Interferon-Induced Depression in Chronic Hepatitis C: A Review of Its Prevalence, Risk Factors, Biology, and Treatment Approaches
Gregory M. Asnis, MD* and Richard De La Garza, II, PhDt
Abstract: Hepatitis C viral infection is a global health problem that affects approximately 4 million people in the United States. Combination treatment with pegylated interferon (IFN)-a plus ribavirin has been shown to be most effective in treating patients with chronic hepatitis C (CHC). Despite its efficacy, one of the most common side effects of this regimen is depression. Whereas IFN-a has been found to induce depression in chronic myelogenous leukemia, melanoma, and renal cell carcinoma, CHC patients may be especially prone to develop IFN-induced depression. This review includes a summary of differences between IFN-a and IFN-ß and addresses whether pegylation of IFN (versus nonpegylated IFN) gives rise to a treatment with reduced potential to induce depressive symptoms. Consideration is also given to evidence showing that treatment with ribavirin may contribute to IFN-induced depression. Thyroid disorders and anemia (as well as other medical conditions) have also been associated with IFN exposure and may account for some incidences of depression in CHC patients. Evidence is reviewed indicating that prior psychiatric and mood disorders (especially previous episodes of major depressive disorder), just prior to IFN treatment, contribute to the propensity to develop depression during treatment. In addition, a brief description is provided of potential biological mechanisms of IFN-induced depression (ie, monoamines, hypothalamic-pituitary-adrenocor- tical [HPA] axis, proinflammatory cytokines, peptidases, inter- cellular adhesion molecule-1, and nitric oxide). Finally, a discussion is provided on the use of antidepressants as a preventative versus restorative treatment, including a commen- tary on risks of using antidepressants in this patient population.
Key Words: hepatitis C, interferon, pegylated interferon, cytokines, hypothalamic-pituitary-adrenocortical (HPA) axis, antidepressants, major depressive disorder
(J Clin Gastroenterol 2006;40:322-335)
From the *Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Montefiore Medical Center, Anxiety and Depression Program, Bronx, New York; and tThe David Geffen School of Medicine at UCLA, Department of Psychiatry and Biobehavioral Sciences, Los Angeles, California. Supported by Roche Labs, Inc.
Reprints: Gregory M. Asnis, MD, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Monte- fiore Medical Center, Anxiety and Depression Program, Klau Basement, 111 E. 210th Street, Bronx, NY 10467 (e-mail: asnisarts@ aol.com)
Copyright @ 2006 by Lippincott Williams & Wilkins
INTRODUCTION
Hepatitis C viral (HCV) infection is a global health problem that affects approximately 170 million people worldwide,1 including about 4 million in the United States.2 Up to 85% of HCV-infected individuals may develop long-term chronic hepatitis C (CHC), a disease state associated with serious clinical sequelae, including hepatic fibrosis, cirrhosis of the liver, and hepatocellular carcinoma.36 It has been estimated that up to 20% of CHC patients will develop liver cirrhosis over a 20- to 25- year period, and these individuals are at increased risk for developing end-stage liver disease and/or hepatocellular carcinoma.3,4 In fact, CHC is the leading cause of liver transplantation in the United States. Thus, aggressive antiviral treatments to successfully induce a viral remis- sion constitute a major goal for reducing the morbidity and mortality associated with CHC.
The current standard of treatment for CHC consists of combination therapy with pegylated interferon-alpha (pegIFN-a) plus ribavirin.3 In clinical trials, more than 50% of CHC patients treated with combination therapy achieved a sustained viral response (SVR), defined as undetectable HCV in the blood 6 months following the end of treatment.4 Despite the efficacy of these com- pounds in treating CHC, depression is a deleterious and often common side effect that can interfere with a successful course of antiretroviral treatment. In this review, we summarize evidence of the association between IFN treatment and the onset of depression in CHC patients, the potential neurobiological mechanisms by which depression may arise, and the pharmacological agents currently used in the treatment or prevention of depression in these patients.
GENERAL CRITERIA FOR IFN-INDUCED DEPRESSION
Technically, depression that arises during IFN treatment is most appropriately designated a substance- induced mood disorder with depressive features. Although this characterization includes a persistent and prominent depressed mood or loss of interest or pleasure, this mood disturbance has few clear anchor points and no associated symptoms and thus lacks clarity. For example, the duration of the core symptom is unspecified. For the purpose of this review, we chose to focus on cases of
IFN-induced depression that satisfy the criteria of major depressive disorder (MDD), as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV- TR),7 ensuring that it is of significant duration and severity and not a transitory phenomenon. In particular, the criteria of MDD are highly structured, including at least a 2-week duration of the core symptom, depressed mood or loss of interest/pleasure, and during this 2-week period the presence of at least five associated symptoms (depressed mood, diminished interest or pleasure, sig- nificant change in weight and/or appetite, significant change in sleep, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness/guilt, decreased concentration, or recurrent thoughts of death or suicidal ideation/behavior).
The prevalence rate of IFN-induced depression reported in the literature has varied widely, from 3% to 45%8 (Table 1),9-13 and this may be due to nonstandar- dized methods of psychiatric assessment, inadequate biometric instruments, or lack of differentiation among depressive symptoms, major depressive episode (MDE), and MDD. Because most health professionals investigat- ing these neuropsychiatric symptoms have been specialists in other areas, including gastroenterologists and infec- tious disease specialists, and not experienced in mental health, it is not surprising that this area is in need of greater clarity.14
Most problematic is that many of these reports have evaluated depressive symptoms as part of a side-effect questionnaire or as part of a self-rating scale specifically developed for the assessment of depressive symptoms (eg, Center for Epidemiologic Studies Depression Scale, Beck Depression Inventory [BDI], Zung Self-Rating Depres- sion Scale [SDS]) or general psychopathology with a depressive subscale (eg, SCL [Symptom Checklist]-90-R). These assessments generally cover a brief period, usually 1 week, and do not by themselves result in a psychiatric diagnosis of MDD, which includes the presence of depressed mood or anhedonia with other key associated
symptoms and the dimension of at least 2 weeks’ duration. Many studies using self-rating scales have utilized cut-off points to establish the diagnosis of MDD without a formal confirmation of the diagnosis according to DSM-IV-TR criteria. Although higher scores on depression self-rating scales often correlate with a diagnosis of MDD,15,16 patients with nondepres- sive diagnoses can have significant depressive symptoma- tology on these scales, thus highlighting the need for a confirmatory psychiatric interview. Medically ill patients, including those awaiting IFN treatment (eg, CHC or multiple sclerosis patients), may have significant depres- sive symptoms. Furthermore, a relatively low score on self-rating scales may be suggestive of a non-MDD yet satisfy a diagnosis of MDD of mild severity.
A potential confounding factor in reports of IFN- induced depression is that patients were frequently included in the final diagnosis if they were on antide- pressant medication prior to initiation of IFN treat- ment.17,18 As described below, concurrent treatment with antidepressants has been shown to reduce the likelihood of experiencing depression during IFN treatment and thus may contribute to the lower depression rates reported in these studies.
The importance of a comprehensive psychiatric evaluation prior to initiating IFN treatment in studies of IFN-induced depression cannot be overemphasized. Patients who already have significant depressive symp- toms or MDD at baseline are clearly more likely to develop a worsening of symptoms during IFN treatment than patients without these conditions. 10,11,19,20
CHC patients are among the largest groups being treated with IFN, and they tend to have a significant history of psychopathology, including a high prevalence of substance or alcohol abuse and addiction.3,21 In reviewing the literature, we have focused on prospective reports in which patients had a psychiatric evaluation at baseline to exclude the possibility of an MDE, MDD, or significant depressive symptomatology, reports that used
| TABLE 1 IFN-induced Depression: Prevalence Rates | ||||
|---|---|---|---|---|
| First Author, Reference | No. of Subjects, Disease | IFN Therapy | Depression Scales | Outcome |
| Miyaoka9 | 66, CHC | IFN-a-2b or lymphoblastic IFN-a or others (6 or 10 MIU/day for | HAM-D DSM IIIR | 44% of patients developed MDD |
| 2 wks, then 3x/wk for 22 wks) | ||||
| Musselman10 | 38, Melanoma | IFN-x-2b (20 MIU/m3 5x/wk for 4 wks, then 10 MIU/m2 3x/wk for 8 wks) | HAM-D Carroll Dep DSM-IV | 11% of patients developed depression on paroxetine antidepressant vs. 45% on placebo |
| Hauser11 | 39, CHC | IFN-x-2b (3 MIU 3x/wk for 6-12 months) | BDI SCID | 33% of patients developed MDD |
| Bonaccorso12 | 27, CHC | IFN-a (3 MIU 3x/wk for 3 months) | MADRS DSM-IV | 41% of patients developed MDD |
| Horikawa13 | 99, CHC | IFN-a or IFN-a-2b (6 or 10 MIU/ day for 4 wks, then 3x/wk for 20 wks) | HAM-D DSM-IV | 23% of patients developed MDD |
CHC, chronic hepatitis C; IFN, interferon; HAM-D, hamilton rating scale for depression; DSM, diagnostic and statistical manual of mental disorders; Carroll Dep, carroll depression scale; BDI, beck depression inventory; SCID, structured clinical interview for DSM-IV Axis I disorders; MADRS, Montgomery Asberg depression rating scale.
standardized rating scales prior to and during IFN treatment, and trials in which patients were not concur- rently being treated with antidepressants for a pre- existing MDD.
PROSPECTIVE PREVALENCE STUDIES OF IFN-INDUCED DEPRESSION
In five prospective trials, the prevalence rates of IFN-induced depression, based on self-rated and/or clinician-rated scales with a structured interview guide or a general psychiatric interview or checklist to confirm MDD, ranged from 23% to 45% (Table 1).9-13 Only one of these studies, however, evaluated patients with a structured comprehensive psychiatric interview (the Structured Clinical Interview for DSM-IV Axis I Dis- orders [SCID-ID]) to firmly establish the lack of a baseline psychiatric disorder, including MDD, and to assess the incidence of any previous or current disor- ders.11 Moreover, although this study evaluated patients weekly, a SCID interview was mandated only for patients with a BDI score of 18 or greater.11 Because a low score on a depression rating scale does not rule out the presence of MDD, the prevalence of IFN-induced depression may have been underestimated in this trial.
In addition, although most of these reports eval- uated patients weekly or every few weeks, one assessed depression at only two time points: baseline and after 3 months of treatment.12 Thus, these evaluations may have missed patients who developed MDD earlier during treatment but remitted prior to the 3-month assessment point. Because severity of depression may decrease with continued IFN therapy,22 more-frequent evaluations are needed to determine the persistence and severity of IFN-induced depression and whether or not it meets the more rigorous criteria of an MDE or MDD.
In summary, as can be seen from Table 1, the literature evaluating the prevalence rates of IFN-induced depression is scant, with only five prospective studies, including a total of 269 IFN-treated patients. These studies predominantly focused on CHC patients; four evaluated CHC patients and one evaluated melanoma patients. The data reveal that IFN-induced depression ranged from 23% to 45% in CHC patients. All studies used unmodified recombinant IFN-a-2a or 2b or natural IFN, and none evaluated pegIFN.
SUBTYPES OF IFN
Although it is clear that IFN exposure is associated with increased incidence of depression, there have been few evaluations of the relationship between frequency and magnitude of depression and the specific types of IFN utilized. The results of one study, in which four different types of IFN-a were administered to 96 CHC patients, suggest that the specific type of IFN used in treatment may have significant impact on the onset and severity of depression, including specific depressive symptomato- logy.23 Depression occurred most often in patients treated with IFN-an1 and least often in those treated with
IFN-an3, whereas treatment with IFN-x2b was asso- ciated with the most severe depression scores and the greatest prevalence of suicidal ideation.
Might a different IFN subtype or form be less depressogenic in the treatment of CHC patients? As discussed, only unmodified or pegIFN-a is approved by the United States Food and Drug Administration (FDA) for the treatment of CHC and is clearly associated with IFN-induced depression. The answer to this question may come from animal models, in that central administration of IFN-a to mice was found to increase immobility time (interpreted as a depressogenic response) in the forced swimming test, in contrast to nonsignificant effects for IFN-B or IFN-y.24
IFN-ß is predominantly used to treat multiple sclerosis. Interestingly, it appears that IFN-ß has a negligible depressogenic effect, as predicted by the aforementioned forced swim test. Despite early evidence suggesting that IFN-B-1b may be associated with depressive symptoms and perhaps suicidal behavior, comprehensive analyses of large placebo-controlled ran- domized trials ( > 350 patients per trial) of IFN-B-la and IFN-B-1b in the treatment of secondary progressive multiple sclerosis failed to report this association.28-30 The lack of IFN-induced depression in patients treated with IFN-ß was remarkable in that many of these patients were treated for 2 to 3 years.
IFN-ß has not been rigorously explored as a treatment for CHC, except in Japan, where it is frequently used in the treatment of CHC and found to have SVRs similar to those with IFN-a in some studies.31 IFN-ß has also been used in cases of CHC that are refractory to IFN-a.32 Unfortunately, specific monitoring for depres- sive symptoms, IFN-induced depression, or other beha- vioral neurotoxic effects such as anxiety have not been assessed in these studies. Thus, whether IFN-ß is less depressogenic than IFN-« and might provide an alter- native to CHC patients, particularly those vulnerable to a depressogenic reaction, awaits clarification.
ALTERNATE FORMS OF IFN
Pegylation of IFN significantly increases its half-life (a result of slower absorption and reduced elimination rates), enabling once-weekly administration.33 In clinical trials comparing pegylated and nonpegylated IFNs, the former were found to be more effective in achieving an SVR and were associated with a lower incidence of adverse events, including depression. For example, among 1121 patients randomized to treatment with pegIFN-a-2a plus ribavirin, pegIFN-x-2a plus placebo, or IFN-a-2b plus ribavirin for 48 weeks, the incidence of depression was 22%, 20%, and 30%, respectively, with a significant difference between the pegIFN-x-2a plus ribavirin and the IFN-x-2b plus ribavirin groups (P = 0.01).34 In contrast, among 1530 patients rando- mized to pegIFN-a-2b plus ribavirin (two-dose regimens) or IFN-a-2b plus ribavirin for 48 weeks, the incidence of depression was similar in all groups, ranging from 29% to
34%, and thus pegylation of IFN-a-2b did not reduce the rate of IFN-induced depression.3
Caution must be taken in interpreting the findings in both trials of pegIFN-x-2a and pegIFN-x-2b, however, because the presence of depression was based on a single symptom obtained from a general side-effect review and did not represent a diagnosis of MDD or substance- induced mood disorder. Nonetheless, pegIFN-x-2a may be less depressogenic than its nonpegylated form, as demonstrated in a recent study of health-related quality of life (QOL) in CHC patients.36 Treatment with pegIFN- a-2a versus unmodified IFN-x-2a was associated with significantly less fatigue (P < 0.01) and less impairment in patient functioning. Although QOL measures are not readily comparable to depression scores, reduced QOL scores have been associated with worsening depression in CHC patients.37,38 Further support that pegIFN-x-2b is no less depressogenic than unmodified IFN-x-2a was provided in a recent report evaluating 98 CHC patients, in which it was found depressive symptoms were equivalent in severity and frequency, as assessed with a self-rating scale, the Hospital Anxiety and Depression Scale (HADS).39 To fully clarify whether pegIFN-x-2a may be less depressogenic than IFN-x-2b, a head-to-head placebo-controlled double-blind study must be con- ducted. At this point such a study has not been undertaken.
CHARACTERISTICS OF IFN TREATMENT
As with most drug-induced side effects, IFN- induced neuropsychiatric side effects, including depres- sion, appear to be related to dose40,41 and duration of treatment.10,11,13 Indeed, the onset of depression does not occur immediately but takes time to develop, with an average onset occurring several weeks (mean, 8-12 weeks) after initiation of treatment.10,11,13 The route of admin- istration may also have an effect on the incidence and magnitude of IFN-induced depression, in that intrave- nously administered IFN was associated with higher depression ratings after 1 month than was subcutaneously administered IFN.42
RIBAVIRIN COADMINISTRATION
In CHC, treatment regimens that include the purine nucleoside analogue ribavirin along with IFN-& have been shown to result in higher SVR rates than IFN alone,43,44 and treatment with pegIFN-a plus ribavirin is more effective than pegIFN-a alone.34,35 Treatment with ribavirin, however, may also contribute to IFN-induced depression.45 This was illustrated in a 36-week placebo- controlled trial in 59 CHC patients, in which oral ribavirin alone (600 mg twice daily) significantly reduced alanine aminotransferase levels (P < 0.001) but had no effect on HCV RNA.46 Interestingly, depression, as recorded on a symptom questionnaire, was reported by 20.7% in the ribavirin group, compared with 3.3% in the placebo group, but this difference was not statistically significant possibly relating to the small sample sizes.
In a separate report comparing psychiatric symp- toms in 44 CHC patients treated for up to 12 months with IFN-x-2b (5 million units, three times per week) and in 40 patients treated with IFN-x-2b (3 to 5 million units, three times per week) plus ribavirin (1000 to 1200 mg per day), patients receiving combination therapy developed sig- nificantly higher-scoring depression (P = 0.005), anxiety (P = 0.032), and irritability/hostility (P = 0.044), suggest- ing that ribavirin may be depressogenic and anxiogenic.4 Recently, it was shown that among 162 CHC patients treated with pegIFN-x-2b plus ribavirin, those who developed moderate to severe depressive symptoms on the Zung SDS during the first 24 weeks of treatment received significantly higher doses of ribavirin (weight- based vs. standard dose), further supporting the role of ribavirin in IFN-induced depression. 48
IS IFN-INDUCED DEPRESSION UNIQUE TO CHC?
IFN-a has been found to induce depression in diseases other than CHC, including chronic myelogenous leukemia, melanoma, and renal cell carcinoma.49 CHC patients, however, may be more prone to develop IFN- induced depression than patients with other disorders, perhaps because of a baseline serotonin (5-HT) system dysfunction.5º CHC patients appear to be more vulner- able to IFN-induced depression than patients infected with hepatitis B virus (HBV).51 In a comparison of 38 patients infected with HCV, 36 infected with HBV, and 58 controls with similar baseline scores on the SDS and the corresponding SDS index, significant increases in the SDS index were observed during treatment of both HBV and HCV patients (P < 0.001 each), returning to baseline after treatment. During treatment, however, the SDS index was higher in HCV- than HBV-infected patients (P = 0.001), and HCV-infected patients had a seven-fold increased frequency of developing severe depression in comparison with HBV patients. Although the authors concluded that HCV infection was responsible for the greater increase in depressive symptoms, these patients, but not those infected with HBV, were also treated with ribavirin (800-1000 mg per day), which may have contributed to the higher incidence of depression reported.45
OTHER MEDICAL CONDITIONS ASSOCIATED WITH IFN EXPOSURE
Thyroid Disorders
Biochemical thyroid dysfunction has been asso- ciated with IFN treatment in 30 (12%) of 254 HCV- infected patients.52 Of these, 20 developed hypothyroid- ism and 10 developed hyperthyroidism, with 9 of the 30 patients developing symptomatic thyroid disease. Although biochemical thyroid dysfunction was not related to IFN dosage or SVR, multivariate analysis showed that female gender and Asian ethnicity were independent predictors of these dysfunctions. Although thyroid disorders, particularly hypothyroidism, are asso- ciated with depression,53 there has been little exploration
of thyroid dysfunction in IFN-induced depression. Of interest, IFN-associated thyroid dysfunction was first observed between 4 weeks and several months after the start of therapy, at about the same time as the onset of IFN-induced depression, suggesting that they may be related.52 In a recent preliminary report in which it was noted that only one of 33 patients developed overt hypothyroidism, a relationship between IFN-induced thyroid dysfunction and depression failed to be estab- lished.54 Because IFN-induced thyroid dysfunction occurs frequently and is treatable, the relationship between these requires further investigation in larger sample sizes.
Anemia
Anemia is associated with fatigue, dyspnea, head- ache, cognitive dysfunction, and compromises of func- tional capacity, leading to reduced QOL in a number of domains.35 In CHC patients, both IFN and ribavirin independently cause anemia, but ribavirin has a signifi- cantly greater impact.56 Anemia is more frequently observed in patients receiving IFN plus ribavirin than in those receiving IFN alone43,44 and is more frequent with unmodified IFN than with pegIFN.34,35 A possible correlation between anemia and certain forms of depres- sion was suggested by the finding that hemoglobin levels at day 7 postpartum were significantly correlated with postpartum depression at day 28.57 The effects of IFN plus ribavirin on hemoglobin levels occur within 2 to 4 weeks, at about the time that IFN-induced depression begins. Thus, aggressive treatment of anemia in CHC patients may alleviate or prevent the onset of depression, decreasing the need for dose reduction and/or disconti- nuation of IFN treatment.
IMPACT OF PSYCHIATRIC HISTORY ON INCIDENCE OF IFN-INDUCED DEPRESSION
Depression at baseline has been reported to be positively correlated with depression scores during IFN-« treatment.10,11,19,48 Moreover, patients who developed MDD during treatment tended to have higher baseline depression scores, although some patients who were minimally depressed at baseline also developed MDD during treatment.10,11,19 Other groups have reported that a history of a mood or nonmood disorder could not predict the development of IFN-induced psychological adverse events, including depression, or the intolerance or withdrawal of IFN.41,58-60
CHC patients tend to have a significant history of psychopathology, including a high prevalence of sub- stance or alcohol abuse and addiction, and a significant presence of anxiety or depressive symptoms and/or disorders.21,61-65 Given the very prominent associations between anxiety and depression and drug addiction,66 it is important to ensure that what appears to be IFN-induced depression is not in fact part of a comorbid condition or the natural course of disease progression for CHC patients. This was illustrated in a study of 50 CHC patients evaluated with the United States National Institute of Mental Health Diagnostic Interview Schedule
to determine psychiatric diagnoses, in which 12 of 35 patients not currently being treated with IFN were diagnosed with MDD.37 Thus, in evaluating depression in CHC patients, studies should include a CHC control group not receiving IFN treatment and/or a placebo group.47,67
POTENTIAL BIOLOGIC MECHANISMS OF IFN- INDUCED DEPRESSION
A considerable amount of evidence suggests that monoamine dysfunction, including especially decreased 5- HT levels, contributes to the etiology of IFN-induced depression. Additional data suggest that the disorder may arise as a result of other biological perturbations, including hypothalamic-pituitary-adrenocortical (HPA) axis activation, proinflammatory cytokine activation, decreased peptidase levels, increased intercellular adhe- sion molecule-1, and increased nitric oxide levels (Fig. 1).
Monoamines, Including Precursors and Metabolites
Depression in untreated CHC patients may result from changes in platelet 5-HT function, with decreased 5-HT concentrations during CHC infection compensated by a decrease in reuptake and metabolism.50 For example, although serum 5-HT concentrations did not differ between 85 untreated CHC patients and 22 controls, 5-HT uptake and monoamine oxidase (MAO)-B activity were significantly lower in CHC patients (P < 0.001 each),50 findings hypothesized to be compensatory to an initial lowering of baseline 5-HT.
Immune system activation, particularly by IFN-Y, impacts the metabolism of tryptophan (a precursor of 5-HT) by inducing expression of indoleamine 2,3-dioxy- genase (IDO), the enzyme that converts tryptophan to N-formylkynurenine, which is further metabolized to quinolinic acid.73-75 Thus, tryptophan is shunted away from the 5-HT pathway to the kynrenine pathway, resulting in a lowering of 5-HT levels. IFN treatment of CHC patients results in a decrease in plasma tryptophan and an increase in plasma kynurenine.76 In cancer patients, IFN-a treatment was found to significantly reduce tryptophan concentration, and this reduction was positively correlated with the development and severity of depressive symptoms (Fig. 2).77
In addition, although all IFN-treated melanoma patients exhibited significant increases in plasma kynur- enine and neopterin and in the kynurenine/tryptophan ratio, individuals who developed MDD exhibited sig- nificantly greater increases in kynurenine and neopterin and more prolonged decreases in tryptophan than nondepressed patients.78 Furthermore, the decreases in plasma tryptophan were significantly correlated with symptoms of depression and anxiety (Fig. 3).78 IFN-a was recently shown to alter editing of mRNA encoding the 5-HT type-2C (5-HT2c) receptor in human glioblas- toma cell lines, leading to the dominant expression of a protein isoform predicted to have reduced G-protein
Cytokines (TNF-a, IL-18, IL-6)
Interferon (Exogenous or Endogenous)
HPA Axis (CRH, ACTH, Cortisol)
coupling functions and suggesting that editing of the 5-HT2c receptor is relevant to the etiology of IFN- induced depression.
An additional mechanism by which IFN can impact 5-HT system functioning is via its effects on increasing MAO-B activity and 5-HT reuptake.80 Although the focus of this article and the literature has been on 5-HT,
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IFN-a has also been found to alter other monoamines, including dopamine and norepinephrine, and these changes may be critical in the etiology of depression.68
HPA axis
IFN-a-induced activation of the HPA axis is believed to occur by direct stimulation of corticotropin- releasing hormone (CRH) and arginine vasopressin
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(AVP), which increase adrenocorticotropin hormone (ACTH) production and result in increased cortisol release (Fig. 1).72,81 Both CRH and ACTH have been reported to be elevated in MDD patients.81,82 Further- more, it is believed that increased levels of these peptides and stress hormones may be directly responsible for anxiogenic and depressogenic effects. The effect of IFN-a on HPA axis response and the development of MDD was assessed in 14 patients with malignant melanoma.83 In response to the first injection with IFN-x (ie, the first treating dose), plasma ACTH and cortisol, but not IL-6, were significantly higher within 3 hours in the seven patients who developed MDD after 8 weeks of therapy than in the seven who did not (Fig. 4).83 These results indicate that the initial responses to IFN-a may be strong predictors of depression onset and severity later during treatment.
Proinflammatory Cytokines
IFN-a activates other proinflammatory cytokines, including interleukin (IL)-18, IL-6, and tumor necrosis factor (TNF)-x (Fig. 1).69,70 These, in turn, activate other proinflammatory cytokines and receptor molecules. Of specific interest is the recent finding that during immu- notherapy with IFN in CHC patients, the rise in IL-6 was significantly correlated with the development of depres- sive and anxiety symptoms.7 This relationship between cytokines, particularly IL-6, and IFN-induced depression has also been suggested for patients with major depres- sion.68 The IFN-a-induced cascade is known to alter monoamine metabolism and to activate the HPA axis,72,83 which in all likelihood also contributes to IFN-induced depression and other neurotoxic effects.
Peptidases
The proline endopeptidases are members of a subfamily of serine proteases that degrade peptides and proteins, including thyrotropin-releasing hormone, sub-
stance P, and IL-6.84 Among these enzymes, prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP IV) may be involved in the pathophysiology of MDD or IFN-induced depression. Plasma DPP IV activity has been found to be lower in patients with MDD than in normal controls, and its concentration was not altered by antidepressants.85,86 Treatment of CHC patients with IFN-a was observed to decrease serum DPP IV activity in a time-dependent manner, and this reduction was significantly correlated with IFN-a-induced increases in the Montgomery and Asberg Depression Rating Scale (MADRS), which measures depression, and the Hamilton Anxiety Rating Scale (HAM-A), which measures anxiety.8
In a prospective study, CHC patients with lower PEP and DPP IV had significantly higher MADRS and HAM-A scores at baseline and during IFN treatment.88 Supportive of these findings in CHC patients, PEP levels in pregnant women at term were found to predict postpartum depression.89 Nevertheless, the role of proline endopeptidases as a predictor of IFN-induced depression requires further exploration.
Intercellular Adhesion Molecule-1 (ICAM-1)
ICAM-1 is a cell adhesion molecule involved in regulating the permeability of the blood-brain barrier.’ Expression of ICAM-1 has been shown to be higher in postmortem samples of the dorsolateral prefrontal cortex of depressed vs. nondepressed subjects.92 In addition, plasma concentrations of the soluble form of ICAM-1 (SICAM-1) were significantly higher in depressed than nondepressed individuals93 and were higher in CHC patients than in controls.94 In a recent prospective study, serum sICAM-1 and symptoms of depression were measured in 48 patients with malignant melanoma before and during treatment with IFN-a.95 After 3 months of IFN treatment, depression scores and serum sICAM-1 levels were both higher than at baseline. Patients who
developed depression had higher sICAM-1 levels than nondepressed patients, and sICAM-1 levels were posi- tively correlated with SDS values, suggesting an associa- tion between the induction of sICAM-1 expression and the development of symptoms of depression during IFN treatment. The evidence suggests that proinflammatory cytokines may cross the blood-brain barrier more readily as a result of increased secretion of sICAM-1, thus contributing to the neurotoxic effects produced by IFN-a treatment.
Nitric Oxide
Various cytokines release nitric oxide (NO), which is known to modulate HPA-axis-related hormones and monoamine neurotransmitter release and reuptake.96 In testing the NO hypothesis of depression, it was recently found that patients had a significantly higher serum level of nitrate, a final metabolite of NO, during depressive episodes than they did after recovery.97 In a subsequent report, the same group also evaluated NO in CHC patients treated with IFN-a.96 The data reveal that those with an early onset of depression (within the first 4 weeks of IFN treatment) had higher levels of serum nitrate, which normalized after treatment and recovery with antidepressants. The findings suggest that CHC patients who have higher IFN-induced NO levels are especially vulnerable to early-onset IFN-induced depression. These findings need replication, particularly because antidepres- sants have been shown to increase serum nitrate levels98 and because the CHC patients in the earlier report were on antidepressants at baseline.
Overall, while the data presented are important to consider, many findings have not been replicated, are based on small sample sizes, and have been conducted in limited study populations. As such, it is premature to suggest a treatment based solely on these potential biological mechanisms. Available evidence specifies that selective serotonin reuptake inhibitors (SSRIs) are effec- tive and there is a very high rate of response. Any other treatment based solely on mechanism is not yet warranted.
PREVENTATIVE VERSUS RESTORATIVE TREATMENT OF IFN-A-INDUCED DEPRESSION
Depression associated with IFN treatment is not only common in CHC patients but also an important reason for decreasing the dose or discontinuing IFN treatment.34,35 As a result, successful treatment of CHC often requires treatment or prevention of IFN-induced depression. Case reports have demonstrated that various classes of antidepressants, including tricyclics, heterocyc- lics, neurotransmitter receptor modulators, and SSRIs, are effective in IFN-induced depression.99 SSRIs have been the most widely studied antidepressants in these case reports, probably because of their extensive safety profile, and have been the most widely used antidepressants over the past decade.
Recently, in an open-label study of CHC patients who developed IFN-induced depression, 11 of 13 patients
(85%) were responsive to treatment with antidepressants; 10 responded to the SSRIs citalopram (n = 9) and fluoxetine (n = 1), and 1 responded to the dopamine and norepinephrine selective antidepressant bupropion.1 In a subsequent open-label study, the SSRI paroxetine significantly improved IFN-induced depression in 11 of 14 CHC patients, allowing IFN treatment to continue uninterrupted.100 Interestingly, the study suggested that IFN-induced depression in CHC patients was very responsive to antidepressant treatment, occurring early (within 2 weeks of treatment) and at unusually low antidepressant doses in comparison to that which occurs in the treatment of major depression. Although the above data is strongly suggestive that antidepressants are effective in treating IFN-induced depression, particularly in CHC patients, none of these studies was placebo- controlled or used double-blind methodology. Thus, a definitive statement awaits appropriate clinical trials.
Pretreatment of psychologically vulnerable patients with antidepressants who are about to start IFN therapy may be an important strategy to be used as an attempt to prevent the onset, incidence, or magnitude of an IFN- induced mood episode. Subsequent to an early report in the animal literature finding that cytokine-induced depression (“sickness behavior”) could be prevented by pretreatment with antidepressants, 01 pretreatment with fluoxetine was shown to prevent the induction of IFN- induced depression in a patient with CHC who previously became depressed while taking IFN when not pretreated with an antidepressant.102
Following this case report, the ability of paroxetine to prevent IFN-induced depression was assessed in 40 patients with malignant melanoma, with use of placebo- controlled double-blind methodology.10 Patients were randomized to treatment with paroxetine or placebo (n = 20 each), starting 2 weeks before and continuing 12 weeks during IFN treatment. Symptoms consistent with a diagnosis of MDD developed in 2 two of 18 patients (11%) in the paroxetine group, vs. 9 of 20 (45%) in the placebo group (relative risk, 0.24; 95% confidence interval [CI], 0.08-0.93) (Fig. 5).1º Moreover, severe depression necessitated the discontinuation of IFN treatment in only 1 of 20 patients (5%) in the paroxetine group, compared with 7 of 20 (35%) in the placebo group (relative risk, 0.14; 95% CI, 0.05-0.85). Further analyses showed that neurovegetative and somatic symptoms of IFN treatment, such as anorexia, pain, and fatigue, appeared within 2 weeks of the beginning of treatment, whereas symptoms of depressed mood, anxiety, and cognitive dysfunctions appeared later, especially in patients who met DSM-IV criteria for MDD.103
Although this study was not specifically conducted in CHC patients, but in melanoma patients, the finding that antidepressants can prevent and/or reduce IFN- induced depression should be able to be generalized to this population. Nonetheless, several groups are currently studying the ability of paroxetine to prevent IFN-induced depression in CHC patients, utilizing similar strict scientific methodology (A. H. Miller and colleagues at
100
Survival Free of Major Depression (%)
80
60
40
Paroxetine
20
Placebo
0
0
2
4
6
8
10
12
Weeks on IFN-a
Emory University, personal communication; G. M. Asnis and colleagues at Montefiore Medical Center, unpub- lished data). Recently, pretreatment with paroxetine was reported to prevent the occurrence of IFN-induced depression in eight CHC patients.104 Although this was an open-label study, the fact that all eight of these CHC patients had previously developed an IFN-induced depression during a previous course of IFN/ribavirin treatment without prophylactic antidepressants is highly suggestive that the preventative antidepressant strategy also works in CHC patients.
RISKS OF USING ANTIDEPRESSANTS
There are a number of risks in using SSRIs or other antidepressants during IFN treatment. First, liver disease may alter the pharmacokinetics of many medications. Inasmuch as antidepressants are predominantly metabo- lized by the liver, CHC may be associated with impair- ments in the ability of the liver to metabolize antidepressants. As a result, blood levels of these drugs would be higher than expected, potentially increasing their side effects and toxicity. Thus, it is of interest that the plasma concentration of citalopram, which is effective in treating MDD in CHC,105 was lower than expected, and there was a tendency for citalopram levels to be lower in subjects receiving IFN than in those not undergoing treatment,106 suggesting that this antidepressant could be safely used during IFN treatment in CHC patients. However, the dose or titration of citalopram may require adjustment to optimize treatment, because some CHC patients being treated with IFN may be more sensitive to
central nervous system effects from psychotropics due to IFN’s neurotoxic effects.
In patients with a personal or family history of bipolar disorder, there is a danger that the combination of IFN and an antidepressant may induce a hypomanic or manic episode. Although there have been case reports of mania and hypomania induced by the antidepressants sertraline, clomipramine, fluoxetine, citalopram, and paroxetine,107-111 these drugs have been found to be less problematic than tricyclic antidepressants (TCAs) or MAO inhibitors in the induction of manic or hypomanic episodes.112 Manic episodes have also been described in case reports of patients treated with IFN and of patients withdrawing from IFN treatment, including a recent report of CHC patients undergoing treatment with pegIFN and ribavirin. 113-120
One of the most common side effects of treatment with pegIFN-a and ribavirin is thrombocytopenia.34 SSRIs have been found to significantly inhibit platelet aggregation induced by adenosine diphosphate, collagen, or thrombin, as well as to reduce the risk of myocardial infarction and platelet 5-HT concentrations.121-124 Thus, the combination of an SSRI with IFN and ribavirin may have additive risks. Indeed, treatment of CHC patients with IFN and ribavirin is associated with retinal hemorrhage, which is usually transient but may be exacerbated by treatment with an SSRI.125-129
DEPRESSION AS A PREDICTOR OF IFN EFFICACY
IFN-induced depression clearly must be aggres- sively treated to increase the likelihood that a patient remains compliant with IFN treatment and that the depression itself does not endanger the well-being of the patient. A number of recent studies suggest that IFN- induced depression or worsening of depressed mood may be a predictor of the antiviral efficacy of IFN in CHC patients. A trial in CHC patients showed an association between IFN-a-induced depression (MDD) and im- proved treatment responses to unmodified IFN.130 Both end-of-treatment response (ETR) and SVR were signifi- cantly higher in patients who developed IFN-x-induced MDD than in those who did not (ETR, 61.5% vs. 26.9%; P = 0.03; SVR, 38.5% vs. 11.5%; P = 0.04), suggesting that IFN-induced MDD may be a predictor of a positive response to IFN-a therapy. The authors suggest that this relationship may relate to optimal IFN dosing, in that the blood level of IFN may have been higher in those patients with IFN-induced depression and viral remission.
In contrast, another recent study that evaluated pegIFN-a-2b/ribavirin in CHC patients showed that a rise in the severity of depression symptoms of over 20 points in the SDS during therapy significantly predicted failure to clear the virus at 24 weeks of continued IFN.131 This study did not control for antidepressant use during any stage of the treatment, in that many of the patients were on antidepressants prior to IFN therapy or early in the course of treatment. Although the study evaluated pegIFN-a and did not evaluate IFN-induced depression
but worsening of depressive symptoms, these findings suggest that IFN-induced worsening of depressive symp- toms has a negative impact on the antiviral effect of IFN.
The authors suggest that it is possible that depressed patients may have been more noncompliant with IFN treatment.13 Alternatively, since depression alters immune functioning, this may have contributed to the lack of viral response. Although these two studies are not directly comparable, it remains unclear whether IFN-induced depression is a positive or negative predictor of the antiviral efficacy of IFN. Further studies will help clarify these issues.
CONCLUSIONS
The 1997 United States National Institutes of Health (NIH) Consensus Panel on Hepatitis C recom- mended excluding patients with unstable psychiatric illnesses, including depression, from treatment with IFN and ribavirin.132,133 In addition, treatment was not recommended for patients abusing alcohol or drugs until abstinence was achieved for at least 6 months. Treatment was also not recommended for patients with a history of MDD or moderate or severe psychiatric disorders, particularly MDD or suicidal ideation not controlled by medication. Unfortunately, such restrictions denied IFN treatment to approximately 50% of the CHC population in need of it.134
As a result of clinical reports suggesting that antidepressants, particularly SSRIs, could successfully treat IFN-induced depression or even prevent it from occurring, a subsequent consensus statement released in 2002 substantially revised the cautionary advice for patients with comorbid psychiatric and substance abuse disorders.3 Although recommending that all intravenous drug users and individuals abusing drugs or alcohol be encouraged to enter a drug-treatment program prior to treatment for CHC, the panel recommended that patients not enrolled in drug-treatment programs or on metha- done replacement still be considered for IFN treatment on a case-by-case basis. This recommendation is particu- larly supported by a number of studies that found that patients who episodically or chronically use hard drugs in methadone maintenance programs could be successfully treated with IFN.135
In this latter study, many of the patients were being treated concurrently with antidepressants, with over 50% being on antidepressants at the beginning of IFN therapy, which may have contributed to the outcome. It should be highlighted that despite this change in recommendations regarding intravenous drug users-both those in metha- done programs and those not completely abstinent from intravenous drug use-these groups, particularly those patients who are still intravenous drug abusers, have not been well studied in controlled prospective trials. The data from some studies suggest that these groups are subject to increased rates of noncompliance, relapse of drug use, reinfection with HCV, and even drug crav- ing.136,137 In addition, a concern, but not an absolute
contraindication for IFN treatment, was continued use or abuse of alcohol, which is an important cofactor in the progression of hepatitis C to advanced liver disease. In this case also, research has minimally evaluated this comorbid interaction.
For a majority of CHC patients, clinical concerns of depression should not deter IFN treatment. Ideally, CHC patients who have opiate intravenous drug abuse problems should be transitioned to methadone substitu- tion programs, stabilized, and then considered for IFN treatment. Those patients with current psychiatric diffi- culties must first have their symptomatology controlled as well as possible prior to initiating IFN. Patients at significant risk for the development of IFN-induced depression should be treated prophylactically with an antidepressant, preferably an SSRI, starting a few weeks prior to the beginning of IFN treatment and continuing throughout the course of IFN treatment. Recent evidence suggests that it may be necessary to continue antidepressant treatment for weeks to months after discontinuing IFN because suicidal behavior and depression can appear or reappear for some time after IFN discontinuation. 13
Patients eligible for prophylactic antidepressant include those with significant depressive and anxiety symptomatology at baseline prior to a course of IFN and those who have developed significant anxiety and depressive symptoms or disorders during previous IFN treatment. In contrast, patients who do not display symptoms of anxiety or depression prior to treatment, those who do not have a psychiatric history, and those who did not develop psychiatric side effects during previous IFN treatment should be administered anti- depressants only if symptoms of depression arise as a result of ongoing treatment. This is particularly impor- tant because IFN-induced depression tends to be of mild to moderate severity, occurs in a minority of patients, and is so readily responsive to antidepressants.8 The potential side effects and complications of antidepressant treatment could then be avoided by most CHC patients.
In summary, it is important to carefully evaluate all CHC patients undergoing treatment for the onset and development of depression. The use of self-rating scales for depression can help sensitize gastroenterologists to the need for more extensive psychiatric evaluations. If depression develops, consideration of antidepressant therapy is warranted in order to increase the likelihood of success with IFN therapy. Consultation and/or a referral to a psychiatrist for those CHC patients who become depressed may be indicated. Rarely, CHC patients undergoing IFN treatment may be nonrespon- sive to antidepressant therapy and may therefore need to have the IFN dose lowered and/or have the drug withdrawn.
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