Molecular Psychiatry (2002) 7, 942–947

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ORIGINAL RESEARCH ARTICLE

A prospective study of the incidence and open-label

treatment of interferon-induced major depressive
disorder in patients with hepatitis C
P Hauser1, J Khosla2, H Aurora2, J Laurin2, MA Kling2, J Hill2, M Gulati2, AJ Thornton1,
RL Schultz1, AD Valentine3, CA Meyers3 and CD Howell2
1
Portland VA Medical Center, Behavioral Health and Neurosciences Division, NW Hepatitis C Field Based Resource
Center/Oregon Health & Sciences University, Portland, OR, USA; 2Baltimore VA Medical Center/University of Maryland
School of Medicine, Baltimore, MD, USA; 3 MD Anderson Cancer Center, Houston, TX, USA

Interferon (IFN) therapy has been associated with the development of Major Depressive Dis-
order (MDD) when given to patients with hepatitis C (HCV). The incidence, time course, risk
factors, and treatment of IFN-induced MDD are poorly understood. The objectives of the
present study were to determine the incidence of IFN-induced MDD, as well as to determine
the efficacy of open-label antidepressant treatment, in particular selective seretonin reuptake
inhibitors (SSRIs) for IFN-induced MDD. Thirty-nine HCV patients on IFN therapy were moni-
tored weekly using the Beck Depression Inventory (BDI). Those who became depressed were
treated with citalopram, a SSRI antidepressant. Main outcome measures included the inci-
dence of IFN-induced MDD, as well as response rates to antidepressants in those patients
who developed IFN-induced MDD. Our results showed that 13 of 39 patients (33%) developed
IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance
use between those who became depressed and those who did not. However, there were sig-
nificantly fewer African American patients in the depressed group. Patients who developed
IFN-induced MDD were on IFN therapy for an average of 12.1 weeks prior to the development
of MDD. Eleven of 13 patients (85%) were responsive to antidepressant treatment. We con-
clude that IFN-induced MDD is common in HCV patients. Health care providers should follow
IFN-treated HCV patients for the development of MDD, particularly between the 2nd and 5th
months of IFN therapy. SSRIs, in particular citalopram, are an effective treatment for IFN-
induced depression in HCV patients.
Molecular Psychiatry (2002) 7, 942–947. doi:10.1038/sj.mp.4001119
Keywords: hepatitis C; interferon; major depressive disorder; citalopram

Introduction annually from hepatitis-associated chronic liver dis-

Chronic hepatitis C (HCV) is a major public health
problem estimated to affect approximately 3–4 million
Americans or 1.8% of the general population in the
United States.1 In veterans treated within VA medical
centers, the limited studies to date suggest that HCV
prevalence rates may be 7–9%, or approximately four-
fold the national average.2 Epidemiological data sug-
gest that those with the highest prevalence of HCV are
African American, male, and 20–39 years of age.3
Among individuals with HCV, 20–25% develop cir-
rhosis of the liver and/or hepatocellular carcinoma
which result in an estimated death rate of 8000–10000
Correspondence: P Hauser, MD, Chief of Psychiatry, Clinical
Director of Behavioral Health and Neurosciences, Associate
Director Northwest Hepatitis C Field Based Center, Portland VA
Medical Center (P3MHDC), 3710 SW US Veterans Hospital Rd,
Portland, Oregon 97201, USA. E-mail: Peter.Hauser2얀med.
va.gov
Received 31 December 2001; revised 7 February 2002; accepted
11 February 2002
ease.4
The most effective and generally available treatment
for HCV is Rebetron, a combination therapy that
includes alpha interferon (IFN) and ribavirin.5 More
recently, pegylated interferon alpha and ribavirin has
been shown to have better sustained virologic response
rates than Rebetron.6 However, IFN causes significant
neuropsychiatric side effects;7 among the most promi-
nent are symptoms of depression and cognitive impair-
ment.8,9 These side effects negatively impact the
patients’ quality of life.10,11
Based on DSM-IV criteria, a depressive syndrome
that occurs during IFN therapy is considered a subst-
ance-induced mood disorder.12 Reported incidence
rates of IFN-induced Major Depressive Disorder (MDD)
range from 0–70% for all diseases,13 and 0–44% for
those with HCV infection.14 Most studies have relied
on patient self report rather than objective criterion-
based instruments and questionnaires to assess IFN-
induced depressive symptomatology. In those studies
that used a specific instrument to assess depression,

higher rates of MDD were found.15 However, various
depression rating scales were used. Other studies have
found that while patients did not meet criteria for
MDD, IFN therapy did cause symptoms of depression,
resulting in high rates of subclinical psychiatric abnor-
malities.8,16
Because of this variability, the actual incidence of
IFN-induced MDD remains largely unsubstantiated.
Few studies have evaluated prospectively symptoms of
depression in patients receiving IFN therapy.
Also unconfirmed is the usual time to development
of MDD in patients on IFN therapy. In HCV patients
undergoing IFN therapy, significant increases in
depression have been reported anywhere from 12
weeks17–19 to 6 months11 after beginning IFN therapy.
The majority of IFN therapy discontinuations that
occur in HCV patients are related to the development
of IFN-induced depression.20 Due to the fact that neur-
otoxic symptoms usually resolve 2–3 weeks after IFN
discontinuation,21 many providers choose to decrease
the dose or completely discontinue IFN therapy when
psychiatric side effects occur. However, withdrawing a
patient who is responding to IFN therapy denies them
access to a potentially life-saving therapy.22
To date, no controlled studies have explored the
efficacy of SSRIs in treating IFN-induced MDD in a
large sample of HCV patients receiving IFN therapy.
Several case reports have suggested that antidepress-
ants,23 and SSRIs in particular,24–26 are useful in ame-
liorating IFN-induced MDD. Also, in patients with
malignant melanoma, prophylactic administration of
SSRIs has been shown to prevent IFN-induced MDD,
thus allowing patients to remain on therapeutic doses
of IFN.27,28
Citalopram is a commonly used SSRI that is reported
to have few metabolic side effects associated with liver
disease and abnormalities.29 In addition, citaprolam
has been shown to be efficacious in ameliorating
depressed mood, melancholia, sleep disturbance, anxi-
ety, cognitive disturbance and psychomotor retar-
dation,29 which are common depressive symptoms
associated with IFN therapy. Therefore, citaprolam is
a reasonable candidate for treating IFN-induced MDD
in patients with hepatitis C.
In summary, the vast majority of HCV studies have
not used objective and validated measures of depress-
ive symptomatology or criterion-based instruments to
determine the MDD diagnosis, nor have they made
these assessments prior to and during IFN therapy.
Also, there is little information on the characteristics
or treatment of IFN- induced MDD. Therefore the pur-
pose of our study was to evaluate prospectively a
cohort of HCV-infected patients prior to and after the
implementation of IFN therapy in order to determine
the following: (1) the incidence of IFN-induced MDD
in HCV patients; (2) in those patients who developed
MDD, the average length of time on IFN therapy until
development of MDD; and (3) the efficacy of the SSRI
citalopram in treating IFN-induced MDD.
Interferon-induced MDD in patients with hepatitis C
P Hauser et al
943
Methods
Participants
Ninety-two patients referred by the Baltimore VA
Medical Center GI Clinic and the University of Mary-
land Hospital Hepatitis C Clinic were screened for the
study. Of these, 53 were enrolled in the study. The
remainder were ineligible as they had a current psychi-
atric or substance abuse history or did not wish to par-
ticipate in the study. All patients had chronic HCV and
were considered eligible for IFN therapy. The 39
patients included in this study had completed at least
2 months of IFN therapy or had developed IFN-
induced MDD during the course of IFN therapy.
Eligibility
The protocol was explained to all patients who then
signed the University of Maryland IRB-approved infor-
med consent. Patients were eligible for the study if for
6 months prior to study entry, they had not had an
active psychiatric illness, had not taken psychotropic
medications, and had abstained from any psychoactive
substance use.
Patients were administered the Structured Clinical
Interview for DSM-IV Axis I Disorders, Version 2.0
(SCID-I/P)30 to determine presence of psychiatric ill-
ness. In addition, present depressive symptoms were
assessed by Beck Depression Inventory (BDI) prior to
starting IFN therapy.31 The BDI is a 21-item self-report
inventory measuring characteristic attitudes and symp-
toms of depression, where a BDI ⬍ 10 is defined as
asymptomatic.32 Any patient who met the criteria for
a current psychiatric illness or had significant symp-
toms of depression (defined as a BDI score ⬎ 15) was
excluded from study participation.
Procedure
After the baseline BDI measurement, patients were pre-
scribed and administered Rebetron combination ther-
apy (IFN)-interferon alfa-2b injection of 3 million
units/3 times per week and ribavirin capsules 600 mg
day−1 for 6–12 months. BDIs were administered weekly
over the course of IFN therapy. If at any point in the
study, patients showed a BDI score of 18 or greater,
they were reevaluated using the SCID-I/P to determine
criteria for MDD. If a patient met criteria for MDD, he
or she was started on antidepressant treatment.
The SSRI citalopram hydrobromide (Celexa) was
used as the antidepressant. The starting dose of citalo-
pram was 20 mg day−1. Patients who showed no change
in BDI score after one week of citalopram treatment
had their dose increased by 20 mg per week to a
maximum dose of 60 mg day−1. Patients who were non-
responsive (BDI score reduction ⬍50%) to a citalopram
dose of 60 mg day−1 for 1 week were then given buprop-
rion as an alternative antidepressant medication.
Patients were considered to be in remission if their BDI
score was ⱕ10.
Statistical analysis
Initial frequency comparisons were made between
patients who developed MDD and those who did not,
Molecular Psychiatry
 Interferon-induced MDD in patients with hepatitis C
P Hauser et al
944
to examine the proportion of patients by gender, ethnic
background, past history of substance abuse and past
history of MDD. Yates corrected chi-square contin-
gency tests (␹2) were used to determine whether the
development of MDD during IFN treatment was asso-
ciated with the aforementioned demographic variables.
Inferential statistics were calculated to examine dif-
ferences between patients who developed MDD and
those who did not. To make comparisons between the
two groups, we accounted for baseline BDI score and
highest BDI score. In MDD patients we measured time
to IFN-induced MDD development (weeks from base-
line BDI score/IFN therapy initiation to MDD
development), escalation of depressive symptoms
(weeks from last BDI ⱕ10 (asymptomatic) to MDD
diagnosis), time to antidepressant efficacy (time to
reduce high BDI score by 50% after SSRI treatment
initiation) and time to remission (time to achieve BDI
ⱕ10 after SSRI treatment initiation) using a previously
reported technique.33 For patients in the MDD group,
additional comparisons were made between BDI score
at baseline, highest BDI score and BDI score after 2
weeks on citalopram (or other antidepressant).
Results
Patient demographics and descriptive statistics are
shown in Table 1.
Of the total sample, 33.3% (13/39) met the criteria
for MDD following initiation of IFN therapy. No sig-
nificant differences were found between the MDD and
non-MDD groups with respect to age. The proportion
of patients with a past history of MDD (␹2 = 0.53, P =
0.48), or substance abuse (␹2 = 2.4, P = 0.12) was not
greater in the MDD group. A significantly greater pro-
portion of Caucasians were in the MDD group than in
the non-MDD group (␹2 = 4.6, P ⬍ 0.05).
At baseline, patients who later met criteria for IFN-
induced MDD had BDI scores that were significantly
higher than non-MDD patients (F = 8.7, P = 0.005). For
Figure 1 Cumulative number of weeks on IFN therapy until
MDD develops.
Molecular Psychiatry
the MDD group, the mean time from baseline to the
development of a diagnosis of MDD was 12.1 weeks
(median = 12; range 1–32 weeks, 6–22 weeks after
removing low and high outliers), with a mean increase
in BDI score of 20.0 ± 6.0 from baseline to MDD diag-
nosis. The patient distribution of weeks on IFN until
MDD diagnosis develops is shown in Figure 1.
In MDD patients, the escalation of depressive symp-
toms was measured as the time between the last BDI
score ⱕ10 until a BDI score ⱖ18. The mean escalation
time was 1.8 ± 2.4 weeks, with a mean increase in BDI
score of 17.3 ± 5.2. Eight patients exhibited a rapid
escalation of depressive symptoms that was ⱕ2 weeks
with a mean increase in the BDI score of 17.3 ± 2.6.
Of the 13 MDD patients who developed depression,
85% (11/13) were responsive to antidepressant treat-
ment. Nine of 11 patients responded to citalopram
within the specified dose range of 20–60 mg day−1
(mean = 36.4 mg day−1). One patient requested treat-
ment with fluoxetine and responded to a dose of 20 mg
day−1. One patient, who failed citalopram treatment,
responded to buproprion at a dose of 300 mg day−1. Of
the two non-responders, one was lost to follow-up and
a second had to discontinue IFN therapy because he
developed IFN-induced MDD with psychotic features.
Patients responsive to antidepressants required an
average of 5.4 (± 6.9) weeks on antidepressants until
efficacy (defined as a decrease in BDI by 50%) was ach-
ieved, and an average of 9.0 (± 11.0) weeks until
remission (defined as a BDI score ⱕ10) was achieved.
The majority of these patients, 73% (8/11) were able
to complete a full course of IFN therapy. One patient
withdrew from IFN therapy for personal reasons even
though his IFN-induced MDD was in remission and
two withdrew from IFN therapy secondary to compet-
ing, unrelated medical conditions.
Discussion
In our prospective study of 39 patients with HCV who
received IFN therapy, 33% (13/39) developed IFN-
induced MDD. In those patients who developed MDD,
depression usually developed between the 6th and
22nd week of IFN therapy (median = 12 weeks). The
mean change in BDI score from baseline to highest BDI
scores was 20 points for MDD patients (SD = 6; range
6–29) and 6.1 in non-MDD patients (SD = 4.6; range
0–17).
In contrast to previous published studies, a past his-
tory of MDD or substance abuse was not associated
with an increased risk of IFN-induced MDD in our
study.19 However we did find that patients who later
met criteria for IFN-induced MDD had baseline BDI
scores that were significantly higher than non-MDD
patients (6.9 ± 5.1 vs 2.8 ± 3.6; F = 8.7, P = 0.005) sug-
gesting that patients with more symptoms of
depression prior to IFN therapy may be at greater risk
of developing IFN-induced MDD as compared with
those who have few or no symptoms of depression.
This finding supports studies of malignant melanoma
patients, that showed depressive symptom scores
 Interferon-induced MDD in patients with hepatitis C
P Hauser et al

945
Table 1 Patient demographics, psychiatric history and BDI scores

Total Depressed Non-depressed

n = 39 n = 13 n = 26

Age, years 44.9 ± 6.9 44.5 ± 7.0 45.1 ± 7.0

Gender, %
Female 33.3 46.2 26.9
Male 66.7 53.8 73.1
Race, %*
African American 51.3 23.1 65.4
Caucasian 48.7 76.9 34.6
Substance Abuse history, %
Yes 69.2 53.8 76.9
No 30.8 46.2 23.1
MDD history, %
Yes 23.1 30.8 19.2
No 76.9 69.2 80.1
Baseline BDI** 4.2 ± 4.5 6.9 ± 5.1 2.8 ± 3.6
Range 0–15 (n = 3 ⬎ 10) 0–15 (n = 1 ⬎ 10)
High BDI 14.9 ± 10.1 26.9 ± 6.3 8.8 ± 4.8
Range 18–39 1–17
Mean change in BDI 10.7 ± 8.3 20.0 ± 6.0 6.1 ± 4.6
Range 6–29 0–17
MDD patients only
Total weeks on IFN to MDD diagnosis, weeks 12.1 ± 8.2 weeks
(range 1–32 weeks)
Escalation of depressive symptoms, weeksa 1.8 ± 2.4 weeks

*P ⬍ 0.05. There were significantly more Caucasians in the depressed than non-depressed group.
**P ⬍ 0.005. The depressed group had a significantly higher baseline BDI score than non-depressed group.
a
Escalation of depressive symptoms was calculated by taking mean number of days that elapsed between a BDI score ⱕ10 and
the BDI score ⱖ18.

before IFN therapy were predictive of MDD develop-
ment during IFN therapy.28,34 However, we wish to
note that the mean baseline BDI score of patients who
subsequently developed IFN-induced MDD was rela-
tively low and did not indicate significant depressive
symptomatology.
More than half of our patients who developed IFN-
induced MDD became depressed during or after the
12th week of IFN therapy, suggesting that patients
should be screened regularly for depression during the
first 6 months of therapy. Furthermore, studies that
screen or assess patients for depression only during the
initial 12 weeks of therapy may grossly underestimate
the actual incidence of IFN-induced depression.
Of the 13 patients who developed IFN-induced
MDD, 85% (11/13) were responsive to antidepressant
treatment. Most of these patients (9/11) responded to
citalopram within the specified dose range of 20–60 mg
day−1 (mean = 36.4 mg day−1). Our results met expec-
tations anticipated from case reports that showed SSRIs
are efficacious.23 Furthermore, in those patients who
responded, efficacy (defined as a decrease in BDI by
50%) was achieved, on average between 5–6 weeks and
remission (defined as a BDI score ⱕ10) was achieved,
on average in 9 weeks. The majority of our patients
with IFN-induced MDD—62% (8/13)-completed a full
course of IFN therapy. Only one patient developed
IFN-induced MDD with psychotic symptoms that
required discontinuation of IFN therapy.
Previous studies have reported that IFN-induced
depression may include suicide ideation as well as
suicide attempts necessitating early discontinuation of
IFN therapy.35 In our study, both MDD and non-MDD
patients reported some symptoms of suicide ideation
(n = 13). However, all of these patients rated them-
selves low on this item (suicidal thoughts without
intent). This low score may have been due in part to
frequent screening for depression using the BDI
(weekly) and diagnosing and treating patients early
during the course of MDD episode development.
We found that when depression developed in our
patients it developed rapidly. In 62% (8/13) of our
patients who developed IFN-induced MDD, BDI scores
increased from 10 or less to 18 or more within 2 weeks.
Our findings suggest that HCV patients undergoing IFN
therapy should be screened ideally every 2 weeks.
Such a recommendation could lead to early inter-
vention by health care practitioners and prevention of
neuropsychiatric side effects that would otherwise
interrupt IFN therapy.
Limitations of our study include a relatively modest
sample size. Access to a larger sample would help to
clarify an optimal time interval for depression screen-
ing as part of the appropriate monitoring of HCV

Molecular Psychiatry
 Interferon-induced MDD in patients with hepatitis C
P Hauser et al
946
patients undergoing IFN therapy. However there are no
prospective studies of HCV patients that have carefully
examined the development and treatment of IFN-
induced depression. Another limitation of our study
is that our patients received combination therapy that
includes alpha interferon and ribavirin. However,
among the treated HCV population, it has been
reported that the neuropsychiatric side is not exacer-
bated by the addition of ribavirin in (Rebetron) therapy,
and ribavirin monotherapy has not been associated
with a high incidence of neuropsychiatric side
effects.20,22 A final limitation of our study was the
open-label design, which may have resulted in an exag-
gerated response rate to antidepressant treatment.
In summary, our study suggests that IFN-induced
MDD is common, occurring in 33% (13/39) of our
patients. However, adjunctive antidepressant treat-
ment, and citalopram in particular, is an effective treat-
ment that can reverse IFN-induced depression and thus
allow continuation of IFN, a potentially life-saving
medication for patients with HCV. We did not find that
HCV patients who develop IFN-induced MDD were
more likely to have a past history of MDD or substance
abuse. Therefore, we cautiously suggest that a past his-
tory of MDD or substance abuse should not automati-
cally exclude HCV patients from IFN therapy.
The high frequency of IFN-induced MDD and the
consideration that most HCV patients develop at least
some symptoms of depression during IFN therapy
raises the question of whether prophylactic antide-
pressant treatment may reduce the risk or prevent IFN-
induced MDD and improve quality of life in HCV
patients on IFN therapy. Studies in malignant mela-
noma patients suggest that prophylactic treatment with
SSRIs prevents IFN-induced MDD and thus allows
patients to remain on IFN therapy.27,28 Our study also
supports the previously reported finding that higher
baseline (pre-IFN therapy) depression scores may pre-
dict subsequent development of MDD.28,34 This sug-
gests an alternative strategy, one that would target
patients with higher depressive symptom scores for
prophylactic treatment with antidepressants. However,
we wish to make clear that in our study the mean base-
line BDI scores for both MDD and non-MDD groups
were ⬍10 (6.9 and 2.8, respectively), suggesting few
symptoms of depression. Currently, we cannot rec-
ommend that a patient with an increased baseline BDI
score be treated prophylactically with antidepressants.
Further research should be conducted before prophy-
lactic antidepressant treatment is routinely prescribed
for HCV patients prior to IFN therapy.
In conclusion, frequent screening for depression
using established instruments offers the health care
provider a tool that allows early intervention with anti-
depressant treatment for IFN-induced MDD. Ultimately
this will reduce mortality as well as permit HCV
patients to complete a full course of IFN therapy and
possibly avoid the complications of advanced liver dis-
ease.
Molecular Psychiatry
Acknowledgements
The authors are grateful to Elizabeth W Ratrie for coor-
dinating the study at the University of Maryland
School of Medicine; to Drs Naomi Tomoyasu and Erick
H Turner for their editorial assistance; to Integrated
Therapeutics, a subsidiary of Schering-Plough Pharma-
ceuticals and to Forest Laboratories for grant support of
this independent investigator initiated study. The first
author also wishes to thank his wife Cathy, his
daughter Katia, and his mother Jirina for their con-
tinued support.
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