Hepatitis C and interferon: Watch for hostility, impulsivity

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CURRENT PSYCHIATRY ONLINE

Med/Psych Update

Vol. 5, No. 8 / August 2006

Hepatitis C and interferon: Watch for hostility, impulsivity

Manic side effects may emerge with antiviral treatment.

Chantal Henry, MD, PhD

Psychiatrist, Hôpital Perrens, Bordeaux cedex, France

t Castéra, MD

Gastrohepatologist, Hôpital Haut Lévêque, Pessac, France

Jacques Demotes-Mainard, MD, PhD

Professor of cellular biology, Hôpital Haut Lévêque, Pessac, France

Pegylated interferon-alpha with ribavirin is the most effective therapy for

chronic hepatitis C infection,1,2 but psychiatric patients often discontinue

IFN-alpha because of its mood side effects.3 Most studies describe

depressive states, although manic symptoms—irritability, aggression, anger,

hostility, emotional lability, anxiety, panic attacks, and insomnia—also

have been reported.4-6

To help you manage adverse mood changes and prevent IFN-alpha treatment

discontinuation in patients with hepatitis C, this article:

reviews studies of patients with a history mood disorders who were treated

with IFN-alpha

explains how to recognize and treat IFN-alpha-induced mood disturbances when

antidepressants are contraindicated.

Psychiatric Patients and IFN Therapy

Chronic hepatitis C infection is common among psychiatric patients. Routine

screening among 1,556 patients admitted to a U.S. public psychiatric

hospital across 3 years identified 133 patients (8.5%) who were positive for

hepatitis C virus.7

Patients with psychopathologic symptoms before starting IFN therapy may

suffer more-severe adverse psychiatric effects during treatment than those

without psychopathology.8 In fact, mood disorders were considered an

absolute contraindication to IFN therapy until recently.

Now that the National Institutes of Health (NIH) has recommended extending

hepatitis C research and treatment to psychiatric patients,

IFN-alpha-induced mental illness could become more common in clinical

practice. Before the 2002 NIH consensus statement, patients with mental

illness and substance use disorders—who represent >50% of candidates who

need IFN therapy—were excluded from research protocols.

Safely using IFN. Some reports and studies suggest that patients with past

or existing psychiatric disorders can be treated safely and effectively with

IFN-alpha.

In a prospective open-label study, 29 of 31 patients with co-existing

chronic hepatitis C and psychiatric illness completed 6 months of IFN

therapy, 5 million units (MU) three times/week or 5 MU daily. Patients

continued maintenance psychotropics during IFN treatment, and a psychiatrist

monitored psychiatric symptoms.

Psychiatric illness worsened in four patients, and two discontinued IFN

treatment. Serum alanine aminotransferase returned to normal in 22 patients

(71%), and hepatitis C virus RNA cleared from the sera of 15 (48%).9

Another prospective study of 50 patients treated with IFN for chronic

hepatitis found that those with a pre-existing mood or anxiety disorder were

not more likely than others to discontinue IFN therapy.10

Unique to hepatitis therapy? IFN-induced mood disturbances are probably

different in patients with chronic hepatitis C than in those receiving IFN

for other diseases because of differences in regimens and effects of the

underlying pathologies. For example, prescribing a preventative

antidepressant before starting IFN treatment might help cancer patients but

not patients with hepatitis C.11

This distinction could be particularly important when giving IFN-alpha to

patients who are vulnerable to psychiatric illness with impulsive features.

To emphasize this point, we describe clinical features and treatment

response in patients with hepatitis C who were treated in our department.

IFN-Alpha-Induced Moods

In our prospective study of 93 patients, 30 (32%) developed

IFN-alpha-induced mood disorders during the first 12 weeks of treatment.12

Contrary to previous studies focusing on depression, most of our patients

had a mix of manic/hypomanic and depressive symptoms. Twenty-four (13 women

and 11 men, mean age 43) accepted referral to a psychiatrist specializing in

mood disorders to characterize their symptoms.

Mood characteristics. Using DSM-IV criteria, the psychiatrist determined

that IFN-alpha induced both manic/hypomanic and depressive symptoms in many

patients, and the manic/hypomanic features predominated. Five manic symptoms

and three depressive symptoms were present in >50% of patients (Figure 1,

Table 1).

Three patients presented with a manic episode,15 with hypomania with

prevalent irritability and dysphoric features, and 6 with a mixed depressive

state (major depressive episode with at least 3 hypomania symptoms).13 Four

patients (17%) suffered a relapse of alcohol or cannabis abuse.

Nearly all (84%) reported paroxysmal anxiety, and all had emotional

hyperreactivity that the psychiatrist described as a main symptom of a manic

or mixed state.14 Most felt extremely impulsive and feared losing control.

Two faced legal difficulties, and one was in prison.

The patients’ mean Montgomery-Åsburg Depression Rating Scale (MADRS) score

was 16.12 (±1.6), indicating a mild to moderate depressive state. The

highest-scoring items were inner tension, reduced sleep, reduced appetite,

and lassitude (Figure 2).

Their mean Bech-sen Mania Scale15 score was 14.33 (±1.3), indicating

hypomanic or moderate manic symptoms. Hostility was by far the predominant

manic symptom (mean score 3.2/4). Other manic symptom scores ranged from

0.2/4 to 2.1/4 (Figure 3).

Figure 1

Mood symptoms identified in 24 patients after 12 weeks of IFN-alpha

treatment

IFN: Interferon

Source: Reference 12

Figure 2

Depressive symptoms in 24 patients with IFN-induced mood disorder

IFN: Interferon

Source: Reference 12

Figure 3

Manic symptoms in 24 patients with IFN-induced mood disorder

IFN: Interferon

Source: Reference 12

Table 1

Most-prevalent IFN-induced mood symptoms in 24 patients treated for

hepatitis C 5 manic symptoms (% of patients)

3 depressive symptoms (% of patients)

Irritability (100%)

Insomnia or hypersomnia (100%)

Racing thoughts (87%)

Poor appetite or weight loss (92%)

Distractibility (87%)

Psychomotor agitation or retardation (54%)

Insomnia (58%)

Agitation (70%)

IFN: Interferon

Source: Reference 12

Treatment. Given the predominance of manic/hypomanic symptoms, we treated

the 24 patients with low-to-moderate dosages of an atypical antipsychotic

(amisulpride, 100 to 600 mg/d). This medication—not available in the United

States—would be similar to using risperidone, 1 to 6 mg/d. Low-dose

benzodiazepines (clonazepam or alprazolam) were added as needed to manage

insomnia. Antipsychotic treatment enabled 23 of 24 patients (96%) to

continue antiviral therapy.

Five patients had received selective serotonin reuptake inhibitors (SSRIs)

for 1 to 4 weeks before referral to the psychiatrist. Antidepressants

worsened their mood symptoms, which included impulsivity, agitation, and

insomnia. Emotional hyper-reactivity, irritability, hostility, and

impulsiveness improved in all 5 patients within 1 to 2 weeks of stopping

SSRIs and starting the atypical antipsychotic.

Discussion

Accurately characterizing IFN-induced mood states confirmed our published

data showing a mix of manic/hypomanic and depressive symptoms in psychiatric

patients treated for chronic hepatitis C. Irritability and hostility were

the two most prominent symptoms.

These findings differ from those of investigations that identified

depressive symptoms as the hallmark of IFN’s psychiatric side effects.6 Our

data were thoroughly characterized according to DSM-IV-TR criteria, two

mood-rating scales, and a psychiatrist experienced in mood disorders.

Why is mania missed? One possible explanation for these different findings

is that IFN-alpha-induced fatigue and flu-like symptoms could be

misinterpreted as depressive symptoms. Also, most researchers have used

depression rating scales—but not mania scales—and have not considered other

psychiatric diagnostics.16

Self-report questionnaires for evaluating depression also take into account

somatic side effects, resulting in higher rating scores. Moreover, few

studies have included clinical psychiatric interviews and even fewer

diagnostic confirmation by a psychiatrist.

Finally, clinical experience indicates that patients who present with both

manic/hypomanic and depressive symptoms are more likely to complain about

depression than about manic symptoms. Therefore, clinicians may miss manic

symptoms if they don’t actively seek them.

Irritability and hostility. Previous studies have described irritability,

mood lability, and anger/hostility as frequent symptoms4,5 but failed to

consider them as possible manifestations of mania or hypomania. Many of our

patients reported irritability severe enough to interfere with their work,

social, and family relationships.

Hostility was the symptom with the highest score on the Bech-sen Mania

Scale. This objective evidence suggests that investigating the consequences

to patients of increased irritability, impulsivity, or hostility might

reveal some frightening behavior

How to treat these patients. Considerable evidence from characterizing

IFN-induced side effects in patients with hepatitis C points to a syndrome

of depressive and manic/hypomanic symptoms13,17-19 that does not fulfill

criteria for a mixed state. This disorder is not described in DSM-IV-TR and,

unfortunately, usually is misdiagnosed as a depressive state.

Antidepressants can worsen depression by causing agitation and impulsivity

and can increase risk of suicide.17,18,20 By contrast, atypical

antipsychotics have been shown to improve bipolar depression.21,22

We used an atypical antipsychotic to treat patients with prevalent manic or

hypomanic symptoms and those who did not respond to SSRIs. Their IFN-induced

mood disorders improved rapidly on low dosages of amisulpride, and antiviral

therapy discontinuation rates were low (1/24; 4%). By comparison, other

studies have reported antiviral treatment discontinuation rates of 30% to

40% in patients taking antidepressants.23,24

The atypical antipsychotic did not improve our patients’ fatigue and other

neurovegetative symptoms, but antidepressants likewise do not improve these

symptoms.8

Recommendations

This study leads us to warn clinicians that antidepressants can worsen

IFN-alpha-induced mood disorders and to recommend that antipsychotics be

considered:

at least before you decide to discontinue a hepatitis C patient’s IFN-alpha

therapy

or in patients with high irritability and hostility.

To determine whether to use an antidepressant or antimanic agent as

first-line treatment, carefully diagnose the patient’s symptoms as a

manic/hypomanic state, depressive mixed state, or depression. Successful IFN

therapy requires:

psychological support

medication for psychiatric adverse effects

collaboration between the psychiatrist and hepatologist.

IFN-alpha-induced mood disorders are triggered exogenously, do not

correspond to typical features of any classic psychiatric disorder, and

require further study. IFN-induced impulsivity and hostility also need to be

better characterized, particularly as more patients with pre-existing

psychiatric disorders are treated for hepatitis C.

Related resources

Lauer GM, BD. Hepatitis C virus infection. N Engl J Med

2001;345(1):41-52.

Onyike CU, Bonner JO, Lyketsos CG, Treisman GJ. Mania during treatment of

chronic hepatitis C with pegylated interferon and ribavirin. Am J Psychiatry

2004;161:3.

Drug brand names

Alprazolam • Xanax

Amisulpride • (not available in the United States)

Clonazepam • Klonopin

Risperidone • Risperdal

Acknowledgment

This study was conducted with support from the Centre d’Investigation

Clinique INSERM/CHU de Bordeaux.

Referencesz<cut>

http://www.currentpsychiatry.com/article_pages.asp?AID=4318 & UID=

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