Chronic hepatitis C viral (HCV) infection is a major public health concern, with approximately 200 million affected individuals worldwide and a significant rate of progression to end-stage cirrhosis and hepatocellular carcinoma.1 In the psychiatrically ill, the prevalence of HCV is high; one study found the rate of HCV to be 1 1 times greater in individuals with severe mental illness than in the general population.2
Compared to the general population, individuals with chronic HCV have a higher frequency of psychiatric disorders.3 Specifically, the prevalence of preexisting depression among HCV patients ranges from 1 1 % to 30%.4·5 There is also a greater frequency of HCV among veterans, with prevalence rates of 6% to 7% versus 1 .7% in the general population.6,7
In an epidemiologic study of 144,398 unique patients within the Northwest Veterans Integrated Service Network (VlSN 20), 5,500 veterans tested positive for HCV antibodies, and of those infected individuals, 64% had a history of major psychiatric disorder.8 Importantly, several studies report that psychiatric illness, particularly depression, in patients with HCV is one of the main reasons for exclusion from interferon-alfa therapy.9
Available therapies for HCV include interferon-alfa monotherapy and combination therapy with interferon-alfa and ribavirin.10 More recent studies suggest pegylated interferon-alfa in combination with ribavirin may have superior response rates compared with other formulations.11,12
The ultimate goal of interferon-alfa therapy is to induce a sustained viral remission and to inhibit the progression of liver disease. However, therapy with interferon-alfa has been associated with severe neuropsychiatrie side effects in many patients who receive it for treatment of HCV, as well as malignant melanoma and other medical conditions.
Increasingly, hepatologists and other health care providers have recognized the need for a systematic approach to HCV that addresses the co-entwined epidemics of hepatitis C and substance dependence as well as the comorbid psychiatric disorders that are found in HCV. This approach demands active participation from mental health care providers. Although interferon-alfa can lead to severe neuropsychiatrie side effects including suicidally, the published evidence and our own experience suggests many patients with psychiatric diagnoses can be treated safely and effectively even if preexisting psychiatric illness is present.
INTERFERON-ALPHA-INDUCED DEPRESSION FREQUENCY
The actual frequency of interferonalpha-induced depression is not known. Among patients with HCV, the prevalence of interferon-alpha-induced depressive symptoms ranges between 0 and 44%,3 and the onset of these effects usually occurs within 3 months of therapy initiation (Figure, page 387).13
Although these side effects represent a major obstacle to adequate interferon-alfa therapy for patients with HCV, most of the studies on interferon-alpha-induced side effects have not involved patients with HCV. Furthermore, many of these studies did not use objective and validated measures of depressive symptoms or criterion-based instruments. In our recent study of interferon-alfa treatment in 39 HCV patients who did not have an active psychiatric illness and were not using substances in the 6 months prior to the study, 1 3 (33%) developed major depressive disorder as diagnosed by the Structured Clinical Interview for DSM-IV Axis I Disorders, Version 2.0 (SClD) and monitored with weekly assessments using the Beck Depression Inventory (BDI).13
CHARACTERISTICS OF INTERFERONALPHA-INDUCED DEPRESSION
In patients with HCV, the most common and problematic side effects of interferon-alfa therapy are neuropsychiatrie complications that commonly include depression and anxiety, and less commonly mania, delirium, and other psychotic symptoms.14·15 These side effects can compromise otherwise effective therapy and are a source of considerable distress to some patients.
The symptoms of interferon-alphainduced depression in patients with HCV are similar to many of those seen in major depressive disorder and include depressed mood, irritability, emotional lability, agitation, fatigue, apathy, anhedonia, anorexia, psychomotor retardation, sleep disturbance, sexual dysfunction, memory impairment, and diminished ability to concentrate.15,16
Suicidal ideation and behaviors also have been reported to occur with interferon-alfa therapy, although less so than other symptoms of depression.17 Often, these depressive side effects result in antiviral medication dose reduction or complete discontinuation of interferonalfa therapy.615
There are no reliable risk factors that predict who will develop interferonalpha-induced depression. In general, there is a greater likelihood of serious neuropsychiatrie side effects when interferon-alfa is given for longer durations or at higher doses. I8
Studies in malignant melanoma as well as HCV suggest patients who develop interferon-alpha-induced depression have significantly higher subsyndromal depression scores prior to the initiation of therapy compared to patients who do not develop interferon-alpha-induced depression.13·19 However, our prospective study did not confirm that a history of major depressive disorder increased the likelihood of developing interferon-alphainduced depression.13 Taken together, although still within the asymptomatic range, data suggest higher depression baseline scores, obtained using rating scales such as the BDI, may predict greater difficulties with interferonalpha-induced depressive symptoms.19,20
Recent reports raise the possibility that extrahepatic manifestations of HCV can contribute to the development of depression in HCV-infected individuals. Specifically, the observation that HCV can result in cerebral dysfunction,21 in combination with data suggesting the presence of HCV in brain tissue,22 argues for a neuropathogenic effect of the HCV.
However, a recent study found no evidence of a direct relationship between HCV infection and fatigue or depression.23 Instead, the authors concluded that fatigue and depression are only seen in those HCV-infected individuals who are aware they are HCV positive, have advanced liver disease, are seen in specialist referral centers, or have known for years that they are not considered treatment candidates.
Figure: Development of interferon-alfa-induced major depressive disorder in a patient with hepatitis C virus. (BDI = Beck Depression Inventory, MDD = major depressive disorder.)
Because depressive side effects are a common cause for dose reduction or treatment discontinuation,24 there is now a greater need to understand the depressive symptoms associated with interferon-alfa therapy. Investigators have started to more comprehensively characterize the time course and specific depressive symptoms associated with interferonalfa therapy. Although not all patients on interferon-alfa therapy develop depression, for those who do, the depression typically develops rapidly.
In 62% (8 of 13) of patients who developed interferon-alpha-induced major depressive disorder, BDI scores increased from 10 to 18 within 2 weeks (Figure).13 Given this rate of depression escalation, regular screening of patients during interferon-alfa therapy is recommended. Furthermore, the time course of specific interferon-alpha-induced depressive symptom clusters also has been examined recently in patients with malignant melanoma and HCV.
Capuron et al. assessed the expression and treatment responsiveness of specific neuropsychiatrie symptom dimensions in patients with malignant melanoma during the first 12 weeks of interferon-alfa therapy25 Neurovegetative and somatic symptoms including anorexia, fatigue, and pain developed during the first 2 weeks after the initiation of interferonalfa. In contrast, significant increases in symptoms of depressed mood, anxiety, and cognitive dysfunction were reported after 1 2 weeks of interferon-alfa therapy; this occurred only in patients who later developed interferon-alpha-induced depressive disorder.25
Symptoms of depression are among the most common side effects of interferon-alfa therapy, yet no systematic studies have been conducted characterizing the specific interferon-induced depressive features in patients with chronic HCV: We recently identified a unique pattern of interferonalpha-induced depressive symptom dimensions that varies depending on the eventual development of treatmentinduced major depressive disorder.26 Depressive symptoms were grouped into four dimensions based on the BDI (negative cognitions, psychomotor anhedonia, somatic symptoms, and vegetative symptoms).27
Prior to the initiation of interferon-alfa therapy, baseline differences in three of the four symptom dimensions were found for patients who developed major depressive disorder compared to those who did not. During interferon-alfa therapy, all dimensions of the BDI were significantly increased at week 8 for those patients who developed major depressive disorder.
However, for patients who did not develop interferon-alpha-induced major depressive disorder, nonsignificant subsyndromal increases in all depressive symptom dimensions occurred 2 weeks after initiation of interferon-alfa therapy.26 This phenomenological specificity suggests there may be factors that predispose some interferon-alfa recipients to the development of major depressive disorder; such factors have yet to be elucidated.
Phenomenological and neurobiotogical differences in depression have important implications for understanding and treating mood disorders as antidepressant medications have varying efficacies and time courses in regard to ameliorating particular symptoms of depression. In their study on patients with malignant melanoma undergoing interferon-alfa therapy, Capuron et al. found symptoms of depression, anxiety, cognitive dysfunction, and pain were more responsive, whereas symptoms of fatigue and anorexia were less responsive to antidepressant treatment with paroxetine, a selective serotonin reuptake inhibitor (SSRl).25
In HCV patients who developed major depressive disorder, antidepressant treatment resulted in à significant reduction of BDI scores on the dimensions of psychomotor anhedonia, vegetative, and somatic symptoms, but not the dimension of negative cognitions.26 Although larger sample size studies are needed, these findings could have enormous implications for the management of side effects and may suggest strategies for improved adherence to interferon-alfa therapy.
TREATMENT OF INTERFERONALPHA-INDUCED DEPRESSION
Depressive symptoms generally resolve quickly when interferon-alfa therapy is discontinued, but to date, there are no other established alternalive treatments for chronic HCV. The following strategies may help manage interferon-alpha-induced depression, thereby allowing more patients to complete interferon-alfa therapy.
Screening Versus Prophylactic Use of Antidepressants
Review of the literature provides little published information regarding the use of specific depression screening instruments in the care of patients with HCV who are undergoing interferon-alfa therapy. It is currently unknown how many health care providers use standardized symptom rating instruments to assess depression in their patients before or during interferon-alfa therapy.
Optimally, all HCV patients should be screened for psychiatric disorders prior to the start of interferon-alfa therapy. For the purposes of screening patients before as well as during interferon-alfa therapy, various self-rated or clinician-rated depression scales have been used. Some of the more commonly used self-rated instruments are the BDl, the Zung Self-Rating Depression Scale, and the self-rating version of the Montgomery Asberg Depression Rating Scale.28 The Veterans Affairs (VA) Treatment Recommendations have selected the BDI as the symptom rating scale of choice. It is a self-rated instrument and is easy and rapid to use.
Recently, Clark et al. assessed the utility of the Center for Epidemiologic Studies Depression Scale in patients with HCV and found it to be a reliable and valid instrument to screen for depressive symptoms in patients with HCV.29 Taken together, these preliminary reports suggest such depression symptom rating scales tools can provide increased accuracy in assessing patient depressive symptoms as well as objective measurement of changes in mood states during the course of interferon-alfa therapy.
Prior to the initiation of interferon-alfa therapy, patients who screen positive for depression ideally should be referred to a mental health care provider, assessed for presence of a psychiatric disorder, and appropriately treated before starting interferon-alfa therapy. However, because of the common occurrence of depressive side effects during interferon-alfa therapy, some clinicians have argued in support of prophylactic antidepressant use, particularly in those patients who have elevated baseline depression scores.20 In patients with malignant melanoma treated with interferon-alfa, SSRIs have been shown to prevent or decrease the risk of interferonalpha-induced major depression,30,31 thus allowing patients to remain on interferonalfa therapy.
Although prophylactic antidepressant treatment may have benefit for some patients undergoing interferon-alfa therapy, the possibility of adverse events should be carefully considered. Specifically, there is the potential for increased retinal hemorrhaging and cotton-wool spots. The reported incidence of retinopathy in patients receiving interferon-alfa has ranged from 18% to 86% and occurs more frequently in older patients and patients with hypertension, diabetes mellitus, or both.32
In a report from Hejny et al., the authors described seven patients who developed interferon-alfa-associated retinopathy; six of these patients were also receiving antidepressant treatment with paroxetine.33 In addition, the occurrence of retinal hemorrhage and cotton-wool spots in a study of paroxetine prophylaxis for interferon-alfa-treated melanoma patients was three of 20, and in 1 of these patients, the hemorrhages were irreversible.34 Thus, it is important to distinguish symptoms of depression that may be subsyndromal from criterion-based major depression before antidepressant treatment is initiated, as there are potential risks in using antidepressants prophylactically for a non-Food and Drug Administration-approved indication.
There are no published, controlled studies that have investigated prophylactic antidepressant treatment in patients with HCV. We currently are involved in two double-blind, placebo-controlled studies to assess the effects of prophylactic antidepressant treatment on depressive symptoms associated with interferon-alfa therapy in patients with chronic HCV. Results from these and similar studies will help define the efficacy and safety of prophylactic antidepressant treatment as well as premature antidepressant treatment in patients who have some symptoms of depression but do not meet criteria for interferon-alpha-induced major depression.
Department of Veterans Affairs Treatment Recommendations
For patients with chronic HCV, the VA recommends pretreatment screening assessment by mental health providers for psychiatric illness. Guidelines state that:
All patients should undergo careful evaluation for uncontrolled, severe psychiatric disorders, particularly depression and suicide risk. Uncontrolled depression is an absolute contraindication to interferon-based therapies. Psychiatric disorders in full remission are not a contraindication to interferon therapy. Patients stabilized on antidepressant therapy should be considered for interferon-based therapy, provided mental health professionals monitor them closely.
During interferon-alfa therapy, the VA additionally recommends that35:
Patients not exhibiting depression before treatment should be evaluated for depression regularly (eg, every clinic visit - more frequent monitoring is advised in patients with psychiatric disease) until week 16. Pending further empirical support, the use of standardized questionnaire (eg, BDI, Brief Symptom Inventory) at each clinic visit, particularly in patients with symptoms of depression, until week 16 of treatment is encouraged. Patients with scores above clinical cutoffs should be considered for antidepressant treatment. Mental health professionals should be consulted in such patients. Also, patients with pretreatment scores below clinical cutoffs should receive a clinical evaluation by a mental health professional if their depression scores increase during treatment.
Although antidepressants are commonly prescribed for interferonalpha-induced depression, to date no controlled studies have been published regarding their efficacy in a large sample of HCV patients on interferon-alfa therapy. Importantly, there is anywhere from a 20- to 50-fold difference in the sample sizes of studies on HCV-related liver disease compared with studies that have examined strategies for the management of interferon-alfa side effects.
Several casé reports have been published suggesting that antidepressants, primarily SSRIs, are efficacious in ameliorating interferon-alpha-induced major depression.36'39 Furthermore, a recent study found that HCV patients undergoing interferon-alfa therapy had decreased levels of serum serotonin and that these serum concentrations were correlated to changes in depression scores on the Montgomery Asberg Depression Rating Scale, a validated screening instrument for depression.40
These data suggest serotonin depletion may explain, in part, interferon-alphainduced depression and also support SSRI antidepressant use. In regard to the safety of SSRI treatment for patients with HCV, one recent stuáy showed that major depressive disorder in HCV patients not undergoing interferon-alfa therapy is easily and safely treated with SSRIs and that SSRIs did not change liver function tests in these patients.41
Our prospective study provides preliminary evidence that adjunctive antidepressant treatment of interferonalpha-induced depression is effective, thereby allowing the continuation of interferon-alfa therapy in patients who develop interferon-alpha-induced major depression.1'5 In our study, 11 (84%) of 13 patients who received antidepressant treatment responded and remained on interferon-alfa therapy. Nine patients responded to Citalopram, one asked to be treated with fluoxetine as he had previously responded to it, and one responded to bupropion after having only a partial response to Citalopram at the maximal dose of 60 mg.
The remaining two patients failed all antidepressant treatment, and one of these patients became psychotic; these two patients were withdrawn from interferonalfa therapy. These findings suggest SSRIs, and Citalopram in particular, are an effective treatment that can reverse interferonalpha-induced depression and thus allow continuation of interferon-alfa therapy.
OTHER TREATMENT OPTIONS
Aside from the aforementioned reports that used SSRIs, there are no studies that have used other classes of antidepressants for the treatment of interferon-alphainduced depression. However, psychostimulants also may be an option for some patients. One pilot study of adjunctive methylphenidate and exercise in patients with malignant melanoma on interferonalfa therapy found the combination of methyl-phenidate and exercise appeared to reduce fatigue and have a positive effect on cognitive function.42
In addition to psychostimulants, the use of opioid antagonists also has been considered as a possible treatment for interferon-alpha-induced depression. Results from a pilot study of nine patients who had hematologic malignancies and were treated with naltrexone showed the majority of patients experienced complete or moderate relief of interferon-alpha-induced side effects.43 Collectively, these preliminary reports suggest possible alternative interventions against interferon-alfa depressive side effects and provide support for the role of other neurotransmitter systems (ie, dopaminergic and opioid) in mediating interferon-alfa neurotoxicity.
Based on current VA treatment guidelines, limited empirical data, and clinical experience, we offer the following recommendations for the management of depression during HCV interferon-alfa treatment:
* Obtain a thorough psychiatric history, including depression screening.
* Develop relationships with mental health providers.
* Treat preexisting depression before starting interferon-alfa therapy.
* Evaluate patients for the development of depression at least every 2 weeks after the initiation of interferon-alfa therapy using the BDI or other validated rating scales.
* If depression develops, initiate SSRI antidepressant treatment and continue to monitor mood symptoms during the course of therapy.
Hepatitis C preferentially affects mentally ill patients and veterans. Evidence of existing depression prior to interferon-alfa therapy should not automatically exclude patients from interferon-alfa therapy, particularly with close mental health follow-up. Although interferon-alfa neurotoxicity is poorly understood, recent efforts to characterize depressive side effects have become increasingly important and may ultimately contribute to the identification of more effective treatment strategies for patients undergoing interferon-alfa therapy. Finally, depression is a common side effect of interferon-alfa therapy that can be treated safely and effectively with SSRIs and should not interrupt potentially lifesaving therapy.
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