1. health and fitness
2. therapy

M ed/Psych Update
Hepatitis C: How to manage
mood during interferon treatment
Support patients through lengthy antiviral regimen
edia
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Kari A. Martin, MD
Instructor of psychiatry
Department of psychiatry and psychology
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Cop For pe
Lois E. Krahn, MD
Chair and professor of psychiatry
Department of psychiatry and psychology
Marianne J. Rosati, MSN, CRNP
Instructor in medicine
Division of transplantation medicine and hepatology
Vijayan Balan, MD
Professor of medicine
Department of internal medicine
Division of transplantation medicine
Mayo Clinic Arizona
Scottsdale, AZ
M
r. 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.
© 2006 Getty / Harald Sund
continued
VOL. 5, NO. 11 / NOVEMBER 2006
69
For mass reproduction, content licensing and permissions contact Dowden Health Media.
M ed/Psych Update
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
<1%
• how to manage treatment’s
psychiatric side effects.
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
* Patients could have more than one risk factor for hepatitis C transmission
years. Patients with unrecognized
Source: Centers for Disease Control and Prevention. Hepatitis surveillance report.
HCV infection usually are first
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention; 2006. no. 61.
treated by primary care physicians, who notice elevated liver
function and refer them to a
hepatologist or gastroenterologist.
IV drug use causes >40% of HCV infections in
In the United States, HCV is transmitted
the United States,1 and substance abusers have
most frequently through IV drug use, sexual
increased rates of psychiatric illness, particularly
activity, and surgery (Table 1). Nearly all IV drug
major depression. But substance use does not
account fully for the link between HCV infection
abusers (65% to 90%) have been exposed to
and depression. A depressive syndrome may
HCV.1 After exposure, 70% of patients develop
explain why depression’s mood and somatic sympchronic HCV infection. The disease often is
toms are seen in significantly more HCV-infected
asymptomatic for many years, and some patients
drug users than in noninfected drug users.2
never show symptoms. If symptoms develop, they
are usually nonspecific, such as fatigue, abdomiPsychiatrists are often called on to treat
HCV-associated depression and other psychiatric
nal discomfort, and nausea, and rarely jaundice
symptoms—irritability, insomnia, and impaired
and dark urine (Box, page 72).
concentration—and to support patients who purOver time, the disease can progress to cirrhosue a cure through lengthy interferon treatment.
sis and hepatocellular carcinoma. Ten percent to
To help you collaborate in the medical/psychi20% of HCV patients develop cirrhosis a mean 20
atric care of these patients, this article discusses:
years after infection. Serious complications devel• hepatitis C’s natural history
op more rapidly in patients who:
• diagnostic evaluation
• are age >40 when infected
• treatment options
• abuse alcohol
Blood transfusion
<1%
continued on page 72
70
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VOL. 5, NO. 11 / NOVEMBER 2006
M ed/Psych Update
continued from page 70
• 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.
Box
Hepatitis C: Risk of infection
and disease progression
❚
HCV affects 2% of the U.S. population but
20% of persons with severe mental illness
❚
Average annual new infections declined to
36,000 in 1996 from a high of 230,000 in the
1980s, which for reasons that are unclear
correlates with a decrease in cases among
IV drug users
❚
Progression of HCV infection is the leading
cause of liver transplants in the United States
❚
Persons infected with HCV are at an
increased risk for disease progression if they
drink alcohol (>2 drinks/day for men under
age 65, >1 drink/day for nonpregnant women
and all persons over age 66), are age >40
years at time of infection, or are HIV-positive
❚
Deaths from acute liver failure are rare
❚
Chronic HCV infection causes 8,000 to 10,000
deaths per year
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
Source: References 24 and 25
Whether or not patients with a psychiatric
history are at increased risk, the incidence of
neuropsychiatric effects with IFN remains high
(Table 2, page 77) 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 selfmedicate underlying mood and anxiety
symptoms).
continued on page 77
72
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continued from page 72
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 accel-
erate 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
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
< 1%
Psychotic disorder
< 1%
Suicide
< 1%
* In patients without a history of psychiatric disorders
Source: References 19 and 20
patients to address chemical dependency as a prerequisite for hepatitis C treatment.
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.
continued
VOL. 5, NO. 11 / NOVEMBER 2006
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M ed/Psych Update
Table 3
• liver biopsy with portal or
bridging fibrosis
• and at least moderate inflammation and necrosis.
HCVab
If positive then do a HCV Riba
Forty-eight weeks of treatment
HCV Riba
If positive 2 bands or more, then
are recommended for patients with
do a HCV Genotype and HCV PCR
HCV genotype 1 (70% of patients)
HCV Genotype
Genotype determines duration of
and 24 weeks for those with HCV
treatment
genotypes 2 and 3 (15% to 25%
patients).
HCV PCR Qualitative
Confirms presence of the virus
Some patients—particularly those
and/or Quantitative
with genotype 1b—do not respond
Determines the extent of liver
Liver biopsy
to IFN therapy. For nonresponders,
damage from fibrosis or cirrhosis
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.
IFN plus ribavirin. The mainstay of HCV therapy
is IFN, a cytokine immunotherapeutic agent. A
Side effects. Sustained response rates 6 months
long-acting IFN administered weekly—called
after patients complete interferon treatment are:
pegylated because the compound is bound to
• 30% to 59% for genotype 1
polyethylene glycol—doubles the sustained viral
• 60% to 90% for genotypes 2 or 3.15-18
response rate and is now widely used.
Reaching this goal is difficult, however,
Pegylated interferon is often combined with
because 48 weeks or more of a typical treatment
ribavirin—an oral nucleoside analog that has
program is fraught with multiple physical and
been shown to improve outcomes. Ribavirin
psychiatric side effects. The most common physincreases the risk of hemolysis, however, which
ical side effects of IFN treatment include initial
mandates frequent blood count monitoring. The
flu-like symptoms followed by sleep disturbance,
NIH recommends pegylated interferon and ribcognitive impairment, and fatigue.
avirin for patients with:
Many of IFN’s early side effects are neu• detectable HCV RNA viral loads >50
rovegetative and overlap with psychiatric sympcopies per ml of blood
toms. The more specific psychiatric side effects of
irritability, anxiety, insomnia, depression, and
impaired concentration develop in 1 to 32 weeks
Psychiatrists are often consulted to
of treatment (mean 12.1 weeks).19,20 Fatigue and
manage side effects—such as depression,
depression are the main reasons 10% to 14% of
insomnia, impaired concentration, and
outpatients in large randomized trials discontinirritability—of hepatitis C viral infection
ue HCV treatment.21
and its treatment. Prophylactic
antidepressants and careful monitoring
CASE CONTINUED: PREVENTING RELAPSE
during interferon therapy can improve
During therapy, Mr. R completes the BDI and Fatigue
patient outcome.
Line
HCV testing protocols
Bottom
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.
u
u
u
u
u
u
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.
HCV Advocate/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.
References
1. McCarthy JJ, Flynn N. Hepatitis C in methadone maintenance
patients: prevalence and public policy implications. J Addict Dis
2001;20(1):19-31.
2. Johnson ME, Fisher DG, Fenaughty A, Theno SA. Hepatitis C virus
and depression in drug users. Am J Gastroenterol 1998;93;85-9.
3. Hauser P, Khosla J, Aurora H, et al. A prospective study of the
incidence and open-label treatment of interferon-induced major
depressive disorder in patients with hepatitis C. Mol Psychiatry
2002;7(9):942-7.
4. Capuron L, Ravaud A, Neveu PJ, et al. Association between
decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry
2002;7(5):468-73.
5. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the
prevention of depression induced by high-dose interferon alpha. N
Engl J Med 2001;29;344(13):961-6.
6. Ho SB, Nguyen H, Tetrick LL, et al. Influence of psychiatric diagnoses on interferon-alpha treatment for chronic hepatitis C in a
veteran population. Am J Gastroenterol 2001;96(1):157-64.
7. Pariante CM, Landau S, Carpiniello B; Cagliari Group. Interferon
alfa-induced adverse effects in patients with a psychiatric diagnosis
(letter). N Engl J Med 2002;11;347(2):148-9.
8. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa2b plus ribavirin compared with interferon alfa 2b plus ribavirin for
initial treatment of chronic hepatitis C: A randomized trial. Lancet
2001;22;358(9286):958-65.
9. Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective
study of neuropsychiatric symptoms associated with interferon-alfa
2b and ribavirin therapy for patients with chronic hepatitis C.
Psychosomatics 2003;44(2):104-12.
continued
78
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pSYCHIATRY
VOL. 5, NO. 11 / NOVEMBER 2006
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M ed/Psych Update
10. Horikawa N, Yamazaki T, Izumi N, Uchihara M. Incidence and
clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: A prospective study.
Gen Hosp Psychiatry 2003;24:34-8.
11. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a
plus ribavirin for chronic hepatitis C virus infection. N Engl J Med
2002;26;347(13):975-82.
12. Dieperink E, Ho SB, Tetrick L, et al. Suicidal ideation during
interferon-alpha2b and ribavirin treatment of patients with chronic
hepatitis C. Gen Hosp Psychiatry 2004;26(3):237-40.
13. Rifai MA, Moles JK, Lehman, LP, Van der Linden BJ. Hepatitis C
screening and treatment outcomes in patients with substance
use/dependence disorders. Psychosomatics 2006;(2):112-21.
14. Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label
trial of citalopram for major depression in patients with hepatitis C.
J Clin Psychiatry 2002;63(3):194-8.
15. Rosenberg SD, Swanson JW, Wolford GL, et al. Blood borne infections and persons with mental illness: the five-site health and risk
study of blood-borne infections among persons with severe mental
illness. Psychiatr Serv 2003:54:827-35.
16. Dominitz JA, Boyko EJ, Koepsell TD, et al. Elevated prevalence of
hepatitis C infection in users of United States veterans medical centers. Hepatology 2005;41;88-96.
17. Bini EJ, Brau N, Currie S, et al. Prospective multicenter study of
eligibility for antiviral therapy among 4,084 U.S. veterans with
chronic hepatitis C infection. Am J Gastroenterol 2005;100:1772-9.
18. Rifai MA, Moles JK, Short DD. Hepatitis C treatment eligibility
and outcomes in patients with psychiatric illness. Psychiatr Serv
2006:57:(4):570-2.
19. Pegasys [package insert]. Roche Pharmaceuticals, Nutley, NJ, 2002.
20. PEG-Intron [package insert]. Schering Corp, Kenilworth, NJ, 2001.
21. Geppert CM, Dettmer E, Jakiche A. Ethical challenges in the care
of persons with hepatitis C infection: a pilot study to enhance
informed consent with veterans. Psychosomatics 2005;46(5):392-401.
22. D’Innella P, Zaccala G, Terazzi M, Olgiati P, Torre E. Protective
effect of olanzapine in psychotic disorder induced by interferonalpha. Recenti Prog Med 2003;4(7-8):343-4.
23. Martin KA, Krahn LE, Rosati MJ, Balan V. Modafinil’s use in combating interferon induced fatigue. Dig Dis Sci. In press.
24. Centers for Disease Control and Prevention. Recommendations for
prevention and control of hepatitis C virus (HCV) infection and
HCV-related chronic disease. MMWR 1998;47(RR-19):1-54.
25. Rosenberg SD, Goodman LA, Osher FC, et al. Prevalence of HIV,
hepatitis B, and hepatitis C in people with severe mental illness.
Am J Public Health 2001;91(1):31-7.
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