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REVIEW ARTICLE Table of Contents   
Year : 2006  |  Volume : 12  |  Issue : 2  |  Page : 59-67
Neuropsychiatric side-effects of interferon alfa therapy for hepatitis C and their management: A review

Department of Psychiatry,College of Medicine, King Khaled University Hospital King Saud University, Riyadh, Saudi Arabia

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Date of Submission18-Apr-2006
Date of Acceptance01-May-2006


Background:Interferon-Alfa (IFN-α) has been the mainstay of treatment for chronic hepatitis C. It has the potential to alter the course of chronic hepatitis C and prevent complications. Aims: This review summarizes current knowledge about the presentation, mechanism, course, and treatment of neuropsychiatric problems associated with interferon alfa (IFN-α) treatment. Methods: Studies were identified by computerized searches, and further references were obtained from bibliographies of the reviewed articles. Results: Neuropsychiatric symptoms frequently occur in hepatitis C patients treated with IFNAlfa. These side effects are troublesome and frequently account for dose reduction or treatment discontinuation. Sometimes, they could be serious and possibly life threatening. Frequent psychiatric evaluations of high risk individuals and, when required, early administration of antidepressants could possibly help to avoid the development of an impending depression or reduce its severity and duration and thus increase adherence to treatment. Conclustion: Greater cooperation between psychiatrists and hepatologists would mean less risk of having the serious side effects with more importance needs to be given to the identification of patients at risk.

Keywords: Interferon, Neuropsychiatric side effects, Depression, Treatment.

How to cite this article:
Al-Huthail YR. Neuropsychiatric side-effects of interferon alfa therapy for hepatitis C and their management: A review. Saudi J Gastroenterol 2006;12:59-67

How to cite this URL:
Al-Huthail YR. Neuropsychiatric side-effects of interferon alfa therapy for hepatitis C and their management: A review. Saudi J Gastroenterol [serial online] 2006 [cited 2022 Jul 3];12:59-67. Available from:

Interferons [IFN] are proteins belonging to the familyof cytokines. Due to their stimulating effect on immuneresponses, IFNs are used in the treatment of several pathologiesassociated with immunological disturbances [1]. IFN-Alfa hasbeen the mainstay of treatment for chronic hepatitis C[2]. Atpresent, optimal treatment for HCV infection consists ofcombination antiviral therapy with pegylated interferon-Alfaand ribavirin[3].Treatments utilizing interferon-Alfa have thepotential to alter the course of chronic hepatitis C and preventcomplications[4].Recent advances in therapy with pegylatedIFN-Alfa have significantly improved treatment outcome[5].Unfortunately; many severely ill patients are not receivingIFN-Alfa because of concerns regarding neuropsychiatricside effects[6].

   Neuropsychiatric side effects of Interferon-Alfa Top

Neuropsychiatric symptoms frequently occur in hepatitisC patients treated with IFN-Alfa. These symptoms includecognitive, affective, and behavioral components that are noteasily distinguished from each other or from depression.These side effects are troublesome and frequently account fordose reduction or treatment discontinuation[2].

Neuropsychiatric side effects include lethargy, somnolence,fatigue, drowsiness, disorientation, impaired concentration,irritability, emotional liability, social withdrawal, depression,and hopelessness[7],[8]. In addition, anxiety symptoms, such asanxious mood, tension, irritability, and fear[9].

Mania[10], sexual dysfunction, memory impairment,and cognitive dysfunction[11] have been described too.Longer latencies in the test of reaction time, indicatingneuropsychological changes, have been reported as early asthe fifth day of IFN-Alfa treatment [12].

Although most cases of depression are mild to moderate inseverity[13], suicidal ideation and successful suicides during orshortly after Interferon Alfa therapy for chronic viral hepatitishave been reported[14]. The neuropsychiatric side effects ofInterferon Alfa, particularly depression, are among the mostcommon causes of dose reduction or discontinuation oftherapy[13],[15].

Until now only a limited number of studies have beendevoted to the problem of depression[16]. The incidence ofInterferon Alfa-induced depression in patients who havehepatitis C reportedly ranges from 3% to 44 %[15],[17][18][19][20][21][22][23], butlarge, randomized trials that used standardized psychiatricevaluation methods indicate an incidence of approximately20% to 30% [Table - 1][17],[20],[24].

Of course, the term "depression" has several meanings,ranging from transient sadness to the syndrome of majordepression. Also, patients experiencing fatigue, malaise, orcognitive changes may complain of being "depressed"[2].

In a review of the safety of interferon, based on reportsof adverse events to the Food and Drug Administration,depression, suicidal ideation, attempted suicide, and completedsuicide constituted approximately 4% of all adverse eventsreported[25].

The substantial variation in the incidence of depressionon Interferon Alfa across published studies may be due todifferent dosing schedules, composition of study cohorts, andexclusion criteria [26].

In a prospective study on a large number of patients withchronic hepatitis C undergoing Interferon-Alfa therapy doneby Horikawa et al, there was a tendency for major depressionto occur more frequently in the earlier stage of treatment;73.9% of patients developed depression during the first 8weeks of the 24-week treatment period[19].

In another prospective study, the mean time from initiationof Interferon Alfa to development of Major Depression was12.1 weeks [range 1 to 32 weeks][27].

Beratis et al reported that approximately one third of thepatients treated with low-dose Interferon Alpha developedMajor Depression within a month from the onset of InterferonAlfa therapy[28].

These results suggest that patients should be screenedregularly for depression during the first six months ofInterferon Alpha therapy[27]. However, the risk of depressioncontinues and appears to be higher with longer duration oftherapy [24].

Monitoring every 2-4 weeks during the first 3 months ofhepatitis treatment appears sufficient for identifying patientswho may require psychiatric intervention(2).

The most replicated risk factor for developing depression isthe presence of mood symptoms prior to treatment[2],[27],[29][30][31][32][33].

It has been demonstrated that the effects of IFN-Alfa onmood depend on the initial affective state of the patients, withhigher depressive mood scores before treatment associatedwith higher depressive symptoms during treatment[34].

Hauser et al prospectively assessed the incidence ofInterferon Alfa-induced depression in Hepatitis C patientsand found that advanced age, past major depressive disorder[MDD] diagnosis, and past substance abuse were not morefrequent in patients who developed MDD [27]. Other than race,being more in Caucasians compared to African Americans[P<0.05], the only observed difference between patients whodeveloped MDD and those who did not was pre-Interferon-Alfa Beck Depression Inventory [BDI] score. Baselinedepression ratings were significantly higher in the patientswho later developed MDD compared with the non-MDDpatients [P=0.005]. Similar observations regarding baselinedepression ratings and the development of depression duringInterferon Alfa therapy have been observed by others [18],[33].

The Beck Depression Inventory is an excellent choicefor symptom monitoring; it performed well and is easy toadminister and score[18].

On the basis of their prospective study, Dieperink et alpropose that a score of 10 to 15 would indicate the need forclinical evaluation, and a score of 15 or more would stronglysuggest that antidepressant treatment be initiated. Furthermore,as higher baseline BDI scores predicted the development ofmajor depressive disorder symptoms, the data suggest thatpatients with baseline BDI scores above 6 may benefit fromantidepressant therapy before initiating IFN-Alfa therapy[18].

When Otsubo and colleagues[21] compared the patients whoexperienced depression during interferon treatment to thosewho did not, the depressed group showed significantly higherscores on the Eysenck Personality Questionnaire[35], moresevere depressed mood, and more severe sleep disturbancesbefore the start of interferon therapy.

Even if they were not initially depressed, patients whosescores using Montgomery-Asberg Depression Rating Scale[MADRS][34] or Minnesota Multiphasic Personality Inventory[MMPI][36] before the beginning of treatment were abovea certain cut-off were more likely to develop depressivesymptoms during IFN therapy.

The Hamilton Depression Rating Scale Score [HDRSS]determined before the initiation of IFN-Alfa therapy identifies,with a great degree of certainty, those patients who would notdevelop MD during treatment, as well as those who are at ahigh-risk for suffering such an episode [28].

Besides the Beck Depression Inventory, the Zung Self-Rating Depression[37] is a useful instruments for monitoringdepressive mood changes during IFN-Alfa treatment.

These findings provide an easy way to identify patients whoare at risk for IFN-Alfa induced depression and demonstratethe usefulness of a routine psychiatric assessment beforeinitiating IFN-Alfa treatment.

Depressive symptoms immediately before treatmentmay be more important than a history of psychiatric illnessor treatment in predicting the intensity of depression thatdevelops during interferon therapy[2],[19].[38].

In the study by Pariante et al[39], previous or currentpsychiatric illness did not predict discontinuation of IFN-Alfatherapy or the development of psychiatric adverse effects[2].

Treatment with IFN-Alfa does not necessarily increasethe risk for depression in patients with preexisting mentalillness[39],[40],[41]

Base-line anxiety scores were also predictive of developmentof symptoms of anxiety after Interferon therapy [29],[32].

Thus, screening for symptoms of anxiety, as well asdepression, before beginning interferon-Alfa therapy may helpto identify patients at high risk for psychiatric complicationsof interferon therapy[32].

The identification of patients at risk must be as precociousas possible because the depressive syndrome can settle assoon as the 1st week, with a peak in frequency during the 1stand 3rd months[1].

Renault et al[15] found that prior family history of psychiatricillness did not predict the development of depressive symptoms.However, Dieperink et al found that family history predicteda seven-fold increase in likelihood of requiring psychiatricintervention. They suggest that Hepatitis C patients with afamily history of mood disorders should be followed closelyfor depressive symptoms and treated aggressively if theyarise[2].

Other potential, rather controversial sometimes, risk factorsinclude advanced age[27], being female and increasing IFNAlfadosage and treatment duration[29] .

A history of mental disorders has not been found to be a riskfactor of those for patients undergoing IFN therapy[40],[42],[27],[15].In addition, Horikawa et al confirmed the results of previousstudies showing that the type of IFN-Alfa [43]and values ofGOT and GPT before therapy[15] were not risk factors fordepression [19].

Suicidal ideation has been reported, and completed suicidehas occurred during the course of IFN-Alfa therapy[1],[14],[32],[44],[45].

Interestingly, before beginning IFN treatment most ofthe patients who developed suicide ideations had no knownpsychiatric disorders, and had liver disease with a good shorttermprognosis[46],[47]. Noteworthy is the fact that suicidalimpulses have been reported even after the discontinuationof IFN treatment[47] and this is in keeping with the notionthat IFN-related neurotoxicity is not always promptlyreversible with the interruption of treatment or may even beirreversible[48],[49],[50].

Attempts to screen for patients at risk for development ofmajor depression and suicidal behavior have not been verysuccessful [34].

There has also been a report of a patient with a knownschizoaffective disorder who had suicidal ideation underinterferon therapy but responded favorably to treatment withnefazodone and flupentixol [51]. Another important aspect ofpsychiatric screening includes a careful history of adverselife events and patient reaction to stressful life events, asthose who are unable to cope with such events may developsevere depression. This hypothesis is supported by thefindings of Maunder et al., who reported on the emergence ofposttraumatic stress disorder during IFN-Alfa treatment forhepatitis C in three patients [52].

IFN-Alfa induced mania or hypomania has been reported,and presents a challenge for the psychiatric management[31]. Itis important to know that mania may follow depression andmay occur even after discontinuation of interferon-Alfa [31] .

   Mechanisms of Interferon-Associated Neuropsychiatric Changes Top

The mechanisms of IFN-Alfa induced depression remainpoorly understood[16],[53], but effects can be mediated by way ofneurotransmitter, neuroendocrine, or cytokine pathways[2],[11],[54],[55],[56].

Plasma concentrations of Serotonin[57] and tryptophan [2],[57],[58]have been shown to be significantly reduced during IFN-Alfatherapy.

Evidence implicating the importance of tryptophan indepression comes from both treatment[59],[60] and tryptophandepletionstudies[61],[62],[63].

IFN-Alfa can alter the metabolism of tryptophan byactivating indoleamine 2,3-deoxygenase, which leads toincreased production of l-kynurenine[57],[58],[64].

The evidence of selective serotonin reuptake inhibitor [SSRI]efficacy in patients who have interferon-induced depression isalso consistent with this etiologic hypothesis[2].[7],[58],[65],[66],[67],[68],[69],[70].

Neurotransmitter levels are also acutely increased byIFN-Alfa. Norepinephrine and epinephrine increase withadministration of IFN-Alfa in healthy volunteers [71]. Persistentelevation of amines in patients treated with IFN-Alfa is apossible mechanism of depression, as it is thought that longtermadministration of amine agonists may result in downregulationand subsensitivity of receptors [72].

IFN-Alfa and ACTH have been reported to be antigenicallyand structurally related [11],[73], and IFN-Alfa induces increasedplasma cortisol levels acutely [71],[74]. This suggests anotherpossible mechanism for IFN-Alfa induction of depression,since chronically increased hypothalamic-pituitary-adrenal[HPA] activity is associated with depression [56],[75],[76],[77],[78].

IFN-Alfa also alters thyroid function. Hypothyroidism orhyperthyroidism develops in 2.5%-20% of patients [79],[80], andthis may cause or exacerbate neuropsychiatric symptoms[56].

IFN-Alfa induction of secondary cytokines, such asinterleukin- 1 [IL-1], IL-2, IL-6, and tumor necrosis factor alfa,may also contribute to neuropsychiatric symptoms [2],[78],[81],[82],[83].

Secondary cytokines may activate the HPA axis, which mayin turn cause depressive symptoms [2].

In neuro-imaging studies, depression has been linked todecreased activation in the dorsolateral prefrontal cortex, aphenomenon that is also seen with IFN-Alfa treatment [84].

IFN-Alfa may act as a central dopamine agonist through anopioid-associated mechanism [85]. Dopamine neurotransmissionabnormalities have been implicated in the etiology of mania[86].

Ultimately, the precise mechanisms involved in theevolution of mania during interferon treatment remain amatter of speculation, but several lines of evidence havepointed to neuroendocrine, neurotransmitter, and cytokinepathways [82],[83].

   Treatment of IFN-Alfa Neuropsychiatric Side Effects Top

Not only are mental side effects through IFN-Alfa treatmenta burden to the patient by their mere existence, but they alsolead to a poorer virological outcome [87],[88].

Dose reduction and discontinuation of interferon canbe effective interventions for mania, depression, and otherinterferon-related neuropsychiatric syndromes [15], but whenthe psychopathology is severe or persistent, pharmacotherapywith psychotropic agents is necessary. [11],[15],[89]

Patients should be informed that they may be at greater riskof developing depression, and an individualized decision canbe made by patient and clinician [2],[18].

The appearance of mild symptoms of depression shouldprompt an increase of patient contact with the physician byoffice visit or by phone [90].

Several studies and case reports demonstrate thatantidepressants effectively treat IFN-Alfa-induced depressiononce it has developed, allowing the vast majority of subjectsto complete treatment successfully [2],[29],[39],[65],[66],[68],[70],[91],[92].

SSRIs are generally considered beneficial and well toleratedin treating depression in this patient population [1],[2],[18],[19],[29],[32],[65],[68],[70], whereas tricyclic anti-depressants may be less desirable,potentiating cognitive dysfunction related to IFN or cirrhosis[66],[92].

In particular, paroxetine, at dosages ranging from 20 to 50mg/day, seems to be particularly suitable for patients, as it hasa strong anxiolitic effect among SSRIs, and IFN-Alfa relateddepression is often associated with generalized anxiety [1].

Also Citalopram has been reported to be effectivefor the acute treatment of IFN-Alfa induced depressivesymptoms[53].

With regard to antidepressant safety, hepatotoxicity hasrarely been seen with SSRI treatment in the general population[93].

However, there is the potential for increased retinalhemorrhaging and cotton wool spots. Incidences ofretinopathy in patients receiving IFN-Alfa have ranged from18% to 86% and are found more frequently in older patientsand in patients with hypertension and/or diabetes mellitus[94].

Although retinal hemorrhage is a rare side effect ofparoxetine [less than 1 in 1000], given the developmentof retinal hemorrhages during Interferon alfa therapy insome patients taking paroxetine[32],[95], regular funduscopicexaminations should be performed and patients with visualsymptoms should be referred promptly to an ophthalmologist,whether or not paroxetine is used[32].

Another concern is the likelihood that SSRIs increasethe risk of gastrointestinal bleeding de[96],[97]. Patients withhepatitis C and compromised liver function are at a greaterrisk for gastrointestinal bleeding[98].

Sulpiride has been reported to be effective for the depressivesymptoms de[99],[100] and irritability [100] that is also frequentlyfound during IFN therapy[15],[44],[101],[102]. In addition, in generalsulpiride has only minor adverse effects at low dosage[100].According to some case reports [66],[67],[68],[92], imipramine,nortriptyline, fluoxetine, paroxetine and sertraline areeffective in treating depressive symptoms[19].

Depression may also worsen after discontinuation ofinterferon-Alfa application, and therefore antidepressanttreatment should not be stopped prematurely[103].

Other pharmacologic strategies have included the use ofmethylphenidate for fatigue and naltrexone for neurotoxicityand cognitive dysfunction[11],[104].

Mania, especially when severe, is a clinical emergency.When this occurs, IFN-alfa and antidepressants should bestopped, an emergency psychiatric consultation should beobtained, and treatment with a mood stabilizer should beinitiated [29].

Some authors recommend to generally discontinueIFN-Alfa when manic symptoms come to the fore [29],[105].However, under close monitoring and adequate treatment,mania does not necessarily require discontinuation of IFNAlfatherapy. If mania is severe or difficult to control,IFN-Alfa should be discontinued, but resuming antiviraltreatment should be considered after remission of manicsymptoms [106].

Interferon-Alfa-induced mania responds to thepharmacological agents typically used for treating mania.Several reports document treatment successes withhaloperidol and other "typical" neuroleptics, risperidone andolanzapine, lithium, gabapentin, and carbamazepine [56],[107],[108],[109],[110]. Successful resumption of IFN-Alfa after treatment ofinterferon-induced mood disorder has also been reported.

Nonpharmacological interventions may also be usefulfor interferon-alfa-induced depression. Exercise has beenshown to be helpful in patients with major depression [111]and may improve some IFN-Alfa associated symptoms. Inaddition, supportive psychotherapy may improve toleranceof symptoms, as may other more specific psychotherapies,but we know of no available data on these interventions [2].

Further research is required to show whether interferoninduceddepression represents a subtype of depression withcharacteristic features [112].

   Interferon-Alfa treatment in patients who have active psychiatric illness Top

Several studies have addressed the issue of IFN therapy inpatients who have chronic hepatitis C who have concomitant,active psychiatric illness[42],[113],[114]. Patients with a previoushistory of psychiatric illness are usually maintained on theirmedications[106].

Two studies found no statistically significant difference inneuropsychiatric side effects that were present during IFNAlfatherapy between patients who had preexisting psychiatricillnesses and patients who did not have preexisting psychiatricillnesses[113],[114].

With improvement in antiviral therapy, patients whohave preexisting psychiatric disorders can probably beoffered such therapy safely with appropriate monitoring andmanagement[113],[114].

   Prophylactic antidepressant use Top

Schaefer et al prospectively studied the efficacy of a preemptivetreatment with Citalopram to prevent depressionduring hepatitis C treatment with pegylated IFN-Alfa plusribavirin. They found that Citalopram significantly reducedthe incidence of major depression during the first six monthsof antiviral treatment as compared to two control groups[P=0.032] [53].

A recent prospective controlled study[32] has shown thatparoxetine is useful in preventing depression in hepatitispatients undergoing IFN therapy.

Results from other prospective studies[32],[115] indicate thatantidepressant treatment may prevent interferon-induceddepression.

Some authors support the prophylactic use of antidepressantsfor all patients receiving interferon to treat HCV; othershave raised concern about potential risks like retinal andgastrointestinal hemorrhage and stimulation of secondarymania [27],[53],[105]. Furthermore, a significant proportion ofinitially nondepressed patients will not require antidepressanttreatment [18].

If depression is present before initiation of antiviraltreatment, SSRI administration can render antiviral therapyfeasible [28],[116].

It is probably justified to recommend prophylacticantidepressant treatment to patients with baseline BDI scoresabove 10 [18].

   Summary Top

Now we are gaining insight into the treatment and themechanisms of major depressive disorders induced by IFNAlfa.

Neuropsychiatric side effects of IFN-Alfa occur in asignificant number of patients and can be severe and lead tocessation of treatment.

IFN-Alfa induced depression can be severe with high riskof suicidality. Early recognition and effective treatment ofdepression prior to and during IFN-Alfa therapy is importantfor the adherence to antiviral treatment, for the antiviraloutcome, and to improve the quality of life of hepatitis Cpatients.

Pretreatment mood disturbances, even when subsyndromal,are the most reliable predictor of developing both depressivesymptoms and major depressive disorder during IFN-Alfatherapy. Additionally, they are more relevant than past mooddisturbance for identifying at-risk patients.

Psychiatric consultation prior to the therapy can be helpfulin selecting candidates for interferon. A thorough reviewof psychiatric symptoms and past psychiatric history isespecially recommended. Patients with current depressivesymptoms or a history of psychiatric illness should beevaluated for psychiatric treatment. Treatment of preexistingmood disorders may be helpful in preventing the developmentof interferon-induced depression.

Additional studies are needed to evaluate the potential risksand benefits of prophylactic antidepressant therapy in patientswho have chronic hepatitis C and to develop a strategy toselect patients at risk for IFN-Alfa -induced depression [115].

Severe, uncontrolled psychiatric disease, particularlydepression with current suicidal risk, is an absolutecontraindication to IFN-Alfa therapy[27].

Psychiatric disorders that are in remission or stabilizedare not contraindications to IFN-Alfa therapy, and patientsshould be maintained on their medications. However, it isrecommended that mental health care providers be involvedwith the patient during antiviral therapy.

The use of a standardized questionnaire such as the BDI isencouraged at every office visit, particularly in patients whohave symptoms of depression.

Patients who develop interferon-induced depressionshould be considered for antidepressants. SSRIs aregenerally considered beneficial and well tolerated in treatingdepression in this patient population. If suicidal ideation ispresent, interferon should be discontinued. Further researchis needed to examine the long-term safety and efficacy ofantidepressant therapy in this population with compromisedliver function[67].

Greater cooperation between psychiatrists and hepatologistswould mean less risk of worsening the psychiatric symptoms[42].More importance needs to be given to the identification ofpatients at risk of depression before starting therapy, in orderto permit an adequate monitoring or the adoption of correctivemeasures [1] .

   References Top

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Correspondence Address:
Yaser R Al-Huthail
Department of Psychiatry College of Medicine, King Khaled University Hospital King Saud University, Riyadh P.O.Box 7805, Riyadh-11472
Saudi Arabia
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DOI: 10.4103/1319-3767.27847

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