This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Capuron, L. Articles by Dantzer, R. Search for Related Content PubMed PubMed Citation Articles by Capuron, L. Articles by Dantzer, R. Social Bookmarking                            What's this?

Early Depressive Symptoms in Cancer Patients Receiving Interleukin 2 and/or Interferon Alfa-2b Therapy

From the Institut National de la Santé et de la Recherche Médicale U 394, Neurobiologie Intégrative, Institut François Magendie, and Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France.

Address reprint requests to Lucile Capuron, PhD, Institut National de la Santé et de la Recherche Médicale U 394, Neurobiologie Intégrative, Institut François Magendie, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France; email lucile.capuron{at}vignemale .bordeaux.inserm.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INF-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INF-2b in cancer patients during the first days of cytokine immunotherapy.

PATIENTS AND METHODS: The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INF-2b (n = 6); or with INF-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment.

RESULTS: Patients treated with IL-2 alone or in association with INF-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INF-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INF-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints.

CONCLUSION: IL-2 and INF-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CYTOKINES ARE soluble mediators that are synthesized and released by activated immune cells and stimulate proliferation and differentiation of immunocompetent cells. Because of their stimulating effects on immune responses, cytokines are used in the treatment of several pathologies associated with immunologic disturbance, such as multiple sclerosis, chronic hepatitis, AIDS, and cancer.

The main cytokines used in oncology are interferon alfa-2b (INF-2b), used in the treatment of high-risk metastatic melanoma,¹ and interleukin (IL)-2, used in the treatment of metastatic renal cell carcinoma.^2-5 The main drawbacks of these agents are their side effects. The incidence and severity of these side effects depend on the dose and the route and order of administration of the cytokine, and the side effects are usually reversible within a few days after cessation of treatment.⁶ The intensity of these side effects may be detrimental to the patient’s quality of life and may necessitate high medical supervision with symptomatic treatment and adjustment or discontinuation of the specific antitumoral treatment.^1-4,7,8

Mechanisms of the side effects of cytokine therapy remain unclear. Cytokines may be directly or indirectly toxic, via the production of other cytokines (IL-1, IL-6, tumor necrosis factor, or interferon gamma).⁹ The neuropsychiatric complications that accompany cytokine treatment suggest that cytokines act in the CNS. Cytokines have neuroregulatory functions and act as the main mediators of communication between the immune system and the CNS.¹⁰ They induce fever by increasing the hypothalamic thermoregulatory set point,¹¹ activate the hypothalamic-pituitary-adrenal axis,^12,13 and alter brain neurotransmitter levels.¹⁴ In addition, cytokines induce profound behavioral alterations in the form of sickness behavior.^10,15 These central effects of cytokines are mediated by cytokine receptors localized on various brain structures, such as the hippocampus, hypothalamus, cerebral cortex, choroid plexus, and cerebellum.^16,17

The neuropsychiatric complications induced by cytokines are numerous. In addition to flu-like symptoms, patients receiving cytokine immunotherapy, mainly with IL-2 or INF-2b, report sleep disturbance, loss of appetite, depressed activity levels, loss of interest in usual activities, and mood and cognitive disorders.^18-21 Similar symptoms develop in animals injected with cytokines, and some of these symptoms are indicative of depression or anxiety states.²² For example, systemic administration of IL-2 to rats induces anhedonia in the form of decreased responding for rewarding lateral hypothalamic stimulation.²³

Several clinical studies have investigated the neuropsychiatric effects of IL-2 and INF-2b treatments. In early studies, IL-2 was administered intravenously (IV)¹⁹ and the occurrence of severe behavioral alterations in treated patients was largely related to this mode of administration, of which the toxicity is now well known. In most cases, the neuropsychiatric effects of cytokines are usually described after several weeks of treatment, when they are severe and clinically obvious.^8,21,24 However, the time course of development of these effects remains largely unknown, and their early manifestations have not been studied.

The purpose of the present study was to investigate the possibility of occurrence of subtle mood changes in cancer patients during the first days of treatment with cytokines. We focused on the depressive and anxiety symptoms induced by IL-2 and/or INF-2b immunotherapy in patients with renal cell carcinoma or melanoma. Because this study was carried out in a clinical setting, different modalities of treatment were used, which enabled us to specify the influence of the therapeutic protocol on the appearance of neuropsychiatric effects.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
The present experiment was carried out at Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France. The study was approved by the local committee for the protection of patients in biomedical research (CCPPRB Bordeaux A). Written informed consent was obtained from each patient participating in the study.

Between July 1997 and May 1999, 48 cancer patients were enrolled onto the present study. Patients were divided into four treatment groups (Table 1).

The second group (IL-2+INF-2b treatment group) included six patients (five men and one woman) with metastatic renal cell carcinoma. The mean age was 50.2 ± 11.2 years. Patients were treated with SC IL-2 and INF-2b. IL-2 was administered in two injections per day for 5 consecutive days. The daily dose was 18 x 10⁶ IU/m². INF-2b was administered on days 1, 3, and 5 in doses of 6 x 10⁶ IU.²⁵

The third group (SC INF-2b treatment group) consisted of eight patients with metastatic renal cell carcinoma treated with INF-2b. There were four men and four women, and the mean age was 60.0 ± 12.9 years. INF-2b was administered SC on days 1, 3, and 5 in daily doses of 18 x 10⁶ IU.

The fourth group (IV INF-2b treatment group) included 14 patients with high-risk metastatic melanoma treated with adjuvant high-dose INF-2b according to the protocol of Kirkwood et al.¹ There were seven men and seven women, and the mean age was 41.2 ± 13.9 years. INF-2b was injected IV in daily doses of 20 x 10⁶ IU/m² for 5 consecutive days.

None of the study participants had a psychiatric history or affective disorder before initiation of treatment. Psychologic evaluation was not done when patients experienced World Health Organization (WHO) grade 2 fever, headache, myalgia, or vomiting event.²⁶ Mood assessment was conducted by one investigator (L.C.), and medical follow-up was performed by one physician (A.R.).

Mood Assessment
Mood was assessed using the French version of the Montgomery and Asberg Depression Rating Scale (MADRS)²⁷ and the French version of the Covi scale.²⁸ The MADRS measures the intensity of depressive symptoms through evaluation of 10 specific items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts). The Covi scale measures the intensity of anxiety symptomatology through evaluation of three general items (anxiety perceived by the examiner in the patient’s verbal report, anxiety perceived in the patient’s behavior, and intensity of somatic complaints reported by the patient). These scales were used on the first day of patient hospitalization before initiation of treatment (day 1) and on days 3 and 5 of treatment. Neuropsychiatric evaluations were carried out between 10:00 AM and 12:00 noon, whereas cytokine therapy was administered in the afternoon, with the exception of treatment with IL-2 in combination with INF-2b. In that treatment, the first injection of IL-2 was given in the morning, so the neuropsychiatric evaluation was sometimes performed between this injection and the other two.

Because two types of cancer (renal cell carcinoma and melanoma) were considered in our study, we verified that there was no bias in the form of significant differences in mood scores between these two populations at the start of the study (data not shown).

Clinical and Biologic Work-up
Patients were hospitalized for 6 days during initiation of treatment (1 pretreatment day and treatment days 1 through 5). Blood pressure, temperature, and heart rate were measured at least once a day, for determination of toxicity (WHO toxicity scale).²⁶ Two or three times during the week, leukocyte and absolute neutrophil counts were performed and creatinine and transaminase levels were determined.

Associated Medications
Several medications were used to control side effects due to cytokine therapy: paracetamol was systematically administered to all participants to prevent cytokine therapy–induced fever and flu-like symptoms; ketoprofen was administered to three patients who developed fever and associated symptoms despite administration of paracetamol; antiemetic medication (ondansetron, metopimazine, and metoclopramide) was administered to 14 patients as needed; and morphine-like drugs, hypnotics, and anxiolytics were used for pain and sleep disturbance when necessary.

Statistical Analysis
For each variable, mean scores were compared by two-way analysis of variance, with groups as an independent factor and days as a repeated-measures factor. Post hoc analyses (Newman-Keuls tests) were performed when appropriate.

The relationship between MADRS scores on day 3 and MADRS scores on day 5 was calculated using simple regression analysis. All tests of statistical significance were two-sided.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Depressive Symptoms
As shown in Fig 1, IL-2 administered alone or in combination with INF-2b induced depressive symptoms on day 5 that were initiated on day 3. Analysis of variance indicated significant group (F(3,44) = 3.02, P = .039) and time (F(2,88) = 11.83, P = .00001) effects and a significant interaction between the group and day factors (F(3,44) = 3.61, P = .003). Simple main effects showed that whereas they were comparable in terms of MADRS scores before treatment, groups were significantly different on day 5 (day 1: F(3,70) = 1.25, P = .297; day 5: F(3,70) = 7.03, P = .0003), and simple main effects also demonstrated that only patients treated with IL-2 alone (F(2,88) = 6.39, P = .0026) and patients treated with the two cytokines (F(2,88) = 13.15, P = .00001) had increased depression scores during the first week of treatment. Post hoc analyses (Newman-Keuls tests) showed that patients treated with IL-2 alone had significantly lower mean MADRS scores on day 1 than on day 3 (P = .029). At this time in treatment, three of these patients had severe depressive symptoms (MADRS score > 15^29,30). Likewise, patients treated with the two cytokines had higher depression scores on day 3 than before treatment, although the difference was not significant. Depressive symptoms became more pronounced and clear-cut on the fifth day of treatment in patients treated with IL-2 alone and in patients treated with IL-2 and INF-2b. At this time in treatment, the two groups of patients had significantly increased MADRS scores compared with day 1 scores (IL-2 treatment group: P = .0024; IL-2+INF-2b treatment group: P = .0035). In contrast, no change in MADRS scores was observed for patients treated with INF-2b alone, whatever the dose and the mode of administration. Complementary analysis showed that the depressive symptoms on day 5 were significantly more pronounced in patients treated with the two cytokines than in patients treated with IL-2 alone (Newman-Keuls test, P = .041). Three of six patients treated with IL-2 and INF-2b and five of 20 patients receiving IL-2 alone had severe depressive symptoms on day 5 (MADRS score > 15). In the group of patients treated with INF-2b alone, only three of 22 had severe depressive symptoms on the fifth day of treatment.

View larger version (27K): [in this window] [in a new window]   Fig 1. MADRS depression scores on day 1 (before treatment; ), day 3 (), and day 5 (). *P < .05; **P < .01.

View larger version (11K): [in this window] [in a new window]   Fig 2. Relationship between MADRS scores on days 3 and 5 of patients treated with IL-2, alone or in combination with INF-2b. Scores on day 3 significantly predicted scores on day 5: Y = 0.86X + 4.28; R = 0.632, P < .001.

Anxiety Symptoms
Figure 3 shows the anxiety scores of the treatment groups on days 1, 3, and 5. There was a significant interaction between group and day factors (F(6,88) = 2.63, P = .021). Simple main effects showed that on the fifth day of treatment, the mean Covi scale scores differed between groups (F(3,84) = 3.09, P = .031), whereas they were comparable before initiation of treatment and on the third day of therapy (P = .236 and P = .925, respectively). Only patients treated with the two cytokines had increased anxiety scores (F(2,88) = 5.65, P = .0049). Post hoc analysis (Newman-Keuls test) showed that the Covi scale scores of these patients were significantly higher on day 5 than on day 1 (P = .016). Patients treated with IL-2 alone or INF-2b alone had no anxiety symptoms during treatment.

View larger version (24K): [in this window] [in a new window]   Fig 3. Covi scale anxiety scores on days 1 (), 3 (), and 5 (). *P < .05.

Other Adverse Effects of Treatment
Other side effects induced by IL-2 and INF-2b therapy were scored using WHO criteria so that any influence on neuropsychiatric assessment might be detected. Asthenia and nausea occurred more commonly in patients treated with IL-2 in combination with INF-2b, whereas leukopenia was more frequent in patients treated with high-dose IV INF-2b (Table 3). Fever episodes were widely reported, especially in patients treated with IL-2 alone.

Medications used for alleviating the somatic side effects of cytokine therapy had no apparent effect on the development of depressive symptomatology. All patients were administered paracetamol. One of the three patients who were administered ketoprofen had increased MADRS scores.

Nonparametric correlation analysis was also used to verify that the development of depressed mood during cytokine immunotherapy was not related to intake of antiemetic medication, psychotropic drugs such as anxiolytics or hypnotics for sleep disturbance, or morphine-like drugs, codeine, or other analgesics for pain control. Administration of antiemetics had no influence on MADRS and Covi scale scores on day 5 ( = 0.08 and = 0.148, respectively; P > .05). Further, administration of analgesics before or during treatment was not associated with increased depression scores on day 5. Administration during the first therapeutic week of anxiolytics or hypnotics for sleep disturbance was positively correlated with MADRS scores on day 5 ( = 0.364, P = .012). This is not surprising given that sleep disturbance is one of the most common symptoms of depression. In contrast, use of hypnotics before initiation of treatment was not associated with increased MADRS scores on day 5.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the present study, the early psychiatric effects of SC IL-2 and INF-2b were studied in 48 patients with melanoma or renal cell carcinoma. IL-2 alone or in combination with INF-2b increased depression scores on the MADRS as early as treatment day 3, and the scores on that day predicted those reached on day 5. INF-2b alone had no effect during the first 5 days of treatment. In contrast with the changes observed on the MADRS, anxiety scores on the Covi scale were not affected by cytokine treatment, except in patients receiving IL-2 in combination with INF-2b. The higher Covi scale scores of these patients on day 5 were entirely accounted for by increased somatic complaints.

IL-2 alone or in combination with INF-2b has repeatedly been reported to induce a range of neurotoxic effects, including fatigue, decreased mental performance, depression, and, in a minority of cases, confusion and psychosis.^19,31 Although they spontaneously regress after cessation of cytokine therapy,¹⁹ their impact on patients’ ability to function may make it necessary to reduce doses and even stop immunotherapy. In our study, cytokine therapy was not adjusted in response to alterations in mood during the first week of therapy. A neuropsychiatric evaluation carried out at the end of the fourth week of immunotherapy revealed that of the 11 patients who had increased MADRS scores on day 5, four had dropped out of the study because of general intolerance, four still had depressive symptomatology (symptoms had worsened in three), and three had experienced some regression of their symptoms. It is important to be able to identify as soon as possible those patients who are at risk for neuropsychiatric complications so that early-intervention strategies, such as administration of antidepressant drugs, can be instituted.³² It is also important to be able to predict these manifestations of toxicity as soon as possible after initiation of treatment. However, there are few detailed reports of the neuropsychiatric effects of immuno-therapy in cancer patients, and reports of observations made early in treatment are scarcer still. In the first systematic study of the neuropsychiatric effects of IL-2, depression, as measured by the Beck Depression Inventory, was observed only when IV IL-2 was injected in combination with lymphokine-activated killer cells, and it occurred after 2 weeks of treatment.¹⁸ The high doses of IV IL-2 administered in these pioneering studies also induced severe behavioral and cognitive changes. Psychologic and psychiatric effects of recombinant IL-2 therapy were described in a more recent study involving patients with advanced colorectal cancer who received IV injections of chemotherapy alone or IL-2 and chemotherapy.^33,34 Compared with patients given chemotherapy only, patients who received immunochemotherapy reported reduced energy, impaired confidence, worse depressed mood, and more confusion. Deterioration in scores on cognitive tests occurred progressively and increased with repetition of treatment. Of 17 patients, one became confused and another developed psychotic episodes in response to immunochemotherapy.

SC administration is associated with a decrease in the frequency and severity of side effects including the neurotoxic effects of IL-2. In our study, although most patients developed fever and neurovegetative symptoms, none developed agitation, confusion, or aggressive behavior. Mood assessment using the MADRS revealed relatively subtle effects of the treatment, well before the development of a full-blown depressive episode. The increase in MADRS score was not due exclusively to the neurovegetative symptoms but reflected authentic changes in mood states. Patients with high MADRS scores on day 5 displayed depressed mood and sadness, reported loss of interest and pleasure in usual activities, and complained of inner tension and cognitive disturbances. These patients differed from other patients before the start of treatment mainly in terms of lassitude, which might therefore be considered as a potential predisposing factor for depressive symptoms during cytokine treatment.

The lack of effect of INF-2b on MADRS scores might seem surprising given that this cytokine has repeatedly been reported to have the same mood depressing effects as IL-2.^35,36 However, all these studies were conducted after several weeks of INF-2b treatment, and we earlier confirmed that INF-2b treatment increases MADRS scoresafter 1 month of treatment.¹⁸ The most likely explanation therefore is that the development of depressive symptoms in response to INF-2b therapy requires several weeks of treatment. However, our results indicate that even if INF-2b does not by itself induce depressive symptoms during the first week of immunotherapy, it might act synergistically with IL-2 and amplify the neuropsychiatric effect of this cytokine, given that the depressive symptoms induced by IL-2 administered with INF-2b were more pronounced than those induced by IL-2 alone. This interpretation needs to be confirmed, however, because the more severe depressive symptoms observed in patients treated with the two cytokines might also be due to the higher dose of IL-2 administered in this therapeutic protocol.

Although IL-2 alone or in combination with INF-2b induced depressive symptoms, of high intensity in some cases, it did not cause any real anxiety, as measured by the Covi scale. Anxiety scores at the end of the first week of treatment were not significantly different from those obtained before initiation of therapy among patients treated with IL-2 alone or INF-2b alone. Covi scale scores of patients treated with the two cytokines were increased on day 5 compared with day 1, but they were more the reflection of an increase in somatic complaints associated with the side effects of treatment than the sign of a specific anxiety syndrome. This dissociation between anxiety and depression was unexpected, in view of the overlap between these disorders in clinical practice.³⁷ A possible explanation is that patients were already apprehensive before the start of treatment. However, patients in the present study had an initial mean Covi scale score of 2 to 3, whereas among patients with anxiety disorders, this score is usually higher than 6.³⁸ The most parsimonious explanation is therefore that cytokine therapy may exert specific effects on mood. This interpretation is in accordance with the observation of a lack of anxiety symptoms after 6 months of INF-2b therapy in patients with chronic hepatitis C, despite the development of depressive symptoms.³⁶ Nevertheless, in the present study, MADRS scores were positively correlated with Covi scale scores (R = 0.86, P < .0001), indicating that depressive mood overlaps with anxiety at the individual level.

There has been relatively little investigation into the mechanisms of effects on the brain by cytokines used in immunotherapy. The range of symptoms observed is consistent with a frontal-subcortical brain dysfunction that still needs to be confirmed using brain imagery.²¹ IL-2 and INF-2b have profound effects on behavior and neurotransmitter metabolism in laboratory animals. Short-term administration of IL-2 had no anxiogenic-like effect but decreased responding for rewarding brain self-stimulation in both rats and mice, an effect interpreted in terms of anhedonia.^14,39 Long-term IL-2 therapy impaired performance of a spatial learning task involving the Morris water maze,¹⁴ an effect consistent with the cognitive alterations displayed by IL-2–treated cancer patients.³³ Short-term IL-2 treatment inhibited dopamine release from the nucleus accumbens in rats, whereas long-term administration of IL-2 increased utilization of norepinephrine in the hippocampus and prefrontal cortex and utilization of serotonin in the hippocampus but not in the prefrontal cortex, where it decreased.¹⁴ IL-2 also modulated hippocampal acetylcholine release in a biphasic manner, depending on the dose,⁴⁰ and this effect was also induced by INF-2b. In contrast to IL-2, INF-2b regularly induced anorexia and depression of motor activity in mice.⁴¹ These effects were evident from the first administration of INF-2b, and they were not mediated by prostaglandins⁴² but were mediated by opioids, given that they were inhibited by pretreatment with naloxone, an antagonist of opiate receptors.⁴³ INF-2b has a wide range of effects on brain neurotransmitters, including enhancement of the transcriptional regulation of the serotonin transporter,⁴⁴ stimulation of the release of corticotropin-releasing factor from the amygdala and hypothalamus,⁴⁵ and inhibition of dopaminergic neurotransmission with repeated administration.⁴⁶ Although these effects cannot yet account for the neuropsychiatric effects of immunotherapy in cancer patients, they are consistent with a neurotropic activity of IL-2 and INF-2b and a different profile of activity for these two cytokines.

In conclusion, the results of the present study demonstrate that mild depressive symptoms are apparent after only 2 days of SC IL-2 immunotherapy alone or in combination with INF-2b and increase rapidly after 2 more days of treatment; 23% of the study patients had severe depressive symptoms (MADRS scores > 15) in this time. These depressive symptoms are not associated with increased anxiety and are not observed in response to INF-2b treatment alone. Studies should be conducted to determine whether these early symptoms can be used as predictors of neuropsychiatric complications and indicators of the need to modulate therapeutic interventions.

	ACKNOWLEDGMENTS

 
Supported by Institut National de la Santé et de la Recherche Médicale, the Ligue Nationale de Lutte Contre le Cancer, and the Fondation Pour la Recherche Médicale.

We thank all of the patients for their participation in our study, the hospital staff for their enthusiastic collaboration, and C. Charles, RN, Institut Bergonié, and C. Henry, MD, and F. Radat, MD, Department of Psychiatry, University of Bordeaux II, for their invaluable help.

	NOTES

 
Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial. J Clin Oncol 14:7-17, 1996[Abstract]

2. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-897, 1987[Abstract]

3. Sleijfer DT, Janssen RA, Buter J, et al: Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis. J Clin Oncol 10:1119-1123, 1992[Abstract]

4. Négrier S, Escudier B, Lasset C, et al: Interleukin-2, interferon or both in 425 patients with metastatic renal cell cancer: Results of a multicenter randomized trial. N Engl J Med 338:1272-1278, 1998[Abstract/Free Full Text]

5. Ravaud A, Debled M: Present achievements in the medical treatment of metastatic renal cell carcinoma. Crit Rev Oncol Hematol 31:77-87, 1999[Medline]

6. Fenner MH, Hanninen EL, Kirchner HH, et al: Neuropsychiatric symptoms during treatment with interleukin-2 and interferon-alpha. Lancet 341:372, 1993 (letter)

7. Ravaud A, Négrier S, Lakdja F, et al: Effets secondaires de l’interleukine-2. Bull Cancer 78:989-1005, 1991[Medline]

8. Ravaud A, Bedane C, Geoffrois L, et al: Toxicity and feasibility of adjuvant high dose interferon alpha-2b in patients with melanoma in clinical oncologic practice. Br J Cancer 80:1767-1769, 1999[Medline]

9. Plata Salaman CR: Immunoregulators in the nervous system. Neurosci Biobehav Rev 15:185-215, 1991[Medline]

10. Dantzer R, Bluthé RM, Layé S, et al: Cytokines and sickness behavior. Ann N Y Acad Sci 840:586-590, 1998[Medline]

11. Kluger M: Fever: Role of pyrogens and cryogens. Physiol Rev 71:93-127, 1991[Abstract]

12. Besedovsky HO, Del Rey AE, Sorkin E: Immune-neuroendocrine interactions. J Immunol 135:817-822, 1985

13. Buckingham JC, Loxley HD, Christian HC, et al: Activation of the HPA axis by immune insults: Roles and interactions of cytokines, eicosanoids, and glucocorticoids. Pharmacol Biochem Behav 54:285-298, 1996[Medline]

14. Anisman H, Merali Z: Anhedonic and anxiogenic effects of cytokine exposure, in Dantzer R, Wollman EE, Yirmiya R (eds): Cytokines, Stress and Depression. New York, NY,Plenum, 1999, pp 199-233

15. Dantzer R, Bluthé RM, Kent S, et al: Behavioral effects of cytokines: An insight into mechanisms of sickness behavior, in De Souza (ed): Neurobiology of Cytokines: Part B. San Diego, CA, Academic Press, 1993, pp 130-150

16. Hopkins SJ, Rothwell NJ: Cytokines and the nervous system: I. Expression and recognition. Trends Neurosci 18:83-88, 1995[Medline]

17. Rothwell NJ, Hopkins SJ: Cytokines and the nervous system: II. Actions and mechanisms of action. Trends Neurosci 18:130-136, 1995[Medline]

18. Capuron L, Ravaud A: Prediction of the depressive effects of interferon alfa therapy by the patient’s initial affective state. N Engl J Med 340:1370, 1999 (letter)[Free Full Text]

19. Denicoff KD, Rubinow DR, Papa MZ, et al: The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107:293-300, 1987

20. Valentine AD, Meyers CA, Kling MA, et al: Mood and cognitive side effects of interferon-alfa therapy. Semin Oncol 25:39-47, 1998 (suppl 1)[Medline]

21. Meyers CA: Mood and cognitive disorders in cancer patients receiving cytokine therapy, in Dantzer R, Wollman EE, Yirmiya R (eds): Cytokines, Stress and Depression. New York, NY,Plenum, 1999, pp 75-81

22. Yirmiya R: Endotoxin produces a depressive-like episode in rats. Brain Res 711:163-174, 1996[Medline]

23. Anisman H, Kokkinidis L, Borowski T, et al: Differential effects of interleukin (IL)-1beta, IL-2 and IL-6 on responding for rewarding lateral hypothalamic stimulation. Brain Res 779:177-187, 1998[Medline]

24. Renault PF, Hoofnagle JH, Park Y, et al: Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 147:1477-1580, 1987[Abstract/Free Full Text]

25. Négrier S, Ravaud A, Delva R, et al: Combination of cytokines in metastatic renal cell carcinoma: Is the subcutaneous route less active than the intravenous route? Proc Am Soc Clin Oncol 18:331a, 1999 (abstr 1273)

26. World Health Organization: Handbook for Reporting Results of Cancer Treatment [WHO publication no. 48]. Geneva, Switzerland, World Health Organization, 1979

27. Montgomery SA, Asberg A: A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382-389, 1979[Abstract/Free Full Text]

28. Covi L, Lipman R, McNair DM, et al: Symptomatic volunteers in multicenter drug trials. Prog Neuropsychopharmacol 3:521-533, 1979[Medline]

29. Bouvard M, Cottraux J: Echelle de dépression de Montgomery et Asberg, in Cottraux J (ed): Protocoles et Échelles d’Évaluation en Psychiatrie et en Psychologie. Paris, France,Masson, 1998, pp 139-141

30. Pellet J, Faure F, Lang F, et al: Etude de l’échelle de ralentissement sur un échantillon de sujets non ralentis, non déprimés. Psychol Med 18:1017-1020, 1986

31. Smith JH, Khayat D: Residual acute confusional and hallucinatory syndromes induced by interleukin-2/alfa-interferon treatment. Psychooncology 1:115-118, 1992

32. Miller A, Musselman D, Penna S, et al: Pretreatment with the antidepressant paroxetine prevents cytokine-induced depression during interferon-alpha therapy for malignant melanoma. Neuroimmunomodulation 6:237, 1999 (abstr)

33. Walker LG, Wesnes KP, Heys SD, et al: The cognitive effects of recombinant interleukin-2 (rIL-2) therapy: A controlled clinical trial using computerised assessments. Eur J Cancer 32A:2275-2283, 1996

34. Walker LG, Walker MB, Heys SD, et al: The psychological and psychiatric effects of rIL-2 therapy: A controlled clinical trial. Psychooncology 6:290-301, 1997[Medline]

35. Pavol MA, Meyers CA, Rexer JL, et al: Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia. Neurology 45:947-950, 1995[Abstract]

36. Hunt CM, Dominitz JA, Bute BP, et al: Effect of interferon-alpha treatment of chronic hepatitis C on health-related quality of life. Dig Dis Sci 42:2482-2486, 1997[Medline]

37. Goldberg RJ: Diagnostic dilemmas presented by patients with anxiety and depression. Am J Med 98:278-284, 1995[Medline]

38. Lecrubier Y: Echelle de gravité de l’anxiété de Covi, in Guelfi JD (ed): L’Évaluation Clinique Standardisée en Psychiatrie. Boulogne, France,Pierre Fabre, 1997, pp 303-307

39. Anisman H, Kokkinidis L, Merali Z: Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation. Brain Res 731:1-11, 1996[Medline]

40. Hanisch UK, Seto D, Quirion R: Modulation of hippocampal acetylcholine release: A potent central action of interleukin-2. J Neurosci 13:3368-3374, 1993[Abstract]

41. Dunn AL, Crnic LS: Repeated injections of interferon-alpha A/D in Balb/c mice: Behavioral effects. Brain Behav Immun 7:104-111, 1993[Medline]

42. Crnic LS, Segall MA: Prostaglandins do not mediate interferon-alpha effects on mouse behavior. Physiol Behav 51:349-352, 1992[Medline]

43. De Sarro GB, Masuda Y, Ascioti C, et al: Behavioural and ECoG spectrum changes induced by intracerebral infusion of interferons and interleukin 2 in rats are antagonized by naloxone. Neuropharmacology 29:167-179, 1990[Medline]

44. Morikawa O, Sakai N, Obara H, et al: Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 349:317-324, 1998[Medline]

45. Raber J, Koob GF, Bloom FE: Interferon-alpha and transforming growth factor-beta 1 regulate corticotropin-releasing factor release from the amygdala: Comparison with the hypothalamic response. Neurochem Int 30:455-463, 1997[Medline]

46. Shuto H, Kataoka Y, Horikawa T, et al: Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain. Brain Res 747:348-351, 1997[Medline]

Submitted August 13, 1999; accepted January 24, 2000.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Elovainio, A.-M. Aalto, M. Kivimaki, S. Pirkola, J. Sundvall, J. Lonnqvist, and A. Reunanen Depression and C-Reactive Protein: Population-Based Health 2000 Study Psychosom Med, May 1, 2009; 71(4): 423 - 430. [Abstract] [Full Text] [PDF]

				P. B. Jacobsen and H. S. Jim Psychosocial Interventions for Anxiety and Depression in Adult Cancer Patients: Achievements and Challenges CA Cancer J Clin, July 1, 2008; 58(4): 214 - 230. [Abstract] [Full Text] [PDF]

				J. E. Dimsdale and R. Dantzer A Biological Substrate for Somatoform Disorders: Importance of Pathophysiology Psychosom Med, November 1, 2007; 69(9): 850 - 854. [Abstract] [Full Text] [PDF]

				T. Rich, P. F. Innominato, J. Boerner, M. C. Mormont, S. Iacobelli, B. Baron, C. Jasmin, and F. Levi Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1757 - 1764. [Abstract] [Full Text] [PDF]

				L. E. Carlson, M. Speca, K. D. Patel, and E. Goodey Mindfulness-Based Stress Reduction in Relation to Quality of Life, Mood, Symptoms of Stress, and Immune Parameters in Breast and Prostate Cancer Outpatients Psychosom Med, July 1, 2003; 65(4): 571 - 581. [Abstract] [Full Text] [PDF]

				J. Pasic, W. C. Levy, and M. D. Sullivan Cytokines in Depression and Heart Failure Psychosom Med, March 1, 2003; 65(2): 181 - 193. [Abstract] [Full Text] [PDF]

				E. D. Caine and S. R. Schwid Multiple sclerosis, depression, and the risk of suicide Neurology, September 10, 2002; 59(5): 662 - 663. [Full Text] [PDF]

				L. CAPURON, R.-M. BLUTHE, and R. DANTZER Cytokines in Clinical Psychiatry Am J Psychiatry, July 1, 2001; 158(7): 1163 - 1163. [Full Text]

				L. Capuron, A. Ravaud, and R. Dantzer Timing and Specificity of the Cognitive Changes Induced by Interleukin-2 and Interferon-{alpha} Treatments in Cancer Patients Psychosom Med, May 1, 2001; 63(3): 376 - 386. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Capuron, L. Articles by Dantzer, R. Search for Related Content PubMed PubMed Citation Articles by Capuron, L. Articles by Dantzer, R. Social Bookmarking                            What's this?