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EVIDENCE-BASED SERIES #13-6

PRACTICE GUIDELINE – page 1

Evidence-based Series #13-6: Section 1

The Management of Depression in Cancer Patients: A Clinical Practice Guideline

G. Rodin, M. Katz, N. Lloyd, E. Green, J.A. Mackay, R. Wong,

and members of the Supportive Care Guidelines Group

A Quality Initiative of the

Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO)

Report Date: October 17, 2006 Question

What is the efficacy of pharmacological and nonpharmacological treatments for major depression and other depressive disorders in cancer populations? Outcomes of interest include symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life. Target Patient Population

These recommendations apply to adult cancer patients with a diagnosis of major depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. Such symptoms are frequent as a non-specific manifestation of distress and/or in association with pain or other suffering. For the purposes of this report, the conclusions were based on evidence from studies of two categories of patients:

A. Patients diagnosed with major depression by a structured diagnostic interview. This is the gold standard for the diagnosis of a depressive disorder.

B. Patients with depressive symptoms scoring greater than 14 on the first 17 items of the Hamilton Depression Rating Scale, greater than or equal to eight on the Hospital Anxiety and Depression Scale, or above the equivalent cut-off on another validated assessment scale. These measures were developed to assess symptoms and are used for screening but are less stringent methods to diagnose depressive disorders, because they may be associated with false positives and false negatives. Some but not all of these patients may have been suffering from major depression, dysthymic disorder, adjustment disorder with depressed mood, or minor depression (see Appendices 1 and 2 of the Systematic Review for diagnostic criteria for these depressive disorders).

Target Provider Population

The guidelines are intended for both oncology health professionals as well as mental health professionals engaged in the treatment of cancer patients. Referral to a mental health specialist may be valuable for cancer patients diagnosed with major depression but this may not



always be feasible. The rate of detection of depressive disorders in this and other populations is increased by the use of screening measures but there is no evidence that the nature of the disorders or their response to treatment varies by the method of detection or presentation. Recommendations

There is an absence of clear evidence derived from randomized controlled trials in cancer patients on which to inform the conclusions; therefore, the following recommendations reflect the expert consensus of the guideline panel members (which comprises nurses, palliative care physicians, medical, surgical, and radiation oncologists, an anesthetist, radiation therapists, methodologists, administrators, two psychiatrists and one psychologist) informed by the evidence reviewed and feedback from Ontario health care providers.

Treatment of pain and other reversible physical symptoms should be instituted prior to the initiation of specific antidepressant treatment.

Antidepressant medications should be considered to treat moderate to severe major depression in cancer patients. Current evidence, however, does not support the relative superiority of one pharmacological modality of treatment over another nor the superiority of pharmacological versus psychosocial interventions. The choice of an antidepressant should be informed by the side effect profiles of medication, tolerability of treatment including the potential for interaction with other current medications, response to prior treatment, and patient preference.

Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacological interventions. Psychosocial treatment approaches that may be of value include those that provide information and support and which address emotional, cognitive, and/or behavioural factors.

Qualifying Statements

Referral to a mental health specialist is appropriate where the diagnosis of depression is unclear, the syndrome is severe, the patient is not responding to treatment, or there are other complicating factors that may affect the choice of treatment.

Key Evidence

One systematic review, ten randomized trials, and one comparative cohort study were included in this systematic review of the evidence. Six of the trials compared pharmacologic treatments, four trials compared various non-pharmacological therapies, and one trial compared pharmacologic therapy to relaxation. The treatment period and follow-up was short in the trials of pharmacological treatments (10 days – 12 weeks), which limits the conclusions that can be reached regarding long-term treatment.

The systematic review of 24 studies in cancer patients, six focused on antidepressant agents and 18 on psychosocial interventions, found limited evidence in favour of both treatments. However, few studies in the review focused on patients diagnosed with a depressive disorder; most were preventive studies or included patients with mild depressive symptoms.

Two drug trials, which compared mianserin to placebo, detected a significant benefit with treatment. In another trial, alprazolam was found to be superior to progressive muscle relaxation in reducing depressive symptoms.

Four of the drug trials found no significant difference between groups on a measure of depression. Two of those trials compared low-dose fluoxetine to placebo, one compared fluoxetine to desipramine, and one compared paroxetine to amitriptyline. In these latter two studies, there were significant pre-post treatment effects for both active comparators; but the significance of these findings in the absence of placebo comparators is limited. Only one of



the pharmacologic trials assessed outcome based on remission of depressive symptoms to within the normal range as opposed to response, which is a less stringent outcome.

Two of the four trials that assessed non-pharmacological therapies for the management of depression found a significant difference between treatment groups. One trial found a benefit in using a multi-component nurse delivered intervention, with a reduction in the number of patients diagnosed with major depression, and the other positive trial found the use of an orientation program to be beneficial in reduction of depressive symptoms. In both trials, the control group received usual care. Neither group psychotherapy nor adjuvant psychological therapy (cognitive behavioural therapy) was found to significantly reduce depressive symptoms in the other two non-pharmacological trials.

Four of the eleven trials included only patients diagnosed with major depression through structured diagnostic interview. The remaining seven trials included patients with depressive symptoms above a predefined cut-off score using a validated assessment tool. Significant benefit on depression measures were found in two of the former studies and in three of the latter studies.

Future Research

Large multicentre studies of patients with histologically similar cancers are required to evaluate the efficacy of antidepressant interventions including the relative benefit of psychological versus pharmacological interventions in specific cancers (in which there may be different medication side effect profiles, physical symptoms and psychosocial problems) and the efficacy of specific antidepressant medications with respect to broader health care outcomes. Indications that may be of interest include the potential value of mirtazapine in the treatment of mood disorders accompanied by nausea, weight loss, insomnia, or anxiety; the use of dual action antidepressants such as mirtazapine, venlafaxine, and duloxetine in the treatment of comorbid pain and depression; and the use of sustained release bupropion for cancer patients with significant symptoms of depression and fatigue.

Further studies are needed to evaluate the relative effectiveness and tolerability of newer antidepressant treatments and the use of combination strategies for treatment-resistant depressive disorders. The latter potentially include the use of two antidepressant medications used in combination, and antidepressants combined with either lithium or atypical antipsychotics.

Research is needed to identify strategies to improve the rates of detection and treatment completion of cancer patients with depressive disorders.

Funding

The PEBC is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies.

Copyright

This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care

Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified

clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.



Contact Information For further information about this series, please contact Dr. Rebecca Wong, Chair, Supportive Care

Guidelines Group, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9; TEL 416-946-2126; FAX 416-946-4586;

Email [email protected].

For information about the PEBC and the most current version of all reports, please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at:

Phone: 905-525-9140, ext. 22055 Fax: 905-522-7681

mailto:[email protected]


SYSTEMATIC REVIEW – page 1


The Management of Depression in Cancer Patients: A Systematic Review





Report Date: October 17, 2006 QUESTION

What is the efficacy of pharmacological and nonpharmacological treatments for major depression (MD) and other depressive disorders in cancer populations? Outcomes of interest include symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life (QOL). INTRODUCTION

Depressive disorders such as MD, dysthymic disorder (DD), minor depression, and adjustment disorder with depressed mood are associated with significant disability, impaired QOL, and increased health care utilization. Individuals with cancer and other serious medical conditions are at increased risk for persistent depressive symptoms and disorders compared to the general population (1-4). Berard et al. (5) diagnosed MD in 14% of patients from three cancer groups, and Breitbart et al. (6) in 16% of palliative care patients. These rates are two to four times that found in the general population (7). MD is defined by depressed mood and/or loss of interest in nearly all activities for at least two weeks, accompanied by a minimum of three or four of the following symptoms (for a total of at least five symptoms): insomnia or hypersomnia, feelings of worthlessness or excessive guilt, fatigue or loss of energy, diminished ability to think or concentrate, substantial

change in appetite or weight, psychomotor agitation or retardation, and recurrent thoughts of death or suicide. Among patients with MD, the level of illness ranges from mild to severe (see Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV criteria in Appendix 1). Whooley and Simon (8) outlined the distinction between MD and other subtypes of depression including DD and minor depression, a summary of which can be found in Appendix 2. The diagnosis of MD may be partially confounded by symptoms related to the physical effects of cancer and by “realistic” feelings of sadness; although evidence suggests that a valid diagnosis of MD can nevertheless be made in this context (9). Screening instruments may be used to increase the rate of detection of depressive symptoms, but the diagnosis of MD must be confirmed with a clinical interview conducted by a trained clinician. The three instruments that have been most widely used (10) to screen for depression in the medically ill are: the Centre for



Epidemiological Studies-Depression (CES-D) scale (11), the Beck Depression Inventory (BDI-IA and BDI-II) (12), and the Hospital Anxiety and Depression Scale (HADS) (13). A fourth and newer scale whose use is rapidly spreading is the Patient Health Questionnaire (PHQ)-9 (14). Depression screening has resulted in increased recognition of depressive disorders but its effect on overall management of depression or in improving outcomes has been mixed (15,16), largely because of inadequate follow-up to confirm the diagnoses and the failure to initiate and/or continue treatment. Depressive disorders have been shown in the general population to be highly responsive to structured forms of psychotherapy and to pharmacological interventions (17-19). Guidelines for the treatment of MD have been published based on such evidence (20,21) and have also been developed by professional organizations such as the American Psychiatric Association (22) and the Canadian Psychiatric Association (23,24). MD has also been reported to be responsive to treatment in medically ill populations (9), but there are far fewer randomized controlled trials (RCTs) in such populations than in primary care or psychiatric populations. It may be assumed that much of the evidence and the guideline recommendations are applicable to cancer patients; however, there are factors that complicate the treatment of depressive disorders in cancer patients including the diagnostic overlap of the symptoms of depression with those of cancer and the higher rates of side-effects related to medication and treatment withdrawal in this population (9). Treatment evaluation may also be complex because of co-morbid factors that contribute to depression in medical populations, and which require prior or simultaneous treatment. For example, studies have consistently shown that cancer pain is associated with the development and exacerbation of psychological distress, most notably depression (25-28) and hopelessness (29). The assessment and treatment of pain may be an essential step when pain and mood disturbance coexist (30). Both pharmacotherapy and structured forms of psychotherapy have been shown to be effective in the treatment of MD, DD, and minor depression (17-19,31). Some carefully designed studies have shown that the combination of pharmacotherapy and psychotherapy is more effective in the treatment of chronic and more severe forms of depression than either modality alone (18,32). Antidepressant medications, particularly the selective serotonin reuptake inhibitors (SSRIs), are the most commonly studied interventions for MD and DD, although psychotherapeutic interventions, psychostimulants, and electroconvulsant treatment have also been shown to be effective (9). Furthermore, there is evidence that untreated depression adversely affects other health outcomes in cancer and other medical populations (33-36). However, the evidence for the effectiveness and tolerability of antidepressant treatment in cancer patients with depressive disorders has not previously been systematically reviewed. The potential for depression in cancer patients to be associated with different side-effects, drug-drug interactions, treatment continuation rates, and treatment outcomes provided the impetus for developing this systematic review and corresponding practice guideline specific to the management of depressive disorders in this population. In order to better delineate any treatment effects, the review focuses on a clearly defined depressive syndrome. METHODS

This systematic review was developed by Cancer Care Ontario’s Program in Evidence-based Care (PEBC) using the methods of the Practice Guidelines Development Cycle (37). Evidence was selected and reviewed by two members of the PEBC’s Supportive Care Guidelines Group and methodologists.

This systematic review is a convenient and up-to-date source of the best available evidence on the management of depression in cancer patients. The body of evidence in this review is primarily comprised of mature RCT data. That evidence forms the basis of a clinical practice guideline developed by the Supportive Care Guidelines Group. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario,



Canada. The PEBC is supported by, but editorially independent of, Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. Literature Search Strategy

MEDLINE (1985 to June Week 2 2005), EMBASE (1980 to 2005 Week 25), CINAHL (1982 to June Week 3 2005), PsycInfo (1985 to June Week 2 2005), and the Cochrane Library (Issue 2, 2005) databases were searched using terms for depressive disorders, pharmacological and nonpharmacological treatments, and publication types and study designs (Appendix 3). In addition, conference proceedings from the World Congress of Psycho-Oncology, the American Psychiatric Association (http://www.psych.org/public_info/libr_publ/abstracts.cfm), the Academy of Psychosomatic Medicine (http://psy.psychiatryonline.org/contents-by-date.0.shtml), and the American Psychosomatic Society (http://www.psychosomatic.org/events/events_past_meetings.htm) were searched for abstracts of relevant trials. The Canadian Medical Association Infobase (http://mdm.ca/cpgsnew/cpgs/index.asp) and the National Guidelines Clearinghouse (http://www.guideline.gov/index.asp) were also searched for existing evidence-based practice guidelines. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from those sources were searched for additional trials, as were the reference lists from relevant review articles.

An updated search for practice guidelines, systematic reviews, and meta-analyses was conducted in July 2006. Relevant articles were selected and reviewed by one reviewer.

Study Selection Criteria Inclusion Criteria

Articles were selected for inclusion in this systematic review of the evidence if they met all the following criteria: 1. The article was a systematic review, meta-analysis, evidence-based practice guideline, or a

fully published or abstract report of a randomized or non-randomized controlled trial of an antidepressant treatment compared to observation, placebo, or other active treatment (including pharmacologic and nonpharmacologic) in adult patients. Comparative studies, including prospective cohort, case control, and cross-sectional studies were also eligible for inclusion.

2. The study populations included either: Category A: patients diagnosed with MD, DD, adjustment disorder, or minor depression, through a structured diagnostic interview, or Category B: patients with depressive symptoms scoring greater than 14 on the first 17 items of the Hamilton Depression Rating Scale (HDRS) or equivalent on another validated assessment scale for depression. The latter criterion was added after the initial search and selection due to the relative paucity of studies that met criterion A.

3. The study population included patients with cancer of any histological type. 4. The trial included a standardized outcome measure of depressive symptoms or disorders.

Exclusion Criteria

Letters, comments, editorials, and review papers were excluded. Trials published in a language other than English were also excluded. Synthesizing the Evidence

Due to the heterogeneity of treatments used and variability of reported outcomes, meta-analysis was not used to synthesize the results.

http://www.psych.org/public_info/libr_publ/abstracts.cfm

http://psy.psychiatryonline.org/contents-by-date.0.shtml

http://www.psychosomatic.org/events/events_past_meetings.htm



RESULTS Literature Search Results

Table 1 provides a summary of the eleven fully published trials comparing various interventions (pharmacological or nonpharmacological) for the treatment of depression that were included in this review of the evidence. No abstract reports were considered eligible. One systematic review of treatment for depressive symptoms in patients with cancer was identified in July 2006 and included in this review. Several clinical practice guidelines for the treatment of MD and DD were identified but were excluded from this review because they did not provide recommendations specific to the target population of cancer patients. One Cochrane systematic review of antidepressant treatment for depression in medical illness was identified (38) but was largely based on data from studies of patients with other medical illnesses (only two of the 18 studies in the review included cancer patients (39,40). That review was subsequently withdrawn from the Cochrane Library pending updating. One meta-analysis of the effect of psychological interventions on depression in cancer patients was considered but deemed ineligible because the focus of the trials in the analysis was preventative and patients were selected based on their cancer diagnosis rather than on psychological criteria (41). Therefore, most trials in that analysis included patients with mild depressive symptoms which were not above the predetermined cut-off in terms of severity. Table 1. Studies included in this evidence-based report.

Author, year (reference) Comparisons

Category A: diagnosis of major depression by structured diagnostic interview

Pharmacological trials

Costa 1985 (39) mianserin vs. placebo

Razavi 1996 (42) fluoxetine vs. placebo

Holland 1998 (43) fluoxetine vs. desipramine

Nonpharmacological trials

Sharpe 2004 (44,45) multi-component nurse-delivered intervention vs. usual care

Category B: depressive symptoms above cut-off

Pharmacological trials

Fisch 2003 (46) fluoxetine vs. placebo

Holland 1991 (47) alprazolam vs. progressive muscle relaxation

Pezzella 2001 (48,49) paroxetine vs. amitriptyline

van Heeringen 1996 (40) mianserin vs. placebo

Nonpharmacological trials

Greer 1992 (50); Moorey 1994 (51) adjuvant psychological therapy vs. no therapy

Kissane 2003 (52) group psychotherapy + relaxation vs. relaxation alone

McQuellon 1998 (53) orientation program vs. usual care Abbreviations: vs., versus.

Systematic Reviews In a well-conducted systematic review of treatment for depression or depressive symptoms in patients with cancer, Williams and Dale searched electronic databases from 1960 to 2005 (PubMed, CINAHL, the Cochrane Library databases, DARE, and PsycARTICLES), provided detailed search terms and study selection criteria, conducted independent data extraction and evaluated each study using a published quality assessment tool (54). The review included twenty-four studies; six focusing on pharmaceutical agents and 18 on psychotherapeutic interventions. Most studies in the Williams and Dale review (54) were preventive and did not require a pre-treatment threshold for depressive symptoms; therefore, only three of those studies (40,42,46) were also included in the current PEBC review.



The review concluded that there was some evidence for the effectiveness of antidepressant medications in reducing depressive symptoms in cancer patients, although it cautioned against identifying specific medications based on the evidence available. There was also limited evidence in favour of psychotherapeutic interventions for this indication particularly cognitive behavioural therapy and social support. While emphasizing that cancer patients should not be denied treatment for depression because of a lack of evidence for effectiveness in the population, the review authors also commented on the need for further high-quality research and the limitations of the current evidence, including small sample sizes, lack of control for potential confounders, limited information on tolerability of antidepressants in this population, and the lack of studies involving patients with significant psychological morbidity. Study Quality Pharmacological trials

A total of seven trials assessing pharmacological treatment agents were included (39,40,42,43,46-48). Three randomized, double-blind trials met the Category A inclusion criteria in which the diagnosis of depressive disorder is made by structured diagnostic interview (39,42,43). While these three trials were described as randomized, the method used to generate the sequence of randomization was not described. Two of the trials were adequately double-blinded (39,42) and one trial did not describe how blinding was achieved (43). Razavi et al. (42) described sample size and power calculations but did not achieve the required sample size (60 patients per treatment group) to detect the prespecified treatment difference. Costa et al. conducted intention-to-treat (ITT) analyses (39) and Razavi reported some analyses on an ITT basis (42). The remaining four RCTs met the Category B inclusion criteria of depressive symptoms above a predefined cut-off score on a self-report measure (40,46-48). Three of these four trials were described as double-blind (40,46,48). Holland et al. did not employ blinding in their methods (47). Two trials did not provide a sufficient description of how randomization was achieved (40,48). Two trials described power and sample size calculations based on QOL (46) or depression (48) as the primary outcome; both trials met the target sample at randomization but not for the final analyses. Withdrawals were well described in all seven trials included in this category. Four of the seven trials were sponsored by pharmaceutical companies (40,42,43,47). Nonpharmacological trials

Four trials assessed nonpharmacological treatments for depression (44,50,52,53). One non-randomized comparison of two sequentially recruited cohorts met the Category A inclusion criterion of the diagnosis of depressive disorder being made by structured diagnostic interview (44). Sharpe et al. described sample size and power calculations, met the target sample size, and reported results based on an ITT analysis (44). The primary outcome was assessed from audiotapes and/or notes by a psychiatrist blinded to patient treatment status. The remaining three RCTs met the Category B inclusion criteria of depressive symptoms with a severity above a predefined cut-off score (50,52,53). Patient self-reports of symptoms were used as the outcome measure. None of these trials was blinded. One trial did not provide a sufficient description of how randomization was achieved (53). Withdrawals were well described in all four trials included in this category. Trial Characteristics

The method by which patients were initially screened for depression and the way in which treatment efficacy was measured varied considerably between trials. Those details are outlined in Table 2. Descriptions of the trials included in this report and their results are provided in Tables 3 and 4.



Table 2. Screening tools, cut-off scores and instruments used to assess treatment efficacy. Author, year (reference)

Depression screening instrument(s) and score required for trial eligibility

Instrument(s) used to assess efficacy Definition of response

HDRS HADS MADRS CGI Other

Pharmacological Trials

Costa 1985 (39) Psychiatric & neurologic evaluation, ZSRDS ≥41, and HDRS ≥16 (items 1-17)

√ -- -- √ - S √ - I

ZSRDS NR

Razavi 1996 (42) DSM-III criteria met for major depressive disorder (MDD) or adjustment disorder, and HADS ≥13

-- √ √ -- SCL90-R SQOLI

success rate: HADS score <8 after the 5-week treatment period

Holland 1998 (43) DSM-III-R criteria met for MDD (>30days) or adjustment disorder with depressed mood (>60days and >14 on first 17 items of HDRS)

√ -- -- √ - S PGI FLIC SF-36

NR

Fisch 2003 (46) TQSS1 ≥2

-- -- -- -- FACT-G ZSRDS

response in overall QOL as determined by FACT-G defined as best change

2 score of ≥6

Holland 1991 (47) ≥6 on Covi Anxiety Scale or Raskin Depression Scale

√ -- -- -- ABS SCL-90

NR

Pezzella 2001 (48,49)

ICD-10 criteria met for mild, moderate, or severe depressive episode, and MADRS ≥16

-- -- √ √ FLIC PGE

proportion of patients with ≥50% reduction in MADRS score at weeks 3, 5, 8, and endpoint

van Heeringen 1996 (40)

HDRS ≥16 on the 21-item scale √ -- -- --

-- ≥50% decrease in baseline HDRS score

Nonpharmacological Trials

Sharpe 2004 (44,45) SCID telephone interview and HADS (cut-off of 15 on 14-item scale)

-- √ -- -- SCID NR

Greer 1992 (50) Moorey 1994 (51)

HADS ≥8 on depression, or ≥10 on anxiety, or MAC ≥12 on helplessness and ≤47 on fighting spirit

-- √ -- -- -- NR

Kissane 2003 (52) MILP -- √ -- --

ABS MAC MILP

NR

McQuellon 1998 (53) NR -- -- -- -- CES-D NR Abbreviations: ABS, Affects Balance Scale; CES-D, Center for Epidemiologic Studies-Depression Scale; CGI-I/S, Clinical Global Impression of Illness Improvement/Severity; DSM-III, Diagnostic and Statistical Manual of Mental Disorders, 3

rd edition; EI, Efficacy Index; FACT-G, Functional Assessment of Cancer Therapy-General; FLIC, Functional Living Index: Cancer; HADS, Hospital

Anxiety and Depression Scale; HDRS, Hamilton Depression Rating Scale; ICD – International Classification of Diseases; MAC, Mental Adjustment to Cancer scale; MADRS, Montgomery Asberg Depression Rating Scale; MDD, major depressive disorder; MILP, Monash Interview for Liaison Psychiatry; NR, not reported; PGE, Patient’s Global Evaluation; PGI, Patient’s Global Impression; QOL, quality of life; SCID, Structured Clinical Interview for DSM-IV; SCL-90(-R), Symptom Checklist-90 (-Revised); SF-36, Short Form 36 Health Survey; SQOLI, Spitzer Quality of Life Index; TQSS, Two-Question Screening Survey; ZSRDS, Zung Self-Rating Depression Scale. 1 – Questions asked during the Two-Question Screening Survey were: 1) “During the past month, have you often been bothered by feeling down, depressed, or hopeless?” and 2) ”During the past month, have you often been bothered by having little interest or pleasure in doing things?”. Responses scored as 0, not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. 2 – The “best-change score” was defined as the difference between baseline FACT-G score and the average of the best consecutive scores.



Table 3. Descriptions of trials included in this systematic review.

Author, year (reference)

No. of Patients

1 Treatment Groups2

Cancer/Stage % Patients Receiving

Chemotherapy

Study Design / Blinding

Study Period


Costa 1985 (39) 36 (36) 37 (37)

20-40mg mianserin Placebo

breast, ovarian, cervical, other

97% total received chemotherapy and/or

radiotherapy

RCT/ Double blind

4 weeks

Razavi 1996 (42) 45 (30) 46 (39)

20mg fluoxetine Placebo

gynecological, breast, haematological

NR RCT/ Double blind

5 weeks

Holland 1998 (43) 21 (21) 17 (16)

20-60mg fluoxetine 100-150mg desipramine

breast, colorectal, gynecological


6 weeks

Fisch 2003 (46) 83 (38) 80 (45)

20mg fluoxetine Placebo

advanced cancer 71% 64%

3

RCT/ Double blind

12 weeks

Holland 1991 (47) 87 (70) 87 (77)

1.5mg alprazolam tid Progressive muscle relaxation tid

all cancer patients NR RCT/ Open

4

10 days

Pezzella 2001 (48,49) 89 (88) 90 (87)

20-40mg paroxetine 75-150mg amitriptyline

breast / any stage 100% 100%

RCT/ Double blind

8 weeks

van Heeringen 1996 (40) 28 (28) 27 (27)

60mg mianserin Placebo

breast / stage I/II, no metastases


6 weeks


Sharpe 2004 (44,45) NA (30)

NA (30)

Multi-component nurse-delivered intervention

Usual care

breast, gynecological, bladder, prostate, testicular, colorectal

NR 5 Cohort 6 months

Greer 1992 (50) Moorey 1994 (51)

85 (72) 89 (84)

Adjuvant psychological therapy No therapy

all cancer patients 6 NR RCT/

Open 4

4 months

12 months

Kissane 2003 (52) 154 (NR) 149 (NR)

Group psychotherapy + relaxation Relaxation alone (control)

breast / stage I/II 95% total RCT/ Open

4 12 months

McQuellon 1998 (53) 7

(78) (72)

Orientation program + usual care Usual care

all cancer patients NR RCT/ Open

4 1 week

Abbreviations: NA – not applicable; No., number; NR, not reported; RCT, randomized controlled trial; tid, three times daily. 1 – Number of patients randomized followed by number of patients included in analyses in parentheses. 2 – Treatment schedules, interventions, and programs described in Appendix 4. 3 – In total, 87% of fluoxetine patients and 77% of placebo patients were receiving some type of cancer treatment. 4 – Blinding of outcome assessors is not methodologically possible in this type of research. 5 – 27% of patients in the intervention group and 7% in the usual care group were also receiving active cancer treatment (not specified). 6 – Except cerebral tumours and non-melanoma skin cancers. 7 – A total of 180 patients were randomized in this study.



Table 4. Results of trials included in this systematic review. Author,

year (reference)

Treatment Groups

Symptomatic Improvement at end of treatment Withdrawals

# pts (%)

Adverse Effects

# pts (%) HDRS

Mean (SD) HADS

Mean (SD) MADRS

CGI Mean (SD)

Other, mean (SD) unless stated otherwise


Costa 1985 (39)

mianserin placebo

8.19 (6.38) 13.2 (9.79) p<0.01

1

NR NR CGI-S:

0.88 (1.42) 2.08 (1.92) p<0.025

1

CGI-I (# responsive pts): 28 18 p<0.025

ZSRDS:

34.2 (11.7) 42.5 (13.8) p<0.05

1

EI:

3.04 (1.22) 1.98 (1.44) p<0.025

7 (19%) 15 (41%) p<0.05

Overall: 17/36 (47%) 11/37 (30%) p>0.05

Razavi 1996 (42)

fluoxetine placebo

NR Change in mean, baseline - wk5 NR Change in mean, baseline - wk5 SCL-90-R: GSI depression -0.5 -0.8 -0.4 -0.6 p=0.02 NS

15 (33%) 7 (15%) p=0.04

Overall: 30/45 (67%) 27/46 (59%) p=0.43

-7.7 -6.0

-12.5 -10.2

Holland 1998 (43)

fluoxetine desipramine

Baseline to endpoint p>0.05

NR NR Baseline to endpoint CGI-S: p>0.05

Final visit PGI: p>0.05

6 (28.6%) 7 (41.2%) p=0.64

2

Dry mouth: 14/21 (66.7%) 4/17 (23.5%) p=0.008

Fisch 2003 (46)

fluoxetine placebo

NR NR NR NR ZSRDS (total score SD): 21.14 (5.57) 22.54 (6.53)

45 (54%) 35 (44%)

Emesis (final visit): 9/27 (33%) 2/43 (4.6%) p=0.01

Holland 1991 (47)

alprazolam progressive muscle relaxation

8.68 (5.55) 9.93 (6.43) p=0.08

1

NR NR NR ABS-depression: 6.40 (4.38) 7.66 (4.32) p=0.04

1

SCL-90 depression: 1.14 (0.85) 1.23 (0.84) p>0.05

1

17 (20%) 10 (11%) p=0.21

2

Drowsiness (↓ dose): 5/70 (7%) NR

Pezzella 2001 (48,49)

paroxetine amitriptyline

NR

NR % (#) pts with

≥50%

reduction 44% (38/87) 38% (33/87) p=0.441

2.4 (1.2) 2.6 (1.3) p=0.244

PGE

2.4 2.3 p=0.966

17 (19%) 22 (24%) p=0.49

2

Overall: 47/88 (53%) 53/89 (60%)

Van Heeringen 1996 (40)

mianserin placebo

Mean change from baseline

3

-13.6 -6.0, p=0.004

1

NR NR NR NR 6 (21%) 15 (56%) p=0.014

Overall: 11/28 (39%) 17/27 (63%) p=0.14



Author, year

(reference) Treatment Groups

Symptomatic Improvement at end of treatment Withdrawals

# pts (%)

Adverse Effects

# pts (%) HDRS

Mean (SD) HADS

Mean (SD) MADRS

CGI Mean (SD)

Other, mean (SD) unless stated otherwise


Sharpe 2004 (44,45)

intervention

4

usual care

NR 7.0 (4.1) 9.6 (4.7) p=0.061

1

NR NR SCID % (#) pts with no MDD: 81% (22) 42% (11), p=0.02

In total, 28 of 30 patient pairs assessed at 3m and 26 pairs at 6m

NA

Greer 1992 (50) Moorey 1994 (51)

adjuvant psychological therapy no therapy

NR % (#) pts with HADS ≥8 at 4m 12m

1

18% 11% (11/61) (7/62) 22% 18% (17/76) (13/71) 2p=0.55

p=0.40

NR NR MAC, % (#) pts with abnormal score at 4m 12m

1

21% (13/61) 23% (14/61) 34% (26/76) 28% (20/72) p=0.10

2 p=0.64

2

lost before 8wk follow up: 13 (15%) 5 (6%) p=0.06

2

NA

Kissane 2003 (52)

group psychotherapy + relaxation relaxation alone

NR Change from baseline-12m -0.9 (3.5) -0.6 (2.7) p=0.70

1

NR NR ABS (negative symptom total): Change from baseline-12m -3.6 (11.3) -1.2 (10.2) p=0.19

5

18 (12%) 14 (9%) p=0.64

2

NA

McQuellon 1998 (53)

orientation program

6 +

usual care

usual care

NR NR NR NR CES-D, % (#) pts positive for depressive symptoms

9% (6/64) 45% (32/71) p<0.001

1

total of 30 withdrawals (20%)

NA

Abbreviations: ABS, Affects Balance Scale; CES-D, Center for Epidemiologic Studies-Depression Scale; CGI-I/S, Clinical Global Impression of Illness Improvement/Severity; EI, Efficacy Index; GSI – Global Severity Index; HADS, Hospital Anxiety Depression Scale; HDRS, Hamilton Depression Rating Scale; m, month(s); MAC, Mental Adjustment to Cancer scale; MADRS, Montgomery Asberg Depression Rating Scale; MDD, major depressive disorder; NA, not assessed; NR, not reported; NS, not statistically significant; PGE, patient’s global evaluation; PGI, Patient’s Global Impression; pts, patients; SCID, Structured Clinical Interview for DSM-IV; SCL-90(-R), Symptom Checklist-90 (Revised); SD, standard deviation; ZSRDS, Zung Self-Rating Depression Scale; wk, week. 1 – No significant differences reported at baseline. 2 – Chi square reviewers’ calculation: http://department.obg.cuhk.edu.hk/researchsupport/Independent_2x2_table.asp. 3 – The more negative the score (i.e., greater reduction in HDRS score) the greater the improvement in depressive symptoms. 4 – Multi-component nurse-delivered intervention (see Appendix 4). 5 – The intervention group had significantly higher negative affect scores (p=0.01) and lower positive affect scores (p=0.001) at baseline. 6 – Orientation program described in Appendix 4.



Outcomes Symptomatic Improvement Pharmacological trials

Of the seven trials included in this category, three detected significant differences between treatment groups on a measure of depression (39,40,47). Both studies that compared mianserin to placebo reported greater symptomatic improvement in the active treatment group (39,40). When compared with placebo, Costa et al. (39) reported significant improvement in depressive symptoms on all four symptom measure scales, a significantly greater absolute number of responders (criteria not reported), and a significantly greater efficacy index (EI) score favouring mianserin. Van Heeringen and Zivkov (40) found significantly more responders, defined as patients with ≥50% decrease in HDRS scores (19 versus 10, respectively; p=0.044), and a significantly greater mean change score from baseline on the HDRS in the mianserin group compared to the placebo group. Finally, Holland et al. (47) found that patients randomized to alprazolam experienced a significant reduction in depressive symptoms on the Affects Balance Scale (ABS) and a marginally significant reduction on the HDRS scale compared to the muscle relaxation group. No significant difference was detected on the Symptom Checklist-90 (SCL-90) depression subscale. Of the remaining four studies in this category, two placebo-controlled trials failed to detect a difference on depression measures between active treatment and placebo (42,46), while the other two trials compared active treatments and found significant pre-post improvements in depressive scores, but no between group differences (43,48). Razavi et al. (42), found no significant differences between patients randomized to fluoxetine versus placebo on patient-reported or observer-reported symptom scales (HADS and Montgomery-Asberg Depression Rating Scale [MADRS], respectively). Although there was a small statistically significant benefit for fluoxetine over placebo on the Global Symptom Index of the Symptom Checklist-90 revised (SCL-90-R), no significant difference was reported on the depression subscale. Similarly, success rates, defined as a score of less than 8 on the HADS after five weeks of treatment, were similar for both groups in an ITT analysis (11% versus 7% of patients, respectively) However, only low-dose fluoxetine (20 mg) was evaluated in that study, and the duration of treatment (five weeks) was very short. Fisch et al. (46) also failed to detect a difference between low-dose fluoxetine and placebo on best-change scores for depression over 5 visits (approximately 12 weeks) (p=0.35) or in an adjusted regression analysis (p=0.14). There was a significant interaction between visit interval and treatment in favour of fluoxetine over placebo (p=0.0005); however, there was also a high proportion of missing data (44%-54% by the final visit) and it is unclear if this was accounted for in the analysis. While both fluoxetine-treated and desipramine-treated patients showed significant improvement in symptoms of depressive disorder from baseline to endpoint based on HDRS and Clinical Global Impression of Illness Severity (CGI-S) scores, no significant difference in treatment efficacy between groups was detected in the trial by Holland et al. (43). With its small sample size, however, the trial may not have been sufficiently powered to detect a difference. In the Pezzella et al. (48) trial, no significant difference between groups in CGI or Patient’s Global Evaluation (PGE) scores was detected. Further, there was no significant difference in the proportion of patients with a ≥50% reduction in MADRS scores from baseline to the endpoint of the trial, although significant pre-and post differences were seen in depressive scores for both active treatments. Nonpharmacological trials

Two of the four nonpharmacological studies reported greater symptomatic improvement in the active treatment group (44,53). In the Sharpe et al. trial (44), significantly fewer patients randomized to specialized nursing care met the MD criteria and those patients reported fewer depressive symptoms at three (p=0.001) and six months (p=0.006) compared to those randomized to usual care. However, significantly greater improvement in depressive symptoms



was reported in the intervention group compared to the usual care group at three months (p=0.006) and a marginally significant improvement was detected at six months (p=0.061) (44). Although no significant differences were reported between groups at baseline, there was a substantial difference between the numbers of patients previously prescribed an antidepressant agent in the intervention group (50%) compared with the usual care group (17%). In addition, the intervention group was more likely to have received treatment for depression from their doctor, including antidepressants as a result of the intervention (90% of patients versus 50% of patients in the usual care group), making it difficult to evaluate the impact of the intervention alone. McQuellon et al. (53) reported that significantly fewer patients allocated to an orientation program (consisting of a tour of the oncology clinic, a description of clinic procedures, provision of information, and a question and answer session) met screening criteria for depressive symptoms one week post-intervention relative to patients receiving usual care (p<0.001). Overall, no significant differences in patients’ HADS subscores for depressive symptoms were detected by Greer et al. (50). Those receiving adjuvant psychotherapy reported significantly higher scores on the fighting spirit concept and lower scores on the helplessness measure than did those receiving no therapy at 2 months follow-up, although the differences were not significant at 4 months (50). Follow up scores at one year, as reported by Moorey et al. (51), showed no significant differences on change from baseline between groups in mental adjustment to cancer (MAC) scores or HADS scores for depression (fighting spirit, p=0.45; helplessness, p=0.11; depression, p=0.20). In the Kissane et al. trial (52), no significant difference was detected between patients receiving cognitive-existential group therapy plus relaxation compared to those receiving relaxation therapy alone. Discontinuation Rate Pharmacological trials

The discontinuation rate in the drug treatment groups ranged from 19% to 54% compared to 15% to 56% in the placebo groups. In two of the seven trials assessing drug therapies (39,40), significantly more patients in the placebo groups dropped out compared to experimental group patients. There was, however, no significant difference between groups in the number who dropped out due to adverse effects (p=0.704) (40). In contrast, Razavi et al. (42) reported significantly more patients dropping out of the treatment arm (fluoxetine) compared to placebo (p=0.04). Side effects were the most common reason for withdrawal causing seven patients (16%) in the fluoxetine arm to discontinue treatment. No patients in the placebo arm withdrew due to side effects (42). Although only 46% of patients enrolled in the fluoxetine group and 56% in the placebo group in the Fisch et al. trial completed assessments at the final study visit, only six were reported to have discontinued treatment (46). Of the four patients who withdrew in the fluoxetine arm, two did so because of daily headaches and two because of nausea and vomiting. In the placebo arm, one patient withdrew because of non-specific side effects and one because of nausea and vomiting (46). There was no significant difference in withdrawals due to adverse effects between the fluoxetine and desipramine groups in the Holland et al. trial (43). In the other trial by Holland et al. (47), there were more dropouts in the alprazolam arm, mainly due to drowsiness, compared to the relaxation arm. Seventeen patients in the paroxetine group (19%) and 22 patients in the amitriptyline group (24%) withdrew from the Pezzella et al. trial (48). Adverse effects were the most common reason for discontinuation, which led nine patients in the paroxetine group (10.2%) and ten patients in the amitriptyline group (11.5%) to withdraw. Nonpharmacological trials

The non-participation and discontinuation rates in the nonpharmacological studies also tended to be high, in some cases even higher than in the drug treatment group. In the



sequential cohort study reported by Sharpe et al. (44), thirty seven per cent of patients assessed as eligible during the usual care recruitment period declined participation (31/83) and 53% of eligible patients (34/64) declined participation during the intervention recruitment period. The reasons included lack of time, distance, and a preference not to discuss emotional matters. The report fails to describe what happened to the eligible but non-participating patients. Of the original 147 patients who screened positive for MD, two groups of 30 patients were matched. Of these sixty patients, there were no reported withdrawals, although four patients died during the study, and two were lost to follow-up. In the trial by Greer et al. (50), 18 of 174 patients (10%) were lost before the eight-week follow-up for the following reasons: three died, three were too ill for assessment, four refused, seven had moved, and follow-up of one patient was omitted at the request of the patient’s general practitioner. More patients receiving adjuvant psychological therapy withdrew from the study compared to the group receiving no therapy (p=0.06). Withdrawals in the trial by Kissane et al. (52) were comparable in both treatment arms. A total of 30 patients (20% of those randomized) withdrew or did not return for follow-up in the McQuellon et al. trial (53). The breakdown of withdrawals by treatment group was not reported. Quality of Life

Only three of the eleven included trials provided data on QOL (42,46,48). One of the three trials detected a significant improvement with treatment (46). While Holland et al. (43) indicated that QOL was evaluated, data were not reported. Razavi et al. (42) assessed changes in QOL using the Spitzer Quality of Life Index (SQOLI) and found no significant differences in mean score increase over five visits between fluoxetine versus placebo (2.0 versus 1.1, respectively). Similar to the results for the depression assessment, Fisch et al. observed no significant QOL benefit (according to Functional Assessment of Cancer Therapy-General [FACT-G]) for fluoxetine compared with placebo on best-change scores over the study; however, a significant improvement from baseline in QOL was detected in patients treated with fluoxetine compared with placebo patients on a longitudinal analysis (p=0.01) (46). Pezzella et al. (48) evaluated QOL using the Functional Living Index Cancer (FLIC) subscale. No significant difference in mean change scores from baseline to endpoint was detected between the paroxetine and amitriptyline (24 and 17.5, respectively) treatment arms (p=0.282). None of the trials assessing nonpharmacological agents assessed QOL. Adverse Effects Pharmacological trials

Adverse effects were reported in all of the pharmacological trials. In three of the four trials in which an antidepressant was compared to placebo, adverse effects were more frequent in the antidepressant arm (39,42,46), while they were more common in the placebo arm in the van Heeringen trial (40). The most frequent adverse effect of mianserin in the Costa et al. trial (39) was drowsiness, which was reported in six patients in the first week. Although there was a significant difference between groups in the overall number of withdrawals from the van Heeringen and Zivkov trial (40), there was no significant difference in withdrawals due to adverse effects (p=0.704). Initial effects related to mianserin (that disappeared later in the study) included sedation, tiredness, drowsiness, and slowed thinking. The two studies that compared fluoxetine to placebo reported similar adverse effects (42,46). Digestive and neuropsychiatric toxicities were more common in the fluoxetine group (24% and 49%, respectively) compared to placebo (13% and 35%, respectively), but these differences were not statistically significant (p=0.16 and p=0.17, respectively) (42). Fisch et al. (46) reported a significantly higher frequency of emesis in fluoxetine-treated patients compared to placebo. No other toxicities were reported.



There was no significant difference in withdrawals due to adverse events in the Holland et al. trial (43). Six patients withdrew in the fluoxetine group because of adverse effects which included somnolence, tachycardia, abnormal thinking, symptoms of depersonalization, and pain. Four desipramine-treated patients withdrew because of symptoms which included dyspepsia, abnormal thinking, pain, and somnolence. The only significant difference was in the incidence of dry mouth, which was more frequent in fluoxetine-treated patients (p=0.008) (43). In the trial by Holland et al. (47), five of the 70 patients in the alprazolam arm required a dose reduction to 0.25mg due to drowsiness and sedation. Additional drug-related adverse effects included light-headedness (eight patients), sleepiness/grogginess (two patients), nightmares (one patient), facial edema (one patient), and nausea and vomiting (one patient), although none of these patients required a dose reduction (47). There was a high incidence of adverse effects in the Pezella et al. trial (48) but no statistically significant difference between drug treatment groups was reported. Nine of the 88 patients in the paroxetine group were withdrawn from the trial because of adverse effects. For six of these nine patients, the adverse effects included abdominal pain, tremor, dry mouth, insomnia, agitation, confusion, dizziness, headache, and abnormal thinking. Between ten and twelve patients in the amitriptyline group were also withdrawn due to adverse effects and in six of these patients effects included abdominal pain, tremor, dry mouth, insomnia, anxiety, asthenia, depersonalization, nervousness, somnolence, and vertigo. The most frequent adverse effects overall were nausea (13.6%) and leukopenia (10.2%) in the paroxetine group, and dry mouth (14.6%) and constipation (11.2%) in the amitriptyline group (48). Nonpharmacological trials

Adverse effects were not evaluated in the four trials assessing nonpharmacologic interventions (44,50,52,53). DISCUSSION Interpretation of the Evidence from Included Trials Pharmacological Trials

Overall, limited evidence from three positive randomized trials (including a total of 302 patients) (39,40,47) and two trials that compared active treatments and showed both arms improved equally in terms of depressive symptoms (43,48) suggests that cancer patients may benefit from pharmacological treatments of depression. The antidepressant used in two of the positive RCTs was mianserin, a dual-acting antidepressant not currently widely available, but with properties similar to the more widely available and newer dual-acting antidepressant, mirtazapine. In the Costa et al. trial (39), a significant symptomatic improvement in the mianserin group was detected compared to placebo, based on an ITT analysis. Although the withdrawal rate was significantly greater in the placebo group, adverse events were more frequent in the treatment group but that difference was not statistically significant. In the van Heeringen and Zivkov study (40), the mianserin group had a significantly greater reduction in depression scores and a greater proportion of treatment responders than in the placebo group. In that study, the withdrawal rate in those treated with mianserin was significantly less than in those treated with placebo.

The third positive trial (47) provides more modest support for the benefit of pharmacological treatment and should be interpreted more cautiously since it compared a pharmacological treatment (alprazolam) to a non-pharmacological treatment (progressive muscle relaxation. In that study, the alprazolam-treated group reported significantly more improvement on the Affects Balance Scale (ABS), although no significant difference between groups was demonstrated on the HDRS or the SCL-90. The improvement on the ABS may reflect greater emotional well-being, but this measure is not designed to detect depressive disorders.



Three of the four trials assessing pharmacological agents that detected no significant difference between treatments (42,43,48) were of similar methodological quality to the positive trials. In both the Holland et al. (43) and Pezzella et al. (48) studies, antidepressant treatment was associated with an improvement in symptoms. However, both trials were designed to compare two active treatments rather than to evaluate the efficacy of each individual treatment and are therefore limited in determining whether either group’s improvement was attributable to medication effects. Neither Razavi et al. (42) nor Fisch et al. (46) detected a significant difference in depressive symptoms between fluoxetine versus placebo. It should be noted, however, that not all data analyses in the Razavi et al. trial were performed on an ITT basis, and that the patients who withdrew in the fluoxetine and placebo arms were not included in the final analysis (42). In both trials, the study results were limited by the low dose of fluoxetine that was used. The methodology and study quality of the Fisch et al. (46) trial have been subject to significant criticism (55-57). Concern has been raised around the screening instrument and recruitment standards. Fisch et al. (46) employed a two-question screening survey to determine possible candidates for this study. Despite such wide entry criteria, only 163 patients were recruited over 2 years across 15 separate sites. The study also experienced an unusually high attrition rate. Over 18% of all patients did not complete any follow-up and by the final follow-up period, approximately 50% of patients were still involved in the study; however researchers made no attempt to lower or alter the dosage level. Patient and medical care in the Fisch et al. (46) trial are also a cause for concern. Medications were mailed out to patients, with researchers relying on self-reported assessment to determine if and how the medication was used. Due to such scrutiny, the findings of this trial should be interpreted with caution. It should be noted that newer antidepressant agents, such as escitalopram, citalopram, mirtazapine, venlafaxine, duloxetine, and bupropion have not been evaluated within the cancer population nor has a trial of methylphenidate been reported within this population. Nonpharmacological Trials

The evidence for non-pharmacological treatment of depression in cancer patients is similarly mixed, with positive findings in two (44,53) of the four studies of psychosocial interventions (44,50,52,53). One of the positive studies was a sequential cohort study in which a psychological intervention was administered to patients diagnosed with MD through a structured diagnostic interview (Category A) (44). The treatment was a multi-component nurse-delivered intervention, which consisted of education about depression, up to ten 30-minute sessions of problem-solving therapy, consideration of antidepressant therapy through discussion with the general practitioner, and coordinating and monitoring treatment. This intervention resulted in a significantly greater reduction in both diagnoses of MD and in depressive symptoms compared to the usual care control group. The mechanism for this improvement may be complex since the intervention patients were actually treated by their physicians with antidepressants at a higher rate than the control group as a result of the intervention. However, it should be noted that 44% of eligible patients refused to participate in this study and the potential for selection bias must be considered. In addition, patients in the usual care arm were all recruited (and some would have completed treatment and assessment) prior to those in the intervention arm, which increases the potential for bias in the subsequent matching of the usual care patients with the intervention patients, although the two groups were reported to be similar on key pre-treatment variables.

In the other positive study (53), patients with elevated scores on the CES-D who received an orientation program plus usual care were significantly less likely to screen positive for depressive symptoms at the end of the intervention than were those receiving usual care. By contrast, the studies by Greer et al. (50) and Kissane et al. (52) failed to detect a significant benefit of therapy. Both of these randomized trials had larger sample sizes and longer periods of follow-up than that of the positive studies.



Other Evidence from Non-Cancer Patients

Given the limited evidence available on treatment for depression in cancer patients, evidence in non-cancer patients was considered. However, it should be emphasized that a systematic search for evidence regarding the effectiveness of antidepressant treatments in the general population was not performed for this report. Treatments effective for depression in the general population are likely to have similar effects in cancer patients. However, factors that may complicate the diagnosis and treatment of depression in cancer populations must also be considered, including overlap of symptoms of depression and cancer, the potential for interaction between treatments for the two disorders or their sequelae, and greater sensitivity to side effects in cancer and other medical populations. The latter has been associated with poorer compliance to antidepressant medication treatment recommendations (58).

Evidence from the general population as well as from other medical conditions suggests that screening for depression may result in increased recognition of depression but evidence for the positive impact of such screening on the management of depression or on outcome has been mixed (15,16). Strong evidence indicates that both psychological and pharmacological interventions are effective in the treatment of MD and DD (17) and minor depression (18,19) in the general population and that a combination of the two treatments can provide greater benefit compared with pharmacological treatment alone (59). A recent meta-analysis of 89 controlled treatment studies of major depression and other depressive disorders in older adults showed that antidepressant treatments were effective with moderate to large effect sizes that did not differ between pharmacotherapy and psychotherapy (60). Psychotherapeutic interventions, such as interpersonal therapy (IPT), cognitive behavioural therapy (CBT) and problem-solving interventions have also been shown to be as effective as pharmacotherapy for the treatment of milder depression in the general population (61). Pharmacological interventions include tricyclic and heterocyclic antidepressants, SSRIs, and psychostimulants. A recent systematic review, involving 15 trials and 2,753 patients, confirmed the benefit for both SSRIs and tricyclic antidepressants (TCAs) over placebo in the treatment of depression in primary care (62) and a systematic review and meta-analysis by the Cochrane Collaboration provided evidence that SSRIs, TCAs, and other antidepressants improve depressive symptoms in patients with a wide variety of physical illnesses significantly more often than does either placebo or no treatment (38), although that report is currently being updated. Meta-analyses suggest the overall efficacy of SSRIs is not significantly different from TCAs in general (63) or amitriptyline in particular (64). However, overall drop-out rates, drop-out rates due to side effects, and frequency of side effects were significantly higher with TCAs, including amitriptyline, compared with SSRIs (63,64). Evidence for the efficacy and tolerability of newer agents, such as venlafaxine, are becoming available (65,66).

Evidence-based practice guidelines from established organizations, including the Canadian Psychiatric Association (23,24), the American Psychiatric Association (22), and the National Institute for Clinical Excellence (20) support the use of antidepressant medications and/or psychotherapy for the treatment of depressive disorders in the general population, with recommendations on specific treatments or modalities dependent on the severity of the disorder, patient preference, safety and individual tolerability of antidepressant medications, and other complicating factors. Common adverse effects associated with specific antidepressants are summarized in the guidelines (22,23). CONCLUSION The evidence for the effectiveness of treatment for MD and other depressive disorders in cancer patients is limited and of modest quality. Studies conducted to date have methodological shortcomings, with small sample sizes and high withdrawal rates and it is not clear that all included studies were sufficiently powered to detect a difference between



treatments. For the trials of pharmacological agents, placebo comparisons are limited and dosing is not always adequate. Few trials used structured diagnostic interviews to establish inclusion criteria or remission rates, both of which are now considered to be the gold standard for depression trials (9). In particular, there is a lack of evidence regarding the benefit of the most modern pharmacological agents to treat depressive disorders. The findings from studies conducted thus far in cancer patients with depressive disorders or with significant depressive symptoms provide only modest evidence for the benefit of pharmacological and psychosocial interventions. This evidence does not support the superiority of one modality of treatment over another. It suggests that withdrawal rates tend to be high with interventions of both kinds and in placebo groups, and that adverse effects are particularly common with pharmacological treatments. Although the evidence in the cancer population is limited, it is not inconsistent with that available for the general population, and treatment guidelines at present must be based not only upon this limited evidence but also on data derived from the general population, other medically ill populations, and on the clinical expertise and consensus of the expert panel. Based on such evidence and clinical expert opinion, combined approaches to the treatment of depression may be the most effective. Given the potential for drug interactions and increased side effects that may affect the treatment tolerability or acceptability, cancer patients receiving antidepressant medications should be closely monitored throughout treatment.

There is a pressing need for further research in cancer patients to demonstrate the relative effectiveness and tolerability of the newer antidepressant treatments of all kinds and of strategies to improve treatment compliance and completion. Future studies would benefit from multi-site collaborations to achieve larger sample sizes of patients with specific types of cancer, which may be associated with different side-effect profiles with antidepressant medication treatment and to determine the relative benefit of psychosocial, pharmacological and combined treatments. ONGOING TRIALS

The National Cancer Institute clinical trials database on the Internet (http://www.cancer.gov/search/clinical_trials/) was searched for reports of new or ongoing RCTs. No new trials were identified. CONFLICT OF INTEREST

Dr. Katz has acted as a consultant or received honoraria from Wyeth, a manufacturer of venlafaxine; Lundbeck, a manufacturer of escitalopram and citalopram; and Organon, a maker of mirtazapine. No other potential conflicts of interest were declared by the authors of this Evidence-Based Series report. JOURNAL REFERENCES

Rodin G, Lloyd N, Katz M, Green E, Mackay JA, Wong RKS, Supportive Care Guidelines Group of Cancer Care Ontario Program in Evidence-based Care. The treatment of depression in cancer patients: a systematic review. Support Care Cancer. 2007;15(2):123-36. DOI 10.1007/s00520-006-0145-3 The original publication is available through http://www.springerlink.com/home/main.mpx.

Rodin G, Katz M, Lloyd N, Green E, Mackay JA, Wong RKS, Supportive Care Guidelines Group of Cancer Care Ontario Program in Evidence-based Care. Treatment of depression in cancer patients. Curr Oncol. 2007;14(5):180-8. The original publication is available through http://www.current-oncology.com/index.php/oncology.

http://www.springerlink.com/home/main.mpx

http://www.current-oncology.com/index.php/oncology

http://www.current-oncology.com/index.php/oncology



For a complete list of the Supportive Care Guidelines Group members, please visit the CCO Web site at http://www.cancercare.on.ca/

Funding

The PEBC is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies.

Copyright

This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care

Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified


Contact Information

For further information about this series, please contact Dr. Rebecca Wong, Chair, Supportive Care Guidelines Group, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9; TEL

416-946-2126; FAX 416-946-4586; Email [email protected].

For information about the PEBC and the most current version of all reports,

please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-525-9140, ext. 22055 Fax: 905-522-7681




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23. Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT). Clinical guidelines for the treatment of depressive disorders. Cdn J Psychiatry 2001;46(Suppl 1):1S-90S.

24. Canadian Psychiatric Association. CPA Position Statement. Prescribing antidepressants for depression in 2005: recent concerns and recommendations. Cdn J Psychiatry 2004;49:1-6.

25. Heim HM, Oei TP. Comparison of prostate cancer patients with and without pain. Pain 1993;53:159-62.

26. Kelsen DP, Portenoy RK, Thaler HT, Niedzwiecki D, Passik SD, Tao Y, et al. Pain and depression in patients with newly diagnosed pancreas cancer. J Clin Oncol 1995;13:748-55.

27. Kaasa S, Malt U, Hagen S, Wist E, Moum T, Kvikstad A. Psychological distress in cancer patients with advanced disease. Radiother Oncol 1993;27:193-7.

28. Spiegel D, Sands S, Koopman C. Pain and depression in patients with cancer. Cancer 1994;74:2570-8.

29. Sela RA, Bruera E, Conner-spady B, Cumming C, Walker C. Sensory and affective dimensions of advanced cancer pain. Psychooncology 2002;11:23-34.

30. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med 2003;163:2433-45.

31. Thase ME, Fava M, Halbreich U, Kocsis JH, Koran L, Davidson J, et al. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 1996;53:777-84.

32. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000;342:1462-70.

33. Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence of psychological response on survival in breast cancer: a population-based cohort study. Lancet 1999;354:1331-6.

34. Loberiza FR, Jr., Rizzo JD, Bredeson CN, Antin JH, Horowitz MM, Weeks JC, et al. Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases. J Clin Oncol 2002;20:2118-26.

35. Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, Jr., et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002;288:701-9.

36. House A, Knapp P, Bamford J, Vail A. Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001;32:696-701.

37. Browman GP, Levine MN, Mohide EA, Hayward RS, Pritchard KI, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502-12.

38. Gill D, Hatcher S. Antidepressants for depression in medical illness. Cochrane Database Syst Rev 2000;Issue 2:Art. No.:CD001312. DOI: 10.1002/14651858.CD001312.pub2.

39. Costa D, Mogos I, Toma T. Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatrica Scandinavica, Suppl 1985;320:85-92.

http://www.icsi.org/knowledge/detail.asp?catID=29&itemID=180



40. van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry 1996;169:440-3.

41. Sheard T, Maguire P. The effect of psychological interventions on anxiety and depression in cancer patients: Results of two meta-analyses. Br J Cancer 1999;80:1770-80.

42. Razavi D, Allilaire JF, Smith M, Salimpour A, Verra M, Desclaux B, et al. The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand 1996;94:205-10.

43. Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology 1998;7:291-300.

44. Sharpe M, Strong V, Allen K, Rush R, Maguire P, House A, et al. Management of major depression in outpatients attending a cancer centre: a preliminary evaluation of a multicomponent cancer nurse-delivered intervention. Br J Cancer 2004;90:310-3.

45. Sharpe M, Strong V, Allen K, Rush R, Postma K, Tulloh A, et al. Major depression in outpatients attending a regional cancer centre: Screening and unmet treatment needs. Br J Cancer 2004;90:314-20.

46. Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol 2003;21:1937-43.

47. Holland JC, Morrow GR, Schmale A, Derogatis L, Stefanek M, Berenson S, et al. A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. J Clin Oncol 1991;9:1004-11.

48. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: A comparison between paroxetine and amitriptyline. Br Cancer Res Treat 2001;70:1-10.

49. Moslinger-Gehmayr R, Zaninelli R, Contu A, Oberhoff C, Gutschow K, Schindler AE, et al. [A double-blind comparative study of the effectiveness and tolerance of paroxetine and amitriptyline in treatment of breast cancer patients with clinically assessed depression]. Zentralbl Gynakol 2000;122:195-202.

50. Greer S, Moorey S, Baruch JD, Watson M, Robertson BM, Mason A, et al. Adjuvant psychological therapy for patients with cancer: a prospective randomised trial. BMJ 1992;304:675-80.

51. Moorey S, Greer S, Watson M, Baruch JDR, Robertson BM, Mason A, et al. Adjuvant psychological therapy for patients with cancer: Outcome at one year. Psychooncology 1994;3:39-46.

52. Kissane DW, Bloch S, Smith GC, Miach P, Clarke DM, Ikin J, et al. Cognitive-existential group psychotherapy for women with primary breast cancer: a randomised controlled trial. Psychooncology 2003;12:532-46.

53. McQuellon RP, Wells M, Hoffman S, Craven B, Russell G, Cruz J, et al. Reducing distress in cancer patients with an orientation program. Psychooncology 1998;7:207-17.

54. Williams S, Dale J. The effectiveness of treatment for depression/depressive symptoms in adults with cancer: a systematic review. Br J Cancer 2006;94:372-90.

55. Alliot C. Fluoxetine versus placebo in advanced cancer outpatients. J Clin Oncol 2004;22:204-5.

56. Coyne JC, Palmer SC, Shapiro PJ. Prescribing antidepressants to advanced cancer patients with mild depressive symptoms is not justified. J Clin Oncol 2004;22:205-6.

57. Erwin BA, Sullivan PA, ten Have TR. Trial of antidepressants for mildly depressed cancer patients should have been reported in a manner allowing independent evaluation of investigators' claims. J Clin Oncol 2004;22:753-4.



58. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Patient adherence in the treatment of depression. Br J Psychiatry 2002;180:104-9.

59. Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Combined pharmacotherapy and psychological treatment for depression: a systematic review. Arch Gen Psychiatry 2004;61:714-9.

60. Pinquart M, Duberstein PR, Lyness JM. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry 2006;163:1493-501.

61. Barrett JE, Williams JW, Jr., Oxman TE, Frank E, Katon W, Sullivan M, et al. Treatment of dysthymia and minor depression in primary care: a randomized trial in patients aged 18 to 59 years. J Fam Pract 2001;50:405-12.

62. Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 2005;3:449-56.

63. Macgillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326:1014-doi:10.1136/bmj.326.7397.1014.

64. Guaiana G, Barbui C, Hotopf M. Amitriptyline versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 2003;Issue 2:Art. No.: CD004186. DOI: 10.1002/14651858. CD004186.

65. Smith D, Dempster C, Glanville J, Freemantle N, Anderson I. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry 2002;180:396-404.

66. Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev 2005;Issue 4:Art. No.: CD004185. DOI:10.1002/14651858. CD004185.pub2.

67. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. DSM-IV. Washington (D.C): American Psychiatric Association; 1994.



Appendix 1. Summary of DSM-IV criteria for major depressive disorder, dysthymic disorder, and adjustment disorder (67) Major Depressive Disorder Dysthymic Disorder Adjustment Disorder

1

A. Five or more of the following symptoms present during the same 2-week period and representing a change from previous functioning. At least one of the symptoms is either 1) depressed mood, or 2) loss of interest or pleasure

depressed mood most of the day nearly every day

markedly diminished interest or pleasure in all or almost all activities most of the day, nearly every day

significant weight loss when not dieting or weight gain (e.g. a change in 5% body weight in one month) or decrease or increase in appetite nearly every day

insomnia or hypersomnia nearly every day

psychomotor agitation or retardation nearly every day

fatigue or loss of energy nearly every day

feelings of worthlessness or excessive or inappropriate guilt nearly every day

diminished ability to think or concentrate nearly every day

recurrent thoughts of death, recurrent suicidal ideation or a suicide attempt

A. Depressed mood for most of the day, for more days than not, for at least 2 years

A. The development of emotional or behavioural symptoms in response to an identifiable stressor(s) occurring within 3 months of the onset of the stressor(s).

B. Symptoms cause clinically significant distress or impairment in social or occupational functioning

B. Presence while depressed of two or more of the following:

poor appetite or overeating

insomnia or hypersomnia

low energy or fatigue

low self esteem

poor concentration or difficulty making decisions

feelings of hopelessness

B. These symptoms or behaviours are clinically significant as evidenced by either of the following:

marked distress that is in excess of what would be expected from exposure to the stressor

significant impairment in social or occupational (academic) functioning

C. Symptoms not due to the direct physiological effects of a substance or general medical condition

C. Symptoms have not been absent for more than 2 months during the 2 year period

C. The stress-related disturbance does not meet the criteria for another specific Axis I disorder and is not merely an exacerbation of a pre-existing Axis I or Axis II disorder

D. Symptoms not better accounted for by bereavement D. Symptoms not due to the direct physiological effects of a substance or medical conditions

D. The symptoms do not represent bereavement.

E. Symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning

E. Once the stressor (or its consequences) has terminated, the symptoms do not persist for more than an additional 6 months.

Abbreviations: DSM, Diagnostic and Statistical Manual of Mental Disorders 1 – can be acute (if the disturbance lasts less than 6 months) or chronic (if the disturbance lasts for 6 months or longer); one subtype, according to predominant symptoms, is adjustment disorder with depressed mood (the specific stressor can be specified on Axis IV)



Appendix 2. Diagnostic categories for depression1

Diagnostic category

Criteria2

Duration

Minor depression 2 to 4 depressive symptoms, including depressed mood or anhedonia3 ≥2 weeks

Dysthymia 3 or 4 dysthymic symptoms, including depressed mood4 ≥2 years

Major depression ≥ 5 depressive symptoms, including depressed mood or anhedonia ≥2 weeks

Mild Few (if any) symptoms in excess of those required for the diagnosis; minimal impairment in functioning

Moderate Greater number and intensity of depressive symptoms; moderate impairment in functioning

Severe Marked intensity and pervasiveness of depressive symptoms; substantial impairment in functioning

1 – Appendix reproduced from Table 1 in Whooley & Simon (8). Copyright © 2000 Massachusetts Medical Society. All rights reserved. 2 – Criteria are from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (67), which includes diagnostic criteria for major depression and dysthymia but only research criteria for minor depression. 3 – Depressive symptoms include depressed mood, anhedonia, weight change, sleep disturbance, psychomotor problems, lack of energy, excessive guilt, poor concentration, and suicidal ideation. 4 – Dysthymic symptoms include depressed mood, poor appetite or overeating, sleep disturbance, lack of energy, low self-esteem, poor concentration, and hopelessness.



Appendix 3. Search terms for electronic databases.

Disorder Disease Treatment Publication Type / Study Design

Depressive disorder (MeSH) Neoplasms (MeSH) Antidepressant (MeSH) Practice guidelines

Dysthymic disorder (MeSH) Cancer (text word) Antidepressant medications (text word) Systematic reviews

Major depression (text word) Tumour or tumor or neoplasm: (text word)

Pharmacotherapy (MeSH) Meta-analyses

Drug therapy (MeSH) Reviews

Serotonin uptake inhibitors (MeSH) Randomized controlled trials

Antidepressive agents, tricyclic (MeSH) Controlled clinical trials

Antidepressive agents, second-generation (MeSH)

Psychotherapy (MeSH)

Cognitive therapy (MeSH)

Group psychotherapy (MeSH)

Counselling therapy (text word)

Interpersonal psychotherapy (text word)

Abbreviations: MeSH – medical subject heading.



Appendix 4. Treatment schedule for included trials. Author, year (reference)

Treatment Groups Dose/ Treatment Schedule Comments


Costa 1985 (39)

mianserin placebo

20-40 mg/day week 1: 10mg bid weeks 2-5: 20mg bid

Razavi 1996 (42)

fluoxetine placebo

20 mg/day -

Fisch 2003 (46) fluoxetine placebo

20 mg/day After 12-week study period, patients were given option to continue the study drug for up to nine more months

Holland 1998 (43)

fluoxetine desipramine

20 mg/day (am: 20mg fluoxetine; pm: placebo) 25 mg/day (am: placebo; pm: 25mg desipramine)

Fluoxetine maintained at 20mg/day through week 4 then could be increased by 20 mg/week during days 29-42. Desipramine further titrated in 25 mg/week increments to 100 mg/day at week 4 (maximum 150mg/day)

Holland 1991 (47)

alprazolam PMR

0.5mg tid x10 days perform PMR at home tid x10 days

Patients in PMR group had an initial training session with a behavioural psychologist and then listened to an audiotape of the session tid at home

Pezzella 2001 (48,49)

paroxetine amitriptyline

20-40 mg/day 75-150 mg/day

72 patients (82%) remained on 20mg/day throughout the study. Three titrated to 40mg/day. 74 patients (85%) in amitriptyline group remained on 75mg/day

van Heeringen 1996 (40)

mianserin placebo

60 mg/day week 1 dose: 30 mg/day


Sharpe 2004 (44,45)

multi-component nurse-delivered care usual care

Multi-component care: nurse-delivered care comprised 1) education about depression 2) up to ten 30-minute sessions of problem-solving therapy 3) consideration of antidepressant therapy through discussion with GP 4) coordinating and monitoring treatment Usual care alone: practitioners managed patients “as they normally would”

-

Greer 1992 (50) Moorey 1994 (51)

adjuvant psychological therapy no therapy

NA Adjuvant psychological therapy is a cognitive-behavioural treatment program specific to cancer patients

Kissane 2003 (52)

group psychotherapy + relaxation relaxation alone

20 weekly 90 minute sessions of cognitive-existential group therapy + 3 relaxation classes 3 relaxation classes (50 minutes of PMR with guided imagery)

Women in the control group were given a relaxation tape for continued use at home

McQuellon 1998 (53)

orientation program + usual care

usual care

Usual care included assessment of study questionnaires followed by usual clinic procedures (vital signs and placement in exam room). Intervention group received usual care plus orientation program: tour of oncology clinic, description of clinic procedures, provision of information, Q & A session

-

Abbreviations: bid, twice daily; GP, general practitioner; mg, milligram(s); NA, not applicable; PMR, progressive muscle relaxation; Q & A, question and answer; tid, three times daily.


DEVELOPMENT AND METHODS – page 1


The Management of Depression in Cancer Patients: Guideline Development and External Review - Methods and Results





Report Date: October 17, 2006 THE PROGRAM IN EVIDENCE-BASED CARE

The Program in Evidence-based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO) (1). The PEBC mandate is to improve the lives of Ontarians affected by cancer, through the development, dissemination, implementation, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer care.

The PEBC supports a network of disease-specific panels, called Disease Site Groups (DSGs) and Guideline Development Groups (GDGs), mandated to develop the PEBC products. These panels are comprised of clinicians, other health care providers, methodologists, and community representatives from across the province.

The PEBC is well known for producing evidence-based practice guideline reports, using the methods of the Practice Guidelines Development Cycle (1,2). The PEBC reports consist of a comprehensive systematic review of the clinical evidence on a specific cancer care topic, an interpretation of and consensus agreement on that evidence by our DSGs and GDGs, the resulting clinical recommendations, and an external review by Ontario clinicians in the province for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each clinical practice guideline report, through the periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original clinical practice guideline information. The Evidence-based Series Each Evidence-based Series is comprised of three sections. Section 1: Clinical Practice Guideline. This section contains the clinical recommendations

derived from a systematic review of the clinical and scientific literature and its interpretation by the DSG or GDG involved and a formalized external review by Ontario practitioners.

Section 2: Systematic Review. This section presents the comprehensive systematic review of the clinical and scientific research on the topic and the conclusions reached by the DSG or GDG.



Section 3: Guideline Development and External Review - Methods and Results. This section summarizes the guideline development process and the results of the formal external review by Ontario practitioners of the draft version of the clinical practice guideline and systematic review.

DEVELOPMENT OF THIS EVIDENCE-BASED SERIES Development and Internal Review

This evidence-based series was developed by the Supportive Care Guidelines Group (SCGG) of CCO's PEBC. The SCGG comprises medical, radiation, and surgical oncologists; psychiatrists; palliative care physicians; nurses; radiation therapists; methodologists; administrators; a psychologist; and an anesthetist. The series is a convenient and up-to-date source of the best available evidence on the management of depression in cancer patients, developed through systematic review, evidence synthesis, and input from practitioners in Ontario. Guideline Development Group Consensus

The SCGG members raised three questions during the initial discussions about developing a guideline for the treatment of depressive disorders in cancer patients. First, they wanted to know, “How valid and reliable is the diagnosis of depressive disorder in cancer patients, and what is the prevalence and course of this condition in the cancer population?” Members also asked, “To what extent do systematic reviews, meta-analyses, and randomized controlled trials confirm the efficacy of antidepressant treatments in the cancer population?” Finally, members inquired about existing guidelines for the treatment of depressive disorders in cancer patients and in other populations. The evidence suggests that a valid and reliable diagnosis of MD can be made in this population despite the overlap of symptoms of depression with those of cancer and its treatment. Depressive symptoms have been shown to persist and to be associated with significant morbidity in medically ill populations. Because milder depressive symptoms are a common non-specific manifestation of distress in cancer patients, a group decision was made to focus on the syndrome of MD, for which specific interventions have been developed. The gold standard for the diagnosis of MD is a structured diagnostic interview. It was decided that a guideline that focused on the screening and diagnosis of depression in cancer patients would be a topic for future consideration. The version of the guideline circulated for external review incorporated feedback from SCGG members on a draft version that was first circulated in January 2005 and again in May 2005. The most notable change resulting from SCGG members’ feedback was the division of the guideline into two categories of evidence: pharmacological trials versus non-pharmacological trials. Further, the guideline was revised to clearly indicate which recommendations are based on the evidence reviewed and which are based on consensus recommendations.

In the final SCGG review of the report in October 2006, the only revision required was an increased emphasis in the Introduction section of the Systematic Review (section 2) on the mixed evidence regarding the impact of screening on patient outcomes. External Review by Ontario Clinicians

Following review and discussion of sections 1 and 2 of this evidence-based series, the SCGG circulated the clinical practice guideline and systematic review to health care providers in Ontario for review and feedback. Box 1 summarizes the draft clinical recommendations that were distributed for external review.



BOX 1: DRAFT RECOMMENDATIONS (external review report of September 19, 2005)

Target Population These recommendations apply to adult cancer patients with a diagnosis of major

depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. Such symptoms are frequent as a non-specific manifestation of distress and/or in association with pain or other suffering. For the purposes of this report, the conclusions were based on evidence from studies of two categories of patients:

A. Patients diagnosed with major depression by a structured diagnostic interview. This is the gold standard for the diagnosis of a depressive disorder.

B. Patients with depressive symptoms scoring greater than 14 on the first 17 items of the Hamilton Depression Rating Scale, greater than or equal to eight on the Hospital Anxiety and Depression Scale, or above the equivalent cut-off on another validated assessment scale. These measures were developed to assess symptoms and are used for screening but are less stringent methods to diagnose depressive disorders, because they may be associated with false positives and false negatives. Some but not all of these patients may have been suffering from major depression, dysthymic disorder, adjustment disorder with depressed mood, or minor depression (see Appendices 1 and 2 [of section 2 of this report] for diagnostic criteria for these depressive disorders).

Recommendations There is an absence of clear evidence derived from randomized controlled trials in

cancer patients on which to inform the conclusions. Based on the evidence reviewed and the expert consensus of the guideline panel members (which comprises nurses, palliative care physicians, medical, surgical, and radiation oncologists, an anesthetist, radiation therapists, methodologists, and administrators) and two psychiatrists on the guideline panel it is recommended that:

Antidepressant medications should be considered to treat moderate to severe major depression in cancer patients. Current evidence, however, does not support the relative superiority of one pharmacological modality of treatment over another nor the superiority of pharmacological versus psychosocial interventions. Both of the positive placebo-controlled pharmacological studies were with mianserin, a dual-acting antidepressant currently unavailable in North America.

Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacological interventions.

Psychosocial treatment approaches that may be of value include those that provide information and support and which address emotional, cognitive, and/or behavioural factors.

Although there are no randomized controlled trials of several antidepressants currently in wide use (e.g., escitalopram, citalopram, mirtazapine, venlafaxine, duloxetine, and bupropion) in cancer patients and other medically ill populations, consensus among two psychiatrists on the guideline panel led to the recommendations that the following pharmacological agents may be of value: o Escitalopram or citalopram may be preferable to older selective serotonin reuptake

inhibitors due to the more favourable side effect profile and more limited potential for drug interactions involving the cytochrome P450 system in the liver.

o Mirtazapine may be of particular value to treat mood disturbances accompanied by nausea, weight loss, insomnia, and/or anxiety.



o Greater efficacy and pain relief (especially of neuropathic pain) may result from treatment with dual action antidepressants such as mirtazapine, venlafaxine, and duloxetine.

o Bupropion (sustained release) may be of particular value for cancer patients with significant symptoms of depression and fatigue.

o Psychostimulants may be of value for patients with depressive symptoms associated with apathy and psychomotor retardation.

o Treatment of pain and other reversible physical symptoms should be instituted prior to the initiation of specific antidepressant treatment.

Methods

Feedback was obtained through a mailed survey of 236 health care providers in Ontario including 101 psychiatrists, 40 medical oncologists, 41 pharmacists, 39 nurses, and 15 palliative care physicians. The survey consisted of items evaluating the methods, results, and discussion used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed out over a period of four months (September through December 2005) as contact information for additional provider groups became available. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The SCGG reviewed the results of the survey. Results

In total, 75 responses were received out of the 236 surveys sent (32% response rate). Responses include returned completed surveys as well as phone, fax, and email responses. Forty-four respondents, including 13 medical oncologists, 11 nurses, 10 psychiatrists, 7 palliative care physicians, and 3 pharmacists, indicated that the report was relevant to their clinical practice and completed the survey. Key results of the external review survey, separated by respondent discipline, are summarized in Table 1. Among all respondents, 36 (82%) agreed with the draft recommendations as stated (7% neither agreed nor disagreed), 30 (68%) agreed that the report should be approved as a practice guideline (14%, neither agreed nor disagreed), and 32 (73%) indicated they would be likely to use the guideline in their own practice (18%, were unsure). Summary of Practitioner Comments and the Responses of the SCGG

Twenty-one respondents (48%) provided written comments related to the content of the report. The main points contained in the written comments are summarized below, along with responses of the SCGG. Comments on the Recommendations 1. A number of respondents commented on the lack of evidence for most of the specific agents

recommended and the limitations of having only two psychiatrists as the source of consensus.

The authors acknowledged the limitations of the current evidence, considered the disparity between available research evidence and current practice, and discussed the value of providing guidance for clinicians in the absence of evidence. Although opinions varied, the authors agreed that recommendations for specific antidepressants in the absence of evidence would not be provided within the current guideline. Instead, recommendations on future research to evaluate specific antidepressants are provided.



Table 1. Responses to eight items on the external review survey.

Item

Number (%) a

Strongly agree or

agree

Neither agree nor disagree

Strongly disagree or

disagree

The rationale for developing a guideline, as stated in the “Introduction” section of the report, is clear.

Psychiatrists 9 (90%) 1 (10%) 0

Medical oncologists b1

11 (85%) 1 (8%) 0

Nurses 9 (82%) 0 2 (18%)

Palliative Care Physicians 7 (100%) 0 0

Pharmacists 3 (100%) 0 0

There is a need for a guideline on this topic.

Psychiatrists 10 (100%) 0 0


9 (69%) 3 (23%) 0

Nurses 9 (82%) 0 2 (18%)

Palliative Care Physicians 7 (100%) 0 0


The literature search is relevant and complete.

Psychiatrists b1

7 (70%) 2 (20%) 0


10 (77%) 2 (15%) 0

Nurses b1

6 (55%) 2 (18%) 2 (18%)

Palliative Care Physicians 3 (43%) 4 (57%) 0

Pharmacists 1 (33%) 1 (33%) 1 (33%)

The results of the trials described in the report are interpreted according to my understanding of the data.

Psychiatrists 8 (80%) 1 (10%) 1 (10%)


7 (54%) 5 (38%) 0

Nurses 8 (73%) 1 (9%) 2 (18%)

Palliative Care Physicians b2

4 (57%) 1 (14%) 0


The draft recommendations in the report are clear.

Psychiatrists 10 (100%) 0 0


12 (92%) 0 0

Nurses 9 (82%) 0 2 (18%)


4 (57%) 0 2 (29%)


I agree with the draft recommendations as stated.

Psychiatrists 9 (90%) 0 1 (10%)


11 (85%) 1 (8%) 0

Nurses 8 (73%) 2 (18%) 1 (9%)


5 (71%) 0 1 (14%)


This report should be approved as a practice guideline.

Psychiatrists 7 (70%) 2 (20%) 1 (10%)


11 (85%) 1 (8%) 0

Nurses b1

6 (55%) 2 (18%) 2 (18%)

Palliative Care Physicians 4 (57%) 1 (14%) 2 (28%)

Pharmacists 2 (67%) 0 1 (33%)

If this report were to become a practice guideline, how likely would you be to make use of it in your own practice?

Very likely or likely

Unsure Not at all likely or unlikely

Psychiatrists 6 (60%) 3 (30%) 1 (10%)


10 (77%) 2 (15%) 0

Nurses b1

8 (73%) 2 (18%) 0

Palliative Care Physicians 5 (71%) 1 (14%) 1 (14%)


a Percentages may not total 100% due to rounding errors. bx 'x' individuals did not respond to this question.



2. It was suggested that the sub-recommendation on "treatment of pain" be a main

recommendation and that the recommendation was too rigid; with concurrent use of pain management and antidepressant medications sometimes appropriate.

The SCGG revised the ordering of the recommendations in the Clinical Practice Guideline section of this report as suggested; however, the wording of the current recommendation was not revised because the group felt it did not preclude concomitant pain management and depression treatment.

3. One respondent noted that tricyclic antidepressants could be mentioned if only to

discourage use in major depression unless being used as an adjuvant agent in analgesia. Although newer classes of antidepressants have fewer side effects than tricyclics, they have not been shown to be more effective and the SCGG disagree that the use of tricyclics should be explicitly discouraged at this time.

4. Section 1 could also include discussion of when to defer to a specialist (psychologist, social

worker, psychiatrist) and issues involved in the collaborative care of cancer patients. The SCGG emphasize the need for all health care providers to be alert to signs and symptoms of depression in cancer patients and suggest that deferral to a mental health specialist is most appropriate where the diagnosis of depression is unclear, the syndrome is severe, the patient is not responding to treatment, or there are other complicating factors that may affect the choice of treatment. A Qualifying Statement to this effect has been added to the Clinical Practice Guideline section of this report.

5. The short follow-up of the studies in the review should be highlighted in the recommendations.

The short treatment period and follow-up, particularly in the pharmacological trials, is acknowledged and a statement to this effect has been added to the Key Evidence section of the Clinical Practice Guideline section of this report.

Comments on the Evidence 6. Respondents commented on a number of studies that they felt were of interest (3,4) or

should be included in the report (5-9), the need for information on the use of chemotherapy (a potential confounder) in the reported trials, and the need for clearer identification of the evidence for treatment of depression in other medically ill populations.

Although of interest, none of the studies identified by the external reviewers met the predefined inclusion criteria for the systematic review of the evidence; they were non-comparative (6,7), did not involve current cancer patients (3,4), or did not meet the specified criteria for depression (5,8,9). The SCGG added information on the use of chemotherapy in the reported studies, where available, to Table 3 in the Systematic Review section of this report and expanded the discussion of the evidence on treatment of depression in other populations in the Discussion section of the Systematic Review (section 2 of this report).

Comments on the Report Format or Structure 7. One respondent found the literature review confusing although did not provide detailed

comments and some indicated that a summary of more than one page was not helpful. The SCGG recognize the utility of a succinct guideline and feel that the three-page guideline section of this report provides the recommendations, and the



corresponding evidence relating to the recommendations, in as concise a format as possible.

Other Comments 8. Several respondents thought the review was well-done and the guideline an important

initiative. No response required.

9. One respondent felt that the definition of depression was narrow.

The SCGG chose to focus on a well-defined syndrome for this evidence-based series report and a statement to this effect was added to the Introduction. A review of evidence for a broader spectrum of adjustment disorders may be an appropriate topic for a future report.

10. A number of respondents commented on screening for depression. One felt that the review

should include stronger emphasis on the need for systematic screening, although this may require reorganization of resources, one suggested a recommended screening tool for depression in cancer patients would be useful, and one indicated that the use of screening tools is of limited benefit with patients with depersonalization, who benefit little by using antidepressants.

As indicated in the Introduction and Discussion of the Systematic Review in this report, evidence for a positive impact of screening for depression in primary care populations has been mixed (10,11) and, since a systematic review of the evidence on screening was not conducted, the SCGG have not made recommendations on the need for systematic screening programs at this time. Instead, when depression is detected, the SCGG emphasize the need for appropriate treatment, follow-up, and referral where necessary. With regard to the evaluation of depression screening tools, that topic is beyond the scope of the current report and will be considered for future report development.

11. Pharmacological treatment needs to be more clearly standardized in order to be evaluated.

Different medication doses (e.g. 37.5-375 mg venlafaxine) can produce very different results.

The SCGG consider the exploration of the specificity and dose range of different pharmacological agents to be an appropriate focus of future research and emphasize the need to consider the potential increased sensitivity of cancer patients to treatment side effects.

12. Two respondents commented on the need to get family doctors, oncologists, and other

specialists, involved in the assessment and treatment of depression in cancer patients to ensure that treatment is offered where indicated. One indicated that support from psychiatrists would be needed for this and one suggested that support for the families and caregivers of patients should also be considered since they are at higher risk for depression.

The SCGG acknowledge the need for a range of health care professionals to become involved in the assessment and treatment of depression in cancer patients and hope that this report will provide guidance regarding treatment options. The group also recognize the importance of the broader issue of assessment and treatment of families and caregivers of cancer patients; however, that is outside of the scope of the current report. Guidelines for treatment of depression in non-medical populations would apply for that population.



13. The medication 'mianserin' is not in the Compendium of Pharmaceutics and Specialties

(CPS). This drug, a tetracyclic antidepressant, is non-proprietary; however, as indicated in the report, it is not currently available in North America.

14. One respondent suggested surveying those who are in leadership positions since best

clinical care requires application of the best available evidence by clinical staff supported by strong management/business cases.

The final report will be posted on the Cancer Care Ontario web site and the SCGG will also consider distribution of the report to appropriate clinical and policy leaders in Ontario.

Report Approval Panel The final Evidence-based Series report was reviewed and approved by the PEBC Report Approval Panel (RAP) in October 2006. The Panel consists of two members including an oncologist, with expertise in clinical and methodology issues. Key issues raised by the Panel included: a need for clarification on the intended provider audience for the report and consideration of the presentation of the information for the specific audience; a suggestion to separate the practitioner feedback results by clinician types; and, given the limited evidence for treatment options in cancer patients, a request for further discussion of evidence for treatment effectiveness in non-cancer populations. Modifications/Actions The guideline is intended for both oncology health professionals as well as mental health professionals engaged in the treatment of cancer patients and, in response to the RAP feedback, the SCGG added a section on the target provider population to the guideline. Although mental health professionals may have more expertise in the use of screening tools for depression, it is not clear that the method of detection or presentation of depression affects treatment outcomes; therefore, the SCGG believe that this guideline is also appropriate for oncology health professionals. As suggested, the practitioner feedback responses in Table 1 have been separated for the different practitioner groups responding to the survey and the Discussion section of the Systematic Review (section 2) has been revised to provide additional comments on the efficacy of treatments for depression in non-cancer populations.

ONGOING DEVELOPMENT AND MAINTENANCE This report reflects the integration of the draft recommendations with feedback obtained from the internal and external review processes and has been approved by the SCGG. PEBC reports are reviewed within five years of completion and updated reports will be posted on the CCO web site at: www.cancercare.on.ca.

Funding The PEBC is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

All work produced by the PEBC is editorially independent from its funding agencies.

Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein

may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.



Disclaimer

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified


Contact Information

For further information about this series, please contact Dr. Rebecca Wong, Chair, Supportive Care Guidelines Group, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9; TEL

416-946-2126; FAX 416-946-4586; Email [email protected].

For information about the PEBC and the most current version of all reports,

please visit the CCO Web site at http://www.cancercare.on.ca/ or contact the PEBC office at: Phone: 905-525-9140, ext. 22055 Fax: 905-522-7681




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