Antidepressants for the treatment of depression in people with cancer
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 a negative impact in terms of quality of life, compliance with anticancer treatment, suicide risk and possibly 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 evaluate 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 used standard, extensive Cochrane search methods. The latest search date was November 2022.
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
We used standard Cochrane methods. Our primary outcome was 1. efficacy as a continuous outcome. Our secondary outcomes were 2. efficacy as a dichotomous outcome, 3. Social adjustment, 4. health‐related quality of life and 5. dropouts. We used GRADE to assess certainty of evidence for each outcome.
We identified 14 studies (1364 participants), 10 of which contributed to the meta‐analysis for the primary outcome. Six of these compared antidepressants and placebo, three compared two antidepressants, and one three‐armed study compared two antidepressants and placebo. In this update, we included four additional studies, three of which contributed data for the primary outcome.
For acute‐phase treatment response (six to 12 weeks), antidepressants may reduce depressive symptoms when compared with placebo, even though the evidence is very uncertain. This was true when depressive symptoms were measured as a continuous outcome (standardised mean difference (SMD) −0.52, 95% confidence interval (CI) −0.92 to −0.12; 7 studies, 511 participants; very low‐certainty evidence) and when measured as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; 5 studies, 662 participants; very low‐certainty evidence). No studies reported data on follow‐up response (more than 12 weeks). In head‐to‐head comparisons, we retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) and for mirtazapine versus TCAs. There was no difference between the various classes of antidepressants (continuous outcome: SSRI versus TCA: SMD −0.08, 95% CI −0.34 to 0.18; 3 studies, 237 participants; very low‐certainty evidence; mirtazapine versus TCA: SMD −4.80, 95% CI −9.70 to 0.10; 1 study, 25 participants).
There was a potential beneficial effect of antidepressants versus placebo for the secondary efficacy outcomes (continuous outcome, response at one to four weeks; very low‐certainty evidence). There were no differences for these outcomes when comparing two different classes of antidepressants, even though the evidence was very uncertain.
In terms of dropouts due to any cause, we found no difference between antidepressants compared with placebo (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low‐certainty evidence), and between SSRIs and TCAs (RR 0.83, 95% CI 0.53 to 1.22; 3 studies, 237 participants).
We downgraded the certainty of the evidence because of the heterogeneous quality of the studies, imprecision arising from small sample sizes and wide CIs, and inconsistency due to statistical or clinical heterogeneity.
Despite the impact of depression on people with cancer, the available studies were few and of low quality. This review found a potential beneficial effect of antidepressants against placebo in depressed participants with cancer. However, the certainty of evidence is very low and, on the basis of these results, it is difficult to draw clear implications for practice. 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 drug to prescribe may be based on the data on antidepressant efficacy in the general population of people with major depression, also taking into account that data on people with other serious medical conditions suggest a positive safety profile for the SSRIs. Furthermore, this update shows that the usage of the newly US Food and Drug Administration‐approved antidepressant esketamine in its intravenous formulation might represent a potential treatment for this specific population of people, since it can be used both as an anaesthetic and an antidepressant. However, data are too inconclusive and further studies are needed. We conclude that 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 Vita, Beatrice Compri, Faith Matcham, Corrado Barbui, Giovanni Ostuzzi
Plain language summary
Antidepressants for the treatment of depression in people with cancer
This review found a potential beneficial effect of antidepressants against placebo (a pretend treatment) in depressed people with cancer. However, evidence is uncertain and it is difficult to draw clear conclusions. The use of antidepressants in people with cancer should be considered on an individual basis.
What is the issue?
Depression is frequent amongst people with cancer. Often depressive symptoms are a normal reaction or a direct effect of such a severe and life‐threatening illness. Therefore, it is difficult to establish when depressive symptoms become a proper disorder and need to be treated with medicines. Current scientific literature reveals that depressive symptoms, even when mild, can have an impact on the course of cancer, reducing people's overall quality of life and affecting their compliance with anticancer treatment, as well as possibly increasing the likelihood of death.
What did we want to find out?
We wanted to assess the effectiveness and acceptability of antidepressants for treating depressive symptoms in people with cancer at any site of the body and severity.
What did we do?
We searched medical databases for well‐designed clinical studies comparing antidepressants versus placebo, or antidepressants versus other antidepressants in adults with a diagnosis of cancer and depression.
What did we find?
We reviewed 14 studies assessing the effectiveness of antidepressants in 1364 participants. We found that antidepressants may reduce depressive symptoms after six to 12 weeks of treatment in people with cancer. There was not enough evidence to determine how well antidepressants were tolerated in comparison with placebo. The results did not show whether any particular antidepressant was better than any other antidepressant in terms of beneficial or harmful effects.
What are the limitations of the evidence?
Our certainty in 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. We observed a small potential beneficial effect of antidepressants in treating depressive symptoms in people with cancer. However, this finding was supported by very low‐quality evidence. To better inform doctors and patients, we need larger studies that randomly assign people to different treatments. Currently, it is difficult to draw reliable conclusions about the effects of antidepressants on depression in people with cancer. Our review seems to indicate that people with cancer should be treated in a similar way to the general population for the management of depressive symptoms.
How up to date is this evidence?
The evidence is current to November 2022.
Giovanni Vita, Beatrice Compri, Faith Matcham, Corrado Barbui, Giovanni Ostuzzi
Implications for practice
There is a very low number of randomised controlled trials assessing the efficacy of antidepressants in people with cancer, 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 certainty. Data from the review revealed a small beneficial overall effect of antidepressants as a class over placebo, even though the certainty of evidence is very low.
This review found a small beneficial effect of selective serotonin reuptake inhibitors (SSRIs) compared to placebo in people with cancer and depression. Although the certainty of evidence of these results is very low, SSRIs are the first‐line treatment for the management of clinically relevant depression and their efficacy in the general population has been showed by various clinical studies (Cipriani 2009). According to the evidence at our disposal, SSRIs seem to be effective also in individuals with cancer, and they should probably only be prescribed as first‐line treatment when depressive symptoms become clinically relevant.
Esketamine and mianserin (included in the 'other antidepressants class') have a small beneficial effect against placebo. Mianserin is considered to have a similar profile to mirtazapine, the efficacy of which has been largely demonstrated, but with a possible unfavourable tolerability profile with respect to SSRIs (Cipriani 2009). In contrast, esketamine has been approved as an antidepressant (Kim 2019). Since the intravenous formulation of esketamine can be used also as an anaesthetic, it can prove useful in the treatment of those people with cancer who have to undergo a surgery. 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 differences between the various classes of antidepressants (in head‐to‐head comparisons) emerged.
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 multidimensional approach, encompassing biological, social and psychological issues, as highlighted by previous reviews (Akechi 2008; Galway 2012; Smith 2015). 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 (Grassi 2018; 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 people 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 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 RCTs 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 study may be not considered as a priority for anticancer 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 studies 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 amongst 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‐randomised controlled studies are available on the effect of mirtazapine for insomnia and hyporexia, or duloxetine for pain perception, hot flushes, etc. In actuality there are no RCTs in people with cancer available with these compounds.
There is a growing interest in discussing the potential benefit of intravenous esketamine in reducing depressive symptoms. Two studies included in this update studied the efficacy of intravenous esketamine in participants with cancer who undergo a surgical operation, showing a potential positive effect over placebo, especially in the short‐term follow‐up assessments (Liu 2021; Wang 2020).
Other studies showed promising results concerning the use of psychedelics and psychostimulants (psylocibin, methylphenidate) to treat depression in people with cancer (Griffiths 2016; NCT01219673). However, these studies were not included in the meta‐analysis since the use of these drugs is not approved by the US Food and Drug Administration to treat depression.
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 studies comparing commonly used antidepressants (SSRIs, serotonin‐noradrenaline reuptake inhibitors, mirtazapine) versus placebo in individuals with cancer and depressive symptoms, with or without a formal diagnosis of a depressive disorder.