Hepatitis C Treatment for People With Severe Mental Illness & Depression

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Hepatitis C Treatment for People With Severe Mental Illness &

Depression

Psychosomatics 47:93-107, April 2006

A. Mistler, M.D., F. Brunette, M.D., J. Marsh, M.D.,

M. Vidaver, M.D., Ravi Luckoor, M.D., and Stanley D.

Rosenberg, Ph.D.

Received May 7, 2004; revised June 16, July 28, 2004; accepted March

31, 2005. From Dartmouth Medical School, Hanover NH and New Hampshire

Hospital, Concord, NH. Send correspondence and reprint requests to

A. Mistler, M.D., at the New Hampshire Hospital Unit C, 36

Clinton St., Concord, NH 03301. e-mail: .A.Mistler@...

…….In summary, small, uncontrolled studies suggest that

antidepressant treatment of IFN-MDD (including related cognitive

problems) is effective, but larger controlled studies are needed, and

the mechanisms of the medication's impact on IFN-MDD are still

unclear.75 It is currently recommended that persons with depression

symptoms at baseline should be offered antidepressant medication and

that IFN treatment should be delayed until symptoms abate. Also,

pretreatment with antidepressants may prevent the development of IFN-

MDD46 in persons without baseline symptoms, but some experts

recommend waiting to use antidepressant medications until depression

side effects emerge.84 If IFN treatment-emergent depressive symptoms

are severe or a patient elects to avoid medication treatment of them,

IFN discontinuation may be necessary. Case reports also suggest that

IFN-induced mania and psychosis also respond to IFN

discontinuation.68,69……Three published studies54,56,91 report

good treatment adherence, low drop-out rates, and good side-effect

tolerability in psychiatrically impaired patients by using assertive

psychiatric management, close monitoring, and adjustment of

psychiatric medication to address the psychiatric side effects of

antiviral medications…..

ABSTRACT

Over 4 million people in the United States are chronically infected

with hepatitis C virus (HCV), and, if untreated, over 20% of these

will progress to more serious disease. Persons with severe mental

illness (SMI) have markedly elevated rates of HCV infection, but

treatment of persons with SMI and HCV has been controversial.

Effective antiviral treatment is available, but side effects include

depression and other neuropsychiatric symptoms. This article reviews

the available data on neuropsychiatric side effects of interferon

(IFN) treatment, discusses the limitations of the current research,

and makes recommendations regarding HCV treatment in persons with SMI.

INTRODUCTION

The hepatitis C virus (HCV) is a common chronic blood-borne

infection, with an estimated prevalence of 1.8% in the United States

population. Moreover, an estimated 20% of persons with severe mental

illness (SMI)1-3 are infected. Approximately 20% of chronically

infected individuals will develop cirrhosis, and approximately 3%

will develop hepatocellular carcinoma. The most common transmission

risks for persons with SMI are drug-use behaviors and sexual

behaviors related to drug use.3-6

The current standard for the medical treatment of chronic active HCV

infection is a weekly injected pegylated version of interferon alpha-

2b, with daily, oral ribavirin.7-10 Of patients infected with

Genotypes 2 and 3, 76%-82% achieve sustained virologic response, as

do 50% of patients with Genotype 1.11,12 Higher doses of interferon-

alpha cause more effects,11,12 most commonly headache, nausea, fever,

muscle aches, and fatigue. The most serious side effects are

hematologic abnormalities, which occur in up to 20% of patients.11,13

Tolerance to the common side effects occurs over weeks, and dangerous

side effects are managed with dose-reduction. Discontinuation of IFN

is most commonly attributed to fatigue.14

NIH Consensus Guidelines indicate that persons with substance use

disorders, mental illness, or HIV should be considered for hepatitis

treatment on a case-by-case basis. However, most trials of both alpha-

and pegylated interferon excluded clients with SMI because of

concerns regarding potential psychiatric, cognitive, and other common

side effects.15-17 Emerging studies now suggest that persons with SMI

can tolerate treatment and that neuropsychiatric side effects are, in

some cases, preventable, and, in most cases, treatable. Severe

neuropsychiatric side effects due to IFN are uncommon and reversible.

Interferon Side Effects IFN is a potent inducer of proinflammatory

cytokines. Cytokines cause a variety of changes in the brain that

lead to symptoms similar to major depression (anhedonia, reduced

activity, listlessness, hyperalgesia, altered sleep, altered

appetite, and poor memory).18 IFN-induced major depressive disorder

(MDD) is classified as a substance-induced MDD by current diagnostic

standards.19

To clarify the risk of developing IFN-MDD in patients treated for HCV

infection, we surveyed the literature on depression side effects

associated with IFN treatment (Table 1). We include studies of at

least 10 patients that utilize at least two time-points to assess

mood symptoms or IFN-MDD over time. The strongest evidence regarding

whether IFN causes mood side effects comes from studies using

comparison groups, a design used by only four published prospective

studies.20-23 The studies provide mixed evidence for whether IFN is

associated with higher rates of mood problems. In two studies that

used measures targeting depressive symptoms specifically, mean

depression scores on self-report measures were higher in the IFN-

treated groups.21,24 In the study by Mc and colleagues,25 a

structured interview was also used, and very high rates of IFN-MDD

(62.9%) were found. However, this small patient group was unique in

that patients were later found to have high rates of co-occurring,

untreated HIV infection. In two studies that did not use ideal

measures of depression, the prevalence of depressed mood or

depression scores were not different between treated and untreated

patients.20,22

Table 1 also lists 13 uncontrolled, prospective studies designed to

assess IFN side effects. In six prospective studies using researcher

measures to report IFN-MDD prevalence, IFN-MDD occurred in 19.2%-45%

of IFN-treated HCV or cancer patients.26,27 One of these studies

reported that depressive scores increased,28 and, in another,

structured clinician interviews showed mood symptoms to be

decreased.29

Seven studies utilizing self-report measures of depression show a

wide range of mood changes. In the only clinical trial to use a

standardized self-report measure of depression, Bernstein et al.14

assessed 448 HCV patients with the Beck Depression Inventory and

found that 18% of HCV patients developed mild depressive symptoms,

and an additional 15.7% developed moderate-to-severe IFN-MDD. Three

other studies found IFN-MDD in 25.9%-33% of patients,30-32 whereas

two found depression symptoms in only 5.2%33 to 9.5%,34 and two

reported no change in depressive symptoms over time or no new

diagnoses of IFN-MDD.35,36 In summary, studies using researcher-

administered measures designed to assess depression showed that about

one-third of persons experienced IFN-MDD, whereas studies using self-

report measures reported a wide range, from 0% to 33%.

Industry-funded IFN trials use physician report, rather than more

rigorous researcher measures, to assess depressive side effects, and

tend to exclude persons with psychiatric symptoms or history. Seven

prospective clinical trials of IFN (in HCV or cancer patients)13,37-

42 reported that approximately one-fourth (9%-40%) of IFN-treated

patients experienced mood symptoms (not IFN-MDD), a much higher rate

than the low rates reported in retrospective studies (0.9%-2.2% of

HCV or melanoma patients).43,44 A recent trial of intramuscular

pegylated IFN (dosed weekly) suggests that depressed mood occurs less

often with this medication than the old type of oral IFN-alpha (20%

versus 30%).38

Rate of withdrawal from IFN treatment due to mood changes is another

indicator of the burden of mood changes. Notably, retrospective

studies of HCV-infected psychiatric patients report that only 6%-18%

of patients withdrew from IFN treatment for any reason.45,46

Withdrawal due to depressive symptoms in other studies (Table 1)

ranges widely, from 0.04%13 to 21.6%,39 and up to 45%, in a small

sample of melanoma patients.46 Many prospective studies document

suicidal thoughts in small numbers (0.33%-3.4%) of IFN-treated

patients,14,40,43 but higher rates have been reported in intravenous

drug users with HCV (19.2%47). Two studies26,29 reported that

suicidal thoughts were reduced, rather than elevated, after 3 months

of IFN treatment. Retrospective studies and large retrospective

surveys report suicide attempts in 2 of 11,241,48 3 of 2,575,26 and 2

of 987 patients;44 others report completed suicides: 1 in 72139 and 2

in 2,575.26

Clinical lore suggests that higher doses and longer length of IFN

treatment lead to worse mood problems,43 but evidence from

prospective studies and clinical trials does not support this

contention.22,26,32,41,42,49,50 The evidence is also mixed as to

whether mood symptoms peak early (e.g., 2-6 weeks)21or later (e.g., 3-

6 months).31 Changes in mood and cognition tend to occur weeks or

months after treatment, in contrast to changes in energy, appetite,

and psychomotor speed, which occur within days.28,29,31,40,51 Neither

social support nor gender appear to be related to the development of

depression.24,52,53 Moreover, depression symptoms usually resolve

rapidly when treated with antidepressant medication or when the IFN

is discontinued.24,40

Little research has addressed the question of whether previous

psychiatric illness increases the likelihood of developing

psychiatric symptoms during IFN treatment. Although two groups 45,54

documented that 82%-94% of persons with significant psychiatric

disorders were able to complete IFN treatment without " clinical

problems, " no research has systematically studied IFN treatment and

side effects in persons with severe psychiatric disorders such as

schizophrenia and bipolar disorders. Other studies included persons

with psychiatric disorders and monitored them over time. In 7 of 10

prospective studies, baseline depressive symptoms predicted the

development of MDD during IFN treatment.28,45,46,52,55,56 In

contrast, four other studies found that previous history of

depressive disorder did not predict the development of depression

symptoms.27,33,36 Two retrospective studies found that a history of

psychiatric illness or neurologic illness40,57 was associated with

psychiatric or neurologic symptoms during treatment.

In summary, the strongest research suggests that mild-to-moderate

depression symptoms occur in 20%-40% of IFN-treated patients, whereas

severe IFN-MDD occurs in fewer than 10%. Depression symptoms at the

time of treatment initiation increase the likelihood of developing

depression during IFN treatment, but, as will be discussed later in

this article, the depressive symptoms that develop during IFN

treatment appear to be treatable with antidepressant medication.

Other Neuropsychiatric Symptoms Induced by IFN

Anxious mood has been reported in up to one-fourth (7.4%-28.1%) of

untreated HCV patients49,58-61 and in about one-fifth (2.0%-16%) of

IFN-treated HCV patients.27,31,42 Two prospective studies reported an

increase in anxiety symptoms over time during IFN treatment,42,46

whereas another reported a reduction in the number of patients with

anxious mood.31 In a retrospective study, only 1.4% of 943 treated

HCV patients were diagnosed with IFN-induced anxiety disorder, and

all were able to complete IFN treatment.62 IFN-induced anxiety

appears to be mild and uncommon.

Few data are available to inform clinicians about the risk for other

psychiatric symptoms, such as mania or psychosis, or whether persons

who live with SMI are at risk for illness exacerbation. Several

groups found good tolerability of IFN treatment in SMI patients45,54

and low rates of treatment-discontinuation in psychiatric

patients,27,45,63 but two retrospective studies found increased

neurologic or psychiatric symptoms in psychiatric patients.40,57 Case

reports document that mania and psychosis occur in small numbers of

IFN-treated patients,26,64-69 but no prospective studies carefully

assess their incidence in persons with psychiatric disorders.

IFN treatment may induce cognitive impairment (e.g., in memory and

concentration), in addition to the cognitive problems associated with

untreated HCV infection, which have been reported in up to 50% of HCV

patients.59,60 Formal prospective neuropsychological testing in

treated individuals, compared with control subjects, offers the most

accurate measure of the prevalence and type of cognitive changes with

IFN treatment. However, only three small studies prospectively

assessed cognitive functioning with neuropsychological testing in IFN-

treated patients (Table 2).20,35,50 The only prospective, randomized,

controlled trial of IFN treatment using neuropsychological testing

(in melanoma patients) found no differences in measures of

concentration or memory between persons taking IFN and control

subjects.20 A small, uncontrolled, prospective study of IFN-treated

HIV patients showed no change in cognitive functioning over time.35

In contrast, Capuron and colleagues49 showed slowing of cognitive

performance, which started after days of treatment and correlated

with depression symptoms after 1 month of treatment. An uncontrolled

prospective study of HCV patients found that 34% of 56 patients

experienced decreased cognitive functioning, which correlated with

EEG changes, but not with depression scores.70 The results of two

prospective studies using self-report measures, which document

subjective changes in memory and concentration, also conflict,53,71

but up to 30% of patients reported problems with concentration. Three

other prospective studies used unstructured clinical assessments. One

reported the development of cognitive problems in 13% of IFN-treated

patients with cancer,72 and two reported delirium in about 5% of

patients with cancer or chronic viral infections.29,33,40,72

Similarly, a cross-sectional study using neuropsychological testing

found that cancer patients treated with IFN experienced more problems

in cognitive speed, verbal memory, and executive functioning than

untreated cancer patients.73 Three case series (N=46) further

documented problems with memory, concentration, slowing, and

delirium.29,74 Renault et al.32 and et al.73 reported that

delirium and cognitive changes were associated with a history of or

current cerebral insult, such as brain injury or metastases.

Cognitive problems resolved with discontinuation of medication44,70

or treatment with antidepressant medication.46,75

Summary of IFN-Induced Cognitive Changes

Problems with cognitive functioning have been reported in patients

with chronic HCV infection, but evidence of IFN-induced cognitive

decline is mixed and mostly limited to small, uncontrolled studies.

The best research to-date suggests that use of moderate-dose IFN to

treat persons with HCV is unlikely to cause significant cognitive

problems in the majority of persons who do not have a history of

previous cerebral insult. Further studies of cognitive side effects

of IFN treatment of HCV patients are needed.

Potential Mechanisms of Neuropsychiatric Side Effects

Using brain imaging, EEG, and assays of hormones and peptides,

studies in animals and humans show significant changes during

treatment with IFN-alpha, pointing to potential mechanisms by which

this medication causes changes in mood and cognition. One PET76 and

two EEG56,70 studies showed IFN-induced frontal lobe changes in the

brain associated with change in incentive or ability to perform

cognitive, verbal, or motor tasks. IFN-alpha may induce a toxic

encephalopathy (delirium), which interferes with frontal lobe

functioning, particularly when the medication is delivered in high

doses or to persons with previous brain injury. When the medication

is used in low or moderate doses, subjective or milder objective

cognitive changes can occur, possibly related to the IFN-induced

depressive disorder75 or milder encephalopathy.70

IFN-induced depressive symptoms and disorders are thought to be due

to cytokine-induced abnormalities in the hypothalamic-pituitary-axis,

neurotransmitter systems, or other mechanisms.77 In cancer patients

who develop IFN-MDD, ACTH and cortisol were increased.78 In animals,

serotonin metabolism was altered after IFN treatment, shunting

tryptophan away from serotonin production.75 In IFN-treated humans,

serum 5-HT and plasma tryptophan were reduced, and serum kynurenine

was increased,26 suggesting that IFN induces depression through

catabolism of tryptophan to kynurenine, resulting in lowered

serotonin levels. This hypothesis is supported by the effectiveness

of serotonin-reuptake inhibitors in treating IFN-MD.46 Also, studies

in animals and humans showed that IFN depleted dopamine, slowed

metabolic activity in the prefrontal cortex, and increased activity

in the putamen and globus pallidus, similar to the abnormalities of

Parkinson's disease.79 These changes in the frontostriatal areas

correlated with IFN-induced psychomotor slowing, fatigue, and

anhedonia, suggesting that dopaminergic agents may reduce slowing;

however, these agents have not been formally tested in IFN-treated

humans.

Prevention and Treatment of Neuropsychiatric

Side Effects Education, assessment, monitoring, and medication

treatments are important aspects of the management of

neuropsychiatric side effects of interferon (IFN).38,45,80-83

Education before treatment is recommended for helping clients

anticipate and manage side effects,80 and patients must be assessed

at baseline and monitored regularly and frequently for

neuropsychiatric symptoms.

Table 3 summarizes studies on the impact of antidepressant treatment

on IFN-MDD; these include one randomized, placebo-controlled trial of

prevention,46 three open-treatment trials,14,30,84 and four treatment

case reports.85-88 One controlled study reported that pretreatment

with antidepressant medication dramatically reduced the development

of IFN-MDD.46 Uncontrolled studies using antidepressants to treat

newly-emerged IFN-MDD report improvements in 73.3%-90% of

patients.14,30,84 Four case reports (N=21) also report improvement in

depression and anxiety symptoms with antidepressant

medication.56,85,86,88 One study71 reported that mood and cognitive

symptoms responded to antidepressants, whereas fatigue and anorexia

did not. Naltrexone treatment resulted in improvement in cognition

and emotional symptoms in five of nine IFN-treated CML patients.89

In summary, small, uncontrolled studies suggest that antidepressant

treatment of IFN-MDD (including related cognitive problems) is

effective, but larger controlled studies are needed, and the

mechanisms of the medication's impact on IFN-MDD are still unclear.75

It is currently recommended that persons with depression symptoms at

baseline should be offered antidepressant medication and that IFN

treatment should be delayed until symptoms abate. Also, pretreatment

with antidepressants may prevent the development of IFN-MDD46 in

persons without baseline symptoms, but some experts recommend waiting

to use antidepressant medications until depression side effects

emerge.84 If IFN treatment-emergent depressive symptoms are severe or

a patient elects to avoid medication treatment of them, IFN

discontinuation may be necessary. Case reports also suggest that IFN-

induced mania and psychosis also respond to IFN discontinuation.68,69

Treatment of Persons With Severe Mental Illness and Hepatitis C Virus

Despite concerns about the ability of severely mentally ill clients

to tolerate side effects and adhere to HCV treatment, the feasibility

and safety of treating SMI clients has been demonstrated.54,56,90

Three published studies54,56,91 report good treatment adherence, low

drop-out rates, and good side-effect tolerability in psychiatrically

impaired patients by using assertive psychiatric management, close

monitoring, and adjustment of psychiatric medication to address the

psychiatric side effects of antiviral medications. Equal rates of

viral response were also reported in persons with mental illness

and/or drug addiction. However, additional systematic trials of

treatment adherence, side-effect management, and HCV treatment

outcome for people with SMI are needed to confirm these observational

studies.

Treatment of HCV-Infected Persons With SMI and Comorbid Substance-Use

Disorders

Persons infected with HCV are advised to avoid all liver toxins,

including alcohol. Although one study showed that heavy alcohol use

was correlated with lack of treatment response in methadone patients

with HCV, medication nonadherence, rather than toxic effects of

alcohol, mediated that lack of response.92 Thus, rather than simply

withholding treatment from persons with substance-use disorders,

their ability to attend appointments and adhere to medication should

be demonstrated before initiation of HCV treatment. Also, integrated

dual-disorder treatment is effective for persons with SMI,93 and it

should be offered.

Treatment of Patients Co-Infected With HIV

Co-infection with HIV is common in clients with SMI. For example, in

a recent study of SMI clients in a large urban area, 15% of all HCV-

positive participants were HIV-co-infected, and 67% of those

seropositive for HIV were also HCV-positive.94 Although HIV co-

infection may complicate the course and treatment of HCV, it also

increases the importance of treatment.95 Morbidity and mortality are

more common in co-infected groups, as compared with matched HIV- or

HCV-mono-infected patients.96,97 HCV treatment is safe and tolerable

in co-infected individuals,98,99 but studies to-date do not assess

whether treatment outcomes are as good, and co-infected patients may

be more likely to develop psychiatric side effects from IFN.24

Co-infected patients with mental illness need the same type of

intensive supports and psychiatric assessment that other mono-

infected patients need. et al.99 demonstrated that a nurse and

case-manager team can effectively deliver this assessment and support

to co-infected patients with mental illness and/or substance-use

disorders. However, those prescribing psychotropic medications need

to be aware of the potential for interactions between medications

used to treat infectious disease and those used to treat psychiatric

illness. Psychotropic medications that share the same metabolic

pathways as HCV medications should be used judiciously.

Treatment Recommendations for SMI Patients With HCV

Persons with severe mental illness (SMI) who meet medical criteria

for hepatitis C virus treatment should be offered HCV treatment if

they are able to attend medical appointments, are engaged in

psychiatric and substance-abuse treatment, and are willing to be

monitored by psychiatric and medical staff. When treating persons

with SMI, proper informed-consent processes should be applied.

Education about the effectiveness of the treatment and the potential

for occurrence of reversible and treatable neuropsychiatric side

effects should be provided. SMI patients, like all IFN-treated

patients, should be frequently monitored for neuropsychiatric side

effects as well as recurrence of substance-abuse and psychiatric-

disorder symptoms. SMI patients may require increased support by case-

management and therapeutic staff. Antidepressant pretreatment for IFN-

MDD should be offered to clients with current or past mood disorders,

and other psychopharmacologic interventions should be enhanced as

needed.

CONCLUSIONS

A growing literature documents the neuropsychiatric side effects of

interferon treatment for hepatitis C infection, predominantly, mood

changes, which are preventable and treatable with antidepressant

medications. The bulk of the data come from small studies, most of

which did not include persons with severe mental illness. However,

the evidence to-date suggests that persons with severe mental illness

can be safely and effectively treated for hepatitis C virus

infection. Medically eligible persons with SMI should be offered

hepatitis C virus treatment. Further research is needed to clarify

the risks and benefits of hepatitis C virus treatment in persons with

severe mental illness.

REFERENCES

54. Schaefer M, Schmidt F, Fowaczny C, et al: Adherence and mental

side effects during hepatitis C treatment with interferon alfa and

ribavirin in psychiatric risk groups. Hepatology 2003; 37:443-451

[CrossRef][Medline]

55. Hauser P, Soler R, S, et al: Prophylactic treatment of

depression induced by interferon-alpha. Psychosomatics 2000; 41:439-

441[Free Full Text]

90. Sylvester DL: Treating hepatitis C in methadone-maintenance

patients: an interim analysis. Drug Alcohol Depend 2002; 67:117-123

[CrossRef][Medline]

91. Drake RE, Mueser KT, et al: A review of treatment for clients

with severe mental illness and co-occurring substance-use disorders.

Psychosocial Rehabilitation Journal 2004

(54) Hepatology. 2003 Feb;37(2):443-51.

Adherence and mental side effects during hepatitis C treatment with

interferon alfa and ribavirin in psychiatric risk groups.

Schaefer M, Schmidt F, Folwaczny C, Lorenz R, G, Schindlbeck

N, Heldwein W, Soyka M, Grunze H, Koenig A, Loeschke K.

Department of Psychiatry, Charite, Humboldt University, Berlin,

Germany. martin.schaefer@...

ABSTRACT: Psychiatric disorders or drug addiction are often regarded

as contraindications against the use of interferon alfa (IFN-alpha)

in patients with chronic hepatitis C. Our aim was to obtain

prospective data on adherence to as well as efficacy and mental side

effects of treatment with IFN-alpha in different psychiatric risk

groups compared with controls. In a prospective trial, 81 patients

with chronic hepatitis C (positive hepatitis C virus[HCV] RNA and

elevated alanine aminotransferase [ALT] level) and psychiatric

disorders (n = 16), methadone substitution (n = 21), former drug

addiction (n = 21), or controls without a psychiatric history or drug

addiction (n = 23) were treated with a combination of IFN-alpha-2a 3

MU 3 times weekly and ribavirin (1,000-1,200 mg/d). Sustained

virologic response (overall, 37%) did not differ significantly

between subgroups. No significant differences between groups were

detected with respect to IFN-alpha-related development of depressions

during treatment. However, in the psychiatric group, significantly

more patients received antidepressants before and during treatment

with IFN-alpha (P <.001). Most of those who dropped out of the study

were patients with former drug addiction (43%; P =.04) compared with

14% in the methadone group, 13% in the control group, and 18% in the

psychiatric group. No patient in the psychiatric group had to

discontinue treatment because of psychiatric deterioration. In

conclusion, our data do not confirm the supposed increased risk for

IFN-alpha-induced mental side effects and dropouts in psychiatric

patients if interdisciplinary care and antidepressant treatment are

available. Preexisting psychiatric disorders or present methadone

substitution should no longer be regarded as contraindications to

treatment of chronic hepatitis C with IFN-alpha and ribavirin in an

interdisciplinary setting.

Full text Extracts

In conclusion, our prospective controlled study evaluating IFN-a

therapy in various psychiatric risk groups with chronic hepatitis C

should encourage physicians to offer this effective therapy to these

patients. Although

psychiatric-risk patients need special psychiatric care, this can be

achieved in an interdisciplinary setting. Because of the frequent

psychiatric changes during treatment withIFN-a, we recommend close

cooperation with a psychiatrist starting before treatment. Our

results add objective psychiatric data to the present discussion

concerning the tenability of psychiatric contraindications to IFN-a

and the practicability of IFN-a during methadone substitution.

Six patients in the psychiatric group had major depression, one had a

general anxiety disorder, 2 had schizoaffective disorder, 4 had

chronic schizophrenia, and 3 had severe borderline personality

disorder combined with a major depression. Five patients in this

group also had a history of former drug abuse, and 2 patients with

schizophrenic disorders additionally received methadone.

Use of Antidepressants. Overall, 4 of the 81 patients (5%) were on

antidepressants before and 13 of 81 patients (16%) received

antidepressants during treatment with IFN-a for hepatitis C (Table

3). For 6 of the patients in the psychiatric group, an additional

antidepressant treatment was initiated during the first 2 weeks of

treatment because of preexisting depression. The following

antidepressants were used: citalopram (10 times), mirtazapine (3

times), nefazodone (one time), paroxetine (2 times), fluoxetine (one

time), and amitriptyline (one time). We found significant group

differences in use of antidepressants before (P .0322) and highly

significant differences (P .0001) at the end of the treatment with

IFN-a, with the most frequent use in the

psychiatric group. Regarding the influence on liver function,

antidepressant treatment did not influence ALT levels during or after

treatment compared with patients not taking antidepressants. Relapse

after treatment was also not related to antidepressants.

Response. In the intention-to-treat analysis, at the end of

treatment, 47% of all patients were HCV RNA negative (virologic

response): 34% with genotype 1, 71% with genotype 2, 60% with

genotype 3, and 33% with genotype 4 (Table 2). During the 6 months

after the end of therapy, 11% (only genotypes 1 and 3) of all

patients experienced a relapse without significant differences

between treatment groups. Overall, 37% of the patients showed a

sustained virologic response: 35% in the control group, 38% in the

psychiatric group, 43% in the methadone group, and 28% in the former

addiction group. Group differences were not significant. A sustained

response was shown in 22% of the patients with genotype 1, 71% with

genotype 2, 47% with genotype 3, and 33% with genotype 4.

Dropouts. Therapy was discontinued early in 22% of the patients;

reasons were somatic (5%) or psychiatric (2%) side effects, relapse

in drug and alcohol abuse (2%), and noncompliance (13%). A total of

13% in the control group and 14% in the methadone group dropped out,

mostly because of noncompliance. A total of 18% of the psychiatric

group discontinued treatment because of somatic complications or

noncompliance. No patients in the psychiatric group had to stop

treatment because of psychiatric side effects. In 43% of patients in

the former addiction group (P .01 vs. patients in the control and

psychiatric groups), treatment was terminated prematurely because of

noncompliance (13%), depression (5%), suicidal thoughts (5%), relapse

in alcohol or drug abuse (10%), or somatic side effects (10%). The

dropout rate was highest during the first 2 months of therapy.

Depression and Psychiatric Side Effects. The incidence of depression

before and during treatment with IFN-a is shown in Table 3. More

patients in the psychiatric group were in a depressed mood when

entering the study (P .001 vs. all other subgroups). A total of 16%

of all patients developed a new depression during treatment with IFN-

a . We found no significant differences in frequency and severity of

new depressions during

treatment between the groups. However, patients with drug addiction

tended to have more often but milder depressions, whereas the

severity of depressive episodes in patients in the control and

psychiatric groups

tended to be moderate or severe. Suicidal thoughts were reported in

4% to 6% of patients, without significant differences between the

subgroups. Only 2 patients (3%) dropped out because of a worsening of

preexisting depression or development of suicidal thoughts. However,

none of these patients had to stop treatment from the psychiatric

point of view and suicidal thoughts disappeared under psychiatric

care in all cases. Depression before or during treatment had no

statistically significant influence on therapeutic outcome (sustained

response) or dropout rate. In addition, patients with depression had

significantly less problems with alcohol consumption during treatment

(P .046).

As expected, craving for drugs or alcohol was reported less

frequently in controls compared with patients in the psychiatric

group (P .02), methadone group (P .001), and former addiction group

(P .001). The most frequent psychiatric side effect was

irritability. The frequency of sleeping disturbances, concentration

difficulties, and irritability did not differ significantly between

groups (Table 3). Sleeping disturbances were treated with

benzodiazepines (zolpidem or zopiclone) in 28%. Admission to the

psychiatric ward was necessary for 3 patients in the psychiatric

group and 2 patients in the methadone and former addiction groups but

for none of the controls. It could not be determined in any case that

admission was caused by a direct association with psychiatric side

effects of treatment with IFN-a .

Use of Antidepressants. Overall, 4 of the 81 patients (5%) were on

antidepressants before and 13 of 81 patients (16%) received

antidepressants during treatment with IFN-a for hepatitis C (Table

3). For 6 of the patients in the psychiatric group, an additional

antidepressant treatment was initiated during the first 2 weeks

of treatment because of preexisting depression. The following

antidepressants were used: citalopram (10 times), mirtazapine (3

times), nefazodone (one time), paroxetine (2 times), fluoxetine (one

time), and amitriptyline (one time). We found significant group

differences in use of antidepressants before (P .0322) and highly

significant differences (P .0001) at the end of the treatment with

IFN-a, with the most frequent use in the

psychiatric group. Regarding the influence on liver function,

antidepressant treatment did not influence ALT levels during or after

treatment compared with patients not taking antidepressants. Relapse

after treatment was also not related to antidepressants.

In all patients who had depression during treatment with IFN-a,

improvement was possible with psychiatric and psychopharmacologic

support. Novel antidepressants with less sedation (selective

serotonin reuptake inhibitors) and benzodiazepines were especially

effective in treating sleeping disturbances, irritability, and

depression. The successful use of selective serotonin reuptake

inhibitors for the management of IFN-a -related psychiatric effects

has been described in several case reports.27-30 Most patients in the

psychiatric group continued treatment with antidepressants because of

a preexisting depression. Only one patient

developed a new major depressive episode, although he received

treatment with antidepressants. The earlier use of antidepressants in

the psychiatric group may explain the low incidence of major

depressive

episodes and suicidal syndromes. Recently, Musselman et al. showed

that pretreatment with paroxetine as an antidepressant was highly

effective in preventing depression and reducing the dropout rate

during adjuvant treatment of melanoma with IFN- .31 In addition,

Kraus et al. reported high efficacy in treating acute IFN-a -

associated depressive symptoms.28 Thus, our data extend the efficacy

of antidepressants in preventing and treating IFN-a -associated

depressive episodes, especially in psychiatric patients and patients

with methadone substitution and chronic hepatitis C. Overall, the low

rate of dropouts due to psychiatric side effects may be in part the

result of the timely use of antidepressants in all groups. Moreover,

the high dropout rate of patients with former drug addiction may also

be explained by the significantly less frequent use of

antidepressants in this group.

Interestingly, we could not find differences in ALT levels during and

after treatment with IFN- in patients who received treatment with

antidepressants compared with others. Thus, antidepressants did not

affect liver function during treatment of hepatitis C. However,

controlled studies focusing on the efficacy of antidepressants in

preventing psychiatric side effects of IFN-a and interactions with

response and liver enzymes during and after treatment of hepatitis C

are needed.