Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have been shown to have a negative impact in terms of quality of life, compliance with anti‐cancer treatment, suicide risk and likely even the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results.
To assess the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage).
We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 6), MEDLINE Ovid (1946 to June week 4 2017), Embase Ovid (1980 to 2017 week 27) and PsycINFO Ovid (1987 to July week 4 2017). We additionally handsearched the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug‐approving agencies for published, unpublished and ongoing controlled trials.
We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis).
Data collection and analysis
Two review authors independently checked eligibility and extracted data using a form specifically designed for the aims of this review. The two authors compared the data extracted and then entered data into Review Manager 5 using a double‐entry procedure. Information extracted included study and participant characteristics, intervention details, outcome measures for each time point of interest, cost analysis and sponsorship by a drug company. We used the standard methodological procedures expected by Cochrane.
We retrieved a total of 10 studies (885 participants), seven of which contributed to the meta‐analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants, and one three‐armed study compared two antidepressants and placebo. In this update we included one additional unpublished study. These new data contributed to the secondary analysis, while the results of the primary analysis remained unchanged.
For acute‐phase treatment response (6 to 12 weeks), we found no difference between antidepressants as a class and placebo on symptoms of depression measured both as a continuous outcome (standardised mean difference (SMD) −0.45, 95% confidence interval (CI) −1.01 to 0.11, five RCTs, 266 participants; very low certainty evidence) and as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants; very low certainty evidence). No trials reported data on follow‐up response (more than 12 weeks). In head‐to‐head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, showing no difference between these two classes (SMD −0.08, 95% CI −0.34 to 0.18, three RCTs, 237 participants; very low certainty evidence). No clear evidence of a beneficial effect of antidepressants versus either placebo or other antidepressants emerged from our analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low certainty evidence). In terms of dropouts due to any cause, we found no difference between antidepressants as a class compared with placebo (RR 0.85, 95% CI 0.52 to 1.38, seven RCTs, 479 participants; very low certainty evidence), and between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the certainty (quality) of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity.
Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo. On the basis of these results, clear implications for practice cannot be deduced. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head‐to‐head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. To better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.
Giovanni Ostuzzi, Faith Matcham, Sarah Dauchy, Corrado Barbui, Matthew Hotopf
Plain language summary
Antidepressants for the treatment of depression in people with cancer
The issue Depressive states are frequent among people suffering from cancer. Often depressive symptoms are a normal reaction or a direct effect of such a severe and life‐threatening illness. It is therefore not easy to establish when depressive symptoms become a proper disorder and need to be treated with drugs. Current scientific literature reveals that depressive symptoms, even when mild, can have a relevant impact on the course of cancer, reducing people's overall quality of life and affecting their compliance with anti‐cancer treatment, as well as possibly increasing the likelihood of death.
The aim of the review It is important to assess the possible beneficial role of antidepressants in adults (aged 18 years or above) with cancer. The aim of this review is to assess the efficacy and acceptability of antidepressants for treating depressive symptoms in patients with cancer at any site and stage.
What are the main findings? We systematically reviewed ten studies assessing the efficacy of antidepressants, for a total of 885 participants. The evidence is current to 3 July 2017. Due to the small number of people in the studies, and issues with how the studies reported what was done, there is uncertainty over whether antidepressants were better than placebo in terms of depressive symptoms after 6 to 12 weeks of treatment. We did not have enough evidence to determine how well antidepressants were tolerated in comparison with placebo. Our results did not show whether any particular antidepressant was better than any other in terms of both beneficial and harmful effects. To better inform clinical practice, we need large studies which randomly assign people to different treatments. Currently, we cannot draw reliable conclusions about the effects of antidepressants on depression in people with cancer.
Certainty of the evidence The certainty of the evidence was very low because of a lack of information about how the studies were designed, low numbers of people in the analysis of results, and differences between the characteristics of the studies and their results.
What are the conclusions? Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo.
Giovanni Ostuzzi, Faith Matcham, Sarah Dauchy, Corrado Barbui, Matthew Hotopf
Implications for practice
There is a very low number of randomised trials assessing the efficacy of antidepressants in cancer patients, despite the relevance of this issue. Moreover, evidence for the effects we have found in terms of the efficacy and acceptability of antidepressants in people with cancer is of very low quality. Data from the present review failed to reveal any statistically significant beneficial effect of these drugs over placebo, with the only exception of mianserin (see ). Although this drug was compared with placebo in two studies only, with small numbers of included participants, it showed some beneficial effects in terms of efficacy and acceptability. Mianserin is often used in oncological settings for its beneficial profile on sleep and appetite, as well as mood. Conversely, this drug is seldom used in routine clinical practice in psychiatric settings and very few data from randomised controlled trials (RCTs) are available on its efficacy in people with major depression. This compound is considered to have a similar profile to mirtazapine, the efficacy of which has been largely shown, but with a possible unfavourable tolerability profile with respect to selective serotonin reuptake inhibitors (SSRIs) (Cipriani 2009). The efficacy, tolerability and acceptability of these drugs in severely medically ill people is yet to be assessed. Thus, the clinical meaning of these results is uncertain and no clear implications for clinical practice can be drawn. Similarly, no significant differences between one drug and another emerged (see ).
Finding an appropriate treatment for depressive symptoms in people with cancer is a relevant goal in routine clinical practice, as shown by the ongoing discussion in the scientific literature. There is a growing awareness of the need for a multi‐dimensional approach, encompassing biological, social and psychological issues, as highlighted by previous reviews (Akechi 2008; Galway 2012). A proper evaluation of subthreshold depressive symptoms seems essential, also considering their potentially relevant impact on the prognosis of cancer, although it is not easy to discern when it is worthwhile to introduce an antidepressant. Very few and unspecific indications could be derived from the available guidelines (NICE 2009; Rayner 2011b). In general, based on the results of the current review, the possible role of antidepressants is still controversial and should be assessed each time by the clinician on an individual basis. The choice of which antidepressant to prescribe can hardly be made on the basis of this review; rather, it may be based on the data on antidepressant efficacy in the general population of individuals with major depression. Additionally, the data on antidepressant efficacy in medically ill people — which suggest a positive safety profile of SSRIs (Rayner 2010; Rayner 2011a) — may also be considered.
Implications for research
The results described in this systematic review come from evidence of very low certainty according to the GRADE methodology. Moreover, in many cases studies were financially supported by pharmaceutical industries. Consequently, there is a high risk that these studies do not provide sufficient and adequate information for clinicians in real‐world settings. The present review highlights the strong need for further studies, which should be conducted to high methodological standards and with the primary intent of providing clinicians with useful practical data on the effectiveness of antidepressant drugs, firstly over placebo and subsequently in head‐to‐head comparisons. Alongside rating scales, pragmatic outcome measures, such as quality of life and social functioning, should also be considered.
Despite the high prevalence of depression in people with cancer and its substantial impact, the number of randomised trials assessing the efficacy of antidepressants in oncology is still very low. We recognise that these studies are extremely difficult to conduct, as depression is not always considered a major concern by doctors and by people with cancer, who are sometimes reluctant to admit its existence. Moreover, promoting this type of trial may be not considered as a priority for anti‐cancer research funding agencies.
Further basic research on the pathogenetic pathways of depression in medically ill people is needed. This could be helpful for identifying possible therapeutic targets, and would also allow the assessment of new, possibly effective drugs with comparative study designs. In recent years, we witnessed a growing interest in detecting possible specific mechanisms involved in pathogenesis of depressive experiences in different types of cancer (Bowinik 2014; Sotelo 2014).
Generally SSRIs are considered to have a good therapeutic index among antidepressants. However, some other antidepressants could be theoretically helpful in this particular population, being possibly effective not only for depression, but also for medical symptoms. For example, some non‐controlled studies are available on the effect of mirtazapine for insomnia and hyporexia, or duloxetine for pain perception, hot flushes and so on. In actuality no randomised trials in people with cancer are available with these compounds.
In line with the conclusions from the previous version of this review, in order to increase the evidence on the compelling issue of depressive symptoms in people with cancer, there is a need for large, simple, pragmatic RCTs comparing commonly used antidepressants (SSRIs, serotonin‐norepinephrine reuptake inhibitor (SNRIs), mirtazapine) versus placebo in individuals with cancer and depressive symptoms, with or without a formal diagnosis of a depressive disorder.Get full text at The Cochrane Library
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