ARTICLE
Auteur(s) : Ricard
Navinés1,2, Esther Gómez-Gil2, Susana
Puig3, Inmaculada Baeza4,5, Joan De
Pablo2, Rocío Martín-Santos1,2,5
1Unitat de Recerca Farmacològica (URF), Institut
Municipal d’Investigació Mèdica (IMIM), Doctor Aiguader 88,
E-08003, Barcelona, Spain
2Department of Psychiatry, Institut de Neurociències,
Hospital Clínic, Universitat de Barcelona, IDIBAPS, Barcelona,
Spain
3Melanoma Unit, Dermatology Department, Hospital Clínic,
Universitat de Barcelona, IDIBAPS, Barcelona, Spain
4Child and Adolescent Psychiatry and Psychology
Department, Hospital Clínic, Universitat de Barcelona, IDIBAPS,
Spain
5Centro de Investigación Biomédica en Red de Salud
Mental (CIBERSAM)
accepté le 12 Juillet 2009
Malignant melanoma is a tumor resulting from the malignant
transformation of melanocytes or tanning cells. It is the most
lethal type of skin tumor and its incidence is rising very fast
[1]. The main and often necessary treatment of malignant melanoma
is surgical removal. Moreover, numerous adjuvant immunotherapeutic
strategies have been developed [2]. Interferon-alpha-2b (IFN-alpha)
is an adjuvant treatment for patients with malignant melanoma at
high risk of recurrence [3, 4].
Melanoma patients often experience adjustment difficulties,
including distress; fear of death, recurrence or progression of
disease; changes in quality of life and social relationships; and
finally, depressive or anxiety disorders [5]. In addition,
interferon is associated with a number of toxicities, including
adverse effects on the central nervous system [6]. During
treatment, interferon may cause severe neuropsychiatric syndromes,
such as depressive symptoms, cognitive disturbances, chronic
fatigue syndrome, dysphoria, anxiety symptoms, anorexia, mania and
psychotic states [7-10]. It is difficult to define the relationship
between IFN-alpha treatment and neuropsychiatric complications
because there is a lack of specific studies. The mechanisms by
which IFN-alpha is able to influence brain function are unclear,
but several hypotheses had been proposed. First, interferon is able
to produce depressive symptoms through the central serotoninergic
system [11]. Second, by enhancing the production of hormones of the
hypothalamic-pituitary-axis (HPA), such as corticotrophin releasing
factor (CRF), because overproduction of CRF causes symptoms such
anxiety, anorexia, weight loss, changes in sexual behavior, changes
in body care activities and changes in sleeping pattern [12].
Finally, interferon stimulates the production of proinflamatory
cytokines, which may also activate the HPA axis [13].
However, the risk of depression induced by interferon is
difficult to assess. Interferon-induced depression may be connected
with depressive adjustment disorders starting at the beginning of
treatment (figure
1). These problems are more concerned with the announcement
of the diagnosis or with relapse of the illness, and its
seriousness than with the toxicity of the IFN-alpha molecule [14].
Nevertheless, there seems to be a relationship between the
prescription of interferon and the appearance of psychic disorders
[14]. On the other hand, both melanoma and interferon treatment can
provoke fatigue, irritability, anorexia, and other manifestations
also seen in depression [15]. Moreover, interferon is often part of
a combined drug treatment that may show additive toxicities
[2].
The aim of this prospective study was to illustrate clinical and
management differences between primary and IFN-induced depressive
disorders in all inpatients with malignant melanoma treated with
IFN-alpha and referred to the psychiatry consultation-liaison team
during a two year period.
Methods
The sample included all consecutive inpatients with malignant
melanoma treated with IFN-alpha-2b referred to the psychiatric
consultation-liaison service during a two year period in a general
teaching hospital (Hospital Clínic, Barcelona, Spain). Each patient
was interviewed in private on the dermatology ward using a
semi-structured interview. Moreover, at the initial psychiatric
evaluation, the Global Assessment of Functioning (GAF) and the
Clinical Global Impression-Severity of Illness (CGI-S) scale were
scored. At the end of hospitalization the Clinical Global
Impression-Improvement of Illness (CGI-I) was scored. Written
informed consent was obtained. The study protocol was approved by
the institutional review board.
The semi-structured interview included socio-demographic and
clinical variables: melanoma stage and adjuvant therapy received;
reasons for referral; time of onset; current psychiatric diagnosis,
lifetime psychiatric diagnosis, and type and dosage of
psychopharmacological treatment prescribed. Diagnostic assessment
was formulated according to the revised fourth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR;
American Psychiatric Association, 2000). Assignment of the current
psychiatric DSM-IV diagnosis required agreement between all the
consultation-liaison psychiatric staff involved in each case (a
psychiatrist in training, a psychiatry nurse and a senior
consultant).
The GAF is an observer-based rating scale for the current
overall functioning of a patient on a continuum from the most
severe mental disorder to complete mental health that was defined
as Axis V of the DSM-IV-R. Scale values range from 1 (sickest
individual) to 100 (the healthiest individual) [16]. A score
of 100 on GAF means superior functioning whereas a score of 40 or
below means some impairment in reality testing and communication or
major impairment in several areas, such as work or school, family
relations, judgment, thinking, or mood.
The CGI-S scale was used to rate psychiatric illness severity
[17]. The CGI-S scale requires the clinician to rate the severity
of the patient’s illness on a seven-point scale in which, 1 is
normal (not at all ill); 2 is borderline mentally ill; 3 is mildly
ill; 4 is moderately ill; 5 is markedly ill; 6 is severely ill; and
7 is among the most extremely ill.
The CGI-I scale was used to rate psychiatric illness severity
[17]. The CGI-I scale is a clinician-assessed seven-point score
that ranges from 1 (“very much improved”) to 7 (“very much worse”);
2 is much improved; 3 is minimally improved; 4 is no change; 5 is
minimally worse; 6 much worse.
Statistical analyses of data were carried out following a
descriptive study according to the statistical program SPSS.12 v.
Yates corrected chi-square contingency test (x2) between
the adjustment disorder group and the interferon-induced depressive
disorder group. Significant level was establish at p < 0.05.
Results
During the study period, 46 patients were referred from the
dermatology hospitalization department for psychiatric
consultation. The dermatological diagnoses were: malignant melanoma
in 34 patients, dermatitis in 5 patients, psoriasis in 3 patients,
Sézary syndrome in 2 patients, scleroderma in 1 patient and
delusion of infestations in 1 patient. Thirty-one patients with
malignant melanoma (67%) were treated with IFN-alpha-2b and were
included in the current study.
The characteristics of the 31 patients with malignant melanoma
treated with IFN-alpha-2b were: 19 (61.2%) were females and 12
(38.7%) were males; 5 (16%) aged less than 30 years, 13 (41.9%)
aged 30-49 years and 13 (41.8%) aged 50 years or older. Reason for
referral were depressive and/or anxiety symptoms in twenty-four
patients (77.4%), behavior disorders in five patients (16.1%), and
insomnia in two patients (6.5%). The main DSM-IV-TR diagnoses were
depressive adjustment disorders in 14 patients (45.16%), followed
by IFN-induced depressive disorders in 6 patients (19.36%), anxiety
disorders in four patients (12.9%), delirium in three patients
(9.68%), personality disorders in two patients (6.45%) and no
psychiatric diagnosis in two patients (6.45%). Thirteen patients
had lifetime psychiatric diagnoses: 5 patients had mixed
depressive-anxiety adjustment disorders prior to the melanoma
diagnosis; 4 patients had major depressive disorders; 2 patients
had generalized anxiety disorders and 2 patients had personality
disorders.
Depending on the stage of the malignant melanoma, the
IFN-alpha-2b treatment regimen was different. All patients for a
resected stage II/III melanoma (51.5%), were treated with a
high-dose regimen involving an induction phase of intravenous
IFN-alpha-2b 20 MU/m2/5 days a week for 4 weeks followed
by a maintenance phase of subcutaneous 10 MUI/m2/3 days
a week for 11 months and then 5 MUI/m2/8 days a week for
21-28 days. Of these patients, 19% received the interferon regimen
in combination with other adjuvant immunosuppressant agents.
Patients in stage IV (48.3%) were treated with interferon in
combination with chemotherapy. The average time of hospitalization
was 17 (4.1) days. Table 1 shows
comparisons of the two main diagnosis groups: adjustment depressive
disorder and IFN-induced depressive disorder.
Table 1 Adjustment depressive disorder versus
interferon-induced depressive disorder
|
|
Adjustment depressive disorder
|
Interferon-induced depressive disorder
|
|
|
Characteristics
|
|
N
|
%
|
N
|
%
|
p
|
|
|
14
|
70
|
6
|
30
|
0.200
|
|
Age
|
Under 30 years
|
3
|
21
|
1
|
17
|
|
|
30-45
|
5
|
36
|
3
|
50
|
|
|
46-64
|
4
|
28
|
2
|
33
|
|
|
65 or older
|
2
|
14
|
–
|
–
|
|
|
Melanoma stage and adjuvant therapy
|
Stage II
|
|
|
|
|
0.019
|
|
Interferon-alpha
|
–
|
–
|
2
|
33
|
|
|
Stage III
|
|
|
|
|
|
|
Interferon-alpha
|
2
|
14
|
3
|
50
|
|
|
Interferon in combination
|
1
|
7
|
–
|
–
|
|
|
Stage IV
|
|
|
|
|
|
|
Interferon in combination
|
11
|
79
|
1
|
17
|
|
|
DSM-IV-R Lifetime psychiatric diagnosis
|
Yes
|
5
|
36
|
1
|
17
|
0.070
|
|
No
|
9
|
64
|
5
|
83
|
|
|
GAF score
|
Good (> 80)
|
4
|
29
|
2
|
33
|
1.0
|
|
Mild (61-80)
|
3
|
21
|
–
|
–
|
|
|
Moderate (51-60)
|
5
|
36
|
4
|
67
|
|
|
Severe (< 50)
|
2
|
14
|
–
|
–
|
|
|
Psychopharmacological treatment
|
SSRI and BZD
|
11
|
79
|
3
|
50
|
0.060
|
|
SSRI alone
|
3
|
21
|
3
|
50
|
|
|
CGI-S
|
Not at all ill
|
–
|
–
|
–
|
–
|
0.044
|
|
Borderline mentally ill
|
–
|
–
|
–
|
–
|
|
|
Mildly ill
|
–
|
–
|
–
|
–
|
|
|
Moderately ill
|
8
|
57
|
–
|
–
|
|
|
Markedly ill
|
2
|
14
|
1
|
17
|
|
|
Severely ill
|
4
|
29
|
5
|
83
|
|
|
CGI-I
|
Not assessed
|
–
|
–
|
–
|
–
|
0.029
|
|
Very much improved
|
–
|
–
|
3
|
50
|
|
|
Much improved
|
2
|
14
|
3
|
50
|
|
|
Minimally improved
|
7
|
50
|
–
|
–
|
|
|
No change
|
5
|
36
|
–
|
–
|
|
|
Minimally worse
|
–
|
–
|
–
|
–
|
|
|
Much worse
|
–
|
–
|
–
|
–
|
|
Discussion
Interferon-alpha is of high interest in the adjuvant treatment of
malignant melanoma but psychiatric side effects can occur and lead
to a reduction or discontinuation of treatment [2]. In the present
series of 31 inpatients with malignant melanoma treated with
interferon and referred for psychiatric consultation, depression
was the most common diagnosis, more than half of the sample.
A primary disorder, adjustment depressive disorder, was the
most common psychiatric diagnosis. Several studies have shown that
half of all cancer patients have a psychiatric disorder, usually an
adjustment disorder with depression [18]. IFN-induced depression
occurred in a few patients, which in turn were the most severe.
Other patients treated with IFN-alpha, such as chronic hepatitis C
patients, have shown a greater prevalence of IFN-induced depression
[7]. Nevertheless, the results of the study are in accordance with
a recent study showing fewer psychiatric side effects than
anticipated in oncology patients treated with IFN-alpha [19]. Both
in primary and secondary depression, clinical management and
antidepressant treatment allowed continuation of interferon
therapy.
The association of interferon treatment with other psychiatric
side effects besides depression is widely reported [8, 9]. Other
reasons for referral to psychiatric consultation in our study were
anxiety disorders, behavior disorders, insomnia and others.
Similarly, it is also difficult to evaluate the role of this drug
in the etiology of these symptoms. In these patients, the
psychiatrist did not attribute these referral symptoms to the use
of interferon.
All except one patient showed clinical improvement with
antidepressant treatment, and a decrease in the doses of interferon
was not needed. The results of the study support that
discontinuation of interferon treatment is not usually required if
a depressive syndrome is diagnosed. Only in one case of IFN-induced
depressive disorder, after counseling with the psychiatrist, was
the IFN-alpha dose reduced, but not stopped.
Primary depressive disorder was associated with a more advanced
melanoma stage (55% in stage IV) but with a lower severity of
depression and a poorer therapeutic response than IFN-induced
depressive disorder. However, as the majority of adjustment
depressive disorders received interferon combined with other
adjuvant immunosuppressants, we cannot exclude that these other
agents may account for the depressive symptoms. Nevertheless, it is
widely recognized that antidepressant treatment, especially
selective serotonin reuptake inhibitors (SSRI), in depressive
adjustment disorders is effective and well tolerated [20].
A recent review in this field provides evidence that
antidepressants cause an improvement in depression, in patients
with a wide range of physical diseases, significantly more
frequently than either placebo or no treatment [21]. Antidepressant
medications should also be considered for the treatment of
moderate-to-severe depression in cancer patients [22].
Interferon-induced depressive disorder was associated with a
higher initial severity of depressive symptoms, but a lower
melanoma stage (II or III) than adjustment depressive disorder.
Moreover the psychopharmacological treatment response was better in
patients with induced-depressive disorder. In this group, in
contrast to the primary depression group, depressive symptoms were
rated as much or very much improved at the end of hospitalization.
Focusing on the effects of interferon, it is described an
antiserotoninergic mechanism. Accordingly, SSRI treatment seems to
be a good option for the treatment of IFN-induced depressive
disorders [23, 24]. Controlled clinical trials of SSRI in
interferon-induced depression are still to be published.
Nevertheless, several case-reports and naturalistic follow-up
studies have documented the usefulness of this group of
antidepressants [7, 25, 26].
In summary, in spite of the small sample size and the lack of a
control group, this preliminary study found that only a small
proportion of hospitalized patients with malignant melanoma treated
with interferon had an interferon-induced depressive disorder.
These cases were the most severe, however, clinical management and
antidepressant treatment allowed continuation of interferon
therapy. Future longitudinal consultation-liaison studies with
larger controlled samples will help in understanding the
relationship between depression and adjuvant interferon treatment
in melanoma patients.
Acknowledgments
The authors thank Marta Pulido, MD, for editorial assistance.
Conflict of interest: none. Financial support: none.
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