n=95 patients with coronary artery disease from a cardiac rehabilitation facility |
Cross-sectional study | IDO (KYN/TRP), MDD (SCID), depressive symptoms (CES-D) | IDO activation was correlated with severity of depressive symptoms among patients with coronary artery disease |
| WICHERS, 2005 | n=16 patients with HCV, free of psychiatric disorders |
Clinical study Therapy with IFN-alpha |
TRP, KYN, KA, IDO, KYN/KA, and depressive symptoms (MADRS) All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated |
MADRS score increased during IFN-alpha treatment as did the IDO activity, and the KYN/KA ratio MADRS score was associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. |
| ZHU, 2013 | n=75 Outpatients with MDD (35 patients treated with sertraline and 40 placebo) | Randomized clinical trial double-blind 4-week trial |
5-MTPOL, MEL, KYN/MEL, and 3-OHKY/MEL ratios post-treatment compared to pretreatment Depressive symptoms (HDRS) | Antidepressant sertraline produced a reduction in the KYN/MEL ratio and 3-Hydroxykynurenine 3-OHKY/MEL ratio in MDD patients, compared to pretreatment |
| ZOGA, 2014 | n=80 females (40 MDD patients and 40 HC) | Case-control study with clinical sample | IDO, TNF-α, IFN-γ, CRP and 5-HT | Higher levels of IDO and inflammatory markers, and lower levels of 5-HT at baseline of patients Undergoing effective treatment decreased IDO and TNF-α and was positively linked to patient improvement |
Legend:
3-HAA = 3-hydroxyanthranilic acid; 3-OHKY = 3-Hydroxykynurenine; 5-HIAA = 5-hydroxyindoleacetic acid; 5-HT = 5-hydroxytryptamine serotonin; 5-MTPOL = 5-Methoxytryptophol; BD = Bipolar Disorder; BDI = Beck Depression Inventory; CES-D = Center for Epidemiological Studies-Depression Scale; CDRS-R = Children’s Depression Rating Scale-Revised; CSF = cerebrospinal fluid; HC = Healthy Control; HCV = hepatitis C virus; HDRS = Hamilton Depression Rating Scale; HSCL-D = Hopkins Symptom Checklist for Depression; IBS = irritable bowel syndrome; IDO = Indoleamine 2,3 dioxygenase; IL-6 = Interleukin IFN-α = Interferon alpha; KA = Kynurenic acid; KAT = kynurenine amino transferase; KMO = kynurenine 3 monooxygenase; 6; K-SADS-PL = Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version; KYN = L-kynurenine; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = Major Depressive Disorder; M-MDD = MDD with melancholic features; MEL = Melatonin; MCP-1 = Monocyte chemoattractant protein 1; PHQ = 9-item Public Health Questionnaire; QUIN = Metabolized to quinolinic acid; SCID = Structured Clinical Interview for DSM Disorders; sIL6R = Soluble IL-6 receptor; SIS = Suicide Intent Scale; SUAS = Suicide Assessment Scale; SOMS = Somatoform Symptoms; SSI = Somatic Symptom Index; sTNFR2 = Soluble tumor necrosis factor receptor 2; TPH-2 = Tryptophan hydroxylase 2; TRP = Catabolizes L-tryptophan.