Psychiatric interferons

Psychiatric adverse effects occur frequently and may include irritability, depression, and rarely, suicidal ideation. Individuals with a history of uncontrolled psychiatric disorders must weigh the risk versus benefit of treatment, as interferon may exacerbate or worsen the psychiatric condition. Patients who develop mild to moderate symptoms may require antidepressants or anxiolytics. Those with severe symptoms including suicidal ideation should have the treatment discontinued immediately.43... 

Neuropsychiatric events Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with and without a previous psychiatric disorder during peginterferon alfa-2b treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons. 

Peg Interferon Alfa 2b (PEG-Intron) [Antiviral/ Immunomodulator] WARNING Can cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disord s. Monitor pts closely Uses Rx Hep C Action Immune modulation Dose 1 mcg/kg/wk SQ 1.5 mcg/kg/wk combined w/ ribavirin Caution [C, X if used w/ ribavirin /-] w/ Hx psychiatric Contra Autoimmune H, decompensated Uvct Dz, hemoglobinopathy Disp Vials 50, 80, 120, 150 mcg/0.5 mL Redipen 50, 80,120,150 mcg/5 mL reconstitute w/ 0.7 mL w/ sterile water SE D ession, insomnia, suicidal behavior, GI upset, neutropenia, thrombocytopenia, alopecia, pruritus Interactions t Myelosuppression W/ antineoplastics t effects OF doxorubicin, theophylline t neurotox W7 vinblastine EMS See Peg Interf on Alfa-2a may cause flu-like Sxs... 

Contraindications History of autoimmune hepatitis or severe psychiatric disorders, hypersensitivity to alpha interferons... 

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline levels and increased methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. 

Interferons should be used with caution in patients with severe renal and hepatic impairment, cardiac disorders, diabetes mellitus, coagulation disorders, epilepsy, and psychiatric disorders. Interferons produce influenza-like symptoms (e.g., fever, chills, headache, myalgia, arthralgia). Other side effects include anorexia, weight loss, bone marrow depression, alopecia, and taste alteration. 

The clinical features, management, and prognosis of psychiatric symptoms in patients with chronic hepatitis C have been reviewed using data from 943 patients treated with interferon alfa (85%) or interferon beta (15%) for 24 weeks (333). Interferon-induced psychiatric symptoms were identified in 40 patients (4.2%) of those referred for psychiatric examination. They were classified in three groups according to the clinical profile 13 cases of generalized anxiety disorder (group A), 21 cases of... 

Psychiatric symptoms have been prospectively examined in 104 patients with chronic hepatitis C, of whom 84 received interferon alfa-2b 15 MU/week and 20 were not treated (338). The incidence of clinically relevant scores for depression, anxiety, or anger/hostility increased from 23% of patients before interferon alfa to 58% of patients during treatment, and returned to 30% and 19% of patients 4 weeks and 6 months after withdrawal respectively. In contrast, there were no significant changes in the reference group. There were also significantly higher scores in the 40 patients who took concomitant ribavirin. Six patients successfully received antidepressant therapy, but withdrawal because of untreatable psychiatric symptoms was needed in 8.3% of patients, i.e. about half of the patients who had interferon-induced major depressive disorders. 

The most typical psychiatric symptoms reported by patients taking interferon alfa are depressive symptoms, at rates of 10-40% in most studies (339-342). In four clinical studies in a total of 210 patients with chronic hepatitis C, the rate of major depressive disorders during interferon alfa treatment was 23-41% (343-346). 

As regular psychiatric assessment is not always possible, the identification of easily detectable predictive factors of severe psychiatric disorders may help select which patients should undergo close psychiatric assessment. In 71 patients treated with interferon alfa alone or combined with ribavirin for chronic hepatitis C, female sex, scores on the MADRS at 4 months of treatment, sleep disorders, and prior antidepressant use were independent risk factors of suicidal behavior or depression (349). This study also suggested that prolonged follow-up is required, as 8% of patients still had suicidal behavior 6 months after the end of treatment. 

Although psychiatric manifestations usually appear during interferon alfa therapy, delayed reactions can occur. 

A 37-year-old man without a previous psychiatric history developed major depression with severe psychotic features within days after the discontinuation of a 1-year course of interferon alfa-2b (353). 

Several mechanisms involved in the pathogenesis of interferon alfa-induced psychiatric adverse effects have been hypothesized (Loftis 175), but the mechanisms by which interferon alfa enters the brain to produce neurotransmitter changes are unclear. In a prospective study in 48 patients who received adjuvant interferon alfa for malignant melanoma there was a positive correlation between the increase in serum concentration of soluble ICAM-1 and depression scores the authors suggested that induction of soluble ICAM-1 by interferon alfa increased the permeability of the blood-brain barrier, allowing the drug to enter the brain more readily (358). 

The relation between interferon alfa-induced depressive disorders and the viral response to treatment has been examined in 39 patients with hepatitis C infection and no history of active psychiatric disease (359). After treatment with interferon alfa-2b and ribavirin for 6-12 months, 13 developed major depressive disorders requiring treatment with citalopram. The end-of-treatment response rates and sustained viral response rates were significantly greater in patients who developed a major depressive disorder than in those who did not (62% versus 27% and 39% versus 12% respectively). Despite the small sample, these results suggest that interferon alfa-induced depression occurs at doses or concentrations that... 

A number of other factors, including genetic or biological factors, that are possibly associated with the development of psychiatric disorders, have been explored. In a retrospective study of 110 patients with chronic hepatitis C, those with the apolipoprotein E e4 allele, the inheritance of which may be associated with several neuropsychiatric outcomes, were more likely than those without this allele to have psychiatric referrals and neuropsychiatric symptoms, in particular irritability, anger, anxiety, or other mood symptoms, during interferon alfa treatment... 

The occurrence of psychiatric disorders has been prospectively investigated in 63 patients who received a 6-month course of interferon alfa (9 MU/week) for hepatitis C (379). All were assessed at baseline with the Structured Clinical Interview for DSM-III-R (SCID) and monitored monthly with the Hopkins Symptoms Checklist (SCL-90). Most had a history of alcohol or polysubstance dependence, and 12 had a lifetime diagnosis of major depression. There were no significant changes in the SCL-90 scores during the 6-month period of survey in the 49 patients who completed the study, even in those who had a lifetime history of major depression. At 6 months, there was probable minor depression in eight patients and major depression in one none had attempted suicide. 

In a prospective study, 50 patients with chronic hepatitis B or C who received 18-30 MU/week of natural or recombinant interferon alfa were followed for 12 months (380). The SCID before starting interferon alfa identified 16 patients with a current psychiatric diagnosis and eight with a previous psychiatric disorder 26 patients free of any psychiatric history constituted the control group. Psychiatric manifestations during treatment occurred in... 

Of 33 patients with chronic hepatitis C treated with interferon alfa, 9 MU/week for 3-12 months, prospectively evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) before and after 12 weeks of treatment, eight developed depressive symptoms, of whom four had major depression without a previous psychiatric history (381). All four recovered after treatment with antidepressants. This study confirmed that a high baseline MADRS is significantly associated with the occurrence of depressive symptoms. 

Cognitive defects, depression, and mania can occur in patients taking interferon alfa. Interferon alfa-induced psychiatric adverse effects and their recommended management have been comprehensively reviewed (383,384,385). 

Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F, Grunze H, Lieb K. Interferon alpha (IFNalpha) and psychiatric syndromes a review. Prog Neuropsychopharmacol Biol Psychiatry 2002 26(4) 731-46. 

Hosoda S, Takimura H, Shibayama M, Kanamura H, Ikeda K, Kumada H. Psychiatric symptoms related to interferon therapy for chronic hepatitis C clinical features and prognosis. Psychiatry Clin Neurosci 2000 54(5) 565-72. 

Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry 2003 64 708-14. 

Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, Rustgi V, Jones EA. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987 147(9) 1577-80. 

Prasad S, Waters B, Hill PB, et al. Psychiatric side effects of interferon alpha-2b in patients treated for hepatitis C. Clin Res 1992 40 840A. 

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. Lancet 1987 2(8569) 1175-8. 

Pariante CM, Landau S, Carpiniello BCagliari Group. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis. N Engl J Med 2002 347(2) 148-9. 

Van Thiel DH, Friedlander L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferon-alpha can be used successfully in patients with hepatitis C virus-positive chronic hepatitis who have a psychiatric illness. Eur J Gastroenterol Hepatol 1995 7(2) 165-8. 

Maes M, Bonaccorso S. Lower activities of serum peptidases predict higher depressive and anxiety levels following interferon-alpha-based immunotherapy in patients with hepatitis C. Acta Psychiatr Scand 2004 109 126-31. 

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. J Gastroenterol Hepatol 2000 15(3) 300-3. 

Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, Heldwein W, Soyka M, Grunze H, Koenig A, Loeschke K. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003 37 443-51. 

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