Interferon alpha (IFNα) and psychiatric syndromes

Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731 – 746

Review

Interferon alpha (IFNa) and psychiatric syndromes A review Martin Schaefera, Marc A. Engelbrechtb, Oliver Gutb, Bernd L. Fiebichb, Joachim Bauerc, Folkhard Schmidtd, Heinz Grunzed, Klaus Liebb,* b

a Department of Psychiatry, Charite´, Humboldt University, Humboldt, Germany Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr. 5, D-79104, Freiburg, Germany c Department of Psychosomatics, University of Freiburg Medical School, Freiburg, Germany d Department of Psychiatry, Ludwig-Maximilians-University of Munich, Munich, Germany

Abstract Interferon alpha (IFNa) is used for the treatment of several disorders, such as chronic hepatitis or malignant melanoma. During the therapy, IFNa may cause severe neuropsychiatric syndromes including depression with suicidal ideation, paranoid psychoses, or confusional states. The reasons and management of these side effects are widely unknown. Our aim is to review research evidence for the contribution of IFNa for the etiopathology of psychiatric syndromes. Therefore, research findings of neuropsychiatric syndromes induced by IFNa treatment, the putative mechanisms underlying those syndromes, and their treatment are reviewed. Furthermore, neuropsychiatric syndromes in diseases with high IFNa levels such as systemic lupus erythematosus (SLE) are discussed. Finally, the question is addressed whether IFNa may contribute to the etiopathology of endogenous psychiatric disorders. IFNa may cause psychiatric syndromes in a subset of treated patients. The underlying pathogenetic mechanisms include various effects on neuroendocrine, cytokine, and neurotransmitter systems. Research data on the role of IFNa in the pathogenesis of endogenous psychiatric disorders are conflicting. Future research should improve our understanding of the role of IFNa for the etiopathology of psychiatric syndromes and has an impact on treatment of IFNa-induced psychiatric syndromes. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Depression; Interferon alpha; Psychiatric disorders; Side effects; Systemic lupus erythematosus

1. Introduction Cytokines are polypeptide mediators who transmit signals from one cell to another and constitute the molecular language of inflammation and immunity. Inflammatory cytokines may be able to induce neuropsychiatric symptoms such as sickness behavior in animals or depression in humans (Kronfol and Remick, 2000; Dantzer, 2001; Yirmiya et al., 2000), which might be pre-

Abbreviations: ACTH, adrenocorticotropin hormone; BBB, Brain – blood barrier; CRH, Corticotropin-releasing hormone; DSM IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; HPA, Hypothalamic – pituitary – adrenocortical; IFNa, Interferon alpha; IL, Interleukin; NMDA, N-methyl-D-aspartate; SLE, Systemic lupus erythematosus * Corresponding author. Tel.: +49-761-270-6501; fax: +49-761-2706667. E-mail address: [email protected] (K. Lieb).

vented by antidepressant treatment (Yamano et al., 2000; Song, 2000). Induction of endogenous cytokines by endotoxins in healthy probands was recently shown to be associated with increase in depressive symptoms and anxiety, even without inducing sickness sympoms (Reichenberg et al., 2001). Especially IL-1, IL-2, IL-6, IL-10, TNF-a, and interferon alpha (IFNa) and gamma (IFNg) where shown to be able to induce neuropsychiatric syndroms in experimental or therapeutic conditions (Kronfol and Remick, 2000). The cytokine IFNa is being used for the treatment of chronic viral diseases such as chronic hepatitis B and C and for the treatment of different malignancies (Table 1). Treatment duration may range from months (hepatitis) to several years (malignant melanoma) and may be complicated by various side effects (Baron et al., 1991; Cirelly and Tyring, 1995; Williams and Linch, 1997). While systemic side effects such as fatigue, fever, chills, myalgia, and nausea occur in most patients and normally disappear

0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 3 2 4 - 4

732

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

after 2 –3 weeks of treatment, more severe side effects may emerge with chronic treatment. These include hematologic, autoimmune, and neuropsychiatric side effects (Dusheiko 1997; Valentine et al., 1998). Among the neuropsychiatric side effects, a spectrum of symptoms may be evoked ranging from mild forms of depression, irritability, lack of motivation, and impaired concentration to more severe disorders such as depression with suicidal ideation or manic/paranoid psychoses and confusional states (Table 2). Because in 10 –20% discontinuation of treatment is due to neuropsychiatric side effects, there is a growing interest for a better understanding of possible underlying mechanisms (Haria and Benfield, 1995). Furthermore, especially for long-term treatment over years, new therapeutic options are needed to reduce frequency and severity of neuropsychiatric side effects. The aim of this article is to review research findings of neuropsychiatric syndromes induced by IFNa treatment and to discuss putative mechanisms underlying IFNa-induced psychiatric syndromes as well as their treatment. Furthermore, neuropsychiatric syndromes in diseases with high intrinsic IFNa levels such as systemic lupus erythematosus (SLE) are discussed. Finally, the question is addressed

Table 1 Major therapeutic uses of IFNa (Cirelly and Tyring, 1995) Cancers Hairy cell leukaemia Multiple myeloma Kaposi’s sarcoma Cervical neoplasia Basal cell cacinoma Squamous cell carcinoma Melanoma Renal cell carcinoma Carcinoid tumors Cutaneous T-cell lymphoma Non-Hodgkin’s lymphoma Viral disorders Condylomata accuminata Verruca vulgaris HIV Hepatitis B and C Myeloproliferative disorders Thrombocytosis Chronic myelogenous leukaemia Polycythaemia vera Idiopathic thrombocythaemia Myeloid metaplasia Rheumatoid and immune-related disorders Rheumatoid arthritis Systemic sclerosis Lupus erythematosus Behcet’s syndrome Atopic dermatitis

Table 2 Psychiatric side effects of IFNa distributed by syndromes Anxiety Agitation Panic attacks Sleeping disturbance Insomnia Excessive sleepiness Irritability Aggressiveness Craving for drugs or alcohol Organic syndromes Lack of concentration Memory disturbance Cognitive dysfunction Psychomotoric retardation Confusion/disorientation Delirium Personality changes Depression Mood instability/fluctuations Reduced self-confidence Loss of interests Ruminative thinking Ambivalence Dysphoria Anhedonia Social withdrawal Emotional indifference Affective rigidity Hopelessness Suicidal thoughts Suicide attempt Mania Psychosis Formal thought disorders Paranoia Hallucinations

whether IFNa may contribute to the etiopathology of endogenous psychiatric disorders.

2. Neuropsychiatric syndromes induced by IFNA therapy The incidence, nature, and severity of neuropsychiatric syndromes induced by IFNa therapy depend possibly on the total dose and particularly on the application form. Severe neuropsychiatric syndromes have been described to occur during high-dose intravenous or intracerebroventricular IFNa therapy of cancer and amyotrophic lateral sclerosis, whereas less severe neuropsychiatric syndromes have been described to occur with subcutaneous chronic low-dose IFNa therapy. However, severe side effects even under

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

low-dose treatment cannot be excluded. Strong correlation to total dose, duration of treatment, or types of interferons could not be confirmed (Fattovich et al., 1996; Malaguarnera et al., 1998; Nozaki et al., 1997). 2.1. Neuropsychiatric syndromes induced by high-dose IFNa therapy Several prospective studies investigated neuropsychiatric effects of short-term application of very high doses of IFNa (up to 900 MU/6 days) given intravenously or intracerebroventricularly for the treatment of different forms of cancer and amyotrophic lateral sclerosis (Table 3). A very high percentage of patients developed an organic mental disorder after a relatively short latency of several days, which was characterised by somnolence, confusion, mental and motor slowing, difficulties of concentration, memory impairment, parkinsonian symptoms, hearing loss, or seizures. Most studies reported fairly prompt resolution of neuropsychiatric side effects after cessation of treatment (Table 3). However, a study by Meyers et al. (1991b) observed persistent effects with low to moderate deficits in cognitive functions even after discontinuation of treatment. This suggests that, at least in some cases, IFNa neurotoxicity may not be completely reversible. Although the clear temporal relationship of IFNa therapy and neuropsychiatric side effects strongly suggests that the neuropsychiatric symptoms are caused by IFNa, other various etiologies may underlie the appearance of behavioral changes and neuropsychological deficits in such patients. Examples are metastatic spread to the brain, paraneoplastic phenomena, metabolic derangements, and alterations following radiation or chemotherapy. It seems probable that patients with cancer as well as patients with preexisting subtle neurologic abnormalities are at increased risk to develop severe IFNa neurotoxicity (Adams et al., 1988). 2.2. Neuropsychiatric syndromes induced by low-dose IFNa therapy Low-dose IFNa therapy (3– 5 MU sc/three times a week) over a period of several months is used for the treatment of chronic hepatitis B or C or over several years for malignant melanoma (Hoofnagle and di Bisceglie, 1997; Sharara et al., 1996; Legha, 1997). Compared to neuropsychiatric side effects occurring with high-dose therapy, neuropsychiatric effects during low-dose therapy are often less severe and occur after a longer latency and in a smaller proportion of patients (Table 4). Psychiatric symptoms most often present as irritability and depression accompanied by impaired concentration, lack of motivation, sleep disturbances, and decreased libido. Other psychiatric symptoms such as mania, paranoid psychosis, and severe anxiety have been described only in single cases (Table 4). In a retrospective survey of adverse events

733

in more than 10,000 patients with chronic hepatitis C treated with IFNa, 10 patients developed psychosis, which was reversible after discontinuation of IFNa, either spontaneously in three patients or with neuroleptic treatment in seven patients (Fattovich et al., 1996). Single cases of manic psychosis have also been described (Janssen et al., 1994; Nozaki et al., 1997; Greenberg et al., 2000), which may occur even 2– 3 years after therapy (Strite et al., 1997). Single cases of attempted and successful suicides during or shortly after withdrawal from low-dose IFN therapy have been described (Fattovich et al., 1996; Hoofnagle et al., 1993; Janssen et al., 1994; Renault et al., 1987; Rifflet et al., 1998), and the incidence of suicides and attempted suicides seems to be higher than in the general population (Janssen et al., 1994). In all described cases, patients developed a psychiatric disorder (mostly severe depression; in one case, a manic psychosis) which led to their suicidal behavior. It is difficult to determine the frequency of psychiatric side effects during IFNa therapy based on the literature. This has several reasons: First, definition of psychiatric symptoms may vary considerably from study to study, e.g., Tong et al. (1997) and Lindsay et al. (1996) called nervousness and irritability, depression, impaired concentration, and fatigue psychiatric symptoms, and therefore observed such ‘‘psychiatric symptoms’’ in a high number (50%) of patients at least once during IFNa therapy for chronic hepatitis C. Second, sensitivity to detect psychiatric symptoms may vary. Without use of assessments by psychiatrists and psychiatric rating scales, the frequency of psychiatric disturbances during IFNa therapy may well be underestimated. In one prospective study, the effect of IFNa treatment on the development of depression in patients with chronic hepatitis was investigated (Hunt et al., 1997). As measured by self-rating scales, depressive symptoms increased significantly during IFNa therapy as compared to baseline conditions without IFNa. In a prospective psychiatrically rated collective of patients with chronic hepatitis C, Miyaoka et al. (1999) diagnosed a depression before the treatment with IFNa in 4.5% patients. Forty-three percent developed a depression according to the diagnostic criteria of DSM-IV during the treatment between weeks 7 and 20. Three percent developed suicidal thoughts. In an own still ongoing prospective study, nearly 50% of the patients developed depressive syndromes, up to 20% a major depression. Suicidal syndromes were found in 6%, irritability in 70%, sleeping disturbances in 55%, fatigue and loss of interests in 70%, and impaired concentration in 50% (Scha¨fer et al., 2000a). From our knowledge, there are only two controlled studies which compared the frequency of psychiatric disorders in treated and untreated patients. In a study by Davis et al. (1989), the frequency of depression in untreated patients was 8% and increased to 9% and 14% during treatment with 1 and 3 MU/three times weekly, respectively, which however was not statistically signific-

734

Table 3 Prospective studies investigating neuropsychiatric side effects with high-dose IFNa therapy Disorder

n

m/f

Age (mean and range)

IFN

Application

Dose (mean and range)

Duration

Test

Latency

no

several days

9

4/5

45 (23 – 59)

a

icv

3 – 9 MU, 3  per week

Lung cancer

9

6/3

64 (53 – 75)

b+a

iv

425 – 800 MU/5 days after 2 weeks, 3  6 MU/week

18 weeks (range 5 – 42 weeks)

no

2 days

Breast cancer

10

0/10

n.d.a.

rIFN

im

160 MU/week

12 weeks

no

3 weeks

Leukaemia

11

n.d.a.

n.d.a.

a2

iv

100 MUm

7 days

no

1 – 3 days

3/2

45 (30 – 65)

rIFN

iv

300 – 900 MU/6 days

6 days

yes

4 – 12 days

n.d.a.

49

a

iv

510 MU/5 days

5 days

yes

5 days

Amyotrophic lateral sclerosis

5

Amyotrophic lateral sclerosis

15

n.d.a. = no data available; icv = intracerebroventricular.

2

/day

Seven of nine patients confusion, lethargy, speech difficulties, unable to follow commands. 33% Parkinsonism, 33% hearing loss, 22% seizures On Day 2: excited, almost euphoric. Then progressive mental and motor slowing, somnolence, lack of initiative, speech perseveration, writing unreadable Six patients profound lethargy and somnolence, five patients frank confusion, loss of concentration, and expressive dysphasias 7 of 11 patients drowsy, withdrawn, slow to answer questions, totally disinterested in their surroundings, sleeping for most of the day. Three of seven patients disoriented in time and place, one patient visual hallucinations Impairment of logical memory, motor accuracy and coordination, psychomotor slowing Significant cognitive deterioration in logical memory task, calculation ability, and signature writing time

Reversibility

References

n.d.a.

Meyers et al., 1991a

14 days posttreatment

Mattson et al., 1983; Niiranen et al., 1988

7 – 10 days posttreatment

Smedley et al., 1983

n.d.a.

Rohatiner et al., 1983

9 days posttreatment

Farkkila et al., 1984; Iivanainen et al., 1985 Poutiainen et al., 1994

3 days posttreatment

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Leptomeningeal disease on the basis of melanoma, breast, or lung cancer or lymphoma

Neuropsychiatric side effects types

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

735

Table 4 Frequency and latency of neuropsychiatric side effects during chronic low-dose IFN therapya Frequency

Latency

References

(A) Psychiatric side effects Depression Irritability

4 – 13%

12 – 36 weeks

Lack of motivation Decreased libido Sleep disturbances

n.d.a. 5% 3 – 6%

n.d.a. n.d.a. n.d.a.

Cognitive disturbances Severe anxiety Paranoid ideation

n.d.a. single cases single cases

12 – 36 weeks n.d.a. 16 weeks

Manic psychosis

single cases

12 weeks, 2 – 3 years

Attempted suicide

single cases

4 – 14 weeks

Committed suicide Return of craving for alcohol or drugs

single cases n.d.a.

19 weeks n.d.a.

Lindsay et al., 1996; Lublin et al., 1996; Neilley et al., 1996; Poynard et al., 1995, 1996 Hoofnagle and di Bisceglie, 1997 Okanoue et al., 1996 Lublin et al., 1996; Neilley et al., 1996 Lindsay et al., 1996 Hoofnagle et al., 1993 Scha¨fer et al., 2000c; Fattovich et al., 1996; Lindsay et al., 1996; Lok et al., 1988; McDonald et al., 1987 Janssen et al., 1994; Strite et al., 1997 Fattovich et al., 1996; Hoofnagle et al., 1993; Janssen et al., 1994; Renault et al., 1987 Janssen et al., 1994 Hoofnagle and di Bisceglie, 1997

(B) Neurologic side effects Hearing loss/tinnitus Seizures

40% single cases

n.d.a. 3 – 10 weeks

Peripheral paraesthesia

single cases

n.d.a.

Peripheral neuropathy

single cases

n.d.a.

Polymyositis

single case

see text

Dusheiko, 1997 Fattovich et al., 1996; Janssen et al., 1990 Guttermann et al., 1982; Muss et al., 1984; Smedley et al., 1983 Fattovich et al., 1996; Negoro et al., 1994; Tambini et al., 1997 Matsuya et al., 1994

a

Chronic low-dose therapy means therapy for months with 3 – 8 MU IFNa/three times per week. n.d.a. = no data available.

ant (Davis et al., 1989). The same was true for irritability and fatigue. Another study observed a rise in psychiatric symptoms, especially depression and anxiety, during IFNa treatment compared with matched controls (McDonald et al., 1987). Although the occurrence of psychiatric symptomatology during IFNa treatment in patients with no psychiatric history and the frequently observed resolution of psychiatric symptoms on discontinuation of therapy suggest that IFNa was the cause of the psychiatric symptoms, it is difficult to determine whether psychiatric disturbances are solely due to IFNa therapy. Besides development of depression during IFNa therapy, in 2 – 30% depressive symptoms are preexisting before treatment. Hepatitis itself is accompanied by fatigue, anhedonia, lack of motivation, impaired concentration, and slight cognitive impairment. In up to 25%, an indication for

antidepressant treatment exists (Yates and Gleason, 1998; Dieperink et al., 2000). Other contributing factors could be, e.g., the secondary psychological impact of primary IFNa-induced symptoms such as fatigue, lack of motivation, or difficulties to concentrate. In this view, depression could be understood as a reaction to the fatigue induced by IFNa. As an alternative hypothesis, IFNa may only induce psychiatric symptoms in patients who are at risk to develop psychiatric disorders. If this were true, IFNa would only act as an unspecific ‘‘stressor.’’ Neurological symptoms such as seizures, peripheral paraesthesias, and neuropathies were described only in single cases (Table 4). Neuropsychological deficits during IFNa therapy may show up as deficits in verbal learning, recall of verbal material, speed and efficiency of cognitive processing, and difficulties in executive functions (Pavol et al.,

736

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

1995). There are no studies that examined whether the cognitive disturbances are caused by or independent of mood disturbances. Electroencephalographic changes during IFNa therapy have been described in different studies (Farkkila et al., 1984; Honigsberger et al., 1983; Mattson et al., 1983; Meyers et al., 1991a; Smedley et al., 1983). They often occur during high-dose therapy, but may also develop with low-dose therapy, especially in older patients or in case of previous brain damage (Suter et al., 1984). They consist of (1) slowing of alpha rhythm with a loss of reactivity to eye opening, (2) diffuse arrhythmic delta slowing, and (3) intermittent, frontal dominant, rhythmic delta activity. Although less frequent, sharp-wave discharges may occur (Suter et al., 1984). However, seizures during IFNa therapy have been described only in a few single cases (Fattovich et al., 1996; Janssen et al., 1990). Interestingly, although EEG changes tend to occur in association with the development of clinical symptoms, the degree of EEG changes does not always correlate with the severity of symptoms of neurotoxicity (Rohatiner et al., 1983). Severe EEG changes may even develop in patients without toxic CNS symptoms. EEG changes have been reported to resolve after cessation of therapy (Rohatiner et al., 1983; Smedley et al., 1983). 2.2.1. Risk factors for neuropsychiatric side effects Table 5 lists the actually known risk factors for the development of neuropsychiatric side effects during IFNa therapy. With respect to psychiatric symptoms, depressive state before treatment with IFN was associated with an increased risk to develop depression during treatment (Capuron and Ravaud, 1999; Miyaoka et al., 1999; Musselmann et al., 2001). Psychosocial problems or psychiatric disorders are also discussed as risk factors for side effects of interferons (McDonald et al., 1987; Ho et al., 2001). Nevertheless, two prospective studies demonstrated that patients with a history of psychiatric disorders can be successfully treated with interferons without increased risk to stop therapy or to develop neuropsychiatric side effects (van Thiel et al., 1995; Pariante et al., 1999). From preliminary results of a still ongoing prospective controlled study, we also cannot confirm any increased risk for severe side effects in a population of

Table 5 Possible risk factors for psychiatric side effects of IFNa

Dose and application form:
intracerebroventricular > intravenous > intramuscular > subcutaneous age

High Organic brain injury or dysfunction (atrophy, trauma, metastasis,. . .) and alcohol abuse
Drug infection
HIV state

Depressive Premorbid personality (typus melancholicus, zyclothymia)
Personality disorder

patients with severe and chronic psychiatric disorders compared to healthy controls.

3. Treatment of neuropsychiatric syndromes induced by IFNA If psychiatric syndromes occur during IFNa therapy, it is proposed to either lower the dose of IFNa or to discontinue IFNa therapy. Most studies support the view that psychiatric side effects of IFNa are reversible after discontinuation of therapy. This, however, is not always the case as was shown in one follow-up study in which certain neuropsychological deficits did persist long after IFNa therapy (Meyers et al., 1991b). Depressive symptoms may also persist long after cessation of IFNa therapy (Rifflet et al., 1998 and own observations), stressing the notion that depressive symptoms may be caused by several factors including psychosocial factors of chronic illness. In these cases, and also in those, in which IFNa cannot be discontinued, the question arises how to treat IFNa-induced psychiatric symptoms. There are no controlled studies investigating treatment strategies of neuropsychiatric side effects of IFNa. However, one can assume that neuropsychiatric symptoms may be managed nearly in the same way as endogenous psychoses. Before starting treatment of side effects, other important reasons for neuropsychiatric symptoms, such as thyroid dysfunction or central metastasis, should be excluded. Sleep disturbance is a very frequent and early side effect which is not always followed by later development of a depressive syndrome. Thus, treatment with short-acting sedatives like zaleplon, zolpidem, or zopiclon may be useful for several days and leads in some cases to a rapid reduction of sleeping disturbance, fatigue, loss of energy, and irritability (own observations). However, in cases with additional depressive symptoms, antidepressant treatment should be initiated. In the case of anxiousness and agitation, benzodiazepines are effective, but treatment duration should be limited and patients should be kept under continuous control. Because of additional sedative effects of IFNa itself, lower doses may be recommended (Scha¨fer et al., 2000b). In the case of depressive symptoms and in the absence of suicidal ideation, nonsedating antidepressants may be preferred to avoid additional induction of fatigue (Valentine and Meyers, 1995). In line with that, Levenson and Fallon (1993) reported the successful treatment of IFNa-induced depression with fluoxetine, Goldman (1994) with nortriptyline, Schramm et al. (2000) with sertraline, and Scha¨fer et al. (2000b) with nefazodone. The use of selective serotonin reuptake inhibitors may even be preferred in view of a recent study demonstrating a stimulation of the transcription of the serotonin transporter by IFNa (Morikawa et al., 1998). This might also explain the increased sensitivity to SSRIs given during IFNa treatment and our observation that also lower dose of antidepressants can be effective in

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

the treatment of depressive syndromes (Scha¨fer et al., 2000b). All case reports show that discontinuation of IFNa treatment may be avoided through early and sufficient psychopharmacological treatment. This confirms experiences in the treatment of multiple sclerosis wherein treatment of depression improved adherence to IFNb1b therapy (Mohr et al., 1997). Apart from the pharmacological treatment of psychiatric side effects, mild forms of depression may also be managed by psychotherapeutic strategies, educating, supporting, and reassuring the patients and their families that the behavioral symptoms are transient, treatable, and biochemically mediated and not the result of the patients’ sudden ‘‘giving up,’’ ‘‘tendency to laziness,’’ or ‘‘self-pity.’’ Attention should also be focused on the prevention of side effects. Besides intensive information of patients and relatives about possible neuropsychiatric side effects, pretreatment with antidepressants may be useful to minimize neuropsychiatric side effects. In a recent prospective, double-blind, placebo-controlled study, paroxetine was shown to be able to reduce neuropsychiatric side effects significantly compared to placebo when given 14 days before highdose adjuvant IFNa treatment for malignant melanoma was started (Musselmann et al., 2001). The incidence of depressive symptoms, anxiety, and neurotoxicity was significantly reduced in the group with paroxetine—‘‘augmentation.’’ Moreover, while in patients receiving placebo the development of depression during IFNa therapy was associated with elevated depression scores before treatment, no association could be observed in the paroxetine pretreated group. However, because some antidepressants have immunomodulatory properties, a successful treatment or prevention of depression during IFNa treatment might counteract the desired immunomodulatory (i.e., antiinfectious or antiproliferative) effects of IFNa (Song, 2000). Because of the importance of these possible negative interactions, further controlled studies about benefit or risks of antidepressant treatment during therapy with IFNa are needed.

4. IFNA as a mediator of neuropsychiatric syndromes in SLE SLE is an autoimmune disease, in which central nervous system (CNS) involvement has been shown to be a relatively common and serious complication of the disease (Kovacs et al., 1993; Lieb et al., 1997). Neurological symptoms may occur as headaches, seizures, neuropathies, and cerebral infarcts; psychiatric symptoms as paranoid psychoses and neuropsychological deficits. The pathogenesis of neuropsychiatric symptoms in SLE has not yet been clarified. Whereas different authors stressed the importance of autoreactive antibodies such as antineuronal antibodies and antiribosomal P protein antibodies for the etiology of neuropsychiatric symptoms associated with SLE (Kovacs et al., 1993; Lieb et al., 1997), it has recently been shown that

737

IFNa may be a possible mediator of neuropsychiatric symptoms in SLE. Elevated serum IFNa levels have been observed in patients with active SLE, and IFNa serum levels have been shown to correlate well with disease activity (Hooks et al., 1979; Ytterberg and Schnitzer, 1982). IFNa has also been detected in the cerebrospinal fluid (CSF) of SLE patients with neuropsychiatric manifestations (Isshi et al., 1994; Lebon et al., 1983; Winfield et al., 1983). The principle CNS manifestation in these patients was psychosis (Lebon et al., 1983; Winfield et al., 1983), disturbances of memory, calculation and orientation with finally gradual loss of consciousness (Isshi et al., 1994), or seizures and coma (Lebon et al., 1983). CSF levels of IFNa correlated well with CNS manifestation, i.e., IFNa disappeared after remission of neuropsychiatric symptoms (Isshi et al., 1994; Lebon et al., 1983). Shiozawa et al. (1992) investigated in more detail the relationship of CSF and serum IFNa to lupus psychosis. They compared IFNa levels in serum and CSF of 6 SLE patients with psychosis with IFNa levels of 11 SLE patients with CNS manifestations other than psychosis (seizures and cerebrovascular disease) and IFNa levels of 8 SLE patients without neuropsychiatric manifestations. Twenty patients with different neurologic diseases served as controls. IFNa levels were increased only in the patients with lupus psychosis: CSF samples of five of the six patients with lupus psychosis showed increased levels of IFNa. In four of these five patients, the level was much higher in the CSF than in the serum. CSF examinations could be repeated in three patients revealing a coincident decrement of IFNa levels with disappearance of psychiatric symptoms. The authors were further able to analyse postmortem brain material of one patient with increased IFNa levels by means of immunohistochemistry and in situ hybridization techniques. IFNa was localized in neurons and glial cells of the frontal, temporal, parietal, and occipital lobes as well as in areas of focal microgliosis. This confirms previous studies of a local synthesis of IFNa in astrocytes of the brain. In conclusion, studies on IFN levels in SLE strongly support the hypothesis that IFNa is a pathogenic element of psychosis in patients with SLE.

5. Putative mechanisms underlying IFNA-induced neuropsychiatric symptoms (Fig. 1) 5.1. Direct or indirect effects of IFNa on CNS functions? IFNa is a molecule with a molecular weight of approximately 19 kDa and is therefore hardly able to cross the blood –brain barrier (BBB) and brain –cerebrospinal barrier (Collins et al., 1985; Wiranowska et al., 1989) (Fig. 1). In line with that, measurable amounts of IFNa in the human CSF occur only after application of very high doses of IFNa (e.g., 100 – 200 MU/day) and repeated intravenous infusions (Farkkila et al., 1984; Mattson et al., 1983; Rohatiner et al.,

738

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Fig. 1. Possible mechanisms which may mediate IFNa-induced neuropsychiatric syndromes.

1983). Nevertheless, IFNa may enter the brain via the circumventricular organs associated with the hypothalamus where there is no BBB (Wiranowska et al., 1989). This enables it to directly influence, e.g., endocrine functions of hypothalamic neurons as discussed below. However, as shown in a study by Dafny et al. (1996) in which single cell recordings in different brain regions were performed, intraperitoneally or intravenously given IFNa modulated neuronal activity not only in the hypothalamus, but also in cortical regions and regions of the limbic system. This indicates that IFNa may affect functioning of different brain regions apart from the circumventricular organs. In addition to direct effects of IFNa, IFNa effects on CNS functions may also be indirect, either by the peripheral induction of other proteins such as cytokines and growth factors which are able to cross the BBB or by the induction of factors produced by endothelial cells or astroglial cells associated with the BBB, which then release proteins after interaction with IFNa at the luminal site. By such mechanisms, IFNa might also be able to induce its own synthesis in cells of the CNS, e.g., astroglial cells. 5.2. Neuromodulatory effects of IFNa One of the first reports demonstrating a functional relationship between IFNa and the CNS was the observation that IFNa enhances the excitability of cultured neurons (Calvet and Gresser, 1979). In several forthcoming in vivo studies in the rat, IFNa was demonstrated to have modulatory effects on the activity of neurons from different brain regions: IFNa caused an increased firing rate of neurons from the somatosensory cortex, hippocampus, and amygdala and caused a decrease in firing rate in the ventromedial hypothalamus (Dafny et al., 1985, 1996). This was independent of whether IFNa was given intravenously or intraperitoneally (Dafny et al., 1996). A neuromodulatory effect of IFNa has also been demonstrated in man by the

measurement of evoked potentials before and during IFNa therapy (Born et al., 1989; Farkkila et al., 1984). The observation by Born et al. (1989) of a shortened latency of visually and brainstem auditory-evoked potentials after the first application of low-dose IFNa was interpreted as an excitatory effect of IFN on CNS activity. In contrast, longer treatment with high doses of IFNa increased latencies of visually and brainstem auditory-evoked potentials and slowed spontaneous EEG activity (Farkkila et al., 1984). These different observations may suggest a dose-dependent effect of IFNa and a differential effect during acute and subacute or chronic treatment. EEG changes as further evidence for a neuromodulatory effect of IFN have been discussed above. An interesting link to depressive disorders is given by the observation that IFN may decrease REM latency (Reite et al., 1987) and enhance immobility in mouse forced swimming test, an animal model of depression (Makino et al., 1998). 5.3. Effects of IFNa on central neurotransmitter system One potential mechanism for IFNa-induced psychiatric symptoms may be direct interaction of IFNa with the opioid receptor system. IFNa has been shown to be structurally related to endogenous opioids (Blalock and Smith, 1980) and to exert opioid-like effects such as analgesia and catatonia. Several studies have demonstrated that the opioid antagonist naloxone may modify IFNa-induced changes in single-cell neuronal activity (Nakashima et al., 1987), EEG (Birmanns et al., 1990), and behavior in the rat. In a small, uncontrolled preliminary study, Valentine et al. (1995) used the m-opioid receptor antagonist naltrexone to treat neuropsychiatric side effects of IFNa in nine patients with hematological malignancies. These patients suffered from headaches, severe fatigue, irritability, anxiety, impaired concentration, depression, or confusion. Seven of these patients experienced complete or moderate relief of neuropsychiatric side effects. Two patients could not tolerate naltrexone side effects. Although this study investigated only a small number of patients and did not use a control group to exclude placebo effects, it supports the role of opioid receptor interaction in IFNa-induced neuropsychiatric effects. There is also some evidence for a modulation of NMDA response by IFNa (Katafuchi et al., 1995). Stimulation of NMDA receptors is known to play an important role in regulating synaptogenesis, neuronal development, and plasticity in the CNS, but may also induce neurotoxicity in high doses (Melrum and Garthwaite, 1990). Studies in mice have indicated an inhibitory effect of repeated IFNa administration on dopaminergic neural activity (Shuto et al., 1997). This may correlate to the sometimes observed phenomenon of motor incoordination and parkinsonism during IFNa therapy, which suggests decreased dopamine levels (Pavol et al., 1995). In a recent study by Morikawa et al. (1998), a transcriptional up-regulation of the serotonin transporter gene by IFNa was demonstrated.

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

5.4. Effects of IFNa on cytokines IFNa is one of the four major types of cytokines, produced by fibroblasts, T- and NK-cells. IFNa itself has an influence on other different immunological parameters, several cytokines, cytokine receptors, and chemokines. IFNa induces IL-1, IL-2, IL-6, TNF, and the IFN-stimulated gene 15. On the other side, IFNa inhibits TNFreceptor, IL-1a, IL-5, IL-6-receptor, and IL-8 (Taylor and Grossberg, 1998). Cytokines are able to cross the BBB and to influence brain function directly or indirectly. Their central effects are currently strongly discussed as mediators for psychiatric disorders by neuropsychoimmunological mechanisms (Song, 2000; Kronfol and Remick, 2000). Especially, IL-2 is known to induce several neuropsychiatric side effects (Licinio et al., 1998). In addition, IL-1 and IFNg, induced by IFNa, can modulate the central neurotransmitters serotonin and glutamate, which are involved in the pathogenesis of several neuropsychiatric disorders (Katafuchi et al., 1995; Valentine et al., 1998; Morikowa et al., 1998). Own preliminary results seem to support our hypothesis that psychiatric side effects may be associated with immunological changes during interferon treatment (Scha¨fer, unpublished data). 5.5. Effects of IFNa on the hypothalamic – pituitary– adrenal (HPA) axis IFNa has not only been shown to be structurally and biologically related to adrenocorticotropic hormone (ACTH) (Blalock and Smith, 1980), but has been demonstrated in several human studies to be able to stimulate the release of cortisol into the blood stream (Menzies et al., 1996). Mu¨ller et al. (1991) and Gisslinger et al. (1993) investigated the induction of hormones of the HPA axis before and after subcutaneous application of IFNa in seven patients with chronic hepatitis B and eight patients with myeloproliferative disorders, respectively. Mu¨ller et al. only investigated short-term effects of 3 MU IFNa given subcutaneously and found that plasma ACTH and cortisol levels increased by about 300% and peaked after 5.2 and 5.8 h. The fact that these stimulatory effects of IFNa were not related to fever or other flu-like symptoms argues against the possibility that stimulation of the HPA axis was simply an epiphenomenon of fever induction. Gisslinger et al. determined plasma ACTH and cortisol levels before, 1 day after the first subcutaneous injection of 5 MU IFNa, and after 3 weeks of IFNa therapy (5 MU/five times a week). A significant stimulation of cortisol secretion was only seen after the first injection with a maximum after 8 h. After 3 weeks of IFNa therapy, no significant stimulation of the HPA axis occurred. However, IFNa was still able to enhance the ACTH and cortisol response to exogenously given corticotropin-releasing hormone (CRH). These results indicate adaptive changes of the HPA axis to repeated administration of IFNa. To determine the side of action

739

of IFNa, Gisslinger et al. performed in vitro experiments using rat hypothalamic organ and pituitary and adrenal cell culture systems. IFNa stimulated hypothalamic CRH and adrenal corticosterone production, but not pituitary ACTH synthesis. These results lend support to the hypothesis that IFNa may stimulate hypothalamic CRH release, which subsequently leads to increased cortisol levels. Neuroendocrine abnormalities such as hypercortisolism have been associated with mood disorders. It may be speculated that affective symptoms observed during treatment with IFNa are the result of IFNa-induced hypercortisolism. Moreover, cognitive changes may result from cortisol effects on hippocampal neurons making them more susceptible to damage. 5.6. Effects of IFNa on thyroid function Thyroid dysfunction may occur in 8– 20% of patients receiving IFNa therapy. The most common psychiatric symptoms caused by hypothyroidism are fatigue and depression, and of hyperthyroidism, irritability and weight loss. Therefore, neuropsychiatric symptoms during IFNa therapy may be secondary to thyroid dysfunction induced by IFNa. Thyroid function must carefully be monitored before and during treatment. In most cases, thyroid dysfunction is reversible when IFNa is discontinued, but it may take up to 18 months to resolve, and in some patients, the hypothyroid state may be permanent (Jones et al., 1998). The presence of antithyroid autoantibodies before treatment may be a predictor for the later development of significant thyroid disease. 5.7. Effects of IFNa on frontal lobe functions Several authors have interpreted the neuropsychiatric effects of IFN as a manifestation of an encephalopathy, which principally interferes with frontal lobe functions (Adams et al., 1984; Pavol et al., 1995). This hypothesis of a principal affection of frontal lobe functions by IFN is based on the following observations: (1) The ‘‘adynamic state’’ during IFN therapy presenting with loss of cognitive, verbal, and motor spontaneity, incentive, and interest can be understood as a disturbance of motivational behavior, which is the clinical hallmark of frontal lobe disorders; (2) Neuropsychological deficits observed during IFN therapy include slowing of cognitive processes, diminished executive skills and memory difficulties which are consistent with frontal – subcortical dysfunction (Meyers et al., 1991b; Pavol et al., 1995); (3) The symptoms of patients receiving IFN are comparable to the symptoms of patients having frontal lobe brain metastases (Adams et al., 1984); (4) EEG studies of patients receiving very high doses of IFN (>100 MU) or IFN intraventricularly (in single cases also with low-dose therapy) have shown reversible global EEG abnormalities (Farkkila et al., 1984; Smedley et al., 1983) with pronounced slowing of frontal lobe waveforms (Honigsberger

740

Table 6 Studies investigating IFNa levels in different psychiatric patient populations n

No. of contr.

Mean age

M/F

Duration of illness

Medication (±)

Detection limit

Experimental procedure

IFN level

References

Part I Acute schizophrenics/ five first admission

15

15

35.3

9/6

–

15/0a

1 U/ml

no IFN detected

Rimon et al., 1983

Acute schizophrenics/ seven first admission

30

30b

40.8

14/16

–

30/0a

1 U/ml

positive IFNa level (8 U/ml) in one schizophrenic patient

Rimon et al., 1985

Schizophrenics

30

30

36.2

17/13

6 months

3/27

n.d.a.

decreased IFN levels

Moises et al., 1985

Schizophrenics

Same patients as in Moises et al. 1985

no detectable IFN activity in serum

Schindler et al., 1986

Schizophrenics

16

IFNa in CSF determined by measurement of the inhibitory effect of virus-induced cytopathic effects in MDBK cells IFNa in serum determined by measurement of the inhibitory effect of virus-induced cytopathic effects in MDBK cells Measurement of IFN in leukocytes stimulated with C. parvum or Newcastle disease virus Measurement of IFN activity in serum expressed as the potential to reduce vesicular stomatitis virus-induced plaque formation Measurement of IFN activity in CSF expressed as the potential to reduce vesicular stomatitis virus-induced plaque formation

One schizophrenic and none depressed patient with positive IFN activity

Roy et al., 1985

Depressives Psychotic patients

11 82

Measurement of IFN activity in serum and CSF expressed as the potential to reduce virus-induced plaque formation

Serum: high titers in 24% of patients vs. 3% of controls, more often in patients with recent onset of disease and no or low medication. CSF: all samples negative

Preble and Torrey, 1985

64

n.d.a.

26

9/7

35.9

1/10 55/27

6.6 years

16/0

11/10 22c/60

n.d.a.

n.d.a. >8 U/ml were considered positive

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Patient population

n

No. of contr.

Mean age

M/F

Part II Acute psychosis

54

54

38

23/31

Acute schizophrenics

34

34

28.5

23/11

9.6 years

23/11

First admission schizophrenics

34

24

20.2

20/14

–

34/0

>25 U/ml were considered positive

First onset schizophrenics

10

15

n.d.a.

n.d.a.

–

10/0

2 U/ml

Schizophrenics

32

65d

48

18/14

22 years

0/32

n.d.a.

Depressives Chronic schizophrenics

13 37

42

48 38.5

2/11 16/21

8 years 12.4 years

0/13 0/37

a b c d

Duration of illness

No antipsychotic drug treatment for at least 2 weeks before admission. Age- and sex-matched patients with affective disorders or borderline disturbances. No or low-dose medication (chlorpromazine equivalents  200 mg/day). One control group for schizophrenic and depressed patients.

Medication (±)

Detection limit

Experimental procedure

IFN level

References

54/0

n.d.a. >5 U/ml were considered positive n.d.a.

Measurement of IFN in serum and CSF by enzyme immunoassay Measurement of IFN production in Sendai-Virus-stimulated leukocytes Measurement of IFN in serum by reduction in vesicular stomatitis virus plaque formation Measurement of IFN in serum by enzyme immunoassay Measurement of spontaneous IFN production of whole blood without and after virus-stimulation

One serum- and one CSF-probe positive

Ahokas et al., 1987

decreased levels

Katila et al., 1989

no differences between patients and controls

Becker et al., 1990

no IFN detected

Gattaz et al., 1992

decreased levels in total group. In schizophrenics: Corr. of high IFN with positive- and low with negative symptoms

Inglot et al., 1994

trend for decreased levels in schizophrenics (about 100 U/ml vs. about 125 U/ml in controls)

Hornberg et al, 1995

kit von Hoffmann La Roche

Measurement of IFNa2 by ELISA in supernatants of whole blood cultures stimulated with Newcastle disease virus

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Patient population

741

742

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

et al., 1983; Mattson et al., 1983; Meyers et al., 1991a; Rohatiner et al., 1983). 5.8. Effects of IFNa on the cerebral blood flow Using single photon emission computed tomography (SPECT), Sasaki et al. (1996) reported a decrease in cerebral blood flow in the inferior frontal cortex in a patient with depressive state during IFN treatment (6 MU/day) for hepatitis C. Cerebral changes were excluded by MRI and EEG. Rapid changes as significant increase in central blood flow after acute injection of IFNb in patients with multiple sclerosis (MS) were detected only in the basal ganglia using SPECT (Mackowiak et al., 1998). Recently, using cerebral [18F]deoxyglucose positron emission tomography (FDGPET), Juengling et al. (2000) found an association of lowdose IFNa therapy with significant prefrontal hypometabolism. While these changes were associated with the depression score, they were also found in clinically nondepressed patients. These results are similar to findings in patients with endogenous depression (Klemm et al., 1996; George et al., 1993). 5.9. Does IFNa contribute to the etiopathology of endogenous psychiatric disorders? In the above sections, we have seen that (1) treatment of IFNa may cause psychiatric syndromes such as depression and paranoid psychosis; (2) IFNa may serve as an endogenous mediator of neuropsychiatric symptoms in SLE; (3) IFNa may have neuromodulatory effects both in vitro and in vivo, mainly affecting the opioidergic, glutamatergic, serotoninergic and dopaminergic system, cytokines, thyroid hormones and the HPA axis; and (4) IFNa may affect frontal lobe functioning. These research findings support the hypothesis that IFNa may contribute to the etiopathology of ‘‘endogenous’’ psychiatric disorders. To test this hypothesis, at least three approaches could be helpful: First, to investigate behavior of IFNa transgenic mice with cerebral overexpression of the IFNa gene; second, to investigate the effects of IFNa in animal models of depression; and third, to measure IFNa levels in blood, serum, or CSF of psychiatric patients. Whereas an IFNa transgenic mouse has already been generated (Akwa et al., 1998), no specific data exist on behavioral abnormalities in these animals. Regarding the effects of IFNa in animal models of depression, one study exists showing that IFNa enhanced immobility in the mouse forced swimming test (Makino et al., 1998). Several studies during the last 15 years have investigated IFNa levels in peripheral blood, serum, and CSF of schizophrenic and depressed patients. These studies were done primarily in the context of the hypothesis of a viral etiology of schizophrenia. Several lines of evidence support such a view of a viral etiology of schizophrenia, namely that viral infections, which lead to increased production of IFNa, may

cause CNS infections with psychiatric symptomatology and that increased antibody titers to certain viruses have been described in serum and CSF of psychiatric patients. Waltrip et al. (1990) proposed a neuroimmunological viral reactivation model of schizophrenia, in which IFNa plays a central role as mediator of the psychiatric and physical manifestations of schizophrenia. Table 6 summarizes 12 studies which measured IFNa levels in peripheral blood, serum, or CSF of psychiatric patients. The overall results of these studies are quite contradictory: In four studies, no IFNa was detectable or no differences between patients and controls existed; in four other studies, decreased IFNa levels were found; and in additional four studies, increased IFNa levels were observed in a very small subset of patients (three studies) or in a high proportion of patients (one study, Preble and Torrey, 1985). Four studies measured IFNa levels in CSF, four in the serum, and four in blood cell cultures. Two of these studies investigated serum levels in addition to CSF levels (Ahokas et al., 1987; Preble and Torrey, 1985). Interestingly, all studies describing decreased IFNa levels in patients were studies of IFNa production in peripheral blood cell cultures with or without virus stimulation. In the studies investigating serum and/or CSF samples, 50% found no changes and 50% increased levels. With respect to medication, six studies investigated IFNa levels in unmedicated patients, four in medicated patients, and two in mixed medicated/unmedicated patients. Interestingly again, all studies describing decreased IFNa levels investigated medicated patients. This seems important since there are studies pointing to an immunosuppressive effect of neuroleptics such as clozapine and haloperidol (Leykin et al., 1997). In contrast, increased levels were found especially in unmedicated patients. The diverging results might be explained by the fact that production and biological activity of IFN in serum and CSF may not be comparable. Some researchers claimed that there is a deficient IFN production in schizophrenic patients. In line with that would be the observation of a certain improvement of schizophrenic psychopathology after administration of IFN (Cabrera Gomez et al., 1994), which was interpreted as a correction of this proposed deficient IFN production (Moises et al., 1985). The fact that the studies of IFN levels in psychiatric patients are quite contradictory, does not, however, necessarily argue against an implication of IFNa in the etiopathology of psychiatric disorders for the following reasons: (1) The blood – brain and CSF –brain barriers are strong implying that IFNa measures in the blood or CSF of psychiatric patients do not necessarily reflect brain levels of IFN; (2) IFNa production, e.g., in conjunction with viral reactivation, may be a local and attenuated process which may locally disturb nerve cell functioning without production of high amounts of IFNa which could be measurable; (3) a resistance to IFNa production in schizophrenic patients as reported by Moises et al. (1985) and

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Katila et al. (1989) may be the reflection of a refractory state of IFNa-producing cells due to relatively high levels of IFN; (4) IFNa is able to influence indirectly the CNS by peripheral induction of several different cytokines. Cytokines are able to cross the BBB and their possible central effects are currently strongly discussed as mediators for psychiatric disorders (Song, 2000; Kronfol and Remick, 2000).

6. Conclusions In conclusion, IFNa may be a potential element in the pathogenesis of a subset of psychiatric disorders, but this has yet to be proven. Further studies should concentrate on the behavioral effects of IFNa in transgenic mice and the effect of IFNa in animal models of depression. Furthermore, the effects of IFNa on brain functions should be determined by functional brain imaging, and local production of IFNa in brains of psychiatric patients should be analysed by postmortem analyses of IFNa levels. To test the treatment options of psychiatric side effects of IFNa therapy, further prospective placebo-controlled studies with antidepressants and opiate antagonists should be performed.

References Adams, F., Quesada, J.R., Guttermann, J.U., 1984. Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. J. Am. Med. Assoc. 252, 938 – 941. Adams, F., Fernandez, F., Mavligit, G., 1988. Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities. J. Neuro-Oncol. 6, 355 – 359. Ahokas, A., Rimon, R., Koskiniemi, M., Vaheri, A., Julkumen, I., Sarna, S., 1987. Viral antibodies and interferon in acute psychiatric disorders. J. Clin. Psychiatry 48, 194 – 196. Akwa, Y., Hasset, D.E., Eloranty, M.L., Sandberg, K., Masliak, E., Powell, H., Whitton, J.L., Bloom, F.E., Campbell, I.L., 1998. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J. Immunol. 161, 5016 – 5026. Baron, S., Tyring, S.K., Fleischmann Jr., W.R., Coppenhaver, D.H., Niesel, D.W., Klimpel, G.R., Stanton, G.J., Hughes, T.K. 1991. The interferons. Mechanisms of action and clinical applications. J. Am. Med. Assoc. 266, 1375 – 1383. Becker, D., Kritschmann, E., Floru, S., Shlomo-David, Y., Gotlieb-Stematsky, T., 1990. Serum interferon in first psychotic attack. Br. J. Psychiatry 157, 136 – 138. Birmanns, B., Saphier, D., Abarmsky, O., 1990. Alpha-interferon modifies cortical EEG activity: dose-dependence and antagonism by naloxone. J. Neurol. Sci. 100, 22 – 26. Blalock, J.E., Smith, E.M., 1980. Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormone and endorphins. Proc. Natl. Acad. Sci. USA 77, 5972 – 5974. Born, J., Spath-Schwalbe, E., Pietrowsky, R., Porzsolt, F., Fehm, H.L., 1989. Neurophysiological effects of recombinant interferon-gamma and -alpha in man. Clin. Physiol. Biochem. 7, 119 – 127. Cabrera Gomez, J.A., Gutierrez, J.R., Lopez, O., Guitierez, B., Garcia, K., Consuegra, J., Cruz, R., Quevedo, A., Capdegille, I., Falcon, M., Ser-

743

rano, S., Galindo, M., Saura, P., Rivero, Y., 1994. Treatment of schizophrenic disorder, paranoid type, with intramuscular recombinant alpha-2b interferon. Biotherapy 7, 7 – 37. Calvet, M.C., Gresser, I., 1979. Interferon enhances the excitability of cultured neurones. Nature 278, 558 – 560. Capuron, L., Ravaud, A., 1999. Prediction of the depressive effects of interferon alpha therapy by the patient’s initial affective state. N. Engl. J. Med. 340, 1370. Cirelly, R., Tyring, S.K., 1995. Major therapeutic uses of interferons. Clin. Immunother. 3, 27 – 87. Collins, J.M., Riccardi, R., Trown, P., O’Neil, D., Poplack, D.G., 1985. Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery. Cancer Drug Delivery 2, 247 – 253. Dafny, N., Prieto-Gomez, B., Reyes-Vazquez, C., 1985. Does the immune system communicate with the central nervous system? Interferon modifies central nervous activity. J. Neuroimmunol. 9, 1 – 12. Dafny, N., Prieto-Gomez, B., Dong, W.Q., Reyes-Vazquez, C., 1996. Interferon modulates neuronal activity recorded from the hypothalamus, thalamus, hippocampus, amygdala and the somatosensory cortex. Brain Res. 734, 269 – 274. Dantzer, R., 2001. Cytokine-induced sickness behavior: where do we stand? Brain Behav., Immun. 15, 7 – 24. Davis, G.L., Balart, L.A., Schiff, E.R., Lindsay, K., Bodenheimer Jr., H.C, Perillo, R.P., Carey, W., Jacobson, I.M., Payne, J., Dienstag, J.L., et al. 1989. Treatment of chronic hepatitis C with recombinant interferon alpha. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N. Engl. J. Med. 321, 1501 – 1506. Dieperink, E., Willenbring, M., Ho, S.B., 2000. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am. J. Psychiatry 157, 867 – 876. Dusheiko, G., 1997. Side effects of alpha interferon in chronic hepatitis C. Hepatology 26, 112S – 121S. Farkkila, M., Iivanaien, M., Roine, R., Bergstrom, L., Laaksonen, R., Niemi, M.L., Cantell, K., 1984. Neurotoxic and other side effects of highdose interferon in amyotrophic lateral sclerosis. Acta Neurol. Scand. 70, 42 – 46. Fattovich, G., Giustina, G., Favarato, S., Ruol, A., 1996. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alpha interferon. J. Hepatol. 24, 38 – 47. Gattaz, W.F., Dalgalarrondo, P., Schroder, H.C., 1992. Abnormalities in serum concentrations of interleukin-2, interferon-alpha and interferongamma in schizophrenia not detected. Schizophr. Res. 6, 237 – 241. George, M.S., Ketter, T.A., Post, R.M., 1993. SPECT and PET imaging in mood disorders. J. Clin. Psychiatry 11, 6 – 13 (Supplement). Gisslinger, H., Svoboda, T., Clodi, M., Gilly, B., Ludwig, H., Havelec, A., Luger, A., 1993. Interferon-alpha stimulates the hypothalamic – pituitary – adrenal axis in vivo and in vitro. Neuroendocrinology, 57, 489 – 495. Goldman, L.S., 1994. Successful treatment of interferon alpha-induced mood disorder with nortriptyline. Psychosomatics 35, 412 – 413. Greenberg, D.B., Lonasch, E., Gadd, M.A., Ryan, B.F., Everett, J.R., Sober, A.J., Mihm, M.A., Tanabe, K.K., Ott, M., Haluska, F.G., 2000. Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Gabapentin may serve as a mood stabilizer. Cancer 89, 356 – 362. Guttermann, J.U., Fine, S., Quesada, J., Horning, S.J., Levine, J.F., Alexanian, R., Bernhardt, L., Kramer, M., Spiegel, H., Colburn, W., Trown, P., Merigan, T., Dziewanowski, Z., 1982. Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann. Intern. Med. 96, 549 – 556. Haria, M., Benfield, P., 1995. Interferon-alpha-2a. Drugs 50, 873 – 896. Ho, S.B., Ngueyen, H., Tetrick, L.L., Opitz, G.A., Basara, M.L., Dieperink, E., 2001. Influence of psychiatric diagnoses on interferon-alpha treatment for chronic hepatitis C in a veteran population. Am. J. Gastroenterol. 96, 157 – 164.

744

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

Honigsberger, L., Fielding, J.W., Priestman, T.J., 1983. Neurological effects of recombinant human interferon. Br. Med. J. 286, 719. Hoofnagle, J.H., di Bisceglie, A.M., 1997. The treatment of chronic viral hepatitis. N. Engl. J. Med. 336, 347 – 356. Hoofnagle, J.H., di Bisceglie, A.M., Waggoner, J.G., Park, Y., 1993. Interferon alpha for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 104, 1116 – 1121. Hooks, J.J., Moutsopoulos, H.M., Geis, S.A., Stahl, N.I., Decker, J.L., Notkins, A.L., 1979. Immune interferon in the circulation of patients with autoimmune disease. N. Engl. J. Med. 301, 5 – 8. Hornberg, M., Arolt, V., Wilke, I., Kruse, A., Kirchner, H., 1995. Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia. Schizophr. Res. 15, 237 – 242. Hunt, C.M., Dominitz, J.A., Bute, B.P., Waters, B., Blasi, U., Williams, D.M., 1997. Effect of interferon-alpha treatment of chronic hepatitis C on health-related quality of life. Dig. Dis. Sci. 42, 2482 – 2486. Iivanainen, M., Laaksonen, R., Niemi, M.L., Farkkila, M., Bergstrom, L., Mattson, K., Niiranen, A., Cantell, K., 1985. Memory and psychomotor impairment following high-dose interferon treatment in amyotrophic lateral sclerosis. Acta Neurol. Scand. 72, 475 – 480. Inglot, A.D., Leszek, J., Piasecki, E., Sypula, A., 1994. Interferon responses in schizophrenia and major depressive disorders. Biol. Psychiatry 35, 464 – 473. Isshi, K., Hirohata, S., Hashimoto, T., Miyashita, H., 1994. Systemic lupus erythematosus presenting with diffuse low density lesions in the cerebral white matter on computed axial tomography scans: its implication in the pathogenesis of diffuse central nervous system lupus. J. Rheumatol. 21, 1758 – 1762. Janssen, H.L., Berk, L., Vermeulen, M., Shalm, S.W., 1990. Seizures associated with low-dose alpha-interferon. Lancet 336, 1580. Janssen, H.L., Brouwer, J.T., van der Mast, R.C., Shalm, S.W., 1994. Suicide associated with alpha-interferon therapy for chronic viral hepatitis. J. Hepatol. 21, 241 – 243. Jones, T.H., Wadler, S., Hupart, K.H., 1998. Endocrine mediated mechanisms of fatigue during treatment with interferon-a. Semin. Oncol. 25 (Suppl. 1), S54 – S63. Juengling, F.D., Ebert, D., Gut, O., Engelbrecht, M.A., Rasenack, J., Nitzsche, E.U., Bauer, J., Lieb, K., 2000. Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology 152, 383 – 389. Katafuchi, T., Take, S., Hori, T., 1995. Roles of cytokines in the neural immune interactions: modulation of NMDA-responses by IFN-alpha. Neurobiology 3, 319 – 327. Katila, H., Cantell, K., Hirvonen, S., Rimon, R., 1989. Production of interferon-alpha and gamma by leukocytes from patients with schizophrenia. Schizophr. Res. 2, 361 – 365. Klemm, E., Danos, P., Grunwald, F., Kasper, S., Mo¨ller, H.J., Biersack, H.J., 1996. Temporal lobe dysfunction and correlation of regional cerebral blood flow abnormalities with psychopathology in schizophrenia and major depression—a study with single photon emission computed tomography. Psychiatry Res. 68, 1 – 10. Kovacs, J.A., Urowitz, M.B., Gladman, D.D., 1993. Dilemmas in neuropsychiatric lupus. Rheum. Dis. Clin. North Am. 19, 795 – 814. Kronfol, Z., Remick, D.G., 2000. Cytokines and the brain: implications for clinical psychiatry. Am. J. Psychiatry 157, 683 – 694. Lebon, P., Lenoir, G.R., Fischer, A., Lagrue, A., 1983. Synthesis of intrathecal interferon in systemic lupus erythematosus with neurological complications. Br. Med. J. 287, 1165 – 1167. Legha, S., 1997. The role of interferon alpha in the treatment of metastatic melanoma. Semin. Oncol. 24 (Suppl. 4), S24 – S31. Levenson, J.L., Fallon, H.J., 1993. Fluoxetine treatment of depression caused by interferon-alpha. Am. J. Gastroenterol. 88, 760 – 761. Leykin, I., Mayer, R., Shinitzky, M., 1997. Short and long-term immunosuppressive effects of clozapine and haloperidol. Immunopharmacology 37, 75 – 86. Licinio, J., Kling, M.A., Hauser, P., 1998. Cytokines and brain function:

relevance to interferon-a induced mood and cognitive changes. Semin. Oncol. 25 (Suppl. 1), S30 – S38. Lieb, K., Vaith, P., Berger, M., Bauer, J., 1997. Systemic immunologic diseases as differential diagnosis in psychiatry. Nervenarzt 68, 696 – 707. Lindsay, K.L., Davis, G.L., Schiff, E.R., Bodenheimer, H.C., Balart, L.A., Dienstag, J.L., Perillo, R.P., Tamburro, C.H., Goff, J.S., Everson, G.T., Silva, M., Katkov, W.N., Goodman, Z., Lau, J.Y., Maertens, G., Gogate, J., Sanghvi, B., Albrecht, J., 1996. Response to higher doses of interferon alpha-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group. Hepatology 24, 1034 – 1040. Lok, A.S., Lai, C.L., Wu, P.C., Leung, E.K., 1988. Long-term followup in a randomised controlled trial of recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection. Lancet 2, 298 – 302. Lublin, F.D., Whitaker, J.N., Eidelman, B.H., Miller, A.E., Arnason, B.G., Burks, J.S., 1996. Management of patients receiving interferon beta-1b for multiple sclerosis: report of a consensus conference. Neurology 46, 12 – 18. Mackowiak, P.A., Siegel, E., Wassermann, S.S., Cameron, E., Nessaiver, M.S., Bever, C.T., 1998. Effects of IFN-beta on human cerebral blood flow distribution. J. Interferon Cytokine Res. 18, 393 – 397. Makino, M., Kitano, Y., Hirohashi, M., Takasuna, K., 1998. Enhancement of immobility in mouse forced swimming test by treatment with human interferon. Eur. J. Pharmacol. 356, 1 – 7. Malaguarnera, M., Di Fazio, I., Restuccia, S., Pistone, G., Ferlito, L., Rampello, L., 1998. Interferon alpha-induced depression in chronic hepatitis C patients: comparison between different types of interferon alpha. Neuropsychobiology 37, 93 – 97. Matsuya, M., Abe, T., Tosaka, M., Yonezawa, K., Ono, A., Ikeda, N., Yoshida, Y., Akahonai, Y., Kurokawa, S., Hayashi, T., et al., 1994. The first case of polymyositis associated with interferon therapy. Intern. Med. 33, 806 – 808. Mattson, K., Niiranen, A., Iivanainen, M., Farkkila, M., Bergstrom, L., Holsti, L.R., Kauppinen, H.L., Cantell, K., 1983. Neurotoxicity of interferon. Cancer Treat. Rep. 67, 958 – 961. McDonald, E.M., Mann, A.H., Thomas, H.C., 1987. Interferons as mediators of psychiatric morbidity. An investigation in a trial of recombinant alpha-interferon in hepatitis-B carriers. Lancet 2, 1175 – 1178. Melrum, B., Garthwaite, J., 1990. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 11, 379 – 387. Menzies, R., Phelps, C., Wiranowska, M., Oliver, J., Chen, L., Horvath, E., Hall, N., 1996. The effect of interferon-alpha on the pituitary – adrenal axis. J. Interferon Cytokine Res. 16, 619 – 629. Meyers, C.A., Obbens, E.A., Scheibel, R.S., Moser, R.P., 1991a. Neurotoxicity of intraventricularly administered alpha-interferon for leptomeningeal disease. Cancer 68, 88 – 92. Meyers, C.A., Scheibel, R.S., Forman, A.D., 1991b. Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41, 672 – 676. Miyaoka, H., Otsubo, T., Kamijima, K., Ishii, M., Onuki, M., Mitamura, K., 1999. Depression from interferon therapy in patients with hepatitis C. Am. J. Psychiatry 156, 1120. Mohr, D.C., Goodkin, D.E., Likosky, W., Gatto, N., Baumann, K.A., Rudick, R.A., 1997. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch. Neurol. 54, 531 – 533. Moises, H.W., Schindler, L., Lreoux, M., Kirchner, H., 1985. Decreased production of interferon alpha and interferon gamma in leucocyte cultures of schizophrenic patients. Acta Psychiatr. Scand. 72, 45 – 50. Morikawa, O., Sakai, N., Obara, H., Saito, N., 1998. Effects of interferonalpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur. J. Pharmacol. 349, 317 – 324. Mu¨ller, H., Hammes, E., Hiemke, C., Hess, G., 1991. Interferon-alpha-2induced stimulation of ACTH and cortisol secretion in man. Neuroendocrinology 54, 499 – 503. Muss, H.B., Kempf, R.A., Martino, S., Rudnick, S.A., Greiner, J.,

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746 Cooper, M.R., Decker, D., Grunberg, S.M., Jackson, D.V., Richards 2nd, F. 1984. A phase II study of recombinant alpha interferon in patients with recurrent or metastatic breast cancer. J. Clin. Oncol. 2, 1012 – 1016. Musselmann, D.L., Lawson, D.H., Gumnick, J.F., Manatunga, A.K., Penna, S., Goodkin, R.S., Greiner, K., Nemeroff, C.B., Miller, A., 2001. Paroxetine for the prevention of depression induced by highdose interferon alpha. N. Engl. J. Med. 344, 961 – 966. Nakashima, T., Hori, T., Kuriyama, K., Kiyohara, T., 1987. Naloxone blocks the interferon-alpha induced changes in hypothalamic neuronal activity. Neurosci. Lett. 82, 332 – 336. Negoro, K., Fukusako, T., Morimatsu, M., Liao, C.M., 1994. Acute axonal polyneuropathy during interferon alpha-2A therapy for chronic hepatitis type C. Muscle Nerve 17, 1351 – 1352. Neilley, L.K., Goodin, D.S., Goodkin, D.E., Hauser, S.L., 1996. Side effect profile of interferon beta-1b in MS: results of an open label trial. Neurology 46, 552 – 554. Niiranen, A., Laaksonen, R., Iivanainen, M., Mattson, K., Farkkila, M., Cantell, K., 1988. Behavioral assessment of patients treated with alpha-interferon. Acta Psychiatr. Scand. 78, 622 – 626. Nozaki, O., Takagi, C., Takaoka, K., Takata, T., Yoshida, M., 1997. Psychiatric manifestations accompanying interferon therapy for patients with chronic hepatitis C: an overview of cases in Japan. Psychiatry Clin. Neurosci. 51, 175 – 180. Okanoue, T., Sakamoto, S., Itoh, Y., Minami, M., Yasui, K., Sakamoto, M., Nishioji, K., Katagishi, T., Nakagawa, Y., Tada, H., Sawa, Y., Mizuno, M., Kagawa, K., Kashima, K., 1996. Side effects of high-dose interferon therapy for chronic hepatitis C. J. Hepatol. 25, 283 – 291. Pariante, C.M., Orrru, M.G., Baita, A., Farci, M.G., Carpnicello, B., 1999. Treatment with interferon-a in patients with chronic hepatitis and mood or anxiety disorders. Lancet 10, 131 – 132. Pavol, M.A., Meyers, C.A., Rexer, J.L., Valentine, A.D., Mattis, P.J., Talpaz, M., 1995. Pattern of neurobehavioral deficits associated with interferon alpha therapy for leukemia. Neurology 45, 947 – 950. Poutiainen, E., Hokkanen, L., Niemi, L., Farkilla, M., 1994. Reversible cognitive decline during high-dose alpha-interferon treatment. Pharmacol., Biochem. Behav. 47, 901 – 905. Poynard, T., Bedossa, P., Chevallier, M., Mathurin, P., Lemonnier, C., Trepo, L., Couzigou, P., Payen, J., Sajus, M., Costa, J.M., 1995. A comparison of three interferon alpha-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group. N. Engl. J. Med. 332, 1457 – 1462. Poynard, T., Leroy, V., Cohard, M., Thevenot, T., Mathurin, P., Opolon, P., Zarski, J.P., 1996. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 24, 778 – 789. Preble, O.T., Torrey, E.F., 1985. Serum interferon in patients with psychosis. Am. J. Psychiatry 142, 1184 – 1186. Reichenberg, A., Yirmia, R., Schuld, A., Kraus, T., Haack, M., Morag, A., Pollma¨cher, T., 2001. Cytokine-associated emotional and cognitivedisturbances in humans. Arch. Gen. Psychiatry 58, 445 – 452. Reite, M., Laudenschlager, M., Jones, J., Crnic, L., Kaemingk, K., 1987. Interferon decreases REM latency. Biol. Psychiatry 22, 104 – 107. Renault, P.F., Hoofnagle, J.H., Park, Y., Peters, M., Jones, D.R., Rustgi, V., Jones, E.A., 1987. Psychiatric complications of long-term interferon alpha therapy. Arch. Intern. Med. 147, 1577 – 1580. Rifflet, H., Vuillemin, E., Oberti, F., Duverger, P., Garre, J.B., Cales, P., 1998. Suicidal impulses in patients with chronic viral hepatitis C treated by alpha interferon. Gastroenterol. Clin. Biol. 22, 353 – 357. Rimon, R., Halonen, P., Lebon, P., 1983. Antibrain antibodies and interferon in the serum and the cerebrospinal fluid of patients with schizophrenia. Adv. Biol. Psychiatry 12, 161 – 167. Rimon, R., Ahokas, A., Hintikka, J., Heikkila, L., 1985. Serum interferon in schizophrenia. Ann. Clin. Res. 17, 139 – 140. Rohatiner, A.Z., Prior, P.F., Burton, A.C., Smith, A.T., Balkwill, F.R., Lister, T.A., 1983. Central nervous system toxicity of interferon. Br. J. Cancer 47, 419 – 422.

745

Roy, A., Pickard, D., Ninan, P., Hooks, J., Paul, S.M., 1985. A search for interferon in the CSF of chronic schizophrenic patients. Am. J. Psychiatry 142, 269. Sasaki, M., Sata, M., Susuki, Y., Uchimura, Y., Murashima, S., Tanaka, K., Uchimura, N., Nakamura, J., Ishibashi, M., Tanikawa, K., 1996. Change in cerebral blood flow in an acute hepatitis C patient with depressive state while receiving interferon. Int. Hepatol. Commun. 5, 354 – 360. Scha¨fer, M., Schmidt, F., Soyka, M., Mo¨ller, H.J., Loeschke, K., 2000a. Psychiatric side effects during combination treatment for chronic hepatitis C with interferon alpha and ribavirin: comparison of psychiatric patients, drug addicts and controls. Eur. Neuropharmacol. 10 (Suppl. 3), S396. Scha¨fer, M., Schmidt, F., Amann, B., Schlo¨sser, S., Loeschke, K., Grunze, H., 2000b. Adding low dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis. Neuropsychobiology 42 (Suppl. 1), 43 – 45. Scha¨fer, M., Boetsch, T., Laakmann, G., 2000c. Psychosis in a methadonesubstituted patient during interferon-alpha treatment of hepatitis C. Addiction 95, 1101 – 1104. Schindler, L., Leroux, M., Beck, J., Moises, H.W., Kirchner, H., 1986. Studies of cellular immunity, serum interferon titers, and natural killer cell activity in schizophrenic patients. Acta Psychiatr. Scand. 73, 651 – 657. Schramm, T.M., Lawford, B.R., Macdonald, G.A., Cooksley, W.G., 2000. Sertraline treatment of interferon-alpha-induced depressive disorder. Med. J. Aust. 173, 359 – 361. Sharara, A.I., Hunt, C.M., Hamilton, J.D., 1996. Hepatitis C. Ann. Intern. Med. 125, 658 – 668. Shiozawa, S., Kuroki, Y., Kim, M., Hirohata, S., Ogino, T., 1992. Interferonalpha in lupus psychosis. Arthritis Rheum. 35, 417 – 422. Shuto, H., Kataoka, Y., Horikawa, T., Fujihara, N., Oiski, R., 1997. Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain. Brain Res. 747, 348 – 351. Smedley, H., Katrak, M., Sikora, K., Wheeler, T., 1983. Neurological effects of recombinant human interferon. Br. Med. J. 286, 262 – 264. Song, C., 2000. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments. Hum. Psychopharmacol. Clin. Exp. 15, 199 – 211. Strite, D., Valentine, A.D., Meyers, C.A., 1997. Manic episodes in two patients treated with interferon alpha. J. Neuropsychiatry Clin. Neurosci. 9, 273 – 276. Suter, C.C., Westmoreland, B.F., Sharbrough, F.W., Hermann Jr., R.C. 1984. Electroencephalographic abnormalities in interferon encephalopathy: a preliminary report. Mayo Clin. Proc. 59, 847 – 850. Tambini, R., Quattrini, A., Fracassetti, O., Nemni, R., 1997. Axonal neuropathy in a patient receiving interferon-alpha therapy for chronic hepatitis C. J. Rheumatol. 24, 1656 – 1657. Taylor, J.L., Grossberg, S.E., 1998. The effects of interferon-a on the production and action of other cytokines. Semin. Oncol. 25 (Suppl. 1), S23 – S29. Tong, M.J., Reddy, K.R., Lee, W.M., Pockros, P.J., Hoefs, J.C., Keffe, E.B., Hollinger, F.B., Hathcote, E.J., White, H., Foust, R.T., Jensen, D.M., Krawitt, E.L., Fromm, H., Black, M., Blatt, L.M., Klein, M., Lubina, J., 1997. Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Consensus Interferon Study Group. Hepatology 26, 747 – 754. Valentine, A.D., Meyers, C.A., 1995. Successful treatment of interferonalpha-induced mood disorder with nortriptyline. Psychosomatics 36, 418 – 419. Valentine, A.D., Meyers, C.A., Talpaz, M., 1995. Treatment of neurotoxic side effects of interferon-alpha with naltrexone. Cancer Invest. 13, 561 – 566. Valentine, A.D., Meyers, C.A., Kling, M.A., Richelson, E., Hauser, P., 1998. Mood and cognitive side effects of interferon-a therapy. Semin. Oncol. 25 (Suppl. 1), S39 – S47.

746

M. Schaefer et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 731–746

van Thiel, D.H., Friedlander, L., Molloy, P.J., Fagiuoli, S., Kania, R.J., Caraceni, P., 1995. Interferon-alpha can be successfully in patients with hepatitis C virus-positive chronic hepatitis who have psychiatric illness. Eur. J. Gastroenterol. Hepatol. 7, 165 – 168. Waltrip, R.W., Carrigan, D.R., Carpenter Jr., W.T. 1990. Immunopathology and viral reactivation. A general theory of schizophrenia. J. Nerv. Ment. Dis. 178, 729 – 738. Williams, C.D., Linch, D.C., 1997. Interferon alpha-2a. Br. J. Hosp. Med. 57, 436 – 439. Winfield, J.B., Shaw, M., Silverman, L.M., Eisenberg, R.A., Wilswon, H.A., Koffler, D., 1983. Intrathecal IgG synthesis and blood – brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. Am. J. Med. 74, 837 – 844. Wiranowska, M., Wilson, T.C., Thompson, K., Prockkop, L.D., 1989. Cer-

ebral interferon entry in mice after osmotic alteration of blood – brain barrier. J. Interferon Res. 9, 353 – 362. Yamano, M., Yuki, H., Yasuda, S., Miyata, K., 2000. Corticotropin-releasing hormone1 receptors mediate consensus interferon-alpha YM643induced depression-like behavior in mice. J. Pharmacol. Exp. Ther. 292, 181 – 187. Yates, W.R., Gleason, O., 1998. Hepatitis C and depression. Depression Anxiety 7, 188 – 193. Yirmiya, R., Pollak, Y., Morak, M., Reichenberg, A., Barak, O., Avitsur, R., Shavit, Y., Ovadia, H., Weidenfeld, J., Morag, A., Newman, M.E., Pollmacher, T., 2000. Illness, cytokines, and depression. Ann. N.Y. Acad. Sci. 917, 478 – 487. Ytterberg, S.R., Schnitzer, T.J., 1982. Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 25, 401 – 406.