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        Platelet serotonin (5-HT) levels in interferon-treated patients
              with hepatitis C and its possible association with
                        interferon-induced depression
   Arne Schäfer1,*, Michael Scheurlen1, Jochen Seufert2, Christian Keicher1, Benedikt Weißbrich3,
                                 Peter Rieger4, Michael R. Kraus1,4
       1
        Medizinische Klinik und Poliklinik II, Department of Gastroenterology, University of Würzburg, Klinikstr. 6-8, D-97070 Würzburg,
           Germany; 2Medizinische Klinik II, Division of Endocrinology and Diabetology, University of Freiburg, Hugstetter Str. 55,
              D-79106 Freiburg, Germany; 3Institute for Virology and Immunobiology, University of Würzburg, Versbacher Str. 7,
            D-97078 Würzburg, Germany; 4Kreiskliniken Altötting-Burghausen, Krankenhausstr. 1, D-8849 Burghausen, Germany




Background & Aims: Interferon-associated depression is a fre-                            Ó 2009 European Association for the Study of the Liver. Published
quent side effect of antiviral therapy for chronic hepatitis C.                          by Elsevier B.V. All rights reserved.
The aim of the present study was to investigate the correlation
between platelet serotonin (5-hydroxytryptamine, 5-HT) concen-
trations and IFN-induced depression.
Methods: The study represents a secondary analysis of a previ-                           Introduction
ously published trial on the efficacy of SSRI medication in HCV
patients on IFN therapy. Ninety-three patients were longitudinally                       Chronic hepatitis C (CHC) infection is a major cause of liver cir-
assessed for depression and platelet serotonin. Evaluation time                          rhosis, bearing a considerable risk of developing subsequent
points were: prior to IFN therapy, at weeks 4, 12, and 24 of IFN                         life-threatening complications such as hepatocellular carcinoma
treatment, and 4 weeks after antiviral treatment. Depression was                         or even death [1]. The state-of-the-art treatment currently con-
assessed using the Hospital Anxiety and Depression Scale (HADS).                         sists of a combination therapy with pegylated interferon (IFN)
Platelet serotonin concentrations were measured by ELISA.                                alfa and ribavirin for 24 or 48 weeks, depending on the viral
Results: Platelet serotonin concentrations were significantly                             genotype as well as other factors such as early viral kinetics
decreased during interferon therapy (p = 0.001) in 74 of the 93                          and pretreatment viral load. A sustained virological response,
patients (79.6%). Clinically relevant depression occurred in                             defined as undetectable virus RNA 6 months after the end of
33.3% of patients – however, IFN-induced depression was not sig-                         IFN therapy, is achieved in 46–80% of all patients treated [2,3].
nificantly linked to either baseline 5-HT concentrations or kinet-                            IFN-associated, therapy-induced clinically relevant or major
ics. In the subgroup of patients with IFN-induced depression who                         depression occurs in up to 40% of patients receiving IFN-based
received the selective serotonin reuptake inhibitor (SSRI) citalo-                       treatment [4–6]. This adverse event may lead to non-compliance
pram (20 mg daily, n = 17), serotonin levels declined further dur-                       or discontinuation of IFN therapy, thereby impairing therapy out-
ing anti-depressant medication, becoming statistically significant                        come. Since selective serotonin reuptake inhibitors (SSRIs) have
within the first 2 weeks (p < 0.001) of SSRI treatment.                                   been shown to alleviate depressive symptoms during IFN therapy
Conclusions: We demonstrate a significant impact of IFN and                               safely and efficiently [7], it is of considerable interest to identify
SSRI intake on platelet serotonin levels, suggesting a biochemical                       HCV patients who are at an increased risk of depression. Using
analogy between 5-HT metabolism in blood platelets and the                               this approach, SSRIs would be administered to those who are
CNS. Platelet 5-HT levels might serve as a surrogate marker for                          most likely to benefit from these agents – in contrast to a general
patient adherence to antiviral and anti-depressant medication.                           SSRI prophylaxis, being recommended by some authors [8,9].
For the prediction of IFN-induced depression, however, platelet                              However, predictive factors for the development of IFN-
5-HT measurements are not suitable.                                                      induced depression are few and their evaluation has yielded
                                                                                         inconsistent results. One promising candidate has recently been
                                                                                         described by our group [10]: We found evidence that a specific
Keywords: Hepatitis C; Interferon alfa; Depression; Serotonin; 5-HT; Platelet.           polymorphism in the serotonin receptor gene (C-1019G of the
Received 30 March 2009; received in revised form 9 July 2009; accepted 3 August          HTR1A gene: homozygosity for the G allele) predisposes to inter-
2009
*
 Corresponding author. Tel.: +49 931 201 70170; fax: +49 931 201 70680.
                                                                                         feron-induced depression. These data suggest a link between
E-mail address: arne.schaefer@mail.uni-wuerzburg.de (A. Schäfer).                        interferon therapy, cerebral serotonin (5-hydroxytryptamine, 5-
Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); ANOVA, analysis of var-            HT) metabolism and treatment-associated depression, thereby
iance; ELISA, enzyme-linked immunosorbent assay; HADS, Hospital Anxiety and              offering a rationale for prophylaxis or therapy with an SSRI
Depression Scale; HCV, hepatitis C virus; IVDU, intravenous drug usage; P, stat-
                                                                                         [10]. A further factor predisposing to the development of
istical probability; SPSS, Statistical Package for Social Sciences; t, evaluation time
point.                                                                                   cytokine-induced depression has been demonstrated in multiple



                                                             Journal of Hepatology 2009 vol. xxx j xxx–xxx




Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007
                                                                      ARTICLE IN PRESS

Research Article
empiric studies: elevated depression scores observed just prior to                         pregnancy or the absence of reliable contraception in female patients, psychiatric
the start of IFN-based antiviral therapy indicate a significantly                           illness (severe depression or psychosis), active intravenous drug use or alcohol
                                                                                           abuse, or insufficient knowledge of the German language. Patients were also
increased risk to develop IFN-induced depression [11,12].                                  excluded from study participation if they fulfilled any other contraindication to
    Based on these findings and the need for a further improve-                             alfa-interferon or ribavirin.
ment of the prediction model for IFN-induced depression, we
prospectively monitored both depressive symptoms and periph-                               Study design, procedures, and interventions
eral platelet serotonin levels in HCV patients who were treated
with peginterferon alfa-2b and ribavirin. These analyses repre-                            The study was designed as a prospective single-center study: In a longitudinal
sent a secondary objective of a study previously published by                              repeated-measures design, we monitored neuropsychiatric symptoms – espe-
our group [7]. Introduction of platelet 5-HT-concentrations as a                           cially depression – during the study period. Study participants were psycho-
                                                                                           metrically evaluated once before therapy, three times during antiviral
parameter is based on previously published findings that the                                treatment (after 4, 12 and 24 weeks of IFN treatment), and 4 weeks after
serotonin metabolism is comparable in blood platelets and the                              the end of combination therapy. These evaluation time points were scheduled
central nervous system (CNS) [13–16]. Given the fact that there                            for all patients, irrespective of the individuals’ virus genotypes. All laboratory
is increasing evidence for the serotonergic system being involved                          analyses and medical examinations (e.g. blood count, transaminases,
                                                                                           HCV RNA, and 5-HT-levels) followed the same schedule. Genotype identifica-
in the development of depression during IFN therapy [4], we
                                                                                           tion and liver biopsy (staging and grading: inflammation, fibrosis, cirrho-
raised and addressed the following research questions:                                     sis) were performed once before therapy. The mode of infection was
                                                                                           documented.
 – Are platelet serotonin levels influenced by treatment with IFN
   and/or SSRI?                                                                            Psychometric assessment
 – Are platelet serotonin levels predictive of IFN-induced
   depression?                                                                             Depression – HADS
 – Can the assessment of platelet serotonin levels be a suitable                           Depression was assessed by the well-validated Hospital Anxiety and Depression
                                                                                           Scale (HADS, German version, as published by Herrmann et al. HADS is a 14-
   surrogate marker for testing patient compliance with both
                                                                                           item questionnaire with the dimensions anxiety and depression. All items
   the antiviral therapy and the treatment of IFN-induced                                  exclusively refer to the emotional state and do not reflect somatic symptoms
   depression with SSRIs? (Secondary study objective)                                      [17].
                                                                                                Moreover, this questionnaire was shown to be suitable for the longitudinal
                                                                                           assessment of depressive symptoms in chronic hepatitis C patients in previous
Patients and methods                                                                       studies [4,6,7,10]. According to the questionnaire’s manual, the cutoff value for
                                                                                           clinically relevant depression was set to 9 or greater [17]. For the purpose of
Patients                                                                                   the present paper, the results of the HADS depression subscale were used; anxiety
                                                                                           scores were not included in the performed statistical analyses.

All hepatitis C outpatients (n = 93) were consecutively enrolled at our institution
(Medizinische Klinik und Poliklinik II, Department of Gastroenterology, Univer-            ELISA (enzyme-linked immunosorbent assay) assay for serotonin – assessment of
sity of Würzburg, Würzburg, Germany) between 2002 and 2005. The presented                  peripheral serotonin levels
patient sample was a subgroup of the study population enrolled in our previously
published controlled study on the efficacy of SSRI therapy for IFN-induced depres-          ELISA assays for serotonin content were performed using a serotonin ELISA Kit
sion in antivirally treated patients with chronic hepatitis C infection [7]. Complete      (RE59121, Immuno-Biological Laboratories, Hamburg, Germany) as previously
sets of laboratory data across the evaluation period were mandatory for the final           described [18] and following the manufacturer’s instructions [19]. At the time
statistical analyses in the present study – therefore, 7 (of 100) patients with            of assay, the sample was thawed on ice and 50 ll was removed to which
incomplete laboratory test results were not included. Subgroup analyses includ-            100 ll of the kit assay buffer was added. Then, 25 ll of kit acylation buffer
ing these ‘‘dropouts” demonstrated, however, that these 7 patients did not differ          was added for a total volume of 175 ll. After incubation at 37 °C for 15 min,
significantly from the remainder of the study group with respect to relevant                125 ll of assay buffer was added to the tubes and the precipitated proteins
patient characteristics (data not shown). Methods and randomization procedures             were removed by centrifugation (10 min at 2000 rpm). Fifty microliters of
have already been described in detail elsewhere and are only briefly dealt with in          the supernatant was added to duplicate wells in the ELISA plate, which was
this paper [7].                                                                            then processed according to the directions of the manufacturer. Samples were
     All patients gave their written informed consent to participate in this study.        read at 405 nm on an ELISA plate reader (Molecular Devices Union City, CA,
The study protocol was approved a priori by the Institutional Review Board for             USA). The amounts of 5-HT were quantified using standards supplied by the
the protection of human subjects at our institution (human research committee)             manufacturer and analyzed using OriginTM software (Microcal Software, North-
and conforms to the ethical guidelines of the 1975 Declaration of Helsinki.                ampton, MA, USA). The serotonin content was determined by comparing the
                                                                                           optical density of the samples with a standard curve containing increasing
Inclusion criteria                                                                         amounts of serotonin [19]. The content of serotonin in platelets is referred
                                                                                           to 109 platelets [19].

At the time of study entry, all patients were serum positive for anti-HCV and had
circulating HCV RNA as confirmed by reverse-transcription PCR (polymerase                   Statistical analysis
chain reaction: Cobas AmplicorTM). The patients had been referred to our institu-
tion for antiviral combination therapy with peginterferon alfa-2b (PegintronTM)            Data were registered and analyzed using the Statistical Package for Social Sci-
plus ribavirin (RebetolTM). Patients with previous therapy attempts (i.e., not treat-      ences (SPSS for Windows, German version 15.0) [20].
ment naive) could be included if they fulfilled all other criteria for this study par-           All tests of significance were two-tailed. p values of <0.05 were considered
ticipation. Furthermore, patients had to be between 18 and 65 years of age at the          statistically significant. Because of the explorative character of the study we did
time of study entry.                                                                       not consider alpha adjustment in multiple comparisons. Moreover, exact calcu-
                                                                                           lated p values are usually provided together with statistical analyses for maxi-
                                                                                           mum transparency and clearness of the data presentation.
Exclusion criteria

                                                                                           Descriptive analysis
Individuals were excluded from participating in the case of advanced liver cirrho-         Results describing quantitative measures are expressed as median or
sis (Child stage B or C), co-infections (hepatitis B virus or HIV), severe internal dis-   mean ± standard deviation or standard error. Qualitative variables are presented
eases (e.g. cancer, ischaemic heart disease or autoimmune disease), current                as counts and percentages.



2                                                           Journal of Hepatology 2009 vol. xxx j xxx–xxx



Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007
                                                                ARTICLE IN PRESS

                                                                                                      JOURNAL OF HEPATOLOGY
Table 1. Socio-demographic and illness-related factors in total study (stratified for patients with vs. without IFN-induced depression during the course of antiviral
treatment).




Tests of significance                                                                 3 additional patients, who had already started their antiviral
We performed t-tests (for independent samples) and analysis of variance (one-        therapy and developed significant depression thereafter, were
way ANOVA) to test for differences in continuous variables (e.g. 5-HT concentra-
tions) between patient subgroups. Longitudinal changes (in e.g. 5-HT concentra-
                                                                                     then treated with citalopram in an open-label fashion. In con-
tions) were tested for using paired t-tests and repeated-measures ANOVA, where       clusion, a total of 17 patients received citalopram starting
appropriate. Chi-squared tests were used to compare frequencies of categorical       approximately at week 12 (11.7 ± 6.7) until the end of their
variables between patient subgroups. Predictive value of 5-HT concentrations         antiviral treatment, and 14 received placebo. Among these latter
was planned to be investigated using binary logistic regression analysis (predic-
                                                                                     14 patients on placebo, 5 more were unblinded and treated with
tion of depression occurrence as dichotomous outcome variable). Explanatory
variables included in the prediction models were absolute values and changes         citalopram as rescue medication due to persisting severe
over time of 5-HT concentrations.                                                    depression. They were able to complete interferon therapy as
                                                                                     scheduled.
                                                                                         The time course of the depression scores of the treatment
Results                                                                              groups has been described elsewhere [7].


Study population                                                                     Time course of platelet serotonin levels
                                                                                     The results of the repeated measurement of platelet 5-HT levels
Ninety-three patients (mean age 40 years, 56% males; Table 1)                        during the study period are shown in Fig. 1. In order to eliminate
were included in the study. None of the included patients had a                      the effect of SSRI treatment, only the results from the patients
history of relevant depression (pretherapeutic HADS score < 9).                      that had not been treated with citalopram are displayed. Normal-
No patient took an anti-depressant medication at the time of                         ized platelet 5-HT levels significantly decreased from baseline
study entry or during the last 6 months before enrolment.                            throughout the time of antiviral treatment, the main effect occur-
                                                                                     ring already during the first 4 weeks (p < 0.001). A total of 74 out
Clinical features                                                                    of 93 study patients (79.6%) showed a decrease in platelet 5-HT
                                                                                     levels during IFN medication. Four weeks after the end of therapy
Depression scores as measured by HADS                                                with peginterferon alfa plus ribavirin, platelet serotonin concen-
As known from previous studies [4,6,7,10], HADS depression                           tration had increased again (Fig. 1).
scores increased significantly but reversibly during the course                           In the subgroup of patients with concomitant citalopram
of antiviral interferon-based therapy. Four weeks after the termi-                   medication due to IFN-induced depression, platelet serotonin
nation of interferon alfa medication, depression levels according                    concentrations showed a further significant decline after initia-
to HADS assessment did not differ significantly anymore from                          tion of the SSRI medication (Fig. 2, p < 0.001). This decline went
baseline values (p = 0.221).                                                         in parallel with the relief of depression, and the reduced level
    A subgroup of n = 31 patients developed clinically relevant                      was kept constant for a 4-week follow-up period. Although
depression (HADS score P 9). Of these, 28 were included into                         citalopram intake led to a significant decline in platelet serotonin
a controlled study of SSRI treatment (citalopram 20 mg daily)                        levels, the extent of symptom relief and the extent of platelet 5-
versus placebo [7]. Following an interim evaluation that showed                      HT alterations were not significantly correlated within the sub-
the significant superiority of the SSRI group over placebo in                         group of patients taking SSRI medication (r = À0.123; p = 0.661).
terms of improvement of depression, the study was terminated;                        In the measurement after 24 weeks of antiviral therapy plus con-


                                                        Journal of Hepatology 2009 vol. xxx j xxx–xxx                                                             3



Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007
                                                                                                                     ARTICLE IN PRESS

Research Article
                                                                     n = 93 (Total sample)                                                                                                               IFN-induced MD (n = 31)
                                                                                                                                                                                                         no IFN-induced MD (n = 62)
                                                    550                                                          p = 0.001                                                                600




                                                                                                                                                  5-HT concentration (ng /10 platelets)
            5-HT concentration (ng /10 platelets)




                                                                                                                                                                                                p = 0.638 NS
                                                    500              p < 0.001
                                                                                                                                                                                                                            p = 0.317 NS
                                                                                   p = 0.149




                                                                                                                                                 9
                                                    450
    9




                                                                                                                                                                                          400
                                                                                                   p = 0.607
                                                    400

                                                    350
                                                                                                                                                                                          200
                                                    300


                                                    250

                                                    200                                                                                                                                     0
                                                                                                                                                                                                Baseline                 4 Weeks IFN
                                                              T1              T2             T3             T4             T5                                                                    (T1)                       (T2)
                                                            (prior to       (4 weeks      (12 weeks      (24 weeks      (4 weeks
                                                            therapy)           IFN)          IFN)           IFN)        after IFN)
                                                                                                                                      Fig. 3. 5-HT levels (mean ± SEM) in subgroups with and without IFN-induced
                                                                                                                                      depression. Absolute values are given for evaluations at baseline as well as after
Fig. 1. Time course of 5-HT levels (mean ± SEM) in the total study sample.
                                                                                                                                      4 weeks of IFN medication. Given p values result from performed t-tests for
Irrespective of occurrence of IFN-induced depression (data controlled for SSRI
                                                                                                                                      independent samples.
medication; all data points without SSRI medication). Given p values result from
performed pairwise t-tests for dependent samples.
                                                                                                                                      antiviral therapy. Fig. 3 compares the patient subgroups accord-
                                                                                                                                      ing to occurrence of depression with respect to their baseline
comitant SSRI treatment (average duration 12.3 weeks), seroto-
                                                                                                                                      5-HT values. Mean values were not significantly different
nin concentrations had again increased more than threefold
                                                                                                                                      between both subgroups (p = 0.638).
above the nadir. In patients not receiving citalopram, serotonin
                                                                                                                                          In a further analysis, we additionally investigated whether
concentrations declined gradually until week 24 of IFN
                                                                                                                                      early kinetics of 5-HT concentrations were predictive of relevant
treatment.
                                                                                                                                      depression later in the course of antiviral therapy. However, nei-
                                                                                                                                      ther 5-HT decline at week 4 nor kinetics at week 12, were signif-
Association between platelet 5-HT levels and the occurrence of IFN-                                                                   icantly related to interferon-induced depression in our study.
induced depression                                                                                                                        Moreover, we could demonstrate that absolute peripheral
Statistical analyses revealed that baseline platelet serotonin lev-                                                                   platelet 5-HT levels were not indicative of the extent of depres-
els were not significantly correlated with either the manifesta-                                                                       sive symptoms at any evaluation time point. There was no signif-
tion itself or the extent of cytokine-linked depression during                                                                        icant correlation between the decrease in platelet serotonin and
                                                                                                                                      the extent of depressive symptom relief in HCV patients concom-
                                                    650                                                                               itantly treated with citalopram.
                                                    600                                                                                   Therefore, 5-HT levels (baseline: p = 0.863; after 4 weeks of
    5-HT concentration (ng /10 9 platelets)




                                                    550                                   Patients with SSRI (n = 17)                 IFN treatment: p = 0.320) did neither alone nor in combination
                                                                                          Patients without SSRI (placebo, n = 14)     with further variables (e.g. baseline depression) significantly con-
                                                    500
                                                                                                                                      tribute to a binary logistic regression model of clinically relevant
                                                    450                                                                               depression according to the HADS instrument.
                                                    400
                                                    350
                                                    300                                                                               Discussion
                                                    250
                                                    200                                                                               So far, no parameter can reliably predict the subgroup of patients
                                                                                                                                      with chronic hepatitis C that will develop a relevant depression in
                                                    150
                                                                                                                                      the course of an interferon-based antiviral therapy. Such param-
                                                    100
                                                                                                                                      eter would firstly allow an individualized anti-depressant pri-
                                                     50                                                                               mary prophylaxis for patients at risk to develop interferon-
                                                      0                                                                               induced major depression [7,10], thereby improving long-term
                                                            T1          Tev      1 week     2 week     4 week       T4       T5
                                                          (before        (event) SSRI        SSRI       SSRI     (24 wk   (4 wk       treatment outcomes with higher SVR rates due to a lower drop-
                                                          IFN                                                      IFN    after IFN   out rate. Secondly, it could allow clinicians to adapt the frequency
                                                          therapy)                                               therapy) therapy)
                                                                                                                                      of psychometric screening and monitoring based on a patient’s
Fig. 2. Time course of platelet serotonin levels (mean ± SEM) in HCV patients                                                         individual risk to become depressive.
with antiviral treatment and clinically relevant depression. Comparisons of                                                               Therefore, in a single-center study, we longitudinally assessed
subgroups with (n = 17) and without (n = 14) SSRI here: citalopram) treatment.
                                                                                                                                      platelet serotonin levels in 93 patients with chronic hepatitis C
Indicated p values result from performed repeated-measures ANOVAs. Time
interval between T1 to Tev varies according to patients’ individual therapy                                                           infection on antiviral treatment to investigate peripheral 5-HT
courses (mean time interval: 11.65 weeks citalopram and 9.21 weeks for placebo                                                        concentrations as a possible early predictor for the development
group).                                                                                                                               of subsequent IFN-induced depressive symptoms.

4                                                                                                           Journal of Hepatology 2009 vol. xxx j xxx–xxx



Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007
                                                           ARTICLE IN PRESS

                                                                                                  JOURNAL OF HEPATOLOGY
    We could, however, show that contrary to our hypothesis                       via the serotonergic pathway [4]. In contrast to our expectations,
platelet serotonin concentrations were not significantly associ-                   we found no association – neither for absolute concentrations nor
ated with either the occurrence or the extent of subsequent                       for changes in serotonin levels – with a subsequent development
IFN-induced depression. This was true for both the absolute sero-                 of IFN-related depressive symptoms. One possible explanation is
tonin concentrations as well as 5-HT kinetics during the first                     that the chosen marker per se is not predictive for occurrence or
12 weeks of antiviral therapy.                                                    extent of IFN-induced depression (see also [16]). A more plausible
    In contrast, we were able to show a marked decrease of plate-                 explanation is that platelet serotonin concentrations, although
let serotonin levels during IFN therapy, indicating an impaired                   running parallel to IFN-induced depression, do not precede it for
activity of the serotonergic system induced by this drug. We                      long enough to be predictive in a given individual. Finally, in this
therefore could confirm the validity of platelet serotonin concen-                 context, it has to be pointed out that the exact mechanism by which
tration as a surrogate marker for serotonergic activity in the cen-               interferon causes depressive symptoms still remains unclear.
tral nervous system suggested by others [13–16]. We could                         Therefore, it might be speculated that 5-HT metabolism is only
demonstrate that peginterferon alfa-2b (in combination with                       one among many pathways [23,24], explaining to some extent
ribavirin) leads to a significant decline in normalized platelet                   the absence of a clear relationship between peripheral 5-HT levels
serotonin levels over time. Additionally and independently, con-                  and IFN-induced depression.
comitant SSRI treatment further reduced intracellular 5-HT plate-                     In summary, our findings clearly demonstrate that in patients
let levels markedly and significantly.                                             with chronic HCV infection and antiviral combination treatment,
    These results are in accordance with recently published find-                  platelet serotonin concentrations are significantly reduced by the
ings by Fontana and co-workers [16]. However, in the Fontana                      impact of both (pegylated) interferon alfa and additional concom-
study [16], the exact relative contributions of IFN and SSRI actions,             itant SSRI (citalopram) medication. This means that in the practi-
respectively, to observed changes in serotonin levels are not                     cal care of chronic HCV infected patients, platelet serotonin
clearly separated, since a subgroup of their patients started IFN                 concentration might serve as an indicator for patient adherence
therapy while already taking an SSRI as anti-depressant medica-                   to IFN and eventually to SSRI medication.
tion. In contrast, our study allows for appreciation of the exact                     However, according to our results, the prediction models that
effect of the SSRI on the total reduction of platelet serotonin levels.           have so far been established [10,12] can obviously not be
    This general time-dependent decline of serotonin levels dur-                  improved by the additional consideration of the absolute levels
ing antiviral treatment for chronic hepatitis C infection supports                and/or the time course of serotonin concentrations in blood
the assumptions that (1) 5-HT activity in the CNS may be well                     platelets. In our view, further studies on the identification of risk
and validly mirrored by platelet serotonin metabolism [13–16],                    factors for IFN-linked mood disorders, in particular depression,
and (2) IFN action potentially leads to 5-HT depletion, explaining                are still needed in order to improve our understanding of both
to some extent the development of depression in patients with                     the prevention and management of this important side effect of
chronic hepatitis C infection and antiviral treatment. As the data                antiviral HCV treatment.
of the patients from the placebo group of the controlled study
suggest, platelet serotonin levels declined throughout the inter-                 Competing interests statement
vention period but did not drop further until the last measure-
ment after week 24 of IFN therapy. Since the intervention                         Michael R Kraus is a member of the Scientific Advisory Board
started at week 12 and was monitored for another 4 weeks (see                     (SAB) of Essex Pharma, a subsidiary of Schering-Plough (Kenil-
above), it seems that the effect of pegylated IFN on the serotoner-               worth, NJ, USA) and has served on speakers bureaus for Scher-
gic system increases with time over a period of approximately                     ing-Plough (Kenilworth, NJ, USA) and Essex Pharma (Munich,
16 weeks and then reaches a plateau.                                              Germany). Arne Schäfer has no competing interests to declare.
    The finding that the already low on-treatment platelet 5-HT                    Michael Scheurlen has no competing interests to declare. Jochen
levels are additionally reduced by citalopram is consistent with                  Seufert has no competing interests to declare. Christian Keicher
the general understanding of SSRI action [10,21]: In those study                  has no competing interests to declare. Benedikt Weißbrich has
patients with IFN therapy and concomitant citalopram treatment,                   no competing interests to declare. Peter Rieger has no competing
presynaptic 5-HT reuptake from the synaptic gap is inhibited by                   interests to declare.
citalopram. This leads to an even further reduced serotonin con-
centration within both the cell bodies of involved CNS neurons                    Acknowledgments
(e.g. raphe nuclei) and obviously also peripheral blood platelets
                                                                                  The present study was supported in part by Essex Pharma (Mu-
[22]. Remarkably, we found in our study that this further decline
                                                                                  nich, Germany), a subsidiary of Schering-Plough (Kenilworth,
by citalopram, whose main effect occurred during the first week
                                                                                  NJ, USA). The sponsor (Essex Pharma, Munich, Germany) was
of treatment, was not durable in spite of ongoing SSRI treatment:
                                                                                  not involved in any way in the design, interpretation, analysis
between week 4 of citalopram therapy and the end of the observa-
                                                                                  or writing of the study.
tion period (week 24 of IFN therapy), serotonin levels had increased
                                                                                  We would like to thank the laboratory staff (Med. Klinik u. Poli-
again to the same range as in the patients that had received only
                                                                                  klinik II, University of Würzburg, 97070 Würzburg, Germany),
placebo. This suggests some kind of rebound in the serotonergic
                                                                                  especially Ms. Luitgard Kraus, for expert technical assistance.
system and an increase of intracellular serotonin concentrations
in the course of a long-term SSRI/IFN combination therapy.                        References
    We had chosen platelet serotonin as a possible predictor for
the occurrence of IFN-induced depression because on the one                        [1] Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med
hand this parameter reflects serotonin concentrations in the CNS                        2001;345:41–52.
                                                                                   [2] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R,
[13–16,22], and on the other hand IFN impairs mental homeostasis
                                                                                       et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b



                                                   Journal of Hepatology 2009 vol. xxx j xxx–xxx                                                                 5



Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007
                                                                     ARTICLE IN PRESS

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6                                                           Journal of Hepatology 2009 vol. xxx j xxx–xxx



Please cite this article in press as: Schäfer A et al. Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible asso-
ciation with interferon-induced depression. J Hepatol (2009), doi:10.1016/j.jhep.2009.10.007

				
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