Annals of Oncology 10: 627-636. 1999.

1999 Kluwer Academic Publishers. Primed in the Netherlands

Review
Depression in breast cancer patients: The need for treatment
M. Aapro1 & A. Cull 2
x

Clinique de Genoher, Genolier, Switzerland; 2Department of Clinical Psychology, Western General Hospital, Edinburgh, UK

Key words: breast cancer, depression, diagnosis, treatment

Sadness, fear, anger, and grief are natural and understandable emotional reactions following a diagnosis of
cancer, and are usually overcome by standard social,
nursing and medical care. However, there is a need to
distinguish between this normal degree of sadness, which
patients might describe as depression, and clinical depression which exceeds the normal reaction in duration
nd/or intensity and which warrants recognition and
remedial intervention. Major depression according to
DSM-IV criteria [1] needs specialised intervention using
adequate psychological and pharmacological treatment
approaches. Furthermore, as many as one-fifth of
cancer patients may develop chronic depressive illness.
Apart from the additional unnecessary suffering this
comorbid depression can cause, many studies have suggested that depressed mood has a negative impact on
disease outcome. Therefore, diagnosis and treatment of
depression among patients treated for cancer may play a
crucial role in the prognosis of the disease, in addition to
improving the quality of life of the patient.
Prevalence

The prevalence of depression in the general population

is approximately 6% [2-4] However, the incidence of
depression in hospitalised medically ill patients is much
higher and has been reported in 22%-24% of patients [5,
6]. Massie and Holland [7] reviewed a number of studies
assessing the occurrence of comorbid depression in
cancer patients and found that the incidence of depression ranged from as high as 58% to as low as
4.5% [8-16]. The wide range in incidences can probably be attributed to variations between studies in patient populations, hospitalisation status, and disease
stage and type. In particular, the prevalence rates may
be affected by the application of different diagnostic
criteria. Standard diagnostic criteria for depression,
such as DSM-IV [1], may also contain a number of
criteria which reflect the symptoms associated with

cancer, leading to difficulties in accurate diagnosis

(Table 1).
Using data collected from three cancer centres where
the diagnostic criteria were based on DSM-III, Derogatis
et al. [13] ascertained that 6% of cancer patients had
major affective disorders and an additional 32% had
adjustment disorders, comprising 12% with depressed
mood, 13% with mixed emotional features, 6% with predominantly anxious mood, and 1% with 'emotion and
conduct' disorders. Also applying DSM-III criteria,
Massie and Holland [17] found that of 546 cancer patients referred for psychiatric consultations, 9% had
major depression and 54% had adjustment disorders, of
whom 47% were diagnosed as depressed, 31% had mixed
mood disorder, and 22% were primarily anxious. In a
study of 50 cancer patients by Hosaka and Aoki [18],
28%) were found to meet DSM-IV diagnostic criteria for
depression.
The incidence of depression in cancer patients appears to be dependent on the disease severity and level of
patient disability. Lansky et al. [15] evaluated 500 women
with cancer (190 of whom had breast cancer), and found
that Karnofsky performance status and history of depression were the factors most commonly associated
with comorbid depression. Similar results in hospitalised
Table I. DSM-IV criteria for major depressive episode [1].
At least five of the following symptoms to be present during the same
two-week period and represent a change from previous functioning: at
least one of the symptoms is either (1) or (2).
(1) Depressed mood most of the day. nearly every day.
(2) Markedly diminished interest or pleasure in all or almost all
activities most of the day, nearly every day.
(3) Significant weight loss or weight gain.
(4) Insomnia or hypersomnia nearly every day.
(5) Psychomotor agitation or retardation nearly every day.
(6) Fatigue or loss of energy nearly every day.
(7) Feelings of worth lessness or excessive or inappropriate guilt nearly
every day.
(8) Diminished ability to think or concentrate, or indecisiveness nearly
every day.
(9) Recurrent thoughts of death, recurrent suicidal ideation or suicide
attempt.

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Introduction

628

Depression and pain

Control of pain plays a key role in determining quality of
life for many patients with cancer. However, the issue of
pain and its relationship to depression in cancer patients
is still poorly understood. It is not yet clear whether

Table 2. Prevalence of depression in breast cancer patients.

Source

Number
of
patients

Prevalence
(%)

Assessment

Maguire et al.,
1978 [23]

201

26"

Structured diagnostic
interview

Silberfarbet al.,
1980 [24]

146

10"

Structured diagnostic
interview

Faberet al.,
1984 [25]

141

19.5"

HSC

Fallowfield et al.,
1990 [26]

269

20

Structured diagnostic
interview

Hopwoodet al.,
1991 [27]

81

20

HADS, RSCL

Hopwoodet al.,
1991 [28]

222

24.5"

HADS, RSCL

Goldberg et al ,
1992 [29]

320

32

RSCL

Pinder etal.,
1993 [30]

139

13

HADS, structured
diagnostic interview

91

55

HADS, structured
diagnostic interview

Ramirez et al ,
1995 [31]

Adapted from McDaniel et al. [22],

Abbreviations: HSC - Hopkins Symptom Checklist [32], HADS Hamilton Anxiety and Depression Scale [33], RSCL - Rotterdam
Symptom Check List [34].
a
Mean prevalence.

depression is causally related to chronic pain or if pain

causes depression. A recent study in patients with cancer indicated that pain may induce clinical depression
[36]. This study of 96 patients with either low or high
pain symptoms found that the incidence of all depressive
disorders was significantly higher in the high pain group
than in the low pain group (33% versus 13%, P < 0.05),
despite a history of major depression being significantly
more common in patients in the low pain group
(P < 0.05).
Current scientific concepts of pain emphasise the
multidimensional nature of the phenomenon, ie., nociception (generated by organic pathology) interacting
with psychosocial factors to determine behaviour. The
cognitive behavioural approach offers a way of thinking
about the relationship between pain and depression
which has implications for management. It focuses on
the role of perceived control over pain and perceived
interference of pain in life activities as mediating the
relationship between pain and depression [37]. While
pain restricts activity, fear and negative thinking about
pain may compound the problem. For example beliefs
that pain cannot be controlled or anticipation of catastrophic consequences may result in avoidance of activities which were previously associated with pleasure and
a sense of achievement. Loss of such activities can act as
a stimulus to depress mood, further confirming the cycle
of negative thinking. Thus, modifying perceived control
of pain and perceived interference of pain in life activ-

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cancer patients were reported by Bukberg et al. [14]:

77% of patients who scored lower than 40 on the Karnofsky scale (those most severely disabled) met the criteria for major depression, whilst only 23% of those with
scores of 60 or above did so.
Assessing the literature, Massie and Holland [7] estimated that a true incidence of major depression among
hospitalised cancer patients with significant levels of
physical impairment is at least 25%. This incidence of
depression in cancer patients is therefore comparable to
that seen in patients with other medical conditions. This
is contrary to the common assumption that cancer patients are more depressed than patients with other illnesses leading to hospitalisation.
The incidence of depression or anxiety, and subsequent suicide, in patients cured of cancer has been considered in a number of studies. Data indicate that cancer
patients in long-standing remission possess similar
anxiety rates to patients with active disease, suggesting
that anxiety in cancer survivors may be persistent and
not related to clinic attendance [19]. A survey of cured
cancer patients by Loge et al. [20] identified depression
and/or anxiety in 27% of respondents (14.5% anxiety;
4% depression; 8.5% anxiety and depression). Major
depression has also been reported to be more common
among suicide victims with cancer in remission than in
suicide victims with terminal cancer [21]. These data
indicate that depression is not only common in cancer
patients, but also in patients cured of cancer, who may
then commit suicide.
A number of studies have examined the incidence
of depression specifically in breast cancer patients and
found that the rate was similar to that of depression
comorbid with other cancers (10%-55%, Table 2). Pinder
et al. [30] studied 139 women with advanced breast
cancer; 25% scored 11 or above on either the self-report
Hospital Anxiety and Depression Scale (HADS) anxiety
or depression subscales, interpreted as indicating probable cases of depression and/or anxiety. In a study of 85
patients with breast cancer [35] 39% were found to be
suffering from a depressive disorder, compared with 11%
of control patients with benign breast disease (P =
0.0003). In addition, dysthymia was found in 15% of the
cancer patients compared with 5% of the control patients (P = 0.03).
Therefore, around a quarter of all breast cancer
patients have comorbid depression. Such comorbid depression significantly increases the burden of distress
and dysfunction for patients with breast cancer. There
is, however, evidence to show that if comorbid depression is recognised, it can be relieved.

629
ities might, in this formulation be expected to relieve
depressed mood. The application of cognitive behavioural techniques to managing the suffering of patients with
cancer pain is discussed in more detail by Fishman [38].
Whatever the initial causal factors of pain and depression, uncontrolled pain results in a vicious circle of
hopelessness and depression [39, 40]. Even if there is no
causal relationship, the presence of comorbid depression reduces the patient's capacity to tolerate pain and is
likely to be associated with an increased requirement for
pain relieving medication. Ideally, pain should be managed by a multidisciplinary pain team, incorporating the
skills of specialists including psychiatrists, as well as
radiologists, surgeons, and oncologists [41].

Effect of depression on breast cancer

The immune system in cancer and depression

The role of the immune system is to recognise and
defend against cells displaying foreign surface proteins,
whether from a pathogen or from alteration of normal
cell proteins. Thus, the continued growth and spread of
cancer cells can result not only from neoplastic transformation, but also from resistance to the host's immune system. Malignant cells can evade host defences
through a variety of mechanisms, including alterations
in the host's T-cell receptor/CD3 complex, or decreased
expression of major histocompatibility antigens on the
tumour cell, or secretion of suppressive cytokines [52].
Despite growing awareness of functional links between the immune system and the nervous system, and
research over the past 20 years into immunological functioning in psychiatric patients, it is still unclear whether
depressive illness leads to an impairment in resistance to
somatic illness (including cancer), as opposed to depression being secondary to physical illness [53]. A metaanalysis of controlled studies of depressed versus healthy
subjects revealed that clinical depression was associated
with lowered proliferative response of lymphocytes to
mitogens, reduced natural killer cell activity, and alterations in numbers of several white blood cell populations [54]. There appeared to be a relationship between
the severity of depression and the degree of changes to
immune functioning. Furthermore, in breast cancer patients, the stress of surgery was reported to be associated
with reduced lymphocyte-activated killer-cell activity
and was related to the severity of concurrent depression
and anxiety [55].
Further studies are required to establish the causal
relationship between depression, immune system changes,
and somatic illness, and to establish the comorbid risk
among patients with mood disorders for physical illnesses, including cancer.

Recognition and diagnosis

It has been demonstrated that emotional disturbance in
cancer patients commonly goes unrecognised and untreated. Early work by Maguire et al. [23] with mastectomy patients demonstrated that not only did staff fail to
recognise affective disorders, but that patients were
often reluctant to disclose their concerns. This observation led to a major body of work concerned with improving staff communication and counselling skills. In
busy routine practice the most effective way of detecting
patients with signs and symptoms of depression is probably through monitoring by specially trained nurses.
The diagnostic criteria for major depression, as defined in DSM-IV [1], include a number of signs and
symptoms which may be difficult to distinguish from

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Depression accompanying chronic medical illness is

associated with increased morbidity, length of stay in
hospital, and overall disability [42-45]. Clearly, patients
with depression and chronic illness will have a poorer
quality of life than those with chronic illness alone.
Additionally, a lack of recognition of depressive disorders may lead to the perception of worsening of the
chronic disorder and possibly to over treatment.
Major depression may also significantly reduce compliance with treatment. This has been shown for patients
with diabetes [46] and coronary heart disease [47]. Importantly, in the treatment of breast cancer, depressive
mood may decrease motivation and compliance with
chemotherapy [48], a critical issue in what may be lifesaving treatment. Ayres et al. [48] utilised two psychological instruments, the Mental Adjustment to Cancer
(MAC) scale and the Affect Balance Scale (ABS), to
assess mood and attitude in 74 women with primary
breast cancer receiving intravenously administered chemotherapy. Patients who achieved higher scores on the
MAC Fighting Spirit and ABS Anxiety, Depression and
Vigour scales were associated with significantly greater
adherence to a chemotherapy regimen (P < 0.05): high
scores on Guilt and Hostility scales were associated with
significantly lower levels of compliance (P < 0.05).
Recognition of depression is particularly important
in this patient population because of the effect of mood
on outcome in cancer patients. Patients who initially
react to a diagnosis of breast cancer with cancer 'denial'
or 'fighting spirit' have been shown to higher diseasefree survival rates at five- and eight-year follow-up than
those who react with stoic acceptance, helplessness, or
hopelessness [49, 50]. Psychosocial intervention to relieve distress in patients with metastatic breast cancer
has also been shown to increase mean survival time
significantly, compared with patients not receiving therapy (36.6 versus 18.9 months) [51].
The presence of depressive mood in patients with
cancer may therefore have a detrimental effect on outcome. Extrapolating from these data, it might be concluded that the long-term prognosis may be seriously

affected in breast cancer patients with major depression.

630
Table 3. Factors associated with increased risk of depression in breast
cancer patients.
- Previous history of treatment for psychiatric illness [12. 58].
- ^ 4 illness related concerns [59].
- Lack of confiding relationship [60].

fied as optimal [61]. These data underline the need for

screening methods and their cut-off scores to be carefully calibrated in the setting in which they are to be
applied. It is important to remember the ideal threshold
is likely to vary with the prevalence of the disorder in the
setting in question.
The RSCL was not designed as a psychiatric screening tool and although the HADS was and is widely used,
there are growing concerns about whether or not it is
effective for identifying patients in routine oncology
practice who warrant intervention. There are a number
of case finding instruments (for depression) which warrant further exploration in oncology [62]. When HADS
is used as the screening tool, subsequent assessment is
required to assess the number and severity of depressive
symptoms relative to recognised diagnostic criteria. A
briefer screening tool may be at least as effective for the
purpose of initial screening, for example the Mental
Health Inventory derived from the Medical Outcome
Survey, which consists of only five items. The performance of such screening tools might be improved by
taking into consideration factors which are known to
influence the vulnerability of patients to affective disorders.
A number of vulnerability factors have been identified as increasing the risk of depression in breast cancer
patients, including a past history of psychiatric illness,
the nature and number of cancer-related concerns, and
the lack of a confiding relationship (Table 3). A previous
history of being treated for psychiatric illness was shown
to be a significant predictor of psychiatric morbidity
following mastectomy by Dean [63], and an association
between past psychiatric disorder and severe depression
in advanced malignant disease has also been demonstrated [12]. More recently, Harrison et al. [64] found
that the nature and number of patients' illness-related
concerns is a useful marker for affective disorders: using
a checklist of concerns, patients with four or more
concerns were found to have significantly more anxiety
or depression. In community samples, the lack of a
confiding relationship has been shown to be associated
with an increased likelihood of depression following
adverse life events [65]. Although a relationship between
confiding concerns and psychological morbidity in cancer patients was not confirmed in a study by Harrison et
al. [64], other work does suggest that the perceived
quality of support from others is a predictor of psychological adjustment in such patients [66,67]. The presence
of risk factors in patients who are distressed should alert
doctors and nurses to the need for more detailed assessment of their mental state. Identification of unresolved

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the effects of cancer or that may be attributable to

cancer (Table 2). The assessment of patients with cancer
is therefore confounded by the difficulty in distinguishing between symptoms of cancer and standard depression markers, such as weight loss, impaired sleep and
insomnia, fatigue, and decreased libido [56].
Several systems of diagnosis modified for use in
medically ill patients have therefore been proposed. One
such system suggests removing anorexia and fatigue
from the list of diagnostic symptoms, as these are commonly associated with either the disease or side effects of
treatment [57]. However, excluding such markers may
decrease the sensitivity of the tests and increase possible
misdiagnosis: the authors therefore suggested that for
clinical purposes, all criteria may be included even if
there is a possibility that the symptoms may be attributed to the disease or treatment. It has also been suggested that more emphasis should be placed on psychological, rather than physical, symptoms, such as feelings
of helplessness, worthlessness, and wishing to die, as
primary criteria for depression [58].
Hopwood et al. [27] compared the screening performance of two questionnaires for psychiatric morbidity
in patients with advanced breast cancer: the Hospital
Anxiety and Depression Scale (HADS) [designed for
physically ill patients] and the Rotterdam Symptom
Checklist (RSCL) [designed specifically for cancer patients]. Results were compared with those of a psychiatrist who used the Clinical Interview Schedule. Seventyfive percent of patients were correctly identified as
suffering from an affective disorder by both the scales:
21% and 26% of 'normal' patients were mis-classified
by the RSCL and HADS, respectively. However, the
authors concluded that both questionnaires had good
predictive value and could be used in patients with
advanced cancer to help screen out those with an affective disorder. These data were confirmed by Ibbotson et
al. [59] in that both HADS and RSCL questionnaires
were found to be effective at detecting major depressive
illness and general anxiety disorders in a wide spectrum
of cancer types, but noted that the optimal cut-off score
varied with the patients disease and treatment status.
Razavi et al. [60] tested the HADS as a screening
method for detecting adjustment disorders and major
depressive disorders in a sample of 210 cancer inpatients. Receiver operating characteristic (ROC) curves
were used to express the relationship between the true
positive rate (sensitivity) and the false positive rate (1 specificity) for each HADS score. This enabled an optimum cut-off point to be chosen that balanced the costs
and benefits of treatment of psychological distress. For
screening for major depressive disorders only, the optimal cut-off score was found to be 19, associated with
70% sensitivity and 75% specificity. For screening for
adjustment disorders and major depressive disorders
together, a cut-off score of 13 which gave 75% sensitivity
and 75% specificity was optimal in this population. A
similar analysis performed in a lymphoma out-patient
population resulted in lower cut-off points being identi-

631

Management of depressed patients with cancer

Pharmacotherapy
As oncology patients receive a high level of concomitant
therapy, it is important that effective antidepressant
treatment is well tolerated and causes minimum side
effects. A low potential for possible drug-drug interactions is also of critical importance. Therefore, emphasis
should be placed on prescribing antidepressants with a
good tolerability profile. The altered absorption of antidepressants due to mucous membrane thickening or gut
atrophy secondary to chemotherapy or radiotherapy
must also be taken into account [75]. Thus, antidepressant drugs with a low therapeutic index, such as the
tricyclic antidepressants (TCAs), should be used with
caution in cancer patients.
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) have a
similar efficacy to the TCAs in depressed patients [7680] but are associated with fewer side effects and, in
particular, have very few anticholinergic effects [81, 82].
Efficacy and safety
To date, there are few published clinical data evaluating
the efficacy of SSRIs in cancer patients, although they
have been demonstrated to be effective in depressed
patients with other comorbid conditions, such as rheumatoid arthritis [83]. A recent multicentre study assessing the efficacy of fluoxetine in controlling anxiety/
depression in patients with cancer [84] did not show
fluoxetine to be effective. A total of 45 patients with
cancer were randomised to receive fluoxetine (20 mg)

and 46 to receive placebo; no differences were observed

between the two groups in the primary criterion for
efficacy (Hospital Anxiety and Depression Scale score
lower than 8 after five weeks), nor for secondary observerrated assessments (Montgomery and Asberg Depression
Rating Scale, HADS or Spitzer Quality of Life Index).
Patients receiving fluoxetine did, however, show a better
overall psychological assessment than those receiving
placebo, when judged by a decrease in the Revised
Symptom Checklist (SCL90-R). Significantly more patients dropped out of the study in the fluoxetine group
than in the placebo group (15 vs. seven patients, respectively; P = 0.04), although the frequency of side effects
was not significantly different between the two treatment
groups. A large, randomised, double-blind study of
paroxetine (20-40 mg) and amitriptyline (75-150 mg) is
currently ongoing in 180 breast cancer out-patients fulfilling the ICD-10 criteria for mild, moderate or severe
depression.
SSRIs have a number of properties which may be
advantageous in the treatment of cancer patients. Unlike
TCAs, SSRIs have the advantage of improving sleep
without causing daytime drowsiness. Comparisons of
paroxetine and TCAs have shown that whilst both improved sleep by comparison with placebo, TCA use was
associated with impaired daytime cognitive and psychomotor functioning [85]. However, agitation has been
reported with fluoxetine use in some patients and it may
be unsuitable for cancer patients who are agitated or
have severe insomnia [81].
Fluoxetine, nefazodone and paroxetine have analgesic properties which may reduce pain [86,87]. Data in
patients with chronic headache have confirmed paroxetine's analgesic efficacy in both open studies [88] and in
a double-blind comparison with sulpiride [89].
Although SSRIs are associated with a lower incidence
of side effects than the TCAs, they are not free from
unwanted effects. Gastrointestinal effects, including
nausea, are recognised side effects of SSRIs and may
present particular problems in patients undergoing
emetic chemotherapy. However, the incidence of nausea
with SSRIs is reported to decrease with continued treatment in depressed patients [82].
Some SSRIs are also associated with weight changes.
Fluoxetine has been reported to induce appetite suppression/weight loss [90], again an undesirable effect in
cancer patients in whom weight loss may occur as a
result of the disease, treatment, or nutritional difficulties. However, whilst paroxetine has been shown to reduce weight in overweight patients, no effect was seen in
non-overweight individuals [91]. One explanation for
this effect might be that appetite suppression/weight
loss is apparent in patients whose weight gain is associated with depression.
Paroxetine may have an advantage over TCAs in the
management of depressed patients at risk of suicide [92]:
a significant reduction in suicidal thoughts (P < 0.01)
and significantly fewer emergent suicidal thoughts
{P < 0.01) were shown with paroxetine by comparison

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concerns may be a useful starting point for intervention

[64].
Clinicians should also be aware that some drugs used
in the treatment of cancer may induce depression e.g.,
chemotherapeutic agents, vincristine, vinblastine, procarbazine, L-asparaginase, amphotericin B and interferon may cause mood changes of depressive nature
[68-70]. Steroids, prednisone and dexamethasone, commonly used with chemotherapy, are also known to cause
psychiatric disturbances which may include emotional
lability, and depression sometimes with suicidal ideation
[71, 72]. Benzodiazepine abuse has also been reported to
aggravate or even unmask depression [73, 74].
There is a need for cancer centres to implement
routine screening for major depression. Advances in
information technology are making this easier but there
is still a requirement for a clinical evaluation of patients
identified as 'cases' by the screening process. This does
not obviate the need for all staff in clinical practice to
acquire communication skills to elicit patients'concerns
and to have the ability (or access to the resources) to
deal with them.

632
with placebo and TCAs. The wide therapeutic margin of
SSRIs also suggests a lower potential for toxic effects in
overdose than TCAs and in general SSRIs are thought to
be safer in overdose [93]. Prevalence of suicide amongst
bone marrow transplant patients has recently been reported as around 3%, so clearly an antidepressant with
the potential to reduce suicidal thoughts will be a favourable treatment for cancer patients [94].

Adverse effects
Adverse effects commonly associated with TCAs limit
their use in this patient population. The most frequently
reported adverse effects related to their anticholinergic
actions - dry mouth, constipation, tachycardia, blurred
vision, urinary retention, and delirium. Orthostatic
hypotension and sedation are also common [95, 103].
Such a wide spectrum of adverse effects are potentially
hazardous for the cancer patient, who may suffer from
narcotic-induced constipation which may be compounded
by the anticholinergic effects of TCAs. For volume depleted patients TCA-induced orthostatic hypertension
may be a further problem. In addition, orthostatic hypertension may lead to falls and fractures in patients with
skeletal weaknesses or bone metastases. Patients with
radiation stomatitis will also require an antidepressant
relatively free from anticholinergic effects. TCA overdose
is potentially fatal as a result of autonomic instability,
cardiac arrhythmia or uncontrollable seizures [95].

Venlafaxine
Venlafaxine is an antidepressant which inhibits both
noradrenaline and serotonin reuptake. There are no
published clinical data evaluating the efficacy of venlafaxine in cancer patients. Although associated with
fewer side effects than the TCAs, venlafaxine has been
reported to induce significant weight loss and appetite
suppression in patients with major depression compared
with placebo (P < 0.05) which may be disadvantageous
in the cancer patient [97]. However, it is unclear whether
or not these patients were initially overweight (i.e., possibly related to depressive symptoms).

Drug interactions
TCAs are metabolised by at least three major cytochrome P450 enzymes, and therefore have the potential
to interact with drugs which interfere with this metabolism. Significant interactions include additive side effects
with other anticholinergic drugs (diphenhydramine,
phenothiazines); other quinidine-like drugs (quinidine,
procainamide); sedatives (ethanol, antihistamines, hypnotics) and hypotensive agents (clonidine, diuretics).
Neuroleptics, fluoxetine and methylphenidate may elevate serum TCA levels, whilst oestrogens, smoking and
inducers of hepatic microsomal enzymes may depress
tricyclic levels [95].

Tricyclic and related antidepressants

Monoamine oxidase inhibitors
Efficacy
Very few trials of TCAs have been carried out in depressed cancer patients, although several studies have
evaluated the effects of TCAs in depressed physically ill
patients. However, their use was associated with a high
incidence of discontinuations due to adverse effects [98,
99]. The efficacy and safety of mianserin 20 30 mg/day
has been assessed in 73 depressed women with cancer:
patients receiving mianserin showed significant improvement over placebo (Hamilton Rating Scale for Depression [HRSD]; P > 0.01) after seven days of treatment
[100]. In a more recent study by Van Heeringen and
Zivkov [101], 55 women with depression and breast
cancer were treated with mianserin 30-60 mg/day for
42 days. HRSD scores were reduced significantly in
the mianserin treatment group compared with placebo
(P ^ 0.05). An open pilot study in 39 depressed cancer

Monoamine oxidase inhibitors (MAOIs) are less commonly used antidepressants than the TCAs. There are no
reports in the literature on the use of MAOIs in depressed cancer patients and they may be considered
unsuitable for this population: dietary restrictions limit
the use of MAOIs, as cancer patients may already have
nutritional deficiencies and/or dietary restrictions related to their cancer. Pain management may also become an issue, as MAOIs are contraindicated with many
narcotic analgesics, especially meperidine, because of
the potential for hypertensive reactions.
Psychotherapy
Critical review [104, 105] and meta-analysis [106] of
published studies have demonstrated that a variety of

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Drug interactions
All SSRIs inhibit the cytochrome P450 enzyme system
to some degree and have the potential for interaction
with concomitant drugs, however, the clinical relevance
of such potential interactions has yet to be clarified.
SSRIs may interfere with the rate of activation of
cyclophosphamide, commonly used in the treatment of
breast cancer. However, although activation of cyclophosphamide may be slowed, the rate of activation is
not thought to be clinically significant [95]. SSRIs which
are highly protein-bound, such as fluoxetine, sertraline,
nefazodone and paroxetine, may interact with other
highly protein-bound drugs, such as cisplatin. Furthermore, fluoxetine has been reported to decrease the
efficacy of a commonly prescribed antiemetic agent,
ondansetron [96].

patients indicated that imipramine 25 mg tds improved

the HRSD scores of treated patients compared with controls not receiving antidepressant therapy [102]. TCA
treatment has also been shown to be effective in relieving
chronic pain, both independently of depression and in
conjunction with relief of depressive symptoms [45].

633
Table 4. Psychoeducational and psychotherapeutic interventions.
Psychoeducational approaches:
educational programmes covering pharmacological and psychological aspects of treatment, specifically including misapprehensions.
Psychotherapeutic intervention.
problem solving patients learn to use their own skill to cope with
problems;
relaxation training - e.g.. muscle relaxation combined with guided
imagery;
behavioural therapies - e g.. activity scheduling;
cognitive strategies e.g., reattribution, reality testing;
cognitive-behavioural therapy e.g . adjuvant psychological therapy.

Psychoeducational approaches
Education for cancer patients tends to cover disease and
treatment information, for example explaining the patient's experience of symptoms or side effects and
challenging misapprehensions about cancer and cancer
therapy [105]; the aim of such therapy is to reduce the
sense of helplessness and inadequacy which stems from
uncertainty, lack of knowledge or mistaken beliefs. Similar attention to information giving is useful in the
management of depression. Among patients with major
depression, a multifaceted structured treatment programme consisting of pharmacological and psychological elements and including specific education to correct
misapprehensions about depression and antidepressant
medication led to improved adherence and depression
outcomes [108]. A comparable structured approach
could prove valuable in the management of depressed
cancer patients.
Psychotherapeutic intervention
A number of psychotherapeutic intervention techniques
are available, including problem-solving, relaxation
training, and cognitive and behavioural therapies.
Problem-solving is a technique in which patients
learn to use their own skills and resources to cope with

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psychological intervention techniques, delivered separately or in combination, either to individuals or groups

of cancer patients, have a beneficial effect on emotional
adjustment. While patients with transient distress are
likely to respond to quite limited intervention, those
with more intense or more sustained psychological morbidity require more specific psychological intervention
and/or psychotropic medication [107]. With minimal
additional training, oncologists can deliver some basic
psychological interventions in routine oncology practice.
Similarly, several techniques can be used by specially
trained nurses. More complex psychotherapeutic interventions, however, require referral to a psychiatrist or
clinical psychologist.
Most psychological interventions are multifaceted,
but they can be broadly classified as psychoeducational
or psychotherapeutic [104]. A combination of both is
frequently used (Table 4).

present and future problems. In the primary care setting,

problem-solving has been shown to be as effective in the
treatment of depression as amitriptyline and more effective than a drug placebo [109]; the intervention was
delivered by general practitioners after a brief training
and patient satisfaction was high. A comparable strategy
could be tailored for depressed patients beset with cancerrelated problems.
A variety of relaxation techniques have been successfully used to help patients control anxiety, pain, insomnia
and anticipatory nausea and vomiting associated with
chemotherapy [110]. In a randomised trial of women with
early stage breast cancer, muscle relaxation combined
with guided imagery resulted in less mood disturbance
than relaxation alone or a control condition in which the
women were encouraged to talk about themselves [111].
Behavioural interventions, for example activity scheduling, are designed to encourage patients to experiment
with feelings of hopelessness/helplessness in a practical
way by engaging in specific tasks which challenge their
negative assumptions [112]. Activities are individually
selected to foster experiences of mastery and pleasure.
A pilot study demonstrated the potential of a behavioural programme in treating psychological distress following mastectomy [113]; the improvement in mood was
better maintained when the programme was used in
combination with anti-depressant medication.
Cognitive approaches interpret the psychological
features of depression as resulting from the patient's
tendency to view the self, the world and the future in a
distorted and unrealistically negative way. Therapy seeks
to demonstrate to patients the relationship between their
emotional distress and underlying negative automatic
thoughts, and a variety of techniques are then used to
help patients to identify and challenge these negative
thoughts e.g., reattribution (looking for alternative explanations), reality testing (what is the evidence to support/contradict the negative beliefs?). The aim of these
strategies is to foster a more positive attitude and a
greater sense of personal control.
Adjuvant psychological therapy (APT) is a cognitivebehavioural therapy developed specifically for cancer
patients. In a prospective randomised trial [114, 115],
APT reduced the proportion of patients with depression
from 40% at baseline to 18% at four months. In the
control group, the proportion of patients who were depressed at baseline and four months were 30% and 23%,
respectively. At one-year follow-up, 11% of patients who
received APT were depressed, compared with 18% of
controls.
Supportive group therapy for patients with metastatic
breast cancer has been shown to result in improved
mood, fewer maladaptive coping responses and reduced
pain [116-118]; interestingly, a significant survival advantage was observed in the intervention group.
Combination of psychoeducational and psychotherapeutic intervention. A six-week intervention package
developed by Fawzy and Fawzy [119] combines health
education with training in stress management and cop-

634
ing skills in the setting of a group which offered social
support and opportunity for emotional expression. A
distinctive feature of this programme is the use of pictures depicting common scenarios for the woman with
breast cancer, including depression: for each scenario, a
pair of pictures illustrated examples of adaptive (i.e.,
active cognitive or behavioural) and maladaptive (i.e.,
avoidant) coping, as stimulus to group discussion. This
intervention model, originally evaluated among patients
with malignant melanoma, has been shown to lead to
sustained improvement in affective state and coping
[120]. Interestingly, this intervention has been shown to
be associated with changes in several immune system
parameters [121] and with lower rates of recurrence and
improved survival [122].

5.
6.
7.
8.

9.
10.
11.

12.

A significant proportion of cancer patients are likely to

experience an adjustment disorder in which depressed
mood is a significant feature, while only a small proportion develop major depressive illness. There is increasing
recognition of the need for medical and nursing staff to
have training in communication skills to improve their
ability to elicit and respond to patient concerns. Improving such communication may prevent the development
of emotional disturbance and improve the detection of
those whose distress warrants intervention.
While cancer patients with a major depressive disorder or a complicated psychiatric history would benefit
from the specialist intervention of a clinical psychologist
or psychiatrist, oncologists should also be prepared to
manage the symptoms of depression when they occur
using both pharmacological and psychological therapies. Research into antidepressant therapy in cancer
patients has shown that TCAs are associated with an
unacceptably high incidence of adverse effects. The
SSRIs, whilst requiring further evaluation in this patient
population, may offer an effective antidepressant therapy with an improved tolerability profile.
There is a growing recognition that quality of life,
rather then just quantity, is the most important goal in
the management of the patient with cancer. Achieving
this goal requires attention to be given to patients'
psychological well being as well as to tumour control
and symptom relief.

13.

14.
15.

16.

17.

18.
19.

20.

21.
22.

23.
24.

25.

References
1. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders. Fourth Edition. Washington, DC:
American Psychiatric Association 1994.
2. Angst J. How recurrent and predictable is depressive illness?
In Montgomery S, Rouillon F (eds): Perspectives in Psychiatry,
Vol. 3. Chichester: Wiley 1992; 1-13.
3 Greenberg PE, Stiglin LE. Finkelstein ST et al. Depression: A
neglected major illness. J Clin Psychiatry 1993: 54: 419 24.
4. Lcpinc J-P. Gastpar M. Mendlewicz J et al. Depression in the

26.

27.

28.

29.

Downloaded from http://annonc.oxfordjournals.org/ by guest on February 18, 2015

Conclusions

community: The first pan-European study DEPRES (Depression

Research in European Society) Int Clin Psychopharmacol 1997:
12: 19-29.
Schwab JJ, Bialow M. Brown JM et al. Diagnosing depression in
medical inpatients. Ann Intern Med 1967; 67: 695-707.
Mofric H, Paykel ES. Depression in medical inpatients. Br J
Psychiat 1975; 126: 346-53
Massie MJ. Holland JC. Depression and the cancer patient. J
Clin Psychiatry 1990; 51 (Suppl 7): 12-17.
Koenig R, Levin SM. Brenman MJ. The emotional status of
cancer patients as measured by a psychological test. J Chron Dis
1967: 20: 923-30.
Hinton J. Psychiatric consultation in fatal illness Proc R Soc
Med 1972, 65: 1035-8.
Craig TJ. Abeloff MD. Psychiatric symptomatology among hospitalized cancer patients. Am J Psychiat 1974; 131: 1323-7.
Plumb MM, Holland JC. Comparative studies of psychological
function in patients with advanced cancer, I: Self-reported depressive symptoms. Psychosom Med 1977; 39: 264-76.
Plumb MM, Holland JC. Comparative studies of psychological
function in patients with advanced cancer, II: Interviewer-rated
current and past psychological symptoms Psychosom Med 1981;
43. 243-54.
Derogatis LR, Morrow GR, Fetting J et al. The prevalence of
psychiatric disorders among cancer patients. JAMA 1983; 249:
751-7.
Bukberg J. Penman D, Holland JC. Depression in hospitalized
cancer patients. Psychosom Med 1984; 46' 199-212.
Lansky SB, List MA, Herrmann CA et al. Absence of major
depressive disorder in female cancer patients. J Clin Oncol 1985;
3: 1553-60.
Evans DL, McCartney CF. NemeroffCB. Depression in women
treated for gynaecological cancer: Clinical and neuroendocrine
assessment. Am J Psychiat 1986; 143: 447-52.
Massie MJ, Holland JC. The cancer patient with pain- Psychiatric complications and their management. Med Clin North Am
1987,71:243-8.
HosakaT, Aoki T. Depression among cancer patients. Psychiat
Clin Neurosci 1996: 50: 309-12.
Thomas SF, Glynne-Jones R, Chait I et al. Anxiety in long-term
cancer survivors influences the acceptability of planned discharge
from follow-up. Psychooncology 1997: 6: 190-6.
Loge JH, Abrahamsen AF, Ekeberg O et al. Psychological
distress after cancer cure: A survey of 459 Hodgkin's disease
survivors. Br J Cancer 1997: 76: 791-6.
Henriksson MM, Isometsa ET, Hietanen PS et al. Mental disorders in cancer suicides. J Affect Disord 1995; 36: 11-20.
McDaniel JS. Musselman DM. Porter MR et al. Depression in
patients with cancer. Diagnosis, biology, and treatment. Arch
Gen Psychiat 1995; 52: 89-99.
Maguire GP, Lee EG. Bevingon DJ et al. Psychiatric problems in
the first year after mastectomy. BMJ 1978; 1: 963-5.
Silberfarb PM. Mauer LH. Crouthamel CS. Psychological aspects of neoplastic disease. I: Functional status of breast cancer
patients during different treatment regimens. Am J Psychiat
1980; 137: 450-5.
Faber JM. Weinerman BH. Kuypers JA. Psychosocial distress in
oncology outpatients. J Psychsoc Oncol 1984: 2: 109-18.
Fallowfield LJ. Hall A. Maguire GP et al. Psychological outcomes of different treatment policies in women with early breast
cancer outside of a clinical trial. BMJ 1990; 301: 575-80.
Hopwood P. Howell A. Maguire P. Screening for psychiatric
morbidity in patients with advanced breast cancer: Validation of
two self-report questionnaires. Br J Cancer 1991: 64: 353-6.
Hopwood P. Howell A. Maguire P. Psychiatric morbidity in
patients with advanced cancer of the breast: Prevalence measured
by two self-rating questionnaires. Br J Cancer 1991: 64: 349-52.
Goldberg JA, Scott RN, Da\ idson PM. Psychological morbidity
in the first year after breast surgery. Eur J Surg Oncol 1992: 18:
327 31.

635
57. Cohen-Cole SA, Brown FW. McDaniel JS. Diagnostic assessment of depression in the medically ill. In Stoudemire A, Fogel B
(eds): Psychiatric Care of the Medical Patient. New York: Oxford
University Press 1993: 53-70.
58. Mermelstein HT. Lesko L. Depression in patients with cancer.
Psychooncology 1992: 1: 199-215.
59. Ibbotson T. Maguire P. Selby P et al. Screening for anxiety and
depression in cancer patients: The effects of disease and treatment. Eur J Cancer 1994: 30A- 37^40.
60. Razavi D, Delvaux N. Farvacques C, Robaye E. Screening for
adjustment disorders and major depressive disorders in cancer
in-patients. Br J Psychiat 1990: 156: 79-83.
61. Razavi D, Delvaux N. Bredart A et al. Screening for psychiatric
disorders in a lymphoma out-patient population. Eur J Cancer
1992; 28A. 1869-72.
62. Mulrow CD, Williams JW Jr. Gerety MB et al. Case-finding
instruments for depression in primary care settings. Ann Intern
Med 1995; 122: 913-21.
63. Dean C. Psychiatric morbidity following mastectomy: Prospective predictors and types of illness. J Psychosom Res 1987: 31.
385-92.
64. Harrison J, Maguire P, Ibbotson Tet al. Concerns confiding and
psychiatric disorder in newly diagnosed cancer patients. A descriptive study. Psychooncology 1994; 3: 173-9.
65. Brown GW, Harris T Social Origins of Depression: A study of
psychiatric disorder in women. London: Tavistock Publications
1978.
66. Spiegel D, Bloom JR, Gottheil E. Family environment as a
predictor of adjustment to metastatic breast carcinoma. Psychooncology 1983; 1: 33-44.
67. Bloom JR, Spiegel. The relationship of two dimensions of social
support to the psychological well being and social functioning of
women with breast cancer. Soc Sci Med 1984; 19: 8317.
68. Holland JC, Fasanello S. Ohnuma T. Psychiatric symptoms
associated with L-asparaginase administration. J Psychiatr Res
1974. 10: 165.
69. Weddington WW. Delirium and depression associated with
amphotericin B. Psychosomatics 1982; 23: 1076-8.
70. Young DK. Neurological complications of cancer chemotherapy.
In Silverstein A (ed): Neurological Complications of Therapy.
Selected Topics New York: Futura Publishing 1982; 57-113.
71. Hall RCW, Popkin MK. Stickney SK et al. Presentation of the
steroid psychoses. J Nerv Ment Dis 1979: 167: 229-36.
72 Levenson JA, Lesko LM. Psychiatric aspects of adult leukemia.
Semin Oncol Nurs 1990, 6: 76-83.
73. Lydiard RB, Laraia MT, Ballenger JC et al. Emergence of
depressive symptoms in patients receiving alprazolam for panic
disorder. Am J Psychiat 1987; 144: 664-5.
74. Rosenbaum JF, Moroz G, Bowden CL. Clonazepam in the
treatment of panic disorder with or without agoraphobia: A
dose-response study of efficacy, safety, and discontinuance.
Clonazepam Panic Disorder Dose-Response Study Group. J
Clin Psychopharmacol 1997; 17: 390-400.
75. Lovejoy NC, Metteis M. Pharmacokinetics and pharmacodynamics of mood-altering drugs in patients with cancer. Cancer
Nurs 1996; 19: 407-18.
76. Stark P, Hardison CD. A review of multicenter controlled studies
of fluoxetine vs. imipramine and placebo in major depressive
disorders. J Clin Psychiat 1985; 46: 53-8.
77. Fawcett J. Zajecka JM. Kravitz HM et al. Fluoxetine versus
amitriptyline in adult outpatients with major depression. Curr
Ther Res 1989; 45: 821-32.
78. Dunbar GC. Cohn JB, Fabre LF et al. A comparison of paroxetine. imipramine, and placebo in depressed out-patients. Br J
Psychiat 1991; 159:394-8.
79. Link C. Dunbar GC. An overview of studies comparing the
efficacy, safety and tolerability of paroxetine and clomipramine.
Nord J Psychiat 1992; 27 (Suppl): 17-22.
80. Stott PC, Blagden MD, Aitken CA. Depression and associated
anxiety in primary care: A double-blind comparison of parox-

Downloaded from http://annonc.oxfordjournals.org/ by guest on February 18, 2015

30. Pinder KL. Ramirez AJ. Black MA et al. Psychiatric disorder in

patients with advanced breast cancer: Prevalence and associated
factors. Eur J Cancer 1993; 29A: 524-7.
31. Ramirez AJ. Richards MA. Jarrett SR et al. Can mood disorder
in women with breast cancer be identified preoperatively? Br J
Cancer 1995: 72: 1509-12.
32. Derogatis LR, Lipman RS. Rickels K et al. The Hopkins Symptom Checklist (HSCL): A self-report symptom inventory. Behav
Sci 1974: 19- 1-15.
33. Hamilton M. A rating scale for depression. J Neurol Neurosurg
Psychiat 1960. 23: 56-62.
34. De Haes JCJM. Pruyn JFA, Van Knippenberg FCE. Klachtenlijst voor kankerpatienten. eerste ervaringen. Ned Tijdschr
Psychol 1983; 38: 403-22.
35. Aragona M, Muscatello MRA. Mesiti M. Prevalence of depressive mood disorders in breast cancer patients of Southern Italy.
Ann N YAcad Sci 1996: 784- 482-5.
36. Spiegel D, Sands, Koopman C. Pain and depression in patients
with cancer. Cancer 1994: 74: 2570-8.
37. Rudy TE, Kerns RD. Turk DC. Chronic pain and depression:
Towards a cognitive behavioural mediation model. Pain 1998; 35.
129-40.
38. Fishman B The treatment of suffering in patients with cancer
pain. In Foley KM (ed): Advances in Pain Research and Therapy, Vol. 16. New York: Raven Press 1992; 301-316.
39. Roth AJ, Breitbart W. Psychiatric emergencies in terminally ill
cancer patients. Hematol Oncol Clin North Am 1996; 10: 23559
40. Spiegel D. Cancer and depression. Br J Psychiatry 1996; 168:
109-16.
41. Aapro MS. New clinical strategies for symptom management
and quality of life enhancement in cancer patients. Eur J Cancer
1997, 33 (Suppl 6): S1-S2.
42. Katon W, Kleinman A, Rosen G. Depression and somatization:
A review. Am J Med 1982, 72. 127-35.
43. Wells KB. Golding JM, Burnham MA. Psychiatric disorder and
limitations in physical functioning in a sample of Los Angeles
general population. Am J Psychiat 1988; 145: 712-7.
44. Wells KB, Golding JM, Burnam MA. Psychiatric disorder in a
sample of the general population with and without chronic
medical conditions. Am J Psychiatry. 1988; 145: 976-81.
45. Katon W. Sullivan MD. Depression and chronic medical illness.
J Clin Psychiatry 1990; 51 (Suppl 6): 3-11.
46. Surridge DHC, Williams Erdahl DL, Lawson JS et al. Psychiatric
aspects of diabetes mellilus. Br J Psychiatry 1984; 145: 269-76.
47. Blumenthal JS. Williams RS, Wallace AG et al. Physiological and
psychological variables predict compliance to prescribed exercise
therapy in patients recovering from myocardial infarction. Psychosom Med 1982; 44- 519-27.
48. Ayres A, Hoon PW, Franzoni JB et al. Influence of mood and
adjustment to cancer on compliance with chemotherapy among
breast cancer patients. J Psychosom Res 1994; 38- 393-402.
49. Greer S. Cancer and the mind. Br J Psychiatry 1983; 143: 535-43.
50. Pettingale KW. Morris T, Gree S et al. Mental attitudes to cancer:
An additional prognostic factor. Lancet 1985; I: 750.
51. Spiegel D, Bloom JR, Kraemer HC et al. Effect of psychosocial
treatment on survival of patients with metastatic breast cancer.
Lancet 1989. II: 888-91.
52. Kavanaugh DY, Carbone DP. Immunologic dysfunction in cancer. Hematol Oncol Clin North Am 1996: 10: 927-51.
53. Anderson JL. The immune system and major depression. Adv
Neuroimmunol 1996: 6: 119-29.
54. Herbert TB. Cohen S. Depression and immunity: A meta-analytic
review. Psychol Bull 1993; 113: 472-86.
55. Sachs G. Rasoul-Rockenschaub S. Aschauer H et al. Lytic
effector cell activity and major depressive disorder in patients
with breast cancer. J Neuroimmunol 1995: 59: 83-9.
56. Kathol RG. Mutgi A, Williams J et al. Diagnosis of major
depression in cancer patients according to four sets of criteria.
Am J Psychiat 1990; 147: 1021 4.

636

81.
82.
83.

84.

85.
86.
87.

89.

90.

91.

92.

93.

94.

95.
96.

97.

98.
99.

100.

101.

102.

103.

104.

105

106.

107
108.

109.

110.
111
112.
I 13.

114.

115.

116
117.
118.

119.
120.

121.

122.

and tricyclic antidepressants. Biomed Pharmacother 1987; 41:

377-82.
Massie MJ. Holland JC. Straker N. Psychotherapeutic interventions. In Holland JC, Rowlands JH (eds): Handbook of
Psychooncology. Chapter 38. New York: Oxford University Press
1989
Fawzy FI. Fawzy NW. Arndt LA et al. Critical review of
psychosocial interventions in cancer care. Arch Gen Psychiatry
1995, 52: 100-13.
Meyer TJ, Mark MM. Effects of psychosocial interventions with
adult cancer patients: A meta-analysis of randomised experiments. Health Psychol 1995; 14: 101-8.
Ramirez AJ. Liaison psychiatry in a breast cancer unit. J R Soc
Med 1989; 82: 15-7.
Katon W, Robinson P. von Korff M et al A mullifaceted
intervention to improve treatment of depression in primary care.
Arch Gen Psychiat 1996; 53: 924-32.
Mynors-Walhs LM, Gath DH, Lloyd Thomas AR et al.
Randomised controlled trial comparing problem solving treatment with amitryptiline and placebo for major depression in
primary care. BMJ 1995; 310: 441-5.
Holland JC, Rowland JH (eds). Handbook of Psychooncology.
New York: Oxford University Press 1989.
Bridge LR, Benson P. Pietroni PC, et al. Relaxation and imagery
in the treatment of breast cancer. BMJ 1988; 297- 1169-72.
Moorey S, Greer S. Psychological Therapy for Patients with
Cancer. Oxford. Heinemann Medical Books 1989.
Tarrier N, Maguire P. Treatment of psychological distress
following mastectomy. An initial report. Behav Res Ther 1984;
22-81-4.
Greer S, Moorey P, Baruch JDR et al. Adjuvant psychological
therapy for patients with cancer. A prospective randomised trial.
BMJ 1992; 304: 675-80.
Moorey S, Greer S, Watson M et al. Adjuvant psychological
therapy for patients with cancer: Outcome at one year. Psychooncology 1994; 3: 39-46.
Spiegel D. Psychosocial intervention in cancer. J Natl Cancer
Inst 1993; 85: 1198-205.
Spiegel D. Psychosocial aspects of breast cancer. Semin Oncol
1997: 24 (SI): 36-47.
Spiegel D. Bloom JR, Yalom I. Group support for patients with
metastatic cancer. A randomised outcome study. Arch Gen
Psychiat 1981; 38: 527-33.
Fawzy FI, Fawzy NW. A structured psychoeducational intervention for cancer patients. Gen Hosp Psychiat 1994; 16: 149-92.
Fawzy FI, Cousins N. Fawzy NWet al. A structured psychiatric
intervention for cancer patients. I changes over time in methods
of coping and affective disorders. Arch Gen Psychiat 1990; 47:
720-5.
Fawzy FI, Kemeny ME. Fawzy NWet al. A structured psychiatric intervention for cancer patients. II changes over time in
immunological measures. Arch Gen Psychiat 1990. 47: 729-35.
Fawzy FI. Fawzy NW. Hyun CS et al. Malignant melanoma:
effects of an early structured psychiatric intervention, coping and
affective state on recurrence and survival six years later. Arch
Gen Psychial 1993: 50: 681-90.

Received 23 February 1998: accepted 19 August 1998.

Correspondence to
Dr M. Aapro
Clinique de Genolier
Genolier
Switzerland

Downloaded from http://annonc.oxfordjournals.org/ by guest on February 18, 2015

88.

etine and amitriptyline. Eur Neuropsychopharmacol 1993: 3:

324-5.
Cooper GL. The safety of fluoxetine an update. Br J Psychiat
1988: 153 (Suppl 3): 77-86.
Jenner PN. Paroxetine: an overview of dosage, tolerability. and
safety. Int Clin Psychopharmacol 1992: 6 (Suppl 4): 69-80
Hunter B, Judge R. Paroxetine in the treatment of depression
associated with rheumatoid arthritis. Presented at the International Academy for Biomedical and Drug Research, Bruges
1996.
Razavi D, Alliaire J-F, Smith M et al. The effect of fluoxetine
on anxiety and depression symptoms in cancer patients. Acta
Psychiatr Scand 1996; 94: 205-10.
O'Hanlon JF. Antidepressant therapy and behavioural competence. Br J Clin Pract 1996; 50: 381-5.
Theesen KA, Marsh WR. Relief of diabetic neuropathy with
fluoxetine. DICP 1989, 23- 572-4.
Pick CG, Paul D, Eison MS et al. Potentiation of opioid analgesia by the antidepressant nefazodone. Eur J Pharmacol 1992; 211:
375-81.
Foster CA, Bafaloukos J. Paroxetine in the treatment of chronic
daily headache. Headache 1994: 34: 587-9.
Langemark M, Olesen J. Sulpiride and paroxetine in the treatment of chronic tension-like headache. An explanatory doubleblind trial. Headache 1994; 34: 20-4.
Fluoxetine data sheet. ABPI Compendium of Data Sheets and
Summaries of Product Characteristics 1996-7. Datapharm Publications Ltd 1996.
Rasmussen JGC, Johnson AM. Stewart BR et al. Presented at
the 17th Collegium Internationale Neuro-Psychopharmacologicum Congress, Kyoto 1990.
Montgomery SA. Dunner DL, Dunbar GC. Reduction of suicidal thought with paroxetine in comparison with reference antidepressants and placebo. Eur Neuropsychopharmacol 1995: 5.
5-13.
Kelvin AS. Hakansson S. Comparative acute toxicity of paroxetine and other antidepressants. Acta Psychiatr Scand 1989; 80
(Suppl 350): 31-5.
Molassiotis A, Morris PJ. Suicide and suicidal ideation after
marrow transplantation. Bone Marrow Transplant 1997: 19: 8790.
Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th edition. New York: Pergamon Press 1990: 12167.
Koriech OM. Fluoxetine treatment comprises the antiemetic
efficacy of ondansetron in cancer patients. J Clin Oncol 1995: 7:
371-2
Cunningham LA, Borison RL, Carman JS et al. A comparison
of venlafaxine, trazodone and placebo in major depression. J
Clin Psychopharmacol 1994; 14: 99-106.
Rifkin A. Reardon G, Siris S et al. Trimipramine in physical
illness with depression J Clin Psychiatry 1985; 56: 4-8.
Popkin MK. Callies AL, MacKenzie TB. The outcome of antidepressant use in the medically ill. Arch Gen Psychiat 1985: 42:
1160-3.
Costa D, Mogos I, Toma T. Efficacy and safety of mianserin in
the treatment of depression of women with cancer. Acta Psychiatr Scand 1985; 72 (Suppl 320): 85-92
Van Heeringen K. Zivkov M. Pharmacological treatment of
depression in cancer patients: A placebo-controlled study of
mainserin. Br J Psychiat 1996: 169: 440-3.
Purohit DR. Vavlakha PL. Modi RS et al.The role of antidepressants in hospitalized cancer patients. J Assoc Physicians India
1978: 26: 245-8.
Jackson WK, Roose SP, Glassman AH. Cardiovascular toxicity