Antidepressants for the treatment of depression in patients with cancer

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects and acceptability of antidepressants for treating depressive symptoms in patients with cancer (any site and stage).

Background

Description of the condition

The prevalence of major depression among cancer patients has been estimated to be around 15% in oncological and haematological settings, with similar rates in palliative care settings. Adding other depressive diagnoses, including dysthymia and minor depression, prevalence rates rise to 20% in oncological and haematological settings, and up to 25% in palliative care settings (Mitchell 2011).

Formulating a diagnosis of depression in patients affected by serious medical conditions is particularly challenging, as several symptoms of the medical condition may overlap with those described in the Diagnostic and Statistical Manual (DSM) ( APA 1994 ) and the International Classification of Diseases (ICD) ( WHO 1992 ) for depression, such as fatigue, weight loss and sleep disturbances. Furthermore, besides physical symptoms, cancer progression is associated with functional, social and relational impairment. Even recurrent thoughts of death might be a normal reaction to a limited life expectancy or to severe pain syndromes. It has recently been reported that atypical depressive symptoms, such as anxiety, despair, inner restlessness and social withdrawal might be more frequent in this population, and need to be taken into account when depressive symptoms are assessed (Brenne 2013).

Cancer may increase patients' susceptibility to depression in several ways. First, a reaction to a severe diagnosis and the forthcoming deterioration of health status may constitute a risk factor for depression; second, treatment with immune response modifiers, chemotherapy regimens, as well as metabolic and endocrine alterations, chronic pain and extensive surgical interventions, may represent additional contributing factors (Irwin 2013; Onitilo 2006).

In patients with cancer, depression and other psychiatric co morbidities are responsible for a worsened quality of life (Arrieta 2013), lower compliance with anti-cancer treatment (Colleoni 2000), prolonged hospitalisation (Prieto 2002), higher suicide risk (Shim 2012) and greater psychological burden on the family (Kim 2010). Furthermore, depression is likely to be an independent risk factor for cancer mortality (Lloyd-Williams 2009; Pinquart 2010), with estimates as high as a 26% greater mortality rate among patients with depressive symptoms and a 39% higher mortality rate among those with a diagnosis of major depression (Satin 2009). The effects of depression on mortality may differ by cancer site, being highest in patients with lung and gastro-intestinal cancer, and lower in those with genitourinary and skin cancer (Onitilo 2006). However, data are sparse and conflicting on this compelling issue (Pinquart 2010). As a consequence, in individuals with cancer, major depression and depressive symptoms may have radically different features compared with individuals without cancer in terms of underlying risk factors, natural history, outcome and antidepressant treatment response (Brenne 2013; Irwin 2013).

Description of the intervention

Antidepressant are the most common psychotropic drugs prescribed for patients with depression. Amongst antidepressants, many different agents are available, including tricyclics (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and other newer agents, such as agomelatine, mirtazapine, reboxetine, and bupropion. It has been repeatedly shown that SSRIs are not more effective than TCAs (Anderson 2000; Mottram 2009), but are better tolerated and safer in overdose than TCAs (Anderson 2000; Barbui 2001; Henry 1995).

In a narrative review covering pharmacological, psychological and psychosocial interventions, Li and colleagues (Li 2012) reported controversial findings on the effectiveness of antidepressants for the prevention and treatment of depressive symptoms in cancer patients. There were few available trials, and the findings were not consistent. It has been suggested that in cancer patients, CANMAT level I evidence (at least two RCTs with adequate sample sizes, preferably placebo-controlled, and/or meta-analysis with narrow confidence intervals (CIs)) is available only for mianserin for the treatment of depressive symptoms and for paroxetine for the prevention of new episodes (Li 2012). A 2012 meta-analysis of the efficacy of psychological and pharmacological interventions (Hart 2012) identified only four eligible trials assessing the efficacy of antidepressant drugs. A more recent meta-analysis, carried out by Laoutidis and colleagues (Laoutidis 2013), found six placebo-controlled trials and three head-to-head trials concerning the treatment of depression in patients with cancer at any stage and site. Among these trials, substantial heterogeneity was found. The meta-analysis showed an improvement in depressive symptoms in patients treated with antidepressants with an overall relative risk of 1.56 (95% CI 1.07 to 2.28). No difference in dropouts was found between groups. Subgroup analysis failed to identify differences between TCAs and SSRIs, and found that subsyndromal depressive symptoms may similarly improve with antidepressant treatment (Laoutidis 2013). Similar findings have been previously shown in physically ill people in a meta-analytic study (Rayner 2010).

A meta-analysis by Walker and colleagues (Walker 2013), which included trials carried out in patients with a formal depression diagnosis, found limited evidence in favour of the use of antidepressant drugs. However, only two placebo-controlled trials were included, and in both of them the antidepressant was mianserin, an agent rarely used in current clinical practice.

Rayner and colleagues (Rayner 2011a) conducted a meta-analytic study on the efficacy of antidepressants in patients receiving palliative care (including cancer and several other life-threatening illnesses) and suffering from depression (including major depressive disorder, adjustment disorder and dysthymic disorder based on standardised criteria, and/or according to a score above a certain cut-off on validated tools) (Rayner 2011a). This review detected a beneficial effect associated with antidepressant treatment, and suggested that in palliative patients milder depressive disorders as well as major depression may be responsive to antidepressant treatment. These findings were incorporated into European guidelines on the management of depression in palliative cancer care (Rayner 2011b), in which use of an antidepressant is recommended, not only in major depression but also in mild depression, if symptoms persist after first-line treatments have failed (including assessment of the quality of relationships with significant others, psychosocial support, guided self-help programmes, brief psychological interventions). However, there is still a lack of evidence as to whether antidepressants are all similarly effective in this population.

How the intervention might work

Antidepressants are a heterogeneous class of drugs, in which a common mechanism of action is not traceable. Their therapeutic action may be related to their ability to affect serotonin, norepinephrine and dopamine neurotransmission systems, according with the broadly studied theory about monoamine dysregulation as the key neurophysiological event underlying mood disorders. However, in recent years, alternative mechanisms have been shown, making progressively clearer the complexity of interactions between several systems on which the action of these drugs rely. For instance, current research on new antidepressant drugs focuses on affecting mechanisms related to glutamate (Lapidus 2013) and melatonin transmission (Hickie 2011), neural proliferation and plasticity in limbic areas (Pilar-Cuéllar 2013), and endocrine system activities (hypothalamic-pituitary-adrenal axis in particular) (Sarubin 2014), as well as anti-oxidant, anti-inflammatory and immunologic pathways (Lopresti 2012).

The extent to which each of these components can contribute to the dysregulation of the brain's homeostatic system could vary extensively among different individuals, according also with several biological, environmental and psychological factors (Shelton 2007). For this reason, even if the efficacy of antidepressants has been proven for some kinds of depressive conditions, we cannot assume these data to be reliable in the same way for cancer patients, for whom several further factors may be involved in the pathogenesis (including psychological, immunologic and metabolic factors, as well as pain and highly distressing treatments).

Why it is important to do this review

Providing better interventions to patients suffering from cancer and depressive symptoms is an important goal. While Cochrane reviews are available on the efficacy of psychotherapy (Akechi 2008) and psychosocial interventions (Galway 2012), no Cochrane review has been performed on the efficacy of antidepressants in this patient population.

Laoutidis 2013,which included patients with depressive disorder and subsyndromal depressive symptoms, identified nine randomised trials and showed antidepressants to be superior to placebo. In their review, however, only trials in English were included, unpublished trials were not sought, and trials with depression as a secondary outcome were excluded. Further, the authors performed a meta-analysis on dichotomous data only.

Considering these limitations and that available systematic reviews provided contrasting findings (Hart 2012; Laoutidis 2013; Li 2012; Rodin 2007), there is still uncertainty as to the true efficacy of antidepressants (Rooney 2010; Rooney 2013; Walker 2013). Moreover, most of the previous reviews focused on elevated depressive symptoms (Hart 2012) or major depression (Iovieno 2011; Ng 2011; Walker 2013), while current findings suggest that depressive symptoms, even in subsyndromal manifestations, could represent an independent risk factor for the burden of disease (Arrieta 2013; Brenne 2013; Pinquart 2010; Satin 2009). Although the efficacy of antidepressants in minor depression, dysthymia and adjustment disorder is still not clear (Barbui 2011; Casey 2011; Silva de Lima 1999; Silva de Lima 2005), different authors suggest that antidepressants are effective in patients suffering from severe medical illness (including cancer), even for subthreshold depressive symptoms (Laoutidis 2013; Rayner 2010; Rayner 2011a).

Objectives

To assess the effects and acceptability of antidepressants for treating depressive symptoms in patients with cancer (any site and stage).

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) only. Trials using quasi-random methods will be excluded. We will include trials published in any language.

Types of participants

We will include adults (18 years or older) with any primary diagnosis of cancer (confirmed with appropriate clinical and instrumental assessment) and major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis of major depression. Participants receiving antidepressants for other indications (e.g. fatigue, neuropathic pain, hot flushes, etc.) will be included only if the criterion of being affected by one of the above-mentioned depressive conditions is met at the time of enrolment.

For trials including patients with a diagnosis of depression, any standardised criteria will be included. Most recent trials use DSM-IV (APA 1994) or ICD-10 (WHO 1992) criteria. Older trials use ICD-9 (WHO 1978), DSM-III (APA 1980)/DSM- III-R (APA 1987) or other diagnostic systems. For trials including patients with depressive symptoms in the absence of a formal diagnosis of major depression, only those employing standardised criteria to measure depressive symptoms and with evidence of adequate validity and reliability will be included. Most recent trials use the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960), the Beck Depression Inventory (BDI) (Beck 1961), the Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery 1979), or the Hospital Anxiety and Depression Scale (HADS) (Zigmond 1983).

Types of interventions

The following antidepressants, reported in the Anatomical Therapeutic Chemical /Defined Daily Dose (ATC/DDD) Index (updated to August 2013) from the WHO Collaborating Centre for Drug Statistics Methodology website (http://www.whocc.no), will be included:

  • non-selective monoamine reuptake inhibitors, such as amitriptyline, desipramine, imipramine, imipramine oxide, nortriptyline, clomipramine, dosulepin, doxepin, opipramol, trimipramine, lofepramine, dibenzepin, protriptyline, iprindole, melitracen, butriptyline, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine;

  • selective serotonin reuptake inhibitors, such as fluoxetine, fluvoxamine, citalopram, escitalopram, paroxetine, sertraline, alaproclate, etoperidone, zimeldine;

  • monoamine oxidase A inhibitors, such as moclobemide, toloxatone;

  • non-selective monoamine oxidase inhibitors, such as isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide, iproclozide;

  • any newer antidepressant and any other non-conventional antidepressive agents, such as mianserin, trazodone, nefazodone, mirtazapine, bupropion, venlafaxine, desvenlafaxine, duloxetine, reboxetine, agomelatine, milnacipran, oxitriptan, tryptophan, nomifensine, minaprine, bifemelane, viloxazine, oxaflozane, medifoxamine, tianeptine, pivagabine, gepirone, vilazodone, Hyperici herba.

The comparison group will be placebo and/or any other antidepressants (head-to-head comparisons).

Trials in which antidepressants are compared with another type of psychopharmacological agent, i.e. psycho-stimulants, anxiolytics, anti-convulsants, anti-psychotics or mood-stabilisers, will be excluded.

Types of outcome measures

Primary outcomes
Efficacy as a continuous outcome

Group mean scores at different time points and, if these are not available, group mean change scores, on Hamilton Rating Scale for Depression (HDRS), Montgomery and Asberg Depression Rating Scale (MADRS) or Clinical Global Impression Rating scale (CGI), or on any other depression rating scale with evidence of adequate validity and reliability, will be extracted and analysed as follows:

  • early response: between 1 and 4 weeks, giving preference to the time point closest to 2 weeks;

  • acute phase treatment response: between 6 and 12 weeks, giving preference to the time point given in the original trial as the study endpoint;

  • follow-up response: between 4 and 6 months, giving preference to the time point closest to 24 weeks.

The acute phase treatment response (between 6 and 12 weeks) will be our primary outcome of interest.

Secondary outcomes
Efficacy as a dichotomous outcome

Treatment responders during the 'acute phase' (between 6 and 12 weeks): proportion of patients showing a reduction of at least 50% on the HDRS or MADRS or any other depression scale (e.g. the Beck Depression Inventory (BDI) or the Center for Epidemiologic Studies Depression Scale (CES-D) scale), or who were 'much or very much improved' (score 1 or 2) on the Clinical Global Impression-Improvement (CGI-I) scale, or the proportion of patients who improved using any other pre-specified criterion.

Social adjustment

Mean scores on social-adjustment rating scales (e.g. Global Assessment of Functioning (GAF)), as defined by each of the trials, during the 'acute phase' (between 6 and 12 weeks),

Health-related quality of life

Mean scores on quality of life (QoL) rating scales during the 'acute phase' (between 6 and 12 weeks). Preference will be given to illness-specific QoL measures, such as the European Organisation for Research and Treatment into Cancer Quality of Life Questionnaire-30 (EORTC QLQ-30) (Aaronson 1993), the Functional Assessment of Cancer Therapy (FACT) scale (Cella 1993) and the Short Form (36) Health Survey (SF-36) (Ware 1980; Ware 1992). When such tools are not employed, we will use a general health-related QoL measure with evidence of adequate validity and reliability, as defined by each of the trials.

Acceptability (dropouts)
  • number of patients who dropped out during the trial as a proportion of the total number of randomised patients (total dropout rate);

  • number of patients who dropped out due to inefficacy during the trial as a proportion of the total number of randomised patients (dropout rates due to inefficacy);

  • number of patients who dropped out due to adverse effects during the trial as a proportion of the total number of randomised patients (dropout rates due to adverse effects).

Acceptability outcomes will be extracted at trial endpoint only.

Search methods for identification of studies

Electronic searches

We will search the following electronic bibliographic databases: MEDLINE (database platform: HEBSCOHost) (1946 to present); EMBASE (database platform: OvidSP) (1980 to present); PsycINFO (database platform: HEBSCOHost) (1987 to present); and the Cochrane Central Register of Controlled Trials (CENTRAL) (database platform: Ovid) (The Cochrane Library, latest issue). For the MEDLINE search strategy see Appendix 1. For other databases the search strategy will be adapted accordingly.

Searching other resources

Handsearches

We will handsearch the trial databases of the following drug-approving agencies for published, unpublished and ongoing controlled trials: the Food and Drug Administration (FDA) in the United States, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, the European Medicines Agency (EMA) in the European Union, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and the Therapeutic Goods Administration (TGA) in Australia. We will additionally search the following trial registers: clinicaltrials.gov in the United States, ISRCTN and National Research Register in the United Kingdom, UMIN-CTR in Japan, the ANZ-CTR in Australia and New Zealand, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal, and controlled-trials.com. We will also handsearch appropriate journals and conference proceedings relating to depression treatment in cancer patients. Websites of the most relevant pharmaceutical companies producing antidepressants (such as GlaxoSmithKline, Sanofi, Janssen, Lundbeck, Pfizer, Abbott, Lilly, Merck) will also be handsearched for published, unpublished and ongoing controlled trials.

We will also search reference lists of included trials and other relevant studies.

Personal communication

We will ask pharmaceutical companies and experts in this field if they know of any trial which meets the inclusion criteria of this review.

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Reference Manager, Endnote) and will remove duplicates. Two review authors (GO and FM) will examine the remaining references independently. We will exclude those trials that clearly do not meet the inclusion criteria, and we will obtain copies of the full text of potentially-relevant references.Two review authors (GO and FM) will independently assess the eligibility of retrieved trials. Disagreements will be resolved by discussion between the two review authors and, if necessary, with a third review author (CB). Reasons for exclusion will be documented. Multiple reports of the same trials will be nested to ensure that no data are included in the meta-analysis more than once.

Data extraction and management

Two review authors (GO and FM), working independently and in duplicate, will extract data from the included trials using a 'data collection sheet' (see Appendix 2), which was developed in accordance with recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (chapter 7). If the trial is a three (or more)-armed trial involving a placebo arm, data will be extracted from the placebo arm as well.

Data will include:

  • first author, year and journal;

  • methodological features (study design, randomisation, blinding and allocation concealment, follow-up period);

  • participant characteristics (gender, age, study setting, number of patients randomised to each arm, depression diagnosis, previous history of depression, cancer site and stage, cancer treatment);

  • intervention details (antidepressant and other interventions employed, dosage range, mean daily dosage prescribed);

  • outcome measures for each time point of interest (continuous measures will encompass mean scores of rating scales, standard deviation or standard error; dichotomous measures will be endpoint response rate and dropout rate);

  • cost analysis, presence of sponsorship by a drug company.

Assessment of risk of bias in included studies

Two review authors (GO and FM) will independently assess the risk of bias of all included trials in accordance with The Cochrane Collaboration's tool in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), which includes the following assessment: random sequence generation and allocation concealment (selection bias), blinding of participants and personnel (detection bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting of outcomes (reporting bias) and other biases (e.g. sponsorship bias). To determine the risk of bias of a trial, for each criterion we will evaluate the presence of sufficient information and the likelihood of potential bias. Each criterion will be rated as 'low risk of bias', 'high risk of bias' or 'unclear risk of bias' (indicating either lack of information or uncertainty over the potential for bias). Particular attention will be given to the adequacy of the random allocation concealment and blinding of participants, personnel and outcome assessors. If inadequate details of methodological characteristics of trials are provided, we will contact the authors in order to obtain further information. If the raters disagree, the final rating will be made by consensus with the involvement (if necessary) of a third review author (CB). Results will be summarised in the 'Risk of bias' graph and a 'Risk of bias' summary and the results of meta-analysis will be discussed and interpreted in light of the findings and with respect to the risk of bias.

Measures of treatment effect

1. Dichotomous data

For dichotomous data, we will calculate the relative risk (RR) with its 95% confidence interval (CI). For statistically significant results, we will calculate the number needed to treat to provide benefit (NNTB).

2. Continuous data

For continuous data we will calculate the standardised mean difference (SMD) with a 95% CI.

Unit of analysis issues

1. Cross-over trials

A major concern of cross-over trials is the carry-over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, the participants can differ systematically from their initial state, even despite a wash-out phase. For the same reason, cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in major depression, we will only use data from the first phase of cross-over trials.

2. Cluster-randomised trials

If cluster randomised trial are identified, we will use the generic inverse variance technique to analyse them appropriately, taking into account intra-class correlation coefficients to adjust for cluster effects. Issues related to the clustering will be managed in accordance with the Cochrane Handbook (section 16.3) (Higgins 2011).

3. Multiple intervention groups

Trials that compare more than two intervention groups of the same drug (i.e. different dosages) will be included in meta-analysis by combining arms of the trials into a single group, for the intervention and for the control group respectively, as recommended in section 16.5 of theCochrane Handbook (Higgins 2011).

Dealing with missing data

At some degree of loss to follow-up, data must lose credibility (Xia 2009). For any particular outcome, should more than 50% of data be unaccounted for, we will not reproduce these data or use them within analyses. If, however, more than 50% of those in one arm of a trial are lost, but the total loss is less than 50%, we will mark such data with (*) to indicate that such a result may be prone to bias. When dichotomous or continuous outcomes are not reported, trial authors will be asked to supply the data.

Dichotomous data will be calculated on a strict intention-to-treat (ITT) basis: dropouts will be always included in this analysis. Where participants have been excluded from the trial before the endpoint, we will assume that they experienced a negative outcome by the end of the trial. For continuous variables, we will apply a loose ITT analysis, whereby all the patients with at least one post-baseline measurement are represented by their last observations carried forward (LOCF), with due consideration of potential biases, including number and timings of dropouts in each arm.

When relevant outcomes are not reported, trial authors will be asked to supply the data. In the absence of data from authors, only validated statistical methods will be employed to impute missing outcomes, with due consideration to the possible bias of these procedure, in accordance with the Cochrane Handbook (Higgins 2011) and with www.missingdata.org.uk. When standard deviations (SDs) are not reported, authors will be asked to supply the data. When only the standard error (SE) or t-statistics or P values are reported, SDs will be calculated according to Altman (Altman 1996). In the absence of data from the authors, we will substitute SDs with those reported in other trials in the review (Furukawa 2006).

Assessment of heterogeneity

We will investigate heterogeneity between trials using the I2 statistic (Higgins 2003, Ioannidis 2008) (I2 equal to or more than 50% will be considered to indicate heterogeneity) and by visual inspection of the forest plots.

Assessment of reporting biases

Data from included trials will be entered into a funnel plot (trial effect against trial variance) to investigate small-study effects (Sterne 2000). We will use the tests for funnel plot asymmetry only if there are at least 10 trials included in the meta-analysis, and results will be interpreted cautiously, with visual inspection of the funnel plots (Higgins 2011). When evidence of small-study effects is identified, possible reasons for funnel plot asymmetry, including publication bias, will be investigated.

Data synthesis

If a sufficient number of clinically-similar studies is available, we will pool their results in meta-analyses. For dichotomous outcomes, we will calculate the risk ratio (RR) for each study and then pool these. For continuous outcomes, we will pool the mean differences (MDs) between the treatment arms at the time point of interest if all trials measured the outcome using the same rating scale, otherwise we will pool standardised mean differences (SMDs).

The following comparisons will be made:

  • Antidepressants versus placebo;

  • Antidepressants versus antidepressants.

Indirect comparison will not be considered for the meta-analysis.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses:

  • psychiatric diagnosis, including major depressive disorder, adjustment disorder, dysthymic disorder, depressive symptoms;

  • previous history of depressive conditions;

  • antidepressant class, including TCAs, SSRIs, SNRIs, other antidepressants;

  • cancer site;

  • cancer stage;

  • gender.

Subgroup analyses will be interpreted with caution, as multiple analyses can lead to false positive conclusions (Oxman 1992).

Sensitivity analysis

We will conduct the following sensitivity analyses for the primary outcome:

  1. excluding trials in which the randomisation process is not clearly reported;

  2. excluding trials with unclear concealment of random allocation;

  3. excluding trials that did not employ adequate blinding of participants, healthcare providers and outcome assessors;

  4. excluding trials that did not employ depressive symptoms as their primary outcome;

  5. excluding trials with imputed data.

'Summary of findings' table

We will prepare 'Summary of findings' tables, summarising the key findings of the systematic review in line with the standard methods described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). These findings will include:

1. antidepressants compared to placebo for depressive symptoms in cancer patients;

1a. efficacy as a continuous outcome;

1b. efficacy as a dichotomous outcome;

1c. acceptability (dropouts);

2. antidepressants compared to other antidepressants for depressive symptoms in cancer patients;

2a. efficacy as a continuous outcome;

2b. efficacy as a dichotomous outcome;

2c. acceptability (dropouts).

Acknowledgements

The authors thank Chris Williams, Robin Grant and Alasdair Rooney for clinical expertise, Gail Quinn (Managing Editor), Tracey Louise Bishop (Assistant Managing Editor) and Jane Hayes (Trials Search Co-ordinator) from the Cochrane Gynaecological and Orphan Cancer Review Group.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological and Orphan Cancer Group.

The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NIHR, National Health Service or the Department of Health (UK).

Appendices

Appendix 1. MEDLINE search strategy

1 exp Neoplasms/
2 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or choriocarcinoma* or lymphoma* or leukemia* or leukaemia* or metastat* or sarcoma* or teratoma*).mp.
3 1 or 2
4 Depression/
5 exp Depressive Disorder/
6 Adjustment Disorders/
7 (depress* or melanchol* or ((adjustment or reactive or dysthymic) adj5 disorder*)).mp.
8 4 or 5 or 6 or 7
9 drug therapy.fs.
10 exp Antidepressive Agents/
11 exp Heterocyclic Compounds/
12 exp Serotonin Uptake Inhibitors/
13 exp Adrenergic Uptake Inhibitors/
14 exp Monoamine Oxidase Inhibitors/
15 (anti-depress* or antidepress* or drug therap* or pharmacotherap* or trycyclic* or TCA* or heterocyclic* or serotonin uptake or SSRI* or SNRI* or monoamine oxidase inhibitor* or MAOI*).mp.
16 (desipramine or imipramine or clomipramine or opipramol or trimipramine or lofepramine or dibenzepin or amitriptyline or nortriptyline or protriptyline or doxepin or iprindole or melitracen or butriptyline or dosulepin or amoxapine or dimetacrine or amineptine or maprotiline or quinupramine or zimeldine or fluoxetine or citalopram or paroxetine or sertraline or alaproclate or fluvoxamine or etoperidone or escitalopram or isocarboxazid or nialamide or phenelzine or tranylcypromine or iproniazide or iproclozide or moclobemide or toloxatone or oxitriptan or tryptophan or mianserin or nomifensine or trazodone or nefazodone or minaprine or bifemelane or viloxazine or oxaflozane or mirtazapine or bupropion or medifoxamine or tianeptine or pivagabine or venlafaxine or milnacipran or reboxetine or gepirone or duloxetine or agomelatine or desvenlafaxine or vilazodone or hyperici herba or hypericum perforatum or st john* wort* or saint john* wort*).mp.
17 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16
18 3 and 8 and 17
19 randomized controlled trial.pt.
20 controlled clinical trial.pt.
21 randomized.ab.
22 placebo.ab.
23 clinical trials as topic.sh.
24 randomly.ab.
25 trial.ti.
26 19 or 20 or 21 or 22 or 23 or 24 or 25
27 18 and 26
28 exp animals/ not humans.sh.
29 27 not 28

key:

mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier

pt=publication type
ab=abstract
sh=subject heading
ti=title

Appendix 2. Data collection sheet

Review author name (GO; FM; CB)

1. First author, Year and Journal ___________

2. Comparisons:
AD1 __________________________________
AD2 __________________________________
AD3 __________________________________
PLB yes [ ] no [ ]

3. Weeks of follow-up |___||___| (insert the longest duration of randomised follow-up)

4. Randomisation |___| 0 = unclear

1 = clearly reported
authors’ statement____________
(If it is unclear please report the authors’ statement)

5. Double blinding |___| 0 = unclear
1 = yes
2 = no

6. Concealment allocation |___|
0 = unclear
1 = yes (clearly mentioned according to the Cochrane Handbook)

7. AD1 sample |___||___||___| AD2 sample |___||___||___| AD3 sample |___||___||___| PLB sample |___||___||___|
(Please insert the number of patients randomised to receive each AD drug)

8. Setting |___|
0 = unclear 2 = outpatients 1 = inpatients 3 = in and outpatients

9. Type of participants |___|
0 = unclear 1 = major depressive disorder 3 = dysthymic disorder
2 = adjustment disorders 4 = depressive symptoms (rating scales)
‘depression’ definition (authors’ statement)____________
(If it is unclear please report the authors’ statement)

10. Diagnostic criteria for 'depression' or depressive symptoms |___|
0 = unclear 3 = ICD-10, DSM-IV
1 = DSM-III 4 = rating scales (HRSD, BDI, etc.)
2 = DSM III-R 5 = implicit criteria (e.g. ICD-9)
diagnostic criteria (authors’ statement)_______________
(If it is unclear please report the authors’ statement)

11. Depressive symptoms employed as |___|
0 = primary trial outcome
1 = secondary trial outcome

12. Previous history of depression |___|
0 = exclusion criteria
1 = patients included N |_________| % |_________|

13. Elderly patients |___|
0 = unclear 2 = yes, some elderly (> 65 year old) patients
1 = no 3 = yes, all are 65 years old or older

14. Gender of patients
male |________________________| N |_________| % |_________|
female |________________________| N |_________| % |_________|

15. Cancer site
(If the study includes a population with mixed cancer diagnosis, please insert the number and/or the percentage of patients for each site. If it is unclear please report the authors’ statement)
site 1 |________________________| N |_________| % |_________|
site 2 |________________________| N |_________| % |_________|
site 3 |________________________| N |_________| % |_________|
site 4 |________________________| N |_________| % |_________|
site 5 |________________________| N |_________| % |_________|
cancer site (authors’ statement)____________

16. Cancer stage |______________________________|

(If the study includes a population with mixed cancer diagnosis, please insert the number and/or the percentage of patients for each stage. If it is unclear please report the authors’ statement)
0 = unclear
1 = Stage 0 (carcinoma in situ; early form) N |_________| % |_________|
2 = Stage I (localised) N |_________| % |_________|
3 = Stage II (early locally advanced) N |_________| % |_________|
4 = Stage III (late locally advanced) N |_________| % |_________|
5 = Stage IV (metastasised) N |_________| % |_________|
cancer stage (authors’ statement)______________________________________

17. Cancer treatment |___|
(If the study includes a population with mixed cancer diagnosis, please insert the number and/or the percentage of patients for each treatment. If it is unclear please report the authors’ statement)
0 = unclear
1 = chemotherapy N |_________| % |_________| 2 = radiotherapy N |_________| % |_________|
2 = surgery N |_________| % |_________|
3 = other treatment |__________________________| N |_________| % |_________|
cancer stage (authors’ statement)_____________

18. Severe adverse events
(if the type or the number of adverse events are not reported or are unclearly reported, please report the authors’ statement)
1. ______________________ N |_________| % |_________|
2. ______________________ N |_________| % |_________|
3. ______________________ N |_________| % |_________|
4. ______________________ N |_________| % |_________|
adverse events (authors’ statement)______________________________________

19. Antidepressant (AD) doses
AD1 dose *METHODS |___||___||___| - |___||___||___| r = unclear
N.B. Is this a fixed or flexible dosing schedule? Fixed Flexible
* (Please consider the range of ID dose reported in the method section of the study report)
**RESULTS |___||___||___| . |___||___| SD |___||___|.|___| r = unclear
N.B. Is this a mean dose? Yes No
** (Please consider the average ID dose administered during the study period or, if this figure is not available, consider the average ID dose received by the majority of patients)
D2 dose *METHODS |___||___||___| - |___||___||___| r = unclear
N.B. Is this a fixed or flexible dosing schedule? Fixed Flexible
**RESULTS |___||___||___| . |___||___| SD |___||___|.|___| r = unclear
N.B. Is this a mean dose? Yes No
AD3 dose *METHODS |___||___||___| - |___||___||___| r = unclear
N.B. Is this a fixed or flexible dosing schedule? Fixed Flexible
**RESULTS |___||___||___| . |___||___| SD |___||___|.|___| r = unclear
N.B. Is this a mean dose? Yes No

20. Mean score AT BASELINE: r = unclear/no data available
AD1
N |___||___||___| HDRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) * Specify the N. of items in HDRS |___||___|
N |___||___||___| MADRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| CGI |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (quality of life)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (social adjustment)
AD2
N |___||___||___| HDRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| MADRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| CGI |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (quality of life)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (social adjustment)
AD3
N |___||___||___| HDRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| MADRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| CGI |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (quality of life)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (social adjustment)
PLACEBO
N |___||___||___| HDRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| MADRS |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| CGI |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (quality of life)
N |___||___||___| _____ |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|) (social adjustment)

EFFICACY AS A CONTINUOUS OUTCOME

21. ENDPOINT RESPONSE WEEK …..…… (choose the time point given in the original study as the study endpoint)
Mean score: r = unclear
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
(Please insert the number of evaluable subjects at follow-up, the mean score at follow-up at the HDRS or MADRS or CGI or any other rating scale. If the study used the LOCF, record the values based on the LOCF. If the SD is not available extract the standard error)

22. 1 to 4 weeks RESPONSE RATE WEEK ……… (choose the time point closest to week 2)
Mean score: r = unclear
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
(Please insert the number of evaluable subjects at follow-up, the mean score at follow-up at the HDRS or MADRS or CGI or any other rating scale. If the study used the LOCF, record the values based on the LOCF. If the SD is not available extract the standard error)

23. 6 to 12 weeks RESPONSE RATE WEEK ……… (choose the time point closest to the original study endpoint)
Mean score: r = unclear
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
(Please insert the number of evaluable subjects at follow-up, the mean score at follow-up at the HDRS or MADRS or CGI or any other rating scale. If the study used the LOCF, record the values based on the LOCF. If the SD is not available extract the standard error)

24. 14 to 24 weeks RESPONSE RATE WEEK ……… (choose the time point closest to week 24)
Mean score: r = unclear
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)

(Please insert the number of evaluable subjects at follow-up, the mean score at follow-up at the HDRS or MADRS or CGI or any other rating scale. If the study used the LOCF, record the values based on the LOCF. If the SD is not available extract the standard error)

EFFICACY AS A DICHOTOMOUS OUTCOME

25.ENDPOINT RESPONSE RATE (6 to 12 weeks) WEEK …..…… (choose the time point closest to the original study endpoint)
50% or greater reduction on ___________________
AD1 50% reduction RESPONDERS |___||___||___| out of |___||___||___| r = unclear
AD2 50% reduction RESPONDERS |___||___||___| out of |___||___||___|
AD3 50% reduction RESPONDERS |___||___||___| out of |___||___||___|
Placebo 50% reduction RESPONDERS |___||___||___| out of |___||___||___|
(Please insert which rating scale has been used, the number of patients with a 50% or more improvement - at the HAM-D, MADRS, or any other depression scale -, and the number of included patients at that time point. Typically, a trial would include N patients, but include N – p – q patients in the assessment, as these p patients have never returned and are hence excluded even from the LOCF analyses and q patients drop out in the course of the treatment and their last observed values are carried forward; in this instance, if q patients are somehow accounted for at the time point in question, then, N – p would be the denominator here. In some instances, only responders among N – p – q patients are reported.)

AD1 CGI-I RESPONDERS |___||___||___| out of |___||___||___| r = unclear
AD2 CGI-I RESPONDERS |___||___||___| out of |___||___||___|
AD3 CGI-I RESPONDERS |___||___||___| out of |___||___||___|
Placebo CGI-I RESPONDERS |___||___||___| out of |___||___||___|
(Please insert the number of patients 'much or very much improved' on CGI-Improvement, and the number of included patients at that time point.)

26. SOCIAL ADJUSTMENT (GAF and others) (6 to 12 weeks) WEEK …..…… (choose the time point closest to the original study endpoint)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)

27. HEALTH-RELATED QUALITY OF LIFE (6 to 12 weeks) WEEK …..…… (choose the time point closest to the original study endpoint)
(give preference to EORTC QLQ-30, FACT, SF-36 and other to illness-specific QoL scales, where available)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Rating scale:______________________________
AD1 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD2 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
AD3 N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)
Placebo N |___||___||___| score |___||___||___|.|___||___| SD |___|.|___||___| (SE |___|.|___||___|)

DROPOUT RATE

28. DROPOUTS = patient discontinuing the study before the end of follow-up r = unclear

Dropouts due to:

AD1

number

AD2

number

AD3

number

PLACEBO

number

A - Inefficacy

B - Side - effects

C - TOTAL*

    
    
    
 

* The total number of dropout patients might not be the sum of dropouts for inefficacy and side-effects, because in some studies patients drop from the study for other/unknown reasons

29. Cost analysis |___|
0 = unclear
1 = yes
2 = no

30. Drug company sponsored trial |___|
0 = unclear
1 = yes, sponsored by a drug company
2 = no
(A trial is judged 'drug company sponsored' if it is so declared in the conflict of interest or in the acknowledgment or if some of the authors are company employees. There may be other instances, and use your common sense)

31. NOTES

Contributions of authors

GO drafted the protocol with input and edits from FM, CB and MH. SD, CB and MH critically revised the protocol. All authors approved the final version.

Declarations of interest

GO, FM, CB and MH have nothing to declare.

SD conducted a multi-centre trial of participants with cancer and depressive symptoms that compared the efficacy of escitalopram versus placebo. This trial was supported financially by the Institut Gustave-Roussy and Lundbeck. To prevent bias the author will not be involved in assessing the eligibility of the study, as well as in the extraction of data and in the quality assessment.

Sources of support

Internal sources

  • Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Italy.

    CB receives salary support from the University of Verona. GO is a Psychiatry trainee and receives salary support in the form of a public grant from the Italian Ministry of Health.

  • Department of Psychological Medicine, The Institute of Psychiatry, King's College London, UK.

    MH and FM receive salary support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

  • Département Interdisciplinaire de Soins de Support, Gustave Roussy, France.

    SD receives salary support from the Institute Gustave Roussy, Paris.

External sources

  • No sources of support supplied

Ancillary