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The treatment of depression in patients with advanced cancer
undergoing palliative care
Annabel Price and Matthew Hotopf
Department of Psychological Medicine, King’s College
London, Institute of Psychiatry, Weston Education
Centre, London, UK
Correspondence to Matthew Hotopf, Professor of
General Hospital Psychiatry, Department of
Psychological Medicine, King’s College London,
Institute of Psychiatry, Weston Education Centre,
10 Cutcombe Road, London, SE5 9RJ, UK
Tel: +44 020 7848 0778; fax: +44 020 7848 5408;
e-mail: [email protected]
Current Opinion in Supportive and Palliative
Care 2009, 3:61–66
Purpose of review
Depression is a common condition affecting those with advanced cancer, but evidence
for effective treatment has been sparse. In recent years, there has been a welcome
increase in research activity, with both pharmacological and nonpharmacological
treatments being trialled.
Recent findings
This review assesses recent studies of pharmacological interventions including
antidepressants and psychostimulants and nonpharmacological interventions including
cognitive behavioural therapy, supportive expressive group therapy, couples therapy,
complex interventions and aromatherapy massage for treatment of depression. Recent
published systematic reviews of interventions for depression are also discussed.
Summary
Recent research efforts have paid particular attention to psychological interventions,
with cognitive behavioural therapy approaches being most evaluated and showing
some encouraging results. Pharmacological interventions remain challenging to assess
using rigorous clinical trial methodology, and clinicians still rely upon data derived from
studies using general populations and those with less advanced disease or other
physical illness. Methodologically sound trials of pharmacological interventions for
treatment of depression in advanced disease remains an area of research need.
Keywords
advanced cancer, depression, palliative care, treatment
Curr Opin Support Palliat Care 3:61–66
ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1751-4258
Introduction
Depression is common in patients with advanced cancer
and affects function, symptoms, prognosis and service
use [1]. A systematic review of depression in palliative
populations by Hotopf et al. in 2002 [2] identified 10
studies that used psychiatric diagnostic interviews on
populations receiving palliative care and found that the
median prevalence estimate of major depression was 15%
(range 5–26%).
Concepts of depression in palliative populations need to
take into consideration the particular set of circumstances
experienced by patients facing terminal illness, including
loss of role and previous function. Efforts have been
made to recognize and manage emotional distress [3,4]
and demoralization [5]; and novel therapeutic interventions aimed at restoring dignity [6,7], meaning [8] and
hope [9–11] are being developed, which include therapies for both the individual, couples [12] and the family.
Research into effective treatments for depression in
advanced disease presents considerable methodological
challenges, including losses to follow-up, changes in
1751-4258 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
disease status, heterogeneity in clinical populations
and reluctance to enter patients into trials. The majority
of patients with advanced disease do not find participation in psychosocial research burdensome, and many
welcome the opportunity to participate [13,14]. Nonetheless, research on the treatment of depression in
specific palliative care cancer populations is sparse, and
it is necessary to make informed decisions on the basis of
research on depression in other physical illnesses.
Barriers to treatment of depression in
palliative care populations
Despite the recognition of depression as a common
condition in patients with advanced cancer, there are
barriers to the detection and effective timely treatment of
the condition. Barriers to detection include misattribution of symptoms of depression to those of the underlying
disease [15], underconfidence in eliciting psychiatric
morbidity by palliative care clinicians and the mistaken
belief that depression is an inevitable consequence of
terminal illness [16]. In their 1999 survey of antidepressant prescribing in the terminally ill, Lloyd-Williams et al.
[17] found that antidepressants were prescribed ‘too
DOI:10.1097/SPC.0b013e328325d17a
62 Psychological and cognitive problems
little, too late’. Most patients were within the last 2 weeks
of life, and inadequate dosing was common. Palliative
care providers lack access to specialist expertise in detecting and managing depression. Price et al. [18] found that
45% of UK hospices had access to neither a psychiatrist
nor a psychologist.
Pharmacological management
Recent efforts have been made to synthesize the available
literature on pharmacological management of depression
and generate clinical practice guidelines and recommendations for treatment. Qaseem et al. [19], in their clinical
practice guideline from the American College of Physicians, have assessed the evidence for treatment of depression at the end of life and found good evidence for the
effectiveness of the long-term use of tricyclic antidepressants (TCAs) or specific serotonin reuptake inhibitors
(SSRIs) and gave a ‘strong recommendation’ for their
use in practice. The evidence was classified as ‘moderate
on average’ using the Grading of Recommendations,
Assessment, Development and Evaluation (GRADE)
classification because it was derived from studies using
patients with cancer, not all of whom were at the end of life.
Miovic and Block [1], following their review of the
evidence for treatment of depression in advanced cancer,
recommend a combination of antidepressant medication,
supportive psychotherapy and patient and family education, although these recommendations were not based
on a systematic review of the literature.
When assessing the evidence from studies specifically
looking at palliative populations, the conclusions are less
clear. Ly and Hotopf [20], in their 2002 systematic review,
found only three published trials, two of which were
placebo controlled and were unable to draw conclusions
about treatment of depression in the palliative setting.
They recommended using the wider literature to inform
the treatment of depression in this group pending further
evidence. In 2000, Gill and Hatcher [21] conducted a
Cochrane review of antidepressants for patients with
depression and physical illness and identified 18 trials,
only two of which studied patients with cancer. The
authors concluded that antidepressants led to improvement of depression for adults with medical illness. This
review has now been withdrawn and is currently being
updated by Rayner et al. [22]
Rodin et al. [23] have published a more recent systematic
review of treatment of depression in cancer patients that
identified seven trials of pharmacological agents up to
2005. Only one of these trials involved a population with
advanced cancer [24] that compared 12 weeks of treatment with fluoxetine with placebo. The trial had several
methodological difficulties, which are described in detail
in the review, including a high-attrition rate in both the
treatment and placebo groups (54 and 44%, respectively).
No significant difference was found in depressive symptoms between the two groups after treatment. On the
basis of evaluation of all seven trials, the authors concluded that there was limited evidence for the effectiveness of pharmacological interventions in treatment of
depression in cancer patients and stressed the need for
further research.
Antidepressants
A recent study has been conducted in order to evaluate
the effectiveness of the antidepressant sertraline in
patients with advanced cancer. Stockler et al. [25] carried
out a multicentre placebo-controlled, double-blind,
randomized controlled trial (RCT) of the SSRI sertraline
for symptoms of depression and survival in patients with
advanced cancer in whom the oncologist ‘doubted the
benefits of treatment with an antidepressant’. The study
was conducted because previous evidence suggested
survival benefits for psychosocial interventions designed
to improve well being [26,27]. The investigators hypothesized that antidepressants may improve psychological
well being and survival for patients with advanced cancer.
One hundred and eighty-nine patients were recruited,
the majority of whom scored low on depression using
the Center for Epidemiologic Studies Depression scale.
The trials monitoring committee suspended the trial
because in interim analyses, the sertraline group
appeared to have a shorter survival time, although the
final analysis did not show a difference between groups.
Sertraline had no significant effect on depression or
anxiety in this group.
In addition, a study assessing an algorithm for pharmacological treatment of depression in advanced cancer
found that a discontinuation of antidepressants was most
often because of their causing delirium [28].
Psychostimulants
Psychostimulants have been recommended as a rapid
onset treatment of depression, especially suitable to
those with a very short life expectancy.
Miovic and Block [1] identified three papers (one review
and two uncontrolled trials, not primarily studying
depression outcomes) looking at the effectiveness of
psychostimulants for people with cancer [29–31]. They
concluded that there were several indications for their
use, including improving mood, appetite, energy and
cognition. They warned, however, about the potential
risk of cardiac death with methylphenidate.
Orr and Taylor [32] in their 2007 review of psychostimulants for treatment of depression concluded that
Treatment of depression in patients with advanced cancer Price and Hotopf 63
in general populations, psychostimulants were not to be
recommended due to concerns about dependency, but
that a role for them could not be ruled out for certain
groups, in which antidepressants would not be practical to
use, highlighting palliative populations.
Fulcher et al. [33], in their 2008 review of treatments
for depression in cancer, identified one uncontrolled prospective study with 41 participants [34] and one systematic
review of methylphenidate in advanced cancer, not containing any randomized controlled trials for treatment
of depression [35]. They concluded, on the basis of the
Oncology Nursing Society Putting Evidence into Practice
(ONS PEP) Weight-of-Evidence Classification Schema,
that methylphenidate is likely to be effective.
Candy et al. [36] conducted a Cochrane review of psychostimulants for treatment of depression in any context
and assessed 24 RCTs, of which 13 contributed data.
None of the studies included patients with advanced
cancer, but some were in physically ill populations. Three
trials demonstrated that oral psychostimulants significantly reduced symptoms of depression compared with
placebo; no significant difference was found between
modafinil and placebo. The authors concluded, however,
that there was insufficient evidence to recommend psychostimulants for depression in practice, and that there
was no evidence to support the use of modafinil for
treatment of depression.
Psychological therapies
Psychological interventions are increasingly seen as part
of a comprehensive package of psychosocial input for
patients with advanced cancer, but as with pharmacotherapy are challenging to evaluate using rigorous methodology. There have been several recently published
reviews of psychological interventions in cancer, but
fewer assessing interventions for advanced cancer
patients. Four recent reviews specifically assessed interventions for this group, two of them using Cochrane
review methodology.
First, Lorenz et al. [37] carried out a systematic review of
interventions to improve palliative care at the end of life.
They synthesized the evidence using the GRADE classification. They found that there was ‘strong, consistent
efficacy from RCTs of various psychosocial interventions’.
These included behavioural therapy, cognitive behavioural therapy (CBT), informational interventions and
individual and group support. No data on the comparative
effectiveness of these interventions were reported.
Second, Qaseem et al. [19] found evidence to recommend the use of psychosocial interventions for treating
patients with cancer who have depression. They classified the strength of evidence as ‘moderate on average’ as
with their recommendation for antidepressants using the
GRADE system.
Third, Akechi et al. [38] reported a Cochrane systematic
review of randomized controlled trials of psychotherapy
among incurable cancer patients. Ten RCTs were identified with 780 participants and six contained sufficient
data to enter into a meta-analysis (four studies of supportive psychotherapy, one CBT trial, and one trial of
problem-solving therapy).
Treatment with psychotherapy was associated with a
significant decrease in depression score [effect size
0.44 (0.80 to 0.08)], but no included study focused
exclusively on patients with clinically diagnosed depression. This review provided evidence for treating patients
with incurable cancer and depressive states with psychotherapy, but did not provide conclusive evidence that
such approaches are effective in patients with major
depressive disorder.
Lastly, Edwards et al. [39] carried out a Cochrane
review of the effects of psychological interventions on
psychological and survival outcomes for women with
metastatic breast cancer, again assessing RCTs. Five
studies were identified: two trials of CBT and three of
Supportive Expressive Group Therapy. The studies had
a wide variation in duration and psychological outcome
measures and were, therefore, not amenable to metaanalysis of psychological outcomes. Benefits were only
evident for psychological outcomes in the short term, and
the authors concluded that there was insufficient evidence to advocate for group psychological therapies being
available to all patients with metastatic breast cancer.
Cognitive behavioural therapy
CBT has been developed in palliative populations using
the model adapted by Moorey [40]. Attempts have been
made to evaluate the training of palliative care practitioners to deliver the therapy to their own patients.
Mannix et al. [41] in their 2006 study showed that brief
training in CBT techniques and supervision over 6
months provides a suitable skill base for delivery of an
appropriate standard of psychological support to patients
at all stages of cancer, and a small uncontrolled mixed
methods feasibility study of CBT by Anderson et al. [42]
showed significant reductions in depression and anxiety
scores after treatment.
Moorey et al. [43] have more recently carried out a larger
cluster RCT on the effect of nurse training in CBT on
the outcome of anxiety and depression in palliative care
patients with advanced cancer. Fifteen nurses were
randomized to a brief CBT training course and 1 year
of weekly supervision or treatment as usual. Individuals
assigned to CBT-trained nurses had a significantly lower
64 Psychological and cognitive problems
anxiety score over time, but depression scores were not
significantly different between groups, although they
reduced in both groups over the trial period. This study
addressed the challenge of conducting a RCT of psychological therapy for patients with advanced cancer by
adapting the standard study design. Despite a high attrition rate due to deteriorating health and death, the study
gained a comparable participation rate to studies of
patients with less advanced disease [44].
Couples therapy
McLean et al. [45] conducted a one-arm preintervention and postintervention prospective study evaluating
marital therapy for couples (n ¼ 16), using emotionally
focused couple therapy for patients with metastatic
cancer or recurrence and their partners. Depression
was measured as a secondary outcome. Participants
attended 8 weekly sessions of therapy, and self-report
measures were completed at baseline, four and eight
sessions and at 3 months postintervention. For both
the couples and patients, there was a significant reduction
in Beck Depression Inventory-II (BDI-II) score after
eight sessions compared with baseline, although patients
showed a greater improvement than couples overall.
Supportive expressive group therapy
Kisssane et al. [46] conducted a RCT of supportive
expressive group therapy (SEGT), a therapy originally
developed by Spiegel et al. [47] for women with metastatic
breast cancer. Two hundred and twenty-seven women
under the age of 70 years, with metastatic breast cancer
and a prognosis of greater than 1 year were randomized to
attend at least 1 year of weekly SEGT sessions and three
sessions of relaxation or three sessions of relaxation only.
The primary outcome of interest was survival, but depression was a secondary outcome measure. At baseline, onethird of the 227 patients randomized had a diagnosis of
depression, evenly distributed between the two study
groups. In those with depression at baseline, there were
significant differences in the depression rates between
groups at 6 months, favouring the treatment arm. In those
without depression at baseline, significantly more patients
remained free of depression in the treatment compared
with the control group at 6 months. These differences did
not remain significant at later time points.
and go beyond the traditional biological or psychological
frameworks and delivery models. In a RCT of ‘Depression
Care for People with Cancer’ [48], a nurse delivered
complex intervention; 200 patients with a cancer prognosis
of more than 6 months and a major depressive disorder of
at least a month’s duration were randomized to usual care
or usual care as well as the intervention. The intervention
consisted of 10 individual sessions, comprising education
about depression, teaching of coping strategies and communicationaboutmanagementof depressionwith patients’
oncologists and general practitioners. The intervention was
delivered by nurses with no specialist mental health experience. Patients in the intervention group scored significantly
lower on the primary outcome (depressive symptoms
measured at 3 months), and this difference persisted over
the 12-month follow-up period. There was also a significant
reduction in anxiety scores compared with usual care.
Although this study was of patients with relatively good
prognoses, complex multimodal interventions may be
effective in more advanced disease.
Complementary therapies
Palliative care providers in UK frequently offer complementary therapies [18]. There is little systematic evidence for most such techniques, but one exception is a
trial by Wilkinson et al. [49] who assessed the effectiveness of aromatherapy massage for management of depression and anxiety for patients with cancer. In a pragmatic,
multicentre two-arm RCT, 288 patients were randomized
to treatment with 4 weekly sessions of aromatherapy
massage or treatment as usual. Over half the participants
were described as having advanced cancer. Participants
of sufficient concern, as to require a psychiatric assessment, were excluded from the trial. Patients receiving
aromatherapy massage had no significant improvement in
clinical anxiety or depression or both, compared with
those receiving usual care at 10-weeks postrandomization
[OR (odds ratio 1.3 (0.9–1.7)], but a benefit was seen at
6 weeks [OR 1.4 (1.1–1.9)]. Patients in the treatment
arm reported greater improvement to self-reported
anxiety at both 6 and 10 weeks.
This study provided evidence for SEGT in both improving and preventing depression in women with metastatic
breast cancer. However, the results may not translate well
to populations with more advanced cancer as the therapy
was prolonged.
This is the first study of a complementary therapy for a
physically ill population to use rigorous clinical trial
methodology. It was not possible to blind the participants, and as with the psychotherapy trials, no account
was taken of the nonspecific components of the treatment, but other elements of a RCT were adhered to, but
the trial has the advantage of having randomized large
numbers.
Complex interventions
Conclusion
A creative approach is being made to developing therapies
that address the complex needs of patients with cancer
Over the past 2 years, there has been an increased
contribution to the research literature on the treatment
Treatment of depression in patients with advanced cancer Price and Hotopf 65
of depression for patients with advanced disease, including cancer. The existing literature has been synthesized,
and new studies highlight promising interventions and
future research directions.
Recent research efforts have paid particular attention to
psychological interventions, with CBT approaches being
most evaluated and showing some encouraging results.
Pharmacological interventions remain challenging to
assess using rigorous clinical trial methodology, and clinicians still rely upon data derived from studies using
general populations and those with less advanced disease
or other physical illness. Methodologically sound trials of
pharmacological interventions for treatment of depression in advanced disease remains an area of research
need.
Acknowledgements
Annabel Price is partly funded by St Christopher’s Hospice, Sydenham.
Matthew Hotopf is funded by the South London and Maudsley
NHS Foundation Trust/Institute of Psychiatry NIHR Biomedical
Research Centre.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 86–87).
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