Hepatitis C: How to manage mood during interferon treatment

Mr. R, age 39, is found to have elevated liver function during a routine physical exam by his primary care physician. Subsequent testing reveals chronic hepatitis C viral (HCV) infection.

Starting at age 17, Mr. R abused alcohol and drugs and occasionally shared IV needles. He stopped using street drugs at age 28 when he lost contact with his drug abusing friends and is now married and has two children. In the past 10 years he has had two episodes of major depression, successfully treated with fluoxetine, 40 mg/d. He has no physical or psychiatric symptoms of HCV infection.

IV drug use causes >40% of HCV infections in the United States,¹ and substance abusers have increased rates of psychiatric illness, particularly major depression. But substance use does not account fully for the link between HCV infection and depression. A depressive syndrome may explain why depression’s mood and somatic symptoms are seen in significantly more HCV-infected drug users than in noninfected drug users.²

Psychiatrists are often called on to treat HCV-associated depression and other psychiatric symptoms—irritability, insomnia, and impaired concentration—and to support patients who pursue a cure through lengthy interferon treatment. To help you collaborate in the medical/psychiatric care of these patients, this article discusses:

• hepatitis C’s natural history
  
• diagnostic evaluation
  
• treatment options
  
• how to manage treatment’s psychiatric side effects.
  

Table 1

How Americans contract hepatitis C viral infection

Risk factor	Percentage of U.S. cases*
IV drug use	42%
Having >1 sexual partner	27%
Surgery	19%
Sexual contact with a hepatitis C patient	14%
Household contact with a hepatitis C patient	6%
Percutaneous injury (needlestick)	5%
Employment in medical/dental field	4%
Hemodialysis
Blood transfusion
* Patients could have more than one risk factor for hepatitis C transmission
Source: Centers for Disease Control and Prevention. Hepatitis surveillance report. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2006. no. 61.

Course of Chronic HCV

Mr. R’s primary care physician refers him to a gastroenterologist for liver function evaluation and treatment. Polymerase chain reaction testing reveals a detectable viral level, genotyping indicates that he has HCV type 1a, and liver biopsy shows moderate fibrosis.

As part of the clinic’s treatment protocol, Mr. R is referred to a psychiatrist for evaluation.

The typical interval from HCV infection to diagnosis is 10 to 30 years. Patients with unrecognized HCV infection usually are first treated by primary care physicians, who notice elevated liver function and refer them to a hepatologist or gastroenterologist.

In the United States, HCV is transmitted most frequently through IV drug use, sexual activity, and surgery (Table 1). Nearly all IV drug abusers (65% to 90%) have been exposed to HCV.¹ After exposure, 70% of patients develop chronic HCV infection. The disease often is asymptomatic for many years, and some patients never show symptoms. If symptoms develop, they are usually nonspecific, such as fatigue, abdominal discomfort, and nausea, and rarely jaundice and dark urine (Box).

Over time, the disease can progress to cirrhosis and hepatocellular carcinoma. Ten percent to 20% of HCV patients develop cirrhosis a mean 20 years after infection. Serious complications develop more rapidly in patients who:

• are age >40 when infected
  
• abuse alcohol
  
• have HIV or coexistent liver disease.
  

HCV diagnosis and treatment causes great stress for patients and their families, especially if the disease was transmitted through drug use or sexual activity. Most HCV clinics require that patients meet with mental health clinicians for psychosocial assessment before starting IFN treatment.

Mood Symptoms with IFN

Significant depressive symptoms occur in 21% to 58% of patients receiving interferon, with major depressive disorder developing at a mean 12 weeks (range 1 to 32 weeks) after therapy begins.³ Other patients develop depressive symptoms that do not meet DSM-IV-TR criteria for major depression.

Manic and hypomanic symptoms also may emerge, such as elevated mood, irritability, inflated self-esteem, insomnia, talkativeness, racing thoughts, distractibility, agitation, and excessive pursuit of pleasurable activities.

The mechanism for psychiatric side effects with IFN is unknown, but nutritional and metabolic alterations are thought to be responsible. One theory holds that IFN decreases CNS tryptophan levels by disrupting the transporter that ferries this essential amino acid across the blood-brain barrier. Deficient tryptophan—the rate-limiting step in serotonin synthesis—results in decreased serotonin levels.⁴ Another possible explanation is that interferon disrupts the hypothalamic-pituitary axis or more directly alters neural functioning.

Patient history of depression. One study asserted that patients with a history of depression or increased depressive symptoms at baseline are more susceptible to IFN-related psychiatric side effects such as irritability, insomnia, depression, and impaired concentration.⁵ Other studies, however, show no statistically significant difference in neuropsychiatric symptoms during IFN therapy in patients with preexisting psychiatric disorders and those without such a history.^6,7

 

Box

Whether or not patients with a psychiatric history are at increased risk, the incidence of neuropsychiatric effects with IFN remains high (Table 2) and warrants attention.^8-11

Psychiatric assessment. Assess all IFN candidates for present or past psychiatric disorders, including:

• depression
  
• suicidal thoughts (in one study, 43% of patients on IFN therapy reported suicidal ideation)¹²
  
• bipolar disorder (selective serotonin reuptake inhibitors [SSRIs] could induce mania or aggravate cycling)
  
• chemical dependency (substance abuse may represent the patient’s attempt to self-medicate underlying mood and anxiety symptoms).
  

Perform a baseline psychiatric exam to evaluate the patient’s emotional suitability for treatment and to screen for depression, anxiety disorders, posttraumatic stress disorder, bipolar disorder, and personality disorders. Evaluate the patient’s social support system, which may be augmented with group or individual therapy if deficient. Assess for depression and other psychiatric symptoms periodically and in some cases weekly during antiviral therapy.

Case Continued: Getting Ready

Although Mr. R no longer uses street drugs, he tells the psychiatrist he drinks 2 to 3 beers nightly. Because alcohol use stresses a compromised liver and could undermine IFN therapy’s effectiveness, he agrees to complete a chemical dependency program, demonstrate 6 months of sobriety before starting HCV treatment, and enroll in a chemical dependency relapse prevention program where unannounced drug and alcohol screenings are conducted.

As his IFN treatment approaches, Mr. R agrees to begin prophylactic citalopram, 20 mg/d, because he may be at increased risk for IFN-induced depression. Although Mr. R’s past depressive episodes responded well to fluoxetine, the psychiatrist chooses citalopram during IFN treatment because of its lower risk of drug-drug interactions.

Alcohol and IFN. Continued alcohol use can accelerate HCV-induced liver disease and reduce the likelihood of viral clearance with IFN treatment. One study showed that individuals who enrolled in a substance abuse treatment program were more likely to complete HCV treatment.¹³

This study also reported that HCV-seropositive patients were more likely to complete a 28-day chemical dependency treatment and remain abstinent 6 months after program discharge, compared with HCV-seronegative patients.¹³ This suggests that a chronic hepatitis C diagnosis motivates patients to address chemical dependency as a pre-requisite for hepatitis C treatment.

Table 2

Psychiatric side effects with interferon/ribavirin treatment*

Side effect	Prevalence
Irritability, anxiety	33% to 45%
Insomnia	30% to 40%
Depression	20% to 31%
Impaired concentration	10% to 17%
Aggressive behavior
Psychotic disorder
Suicide
* In patients without a history of psychiatric disorders
Source: References 19 and 20

Prophylactic antidepressants can be used in patients with a history of depressive episodes or baseline Beck Depression Inventory (BDI) scores >10. Prophylaxis is quite tolerable compared with IFN-induced depression, which has an insidious onset and can be associated with aggression, suicide risk, and interferon discontinuation.

Start antidepressants 2 to 4 weeks before antiviral therapy begins to allow the medication to reach therapeutic efficacy. SSRIs such as paroxetine, 10 to 50 mg/d, and citalopram, 20 to 40 mg/d, have been reported to be effective and do not interact with HCV therapies.^5,14 In our experience, dual-action antidepressants such as duloxetine, venlafaxine, or bupropion also can be beneficial.

IFN Treatment Protocol

Mr. R begins a 48-week IFN protocol. To maximize the treatment’s effectiveness, he is given long-acting pegylated interferon, 180 mcg injected weekly, and takes oral ribavirin, 600 mg twice daily.

IFN plus ribavirin. The mainstay of HCV therapy is IFN, a cytokine immunotherapeutic agent. A long-acting IFN administered weekly—called pegylated because the compound is bound to polyethylene glycol—doubles the sustained viral response rate and is now widely used.

Pegylated interferon is often combined with ribavirin—an oral nucleoside analog that has been shown to improve outcomes. Ribavirin increases the risk of hemolysis, however, which mandates frequent blood count monitoring. The NIH recommends pegylated interferon and ribavirin for patients with:

• detectable HCV RNA viral loads >50 copies per ml of blood
  
• liver biopsy with portal or bridging fibrosis
  
• and at least moderate inflammation and necrosis.
  

 

Forty-eight weeks of treatment are recommended for patients with HCV genotype 1 (70% of patients) and 24 weeks for those with HCV genotypes 2 and 3 (15% to 25% patients).

Some patients—particularly those with genotype 1b—do not respond to IFN therapy. For nonresponders, repeated trials of longer duration or different types of IFN may be tried. Higher IFN dosages or more frequent administration are not viewed as beneficial.

Side effects. Sustained response rates 6 months after patients complete interferon treatment are:

• 30% to 59% for genotype 1
  
• 60% to 90% for genotypes 2 or 3.^15-18
  

Reaching this goal is difficult, however, because 48 weeks or more of a typical treatment program is fraught with multiple physical and psychiatric side effects. The most common physical side effects of IFN treatment include initial flu-like symptoms followed by sleep disturbance, cognitive impairment, and fatigue.

Many of IFN’s early side effects are neurovegetative and overlap with psychiatric symptoms. The more specific psychiatric side effects of irritability, anxiety, insomnia, depression, and impaired concentration develop in 1 to 32 weeks of treatment (mean 12.1 weeks).^19,20 Fatigue and depression are the main reasons 10% to 14% of outpatients in large randomized trials discontinue HCV treatment.²¹

Table 3

HCV testing protocols

HCVab	If positive then do a HCV Riba
HCV Riba	If positive 2 bands or more, then do a HCV Genotype and HCV PCR
HCV Genotype	Genotype determines duration of treatment
HCV PCR Qualitative and/or Quantitative	Confirms presence of the virus
Liver biopsy	Determines the extent of liver damage from fibrosis or cirrhosis

Case Continued: Preventing Relapse

During therapy, Mr. R completes the BDI and Fatigue Severity Scale (FSS) weekly. His pretreatment BDI score of 9 (normal) increases over time to 22 (mild to moderate depression), and his FSS scores range from 4 to 6, indicating fatigue sufficient to impair daily functioning. Medical and psychiatric staff address his symptoms during weekly treatment assessments.

After 12 weeks of treatment his viral levels are undetectable, but he develops severe fatigue and mild irritability that contribute to arguments with his wife. He is referred to supportive counseling, and citalopram is increased to 40 mg/d. His wife tests negative for HCV.

Monitor patients closely during IFN treatment, regardless of whether an antidepressant is prescribed. If depression abruptly worsens or mania emerges, IFN might need to be discontinued until the patient’s psychiatric disorder is stabilized. Adding an atypical antipsychotic—such as olanzapine, 10 to 20 mg/d—can help patients with psychosis, mania, mood lability, impulsivity, or irritability.²²

For patients with substantial fatigue, we may supplement antidepressants with modafinil, 100 to 200 mg/d, which caused some improvement in an open trial as measured by the FSS.²³ Support groups and cognitive-behavioral therapy have shown modest benefit.

Case Continued: Staying Healthy

Mr. R completes treatment, and his prognosis for remaining virus-free remains good. His fatigue and irritability resolve, and his BDI score returns to 9. One year later, he maintains a negative viral load. He periodically returns to his gastroenterologist for monitoring and continues in a chemical dependency relapse prevention program.

Mr. R acknowledges that his HCV-seronegative status motivates him to stay sober. Citalopram was withdrawn 1 month after he completed antiviral treatment, and his wife has not noted resurgent irritability. He has returned to work, and his supervisors report satisfactory task completion.

Related resources

• American Liver Foundation. www.liverfoundation.org.
  
• U.S. Centers for Disease Control and Prevention. Viral Hepatitis. www.cdc.gov/hepatitis.
  
• Hep C Connection. www.hepc-connection.org.
  
• Hepatitis C Support Project. www.hcvadvocate.org.
  
• National Institute of Mental Health. Depression. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• U.S. Department of Veterans Affairs National Hepatitis C Program. www.hepatitis.va.gov.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Modafinil • Provigil
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Martin, Dr. Krahn, and Ms. Rosati report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Balan receives research grants from Novartis, Roche Pharmaceuticals, Schering-Plough, InterMune, SciClone Pharmaceuticals, and Human Genome Sciences.

Mr. R, age 39, is found to have elevated liver function during a routine physical exam by his primary care physician. Subsequent testing reveals chronic hepatitis C viral (HCV) infection.

Starting at age 17, Mr. R abused alcohol and drugs and occasionally shared IV needles. He stopped using street drugs at age 28 when he lost contact with his drug abusing friends and is now married and has two children. In the past 10 years he has had two episodes of major depression, successfully treated with fluoxetine, 40 mg/d. He has no physical or psychiatric symptoms of HCV infection.

IV drug use causes >40% of HCV infections in the United States,¹ and substance abusers have increased rates of psychiatric illness, particularly major depression. But substance use does not account fully for the link between HCV infection and depression. A depressive syndrome may explain why depression’s mood and somatic symptoms are seen in significantly more HCV-infected drug users than in noninfected drug users.²

Psychiatrists are often called on to treat HCV-associated depression and other psychiatric symptoms—irritability, insomnia, and impaired concentration—and to support patients who pursue a cure through lengthy interferon treatment. To help you collaborate in the medical/psychiatric care of these patients, this article discusses:

• hepatitis C’s natural history
  
• diagnostic evaluation
  
• treatment options
  
• how to manage treatment’s psychiatric side effects.
  

Table 1

How Americans contract hepatitis C viral infection

Risk factor	Percentage of U.S. cases*
IV drug use	42%
Having >1 sexual partner	27%
Surgery	19%
Sexual contact with a hepatitis C patient	14%
Household contact with a hepatitis C patient	6%
Percutaneous injury (needlestick)	5%
Employment in medical/dental field	4%
Hemodialysis
Blood transfusion
* Patients could have more than one risk factor for hepatitis C transmission
Source: Centers for Disease Control and Prevention. Hepatitis surveillance report. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2006. no. 61.

Course of Chronic HCV

Mr. R’s primary care physician refers him to a gastroenterologist for liver function evaluation and treatment. Polymerase chain reaction testing reveals a detectable viral level, genotyping indicates that he has HCV type 1a, and liver biopsy shows moderate fibrosis.

As part of the clinic’s treatment protocol, Mr. R is referred to a psychiatrist for evaluation.

The typical interval from HCV infection to diagnosis is 10 to 30 years. Patients with unrecognized HCV infection usually are first treated by primary care physicians, who notice elevated liver function and refer them to a hepatologist or gastroenterologist.

In the United States, HCV is transmitted most frequently through IV drug use, sexual activity, and surgery (Table 1). Nearly all IV drug abusers (65% to 90%) have been exposed to HCV.¹ After exposure, 70% of patients develop chronic HCV infection. The disease often is asymptomatic for many years, and some patients never show symptoms. If symptoms develop, they are usually nonspecific, such as fatigue, abdominal discomfort, and nausea, and rarely jaundice and dark urine (Box).

Over time, the disease can progress to cirrhosis and hepatocellular carcinoma. Ten percent to 20% of HCV patients develop cirrhosis a mean 20 years after infection. Serious complications develop more rapidly in patients who:

• are age >40 when infected
  
• abuse alcohol
  
• have HIV or coexistent liver disease.
  

HCV diagnosis and treatment causes great stress for patients and their families, especially if the disease was transmitted through drug use or sexual activity. Most HCV clinics require that patients meet with mental health clinicians for psychosocial assessment before starting IFN treatment.

Mood Symptoms with IFN

Significant depressive symptoms occur in 21% to 58% of patients receiving interferon, with major depressive disorder developing at a mean 12 weeks (range 1 to 32 weeks) after therapy begins.³ Other patients develop depressive symptoms that do not meet DSM-IV-TR criteria for major depression.

Manic and hypomanic symptoms also may emerge, such as elevated mood, irritability, inflated self-esteem, insomnia, talkativeness, racing thoughts, distractibility, agitation, and excessive pursuit of pleasurable activities.

The mechanism for psychiatric side effects with IFN is unknown, but nutritional and metabolic alterations are thought to be responsible. One theory holds that IFN decreases CNS tryptophan levels by disrupting the transporter that ferries this essential amino acid across the blood-brain barrier. Deficient tryptophan—the rate-limiting step in serotonin synthesis—results in decreased serotonin levels.⁴ Another possible explanation is that interferon disrupts the hypothalamic-pituitary axis or more directly alters neural functioning.

Patient history of depression. One study asserted that patients with a history of depression or increased depressive symptoms at baseline are more susceptible to IFN-related psychiatric side effects such as irritability, insomnia, depression, and impaired concentration.⁵ Other studies, however, show no statistically significant difference in neuropsychiatric symptoms during IFN therapy in patients with preexisting psychiatric disorders and those without such a history.^6,7

 

Box

Whether or not patients with a psychiatric history are at increased risk, the incidence of neuropsychiatric effects with IFN remains high (Table 2) and warrants attention.^8-11

Psychiatric assessment. Assess all IFN candidates for present or past psychiatric disorders, including:

• depression
  
• suicidal thoughts (in one study, 43% of patients on IFN therapy reported suicidal ideation)¹²
  
• bipolar disorder (selective serotonin reuptake inhibitors [SSRIs] could induce mania or aggravate cycling)
  
• chemical dependency (substance abuse may represent the patient’s attempt to self-medicate underlying mood and anxiety symptoms).
  

Perform a baseline psychiatric exam to evaluate the patient’s emotional suitability for treatment and to screen for depression, anxiety disorders, posttraumatic stress disorder, bipolar disorder, and personality disorders. Evaluate the patient’s social support system, which may be augmented with group or individual therapy if deficient. Assess for depression and other psychiatric symptoms periodically and in some cases weekly during antiviral therapy.

Case Continued: Getting Ready

Although Mr. R no longer uses street drugs, he tells the psychiatrist he drinks 2 to 3 beers nightly. Because alcohol use stresses a compromised liver and could undermine IFN therapy’s effectiveness, he agrees to complete a chemical dependency program, demonstrate 6 months of sobriety before starting HCV treatment, and enroll in a chemical dependency relapse prevention program where unannounced drug and alcohol screenings are conducted.

As his IFN treatment approaches, Mr. R agrees to begin prophylactic citalopram, 20 mg/d, because he may be at increased risk for IFN-induced depression. Although Mr. R’s past depressive episodes responded well to fluoxetine, the psychiatrist chooses citalopram during IFN treatment because of its lower risk of drug-drug interactions.

Alcohol and IFN. Continued alcohol use can accelerate HCV-induced liver disease and reduce the likelihood of viral clearance with IFN treatment. One study showed that individuals who enrolled in a substance abuse treatment program were more likely to complete HCV treatment.¹³

This study also reported that HCV-seropositive patients were more likely to complete a 28-day chemical dependency treatment and remain abstinent 6 months after program discharge, compared with HCV-seronegative patients.¹³ This suggests that a chronic hepatitis C diagnosis motivates patients to address chemical dependency as a pre-requisite for hepatitis C treatment.

Table 2

Psychiatric side effects with interferon/ribavirin treatment*

Side effect	Prevalence
Irritability, anxiety	33% to 45%
Insomnia	30% to 40%
Depression	20% to 31%
Impaired concentration	10% to 17%
Aggressive behavior
Psychotic disorder
Suicide
* In patients without a history of psychiatric disorders
Source: References 19 and 20

Prophylactic antidepressants can be used in patients with a history of depressive episodes or baseline Beck Depression Inventory (BDI) scores >10. Prophylaxis is quite tolerable compared with IFN-induced depression, which has an insidious onset and can be associated with aggression, suicide risk, and interferon discontinuation.

Start antidepressants 2 to 4 weeks before antiviral therapy begins to allow the medication to reach therapeutic efficacy. SSRIs such as paroxetine, 10 to 50 mg/d, and citalopram, 20 to 40 mg/d, have been reported to be effective and do not interact with HCV therapies.^5,14 In our experience, dual-action antidepressants such as duloxetine, venlafaxine, or bupropion also can be beneficial.

IFN Treatment Protocol

Mr. R begins a 48-week IFN protocol. To maximize the treatment’s effectiveness, he is given long-acting pegylated interferon, 180 mcg injected weekly, and takes oral ribavirin, 600 mg twice daily.

IFN plus ribavirin. The mainstay of HCV therapy is IFN, a cytokine immunotherapeutic agent. A long-acting IFN administered weekly—called pegylated because the compound is bound to polyethylene glycol—doubles the sustained viral response rate and is now widely used.

Pegylated interferon is often combined with ribavirin—an oral nucleoside analog that has been shown to improve outcomes. Ribavirin increases the risk of hemolysis, however, which mandates frequent blood count monitoring. The NIH recommends pegylated interferon and ribavirin for patients with:

• detectable HCV RNA viral loads >50 copies per ml of blood
  
• liver biopsy with portal or bridging fibrosis
  
• and at least moderate inflammation and necrosis.
  

 

Forty-eight weeks of treatment are recommended for patients with HCV genotype 1 (70% of patients) and 24 weeks for those with HCV genotypes 2 and 3 (15% to 25% patients).

Some patients—particularly those with genotype 1b—do not respond to IFN therapy. For nonresponders, repeated trials of longer duration or different types of IFN may be tried. Higher IFN dosages or more frequent administration are not viewed as beneficial.

Side effects. Sustained response rates 6 months after patients complete interferon treatment are:

• 30% to 59% for genotype 1
  
• 60% to 90% for genotypes 2 or 3.^15-18
  

Reaching this goal is difficult, however, because 48 weeks or more of a typical treatment program is fraught with multiple physical and psychiatric side effects. The most common physical side effects of IFN treatment include initial flu-like symptoms followed by sleep disturbance, cognitive impairment, and fatigue.

Many of IFN’s early side effects are neurovegetative and overlap with psychiatric symptoms. The more specific psychiatric side effects of irritability, anxiety, insomnia, depression, and impaired concentration develop in 1 to 32 weeks of treatment (mean 12.1 weeks).^19,20 Fatigue and depression are the main reasons 10% to 14% of outpatients in large randomized trials discontinue HCV treatment.²¹

Table 3

HCV testing protocols

HCVab	If positive then do a HCV Riba
HCV Riba	If positive 2 bands or more, then do a HCV Genotype and HCV PCR
HCV Genotype	Genotype determines duration of treatment
HCV PCR Qualitative and/or Quantitative	Confirms presence of the virus
Liver biopsy	Determines the extent of liver damage from fibrosis or cirrhosis

Case Continued: Preventing Relapse

During therapy, Mr. R completes the BDI and Fatigue Severity Scale (FSS) weekly. His pretreatment BDI score of 9 (normal) increases over time to 22 (mild to moderate depression), and his FSS scores range from 4 to 6, indicating fatigue sufficient to impair daily functioning. Medical and psychiatric staff address his symptoms during weekly treatment assessments.

After 12 weeks of treatment his viral levels are undetectable, but he develops severe fatigue and mild irritability that contribute to arguments with his wife. He is referred to supportive counseling, and citalopram is increased to 40 mg/d. His wife tests negative for HCV.

Monitor patients closely during IFN treatment, regardless of whether an antidepressant is prescribed. If depression abruptly worsens or mania emerges, IFN might need to be discontinued until the patient’s psychiatric disorder is stabilized. Adding an atypical antipsychotic—such as olanzapine, 10 to 20 mg/d—can help patients with psychosis, mania, mood lability, impulsivity, or irritability.²²

For patients with substantial fatigue, we may supplement antidepressants with modafinil, 100 to 200 mg/d, which caused some improvement in an open trial as measured by the FSS.²³ Support groups and cognitive-behavioral therapy have shown modest benefit.

Case Continued: Staying Healthy

Mr. R completes treatment, and his prognosis for remaining virus-free remains good. His fatigue and irritability resolve, and his BDI score returns to 9. One year later, he maintains a negative viral load. He periodically returns to his gastroenterologist for monitoring and continues in a chemical dependency relapse prevention program.

Mr. R acknowledges that his HCV-seronegative status motivates him to stay sober. Citalopram was withdrawn 1 month after he completed antiviral treatment, and his wife has not noted resurgent irritability. He has returned to work, and his supervisors report satisfactory task completion.

Related resources

• American Liver Foundation. www.liverfoundation.org.
  
• U.S. Centers for Disease Control and Prevention. Viral Hepatitis. www.cdc.gov/hepatitis.
  
• Hep C Connection. www.hepc-connection.org.
  
• Hepatitis C Support Project. www.hcvadvocate.org.
  
• National Institute of Mental Health. Depression. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• U.S. Department of Veterans Affairs National Hepatitis C Program. www.hepatitis.va.gov.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Modafinil • Provigil
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Martin, Dr. Krahn, and Ms. Rosati report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Balan receives research grants from Novartis, Roche Pharmaceuticals, Schering-Plough, InterMune, SciClone Pharmaceuticals, and Human Genome Sciences.

Mr. R, age 39, is found to have elevated liver function during a routine physical exam by his primary care physician. Subsequent testing reveals chronic hepatitis C viral (HCV) infection.

Starting at age 17, Mr. R abused alcohol and drugs and occasionally shared IV needles. He stopped using street drugs at age 28 when he lost contact with his drug abusing friends and is now married and has two children. In the past 10 years he has had two episodes of major depression, successfully treated with fluoxetine, 40 mg/d. He has no physical or psychiatric symptoms of HCV infection.

IV drug use causes >40% of HCV infections in the United States,¹ and substance abusers have increased rates of psychiatric illness, particularly major depression. But substance use does not account fully for the link between HCV infection and depression. A depressive syndrome may explain why depression’s mood and somatic symptoms are seen in significantly more HCV-infected drug users than in noninfected drug users.²

Psychiatrists are often called on to treat HCV-associated depression and other psychiatric symptoms—irritability, insomnia, and impaired concentration—and to support patients who pursue a cure through lengthy interferon treatment. To help you collaborate in the medical/psychiatric care of these patients, this article discusses:

• hepatitis C’s natural history
  
• diagnostic evaluation
  
• treatment options
  
• how to manage treatment’s psychiatric side effects.
  

Table 1

How Americans contract hepatitis C viral infection

Risk factor	Percentage of U.S. cases*
IV drug use	42%
Having >1 sexual partner	27%
Surgery	19%
Sexual contact with a hepatitis C patient	14%
Household contact with a hepatitis C patient	6%
Percutaneous injury (needlestick)	5%
Employment in medical/dental field	4%
Hemodialysis
Blood transfusion
* Patients could have more than one risk factor for hepatitis C transmission
Source: Centers for Disease Control and Prevention. Hepatitis surveillance report. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2006. no. 61.

Course of Chronic HCV

Mr. R’s primary care physician refers him to a gastroenterologist for liver function evaluation and treatment. Polymerase chain reaction testing reveals a detectable viral level, genotyping indicates that he has HCV type 1a, and liver biopsy shows moderate fibrosis.

As part of the clinic’s treatment protocol, Mr. R is referred to a psychiatrist for evaluation.

The typical interval from HCV infection to diagnosis is 10 to 30 years. Patients with unrecognized HCV infection usually are first treated by primary care physicians, who notice elevated liver function and refer them to a hepatologist or gastroenterologist.

In the United States, HCV is transmitted most frequently through IV drug use, sexual activity, and surgery (Table 1). Nearly all IV drug abusers (65% to 90%) have been exposed to HCV.¹ After exposure, 70% of patients develop chronic HCV infection. The disease often is asymptomatic for many years, and some patients never show symptoms. If symptoms develop, they are usually nonspecific, such as fatigue, abdominal discomfort, and nausea, and rarely jaundice and dark urine (Box).

Over time, the disease can progress to cirrhosis and hepatocellular carcinoma. Ten percent to 20% of HCV patients develop cirrhosis a mean 20 years after infection. Serious complications develop more rapidly in patients who:

• are age >40 when infected
  
• abuse alcohol
  
• have HIV or coexistent liver disease.
  

HCV diagnosis and treatment causes great stress for patients and their families, especially if the disease was transmitted through drug use or sexual activity. Most HCV clinics require that patients meet with mental health clinicians for psychosocial assessment before starting IFN treatment.

Mood Symptoms with IFN

Significant depressive symptoms occur in 21% to 58% of patients receiving interferon, with major depressive disorder developing at a mean 12 weeks (range 1 to 32 weeks) after therapy begins.³ Other patients develop depressive symptoms that do not meet DSM-IV-TR criteria for major depression.

Manic and hypomanic symptoms also may emerge, such as elevated mood, irritability, inflated self-esteem, insomnia, talkativeness, racing thoughts, distractibility, agitation, and excessive pursuit of pleasurable activities.

The mechanism for psychiatric side effects with IFN is unknown, but nutritional and metabolic alterations are thought to be responsible. One theory holds that IFN decreases CNS tryptophan levels by disrupting the transporter that ferries this essential amino acid across the blood-brain barrier. Deficient tryptophan—the rate-limiting step in serotonin synthesis—results in decreased serotonin levels.⁴ Another possible explanation is that interferon disrupts the hypothalamic-pituitary axis or more directly alters neural functioning.

Patient history of depression. One study asserted that patients with a history of depression or increased depressive symptoms at baseline are more susceptible to IFN-related psychiatric side effects such as irritability, insomnia, depression, and impaired concentration.⁵ Other studies, however, show no statistically significant difference in neuropsychiatric symptoms during IFN therapy in patients with preexisting psychiatric disorders and those without such a history.^6,7

 

Box

Whether or not patients with a psychiatric history are at increased risk, the incidence of neuropsychiatric effects with IFN remains high (Table 2) and warrants attention.^8-11

Psychiatric assessment. Assess all IFN candidates for present or past psychiatric disorders, including:

• depression
  
• suicidal thoughts (in one study, 43% of patients on IFN therapy reported suicidal ideation)¹²
  
• bipolar disorder (selective serotonin reuptake inhibitors [SSRIs] could induce mania or aggravate cycling)
  
• chemical dependency (substance abuse may represent the patient’s attempt to self-medicate underlying mood and anxiety symptoms).
  

Perform a baseline psychiatric exam to evaluate the patient’s emotional suitability for treatment and to screen for depression, anxiety disorders, posttraumatic stress disorder, bipolar disorder, and personality disorders. Evaluate the patient’s social support system, which may be augmented with group or individual therapy if deficient. Assess for depression and other psychiatric symptoms periodically and in some cases weekly during antiviral therapy.

Case Continued: Getting Ready

Although Mr. R no longer uses street drugs, he tells the psychiatrist he drinks 2 to 3 beers nightly. Because alcohol use stresses a compromised liver and could undermine IFN therapy’s effectiveness, he agrees to complete a chemical dependency program, demonstrate 6 months of sobriety before starting HCV treatment, and enroll in a chemical dependency relapse prevention program where unannounced drug and alcohol screenings are conducted.

As his IFN treatment approaches, Mr. R agrees to begin prophylactic citalopram, 20 mg/d, because he may be at increased risk for IFN-induced depression. Although Mr. R’s past depressive episodes responded well to fluoxetine, the psychiatrist chooses citalopram during IFN treatment because of its lower risk of drug-drug interactions.

Alcohol and IFN. Continued alcohol use can accelerate HCV-induced liver disease and reduce the likelihood of viral clearance with IFN treatment. One study showed that individuals who enrolled in a substance abuse treatment program were more likely to complete HCV treatment.¹³

This study also reported that HCV-seropositive patients were more likely to complete a 28-day chemical dependency treatment and remain abstinent 6 months after program discharge, compared with HCV-seronegative patients.¹³ This suggests that a chronic hepatitis C diagnosis motivates patients to address chemical dependency as a pre-requisite for hepatitis C treatment.

Table 2

Psychiatric side effects with interferon/ribavirin treatment*

Side effect	Prevalence
Irritability, anxiety	33% to 45%
Insomnia	30% to 40%
Depression	20% to 31%
Impaired concentration	10% to 17%
Aggressive behavior
Psychotic disorder
Suicide
* In patients without a history of psychiatric disorders
Source: References 19 and 20

Prophylactic antidepressants can be used in patients with a history of depressive episodes or baseline Beck Depression Inventory (BDI) scores >10. Prophylaxis is quite tolerable compared with IFN-induced depression, which has an insidious onset and can be associated with aggression, suicide risk, and interferon discontinuation.

Start antidepressants 2 to 4 weeks before antiviral therapy begins to allow the medication to reach therapeutic efficacy. SSRIs such as paroxetine, 10 to 50 mg/d, and citalopram, 20 to 40 mg/d, have been reported to be effective and do not interact with HCV therapies.^5,14 In our experience, dual-action antidepressants such as duloxetine, venlafaxine, or bupropion also can be beneficial.

IFN Treatment Protocol

Mr. R begins a 48-week IFN protocol. To maximize the treatment’s effectiveness, he is given long-acting pegylated interferon, 180 mcg injected weekly, and takes oral ribavirin, 600 mg twice daily.

IFN plus ribavirin. The mainstay of HCV therapy is IFN, a cytokine immunotherapeutic agent. A long-acting IFN administered weekly—called pegylated because the compound is bound to polyethylene glycol—doubles the sustained viral response rate and is now widely used.

Pegylated interferon is often combined with ribavirin—an oral nucleoside analog that has been shown to improve outcomes. Ribavirin increases the risk of hemolysis, however, which mandates frequent blood count monitoring. The NIH recommends pegylated interferon and ribavirin for patients with:

• detectable HCV RNA viral loads >50 copies per ml of blood
  
• liver biopsy with portal or bridging fibrosis
  
• and at least moderate inflammation and necrosis.
  

 

Forty-eight weeks of treatment are recommended for patients with HCV genotype 1 (70% of patients) and 24 weeks for those with HCV genotypes 2 and 3 (15% to 25% patients).

Some patients—particularly those with genotype 1b—do not respond to IFN therapy. For nonresponders, repeated trials of longer duration or different types of IFN may be tried. Higher IFN dosages or more frequent administration are not viewed as beneficial.

Side effects. Sustained response rates 6 months after patients complete interferon treatment are:

• 30% to 59% for genotype 1
  
• 60% to 90% for genotypes 2 or 3.^15-18
  

Reaching this goal is difficult, however, because 48 weeks or more of a typical treatment program is fraught with multiple physical and psychiatric side effects. The most common physical side effects of IFN treatment include initial flu-like symptoms followed by sleep disturbance, cognitive impairment, and fatigue.

Many of IFN’s early side effects are neurovegetative and overlap with psychiatric symptoms. The more specific psychiatric side effects of irritability, anxiety, insomnia, depression, and impaired concentration develop in 1 to 32 weeks of treatment (mean 12.1 weeks).^19,20 Fatigue and depression are the main reasons 10% to 14% of outpatients in large randomized trials discontinue HCV treatment.²¹

Table 3

HCV testing protocols

HCVab	If positive then do a HCV Riba
HCV Riba	If positive 2 bands or more, then do a HCV Genotype and HCV PCR
HCV Genotype	Genotype determines duration of treatment
HCV PCR Qualitative and/or Quantitative	Confirms presence of the virus
Liver biopsy	Determines the extent of liver damage from fibrosis or cirrhosis

Case Continued: Preventing Relapse

During therapy, Mr. R completes the BDI and Fatigue Severity Scale (FSS) weekly. His pretreatment BDI score of 9 (normal) increases over time to 22 (mild to moderate depression), and his FSS scores range from 4 to 6, indicating fatigue sufficient to impair daily functioning. Medical and psychiatric staff address his symptoms during weekly treatment assessments.

After 12 weeks of treatment his viral levels are undetectable, but he develops severe fatigue and mild irritability that contribute to arguments with his wife. He is referred to supportive counseling, and citalopram is increased to 40 mg/d. His wife tests negative for HCV.

Monitor patients closely during IFN treatment, regardless of whether an antidepressant is prescribed. If depression abruptly worsens or mania emerges, IFN might need to be discontinued until the patient’s psychiatric disorder is stabilized. Adding an atypical antipsychotic—such as olanzapine, 10 to 20 mg/d—can help patients with psychosis, mania, mood lability, impulsivity, or irritability.²²

For patients with substantial fatigue, we may supplement antidepressants with modafinil, 100 to 200 mg/d, which caused some improvement in an open trial as measured by the FSS.²³ Support groups and cognitive-behavioral therapy have shown modest benefit.

Case Continued: Staying Healthy

Mr. R completes treatment, and his prognosis for remaining virus-free remains good. His fatigue and irritability resolve, and his BDI score returns to 9. One year later, he maintains a negative viral load. He periodically returns to his gastroenterologist for monitoring and continues in a chemical dependency relapse prevention program.

Mr. R acknowledges that his HCV-seronegative status motivates him to stay sober. Citalopram was withdrawn 1 month after he completed antiviral treatment, and his wife has not noted resurgent irritability. He has returned to work, and his supervisors report satisfactory task completion.

Related resources

• American Liver Foundation. www.liverfoundation.org.
  
• U.S. Centers for Disease Control and Prevention. Viral Hepatitis. www.cdc.gov/hepatitis.
  
• Hep C Connection. www.hepc-connection.org.
  
• Hepatitis C Support Project. www.hcvadvocate.org.
  
• National Institute of Mental Health. Depression. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• U.S. Department of Veterans Affairs National Hepatitis C Program. www.hepatitis.va.gov.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Modafinil • Provigil
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Venlafaxine • Effexor
  

Disclosures

Dr. Martin, Dr. Krahn, and Ms. Rosati report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Balan receives research grants from Novartis, Roche Pharmaceuticals, Schering-Plough, InterMune, SciClone Pharmaceuticals, and Human Genome Sciences.