Interferon- in Oncology Patients: Fewer Psychiatric Side Effects Than Anticipated

MARJOLEIN BANNINK, M.D., PH.D., WIM H.J. KRUIT, M.D., PH.D. ARTHUR R. VAN GOOL, M.D., PH.D., STEFAN SLEIJFER, M.D., PH.D. BRONNO VAN DER HOLT, M.SC., ALEXANDER M.M. EGGERMONT, M.D., PH.D. GERRIT STOTER, M.D., PH.D., MICHIEL W. HENGEVELD, M.D., PH.D.

Interferon- (IFN-) treatment in both oncological and hepatological settings is associated with depression. If IFN- treatment induces depression in high numbers, it could serve as a model for studying the pathophysiology of depression, in general. The authors therefore studied 43 oncology patients treated with standard or pegylated IFN- with baseline psychiatric assessment and at regular time-points in the rst 6 months of treatment. Apart from a severe depression because of brain metastases, authors observed only two clinically relevant depressive states. Contrary to ndings in most of the literature, most depressive episodes in this study were self-limiting and short-lasting and were associated with either episodes of u-like symptoms common at the start of the treatment or with concurrent psychosocial events. In the group as a whole, scores on both observer-based and self-report rating scales did not show clinically relevant changes. The results of this study indicate that IFN- treatment is not suitable as a study model for depression in general. (Psychosomatics 2008; 49:5663)

nterferon- (IFN-) is used in a variety of disease conditions, such as chronic viral hepatitis, renal cell carcinoma, and malignant melanoma. Its use is associated with a wide variety of side effects, including burdensome psychiatric side effects.13 The incidence of depressive symptoms and syndromes is described in up to 45% of the patients.2,3 These depressive symptoms can be severe, sometimes prompting dose adjustments or even cessation of treatment, thereby attenuating the efcacy of treatment.

Received June 1, 2006; revised September 15, 2006; accepted September 19, 2006. From the Dept. of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands; and the Dept. of Medical Oncology, Erasmus MCDaniel den Hoed Cancer Center, Rotterdam, the Netherlands. the Dept. of Trials & Statistics, Erasmus MCDaniel den Hoed Cancer Center, Rotterdam, the Netherlands; and the Dept. of Surgical Oncology, Erasmus MCDaniel den Hoed Cancer Center, Rotterdam, the Netherlands. Send correspondence and reprint requests to Dr. Marjolein Bannink, Erasmus, MCDaniel den Hoed Cancer Center, P.O. Box 5201 3008 AE Rotterdam, the Netherlands. e-mail: m.bannink@erasmusmc.nl 2008 The Academy of Psychosomatic Medicine

In addition to the depressive mood disorders, irritable mood has also been described.4 The mood disorders associated with IFN- occur within weeks-to-months after the start of treatment.5,6 The exact psychopathology occurring in IFN-treated patients needs to be described more fully to determine whether this psychopathology is representative of mood disorders as understood in mental health psychiatry. If that is the case, IFN-induced depressions might serve as a study model for mood disorders, in general, or even as a predictive test in future studies.79 Also, better insight into IFN-mediated psychopathology may provide strategies to manage such untoward events more effectively. Although much research has been performed, there are still many questions about IFN-mediated psychopathology that are not yet answered: rst, whether and to what extent other domains of mental functioning besides mood and cognition are also affected by IFN.
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Furthermore, reported frequencies of IFN-induced psychiatric disorder vary widely. Next to differences in the methodology of assessment, differences in patient populations studied or in doses of IFN- applied may underlie the differing incidence across studies. Third, the association of IFN-induced mood disorders with u-like complaints and the time of appearance of the depressive syndromes are subject to ongoing debate. Whereas some suggest that depressive syndromes are closely related or even identical to malaise and sickness behavior, others regard these as clearly different entities. Sickness behavior is a condition observed in laboratory animals injected with pro-inammatory cytokines. In sickness behavior, fever, lethargy, anorexia, diminished sensitivity to pleasurable stimuli such as sucrose, diminished sexual activity, and reduction in grooming are observed. It is considered an organized, evolved behavioral strategy in combating viral and bacterial infections, by saving energy, minimizing risks, and enhancing the immune response.10,11 The most frequently observed acute side effect of IFN-, the so called u-like syndrome, consists of fever, chills, myalgia, headache, malaise, and nausea.12 Almost all patients experience such a u-like syndrome to some degree at the beginning of treatment. It is generally self-limiting and may be regarded as the human counterpart of sickness behavior. It has been suggested that depression evolves out of these somatic complaints and is the result of the same immune activation.13 In accordance with this theory, Wichers et al.14 found that early vegetative symptoms are predictive of higher depressive symptom scores at 8 weeks after initiation of IFN- treatment. Also, in some studies, depressive syndromes seem to occur within the rst 4 weeks after starting IFN-, the same time-period in which u-like complaints are seen.2,6 In other studies, however, the time from start of treatment to the diagnosis of a depressive syndrome is reported to be 2 to 3 months, a point in time in which u-like symptoms have usually abated.15,16 A third possibility is offered by Capuron and Miller,17 who suggest that two distinct syndromes appear separately in the course of the IFN- treatment. The rst, called the neurovegetative syndrome by these authors, features anorexia, psychomotor slowing, and fatigue, appears within 2 weeks of IFN- therapy, and is minimally responsive to serotonergic antidepressants. One could speculate that this neurovegetative syndrome is identical to or overlaps with the u-like syndrome and may be analogous to sickness behavior. The second behavioral syndrome develops shortly afterwards, within the rst 3 months of IFN- therapy; it includes depressed mood
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and cognitive dysfunction and is responsive to serotonergic antidepressants. The aim of this study was to describe in detail emerging psychopathology in IFN-treated oncology patients with renal cell carcinoma or malignant melanoma. We combined the clinical diagnosis of an experienced consultationliaison (CL) psychiatrist and a diagnosis obtained with a structured psychiatric interview, together with validated psychiatric symptom checklists using both observerbased rating scales and self-report questionnaires. Besides establishing the exact incidence, such an approach offers the possibility of gaining better insight into the precise symptomatology of IFN-induced mood disorders and establishing whether or not IFN-induced mood disorders are consistent with those mood disorders seen in mental health psychiatry. These ndings may serve as a model for studying mood disorders, in general. METHOD Participants Eligible patients, who were offered IFN- treatment by their oncologist, had to be between 18 and 75 years of age, uent in the Dutch language, and capable of lling out self-report rating scales and participating in a psychiatric interview. Excluded were patients concurrently using antidepressants, antipsychotics, mood stabilizers, or corticosteroids; patients with current abuse of illicit drugs or alcohol; with major depression according to DSMIV criteria; patients suffering from severe neuropsychiatric disorders; and patients with known CNS metastases. Patients were treated with IFN- for high-risk melanoma or disseminated renal-cell carcinoma (RCC). Patients with a nondisseminated high-risk melanoma were participants in the treatment arm of a randomized European Organization for Research and Treatment of Cancer trial (EORTC 18991), evaluating the efcacy and toxicity of pegylated IFN- (PEG-IFN-) versus control medication. Patients assigned to the treatment arm received PEG-IFN, 6 lg/kg s.c. per week for a period of 8 weeks, followed by 5 years of maintenance treatment with 3 lg/kg s.c. per week. A subgroup of patients with disseminated RCC were participants in the IFN-alone arm of the EORTC 30012 study, comparing the efcacy and toxicity of IFN- alone versus the combination of IFN-, interleukin-2, and 5-uoruracil. Patients randomly assigned to the IFN-alone arm received IFN- in a dose of 6 million units (MU) s.c. on
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Days 1 and 3 for the rst week, followed by 9 MU s.c. 3 times per week. The remaining patients with disseminated RCC treated with IFN- did not participate in EORTC 30012. These patients were treated with IFN- s.c. initially with a dose of 3 MU, 3 times per week, increased within 4 weeks to 9 MU s.c. 3 times per week. Treatment was continued until the disease progressed or there were unacceptable resulting toxicities. In cases of severe (PEG-)IFN-related toxicities, doses were adjusted according to protocol or by 3 MU per occurrence. The study was approved by the medical ethics committee, and all patients gave written consent. Assessments Assessments took place before the start of the IFN- treatment and at 4 weeks, 8 weeks, and 6 months after the start of IFN- treatment or at any time in between when the patient or the attending oncologist contacted us in case of emerging psychopathology. No assessments took place after IFN- was stopped or when patients started using medication from our exclusion list. The presence of a major depressive episode was ascertained with the relevant module of the Mini-International Neuropsychiatric Interview (MINI). The MINI is a short, structured diagnostic interview for DSMIV and ICD10 psychiatric disorders; it was designed to meet the need for a short but accurate structured psychiatric interview.18 If a major depressive episode was present, the MINI module for melancholic features was administered, and the presence or absence of 24 symptoms of depression were recorded, as was the clinical association with ulike-toxicity, dened as fever, chills, muscle and joint pains, malaise, and nausea. Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS).19 The MADRS is an examiner-rated depression scale and one of the most commonly used symptom severity scales for depression. It is also part of the Comprehensive Psychopathology Rating Scale (CPRS). Furthermore, the Brief Anxiety Scale (BAS) was used specically for the item Hostility in order to assess irritability. The BAS is a rating scale suitable for recording anxiety symptoms; it is a subsection of the CPRS.20 All the patient interviews were performed by two CL psychiatrists (ARVG and MB), who recorded their clinical judgment, as well. For the self-report questionnaires, the Hospital Anxiety and Depression Scale (HADS), the Beck Depression Inventory (BDI), and the Symptom Check List90 (SCL
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90) were used. The HADS is a reliable and valid instrument for assessing anxiety and depression in medical patients.21,22 The BDI is a well-validated and reliable 21-item self-report questionnaire designed to measure depressive symptoms.23 The ve somatic items of the BDI were also recorded separately. The SCL90 was used to determine whether other domains of psychic functioning besides mood were affected.24 The SCL90 is a well-validated, multidimensional self-report symptom inventory, designed to assess various dimensions of psychopathology, including irritability.25,26 The Karnofsky Performance Scale (KPS) was used to describe patients general condition.27,28 Statistical Analysis Data were stored using SPSS (Version 11.0) software and analyzed with Stata (StataCorp., 2003; Stata Statistical Software: Release 8.0; College Station, TX; Stata Corporation). Outcomes at 4 and 8 weeks, and at 6 months were compared with those at baseline by use of the Wilcoxon matched-pairs signed-ranks test. All reported p values are two-sided, and we used a signicance level of 0.05. RESULTS Subject Characteristics A group of 46 patients were invited to participate in this study. One patient with melanoma refused; two patients with RCC were excluded because of antidepressant use. The remaining 43 patients, 25 men and 18 women, had a median age of 58 years (range: 3672 years) and were recruited to the study within 36 months. Eight high-risk melanoma patients participated in the treatment arm of the EORTC 18991 and 13 patients with disseminated RCC were treated in the IFN--arm of the EORTC 30012. The remaining 22 patients, all with disseminated RCC, were treated with IFN- outside the framework of these clinical trials. Median weekly doses (range) of PEG-IFN- used in high-risk melanoma patients were the following: at 4 weeks, 6 lg/kg (range: 3 lg/kg6 lg/ kg); at 8 weeks, 3 lg/kg (range: 3 lg/kg6 lg/kg) and at 6 months, 3 lg/kg (range: 1 lg/kg3 lg/kg). Median weekly doses (range) of conventional IFN- used in RCC patients were 27 lg/kg (18 lg/kg27 lg/kg) (MU) at 4 and 8 weeks and at 6 months. From the 43 participating patients, all data-sets were available at baseline; at 4 weeks, the data-set of 39 patients could be evaluated; at 8 weeks, there were 37 patients; and at 6 months, 25 patients; 11 patients had to stop IFN-
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treatment because of progressive disease, 2 because cerebrovascular events, and 3 because of severe nonpsychiatric side effects during the study period of 6 months. Two patients were excluded, one at 6 months because of having started valproate for seizures, and one at 4 weeks because of starting amitriptyline as a hypnotic. Two sets of data are missing because of administrative failure. Psychiatric Outcomes The psychiatric disorders encountered in the rst 6 months of IFN- treatment are summarized in Table 1. One patient contacted us in the third week of treatment because she had felt depressed for 10 days. When we interviewed this patient the next day, a clinical diagnosis of severe depressive episode was made, although not strictly fullling either the DSMIV or the MINI criteria, because she had had depressive symptoms for less than 14 days. The following day, she was admitted to the hospital because she had also developed neurological decits. CNS metastases were revealed, as a consequence of which IFN treatment was stopped. At 4 weeks, two patients had been through a depressive episode, by MINI criteria, which had lasted 2 to 3 weeks. Clinically, these episodes were associated with severe u-like symptoms at the start of the IFN- treatment. Both had no actual depressive disorder at the time of the interview. At 8 weeks, one patient had been through a depressive episode according to the MINI criteria. Clinically, it was diagnosed as a transient anxiety disorder, which resolved completely after she took benzodiazepines as prescribed by her general practitioner for a few days. At the time of the interview, no signs of depressive (or anxiety) disorders were present. At the 6-month assessment point, one patient had been through a depressive episode, according to the MINI criteria. Clinically, this episode was related
TABLE 1.

to resuming his work, and it resolved after 2 weeks, with no diagnosis of depression at the time of the interview. Also, another patient had a depressive episode, according to MINI criteria, at the 6-month assessment point and according to our clinical judgment at the time of the interview. The symptoms had started 2 to 3 months before this 6-month evaluation. The sum score on the MADRS was 29, with scores of 3 out of 6 on the items Apparent Sadness, Reported Sadness, and Inability to Feel, and with scores of 4 out of 6 on the items on sleep disturbance, loss of appetite, concentration difculties, and lassitude. No clear feelings of guilt, self-deprecation, suicidal ideation, or diurnal variation in mood were present. The score on the BDI was 30, and the score on both the HADS Depression and Anxiety subscale was 11. The total score on the SCL90 was 192. The IFN- dosage was decreased, and mirtazapine was started, after which her depression resolved within 6 weeks. This patient was one of those who had been through a depressive episode with a concurrent ulike syndrome during the rst weeks. One patient had no depressive episode according to MINI criteria; however, in our clinical judgment, this patient had Depressive Disorder, Not Otherwise Specied according to the DSMIV classication at 4 and 8 weeks and at 6 months, mostly lacking drive and interest, with hypersomnia and concentration problems, although he did not afrm these problems on the self-rating scales. This patient refused psychiatric intervention and declined PEG-IFN- dose reduction because he wished to persist in his striving for maximal treatment. The scores on the observer-based rating scales for the whole group are shown in Table 2. The MADRS sum score increased slightly at 4 and 8 weeks with no increase in the items on apparent and reported sadness. Scores for the item on the ability to stay interested in others and to enjoy a normal level of interest increased only slightly at 8 weeks,

Psychiatric Disorders in the Course of (PEG-)-IFN- Treatment Patient # 7 16 18 19 11 15 16 Duration Study period 2 weeks 23 weeks 10 days 23 weeks 2 weeks 23 months Type IFN- PEG-IFN- PEG-IFN- PEG-IFN- IFN- IFN- PEG-IFN- PEG-IFN- MINI Criteria Clinical Diagnosis Depression, NOS Malaise associated with u-like syndrome Malaise associated with u-like syndrome Depressive symptoms due to CNS metastases Anxiety disorder, resolved within days by taking benzodiazepines Depressive episode related to resuming work Major depression; PEG-IFN- was reduced; mirtazapine was started Relationship With IFN- Likely Likely Likely Unlikely Possible Unlikely Likely

Time of Onset From start From start From start 10 days after start of IFN- 5 weeks after start of IFN- At 4 months At 4 months

(PEG-)-IFN-: pegylated interferon-alpha; MINI: Mini-International Neuropsychiatric Interview.

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but not at the other evaluation times. The MADRS items that increased further were those on reduced appetite (at 4 and 8 weeks), lassitude (at 4 weeks, 8 weeks, and 6 months) and concentration difculties (at 6 months). None of the other MADRS items increased (results not shown); neither did the BAS item on irritability. Of the self-report scales (summarized in Table 3), the score on the HADS Depression subscale increased at all time-points. The BDI score increased slightly, only reaching statistical signicance at 8 weeks, whereas the somatic items of the BDI increased at 4 weeks and 8 weeks. The SCL90 Total did not increase. Scores on the SCL90 subscale on depression did not increase, nor did the Hostility subscale, an indicator of irritability. The scores on the Anxiety (at 4 weeks) and
TABLE 2.

Interpersonal Sensitivity subscales of the SCL90 (at 4 weeks and 8 weeks) even slightly decreased (results not shown). Of the other subscales, Somatic Complaints increased at all time-points, and the other item subscales decreased at 4 weeks and 6 months. DISCUSSION Our ndings indicate that IFN- treatment, at least in this mixed oncology population on different treatment regimens, could not be regarded as a suitable research model for depression in general. First, the clinical relevance of the observed depressive states was doubtful; and, second, the clinical presentation was heterogeneous. Only two clin-

Scores From Observer-Based Scales at Baseline and Follow-Up, Mean (SD), Median, Range, p-Value Baseline (N43) 4 Weeks (N39) 6.6 (4.4) 7 016 *** 0.3 (0.6) 0 02 NS 0.5 (0.9) 0 03 NS 1.6 (1.3) 2 04 *** 0.9 (1.4) 0 04 NS 1.3 (1.4) 0 04 ** 0.5 (0.9) 0 04 NS 0.3 (0.6) 0 02 NS 90.3 (8.7) 90 70100 NS 8 Weeks (N37) 5.7 (4.2) 5 014 * 0.2 (0.5) 0 02 NS 0.3 (0.8) 0 03 NS 1.3 (1.3) 1 04 *** 1.0 (1.3) 0 03 NS 1.1 (1.5) 0 05 * 0.5 (0.9) 0 03 * 0.6 (0.9) 0 03 NS 89.7 (9.0) 90 70100 NS 6 Months (N25) 5.5 (6.5) 4 029 NS 0.4 (1.1) 0 04 NS 0.4 (0.8) 0 03 NS 0.5 (1.0) 0 04 NS 1.3 (1.6) 0 05 * 1.1 (1.5) 0 04 * 0.4 (0.8) 0 03 NS 0.4 (0.6) 0 02 NS 89.2 (10.0) 90 70100 NS

MADRS: Total

3.9 (3.8) 3 014 0.3 (0.6) 0 02 0.5 (0.8) 0 03 0.3 (0.8) 0 04 0.4 (0.9) 0 04 0.4 (0.8) 0 03 0.3 (0.7) 0 03 0.4 (0.7) 0 02 92.8 (8.8) 90 60100

MADRS: Apparent Sadness

MADRS: Reported Sadness

MADRS: Reduced Appetite

MADRS: Concentration Difculties

MADRS: Lassitude

MADRS: Inability to Feel

BAS: Irritability

Karnofsky Performance Scale

For p-value, differences were compared with baseline by the Wilcoxon signed-rank test. SD: standard deviation. *p 0.05; **p 0.01; ***p 0.001; NS: difference from baseline not signicant.

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ically signicant depressive episodes (as judged by CL psychiatrists) developed in our research population being given IFN- treatment. The clinical relevance of the other four episodes according to the MINI was doubtful, because they lasted less than 3 weeks and were already resolved at the time of the next assessment without psychiatric intervention. In the group as a whole, the results of the psychiatric rating scales were consistent with only rare occurrence of clinically signicant depressive states in this study. On observer-based measures, the MADRS items representing the core symptoms of depression (reported and apparent sadness, and loss of interest and pleasure) did not increase at all except in the case of the item on interest, which was increased at only one assessment time-point, but not to a clinically signicant degree. In contrast, the scores on the items pertaining to reduced appetite and lassitude increased slightly but signicantly at almost all asTABLE 3.

sessment times. These ndings are in accordance with our experience, in that patients with cytokine-induced u-like complaints and malaise do not experience anhedonia in the usual sense, but feel that the somatic complaints block them from participating in potentially pleasurable activities and enjoying these, and are able to differentiate these unpleasant feelings from depressive affects. They have less energy to initiate some activities and they decline other activities, not because they do not feel like it, but, temporarily, to prevent exhaustion and exacerbation of physical symptoms. It is noteworthy to realize that the KPS did not deteriorate despite the increase on several subscales on somatic items of the rating scales. Scores on the Hostility item of the BAS did not increase. On the self-report scales, the SCL90 Depression subscale did not increase; the sum score on the BDI did not increase consistently; and the slight increase on the HADS

Scores From Self-Report Scales at Baseline and Follow-Up, Mean (SD), Median, Range, p-Value Baseline (N43) 4 Weeks (N39) 113.3 (17.6) 106 92159 NS 22.3 (4.9) 21 1635 NS 18.5 (4.8) 17 1231 *** 6.8 (1.0) 6 69 NS 6.5 (4.3) 5 117 NS 4.0 (2.7) 3 112 ** 4.0 (3.4) 3 015 ** 4.0 (3.3) 4 013 NS 8 Weeks (N37) 110.3 (13.9) 107 90145 NS 21.3 (4.2) 20 1638 NS 17.7 (5.3) 17 1240 ** 6.5 (1.0) 6 611 NS 6.1 (3.3) 5 113 * 3.7 (1.8) 3 17 ** 3.5 (2.8) 3 011 ** 4.0 (3.4) 3 015 NS 6 Months (N25) 115.3 (21.3) 112 90192 NS 22.0 (5.4) 21 1641 NS 17.8 (4.5) 17 1230 ** 7.1 (1.2) 7 610 NS 7.0 (6.2) 5 130 NS 3.7 (2.5) 3 113 NS 4.8 (3.0) 4 011 *** 3.9 (3.3) 3 012 *

SCL90 Total

112.6 (16.9) 108 90154 21.8 (5.0) 21 1637 15.9 (4.6) 14 1236 6.6 (1.1) 6 611 5.6 (4.1) 6 014 2.9 (2.3) 2 010 2.6 (2.2) 2 08 4.6 (3.0) 4 113

SCL90 Depression subscale

SCL90 Somatic subscale

SCL90 Hostility subscale

BDI sum score

BDI Items 1520, Somatic items

HADS Depression subscale

HADS Anxiety subscale

For p-value, differences were compared with baseline by the Wilcoxon signed-rank test. SD: standard deviation; SCL90: Symptom Checklist; BDI: Beck Depression Inventory; HADS: Hospital Anxiety and Depression Scale. *p 0.05; **p 0.01; ***p 0.001; NS: difference from baseline not signicant.

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Depression subscale was not clinically relevant. Notably, Somatic Complaints, as measured by the SCL90 subscale (at all time-points) and by the Somatic items of the BDI (at two time-points) increased. This underlines the possibility that, in research on mood disorder induced by IFN, increased scores on depression rating scales could be attributed to an increased score on somatic items. Although our study is one of the larger studies done in this eld, our results must be regarded with some reservation because the sample size limits robust conclusions. The rarity of clinically relevant depressive episodes and the low scores on both the observer- and the self-report questionnaires are clearly in contrast with many other reports on the incidence of depression in IFN- treatment, in which the incidence of depression is much higher.2,3 Also, the sometimes-reported increase in irritability during IFN- treatment could not be conrmed in our study population.3,4,29,30 According to several authors, the level of depressive symptoms at baseline is predictive of the development of IFN-induced psychiatric disturbance at a later time.3,6 This could be a partial explanation for our ndings because, as a group, the mean SCL90 score of our oncology patients during the course of their IFN- treatment is low, as compared with the average range of 113123 in the normal (healthy) Dutch population.26 The scores on the other rating scales conrm the normalcy of our study population, who are able to resist the threats to their mental health by both the oncological disease and the IFN- treatment. One might speculate on the Dutch attitude and ability
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