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Mood, cognition and EEG changes during interferon α (alpha-IFN) treatment for chronic hepatitis C
Journal of Affective Disorders 84 (2005) 93 – 98 www.elsevier.com/locate/jad
Brief report
Mood, cognition and EEG changes during interferon a (alpha-IFN) treatment for chronic hepatitis C Piero Amodioa, Enrico N. De Tonia, Luisa Cavallettoa, Daniela Mapellib, Elisabetta Bernardinelloa, Franco Del Piccoloa, Cristina Bergamellic, Raffaella Costanzoc, Federica Bergamaschic, Stefano Zanone Pomac, Liliana Chemelloa,*, Angelo Gattaa,b,c,d, Giulia Perinic a
Dipartimento di Medicina Clinica e Sperimentale, Clinica Medica 5, Policlinico Universitario, via Giustiniani, 2, 35128, Padova, Italy b Dipartimento di Psicologia Generale, CIRMANMEC, Universita` di Padova, Italy c Dipartimento di Neuroscienze, CIRMANMEC, Universita` di Padova, Italy d Regional Project on Chronic Liver Disease, Regione Veneto, Italy Received 6 July 2004; received in revised form 27 September 2004; accepted 27 September 2004
Abstract Background: This study is aim to investigate concurrent long-term psychiatric, cognitive and neurophysiological measures of aIFN neurotoxicity in the treatment of chronic viral hepatitis. Methods: Twenty patients with HCV hepatitis were enrolled while treated with a-IFN (3–6 MU t.i.w. for 6–12 months). Neurotoxicity was evaluated by psychiatric [Hamilton Depression Rating Scale (HAM-D), Hamilton Scale for Anxiety (HAM-A), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI-Y)], complete cognitive and neurophysiological assessments (EEG spectral analysis, P300). Patients were assessed at baseline (t 0), 2 (t 1) and 6 months (t 2) since the beginning of therapy. Results: Depression scores significantly increased (HAM-D: t 0=4.4F2.6; t 1=8.9F3.9, pb0.001; and t 2=7.7F3.8, pb0.001). A concurrent increase was shown also for anxiety (HAM-A: t 0=6.0F3.2; t 1=9.6F4.5, pb0.005; and t 2=9.1F4.5, pb0.005). Significant neurophysiological effects were also detected: increase of a power ( pb0.05) in frontal derivations, reduction of the mean dominant frequency ( pb0.005) and increase of theta power ( pb0.05) in parietal derivations. In contrast, no significant cognitive changes occurred. Limitations: The study was performed on a relative small sample of patients mainly with observational intentions. Biological data (e.g. blood cytokines samples) are not available: they could have given useful information about biological mechanisms related to the alterations observed.
* Corresponding author. Tel.: +39 049 821 8679. E-mail address: [email protected] (L. Chemello). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.09.004
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Conclusions: a-IFN treatment caused a time-dependent induction of symptoms of mild depression, concurrent anxiety and EEG changes. These psychiatric and neurophysiological changes can better explain the pharmacological profile of a-IFN and could help to address research on at risk population and, particularly, during pegylated-IFN therapy. D 2004 Elsevier B.V. All rights reserved. Keywords: a-interferon; Depression; EEG; Cognition; Chronic hepatitis C
1. Introduction Interferon a (a-IFN) is a first-choice-treatment of chronic hepatitis C (Chemello et al., 1995). However, it is often hampered by adverse reactions, among which neuropsychiatric ones are frequent and impairing (Dieperink et al., 2000; Trask et al., 2000). Depression incidences range between 0% and 38% (Mulder et al., 2000; Otsubo et al., 1999; Quesada et al., 1986): this variability may be due to lack of standardized methods of investigation, severity of underlying disease, dose of a-IFN administered and reporting of somatic complaints as depressive symptoms. Few studies up to date dealt with the cognitive effects of a-IFN in patients with hepatitis, mostly relying on rather insensitive tests such as the Mini Mental State Examination (Kamei et al., 2002; Valentine et al., 1998; Smith et al., 1988). Only one study on long-term neurophysiological findings of a-IFN induced encephalopathy is available (Kamei et al., 2002): this approach could provide objective measures of CNS involvement, similarly to neurophysiological studies of cognitive decline and metabolic encephalopathies (Barrett, 2000; Amodio et al., 1999a,b). We designed a study aiming to investigate the psychiatric, cognitive and neurophysiological effects of a-IFN in patients with chronic hepatitis C at different time-points: before the beginning (t 0) and after 2 (t 1) and 6 months (t 2) from the start of therapy.
2. Methods
were eligible if they have had high serum ALT level on at least two examinations during the last 2 months. The exclusion criteria were the presence of HIV and/or HBV co-infections, autoimmune diseases, liver cirrhosis with a Child-Pugh score N5. Further criteria were: active psychiatric disorders, current psychotropic drug prescription and/or alcohol or substance abuse (cessationb6 months). The patients were treated for 6 or 12 months and with a fixed dose of 3 or 6 MU of a-IFN thrice weekly depending on viral genotype. All patients received also a weight-adapted ribavirin dose (15 mg/kg/day). Safety haematological and biochemical analysis were monitored during the treatment. The study was approved by the local Ethical Committee; all patients gave their consent to the study. 2.2. Psychiatric evaluation Mini International Neuropsychiatric Interview (MINI) (Sheehan and Lecrubier, 1994) was performed during screening visit to exclude the presence of active psychiatric disorder and/or alcohol or substance abuse. At each time-point, all patients underwent a psychiatric evaluation including the 17item version Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960), the Hamilton Scale for Anxiety (HAM-A) (Hamilton, 1959) and two selfadministered scales: the Beck Depression Inventory (BDI) (Beck and Word, 1961) and the State and Trait Anxiety Inventory (STAI-Y) (Spielberg, 1983). Structured and semi-structured interviews (MINI, HAM-D and HAM-A) were all administered by a psychiatrist with 4-year clinical experience.
2.1. Patients 2.3. Electrophysiological assessment Twenty outpatients aged 18–60, with diagnosis of chronic viral hepatitis based on markers positivity (antiHCV-ELISA/HCVRNA-PCR) and on liver biopsy,
Spontaneous closed eye EEG-activity was recorded by digital EEG equipment (System 98, Micromed,
P. Amodio et al. / Journal of Affective Disorders 84 (2005) 93–98
Italy) (Amodio et al., 1999a,b). Spectral analysis (frequency range: 1–26.5 Hz) was carried out on frontal (F3–F4) and parietal (P3–P4) derivations. The variables considered were the mean dominant frequency (MDF) and the relative spectral power of u, y, a and h bands. Auditory P300 evoked potentials were elicited by the standard active odd-ball paradigm. Two hundred stimuli (80 dB signal tones) were administered for each session (frequent and rare tones: 80% and 20%, respectively). Trials in which the counting error was more than five were rejected. The responses recorded from Cz electrode were considered for the analysis. Latency and amplitude were considered abnormal if they were beyond mean+2 S.D. 2.4. Neuropsychological evaluation At each time-point, all patients underwent a neuropsychological evaluation based on paper and pencil tests standardized in Italy (Mondini et al., 2003). The tests evaluate psychomotor speed, arousal, memory, attention, perception, lexical access, visual-spatial abilities and executive functions. They are: digit span test (Wechsler, 1945), trial making test (TMT) (Reitan, 1958), drawing copy test, interference-task test (Belville et al., 1996; Peterson and Peterson, 1959), memory logical story, overlapping figures test (Rey and Benton, 1991), verbal fluency test (Benton and Hamsher, 1976), clock drawing test, abstraction test, cognitive estimation test (Sternberg, 1969), scan test (Amodio et al., 1999b, 1998; Sternberg, 1969), stroop test (Shallice and Evans, 1978; Stroop, 1935), stroop interference and simple reaction time. All the tests were expressed by age and education adjusted Z scores, with the exception of simple reaction times and the interference in Stroop test that were expressed in milliseconds.
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3. Results Ten (50%) out of 20 patients did not respond to therapy (still positive to HCV-RNA in blood at the end of treatment). None needed dose reduction or therapy withdrawal due to neuropsychiatric effects. 3.1. Psychiatric evaluation All patients completed the three assessments. Patients showed a significant increase in HAM-D scores from t 0 to t 1 (t 0=4.4F2.6, t 1=8.9F3.9; pb0.001) and similarly from t 0 to t 2 (t 2=7.7F3.8, pb0.001) (Fig. 1). A concurrent increase was shown also in HAM-A scores (t 0=6.0F3.2, t 1=9.6F4.5, pb0.005 and t 2=9.1F4.5, pb0.005). In contrast, no changes were detectable in the self administered questionnaires for depression and anxiety. No episode of major depression occurred and none of the patients needed antidepressant/anxiolytics therapy. 3.2. Neurophysiological assessment All patients completed baseline and second-month evaluations and two cases did not attend at sixth month visit. No patients had EEG alterations at baseline evaluation. After 6 months but not after 2 months, a relative power significantly increased in frontal derivations (t 0=32.4F7.8% vs. t 2=36.8F7.7%, pb0.05) (Fig. 2), while in parietal derivations MDF decreased
2.5. Statistics Results were expressed as meanFS.E., unless otherwise specified. Changes in psychometric scores and in cognitive tests performances between baseline and any of the subsequent evaluations (t 1 and t 2) were compared using the Wilcoxon test. Repeated measures ANOVA analysis was performed for EEG values recorded during the three occasions of assessment (t 0, t 1 and t 2).
Fig. 1. Graphical representation of changes of the Hamilton depression scale during a-IFN treatment (baseline, t 0, after 2 and 6 months of therapy, t 1 and t 2, respectively).
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Fig. 2. Alpha relative power increase in frontal derivations at baseline (t 0) and after 6 months (t 2) of a-IFN treatment.
(t 0=10.8F1.3 vs. t 2=10.2F0.9 Hz, pb0.005) due to an increase of relative theta power (t 0=14.3F7.0% vs. t 2=17.1F8.9%, pb0.05). No patient had baseline alterations either of P300 latency or amplitude. These parameters did not significantly change during treatment. 3.3. Cognitive evaluation All patients completed the three assessments. No statistical differences emerged between baseline and subsequent time-points evaluations in any of the tests performed.
4. Discussion Consistently with previous studies (Dieperink et al., 2000; Valentine et al., 1998), a-IFN treatment brought about mild symptoms of depression and anxiety detected by HAM-D and HAM-A in patients without psychiatric disorders. The detection of mild depression in 45% of the sample after 6 months of therapy is comparable to the values present in literature (Kraus et al., 2003; Dieperink et al., 2003; Otsubo et al., 1999; Pariante et al., 1999; Hunt et al., 1997).
Our study indicates an higher sensitivity of HAMD and HAM-A compared to BDI and STAI-Y. Lower sensitivity of self-administered scales may be explained by the influence of non-psychiatric side effects in the clinical interview, or on the contrary by a low perception of mild psychiatric symptoms in patients with medical illness (von Ammon, 1995). However, BDI scores showed a slight increase, even not significant (t 0=6.3F5.5, t 1=8.4F5.7, p=0.07 and t 2=9.5F8.2, p=0.08). In a paper by Dieperink et al. (2003), it has been reported as good predictor for the development of a-IFN induced depression. In contrast, STAI-Y did not show any detecting power, resulting to be useless in this type of investigations. A reduction of EEG mean dominant frequency in parietal derivations and a frontalization of a band activities was detected by quantified EEG analysis: this proves a pharmacological effect of a-IFN on SNC with data comparable to those by Kamei et al. (2002). It is noteworthy that EEG changes became significant after 6 months of treatment while psychiatric ones showed a different trend increasing already after 2 months. This suggests the presence of different timings or, alternatively of separate mechanisms in the neurobiological activity of cytokines. Overall, the finding that cognitive tests did not show any worsening during a-IFN therapy contradicts some data (Pavol et al., 1995), but is in line with other works: in the one by Exton et al. (2002), h-IFN in healthy volunteers did not affect cognition, at least after acute administration and in a study on cancer patients a-IFN showed slighter worsening than interleukin-2 (Capuron et al., 2001). Even if important suggestions have been pointed out, this study is limited by the relative small sample. A comparative investigation with pegylated interferons is needed considering that they have become the current therapy for chronic hepatitis C (Manns et al., 2001). Regarding the assessments proposed, we think that psychiatric effects (in particular depression) deserve more attention for their clinical implications (Kraus et al., 2002; Hauser et al., 2002). Other factors that could increase the risk of depression, such as a personal or family history of depression or substance abuse need to be better clarified. (Shaefer et al., 2003; Hensley et al., 2000; Capuron and Ravaud, 1999; Fattovich et al., 1996). Moreover, the interest on the putative explication of the underlying biological
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mechanisms of depression caused by a-IFN (Capuron et al., 2003; Maes et al., 2001) can provide important suggestions for the research in primary depression.
Acknowledgements This study was in part supported by a Regional Project on Chronic Liver Disease entitled: Programma Regionale: Miglioramento della Sorveglianza e Controllo delle Epatopatie Croniche Complicanti Infezione da HCV: Cirrosi Epatica ed Epatocarcinoma, Assessorato Sanita`-Sociale, Direzione per la Prevenzione-Servizio Epidemiologia e Sanita` Pubblica, Regione Veneto, Italy. We thank in particular Dr. F. Toniolo, Dr. G.C. Niero and Dr. A. Ferro for helpful and contribution of the project.
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Chemello, L., Cavalletto, L., Bernardinello, E., et al., 1995. The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. J. Hepatol. 23 (Suppl. 2), 8 – 12. 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. Dieperink, E., Ho, S.B., Thuras, P., Willenbring, M.L., 2003. A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 44, 104 – 112. Exton, M.S., Baase, J., Pithan, V., Goebel, M.U., Schedlowski, M., 2002. Neuropsychological performance and mood states following acute interferon-beta-1b administration in healthy males. Neuropsychobiology 45, 199 – 204. Fattovich, G., Giustina, G., Favarato, S., et al., 1996. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J. Hepatol. 24, 38 – 47. Hamilton, M., 1959. The assessment of anxiety states by rating. Br. J. Med. Psychol. 32, 50 – 55. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56 – 62. Hauser, P., Khosla, J., Aurora, H., Laurin, J., Kling, M.A., Hill, J., et al., 2002. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol. Psychiatry 7, 942 – 947. Hensley, M.L., Peterson, B., Silver, R.T., et al., 2000. Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J. Clin. Oncol. 18, 1301 – 1308. Hunt, C.M., Dominitz, J.A., Bute, B.P., et al., 1997. Effect of interferon-alpha treatment of chronic hepatitis C on healthrelated quality of life. Dig. Dis. Sci. 42, 2482 – 2486. Kamei, S., Sakai, T., Matsuura, M., et al., 2002. Alterations of quantitative EEG and mini-mental state examination in interferon-alpha-treated hepatitis C. Eur. Neurol. 48, 102 – 107. Kraus, M.R., Shaefer, A., Faller, H., Csef, H., Scheurlen, M., 2002. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment. Pharmacol. Ther. 16, 1091 – 1099. Kraus, M.R., Sch7fer, A., Faller, H., Csef, H., Scheurlen, M., 2003. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J. Clin. Psychiatry 64, 708 – 714. Maes, M., Bonaccorso, S., Marino, V., Puzella, A., Pasquini, M., Biondi, M., Arturi, M., Almerighi, C., Meltzer, H., 2001. Treatment with interferon-alpha (alpha-IFN) of hepatitis induces lower serum dipeptidyl peptidase IV activity, which is related to alpha-IFN induced depressive and anxiety symptoms and immune activation. Mol. Psychiatry 6, 475 – 480. Manns, M.P., McHutchinson, J.G., Gordon, S.C., et al., 2001. Peginterferon alpha 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958 – 965. Mondini, S., Mapelli, D., Vestri, A., et al., 2003. Esame Neuropsicologico Breve (ENB). Raffaello Cortina, Padova. Mulder, R.T., Ang, M., Chapman, B., et al., 2000. Interferon treatment is not associated with a worsening of psychiatric
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symptoms in patients with hepatitis C. J. Gastroenterol. Hepatol. 15, 300 – 303. Otsubo, T., 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. Pariante, C.M., Orru, M.G., Baita, A., et al., 1999. Treatment with interferon-alpha in patients with chronic hepatitis and mood or anxiety disorders. Lancet 354, 131 – 132. Pavol, M.A., Meyers, C.A., Rexer, J.L., et al., 1995. Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 45, 947 – 950. Peterson, L.R., Peterson, M.J., 1959. Short-term retention of individual verbal items. J. Exp. Psychol. 68, 193 – 198. Quesada, J.R., Talpaz, M., Rios, A., et al., 1986. Clinical toxicity of interferons in cancer patients: a review. J. Clin. Oncol. 4, 234 – 243. Reitan, R.M., 1958. Validity of the trail making test as an indicator of organic brain damage. Percept. Mot. Skills 8, 271 – 276. Rey, A., Benton, A.L., 1991. Examen de afasia multilingue. AJA Associates, Iowa City, IA. Shaefer, M., Schmidt, F., Folwaczny, C., Lorenz, R., Martin, G., Schindlbeck, N., et al., 2003. Adherence and mental side effects during hepatitis C treatment with interferon alpha and ribavirin in psychiatric risk groups. Hepatology 37, 443 – 451.
Shallice, T., Evans, M.E., 1978. The involvement of the frontal lobes in cognitive estimation. Cortex 14, 294 – 303. Sheehan, D.V., Lecrubier, Y. 1994. Mini International Neuropsychiatric Interview (M.I.N.I.). University of South Florida Institute for Research in Psychiatry, Tampa, Florida and INSERM - Hopital de la Salpe´trie`re, Paris, France. Smith, A., Tyrrell, D., Coyle, K., et al., 1988. Effects of interferon alpha on performance in man: a preliminary report. Psychopharmacology 96, 414 – 416. Spielberg, C.D., 1983. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. Revised edition. Sternberg, S., 1969. Memory-scanning: mental processes revealed by reaction-time experiments. Am. Sci. 57, 421 – 457. Stroop, J.R., 1935. Studies of interference in serial verbal reactions. J. Exp. Psychol. 18, 643 – 662. Trask, P.C., Esper, P., Riba, M., et al., 2000. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J. Clin. Oncol. 18, 2316 – 2326. Valentine, A.D., Meyers, C.A., Kling, M.A., et al., 1998. Mood and cognitive side effects of interferon-alpha therapy. Semin. Oncol. 25, 39 – 47. von Ammon, C.S., 1995. Depression in the medically ill. Critical issues in diagnostic assessment. Psychosomatics 36, 48 – 59. Wechsler, D., 1945. A standardized memory scale for clinical use. J. Psychol. 19, 87 – 95.
Brief report
Mood, cognition and EEG changes during interferon a (alpha-IFN) treatment for chronic hepatitis C Piero Amodioa, Enrico N. De Tonia, Luisa Cavallettoa, Daniela Mapellib, Elisabetta Bernardinelloa, Franco Del Piccoloa, Cristina Bergamellic, Raffaella Costanzoc, Federica Bergamaschic, Stefano Zanone Pomac, Liliana Chemelloa,*, Angelo Gattaa,b,c,d, Giulia Perinic a
Dipartimento di Medicina Clinica e Sperimentale, Clinica Medica 5, Policlinico Universitario, via Giustiniani, 2, 35128, Padova, Italy b Dipartimento di Psicologia Generale, CIRMANMEC, Universita` di Padova, Italy c Dipartimento di Neuroscienze, CIRMANMEC, Universita` di Padova, Italy d Regional Project on Chronic Liver Disease, Regione Veneto, Italy Received 6 July 2004; received in revised form 27 September 2004; accepted 27 September 2004
Abstract Background: This study is aim to investigate concurrent long-term psychiatric, cognitive and neurophysiological measures of aIFN neurotoxicity in the treatment of chronic viral hepatitis. Methods: Twenty patients with HCV hepatitis were enrolled while treated with a-IFN (3–6 MU t.i.w. for 6–12 months). Neurotoxicity was evaluated by psychiatric [Hamilton Depression Rating Scale (HAM-D), Hamilton Scale for Anxiety (HAM-A), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI-Y)], complete cognitive and neurophysiological assessments (EEG spectral analysis, P300). Patients were assessed at baseline (t 0), 2 (t 1) and 6 months (t 2) since the beginning of therapy. Results: Depression scores significantly increased (HAM-D: t 0=4.4F2.6; t 1=8.9F3.9, pb0.001; and t 2=7.7F3.8, pb0.001). A concurrent increase was shown also for anxiety (HAM-A: t 0=6.0F3.2; t 1=9.6F4.5, pb0.005; and t 2=9.1F4.5, pb0.005). Significant neurophysiological effects were also detected: increase of a power ( pb0.05) in frontal derivations, reduction of the mean dominant frequency ( pb0.005) and increase of theta power ( pb0.05) in parietal derivations. In contrast, no significant cognitive changes occurred. Limitations: The study was performed on a relative small sample of patients mainly with observational intentions. Biological data (e.g. blood cytokines samples) are not available: they could have given useful information about biological mechanisms related to the alterations observed.
* Corresponding author. Tel.: +39 049 821 8679. E-mail address: [email protected] (L. Chemello). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.09.004
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P. Amodio et al. / Journal of Affective Disorders 84 (2005) 93–98
Conclusions: a-IFN treatment caused a time-dependent induction of symptoms of mild depression, concurrent anxiety and EEG changes. These psychiatric and neurophysiological changes can better explain the pharmacological profile of a-IFN and could help to address research on at risk population and, particularly, during pegylated-IFN therapy. D 2004 Elsevier B.V. All rights reserved. Keywords: a-interferon; Depression; EEG; Cognition; Chronic hepatitis C
1. Introduction Interferon a (a-IFN) is a first-choice-treatment of chronic hepatitis C (Chemello et al., 1995). However, it is often hampered by adverse reactions, among which neuropsychiatric ones are frequent and impairing (Dieperink et al., 2000; Trask et al., 2000). Depression incidences range between 0% and 38% (Mulder et al., 2000; Otsubo et al., 1999; Quesada et al., 1986): this variability may be due to lack of standardized methods of investigation, severity of underlying disease, dose of a-IFN administered and reporting of somatic complaints as depressive symptoms. Few studies up to date dealt with the cognitive effects of a-IFN in patients with hepatitis, mostly relying on rather insensitive tests such as the Mini Mental State Examination (Kamei et al., 2002; Valentine et al., 1998; Smith et al., 1988). Only one study on long-term neurophysiological findings of a-IFN induced encephalopathy is available (Kamei et al., 2002): this approach could provide objective measures of CNS involvement, similarly to neurophysiological studies of cognitive decline and metabolic encephalopathies (Barrett, 2000; Amodio et al., 1999a,b). We designed a study aiming to investigate the psychiatric, cognitive and neurophysiological effects of a-IFN in patients with chronic hepatitis C at different time-points: before the beginning (t 0) and after 2 (t 1) and 6 months (t 2) from the start of therapy.
2. Methods
were eligible if they have had high serum ALT level on at least two examinations during the last 2 months. The exclusion criteria were the presence of HIV and/or HBV co-infections, autoimmune diseases, liver cirrhosis with a Child-Pugh score N5. Further criteria were: active psychiatric disorders, current psychotropic drug prescription and/or alcohol or substance abuse (cessationb6 months). The patients were treated for 6 or 12 months and with a fixed dose of 3 or 6 MU of a-IFN thrice weekly depending on viral genotype. All patients received also a weight-adapted ribavirin dose (15 mg/kg/day). Safety haematological and biochemical analysis were monitored during the treatment. The study was approved by the local Ethical Committee; all patients gave their consent to the study. 2.2. Psychiatric evaluation Mini International Neuropsychiatric Interview (MINI) (Sheehan and Lecrubier, 1994) was performed during screening visit to exclude the presence of active psychiatric disorder and/or alcohol or substance abuse. At each time-point, all patients underwent a psychiatric evaluation including the 17item version Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960), the Hamilton Scale for Anxiety (HAM-A) (Hamilton, 1959) and two selfadministered scales: the Beck Depression Inventory (BDI) (Beck and Word, 1961) and the State and Trait Anxiety Inventory (STAI-Y) (Spielberg, 1983). Structured and semi-structured interviews (MINI, HAM-D and HAM-A) were all administered by a psychiatrist with 4-year clinical experience.
2.1. Patients 2.3. Electrophysiological assessment Twenty outpatients aged 18–60, with diagnosis of chronic viral hepatitis based on markers positivity (antiHCV-ELISA/HCVRNA-PCR) and on liver biopsy,
Spontaneous closed eye EEG-activity was recorded by digital EEG equipment (System 98, Micromed,
P. Amodio et al. / Journal of Affective Disorders 84 (2005) 93–98
Italy) (Amodio et al., 1999a,b). Spectral analysis (frequency range: 1–26.5 Hz) was carried out on frontal (F3–F4) and parietal (P3–P4) derivations. The variables considered were the mean dominant frequency (MDF) and the relative spectral power of u, y, a and h bands. Auditory P300 evoked potentials were elicited by the standard active odd-ball paradigm. Two hundred stimuli (80 dB signal tones) were administered for each session (frequent and rare tones: 80% and 20%, respectively). Trials in which the counting error was more than five were rejected. The responses recorded from Cz electrode were considered for the analysis. Latency and amplitude were considered abnormal if they were beyond mean+2 S.D. 2.4. Neuropsychological evaluation At each time-point, all patients underwent a neuropsychological evaluation based on paper and pencil tests standardized in Italy (Mondini et al., 2003). The tests evaluate psychomotor speed, arousal, memory, attention, perception, lexical access, visual-spatial abilities and executive functions. They are: digit span test (Wechsler, 1945), trial making test (TMT) (Reitan, 1958), drawing copy test, interference-task test (Belville et al., 1996; Peterson and Peterson, 1959), memory logical story, overlapping figures test (Rey and Benton, 1991), verbal fluency test (Benton and Hamsher, 1976), clock drawing test, abstraction test, cognitive estimation test (Sternberg, 1969), scan test (Amodio et al., 1999b, 1998; Sternberg, 1969), stroop test (Shallice and Evans, 1978; Stroop, 1935), stroop interference and simple reaction time. All the tests were expressed by age and education adjusted Z scores, with the exception of simple reaction times and the interference in Stroop test that were expressed in milliseconds.
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3. Results Ten (50%) out of 20 patients did not respond to therapy (still positive to HCV-RNA in blood at the end of treatment). None needed dose reduction or therapy withdrawal due to neuropsychiatric effects. 3.1. Psychiatric evaluation All patients completed the three assessments. Patients showed a significant increase in HAM-D scores from t 0 to t 1 (t 0=4.4F2.6, t 1=8.9F3.9; pb0.001) and similarly from t 0 to t 2 (t 2=7.7F3.8, pb0.001) (Fig. 1). A concurrent increase was shown also in HAM-A scores (t 0=6.0F3.2, t 1=9.6F4.5, pb0.005 and t 2=9.1F4.5, pb0.005). In contrast, no changes were detectable in the self administered questionnaires for depression and anxiety. No episode of major depression occurred and none of the patients needed antidepressant/anxiolytics therapy. 3.2. Neurophysiological assessment All patients completed baseline and second-month evaluations and two cases did not attend at sixth month visit. No patients had EEG alterations at baseline evaluation. After 6 months but not after 2 months, a relative power significantly increased in frontal derivations (t 0=32.4F7.8% vs. t 2=36.8F7.7%, pb0.05) (Fig. 2), while in parietal derivations MDF decreased
2.5. Statistics Results were expressed as meanFS.E., unless otherwise specified. Changes in psychometric scores and in cognitive tests performances between baseline and any of the subsequent evaluations (t 1 and t 2) were compared using the Wilcoxon test. Repeated measures ANOVA analysis was performed for EEG values recorded during the three occasions of assessment (t 0, t 1 and t 2).
Fig. 1. Graphical representation of changes of the Hamilton depression scale during a-IFN treatment (baseline, t 0, after 2 and 6 months of therapy, t 1 and t 2, respectively).
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Fig. 2. Alpha relative power increase in frontal derivations at baseline (t 0) and after 6 months (t 2) of a-IFN treatment.
(t 0=10.8F1.3 vs. t 2=10.2F0.9 Hz, pb0.005) due to an increase of relative theta power (t 0=14.3F7.0% vs. t 2=17.1F8.9%, pb0.05). No patient had baseline alterations either of P300 latency or amplitude. These parameters did not significantly change during treatment. 3.3. Cognitive evaluation All patients completed the three assessments. No statistical differences emerged between baseline and subsequent time-points evaluations in any of the tests performed.
4. Discussion Consistently with previous studies (Dieperink et al., 2000; Valentine et al., 1998), a-IFN treatment brought about mild symptoms of depression and anxiety detected by HAM-D and HAM-A in patients without psychiatric disorders. The detection of mild depression in 45% of the sample after 6 months of therapy is comparable to the values present in literature (Kraus et al., 2003; Dieperink et al., 2003; Otsubo et al., 1999; Pariante et al., 1999; Hunt et al., 1997).
Our study indicates an higher sensitivity of HAMD and HAM-A compared to BDI and STAI-Y. Lower sensitivity of self-administered scales may be explained by the influence of non-psychiatric side effects in the clinical interview, or on the contrary by a low perception of mild psychiatric symptoms in patients with medical illness (von Ammon, 1995). However, BDI scores showed a slight increase, even not significant (t 0=6.3F5.5, t 1=8.4F5.7, p=0.07 and t 2=9.5F8.2, p=0.08). In a paper by Dieperink et al. (2003), it has been reported as good predictor for the development of a-IFN induced depression. In contrast, STAI-Y did not show any detecting power, resulting to be useless in this type of investigations. A reduction of EEG mean dominant frequency in parietal derivations and a frontalization of a band activities was detected by quantified EEG analysis: this proves a pharmacological effect of a-IFN on SNC with data comparable to those by Kamei et al. (2002). It is noteworthy that EEG changes became significant after 6 months of treatment while psychiatric ones showed a different trend increasing already after 2 months. This suggests the presence of different timings or, alternatively of separate mechanisms in the neurobiological activity of cytokines. Overall, the finding that cognitive tests did not show any worsening during a-IFN therapy contradicts some data (Pavol et al., 1995), but is in line with other works: in the one by Exton et al. (2002), h-IFN in healthy volunteers did not affect cognition, at least after acute administration and in a study on cancer patients a-IFN showed slighter worsening than interleukin-2 (Capuron et al., 2001). Even if important suggestions have been pointed out, this study is limited by the relative small sample. A comparative investigation with pegylated interferons is needed considering that they have become the current therapy for chronic hepatitis C (Manns et al., 2001). Regarding the assessments proposed, we think that psychiatric effects (in particular depression) deserve more attention for their clinical implications (Kraus et al., 2002; Hauser et al., 2002). Other factors that could increase the risk of depression, such as a personal or family history of depression or substance abuse need to be better clarified. (Shaefer et al., 2003; Hensley et al., 2000; Capuron and Ravaud, 1999; Fattovich et al., 1996). Moreover, the interest on the putative explication of the underlying biological
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mechanisms of depression caused by a-IFN (Capuron et al., 2003; Maes et al., 2001) can provide important suggestions for the research in primary depression.
Acknowledgements This study was in part supported by a Regional Project on Chronic Liver Disease entitled: Programma Regionale: Miglioramento della Sorveglianza e Controllo delle Epatopatie Croniche Complicanti Infezione da HCV: Cirrosi Epatica ed Epatocarcinoma, Assessorato Sanita`-Sociale, Direzione per la Prevenzione-Servizio Epidemiologia e Sanita` Pubblica, Regione Veneto, Italy. We thank in particular Dr. F. Toniolo, Dr. G.C. Niero and Dr. A. Ferro for helpful and contribution of the project.
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