Serotonin and its implication in the side-effects of interferon-based treatment of patients with chronic viral hepatitis: Pharmacological interventions

Authors


  • Conflict of interest: The authors have no conflicts of interest to disclose.

Abstract

Depression is a frequent side-effect of interferon-based treatment of patients with chronic viral hepatitis, that may lead to reduction or discontinuation of treatment. Clinical trials data showed the importance of therapy of psychiatric disorders for a successful antiviral treatment. Emerging evidence suggests that interferon may cause depression affecting serotonin synthesis via increased activity of indoleamine 2,3-dioxygenase. Serotonin reuptake inhibitors significantly improve mood disorders, but the use of these drugs requires caution because some studies reported the emergence of mania in patients treated for depression during antiviral therapy. Therefore, this review will examine and discuss the putative role of serotonin and its metabolism in the development of depression during antiviral therapy, focusing on pharmacological interventions to reduce side-effects.

Introduction

Psychiatric symptoms are common in patients with chronic viral hepatitis.[1] A recent study assessing the psychometric properties of the Patient Health Questionnaire as a screening instrument for depression and anxiety in patients with chronic hepatitis C virus (HCV) showed that 23% of patients had psychiatric disorders, particularly major depressive disorders (6.4%), generalized anxiety disorders (7.0%) and panic disorders (5.8%).[2] Similarly, in a group of 75 HCV patients assessed using the Mini International Neuropsychiatric Interview (M.I.N.I. – Plus version), 28% showed a major depressive disorder, 12% specific phobia, 10.7% generalized anxiety disorders, 6.7% mixed anxiety disorders and 6.7% attention deficit hyperactivity disorders.[3]

The development of neuropsychiatric disorders in a relatively high percentage of HCV patients has led to the hypothesis that HCV infection and replication may occur in the brain.[4-6] Two studies have shown that viral quasispecies closely related to those found in the lymphoid system may be present in the brain of HCV patients.[7, 8] This has led to the suggestion that HCV-infected leukocytes may transport viral particles into the central nervous system (CNS).[9] However, it remains to be demonstrated that the presence of HCV in brain tissue may influence CNS function.

Hepatitis C (HCV) and hepatitis B virus (HBV) positive patients often require treatment with interferon (IFN)-α.[10, 11] Premature discontinuation of IFN and ribavirin treatment in HCV patients because of the development of neuropsychiatric symptom is common, particularly in older patients.[12]

The development of psychiatric disorders in HCV patients undergoing treatment often requires consultation with a psychologist/psychiatrist to identify previous anxiety and depressive disorders[13] or risk factors predisposing to these symptoms in order to plan a preventive follow up and/or a psychiatric treatment during antiviral therapy.

The mechanisms leading to the development of IFN-induced psychiatric symptoms are still partially unknown. Some authors speculate that pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) released into the bloodstream by the inflamed liver may interfere with the function of the neuroendocrine system,[14-16] mainly in the hypothalamic–pituitary–adrenal axis, and central adrenergic and serotonergic neurons. This last effect has been suggested to be related to alterations in tryptophan (TRP) and serotonin metabolism.[17] Loftis et al.[18] compared plasma cytokine levels (IL-1b, IL-10 and TNF-α) and Beck Depression Inventory-II of 23 adults with and without HCV. Patients with HCV showed higher TNF-α-values compared to patients without HCV, but in patients with HCV, TNF-α and IL-1b levels were correlated with Beck Depression Inventory-II scores, stressing an association between severity of depressive symptoms and levels of pro-inflammatory cytokines. The changes in cytokine levels appear to decrease serotonin (5-HT) neurotransmission that may be involved in depression induced by IFN therapy. In fact, it has been shown that brain depletion of TRP, a biochemical precursor of serotonin (5-HT), may induce depression.[19, 20] On the other hand, IFN may directly affect 5-HT synthesis via degrading enzyme indoleamine 2,3-dioxygenase (IDO),[21] whereas cytokines may influence 5-HT availability by upregulation of the serotonin transporter (SERT).[22]

Thus, this review will examine and discuss the putative role of 5-HT and its metabolism in the development of depression during antiviral therapy, focusing on pharmacological interventions to reduce psychiatric side-effects.

Tryptophan Metabolism

The digestive system contains approximately 95% of body 5-HT. Most 5-HT is stored in enterochromaffin cells (EC) that release this neurotransmitter in response to mechanical, chemical or nervous stimuli by serotonergic neurons of the raphe nucleus and the brainstem.[23, 24] Serotonin is also present in the CNS,[25] in the autonomic nervous system[26] and in platelet granules.[27] In the brain, it modulates important functions, such as the regulation of affective states, sensory perception and neuroendocrine functions.[28] In the gastrointestinal tract, 5-HT modulates visceral afferent signals, motor function and mucosal secretion. In the liver, it contributes to hepatic wound healing and hepatocyte regeneration after being released from platelets.[29]

Tryptophan, an essential amino acid that contains an indole functional group, is the precursor of 5-HT. Serotonin is formed after irreversible cleavage of the indole ring catalyzed by tryptophan-dioxygenase (TDO) and IDO. TDO is located in the liver and has a very strict substrate specificity acting only on L-TRP, while IDO has a lower substrate specificity and is ubiquitously present in all tissues.[30] Only small amounts of TRP are metabolized into the 5-HT pathway, while most TRP is processed along the kynurenine pathway. It has been shown that increased TRP degradation into kynurenine by IDO, during IFN immune activation,[21, 31] may lead to decreased 5-HT production (Fig. 1). This may, in turn, contribute to the development of depressive symptoms during IFN therapy. The endogenous activity of 5-HT is controlled by a specific SERT that mediates the intracellular reuptake of 5-HT and can be specifically blocked by selective 5-HT reuptake inhibitors (SSRI).[27] Several lines of evidence suggest that changes in the expression of SERT can be associated with dysfunctions of central serotonergic transmission with the development of consequent depressive disorders.[32-34]

Figure 1.

Upregulation of indoleamine 2,3-dioxygenase. Interferon may increase tryptophan degradation into kynurenine by increasing the activity of indoleamine 2,3-dioxygenase, thus reducing the amount of tryptophan available for the synthesis of 5-HT by tryptophan hydroxylase and the aromatic amino acid decarboxylase. 5-HT, serotonin.

The main pathway responsible for the catabolism of 5-HT in both cerebral and peripheral tissues is mediated by the monoamine oxidases (MAO) enzymes and consists of the oxidative deamination of 5-HT into 5-hydroxy-acetaldehyde (5-HIAL). MAO-A isoform is predominantly localized in fibroblasts and in placental tissue, while MAO-B is the only isoform present in platelets and lymphocytes.[35] The intermediate products of this reaction are converted into 5-hydroxyindoleacetic acid and 5-hydroxytryptophol by the action of the aldehyde-dehydrogenase and aldehyde-reductase.[36] The final products are secreted in the blood and are eliminated by renal excretion. In addition, 5-HT may also be excreted in bile after either glucuro- or sulfo- conjugation. In the pineal gland, thyroid and gastrointestinal tract, 5-HT may also serve as a substrate for the synthesis of melatonin (Fig. 2).[37]

Figure 2.

The 5-HT catabolism. MAO is responsible for the catabolism of 5-HT in 5-HIAL. The intermediate product is converted into 5-HIAA and 5-HTOL by aldehyde dehydrogenase and aldehyde reductase, respectively. Another biotransformation pathway is the acetylation by N-acetyl-transferase. This product is converted into melatonin by hydroxyindole O-methyltransferase. 5-HT, serotonin; 5-HIAL, 5-hydroxy-acetaldehyde; N-acetyl-5-HT, N-acetyl-serotonin; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTOL, 5-hydroxytryptophol.

It has been suggested that HCV patients may be particularly prone to the development of psychiatric symptoms when compared to HBV patients.[38]

Several studies have shown that reduced tryptophan levels and increased IDO activity are associated with an increased risk for the development of depressive symptoms during IFN treatment.[21, 39-41] The study of Capuron et al.[39] showed that HCV patients treated with IFN who developed major depression exhibited significant increases in kynurenine and decreases in TRP concentrations. Cozzi et al.[38] showed that HCV patients experience more depression and anxiety symptoms than either healthy volunteers or HBV patients. They also showed that HCV patients had reduced serum tryptophan levels. However, in contrast with other studies,[21, 31] they found reduced IDO activity in macrophages.

Data by Zignego et al.[42] show that HCV-infected patients have lower TRP levels than healthy volunteers and HBV-infected patients. They also demonstrate that viral clearance is associated with normalization of TRP plasma levels and amelioration of psychopathological symptoms.

It has been suggested that another way by which the IFN could influence 5-HT availability could be by cytokine-induced upregulation of SERT. Polymorphisms of the serotonin reuptake transporter promoter (5-HTTLPR) result in a short (S) and a long (L) allele. Genotypes S/S and L/S have a reduced expression and a low efficacy of serotonin reuptake.[43] Several studies indicate that S/S alleles in the 5-HTTLPR increase the risk for major depression.[44, 45] However, only a few studies have investigated SERT activity in patients with HCV before and during IFN treatment.[46, 47]

Lotrich et al.[46] genotyped HCV patients for the 5-HTTLPR (LG, LA and S) alleles and showed that the LA allele was associated with lower rates of major depressive disorders, with the S/S genotype being the least resilient. The overall pattern was similar for both Caucasians and the nine African-Americans, with the LA/LA genotype was the most resilient and S/S the most vulnerable in both groups. When the authors compared the S/S genotype versus LA they confirmed that the S/S genotype was the most vulnerable to the development of depression. Polymorphism of the L allele (LG) resulted in lower transcription efficiency, functionally comparable to that of the S allele.[48]

The analysis of polymorphism of 5-HTTLPR may be useful to predict the development of major depressive disorders before beginning therapy with IFN.

Therefore, the crucial point of depression during IFN therapy is represented by 5-HT availability. This is due to both an increase of IDO activity and a lower efficacy of SERT. In fact, IFN decreases 5-HT concentration because it increases the kynurenine pathway, with consequent reduced tryptophan availability to the 5-HT pathway. As already mentioned, the main circuit responsible for the catabolism of 5-HT in both brain and periphery is mediated by the enzyme MAO and its oxidative deamination to 5-HIAL. MAO inhibitors have a high efficacy in improving mood. The mechanism of their antidepressant action is based on the MAO-A inhibition, particularly their ability to counteract the reduction of 5-HT in the synaptic space.[49] However, the current guidelines for the treatment of the most serious depression disorders suggest SSRI as the first-line treatment for major depressive disorders because of the numerous side-effects of MAO inhibitors.

Impact of SSRI in the Pharmacological Treatment of HCV Patients Before and/or During IFN Treatment

It has been shown that the development of depression during IFN and ribavirin treatment[42, 50] is associated with diminished serotonergic neurotransmission. In treated patients, the onset of depression may lead to either dose reduction or discontinuation of IFN treatment.[17] The most effective initial therapy for HCV patients is the combination of interferon-α-2 plus ribavirin given for 24 or 48 weeks (three times per week). More recently, the addiction of a polyethylene glycol molecule to IFN has increased therapeutic efficacy and has allowed a more convenient once-weekly dosing. Manns et al.,[51] in the seminal paper showing the efficacy of pegylated IFN associated with ribavirin for the treatment of HCV hepatitis, reported that depression occurred in 31%, 29% and 34% of patients receiving ribavirin in combination with high-dose peginterferon, low-dose peginterferon and IFN-α-2b, respectively. Now, triple therapy with telaprevir or boceprevir has been accepted as a standard therapy for patients with HCV genotype 1. In fact, it has been suggested that in naive patients with genotype 1 and negative predictors of response to standard of care (genotype TT of IL-28B or advanced/severe fibrosis), triple therapy should be provided as first-line therapy.[52, 53]

Neri et al.[54] compared the incidence of depressive symptoms in patients with HCV during treatment with either pegylated IFN-α-2a or -2b. A high incidence of depressive symptoms was present in the two groups both at baseline (53% vs 57%) and after 12 weeks of treatment (61% and 65%, respectively). Moreover, three patients in the pegylated IFN-α-2a group required discontinuation of antiviral therapy and admission to a psychiatric unit for the development of severe psychiatric symptoms.

Suicide is the most feared event in patients with severe depression. The true incidence of suicide in HCV patients treated with IFN is unknown but some cases have been described,[55] as well as cases of development of suicide ideation.[56]

However, according to Lang,[57] a personal history of major depression should not be considered a contraindication to IFN treatment, provided that patients receive a psychotropic treatment adapted to the clinical situation.

Selective serotonin reuptake inhibitors have been used for the prevention of IFN-associated depression.[58-60] Citalopram and escitalopram are the most commonly used. Escitalopram is the enantiomer of the citalopram; because of its high selectivity for serotonin reuptake inhibition, it is associated with fewer side-effects.[61]

Schaefer et al.[62] showed that significant depression scores both at baseline and the third month of IFN treatment were present in 70 HCV patients prospectively screened for psychiatric disorders. They concluded that the treatment with IFN and ribavirin should take place in interdisciplinary treatment units in order to manage psychiatric side-effects. In a previous paper, Schaefer et al.[63] divided HCV patients into three groups according to the results of psychiatric evaluation. In the first group were allocated patients with indication for antidepressant treatment due to current mild to moderate depressive symptoms. In the second group were placed patients with psychiatric disorders that did not present depressive symptoms at baseline or during the last 3 months (psychiatric control). In the third group were placed patients with chronic hepatitis C in whom an history of psychiatric disorders or drug addiction was carefully excluded (non-psychiatric control group). The authors demonstrated that HCV patients pretreated with citalopram developed significantly fewer depressive episodes during the first 6 months of antiviral treatment (14%) when compared to the group with previous psychiatric disorders (64%) and to the group of patients without psychiatric risk factors for the development of major depression who were not treated with citalopram (55%).

More recently,[50] they showed that 5-HT concentrations were significantly decreased during IFN therapy, suggesting that IFN may impair the activity of the serotonergic system. Concomitant citalopram treatment further reduced 5-HT platelet concentrations, suggesting an increase in intracellular 5-HT concentration in the course of citalopram/IFN combination therapy. These studies demonstrate that in patients with chronic HCV and concomitant IFN treatment, platelet 5-HT concentrations are significantly reduced by IFN and concomitant citalopram treatment. They suggest that no parameter can predict which subgroup of patients will develop depression in the course of IFN treatment. However, the authors suggest that an antidepressant prophylaxis may be useful in high-risk patients to prevent the development of major depression.

The efficacy of citalopram in the prevention of depression during IFN treatment is still a matter of controversy. Morasco et al.[64] could not demonstrate a significant difference in the development of depression in 39 HCV patients treated with IFN and either with or without citalopram (10.5% vs 20% respectively). They suggest that the prophylactic use is unnecessary, because prophylactic citalopram to HCV patients undergoing antiviral therapy confers no significant advantage for reducing the likelihood of developing major depression. In contrast, in a more recent paper, de Knegt et al.[60] demonstrated that the addition of escitalopram in HCV patients treated with IFN was associated with a significant reduction of depression when compared with placebo (12.5% vs 35.9%, respectively). It is likely that different study design and diagnostic criteria for depression may be responsible for this discrepancy.

However, major depressive disorder is usually recurrent, and national practice guidelines recommend maintenance pharmacotherapy for most patients who are at significant risk of relapse or have a history of recurrent depression, owing to their favorable risk–benefit ratio.[62] Therefore, with IFN treatment being considered a pharmacological risk factor of relapse in patients with a history of depression, SSRI prophylaxis could be recommended.

As already mentioned, depression may be due to the viral infection or to the antiviral treatment. The SSRI usually begin to have an effect after 4–6 weeks. Treatment should follow the guidelines applicable to the treatment of depression.[65, 66]

Recently, Schaefer et al.[67] summarized the current knowledge of HCV infection and the brain; and then classified recommendations on psychiatric management of HCV-infected patients before and during antiviral treatment.

Several authors[68-70] suggest caution when SSRI are given during IFN treatment. The development of manic symptoms has been described in some patients undergoing SSRI treatment during IFN therapy for HCV. Therefore, more data about efficacy and safety are needed before this treatment can be recommended.

In a recent report of the European Association for the Study of the Liver, Zeuzem showed data demonstrating that the new antiviral therapy with IFN-λ and ribavirin had less hematological toxicity and other adverse effects compared with IFN-α and ribavirin. However, the prevalence of psychiatric adverse events (e.g. depression, irritability or insomnia) was higher in the IFN-λ-treated groups than in IFN-α-treated patients (41.4% vs 33.3%).[71] Most of the new treatments with direct acting antivirals are focused on genotype 1; therefore, IFN may continue to play a role in genotype 2 and 3 due to the high treatment success in these genotypes. It is likely that therapeutic strategies for the management of psychiatric side-effects during IFN treatment will remain of interest also in the near future.

It has been shown that IFN-β-1a may represent a potential therapeutic alternative for HCV-infected patients.[72, 73] In a recent study,[74] Arase et al. analyzed the efficacy and safety of combination therapy of IFN-β and ribavirin in patients with HCV genotype 1b who had stopped IFN-α due to depression induced by treatment. They found that combination therapy of IFN-β and ribavirin reduced the aggravation of depressive states when compared to combination therapy of INF-α and ribavirin. The reasons for this different effect on depression are unclear at present and additional studies are required to elucidate this point.

Conclusion

In conclusion, the development of depressive symptoms is common in patients with HCV infection and it may be increased by IFN treatment. It is likely that part of this effect is mediated by IFN-induced depletion of 5-HT, possibly caused by interference with the kynurenine pathway. SSRI, blocking 5-HT reuptake, may improve IFN-induced depressive symptoms in psychiatric patients.

However, the efficacy and safety of SSRI prophylaxis in non-psychiatric patients needs to be confirmed in additional studies.

These medications should be administrated only with appropriate psychological and psychiatric evaluation before and during antiviral therapy.

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