|Year : 2006 | Volume
| Issue : 2 | Page : 59-67
|Neuropsychiatric side-effects of interferon alfa therapy for hepatitis C and their management: A review
Yaser R Al-Huthail
Department of Psychiatry,College of Medicine, King Khaled University Hospital King Saud University, Riyadh, Saudi Arabia
Click here for correspondence address and email
|Date of Submission||18-Apr-2006|
|Date of Acceptance||01-May-2006|
| Abstract|| |
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 2019 Oct 13];12:59-67. Available from: http://www.saudijgastro.com/text.asp?2006/12/2/59/27847
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 . IFN-Alfa hasbeen the mainstay of treatment for chronic hepatitis C. Atpresent, optimal treatment for HCV infection consists ofcombination antiviral therapy with pegylated interferon-Alfaand ribavirin.Treatments utilizing interferon-Alfa have thepotential to alter the course of chronic hepatitis C and preventcomplications.Recent advances in therapy with pegylatedIFN-Alfa have significantly improved treatment outcome.Unfortunately; many severely ill patients are not receivingIFN-Alfa because of concerns regarding neuropsychiatricside effects.
| Neuropsychiatric side effects of Interferon-Alfa|| |
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.
Neuropsychiatric side effects include lethargy, somnolence,fatigue, drowsiness, disorientation, impaired concentration,irritability, emotional liability, social withdrawal, depression,and hopelessness,. In addition, anxiety symptoms, such asanxious mood, tension, irritability, and fear.
Mania, sexual dysfunction, memory impairment,and cognitive dysfunction 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 .
Although most cases of depression are mild to moderate inseverity, suicidal ideation and successful suicides during orshortly after Interferon Alfa therapy for chronic viral hepatitishave been reported. The neuropsychiatric side effects ofInterferon Alfa, particularly depression, are among the mostcommon causes of dose reduction or discontinuation oftherapy,.
Until now only a limited number of studies have beendevoted to the problem of depression. The incidence ofInterferon Alfa-induced depression in patients who havehepatitis C reportedly ranges from 3% to 44 %,, butlarge, randomized trials that used standardized psychiatricevaluation methods indicate an incidence of approximately20% to 30% [Table - 1],,.
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".
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.
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 .
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.
In another prospective study, the mean time from initiationof Interferon Alfa to development of Major Depression was12.1 weeks [range 1 to 32 weeks].
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.
These results suggest that patients should be screenedregularly for depression during the first six months ofInterferon Alpha therapy. However, the risk of depressioncontinues and appears to be higher with longer duration oftherapy .
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,,.
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.
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 . 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 ,.
The Beck Depression Inventory is an excellent choicefor symptom monitoring; it performed well and is easy toadminister and score.
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.
When Otsubo and colleagues compared the patients whoexperienced depression during interferon treatment to thosewho did not, the depressed group showed significantly higherscores on the Eysenck Personality Questionnaire, 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] or Minnesota Multiphasic Personality Inventory[MMPI] 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 .
Besides the Beck Depression Inventory, the Zung Self-Rating Depression 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,..
In the study by Pariante et al, previous or currentpsychiatric illness did not predict discontinuation of IFN-Alfatherapy or the development of psychiatric adverse effects.
Treatment with IFN-Alfa does not necessarily increasethe risk for depression in patients with preexisting mentalillness,,
Base-line anxiety scores were also predictive of developmentof symptoms of anxiety after Interferon therapy ,.
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.
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.
Renault et al 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.
Other potential, rather controversial sometimes, risk factorsinclude advanced age, being female and increasing IFNAlfadosage and treatment duration .
A history of mental disorders has not been found to be a riskfactor of those for patients undergoing IFN therapy,,,.In addition, Horikawa et al confirmed the results of previousstudies showing that the type of IFN-Alfa and values ofGOT and GPT before therapy were not risk factors fordepression .
Suicidal ideation has been reported, and completed suicidehas occurred during the course of IFN-Alfa therapy,,,,.
Interestingly, before beginning IFN treatment most ofthe patients who developed suicide ideations had no knownpsychiatric disorders, and had liver disease with a good shorttermprognosis,. Noteworthy is the fact that suicidalimpulses have been reported even after the discontinuationof IFN treatment and this is in keeping with the notionthat IFN-related neurotoxicity is not always promptlyreversible with the interruption of treatment or may even beirreversible,,.
Attempts to screen for patients at risk for development ofmajor depression and suicidal behavior have not been verysuccessful .
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 . 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 .
IFN-Alfa induced mania or hypomania has been reported,and presents a challenge for the psychiatric management. Itis important to know that mania may follow depression andmay occur even after discontinuation of interferon-Alfa  .
| Mechanisms of Interferon-Associated Neuropsychiatric Changes|| |
The mechanisms of IFN-Alfa induced depression remainpoorly understood,, but effects can be mediated by way ofneurotransmitter, neuroendocrine, or cytokine pathways,,,,.
Plasma concentrations of Serotonin and tryptophan ,,have been shown to be significantly reduced during IFN-Alfatherapy.
Evidence implicating the importance of tryptophan indepression comes from both treatment, and tryptophandepletionstudies,,.
IFN-Alfa can alter the metabolism of tryptophan byactivating indoleamine 2,3-deoxygenase, which leads toincreased production of l-kynurenine,,.
The evidence of selective serotonin reuptake inhibitor [SSRI]efficacy in patients who have interferon-induced depression isalso consistent with this etiologic hypothesis.,,,,,,,.
Neurotransmitter levels are also acutely increased byIFN-Alfa. Norepinephrine and epinephrine increase withadministration of IFN-Alfa in healthy volunteers . 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 .
IFN-Alfa and ACTH have been reported to be antigenicallyand structurally related ,, and IFN-Alfa induces increasedplasma cortisol levels acutely ,. This suggests anotherpossible mechanism for IFN-Alfa induction of depression,since chronically increased hypothalamic-pituitary-adrenal[HPA] activity is associated with depression ,,,,.
IFN-Alfa also alters thyroid function. Hypothyroidism orhyperthyroidism develops in 2.5%-20% of patients ,, andthis may cause or exacerbate neuropsychiatric symptoms.
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 ,,,,.
Secondary cytokines may activate the HPA axis, which mayin turn cause depressive symptoms .
In neuro-imaging studies, depression has been linked todecreased activation in the dorsolateral prefrontal cortex, aphenomenon that is also seen with IFN-Alfa treatment .
IFN-Alfa may act as a central dopamine agonist through anopioid-associated mechanism . Dopamine neurotransmissionabnormalities have been implicated in the etiology of mania.
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 ,.
| Treatment of IFN-Alfa Neuropsychiatric Side Effects|| |
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 ,.
Dose reduction and discontinuation of interferon canbe effective interventions for mania, depression, and otherinterferon-related neuropsychiatric syndromes , but whenthe psychopathology is severe or persistent, pharmacotherapywith psychotropic agents is necessary. ,,
Patients should be informed that they may be at greater riskof developing depression, and an individualized decision canbe made by patient and clinician ,.
The appearance of mild symptoms of depression shouldprompt an increase of patient contact with the physician byoffice visit or by phone .
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 ,,,,,,,,.
SSRIs are generally considered beneficial and well toleratedin treating depression in this patient population ,,,,,,,,, whereas tricyclic anti-depressants may be less desirable,potentiating cognitive dysfunction related to IFN or cirrhosis,.
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 .
Also Citalopram has been reported to be effectivefor the acute treatment of IFN-Alfa induced depressivesymptoms.
With regard to antidepressant safety, hepatotoxicity hasrarely been seen with SSRI treatment in the general population.
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.
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,, regular funduscopicexaminations should be performed and patients with visualsymptoms should be referred promptly to an ophthalmologist,whether or not paroxetine is used.
Another concern is the likelihood that SSRIs increasethe risk of gastrointestinal bleeding de,. Patients withhepatitis C and compromised liver function are at a greaterrisk for gastrointestinal bleeding.
Sulpiride has been reported to be effective for the depressivesymptoms de, and irritability  that is also frequentlyfound during IFN therapy,,,. In addition, in generalsulpiride has only minor adverse effects at low dosage.According to some case reports ,,,, imipramine,nortriptyline, fluoxetine, paroxetine and sertraline areeffective in treating depressive symptoms.
Depression may also worsen after discontinuation ofinterferon-Alfa application, and therefore antidepressanttreatment should not be stopped prematurely.
Other pharmacologic strategies have included the use ofmethylphenidate for fatigue and naltrexone for neurotoxicityand cognitive dysfunction,.
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 .
Some authors recommend to generally discontinueIFN-Alfa when manic symptoms come to the fore ,.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 .
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 ,,,,. 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 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 .
Further research is required to show whether interferoninduceddepression represents a subtype of depression withcharacteristic features .
| Interferon-Alfa treatment in patients who have active psychiatric illness|| |
Several studies have addressed the issue of IFN therapy inpatients who have chronic hepatitis C who have concomitant,active psychiatric illness,,. Patients with a previoushistory of psychiatric illness are usually maintained on theirmedications.
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,.
With improvement in antiviral therapy, patients whohave preexisting psychiatric disorders can probably beoffered such therapy safely with appropriate monitoring andmanagement,.
| Prophylactic antidepressant use|| |
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] .
A recent prospective controlled study has shown thatparoxetine is useful in preventing depression in hepatitispatients undergoing IFN therapy.
Results from other prospective studies, 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 ,,. Furthermore, a significant proportion ofinitially nondepressed patients will not require antidepressanttreatment .
If depression is present before initiation of antiviraltreatment, SSRI administration can render antiviral therapyfeasible ,.
It is probably justified to recommend prophylacticantidepressant treatment to patients with baseline BDI scoresabove 10 .
| Summary|| |
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 .
Severe, uncontrolled psychiatric disease, particularlydepression with current suicidal risk, is an absolutecontraindication to IFN-Alfa therapy.
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.
Greater cooperation between psychiatrists and hepatologistswould mean less risk of worsening the psychiatric symptoms.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  .
| References|| |
|1.||Scalori A, Pozzi M, Bellia V, Apale P, Santamaria G, Bordoni T etal. Interferon-induced depression: prevalence and management.Dig Liver Dis 2005; 37:102-107. |
|2.||Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 2000; 157(6):867-876. |
|3.||Bacon BR. Managing hepatitis C 1. Am J Manag Care 2004; 10(2 Suppl):S30-S40. |
|4.||Marsano LS, Pena LR. The interaction of alcoholic liver disease and hepatitis C 1. Hepatogastroenterology 1998; 45(20):331-339. |
|5.||Corrao G, Carle F, Lepore AR, Zepponi E, Galatola G, Di Orio F. Interaction between alcohol consumption and positivity for antibodies to hepatitis C virus on the risk of liver cirrhosis: a case-control study. Provincial Group for the Study of Chronic Liver Disease 1. Eur J Epidemiol 1992; 8(5):634-639. |
|6.||Williams IT, Sabin K, Fleenor M, Judson F, Mottram K, Poujade J et al. Current patterns of hepatitis C virus transmission in the United States: the role of drugs and sex . Hepatology 1998; 28:497. |
|7.||McDonald EM, Mann AH, Thomas HC. Interferons as mediators of psychiatric morbidity. An investigation in a trial of recombinant alpha-interferon in hepatitis-B carriers 1. Lancet 1987; 2(8569):1175-1178. |
|8.||Smedley H, Katrak M, Sikora K, Wheeler T. Neurological effects of recombinant human interferon 1. Br Med J (Clin Res Ed) 1983; 286(6361):262-264. |
|9.||Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions 1. Neuropsychopharmacology 2002; 26(5):643-652. |
|10.||Greenberg DB, Jonasch E, Gadd MA, Ryan BF, Everett JR, Sober AJ et al. Adjuvant therapy of melanoma with interferonalpha- 2b is associated with mania and bipolar syndromes 1. Cancer 2000; 89(2):356-362. |
|11.||Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy 1. Semin Oncol 1998; 25(1 Suppl 1):39-47. |
|12.||Capuron L, Ravaud A, Dantzer R. Timing and specificity of the cognitive changes induced by interleukin- 2 and interferon-alpha treatments in cancer patients 1. Psychosom Med 2001; 63(3):376-386. |
|13.||Fried MW. Side effects of therapy of hepatitis C and their management 1. Hepatology 2002; 36(5 Suppl 1):S237-S244. |
|14.||Janssen HL, Brouwer JT, van der Mast RC, Schalm SW. Suicide associated with alfa-interferon therapy for chronic viral hepatitis 1. J Hepatol 1994; 21(2):241-243. |
|15.||Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB et al. Psychiatric complications of long-term interferon alfa therapy 1. Arch Intern Med 1987; 147(9):1577-1580. |
|16.||Horsmans Y. Chronic hepatitis C, depression and interferon 1. J Hepatol 2005; 42(6):788-789. |
|17.||Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial 1. Lancet 2001; 358(9286):958-965. |
|18.||Dieperink E, Ho SB, Thuras P, Willenbring ML. A prospective study of neuropsychiatric symptoms associated with interferonalpha- 2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44(2):104-112. |
|19.||Horikawa N, Yamazaki T, Izumi N, Uchihara M. Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study 1. Gen Hosp Psychiatry 2003; 25(1):34-38. |
|20.||Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr. et al. Peginterferon alfa- 2a plus ribavirin for chronic hepatitis C virus infection 1. N Engl J Med 2002; 347(13):975-982. |
|21.||Otsubo T, Miyaoka H, Kamijima K, Onuki M, Ishii M, Mitamura K. [Depression during interferon therapy in chronic hepatitis C patients--a prospective study] 1. Seishin Shinkeigaku Zasshi 1997; 99(3):101-127. |
|22.||Farrell GC. Therapy of hepatitis C: interferon alfa-n1 trials 1. Hepatology 1997; 26(3 Suppl 1):96S-100S. |
|23.||Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M et al. Side effects of high-dose interferon therapy for chronic hepatitis C 1. J Hepatol 1996; 25(3):283-291. |
|24.||McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group 1. N Engl J Med 1998; 339(21):1485-1492. |
|25.||Weiss K. Safety profile of interferon-alpha therapy 1. Semin Oncol 1998; 25(1 Suppl 1):9-13. |
|26.||Schiff ER, Ozden N. Hepatitis C and alcohol 1. Alcohol Res Health 2003; 27(3):232-239. |
|27.||Hauser P. Neuropsychiatric side effects of HCV therapy and their treatment: focus on IFN alpha-induced depression 1. Gastroenterol Clin North Am 2004; 33(1 Suppl):S35-S50. |
|28.||Beratis S, Katrivanou A, Georgiou S, Monastirli A, Pasmatzi E, Gourzis P et al. Major depression and risk of depressive symptomatology associated with short-term and low-dose interferon-alpha treatment J Psychosom Res 2005; 58(1):15-18. |
|29.||Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management 1. CNS Drugs 2005; 19(2):105-123. |
|30.||Reichenberg A, Gorman JM, Dieterich DT. Interferoninduced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study 1. AIDS 2005; 19 Suppl 3:S174-S178. [PUBMED] |
|31.||Reimer J, Backmund M, Haasen C. New psychiatric and psychological aspects of diagnosis and treatment of hepatitis C and relevance for opiate dependence. Current Opinion in Psychiatry 2005; 18:678-683. [PUBMED] |
|32.||Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa 1. N Engl J Med 2001; 344(13):961-966. |
|33.||Miyaoka H, Otsubo T, Kamijima K, Ishii M, Onuki M, Mitamura K. Depression from interferon therapy in patients with hepatitis C 1. Am J Psychiatry 1999; 156(7):1120. |
|34.||Capuron L, Ravaud A. Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state 1. N Engl J Med 1999; 340(17):1370. |
|35.||Eysenck HJ, Eysenck SBG. Eysenck Personality Questionnaire Manual. Educational and Industrial Testing Service, 1975. |
|36.||Scalori A, Apale P, Panizzuti F, Mascoli N, Pioltelli P, Pozzi M et al. Depression during interferon therapy for chronic viral hepatitis: early identification of patients at risk by means of a computerized test 1. Eur J Gastroenterol Hepatol 2000; 12(5):505-509. |
|37.||Schaefer M, Schmidt F, Horn M, Schmid-Wendtner MH, Volkenandt M. Depression during treatment with interferon alpha 1. Psychosomatics 2004; 45(2):176. |
|38.||Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM et al. Depression during pegylated interferonalpha plus ribavirin therapy: prevalence and prediction 1. J Clin Psychiatry 2005; 66(1):41-48. |
|39.||Pariante CM, Orru MG, Baita A, Farci MG, Carpiniello B. Treatment with interferon-alpha in patients with chronic hepatitis and mood or anxiety disorders 1. Lancet 1999; 354(9173):131-132. |
|40.||Mulder RT, Ang M, Chapman B, Ross A, Stevens IF, Edgar C. Interferon treatment is not associated with a worsening of psychiatric symptoms in patients with hepatitis C 1. J Gastroenterol Hepatol 2000; 15(3):300-303. |
|41.||Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups 1. Hepatology 2003; 37(2):443-451. |
|42.||Van Thiel DH, Friedlander L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferon-alpha can be used successfully in patients with hepatitis C viruspositive chronic hepatitis who have a psychiatric illness Eur J Gastroenterol Hepatol 1995; 7(2):165-168. |
|43.||Malaguarnera M, Di F, I, Restuccia S, Pistone G, Ferlito L, Rampello L. Interferon alpha-induced depression in chronic hepatitis C patients: comparison between different types of interferon alpha Neuropsychobiology 1998; 37(2):93-97. |
|44.||Fukunishi K, Tanaka H, Maruyama J, Takahashi H, Kitagishi H, Ueshima T et al. Burns in a suicide attempt related to psychiatric side effects of interferon 1. Burns 1998; 24(6):581-583. |
|45.||Bourat L, Larrey D, Michel H. [Attempted suicide during treatment of chronic viral hepatitis C with interferon. Apropos of 2 cases] 1. Gastroenterol Clin Biol 1995; 19(12):1063. |
|46.||Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon 1. J Hepatol 1996; 24(1):38-47. |
|47.||Rifflet H, Vuillemin E, Oberti F, Duverger P, Laine P, Garre JB et al. [Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha] 1. Gastroenterol Clin Biol 1998; 22(3):353-357. |
|48.||Vesikari T, Nuutila A, Cantell K. Neurologic sequelae following interferon therapy of juvenile laryngeal papilloma 1. Acta Paediatr Scand 1988; 77(4):619-622. |
|49.||Bernsen PL, Wong Chung RE, Vingerhoets HM, Janssen JT. Bilateral neuralgic amyotrophy induced by interferon treatment 1. Arch Neurol 1988; 45(4):449-451. |
|50.||Meyers CA, Scheibel RS, Forman AD. Persistent neurotoxicity of systemically administered interferon-alpha 1. Neurology 1991; 41(5):672-676. |
|51.||Schafer M, Schmidt F, Amann B, Schlosser S, Loeschke K, Grunze H. Adding low-dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis 1. Neuropsychobiology 2000; 42 Suppl 1:43-45. |
|52.||Maunder RG, Hunter JJ, Feinman SV. Interferon treatment of hepatitis C associated with symptoms of PTSD 1. Psychosomatics 1998; 39(5):461-464. |
|53.||Schaefer M, Schwaiger M, Garkisch AS, Pich M, Hinzpeter A, Uebelhack R et al. Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C 1. J Hepatol 2005; 42(6):793-798. |
|54.||Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression 1. Hepatology 2000; 31(6):1207-1211. |
|55.||Trask PC, Esper P, Riba M, Redman B. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions 1. J Clin Oncol 2000; 18(11):2316-2326. |
|56.||Altindag A, Ozbulut O, Ozen S, Ucmak H. Interferonalpha- induced mood disorder with manic features Gen Hosp Psychiatry 2001; 23(3):168-170. |
|57.||Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system 1. J Clin Psychopharmacol 2002; 22(1):86-90. |
|58.||Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy 1. Mol Psychiatry 2002; 7(5):468-473. |
|59.||Lam RW, Levitan RD, Tam EM, Yatham LN, Lamoureux S, Zis AP. L-tryptophan augmentation of light therapy in patients with seasonal affective disorder 1. Can J Psychiatry 1997; 42(3):303-306. |
|60.||Ghadirian AM, Murphy BE, Gendron MJ. Efficacy of light versus tryptophan therapy in seasonal affective disorder 1. J Affect Disord 1998; 50(1):23-27. |
|61.||Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressantinduced remission by rapid depletion of plasma tryptophan 1. Arch Gen Psychiatry 1990; 47(5):411-418. |
|62.||Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN. Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders 1. Arch Gen Psychiatry 1994; 51(9):687-697. |
|63.||Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C. Mood response to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability 1. Neuropsychopharmacology 1996; 15(5):465-474. |
|64.||Russo S, Kema IP, Haagsma EB, Boon JC, Willemse PH, den Boer JA et al. Irritability rather than depression during interferon treatment is linked to increased tryptophan catabolism 20. Psychosom Med 2005; 67(5):773-777. |
|65.||Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C 1. Mol Psychiatry 2002; 7(9):942-947. |
|66.||Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-alpha 1. Am J Gastroenterol 1993; 88(5):760-761. |
|67.||Gleason OC, Yates WR. Five cases of interferon-alphainduced depression treated with antidepressant therapy 1. Psychosomatics 1999; 40(6):510-512. |
|68.||Schramm TM, Lawford BR, Macdonald GA, Cooksley WG. Sertraline treatment of interferon-alfa-induced depressive disorder 1. Med J Aust 2000; 173(7):359-361. |
|69.||Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferonalpha- induced depression in chronic hepatitis C 1. Aliment Pharmacol Ther 2002; 16(6):1091-1099. |
|70.||Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C 1. J Clin Psychiatry 2002; 63(3):194-198. |
|71.||Corssmit EP, Heijligenberg R, Endert E, Ackermans MT, Sauerwein HP, Romijn JA. Endocrine and metabolic effects of interferon-alpha in humans 1. J Clin Endocrinol Metab 1996; 81(9):3265-3269. |
|72.||Siever LJ, Davis KL. Overview: toward a dysregulation hypothesis of depression 1. Am J Psychiatry 1985; 142(9):1017-1031. |
|73.||Blalock JE, Smith EM. Human leukocyte interferon (HuIFN-alpha): potent endorphin-like opioid activity Biochem Biophys Res Commun 1981; 101(2):472-478. |
|74.||Barbarino A, Colasanti S, Corsello SM, Satta MA, Della CS, Rota CA et al. Dexamethasone inhibition of interferonalpha 2-induced stimulation of cortisol and growth hormone secretion in chronic myeloproliferative syndrome 1. J Clin Endocrinol Metab 1995; 80(4):1329-1332. |
|75.||Nemeroff CB, Krishnan KR, Reed D, Leder R, Beam C, Dunnick NR. Adrenal gland enlargement in major depression. A computed tomographic study 1. Arch Gen Psychiatry 1992; 49(5):384-387. |
|76.||Stokes PE, Sikes CR. The hypothalamicpituitary- adrenocortical axis in major depression 1. Endocrinol Metab Clin North Am 1988; 17(1):1-19. |
|77.||Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy 1. Am J Psychiatry 2003; 160(7):1342-1345. |
|78.||Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M et al. Immunotherapy with interferonalpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms 1. Psychiatry Res 2001; 105(1-2):45-55. |
|79.||Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraub B, Murray LM, Hoofnagle JH. Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa 1. Gastroenterology 1992; 102(6):2155-2160. |
|80.||Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L et al. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a 1. Eur J Endocrinol 1995; 132(5):587-593. |
|81.||Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development Trends Pharmacol Sci 1992; 13(1):24-28. |
|82.||Taylor JL, Grossberg SE. The effects of interferonalpha on the production and action of other cytokines Semin Oncol 1998; 25(1 Suppl 1):23-29. |
|83.||Licinio J, Kling MA, Hauser P. Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes 1. Semin Oncol 1998; 25(1 Suppl 1):30-38. |
|84.||Matthews SC, Paulus MP, Dimsdale JE. Contribution of functional neuroimaging to understanding neuropsychiatric side effects of interferon in hepatitis C 1. Psychosomatics 2004; 45(4):281-286. |
|85.||Leigh JP, Bowlus CL, Leistikow BN, Schenker M. Costs of hepatitis C 1. Arch Intern Med 2001; 161(18):2231-2237. |
|86.||Lerner DM, Stoudemire A, Rosenstein DL. Neuropsychiatric toxicity associated with cytokine therapies Psychosomatics 1999; 40(5):428-435. |
|87.||Maddock C, Landau S, Barry K, Maulayah P, Hotopf M, Cleare AJ et al. Psychopathological symptoms during interferonalpha and ribavirin treatment: effects on virologic response 1. Mol Psychiatry 2005; 10(4):332-333. |
|88.||Raison CL, Broadwell SD, Borisov AS, Manatunga AK, Capuron L, Woolwine BJ et al. Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C 1. Brain Behav Immun 2005; 19(1):23-27. |
|89.||Kenilworth NJ. PEG-Intron (Peginterferon alfa- 2b) powder for injection (package information). PMID: 16127955 . 2003. 25-7-2005. Ref Type: Electronic Citation |
|90.||Ward RP, Kugelmas M. Using pegylated interferon and ribavirin to treat patients with chronic hepatitis C 21. Am Fam Physician 2005; 72(4):655-662. |
|91.||Benvegnu L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis 1. Cancer 1998; 83(5):901-909. |
|92.||Goldman LS. Successful treatment of interferon alfa-induced mood disorder with nortriptyline 1. Psychosomatics 1994; 35(4):412-413. |
|93.||Carvajal Garcia-Pando A, Garcia dP, Sanchez AS, Velasco MA, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants 1. J Clin Psychiatry 2002; 63(2):135-137. |
|94.||Hayasaka S, Nagaki Y, Matsumoto M, Sato S. Interferon associated retinopathy 1. Br J Ophthalmol 1998; 82(3):323-325. |
|95.||Hejny C, Sternberg P, Lawson DH, Greiner K, Aaberg TM, Jr. Retinopathy associated with high-dose interferon alfa-2b therapy 1. Am J Ophthalmol 2001; 131(6):782-787. |
|96.||de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study 1. BMJ 1999; 319(7217):1106-1109. |
|97.||van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study MJ 2001; 323(7314):655-658. |
|98.||Loftis JM, Hauser P. Safety of the treatment of interferon-alpha-induced depression 1. Psychosomatics 2003; 44(6):524-526. |
|99.||de Lima MS, Hotoph M, Wessely S. The efficacy of drug treatments for dysthymia: a systematic review and meta-analysis 1. Psychol Med 1999; 29(6):1273-1289. |
|100.||Toru M, Moriya H, Yamamoto K, Shimazono Y. A doubleblind comparison of sulpiride with chlordiazepoxide in neurosis 1. Folia Psychiatr Neurol Jpn 1976; 30(2):153-164. |
|101.||Dusheiko G. Side effects of alpha interferon in chronic hepatitis C 1. Hepatology 1997; 26(3 Suppl 1):112S-121S. |
|102.||Niiranen A, Laaksonen R, Iivanainen M, Mattson K, Farkkila M, Cantell K. Behavioral assessment of patients treated with alpha-interferon 1. Acta Psychiatr Scand 1988; 78(5):622-626. |
|103.||Nickel T, Sonntag A, Backmund M, Pollmacher T. Depression during therapy with interferon alpha-- ow long should an antidepressant treatment last? 1. Pharmacopsychiatry 2005; 38(2):102-104. |
|104.||Valentine AD, Meyers CA, Talpaz M. Treatment of neurotoxic side effects of interferon-alpha with naltrexone 1. Cancer Invest 1995; 13(6):561-566. |
|105.||Crone CC, Gabriel GM, Wise TN. Managing the neuropsychiatric side effects of interferon-based therapy for hepatitis C 1. Cleve Clin J Med 2004; 71 Suppl 3:S27-S32. |
|106.||Onyike CU, Bonner JO, Lyketsos CG, Treisman GJ. Mania during treatment of chronic hepatitis with pegylated interferon and ribavirin 1. Am J Psychiatry 2004; 161(3):429-435. |
|107.||Garcia-Pares G, Domenech C, Gil M. Psychosis induced by interferon-alpha 1. Psychosomatics 2002; 43(5):428-429. |
|108.||Monji A, Yoshida I, Tashiro K, Hayashi Y, Tashiro N. A case of persistent manic depressive illness induced by interferon-alfa in the treatment of chronic hepatitis C 1. Psychosomatics 1998; 39(6):562-564. |
|109.||Schafer M, Boetsch T, Laakmann G. Psychosis in a methadonesubstituted patient during interferon-alpha treatment of hepatitis C 1. Addiction 2000; 95(7):1101-1104. |
|110.||Thome J, Knopf U. Acute psychosis after injection of pegylated interferon alpha-2a 1. Eur Psychiatry 2003; 18(3):142-143. |
|111.||Byrne A, Byrne DG. The effect of exercise on depression, anxiety and other mood states: a review Psychosom Res 1993; 37(6):565-574. |
|112.||Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C 1. Psychosomatics 2001; 42(4):365-367. |
|113.||Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML, Dieperink E. Influence of psychiatric diagnoses on interferonalpha treatment for chronic hepatitis C in a veteran population 1. Am J Gastroenterol 2001; 96(1):157-164. |
|114.||Pariante CM, Landau S, Carpiniello B. Interferon alfainduced adverse effects in patients with a psychiatric diagnosis 1. N Engl J Med 2002; 347(2):148-149. |
|115.||Hauser P, Soler R, Reed S, Kane R, Gulati M, Khosla J et al. Prophylactic treatment of depression induced by interferon-alpha 1. Psychosomatics 2000; 41(5):439-441. |
|116.||Kraus MR, Schafer A, Al Taie O, Scheurlen M. Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression 1. J Viral Hepat 2005; 12(1):96-100. |
Yaser R Al-Huthail
Department of Psychiatry College of Medicine, King Khaled University Hospital King Saud University, Riyadh P.O.Box 7805, Riyadh-11472
Source of Support: None, Conflict of Interest: None
[Table - 1]
|This article has been cited by|
||Treatment of chronic viral hepatitis C in children and adolescents: UK experience
| ||M. Abdel-Hady,S. Bansal,S. M. Davison,M. Brown,S. A. Tizzard,S. Mulla,E. Barnes,P. Davies,G. Mieli-Vergani,D. A. Kelly |
| ||Archives of Disease in Childhood. 2014; 99(6): 505 |
|[Pubmed] | [DOI]|
||Comparison of the prevalence of psychiatric co-morbidities in hepatitis C patients and hepatitis B patients in Saudi Arabia
| ||Alhuthail, Y.R. |
| ||Saudi Journal of Gastroenterology. 2013; 19(4): 165-171 |
||NASPGHAN Practice guidelines: Diagnosis and management of hepatitis c infection in infants, children, and adolescents
| ||Mack, C.L. and Gonzalez-Peralta, R.P. and Gupta, N. and Leung, D. and Narkewicz, M.R. and Roberts, E.A. and Rosenthal, P. and Schwarz, K.B. |
| ||Journal of Pediatric Gastroenterology and Nutrition. 2012; 54(6): 838-855 |
||Prospective study of psychiatric side effects during antiviral therapy of chronic hepatitis C in an Egyptian sample
| ||Elsayed, H. and Elsayed, M. and Arafa, M. and Elbendary, M. |
| ||Middle East Current Psychiatry. 2012; 19(2): 71-77 |
||Prospective study of psychiatric side effects during antiviral therapy of chronic hepatitis C in an Egyptian sample
| ||Hanan Elsayed,Mohamed Elsayed,Mona Arafa,Mahmoud Elbendary |
| ||Middle East Current Psychiatry. 2012; 19(2): 71 |
|[Pubmed] | [DOI]|
||NASPGHAN Practice Guidelines
| ||Cara L. Mack,Regino P. Gonzalez-Peralta,Nitika Gupta,Daniel Leung,Michael R. Narkewicz,Eve A. Roberts,Philip Rosenthal,Kathleen B. Schwarz |
| ||Journal of Pediatric Gastroenterology and Nutrition. 2012; 54(6): 838 |
|[Pubmed] | [DOI]|
||Depression comorbidity in patients with chronic hepatitis C and its possible relation to treatment outcome
| ||Elshahawi, H.H. and Hussein, M.M. and Allam, E.A. |
| ||Middle East Current Psychiatry. 2011; 18(1): 23-28 |
||Management of Hepatitis C Antiviral Therapy Adverse Effects
| ||Hubert Sung, Michael Chang, Sammy Saab |
| ||Current Hepatitis Reports. 2011; 10(1): 33 |
|[VIEW] | [DOI]|
| Article Access Statistics|
| Viewed||6385 |
| Printed||148 |
| Emailed||0 |
| PDF Downloaded||543 |
| Comments ||[Add] |
| Cited by others ||8 |