IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

Abstract

Studies show that administration of interferon (IFN)-α causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-α-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-α treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-α treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-α-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.

Main

Administration of interferon (IFN)-α, a proinflammatory cytokine, is used in the treatment of cancer and hepatitis C (HCV), because of its strong immunomodulatory and antiviral effects. Neuropsychiatric side effects are common during IFN-α treatment. Recent clinical studies have shown that approximately 16–45% of patients treated with IFN-α developed depressive symptoms during the course of therapy.1, 2, 3, 4 Biological mechanisms underlying these IFN-α-induced depressive side effects are still not clear.

Depressive disorders have been linked to a dysregulated serotonin (5-HT) system.5, 6, 7 5-HT is synthesized within the brain from the essential amino acid tryptophan (TRP). Other amino acids, notably tyrosine, valine, phenylalanine, leucine and isoleucine, affect 5-HT precursor availability by competing with TRP for transport across the blood–brain barrier (BBB) and are also referred to as competing amino acids (CAA). Therefore, decreased TRP availability in relation to CAA reduces biosynthesis of 5-HT, which may cause a depressive relapse in subjects susceptible to mood disorders.8, 9, 10

Depression has also been linked with markers of increased immune activation. Increased number of blood leukocytes, increased serum levels of several indicators of activated immune cells, including neopterin, prostaglandin E2, increased concentrations of complement proteins, positive acute phase proteins (APPs) and proinflammatory cytokines and decreased concentrations of negative APPs were found in depressed patients.11, 12, 13, 14 The enzyme indoleamine 2,3-dioxygenase (IDO) constitutes a link between the 5-HT system and immune activation.15 This enzyme is located in nonhepatic organs throughout the body and is also present in monocytes, macrophages and microglial cells within the brain parenchyma.16 IDO activity is mainly induced by the proinflammatory cytokine IFN-γ and converts TRP into kynurenine (KYN), which, in the case of overstimulation, may lead to lowered TRP concentrations.15, 17

KYN is further metabolized into a series of compounds (see Figure 1), some with neurotoxic properties. 3-Hydroxykynurenine (3-OH-KYN) leads to the production of reactive oxygen species that initiate neuronal apoptosis.18, 19 Quinolinic acid (QUIN) is a potent N-methyl-D-aspartate (NMDA) receptor agonist.20, 21, 22 Overstimulation of NMDA receptors leads to neuronal damage.23 Neurotoxicity of KYN and its metabolites has been demonstrated in animal studies19, 20, 24 and studies using human cell cultures.25, 26 KYN is able to pass the BBB27 and human microglia have been shown capable of metabolizing this substance into its toxic metabolites.28 In addition, peripherally immune-induced IDO activation has been shown to increase QUIN in both plasma and CSF with a highly significant correlation between the two measurements.29 This supports the hypothesis that peripherally induced IDO activation is able to cause a neurotoxic challenge.

Figure 1
figure1

Modulation of tryptophan metabolism and induction of the KYN pathway by IDO.

In humans, increased concentrations of toxic KYN metabolites are seen in several neurodegenerative diseases, such as Huntington's disease,30, 31 Parkinson's disease and AIDS–dementia complex, as well as in depression.32 In addition, depression is associated with diffuse cortical and subcortical atrophy. Studies reported changes in the hippocampus,33, 34 striatum35, 36 and the prefrontal cortex.37, 38

IDO-induced neurotoxicity may be reduced by kynurenic acid (KA), another metabolite of KYN, which is known as an antagonist of the glutamate recognition site of the NMDA receptor and thus reduces NMDA overstimulation.39 However, the activity of the KA synthesizing enzyme, KYN aminotransferase (KAT), does not seem able to compete with the direct pathway to QUIN when in competition for the transformation of KYN into its metabolites.40 Furthermore, Saito et al29 found that immune stimulation in gerbils, which increased IDO activity, was also associated with increased activity of the enzyme kynureninase in the brain and lung tissue, and with increased activity of KYN-3-hydroxylase in the lung tissue (see Figure 1). In contrast, it was associated with decreased activity of KAT in the liver, while no changed KAT activity was observed in the brain and lung tissue. Therefore, immune-induced IDO activity may alter the ratio of the toxic quinolinic acid to the protective KA and may thus change the neurotoxic balance.

Since IFN-α treatment enhances immune activation, we hypothesized that IDO activity during treatment increases and that it may play a role in the pathophysiology of IFN-α-induced depressive symptoms (1) by decreasing the TRP/CAA ratio or (2) by induction of the KYN pathway that increases the neurotoxic challenge in the brain.

Materials and methods

Subjects

Twenty one patients with chronic HCV infection, aged 25–57 years and eligible for IFN-α treatment, were recruited. Chronic HCV was defined as: antibodies to HCV positive, HCV-RNA positive and elevated transaminases at least once in the previous 6 months.

Patients had a complete medical history, physical examination and laboratory blood check before study entry. In addition, an ultrasound of the upper abdomen, an ECG, and a pregnancy test (in women of childbearing potential) was carried out. A liver biopsy was performed in most patients.

Excluded were patients currently meeting criteria of axis I psychiatric disorders as defined by DSM-IV or patients currently on antidepressant medication. In addition, patients who had coinfections with hepatitis B virus or human immunodeficiency virus, or patients with a diagnosis of neurological, cardiovascular, endocrine, hematological, signs of cirrhosis, hepatic or renal disease or patients with insufficient knowledge of the Dutch language, were excluded. Patients were recruited from the Academic Hospital Maastricht (AZM) in The Netherlands and from the Ziekenhuis Oost Limburg (ZOL) in Belgium. All patients received IFN-α treatment and ribavirin, both administered in a weight-dependent manner. One patient received IFN-α 2b (Intron A), 3 × 3 MU weekly throughout the study period. Nine patients received Intron A the first 12 days of treatment (10 MU daily in the first 6 days and 5 MU daily after the 6th day). Hereafter, they received a weekly injection of 80–180 μg of PEG IFN-α 2a. Six patients directly started with weekly injections of 80–180 μg of PEG IFN-α 2a. In all patients, ribavirin was administered orally, 1000–1200 mg/day.

The study was approved by the standing Medical Ethics Committee of Maastricht University, and carried out in accordance with the Declaration of Helsinki (Hong Kong Modification, 1989). Written informed consent was obtained from each subject prior to participation.

Biological and psychiatric assessments

Biological and psychiatric assessments were carried out at seven different time points during IFN-α treatment, that is, before and 1, 2, 4, 8, 12 and 24 weeks after starting treatment. In all subjects fasting blood was sampled between 0800 and 0900 for the assay of serum TRP, CAA, KYN and KA. Blood samples were centrifuged at 1500 × g for 10 min at 4°C. Serum was then stored at −20°C until assayed. Total TRP, CAA, KYN and KA were assayed by means of a high-performance liquid chromatography method as explained previously.41 The intra- and interassay CV values obtained in our laboratory were less than 5 and 7%, respectively. TRP, CAA and KYN are expressed as μmol/l and KA as nmol/l. The KYN to TRP quotient was computed, since this ratio allows to estimate IDO activity.42 In addition, the TRP to CAA quotient was computed to estimate the TRP availability to the brain and the KYN to KA quotient was computed to estimate the neurotoxic challenge in the brain.

The presence of depressive symptoms was assessed by the 17-item Hamilton Depression Rating Scale (HAM-D)43 and the Montgomery Asberg Depression Rating Scale (MADRS).44

Statistical analysis

The data were analyzed with the STATA computer program, version 7 (STATA, 2001). Since the two depression rating scales were highly correlated (r=0.72), only results of the MADRS are shown. The MADRS was chosen as the main outcome because it has been used frequently to assess IFN-α-induced depressive symptoms and therefore allows comparison with earlier studies in which this scale was used.

As repeated measurements within the same person were used, the observations cannot be considered independent statistically. Therefore, multilevel random regression models were fitted, using the XTREG procedure in STATA (Statacorp, 2001). This takes into account the fact that level-one units (level of individual observations) were clustered into level-two units (levels of the subjects). Effect sizes of explanatory variables were expressed as regression coefficients (β) from the multilevel models. All analyses were corrected for the following a priori hypothesized confounders: age, sex, smoking, hospital center, benzodiazepine medication, use of marijuana during the study and mode of acquisition of infection. If necessary, variables were ln-transformed in order to improve normality. First, an analysis was performed with time as a dummy variable to assess the effect of individual time points compared with baseline on the total MADRS score. The same analysis was carried out for the ratio KYN/TRP, reflecting IDO activity, in order to see if IDO activity is increased during IFN-α treatment, the ratio TRP/CAA in order to examine if TRP availability to the brain declines and also for the ratio KYN/KA in order to examine if the balance between neurotoxic and neuroprotective metabolites, and thus the neurotoxic challenge, increases during IFN-α treatment. Then, total MADRS score was regressed on the TRP/CAA ratio and KYN/KA ratio in order to examine their relationships with depressive symptoms.

Results

Subject characteristics

In total, 21 patients were included in the study. Four patients dropped out during the study period due to problems unrelated to psychiatric side effects. In addition, one patient was left out of the analyses because of insufficient data. The final study sample consisted of 16 patients, 12 men and four women. Their mean age was 42±7.7 years. In seven of 16 patients, a temporary dose reduction or discontinuation of treatment was necessary due to severe side effects. No patients received antidepressant medication during the study period. A total of 11 patients (68%) reported lifetime drug dependence—these were patients who had acquired the virus by intravenous drug use. Seven of the 16 patients (44%) received low-dosage benzodiazepines during the study and seven out of 16 patients were using some form of drugs: five were regular users of marijuana. Of these five individuals, one used heroin on a regular basis and two individuals were on methadone substitution. Their drug habit was stable throughout the study period.

Depressive symptoms, IDO activity, TRP availability and neurotoxic challenge during IFN-α treatment

Out of 16 patients, five (31%) fulfilled the criteria for Major Depressive Disorder (MDD) at least once during treatment. These five showed no significant difference in baseline MADRS score compared to those who did not develop MDD. Total MADRS score was significantly increased during IFN-α treatment compared to baseline, at all time points (see Table 1, Figure 2). Table 2 shows the means and standard deviations of the measured biological variables during treatment at all time points. In order to improve normality the KYN/TRP ratio, reflecting IDO activity, was ln-transformed. The KYN/TRP ratio was significantly increased compared to baseline at all time points measured during IFN-α treatment. The TRP/CAA ratio was not decreased at any time point after starting treatment compared to baseline. The TRP/CAA ratio showed a nonsignificant increase during treatment. Post hoc analyses showed that both TRP (β=−1.22, P=0.006) and CAA concentrations (β=−20.2, P=0.000) showed a significant decline during IFN-α treatment. The increase in the KYN/KA ratio, indicating higher neurotoxic challenge, was significant compared to baseline for all time points, except for week 2.

Table 1 Multilevel regression analyses indicating differences on each dimension for each time point compared to baseline, with ‘β’ indicating the regression coefficient and ‘P’ the level of significance
Figure 2
figure2

Changes in the MADRS score, the KYN/TRP ratio, the TRP/CAA ratio and the KYN/KA ratio during IFN-α treatment.

Table 2 Means and standard deviations of TRP, CAA, KYN and KA for each time point

TRP availability, neurotoxic challenge and their relationships with the MADRS score

The ratio TRP/CAA was not significantly associated over time with the total MADRS score (β=84.6, P=0.2), whereas post hoc analyses showed that TRP concentrations were associated over time with the total MADRS score (β=0.16, P=0.03). In contrast to the TRP/CAA ratio, the KYN/KA ratio was significantly associated over time with the total MADRS score (β=245.6, P<0.000). Post hoc regression analyses were performed that regressed individual MADRS item scores on the KYN/KA ratio (see Table 3). Relationships with the KYN/KA ratio were significant for the items reflecting observed sadness, tension/irritability, sleep problems, reduced appetite, decreased concentration, decreased energy and decreased interest in social activities. The association of depressive symptoms with KYN concentrations was not significant in post hoc analyses (β=0.5, P=0.7).

Table 3 Associations between individual MADRS items and KYN/KA ratio over all time points during IFN-α treatment

No significant effects of treatment or marijuana use on TRP metabolism were observed during treatment, except that marijuana users exhibited increased KA concentrations. However, the KYN/KA ratio was not significantly different.

Discussion

IFN-α administration significantly increased the KYN/TRP ratio reflecting IDO activity. Although TRP concentrations declined during treatment, the TRP/CAA ratio, reflecting the TRP availability to the brain, did not decrease over time and was not associated with the MADRS score. However, IFN-α treatment induced a shift in the neurotoxic/neuroprotective balance towards a higher KYN/KA ratio, resulting in a greater neurotoxic challenge. Furthermore, the KYN/KA ratio was significantly associated over time with higher MADRS scores. Relating depressive symptoms with KYN concentrations alone did not result in a significant association, showing that it may be the balance between neurotoxic and neuroprotective substances that is important in determining depressive outcome.

Few studies have been performed examining the relationship between the severity of depression and the amount of KYN metabolites. As early as 1974, Mangoni noted a positive correlation between depression scores and the amount of xanthurenic acid, which is metabolized from 3-OH-KYN, in the urine of depressed patients.32 Recently, Maes et al45 showed that pregnant women who responded to delivery with a high increase in anxiety or depression in the early puerperium showed higher plasma KYN concentrations 3 days after delivery than nonresponders.

The finding of the relationship between the neurotoxic/neuroprotective balance and depressive symptoms fits well with the neurodegeneration hypothesis of depression as proposed by Myint and Kim,46 who hypothesized a model that recognizes the diversity of individual biological risk factors, and integrated them into a framework to explain the development of depression. Inability to maintain the balance between pro- and antiinflammatory cytokines or to compensate for stress-induced changes in neuroendocrine and 5-HT metabolism may result in higher HPA activity and increased IDO activity, which both may augment neurodegeneration.46 Reduced gray matter volume in the hippocampus47, 48 and increased neuronal and glial cell packing has been reported, suggesting a decrease in the hippocampal neurophil.49 In addition, studies show loss of prefrontal cortical glia and neurons in patients with mood disorders.37, 38 Although glucocorticoids have been proposed as possible candidates mediating these effects,50 IDO-induced neurotoxicity may represent an additional mechanism by which atrophy is produced. According to the neurodegeneration hypothesis,46 failure to compensate for the neurotoxic effects by increasing concentrations of antiinflammatory cytokines, altering 5-HT function and increasing neuroprotective substances such as KA may result in depression.46

Results of this study support a role for IDO in the pathophysiology of depression through its modulation of the KYN pathway and not through its effect on TRP availability to the brain. This study as well as previous studies have shown that TRP concentrations decrease during IFN-α treatment and are correlated with depressive symptoms.4, 51, 52 Also, results of this study agree with the findings of Capuron et al52 concerning changes in KYN and the KYN/TRP ratio, reflecting IDO activity. However, no decrease in TRP/CAA ratio was found and correlations with depressive symptoms did not reach significance for the TRP/CAA ratio. Although Bonaccorso et al4 also reported no significant change in the TRP/CAA ratio, these results contrast with those found by Capuron et al,51 who did describe a decrease and a significant correlation between the TRP/CAA ratio and depressive symptoms. However, also in this study, a stronger relationship was found between pure TRP concentrations and depressive symptoms. In the absence of any changes in CAA as reported by Capuron et al,51 it is to be expected that pure TRP concentrations will show strong correlations with the TRP/CAA ratio. This could explain why the association between the TRP/CAA ratio and depressive symptoms is in contrast to our finding where changes in CAA alongside TRP changes were found.

An association of TRP concentrations with depressive symptoms may exist because TRP availability to the brain might also be dependent on total and free TRP concentrations aside from the ratio TRP/CAA.53, 54 Therefore, decreased TRP concentrations may have an additional negative effect on mood. Nonetheless, the association between depressive symptoms and TRP concentrations was less significant than that with the ratio reflecting the neurotoxic challenge. On the other hand, associations between TRP concentrations and depressive symptoms may also arise because decreased TRP concentrations could reflect TRP catabolism through IDO activity and therefore represent the increase in neurotoxic KYN metabolites.

There are a number of limitations. In the present study, the neurotoxic challenge was measured indirectly by assuming that, due to the inability of KA to compete with QA when in competition for the transformation of KYN into its metabolites,40 KYN concentration reflects more the neurotoxic than the neuroprotective metabolites. For a more direct approach, future studies should measure concentrations of 3-OH-KYN and QA directly, as well as the activity of the KATs, the enzymes that metabolize KYN into KA.

Second, no clear conclusions can be drawn concerning the effect of treatment differences in IFN-α therapy and marijuana use on TRP metabolism and neurotoxicity, because of the small group size. Also, no study has been performed that examines the effect of ribavirin on TRP metabolism. However, it is known that ribavirin induces a shift from Th2- to Th1-mediated immune response. Therefore, ribavirin may contribute to the activation of IDO and subsequent depressive symptoms. Further studies should examine the effects of treatment and drug use on neurotoxicity and depressive symptoms.

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Acknowledgements

We thank Jim van Os for his critical remarks on this paper.

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Correspondence to M C Wichers.

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Wichers, M., Koek, G., Robaeys, G. et al. IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10, 538–544 (2005). https://doi.org/10.1038/sj.mp.4001600

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Keywords

  • interferon-α
  • depressive symptoms
  • kynurenine pathway
  • neurotoxicity
  • quinolinic acid
  • kynurenic acid

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