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Evidence-Based Reviews

Strategies for treating depression in patients with hepatitis C

Psychiatric symptoms can precede infection or be caused by HCV treatments

Vol. 12, No. 04 / April 2013

Dr. Sostre: Identifying and managing psychiatric symptoms in HCV patients

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.1 The prevalence of HCV among IV drug users is 28% to 90%.1 Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,1 guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.4 Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).4 However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV



HCV antibody

Determines prior exposure to HCV

HCV viral assay

Evaluates for current HCV infection

Liver biopsy

Assesses level of liver damage

HCV genotyping

Provides data to determine duration and intensity of treatment and likelihood of treatment success

HCV: hepatitis C virus
Source: Reference 4

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al1 found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 21,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus


Current rate

Lifetime rate

Mood disorders

34% to 35%


Major depressive disorder

22% to 28%


Anxiety disorders

26% to 44%


Antisocial personality disorder

No rates; lifetime diagnosis

16% to 40%

Psychotic disorders

9% to 17%


Substance use disorder


56% to 86%

Source: References 1,5,6

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.7,8

Box 1

Pathophysiology of fatigue and cognitive deficits in HCV

The pathophysiology of fatigue and neurocognitive dysfunction in hepatitis C virus (HCV) infection is unclear. However, the improvement of chronic fatigue in patients with HCV who receive ondansetron, a 5-hydroxytryptophan-3 receptor antagonist, has implicated abnormal monoaminergic function. Single-photon emission CT studies have found decreased midbrain serotonergic and striatal dopaminergic transmission in some HCV patients with cognitive deficits.7

Recently, data have been mounting on a direct neuropathic effect of HCV, with viral elements found in autopsy brain tissue and cerebrospinal fluid.8 Researchers have suggested that HCV may enter the CNS via a Trojan horse-like mechanism inside infected mononuclear cells.8 More recently, human brain microvascular endothelium, the major component of the blood-brain barrier, has been found to express all major viral receptors that would allow HCV infection of the CNS.9

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.12 To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.22

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.11 When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.2 Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.2

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”11 These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

The role of serotonin metabolism and genetic polymorphisms in depression among hepatitis C virus patients

Altered serotonin metabolism has been linked to depression in hepatitis C virus (HCV) patients treated with interferon-α (IFN-α). Tryptophan can be metabolized towards serotonin via tryptophan hydroxylase and niacin via indoleamine-2,3-dioxygenase (IDO) with kynurenine (KYN) and quinolinic acid (QUIN) as intermediaries. Introduction of IFN-α activates IDO, causing preferential conversion of tryptophan towards the niacin arm away from serotonin and leads to elevated levels of KYN and QUIN. KYN and QUIN are available centrally, are neurotoxic, and have been correlated with increased depressive symptoms in IFN-α-treated patients.a,b A tryptophan-deficient state is created, with less tryptophan being converted to serotonin and subsequently to its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Decreased levels of 5-HIAA in cerebrospinal fluid have been associated with higher depressive symptoms and higher rates of suicide.a,b

Several genetic polymorphisms may help identify patients at risk for developing IFN-α-induced depression. Genes for the 5’ promoter of the serotonin transporter (5-HTTLPR) have been investigated for roles in depression development in patients undergoing immunotherapy. Studies have found that persons with the short allele in the 5-HTTLPR gene are more likely to develop depression than those with the long allele. However, this has not been consistent across racial or ethnic groups.a,b Research also has associated the serotonin (5-HT) transporter, interferon receptor-A1, apolipoprotein ε4 allele, cyclooxygenase 2, and phospholipase A2 with development of a specific subgroup of symptoms.a

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