Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Quinolinic Acid Responses during Interferon-α-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection - A Novel Aspect for Depression and Inflammatory Hypothesis

Abstract

Background

The aim of this exploratory study is to gain for the first time a more comprehensive picture of the impact of changes of quinolinic acid concentrations on depressive symptomatology during and after IFN-α therapy.

Methods

The quinolinic acid concentrations of 35 HCV patients are examined in a prospective survey over the entire period of IFN-α treatment as well as three months later at six different times (baseline, one, three, six and nine months after the beginning of IFN-α treatment, and after the end of treatment).

Results

During IFN-α treatment Hamilton Depression Rating Scale scores rise significantly. At the same time there is greater activity of indoleamine 2,3-dioxygenase, with a resulting increase in plasma kynurenine concentrations. Compared to baseline values quinolinic acid concentrations increase significantly during therapy, reflecting an increased neurotoxic challenge. In addition, patients with higher scores in the Hamilton Depression Rating Scale at six and nine months after starting therapy show significantly higher levels of quinolinic acid concentration.

Conclusions

The increase of quinolinic acid during IFN-α therapy might contribute to depressive symptomatology through the neurotoxic challenge caused by quinolinic acid. Subsequently, our exploratory study results support the inflammatory hypothesis of depression. The awareness of relevant risk factors of IFN-α treatment-induced depression is essential to develop preventative treatment strategies.

Citation: Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, Stauber R, Rothenhäusler H-B (2015) Quinolinic Acid Responses during Interferon-α-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection - A Novel Aspect for Depression and Inflammatory Hypothesis. PLoS ONE 10(9): e0137022. https://doi.org/10.1371/journal.pone.0137022

Editor: Gilles J. Guillemin, Macquarie University, AUSTRALIA

Received: May 19, 2015; Accepted: August 11, 2015; Published: September 14, 2015

Copyright: © 2015 Baranyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This study was supported by a grant from the Pfizer Corporation Austria. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: In addition, Pfizer Corporation Austria along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. has no competing interest to report. This commercial funder does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Abbreviations: 3-HK, 3-hydroxykynurenine; HAMD-17, Hamilton Rating Scale for Depression; HCV, hepatitis C virus; IDO, indoleamine 2,3-dioxygenase; IFN-α, interferon-α; NMDA, N-methyl-D-aspartate; RM-ANOVA, repeated measure design analysis of variance; SD, standard deviation

Introduction

According to a report by WHO, 3% of the world’s population is estimated to be infected with the hepatitis C virus (HCV), an RNA-virus. Particularly in Eastern European and non-industrialized countries a definite increase of patients with chronic hepatitis has been noted over the past few years. Drug addicts injecting intravenously and hemophiliac patients are particularly at risk of becoming infected with the hepatitis C virus [1–6]. 15% to 45% of the individuals who had contact with HCV are suspected to present spontaneous elimination of the virus. However, up to 55%-85% develop the chronic progressive form of the disease. Possible complications of a chronic hepatitis C infection are the progression to liver cirrhosis and the development of hepatocellular carcinoma [1,2].

Treatment of chronic forms of hepatitis C is based on a standard combination therapy of pegylated interferon-α (IFN-α) and ribavirin. Pegylated IFN-α is a pro-inflammatory cytokine and has strong anti-viral and anti-proliferation characteristics [7]. Ribavirin, an oral nucleoside analog, has broad activity against viral pathogens [8]. The treatment goal of chronic hepatitis C therapy is permanent viral eradication indicated by a sustained virological response. The effectiveness of the antiviral therapy has greatly improved in the last years, and the overall rate of sustained virological response is clearly above 50%. However, while treatment with interferon has shown to be successful, it is also often linked with obvious side effects. Often it is not so much the possible somatic side effects such as thyroid dysfunction, headache and anemia but frequent psychic side effects that impair the health-related quality of life of those affected. Many patients develop a IFN-α-induced depressive symptomatology that usually appears within three months after the start of IFN-α treatment [5,9–13].

Minor depressive episodes with increased introspection, low self-esteem, tearfulness, and loss of libido have been observed through detailed examination in 30% to 60% of all patients treated with IFN-α. 20 to 30% of patients treated with IFN-α even develop the full symptomatology of a major depression, with symptoms such as sadness, loss of energy, interest, and joy, anxiety, insomnia, lack of appetite, impaired concentration, suicidal ideation or suicide attempts. Generally patients affected by depressive symptomatology remit after IFN-α treatment has ended [1,5,14–16]. Adherence to the current standard combination is essential to achieve sustained virological response. The psychic side effects of IFN-α therapy in particular are very stressful and not infrequently lead to termination of the therapy [10, 17].

Biological pathways for an IFN- α-induced depressive symptomatology

  1. IFN-α increases the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that is responsible for the breakdown of tryptophan to kynurenine. This results in an increase of kynurenine and in reduced concentration of tryptophan that is available for serotonin synthesis [2, 3, 5, 18–20].
  2. Kynurenine crosses the blood-brain barrier and is broken down into the neurotoxic metabolites 3-hydroxykynurenines and quinolinic acid. Quinolinic acid has agonistic properties on the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a glutamate receptor, and overstimulation leads to neuronal damage. Animal experiments showed that the intrahippocampal injection of quinolinic acid is linked to a substantial loss of hippocampal neurons. This appears to be particularly important, as major depressive disorder might also be associated with hippocampal volume loss [21–23]. Kynurenic acid is synthesized by the enzyme kynurenine aminotransferase. It is a metabolite of kynurenine and an antagonist of the glutamate recognition site of the NMDA receptor. Thus kynurenic acid is neuroprotective and could prevent NMDA overstimulation. IDO increases the activity of the enzyme kynureninase and hinders the activity of kynurenine aminotransferase. IDO activity increases in the case of INF-α therapy. As a result the breakdown of kynurenine is steered in the direction of neurotoxic quinolinic acid, and the concentration of neuroprotective kynurenic acid decreases [21, 23, 24].

Aims of the study

This exploratory study is part of our research project on interferon-α-induced depressive symptomatology. The aim of this research project is to gain a more comprehensive picture of the kynurenine pathway in HCV patients before, during and after IFN-α therapy. A biopsychosocial model of interferon-α-induced depression was already developed in the first published study [5].

Our new study is the first prospective study to assess whether increased quinolinic acid concentrations during IFN-α therapy are linked to depressive symptomatology. Especially for this study our research group developed a new and validated simple liquid chromatography-tandem mass spectrometric method for the determination of quinolinic acid, which is described in detail elsewhere [25]. The quinolinic acid concentrations are measured at six different times before, during and after the end of IFN-α treatment.

Materials and Methods

Participants

The study design is partly described elsewhere [5] but is more extensively detailed here. All patients with chronic hepatitis C infection who had been selected for IFN-α therapy during the study period (February 2009–January 2012) by the hepatologist (R.S.) were asked to participate in this research project.

For this second study a subgroup of patients free of illegal drugs was set up, as the consumption of illegal drugs might influence quinolinic acids concentrations. Thus, the reasons for exclusion from enrolment were expanded in this study and included (1) other chronic liver disease, (2) significant co-morbid conditions (i.e. cardiovascular disease, cancer), (3) acute depression, (4) a diagnosis of neurological disease, and (5) current illegal drug or substance abuse, or participation in a federal drug substitution program. 35 patients were enrolled in this prospective study. All patients were treated in the outpatient clinic of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria and received pegylated IFN-α treatment (peginterferon-α 2a or peginterferon-α 2b) in combination with ribavirin. Both kinds of interferons have nearly the same efficacy, and bring about the same activation of the kynurenine pathway [14]. In this study 29 (82.9%) patients received IFN-α 2a, and 6 (17.1%) patients were treated with IFN-α 2b. Psychiatric and biological assessments were carried out at six different times: before, during (at one, three, six and nine months), and after the end of IFN-α treatment.

The study was approved by the Institutional Review Board of the University of Medicine of Graz, Austria. Data protection met the standards set by Austrian law. All participants in this study gave signed informed consent.

Biological Assessments

Blood was sampled from the fasting subjects between 0900 and 1000 at baseline, one, three, six and nine months after the beginning of the IFN-α therapy, and three months after the end of treatment for the assay of tryptophan, kynurenine and quinolinic acid.

For the research project tryptophan and kynurenine were measured in plasma samples by high-performance liquid chromatography (HPLC) with a simultaneous ultraviolet and fluorometric detection system [5, 26, 27]. In brief, 100 μL plasma sample was deproteinized by adding 100 μL of 5% (v/v) perchloric acid. After vortexing and 5 min centrifugation at 11,000 g, 20 μl of the clear supernatant was injected in the chromatographic system. Separations were achieved on a Chromolith RP18e column (100 x 4.6 mm, 5 μm, Merck Darmstadt, Germany) at 30°C by isocratic elution with a mobile phase (pH 4.9) consisted of 50 mmol/l ammonium acetate, 250 mol/L zinc acetate and 3% (v/v) acetonitrile, at a flow-rate of 0.8 ml/min. Kynurenine and tryptophan were detected on a La Chrom UV-Detector Merck HITACHI L-7400; at 235 nm. Capture and processing of the chromatograms are performed using Merck HITACHI LaChrom-D-7000 HPLC-System-Manager-Software (VWR International GmbH/Scientific Instruments, Darmstadt). The concentrations were determined as the peak measurement against external standards. The method is well established in the Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria, and validated according to international guidelines. All reagents were p.A. grade from Merck (Darmstadt, Germany). Coefficients of variation (CVs) at different concentrations within the same day were in the range of 1.7%-4.3% for kynurenine and 0.7%-2.9% for tryptophan. The CVs between different days were 2.0%-5.4%, 6.3%-9.3% and 8.4%-11.6% respectively.

We developed a new and validated liquid chromatography-tandem mass spectrometric method for the determination of quinolinic acid, which is described in detail elsewhere [25]. Quinolinic acid was measured in frozen EDTA plasma [25, 28]. Within-day coefficients of variation (CVs) and between-day CVs were all below 10%.

Psychiatric Assessments

As already shown in the first study [5], all consenting patients were interviewed before, during (at one, three, six and nine months after the beginning of the IFN-α treatment) and three months after the end of IFN-α therapy by experienced consultant-liaison psychiatrists (A.B., H.-B. R.). At every date of examination all participating patients were examined for the presence of depressive symptoms by using the psychometric observer-rated scale Hamilton Depression Rating Scale (HAMD-17; [29]).

  1. Sociodemographic, HCV Infection and Treatment Characteristics Questionnaire. Collected sociodemographic variables included age, gender, years of education and/or vocational training, and marital status at the time of psychiatric assessment. Marital status was categorized as single, married, or widowed.
    Clinical and treatment characteristics were: subtype of chronic HCV infection, presumed means of transmission, type of IFN-α, dosage of IFN-α, length of time of IFN-α treatment, concomitant pharmaceutical treatment (e.g. ribavirin), and success of treatment.
  2. Hamilton Depression Rating Scale (HAMD-17). The Hamilton Rating Scale for Depression (HAMD-17, Hamilton, 1967) consists of 17 items and is one of the most used instruments for the diagnosis of depressive symptomatology. A score of 18 points or more indicates severe depression, the range of 14–17 points indicates moderate depression, and the range of 10–13 points indicates mild depressive symptomatology [29].

Statistical Analyses

Descriptive statistics were produced based on demographic, treatment-related, biochemical and psychometric data and are presented as mean and standard deviation (SD). Repeated measure design ANOVA (RM-ANOVA) was used to check the effects of IFN-α on Hamilton Depression Rating Scale scores, indoleamine 2,3-dioxygenase (IDO) activity, kynurenine and quinolinic acid concentrations during and after treatment. Furthermore, we performed a bivariate Pearson product-moment correlation between Hamilton Depression Rating Scale scores and quinolinic acid concentrations. All statistic tests were two-tailed, with significance set at p<.05. Due to the exploratory character of this study the results were not α adjusted for multiplicity. All statistical analyses were performed with the R Project for Statistical Computing (R Development Core Team, 2011) and SPSS 20.0 for Windows (IBM-SPSS Statistics).

Results

Sociodemographic and Treatment Characteristics, Presumed Means of Transmission

All participating 35 HCV patients (14 [40%] women, 21 [60%] men) were Caucasian, and the mean age was 46.8 years (SD = 12.7).

In 17 (48.6%) patients the presumed means of transmission was unknown. 15 (42.9%) reported a history of transfusion or medical interventions as a source of HCV infection, and in 3 (8.6%) patients, previous intravenous drug abuse was the presumed means of transmission.

Table 1 summarizes the sociodemographic, clinical and treatment characteristics of the whole sample, including the type of hepatitis, the prescribed medication, the dosage of IFN-α, the duration of IFN-α therapy, and the frequency of treatment success for the examined drug-free subgroup.

thumbnail
Download:
Table 1. Sociodemographic and treatment characteristics.

https://doi.org/10.1371/journal.pone.0137022.t001

Depressive Symptomatology

In our first study [5] we were able to show that patients receiving IFN-α treatment suffer more often from depressive symptoms. This also applies to the drug-free patients of this examined subgroup. Thus while during IFN-α treatment the scores in the Hamilton Depression-Rating Scale increased significantly in the whole group of drug-free patients and after the end of IFN-α therapy, HAMD-17 total scores in all patients returned to values similar to the baseline measurements before IFN-α treatment (HAMD-17: RM-ANOVA[time]: F[5,134] = 10.45, p<0.001). In patients with IFN-α therapy depressed mood (HAMD-17) significantly increased during IFN-α treatment and returned to values similar to the baseline measurements after the end of treatment (RM-ANOVA [time]: F[5,134] = 7.921, p<0.001). Depressive symptomatology displayed during therapy but not before lasted from several weeks up to several months.

Table 2 presents the Hamilton Depression Rating Scale (HAMD-17) scores before, during and three months after IFN-α treatment for the examined drug-free subgroup.

thumbnail
Download:
Table 2. Presents the Hamilton Depression Rating Scale (HAMD-17) scores before, during and three months after IFN-α treatment for the examined drug-free subgroup.

Means and standard deviations of Hamilton Depression Rating Scale (HAMD-17) scores, indoleamine 2,3-dioxygenase (IDO) activity, kynurenine and quinolinic acid concentrations before, during and after IFN-α therapy.

https://doi.org/10.1371/journal.pone.0137022.t002

Indoleamine 2,3-dioxygenase (IDO) Activity

A significant increase in the kynurenine/tryptophan (KYN/TRYP) ratio reflecting IDO activity could also be observed in the examined subgroup of drug-free patients. Thus the kynurenine/tryptophan (KYN/TRYP) ratio increased significantly in all patients compared to baseline at all time points during IFN-α therapy, suggesting an increased catabolism of tryptophan to kynurenine (KYN/TRYP ratio: RM-ANOVA[time]: F[5,120] = 18.99, p<0.001). In addition, kynurenine concentrations increased significantly in all patients during IFN-α treatment compared to baseline (kynurenine: RM-ANOVA[time]: F[5,126] = 5.343, p<0.001).

Table 2 summarizes the indoleamine 2,3-dioxygenase (IDO) activity and kynurenine concentrations before, during and three months after IFN-α treatment for the examined drug-free subgroup.

Quinolinic Acid

Compared to baseline values, quinolinic acid concentrations increased significantly during IFN-α therapy, with peak concentrations six and nine months after the start of treatment. Three months after the end of IFN-α therapy quinolinic acid concentrations returned to values similar to baseline concentrations (quinolinic acid: RM-ANOVA[time]: F[5,128] = 3.48, p = 0.005). Furthermore, patients with higher scores in the HAMD-17 Depression Scale at six and nine months after starting therapy also showed significantly higher levels of quinolinic acid concentrations.

Table 2 shows the quinolinic acid concentrations before, during and three months after IFN-α treatment.

Table 3 presents the bivariate Pearson product-moment correlation coefficients between quinolinic acid concentrations and Hamilton Depression Rating Scale (HAMD-17) scores during and after IFN-α therapy.

thumbnail
Download:
Table 3. Bivariate Pearson product-moment correlation coefficients between quinolinic acid concentrations and Hamilton Depression Rating Scale (HAMD-17) scores before, during and after IFN-α therapy.

https://doi.org/10.1371/journal.pone.0137022.t003

Discussion

Depressive symptomatology is a frequent side effect of IFN-α therapy in patients with chronic hepatitis C infection. In the drug-free subgroup examined for this study the depression scores measured according to HAMD-17 during IFN-α therapy also increased significantly, and a return to baseline depression scores after the end of IFN-α therapy was observed. Previous studies have reported similar increases in depressive symptomatology during IFN-α therapy [1, 14–16]. IFN-α increases the activity of indoleamine 2,3 dioxygenase (IDO) [5]. As expected, the kynurenine/tryptophan ratio reflecting IFN-α-induced IDO activity increased significantly in the drug-free subgroup, suggesting an increased catabolism of tryptophan to kynurenine. This results in an increase of plasma-kynurenine and a decrease of plasma-tryptophan during IFN-α therapy. The actual quinolinic acid concentrations over the entire duration on the therapy and three months after were determined for the first time in this subsequent study, and the results of our study show an increased neurotoxic challenge in drug-free patients during IFN-α therapy. Thus in our study the quinolinic acid concentrations increased significantly during IFN-α therapy and returned to baseline concentrations after end of therapy. The peak values of quinolinic acid were reached six and nine months after the start of the IFN-α therapy. In addition, there was a significant positive correlation between quinolinic acid and the depression scores on the Hamilton Depression Rating Scale at both these times, indicating a higher risk of depressive symptomatology through the neurotoxic challenge caused by the increase of the quinolinic acid. These results are strong evidence, that higher concentrations of quinolinic acid might be essential for the evolution of quinolinic acid induced depressive symptoms. Wichers et al. [23] examined 16 patients undergoing interferon treatment. The total Montgomery-Åsberg Depression Rating Scale score assessed in this study was significantly associated over time with the kynurenine/kynurenic acid ratio. This ratio had been used earlier as an indirect estimation of increased neurotoxic challenge due to the synthesis of neurotoxic kynurenine metabolites. This increased neurotoxic challenge under IFN-α therapy was also confirmed by our research group [5]. Raison et al. [18] could prove in a cross-sectional assessment 12 weeks after the start of IFN-α therapy that patients with chronic HCV-infection had a higher concentration of quinolinic acid in their cerebrospinal fluid in comparison with untreated controls. Even in patients with acute depression not induced by IFN-α, many studies show a specific increase of monocyte-derived cytokines (Il-1, Il-6, TNF-α) and abnormalities of lymphocytes and natural killer cells in the peripheral blood. These neuroinflammatory responses also show up in specific regions of the brain through increased density of microglial cells, which represent the mononuclear phagocyte system of the brain [30,31]. Corresponding with these findings Steiner et al. [30] reported an upregulated production of quinolinic acid by microglia in specific brain regions like the subgenual anterior cingulate cortex and the anterior midcingulate cortex in postmortem brains of acutely depressed patients who had committed suicide. These results might support the immuno- and neurodegeneration hypotheses of depression [30,31]. Quinolinic acid can cause acute or chronic neuronal dysfunction through nine already known mechanisms. (a.) Quinolinic acid is an agonist of the N-methyl-D-aspartate (NMDA) receptor and activates the NMDA receptor in pathophysiological concentrations. The consequence is massive calcium entry into neurons. Neurons in the hippocampus, striatum and neocortex are especially sensitive to quinolinic acid, and these brain areas contain a particularly high number of NMDA receptors [32–35]. (b.) Quinolinic acid could cause disruption of the integrity of the blood-brain barrier [30]. (c.) Quinolinic acid can cause greater glutamate release by neurons and inhibits its reuptake by astrocytes. Excessive microenvironment glutamate concentrations cause neurotoxicity [36, 37]. (d.) A complex of quinolinic acid and iron transfers an electron to oxygen. Thus, reactive oxygen types are formed which mediate lipid peroxidation [38–43]. (e.) Quinolinic acid can potentiate the toxicity of other excitotoxins (e.g. glutamate, glycin and NMDA). The result is progressive mitochondrial dysfunction [44]. (f.) Quinolinic acid may impair autophagy [45]. (g.) Quinolinic acid may lead to cytoskeleton destabilization, causing intermediate filament hyperphosphorylation [46–48]. h.) Quinolinic acid is involved in the dysregulation of astroglial function and gliotoxicity [49, 50]. In addition Guillemin et al. [45] showed that quinolinic acid selectively induces apoptosis of human astrocytes. Astrocytes are known to produce neuroprotective kynurenic acid. As a consequence the apoptosis of astrocytes might lead to lower neuroprotective action against neurotoxic quinolinic acid [51, 52]. (i.) Finally, the neuronal nitric oxide synthase and the inducible nitric oxide synthase may be induced by quinolinic acid. As a consequence, free radical production and oxidative stress are the result of quinolinic acid-induced NOS activity in astrocytes [45, 51].

The Biopsychosocial Factor

There is growing evidence that the etiology of IFN-α induced depression is multifactorial in nature. Quinolinic acid might contribute as one biological key factor to depressive symptoms in patients during IFN-α therapy. In the simultaneously presence of additionally known biopsychosocial factors (e.g. tryptophan availability, gender, preexisting psychiatric vulnerability, means of transmission, low financial security, impaired sexual satisfaction, small circle of friends, impaired physical role, body pain, low general health and vitality, reduced social functioning, impaired mental health and impaired emotional role) depressive symptoms may aggravate to clinical significance or even a depressive episode may become manifest [5]. Thus the impact of quinolinic acid should always be seen in a biopsychosocial context.

Limitations

The indolamine 2,3- dioxygenase (IDO) activity in the human blood can only be described in an indirect way regarding the trytpophan to kynurenin ratio. The expression of IDO is differently inducible in various cell types, including fibroblasts, monocytes, macrophages, and dendritic cells by the pro-inflammatory cytokine interferon-γ. For an exact determination of IDO activity it would be necessary to individually isolate IDO from these various cell types. In the scientific literature, the trytpophan to kynurenin ratio is considered to be a suitable biomarker for IDO activity [3, 23, 53].

During therapy there is an increase of quinolinic acid and of HAMD-17 depression values. This concurrent increase therefore allows for an assertion of an associative correlation. However, theoretical considerations allow for the hypothesis that quinolinic acid increases the risk of depressive symptomatology through its neurotoxic potency. This possible causal link must be clearly established in further confirmatory studies. More studies are required to determine any set patterns. Furthermore, knowledge about the complex interactions of kynurenine pathway, IFN-α treatment and depressive symptomatology is still limited and requires ongoing research.

Conclusions

The increase of quinolinic acid during IFN-α therapy might contribute to depressive symptomatology through the neurotoxic challenge caused by quinolinic acid. Subsequently, our exploratory study results support the inflammatory hypothesis of depression. The awareness of relevant risk factors of IFN-α treatment-induced depression is essential to developing preventative treatment strategies.

Acknowledgments

Department and Institution where this study was carried out: Department of Psychiatry, Medical University of Graz, Auenbruggerplatz 31, 8036 Graz, Austria

Amended Role of Funder statement

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In addition, Pfizer Corporation Austria along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. has no competing interest to report. This commercial funder does not alter our adherence to PLOS ONE policies on sharing data and materials.

Author Contributions

Conceived and designed the experiments: AB AM RJB OAG RS HBR. Performed the experiments: AB AM RJB RS HBR. Analyzed the data: AB AM RJB OAG RS HBR. Contributed reagents/materials/analysis tools: AB AM RJB OAG RS HBR. Wrote the paper: AB AM RJB OAG RS HBR.

References

  1. 1. Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry. 2003; 160: 1342–1345. pmid:12832253
  2. 2. Bonaccorso S, Marino V, Biondi M, Grimaldi F, Ippoliti F, Maes M. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord. 2002a; 72: 237–241.
  3. 3. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-α based immunotherapy are related to interferon-α induced changes in the serotonergic system. J Clin Psychopharmacol. 2002b; 22: 86–90.
  4. 4. Dinwiddie SH, Shicker L, Newman T. Prevalence of hepatitis C among psychiatric patients in the public sector. Am J Psychiatry. 2003; 160: 172–174. pmid:12505819
  5. 5. Baranyi A, Meinitzer A, Stepan A, Putz-Bankuti C, Breitenecker RJ, Stauber R, et al. A biopsychosocial model of interferon-alpha-induced depression in patients with chronic hepatitis C infection. Psychother Psychosom. 2013; 82: 332–340. pmid:23942342
  6. 6. Poutiainen E., Hokkanen L., Niemi M.L., Färkkilä M. Reversible cognitive decline during high-dose alpha-interferon treatment. Pharmacol Biochem. Behav 1994; 47: 901–905. pmid:8029260
  7. 7. Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, et al. Hepatitis C infection, antiviral treatment and mental health: A European expert consensus statement. J Hepatol. 2012; 57: 1379–1390. pmid:22878466
  8. 8. Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 2002; 35: 1002–1009. pmid:11981750
  9. 9. Eccles J, Lallemant C, Mushtaq F, Greenwood M, Keller M, Golding B, et al. Pre-treatment waking cortisol response and vulnerability to interferon α induced depression. Eur Neuropsychopharmacol. 2012; 22: 892–896. pmid:22571879
  10. 10. Leutscher PD, Lagging M, Buhl MR, Pedersen C, Norkrans G, Langeland N, et al. Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C. Hepatology. 2010; 52: 430–435. pmid:20683942
  11. 11. Hauser W, Zimmer C, Schiedermaier P, Grandt D. Biopsychosocial predictors of health-related quality of life in patients with chronic hepatitis C. Psychosom Med. 2004; 66: 954–958. pmid:15564364
  12. 12. Udina M, Castellvi P, Moreno-Espana J, Navinés R, Valdés M, Forns X, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012; 73: 1128–1138. pmid:22967776
  13. 13. Russo S, Kema IP, Fokkema MR, Boon JC, Willemse PH, de Vries EG, et al. Tryptophan as a link between psychopathology and somatic states. Psychosom Med. 2003; 65: 665–671. pmid:12883120
  14. 14. Malaguarnera M, Laurino A, Di Fazio I, Pistone G, Castorina M, Guccione N, et al. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C J Interferon Cytokine Res. 2001; 21: 273–278. pmid:11429157
  15. 15. Miyaoka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K. Depression from interferon therapy in patients with hepatitis C. Am J Psychiatry. 1999; 156: 1120.
  16. 16. Dieperink E, Willenbring M, Ho S.B. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry. 2000; 157: 867–876. pmid:10831463
  17. 17. Fontana RJ, Moyer CA, Sonnad S, Lok ASF, Sneed-Pee N, Walsh J, et al. Comorbidities and quality of life in patients with interferon-refractory chronic hepatitis C. Am J Gastroenterol. 2001; 96: 170–178. pmid:11197249
  18. 18. Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, et al. Depression during pegylated interferon alpha plus ribavirin therapy: Prevalence and prediction. J Clin Psychiatry. 2005; 66: 41–48. pmid:15669887
  19. 19. Neumeister A, Yuan P, Young TA, Bonne O, Luckenbaugh DA, Charney DS, et al. Effects of tryptophan depletion on serum levels of brain-derived neurotrophic factor in unmedicated patients with remitted depression and healthy subjects. Am J Psychiatry. 2005; 162: 805–807. pmid:15800160
  20. 20. Turner EH, Blackwell AD. 5-Hydroxytryptophan plus SSRI for interferon-induced depression: Synergistic mechanisms for normalizing synaptic serotonin. Medical Hypotheses. 2005; 65: 138–144. pmid:15893130
  21. 21. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002; 5: 375–388. pmid:12466036
  22. 22. Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci. 2004; 19: 11–17.
  23. 23. Wichers MC, Koeck GH, Robaeys G, Verkerk R, Scharpé S, Maes M. IDO and interferon-alpha-induced depressive symptoms: A shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005; 10: 538–544. pmid:15494706
  24. 24. Guillemin GJ, Wang L, Brew BJ. Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J Neuroinflammation. 2005; 2: 6.
  25. 25. Meinitzer A, Tomaschitz A, Pilz S, Truber M, Zechner G, Gaksch M, Prietl B, Treiber G, Schwarz M, Baranyi A. Development of a liquid chromatography-mass spectrometry method for the determination of the neurotoxic quinolinic acid in human serum. Clin Chim Acta. 2014; 436C: 268–272.
  26. 26. Hervé C, Beyne P, Jamault H, Delacoux E. Determination of tryptophan and its kynurenine pathway metabolites in human serum by high-performance liquid chromatography with simultaneous ultraviolet and fluorometric detection. J Chromatogr B Biomed Appl. 1996; 675: 157–161. pmid:8634758
  27. 27. Xiao LD, Luo XB, Pi LG, Tang AG. Simultaneous determination of kynurenin and kynurenic acid concentrations in human serum by HPLC with dual wavelengths. Clin Chim Acta. 2008; 395: 178–180. pmid:18534192
  28. 28. Möller M, Du Preezb JL, Harveya BH. Development and validation of a single analytical method for the determination. of tryptophan, and its kynurenine metabolites in rat plasma. J Chromat B. 2012; 898: 121–129.
  29. 29. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967; 6: 78–296.
  30. 30. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation. 2011; 8: 94. pmid:21831269
  31. 31. Steiner J., Bogerts B., Sarnyai Z., Walter M., Gos T., Bernstein H.G., Myint A.M. Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World J Biol Psychiatry. 2012.; 13: 482–492. pmid:21707463
  32. 32. Vandresen-Filho S, Martins WC, Bertoldo DB, Mancini G, De Bem AF, Tasca CI. Cerebral cortex, hippocampus, striatum and cerebellum show differential susceptibility to quinolinic acid-induced oxidative stress. Neurol Sci. 2015; Epub ahead of print.
  33. 33. Prado de Carvalho L, Bochet P, Rossir J. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neuroche Int. 1996; 28: 445–452.
  34. 34. Perkins MN, Stone TW. Pharmacology and regional variations of quinolinic acid-evoked excitations in the rat central nervous system. J Pharmacol Exp Ther. 1983; 226: 551–557. pmid:6308211
  35. 35. Schwarcz R, Köhler C. Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett. 1983; 38: 85–90. pmid:6225037
  36. 36. Busse M, Busse S, Myint AM, Gos T, Dobrowolny H, Müller UJ, et al. Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur Arch Psychiatry Clin Neurosci. 2014; Epub ahead of print.
  37. 37. Tavares RG, Tasca CI, Santos CE, Alves LB, Porciúncula LO, Emanuelli T, Souza DO. Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int. 2002; 40: 621–627. pmid:11900857
  38. 38. Elinos-Calderón D, Robledo-Arratia Y, Pérez-De La Cruz V, Maldonado PD, Galván-Arzate S, Pedraza-Chaverrí J, Santamaría A. Antioxidant strategy to rescue synaptosomes from oxidative damage and energy failure in neurotoxic models in rats: protective role of S-allylcysteine. J Neural Transm. 2010; 117(1): 35–44. pmid:19866339
  39. 39. Behan WM, McDonald M, Darlington LG, Stone TW. Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol. 1999; 128: 1754–1760. pmid:10588931
  40. 40. Behan WM, Stone TW. Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists. Br J Pharmacol. 2002; 135: 1435–1442. pmid:11906956
  41. 41. Braidy N, Grant R, Adams S, Guillemin GJ. Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons. FEBS J. 2010; 277: 368–382. pmid:20015232
  42. 42. Santamaría A, Galván-Arzate S, Lisý V, Rodríguez-Martínez E, Flores A, Galván-Arzate S. Quinolinic acid induces oxidative stress in rat brain synaptosomes. Neuroreport. 2001a; 12: 871–874.
  43. 43. Santamaría A, Jiménez-Capdeville ME, Camacho A, Rodríguez-Martínez E, Flores A, Galván-Arzate S. In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum. Neuroreport. 2001b; 12: 2693–2696.
  44. 44. Schurr A, Rigor BM. Quinolinate potentiates the neurotoxicity of excitatory amino acids in hypoxic neuronal tissue in vitro. Brain Res. 1993; 617: 76–80. pmid:8397046
  45. 45. Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J.; 2012;79:1356–1365.
  46. 46. Pierozan P, Gonçalves Fernandes C, Ferreira F, Pessoa-Pureur R. Acute intrastriatal injection of quinolinic acid provokes long-lasting misregulation of the cytoskeleton in the striatum, cerebral cortex and hippocampus of young rats. Brain Res. 2014; 19; 1577:1–10. pmid:24976581
  47. 47. Pierozan P, Zamoner A, Soska AK, Silvestrin RB, Loureiro SO, Heimfarth L, et al. Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Exp Neurol. 2010; 224: 188–196. pmid:20303347
  48. 48. Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One. 2009; 4: e6344. pmid:19623258
  49. 49. Sundaram G, Brew BJ, Jones SP, Adams S, Lim CK, Guillemin GJ. Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. J. Neuroinflammation. 2014; Epub ahead of print
  50. 50. Lee MC, Ting KK, Adams S, Brew BJ, Chung R, Guillemin GJ. Characterisation of the expression of NMDA receptors in human astrocytes. PLoS One. 2010; 5: e14123. pmid:21152063
  51. 51. Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ. 2009. Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res. 2010; 16: 77–86. pmid:19526301
  52. 52. Myint AM, Schwarz MJ, Steinbusch HW, Leonard BE. Neuropsychiatric disorders related to interferon and interleukins treatment. Metab Brain Dis. 2009; 24: 55–68. pmid:19067144
  53. 53. Mancuso R, Hernis A, Agostini S, Rovaris M, Caputo D, Fuchs D, Clerici M. Indoleamine 2,3 Dioxygenase (IDO) Expression and Activity in Relapsing- Remitting Multiple Sclerosis. PLoS One. 2015; 10(6):e0130715. pmid:26110930