Antidepressants for the treatment of depression in people with cancer

Giovanni Vita; Beatrice Compri; Faith Matcham; Corrado Barbui; Giovanni Ostuzzi

doi:10.1002/14651858.CD011006.pub4

. 2023 Mar 31;2023(3):CD011006. doi: 10.1002/14651858.CD011006.pub4

Antidepressants for the treatment of depression in people with cancer

Giovanni Vita ^1,^✉, Beatrice Compri ¹, Faith Matcham ², Corrado Barbui ³, Giovanni Ostuzzi ³

Editor: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

PMCID: PMC10065046 PMID: 36999619

Abstract

Background

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.

Objectives

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).

Search methods

We used standard, extensive Cochrane search methods. The latest search date was November 2022.

Selection criteria

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.

Main results

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.

Authors' conclusions

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.

Plain language summary

Antidepressants for the treatment of depression in people with cancer

Key messages

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.

Summary of findings

Summary of findings 1. Antidepressants compared to placebo for people with cancer and depression.

Antidepressants compared to placebo for people with cancer and depression
Patient or population: adults with cancer and depression Settings: inpatient and outpatient Intervention: antidepressants Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Antidepressants
Efficacy as a continuous outcome Follow‐up: 6–12 weeks	—	The mean efficacy as a continuous outcome (SMD) in the intervention groups was 0.52 standard deviations lower (0.92 lower to 0.12 lower)	—	511  (7 studies, 8 comparisons)	⊕⊝⊝⊝ Very low^a,b	—
Efficacy as a dichotomous outcome Follow‐up: 6–12 weeks	427 per 1000	316 per 1000 (243 to 410)	RR 0.74  (0.57 to 0.96)	662  (7 studies, 8 comparisons)	⊕⊝⊝⊝ Very low^a,c	—
Dropouts due to any cause (acceptability) Follow‐up: 4–12 weeks	121 per 1000	103 per 1000 (105 to 328)	RR 0.85  (0.52 to 1.38)	479 (9 studies, 10 comparisons)	⊕⊝⊝⊝ Very low^a,d,e	—
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; SMD: standardised mean difference.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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^a Downgraded one level as the general quality of the studies included in the review was poor, with 50% of the studies at high risk of bias in the ROB 2 assessment. Most studies had a very high dropout rate (bias due to missing outcome) and very few studies described the randomisation process in detail. ^b Downgraded two levels due to serious heterogeneity (I² = 74%). An I² statistic between 50% and 75% suggests a serious risk of inconsistency (unexplained heterogeneity), which may arise from relevant differences in populations, interventions and outcomes of the studies entered into the analysis. ^c Downgraded two levels due to serious heterogeneity (I² = 58%). See note ^b. ^d Downgraded one level due to low number of participants recruited and 95% CIs included both no effect and appreciable benefit or appreciable harm, which suggests the risk of very serious imprecision of the results and thus low confidence in their reliability. ^e Downgraded one level due to moderate heterogeneity (I² = 45%). An I² statistic between 30% and 60% suggests a moderate risk of inconsistency (unexplained heterogeneity), which may arise from relevant differences in populations, interventions and outcomes of the studies entered into the analysis.

Summary of findings 2. Selective serotonin reuptake inhibitors (SSRIs) compared to tricyclic antidepressants (TCAs) for people with cancer and depression.

SSRIs compared to TCAs for people with cancer and depression
Patient or population: people with cancer and depression Settings: inpatient and outpatient Intervention: SSRIs Comparison: TCAs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TCAs	SSRIs
Efficacy as a continuous outcome Follow‐up: 6–12 weeks	—	The mean efficacy as a continuous outcome (SMD) in the intervention groups was 0.08 standard deviations lower (0.34 lower to 0.18 higher)	—	237 (3 studies)	⊕⊝⊝⊝ Very low^a,b,c	—
Efficacy as a dichotomous outcome Follow‐up: 6–12 weeks	Study population		RR 1.10 (0.78 to 1.53	199 (2 studies)	⊕⊝⊝⊝ Very low^a,b	—
	388 per 1000	454 per 1000 (256 to 799)
Dropouts due to any cause (acceptability) Follow‐up: 4–12 weeks	Study population		RR 0.83  (0.53 to 1.30)	237 (3 studies)	⊕⊝⊝⊝ Very low^a,b,c	—
	261 per 1000	217 per 1000 (138 to 339)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; SMD: standardised mean difference; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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^a Downgraded one level as no studies described the outcome assessment as blinded. This should be considered a major limitation, which is likely to result in a biased assessment of the intervention effect. ^b Downgraded two levels as very low number of participants recruited (fewer than 100 individuals in both treatment arms) and 95% CIs included both no effect and appreciable benefit or appreciable harm, which suggests the risk of very serious imprecision of the results and thus low confidence in their reliability. ^c Downgraded one level as one study out of three had a high risk of sponsorship bias.

Summary of findings 3. Mirtazapine compared to tricyclic antidepressants (TCA) for people with cancer and depression.

Mirtazapine compared to placebo for people with cancer and depression
Patient or population: adults with cancer and depression Settings: inpatient and outpatient Intervention: mirtazapine Comparison: TCA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mirtazapine	TCA
Efficacy as a continuous outcome Follow‐up: 6–12 weeks	—	The mean efficacy as a continuous outcome (MD) in the intervention groups was 4.80 lower in the intervention group (9.70 lower to 0.10 higher)	—	25 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	—
Efficacy as a dichotomous outcome Follow‐up: 6–12 weeks	77 per 1000	62 per 1000 (46 to 84)	RR 0.81 (0.60 to 1.09)	33 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	—
Dropouts due to any cause (acceptability) Follow‐up: 4–12 weeks	308 per 1000	200 per 1000 (62 to 662)	RR 0.65 (0.20 to 2.15)	33 (1 RCT)	⊕⊝⊝⊝ Very low^b,c	—
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; TCA: tricyclic antidepressant.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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^a Downgraded two levels as overall risk of bias was high according to the RoB 2 assessment, due to missing outcome data. ^b Downgraded two levels as very low number of participants recruited (fewer than 100 individuals in both treatment arms) and 95% CIs included both no effect and appreciable benefit or appreciable harm, which suggests the risk of very serious imprecision of the results and thus low confidence in their reliability. ^c Downgraded one level as overall risk of bias was moderate according to the RoB 2 assessment.

Background

Description of the condition

The prevalence of major depression amongst people with cancer has been estimated at 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 up to 20% in oncological and haematological settings, and up to 25% in palliative care settings (Mitchell 2011; Riedl 2021). However, a precise estimation of the prevalence of depression in people with cancer is difficult due to the influence of many variables, including site and stage of cancer, type of anticancer treatment and diagnostic tools employed (Caruso 2017).

Formulating a diagnosis of depression in people 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 of Mental Disorders (DSM) (APA 1994) and the International Classification of Diseases (ICD) (WHO 1992) for depression, such as fatigue, weight loss and sleep disturbances (Panjwani 2021; Thompson 2017). 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 (Breitbart 2000; Vehling 2017). It has been reported that atypical depressive symptoms, such as anxiety, despair, fatigue, post‐traumatic stress symptoms, body image distortions, 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; Diaz‐Frutos 2016; Ebede 2017; Yi 2017).

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 and chemotherapy regimens, and experiencing of metabolic and endocrine alterations, chronic pain and extensive surgical interventions, may represent additional contributing factors (Adam 2021; Irwin 2013; Onitilo 2006; Sotelo 2014; van Santen 2020).

In people with cancer, depression and other psychiatric comorbidities are responsible for worsened quality of life (Arrieta 2013; Park 2020; Vyas 2017), greater physical symptoms (Fitzgerald 2015), lower compliance with anticancer treatment (Colleoni 2000; Mausbach 2015; Panjwani 2021), prolonged hospitalisation, increased readmissions (Nipp 2017; Pederson 2016; Prieto 2002), delays in treatment and diagnosis (Iglay 2017), disease progression and increased mortality (McFarland 2021; Wang 2020), higher suicide risk (Saad 2019; Shim 2012), and a greater psychological burden on the family (Jacobs 2017; Kim 2010; Oechsle 2019). Furthermore, depression is likely to be an independent risk factor for cancer mortality (Lloyd‐Williams 2009; McFarland 2021; Pinquart 2010; Wang 2020), with estimates as high as a 26% greater mortality rate amongst people with cancer and with depressive symptoms and a 39% higher mortality rate amongst those with a diagnosis of major depression (Satin 2009). The effects of depression on mortality may differ by cancer site, being higher in people with lung, gastrointestinal (in particular, pancreatic), and brain cancer, and lower in those with genitourinary and skin cancer (Hartung 2017; Onitilo 2006). However, data are sparse and conflicting on this compelling issue (Pinquart 2010). As a consequence, individuals with cancer and major depression or 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; Hartung 2017; Irwin 2013).

Description of the intervention

Antidepressants are the most common psychotropic drugs prescribed in people with depression. Amongst antidepressants, many different agents are available, including tricyclic antidepressants (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; Chockalingam 2019; Henry 1995).

In one narrative review covering pharmacological, psychological and psychosocial interventions, Li 2012 reported controversial findings on the effectiveness of antidepressants for the prevention and treatment of depressive symptoms in people with cancer. There were few available studies and the findings were not consistent. It has been suggested that in people with cancer, Canadian Network for Mood and Anxiety Treatments (CANMAT) level I evidence (at least two randomised controlled trials (RCTs) with adequate sample sizes, preferably placebo‐controlled, or meta‐analysis with narrow confidence intervals (CIs), or both) (Kennedy 2016) is available only for mianserin for the treatment of depressive symptoms and for paroxetine for the prevention of new episodes (Li 2012). One meta‐analysis of the efficacy of psychological and pharmacological interventions by Hart 2012 identified only four eligible studies assessing the efficacy of antidepressant drugs. One meta‐analysis found six placebo‐controlled trials and three head‐to‐head trials concerning the treatment of depression in people with cancer at any stage and site (Laoutidis 2013). Amongst these studies, there was substantial heterogeneity (i.e. relevant variability of participants, interventions and outcome due to different clinical, methodological and statistical approaches) (Higgins 2022). The meta‐analysis showed an improvement in depressive symptoms in participants treated with antidepressants, with an overall risk ratio (RR) of 1.56 (95% CI 1.07 to 2.28). There was no difference in dropouts between groups. Subgroup analysis failed to identify differences between TCAs and SSRIs, and found that subsyndromal depressive symptoms (i.e. symptoms that do not reach the status of a formal depressive syndrome as it is described by diagnostic manuals, such as DSM or ICD) may similarly improve with antidepressant treatment (Laoutidis 2013). Similar findings have been previously shown in physically ill people in one meta‐analytic study (Rayner 2010).

A meta‐analysis by Walker 2014, which included trials carried out in people with a formal diagnosis of depression, found limited evidence in favour of the use of antidepressant drugs. However, it included only two placebo‐controlled trials, and both used the antidepressant mianserin, which is an agent rarely used in current clinical practice. More recently, Riblet and colleagues, who systematically reviewed the evidence comparing antidepressants and placebo in individuals with any type and stage of cancer and comorbid depression of any severity, retrieved 10 studies suitable for a meta‐analysis on the efficacy of antidepressants (Riblet 2014). They concluded that fluoxetine, paroxetine and mianserin may improve cancer‐related depression. However, one was a quasi‐randomised trial and two trials included participants who were not depressed at baseline.

Rayner 2011a conducted a meta‐analytic study on the efficacy of antidepressants in people receiving palliative care (including cancer and several other life‐threatening illnesses) and with depression (including major depressive disorder, adjustment disorder and dysthymic disorder based on standardised criteria, or according to a score above a certain cut‐off on validated tools, or both). This review detected a beneficial effect associated with antidepressant treatment and suggested that people in palliative care with 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 and brief psychological interventions). A four‐year historical prospective cohort study demonstrated that increased antidepressant adherence is associated with decreased all‐cause mortality in a large national cohort of people with cancer (Shoval 2019). However, there is still a lack of evidence 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, noradrenaline and dopamine neurotransmission systems, according to the broadly studied theory about monoamine dysregulation as the key neurophysiological event underlying mood disorders. However, 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; Murrough 2017) 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 antioxidant, anti‐inflammatory and immunological pathways (Gobin 2014; Lopresti 2012).

The extent to which each of these components can contribute to the dysregulation of the brain's homeostatic system could vary extensively amongst different individuals and also with several biological, environmental and psychological factors (Shelton 2007). For this reason, even if the efficacy of antidepressants has been proven for some types of depressive conditions, we cannot assume these data to be reliable in the same way for people with cancer, for whom several further factors may be involved in the pathogenesis (including psychological, immunological and metabolic factors, as well as pain and highly distressing treatments). Some authors have suggested a possible beneficial effect of antidepressants in cancer biology (Ahmadian 2017; Chan 2017; Gil‐Ad 2008; Song 2021; Zingone 2017). However, these findings are largely explorative and need to be further investigated; and it is not clear whether the effect of antidepressants may differ according to the specific cancer type or site, or both. Few systematic reviews have explored this issue, retrieving only small numbers of studies from which to draw conclusions (Carvalho 2014; Walker 2014).

In most cases, antidepressant dose should be gradually titrated and it can be some weeks before the treatment takes effect. Antidepressants may require adjustment over time to ensure an appropriate dose is given. Moreover, it has been highlighted that compliance represents a relevant factor for an antidepressant's efficacy (Chong 2011; Vergouwen 2003).

Why it is important to do this review

Providing better interventions for people with cancer and depressive symptoms is an important goal. Single pharmacological, psychological and physical interventions are not an exhaustive response for such a complex and multifaceted condition, which is likely to benefit from integrated, multicomponent approaches (Anwar 2017; Sharpe 2014). With this in mind, a Cochrane systematic review on the efficacy, tolerability and acceptability of antidepressants is needed in addition to existing Cochrane systematic reviews on psychotherapy (McCaughan 2017), psychosocial (Galway 2012; Semple 2013), physical (Furmaniak 2016; Shin 2016) and complementary interventions (Bradt 2015; Cramer 2017).

One systematic review by Laoutidis 2013 included participants with depressive disorder and subsyndromal depressive symptoms and identified nine RCTs for inclusion. It showed antidepressants to be superior to placebo. However, the review included only trials in published in English, they did not seek unpublished studies, and they excluded studies with depression as a secondary outcome. Further, the authors performed a meta‐analysis on dichotomous data only. Another review included people with a diagnosis of depressive disorder, subsyndromal depressive symptoms, and people without an assessment of depressive symptoms at baseline, provided that they received antidepressant treatments for emotionally distressing cancer‐related manifestations (such as fatigue, insomnia, asthenia or cancer pain) (Ostuzzi 2015a). The meta‐analysis showed a beneficial effect of antidepressants over placebo in treating depressive symptoms as a whole, and the positive effect remained when considering separately participants with a formal diagnosis of major depression or depressive symptoms at baseline, and participants for whom antidepressant use was related to other distressing cancer‐related symptoms. In addition, antidepressants were effective in improving quality of life.

Considering these limitations and that available systematic reviews provide contrasting findings (Hart 2012; Laoutidis 2013; Li 2012; Rodin 2007), there is still uncertainty as to the true efficacy of antidepressants (Rooney 2013; Walker 2014). Moreover, most of the previous reviews focused on elevated depressive symptoms (Hart 2012), or major depression (Iovieno 2011; Ng 2011; Walker 2014), 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 people with a severe medical illness (including cancer), even for subthreshold depressive symptoms (Laoutidis 2013; Rayner 2010; Rayner 2011a).

Based on this evidence we carried out a systematic review (Ostuzzi 2015b). In this previous version of the review, we found no differences between antidepressants (as a class) and placebo in treating depressive symptoms (very low‐certainty evidence). Similarly, we found no differences between SSRIs and TCAs (very low‐certainty evidence). In this update, we sought to include new relevant studies or to retrieve new data from studies that were previously awaiting classification.

Objectives

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).

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs. We excluded studies using quasi‐random methods. We included studies published in any language.

Types of participants

We included adults (aged 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. Differently from the previous version of this review, we also included studies where, although a formal diagnosis of depression was not reported, the mean baseline score of validated rating scales measuring depression was consistent with depression of at least moderate severity. The cut‐off scores we used were:

18 or greater using the Hamilton Rating Scale for Depression (HAM‐D) (Cusin 2010);
21 or greater using the Beck Depression Inventory (BDI) (Wang 2013);
22 or greater using the Montgomery‐Åsberg Depression Rating Scale (MADRS) (Masson 2013).

We included participants receiving antidepressants for other indications (e.g. fatigue, neuropathic pain, hot flushes, etc.) only if the criterion of being affected by one of the above‐mentioned depressive conditions was met at the time of enrolment.

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

Types of interventions

We included the following antidepressants, reported in the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) Index (updated to February 2022) from the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology website (www.whocc.no):

non‐selective MAOIs, such as amitriptyline, desipramine, imipramine, imipramine oxide, nortriptyline, clomipramine, dosulepine, doxepin, opipramol, trimipramine, lofepramine, dibenzepin, protriptyline, iprindole, melitracen, butriptyline, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine;
SSRIs, such as fluoxetine, fluvoxamine, citalopram, escitalopram, paroxetine, sertraline, alaproclate, etoperidone, zimelidine;
monoamine oxidase A inhibitors, such as moclobemide, toloxatone;
non‐selective MAOIs, such as isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide, iproclozide;
SNRIs such as venlafaxine, duloxetine, desvenlafaxine, milnacipran, levomilnacipran;
any newer antidepressant and any other non‐conventional antidepressive agents, such as mianserin, trazodone, nefazodone, mirtazapine, bupropion, reboxetine, agomelatine, oxitriptan, tryptophan, nomifensine, minaprine, bifemelane, viloxazine, oxaflozane, medifoxamine, tianeptine, pivagabine, gepirone, vilazodone, Hyperici herba, vortioxetine, esketamine.

The comparison group was placebo or any other antidepressants (head‐to‐head comparisons), or both.

We excluded studies that compared antidepressants were compared with another type of psychopharmacological agent (i.e. psychostimulants, anxiolytics, anticonvulsants, antipsychotics or mood stabilisers).

Types of outcome measures

Primary outcomes

Efficacy as a continuous outcome

We extracted and analysed group mean scores at different time points and, if these were not available, group mean change scores, using the HAM‐D), MADRS or Clinical Global Impression Rating scale (CGI), or on any other depression rating scale with evidence of adequate validity and reliability, as follows:

early response: between one and four weeks, giving preference to the time point closest to two weeks;
acute phase treatment response: between six and 12 weeks, giving preference to the time point given in the original trial as the study endpoint;
follow‐up response: after 12 weeks, giving preference to the time point closest to 24 weeks.

The acute phase treatment response (between six and 12 weeks) was our primary outcome of interest. If the acute phase treatment response was reported, we then reported early response and follow‐up response as secondary outcomes.

Secondary outcomes

Efficacy as a dichotomous outcome

Treatment responders during the 'acute phase' (between six and 12 weeks): proportion of participants showing a reduction of at least 50% on the HAM‐D or MADRS or any other depression scale (e.g. the BDI or the Center for Epidemiologic Studies Depression Scale (CES‐D)), 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 participants who improved using any other prespecified criterion.

Social adjustment

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

Health‐related quality of life

Mean scores on quality‐of‐life rating scales during the 'acute phase' (between six and 12 weeks). We gave preference to illness‐specific quality of life measures, such as the European Organisation for Research and Treatment into Cancer Quality of Life Questionnaire‐30 (EORTC QLQ‐C30) (Aaronson 1993), the Functional Assessment of Cancer Therapy (FACT) scale (Cella 1993), and the 36‐item Short Form Health Survey (SF‐36) (Ware 1980; Ware 1992). When such tools were not employed, we used a general health‐related quality of life measure with evidence of adequate validity and reliability, as defined by each of the trial

Dropouts

Number of participants who dropped out during the trial as a proportion of the total number randomised (total dropout rate, also referred as 'acceptability').
Number of participants who dropped out due to inefficacy during the trial as a proportion of the total number randomised (dropout rates due to inefficacy).
Number of participants who dropped out due to adverse effects during the trial as a proportion of the total number randomised (dropout rates due to adverse effects, also referred as 'tolerability').

We extracted dropouts at trial endpoint only.

Search methods for identification of studies

Electronic searches

We searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2022, Issue 11) in the Cochrane Library (searched 24 November 2022) (Appendix 1), MEDLINE Ovid (1946 to November 2022) (Appendix 2), Embase Ovid (1980 to November 2022) (Appendix 3), and PsycINFO Ovid (1987 to November 2022) (Appendix 4).

Searching other resources

Handsearches

We handsearched the trial databases of the following drug‐approving agencies for published, unpublished and ongoing controlled trials: the US FDA (www.fda.gov), the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK (www.mhra.gov.uk/), the European Medicines Agency (EMA) in the EU (www.ema.europa.eu), the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan (www.pmda.go.jp/english/), and the Therapeutic Goods Administration (TGA) in Australia (www.tga.gov.au/).

We additionally searched the following trial registers: ClinicalTrials.gov in the US (clinicaltrials.gov/), ISRCTN and National Research Register in the UK (www.isrctn.com/), UMIN‐CTR in Japan (www.umin.ac.jp/ctr/), the ANZCTR in Australia and New Zealand (www.anzctr.org.au/), the WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/), and the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal (www.ifpma.org/tag/clinical-trials/).

We also handsearched appropriate journals and conference proceedings relating to depression treatment in people with cancer. We handsearched the websites of the most relevant pharmaceutical companies producing antidepressants, such as GlaxoSmithKline (www.gsk-clinicalstudyregister.com/), Sanofi (www.sanofi.com/en/science-and-innovation/clinical-trials-and-results/), Janssen (www.janssen.com/clinical-trials), Lundbeck (www.lundbeck.com/global/our-science/clinical-trials), Pfizer (www.pfizer.co.uk/clinical-trials), Abbott (www.abbott.com/policies/clinical-trials.html), Lilly (www.lillytrials.com/), and Merck (www.merck.com/research/discovery-and-development/clinical-development/home.html) for published, unpublished and ongoing controlled trials.

We searched reference lists of included trials and other relevant studies.

Personal communication

We contacted the authors of unpublished studies. Only one author provided data from one unpublished study.

Data collection and analysis

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching to a reference management database (Endnote) and removed duplicates. Two review authors (GV and BC) independently examined the remaining references. We excluded those studies that clearly did not meet the inclusion criteria, and we obtained copies of the full text of potentially relevant references. Two review authors (GV and BC) independently assessed the eligibility of retrieved studies. We resolved disagreements by discussion between the two review authors and, if necessary, with a third review author (GO). We documented reasons for exclusion. We collated multiple reports of the same studies to ensure that no data were included in the meta‐analysis more than once.

Data extraction and management

Two review authors (GV and BC), working independently and in duplicate, extracted data from the included studies using a data collection sheet (see Appendix 5), which was developed in accordance with recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022; Chapter 7). If the trial was a three (or more)‐armed trial involving a placebo arm, we also extracted data from the placebo arm.

Data included:

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 participants 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 encompassed mean scores of rating scales, standard deviation (SD) or standard error (SE); dichotomous measures were endpoint response rate and dropout rate, which were calculated on a strict intention‐to‐treat (ITT) basis;
cost analysis (estimates of the cost of resources employed to perform the trial);
presence of sponsorship by a drug company.

Alongside the data that contributed to meta‐analysis, we collected characteristics of participants, settings, interventions and methodological approaches, in order to provide an overall view of the available evidence on this topic (see Description of studies), as well as to perform an accurate assessment of the risk of bias (see Risk of bias in included studies). These elements provided a crucial contribution to the discussion, with particular regards to the clinical applicability of the results of the study (see Overall completeness and applicability of evidence; Implications for practice).

Assessment of risk of bias in included studies

Two review authors (GV and GO) independently assessed the risk of bias of all included studies with the effect of assignment to intervention in accordance with Cochrane's RoB 2 tool (Higgins 2022; Sterne 2019, Chapter 8), which includes the following domains (Appendix 6) (the previous version of the review used the RoB 1 tool).

Bias in the randomisation process
Bias from deviations from the intended interventions
Bias from missing outcome data
Bias in measurement of the outcome
Bias in the selection of reported results

The analysis did not include any cluster or cross‐over RCTs. Risk of Bias 2 does not assess the overall quality of the studies, but it assesses the risk of bias of a specific study outcome at a specific time point (six to 12 weeks).

We performed ROB 2 assessment for:

efficacy at six to 12 weeks as a continuous variable;
efficacy at six to 12 weeks as a dichotomous variable;
acceptability at study endpoint (up to 24 weeks).

To determine the risk of bias for each outcome we evaluated the presence of sufficient information and the likelihood of potential bias in each domain. Two review authors (GV and BC) rated each criterion as 'low risk of bias,' 'high risk of bias' or 'some concerns' using the signalling questions to decide on the overall risk of bias for each domain and how we determined the overall risk of bias for each result. If there were inadequate details of methodological characteristics of studies, we contacted the study authors to request further information. If the review authors disagreed on ratings, we made the final rating by consensus with the involvement (if necessary) of a third review author (GO or CB). We used the RoB 2 Excel tool to manage the assessment and we discussed and interpreted the results of meta‐analysis in light of the findings and with respect to the risk of bias.

Measures of treatment effect

Continuous data

We evaluated the efficacy of treatments as a continuous measure, namely the group mean scores on depression rating scales at the acute phase (between six and 12 weeks). We employed other continuous data for some secondary outcomes, namely efficacy at early response (between one and four weeks), efficacy at follow‐up response (after 12 weeks), social adjustment and health‐related quality of life.

Dichotomous data

We employed dichotomous data for some secondary outcomes, namely efficacy as the number of treatment responders at the acute phase (between six and 12 weeks), and the proportion of dropouts.

Unit of analysis issues

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). Both effects are very likely in major depression, thus we planned to use only data from the first phase of cross‐over trials.

Cluster‐randomised trials

We planned to use the generic inverse variance technique to appropriately analyse cluster‐RCTs, taking into account intraclass correlation coefficients to adjust for cluster effects.

Dealing with missing data

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

We calculated dichotomous data on a strict ITT basis: dropouts were always included in this analysis. Where participants had been excluded from the trial before the endpoint, we assumed that they experienced a negative outcome by the end of the trial. For continuous variables, we applied a loose ITT analysis, whereby all the participants with at least one postbaseline measurement were represented by their last observation carried forward (LOCF), with due consideration of potential biases, including number and timings of dropouts in each arm.

When relevant outcomes were not reported, we asked trial authors to supply the data. In the absence of data from authors, we only employed validated statistical methods to impute missing outcomes, with due consideration of the possible bias of these procedures, in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022) and with www.missingdata.org.uk. When SDs were not reported, we asked authors to supply the data. When only the SE or t‐statistics or P values were reported, we calculated SDs according to Altman 1996. In the absence of data from the authors, we substituted SDs with those reported in other studies in the review (Furukawa 2006).

Assessment of heterogeneity

We investigated heterogeneity between studies using the I² statistic (Higgins 2003; Ioannidis 2008) and by visual inspection of the forest plots. We considered an I² value of 50% or greater to indicate substantial heterogeneity.

Assessment of reporting biases

We planned to use the tests for funnel plot asymmetry to investigate small‐study effects (Sterne 2000), if there were at least 10 studies included in the meta‐analysis, with cautious interpretation of the results by visual inspection (Higgins 2022). Since we were unable to conduct any analysis including at least 10 studies we did not use a funnel plot. When there was evidence of small‐study effects, we aimed to investigate possible reasons for funnel plot asymmetry, including publication bias.

Data synthesis

If a sufficient number of clinically similar studies was available, we pooled their results in meta‐analyses.

For continuous data, we pooled the mean differences (MDs) with a 95% CIs between the treatment arms at the time point of interest, if all studies measured the outcome using the same rating scale; otherwise we pooled standardised mean differences (SMDs). For dichotomous data, we pooled the RR with a 95% CI. For the analysis of dichotomous data, we employed the Mantel‐Haenszel methods. For statistically significant results, we calculated the number needed to treat for an additional beneficial outcome (NNTB). We included studies that compared more than two intervention groups of the same drug (i.e. different dosages) in meta‐analysis by combining arms of the studies into a single group, for the intervention and for the control group respectively, as recommended in Section 23.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). If data were binary, we simply added and combined them into one group or divided the comparison arm into two (or more) as appropriate. If data were continuous, we combined the data following the formula in Chapter 6, Section 6.5.2.10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We included studies that compared two or more antidepressants with placebo as independent comparisons, splitting the 'shared' group (placebo) into two or more groups with smaller sample size (Higgins 2022).

We chose a random‐effects model as heterogeneity was expected (Higgins 2022). We only considered direct comparisons for the meta‐analysis.

Subgroup analysis and investigation of heterogeneity

We aimed to perform the following subgroup analyses for the primary outcome:

psychiatric diagnosis, separating major depressive disorder, and pooling data from studies including only participants with adjustment disorder, dysthymic disorder, depressive symptoms;
previous history of depressive conditions;
antidepressant class, in particular separating SSRIs, TCAs and other antidepressants;
cancer site, separating breast cancer and other sites;
cancer stage, separating early stages (stage 0 and I) and late stages (stage II, III and IV);
gender.

We interpreted subgroup analyses with caution, as multiple analyses can lead to false‐positive conclusions (Oxman 1992).

Sensitivity analysis

We aimed to perform the following sensitivity analyses for the primary outcome:

excluding studies in which the randomisation process was not clearly reported;
excluding studies with unclear concealment of random allocation;
excluding studies that did not employ adequate blinding of participants, healthcare providers and outcome assessors;
excluding studies that did not employ depressive symptoms as their primary outcome;
excluding studies with imputed data.

Summary of findings and assessment of the certainty of the evidence

We prepared three summary of findings tables summarising the key findings of the systematic review in line with the standard methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

We presented the overall certainty of the evidence for each outcome according to the GRADE approach and using the GRADEpro Guideline Development Tool (GRADEpro GDT). This is a web‐based tool for summarising and evaluating the certainty of evidence from scientific data, including systematic reviews and meta‐analyses, which takes into account issues related to internal validity (risk of bias, inconsistency, imprecision, publication bias) and external validity such as directness of results (Schunemann 2019). The GRADE approach categorises the certainty in a body of evidence as ‘high’, ‘moderate’, ‘low’ or ‘very low’ by outcome. This is a result of judgement, but the judgement process operates within a transparent structure. We downgraded the evidence from 'high' certainty by one level for serious (or by two for very serious) concerns for each study limitation.

These findings include:

antidepressants compared to placebo for depressive symptoms in people with cancer:
- efficacy as a continuous outcome;
- efficacy as a dichotomous outcome;
- dropouts due to any cause (acceptability);
antidepressants compared to other antidepressants for depressive symptoms in people with cancer:
- efficacy as a continuous outcome;
- efficacy as a dichotomous outcome;
- dropouts due to any cause (acceptability).

Results

Description of studies

Results of the search

See Figure 1 for an illustration of the process of study selection. The search of the electronic databases retrieved 5712 references. We added 47 further references from the handsearching of articles' references and the websites of drug‐approving agencies and pharmaceutical companies. After eliminating the duplicates, we identified 4567 references for screening. Two review authors (GV, BC) independently checked 100% of the titles, with a 'good' degree of agreement according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022) (simple kappa statistic 0.81). The two review authors discussed the abstracts for which there was inconsistency between them and achieved complete agreement. One review author (GO) checked the remaining abstracts. The two review authors examined the full text of all 100 records identified after the abstract check in detail. Fourteen studies fulfilled the criteria for eligibility and were included in the review (Cankurtaran 2008; Costa 1985; EUCTR2008‐002159‐25‐FR; Fisch 2003; Holland 1998; Liu 2021; Musselman 2006; Navari 2008; NCT00387348; Pezzella 2001; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996; Wang 2020). Ten studies contributed to the meta‐analysis for the primary outcome (Cankurtaran 2008; EUCTR2008‐002159‐25‐FR; Fisch 2003; Holland 1998; Liu 2021; Musselman 2006; Pezzella 2001; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996). Three studies contributed only to the meta‐analysis for secondary outcomes (Costa 1985; NCT00387348; Wang 2020), and Navari 2008 did not provide useful data for the meta‐analysis.

Included studies

We included 14 studies: 12 published studies (Cankurtaran 2008; Costa 1985; Fisch 2003; Holland 1998; Liu 2021; Musselman 2006; Navari 2008; Pezzella 2001; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996; Wang 2020), and two unpublished studies (EUCTR2008‐002159‐25‐FR; NCT00387348). The studies included 1364 participants. A detailed description of each study is reported in the Characteristics of included studies table.

Design and interventions

All included studies were randomised and double‐blind. The participants were followed up for one week in one study (Wang 2020), four weeks in two studies (Costa 1985, NCT00387348), five weeks in one study (Razavi 1996), six weeks in four studies (Cankurtaran 2008; Holland 1998; Musselman 2006; Van Heeringen 1996), eight weeks in two studies (Pezzella 2001; Tavakoli Ardakani 2019), 12 weeks in two studies (EUCTR2008‐002159‐25‐FR; Liu 2021), 24 weeks in one study (Navari 2008), and a mean of 15 weeks in one study (range between four and 24 weeks) (Fisch 2003). Ten studies had two comparison arms (Costa 1985; EUCTR2008‐002159‐25‐FR; Fisch 2003; Holland 1998; Navari 2008; NCT00387348; Pezzella 2001; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996). Eight of these explored the efficacy of an antidepressant versus placebo (Costa 1985; EUCTR2008‐002159‐25‐FR; Fisch 2003; Navari 2008; NCT00387348; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996). Six of these studies used an SSRI (EUCTR2008‐002159‐25‐FR; Fisch 2003; Navari 2008; NCT00387348; Razavi 1996; Tavakoli Ardakani 2019), and two used the tetracyclic antidepressant mianserin (Costa 1985; Van Heeringen 1996). Two studies compared two antidepressants with a two‐arm, head‐to‐head study design (Pezzella 2001: paroxetine versus amitriptyline; Holland 1998: fluoxetine versus desipramine). Three studies used a three‐arm design, comparing paroxetine versus desipramine versus placebo (Musselman 2006), mirtazapine versus imipramine versus control (no placebo) (Cankurtaran 2008), and esketamine versus racemic ketamine versus placebo (Liu 2021). In the latter two cases, only the comparison between mirtazapine and imipramine (Cankurtaran 2008) and esketamine and placebo (Liu 2021) were included in the meta‐analysis. One study used a four‐arm design and compared high‐dose esketamine versus low‐dose esketamine versus racemic ketamine versus placebo (Wang 2020). For this study, we only included the comparison between high‐dose esketamine and placebo in the meta‐analysis. In total, 10 studies compared an antidepressant against placebo and four studies compared two antidepressants with a head‐to‐head design (Cankurtaran 2008; Holland 1998; Musselman 2006; Pezzella 2001). Among these, three studies compared a TCA and an SSRI (Holland 1998; Musselman 2006; Pezzella 2001), while one study compared mirtazapine and TCAs (Cankurtaran 2008).

Sample sizes

The mean number of participants per study was about 97, with a minimum sample size of 24 in NCT00387348 and a maximum of 209 in Wang 2020. Only five studies had more than 100 participants (Fisch 2003; Liu 2021; Navari 2008; Pezzella 2001; Wang 2020).

Setting

Four studies enroled only outpatients (Fisch 2003; Musselman 2006; Navari 2008; Van Heeringen 1996). Two studies enroled only inpatients (Liu 2021; Wang 2020). Two studies enroled both inpatients and outpatients (Cankurtaran 2008; Costa 1985). The remaining six studies did not report the setting clearly (EUCTR2008‐002159‐25‐FR; Holland 1998; NCT00387348; Pezzella 2001; Razavi 1996; Tavakoli Ardakani 2019).

Participants

Four studies excluded people aged over 65 years (Cankurtaran 2008; Holland 1998; Liu 2021; Van Heeringen 1996), and one study excluded people aged over 60 years (Tavakoli Ardakani 2019), while no studies included only elderly participants.

The population of participants was heterogeneous in terms of diagnosis of depression. One study enroled only participants with a diagnosis of major depression based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM‐III) (APA 1980) in association with a score greater than 16 on the 21‐item HAM‐D (Van Heeringen 1996). One study enroled participants with a diagnosis of major depression according to DSM‐IV, to Endicott criteria (APA 1994), and with a score higher than 14 on the HAM‐D‐17 (NCT00387348). One study enroled participants with major depression according to ICD‐10 criteria (Pezzella 2001). Three studies enroled both people with a diagnosis of major depression and people with adjustment disorders based on DSM‐III‐R (Holland 1998), on DSM‐III‐R in association with a score greater than 14 on the first 17 items of the 21‐item HAM‐D(Musselman 2006), or on DSM‐III‐R in association with a score greater than 13 on the HADS (Razavi 1996). However, only people with major depression took part in Musselman 2006. Three studies enroled people with depressive symptoms, but without a formal diagnosis of depression according to a cut‐off score on standardised rating scales, Two‐Question Screening Survey (TQSS) greater than 2 (Fisch 2003; Navari 2008) and HADS greater than 11 (EUCTR2008‐002159‐25‐FR). Costa 1985 used alternative criteria for defining depression (quote: "diagnosis of depression according to the criteria proposed by Stewart [Stewart 1965] for medically ill patients, with slight additional inclusion criteria suggested by Kathol and Petty [Kathol 1981] […]") in association with a cut‐off score on standardised rating scales, Zung Self‐Rating Depression Scale (ZSRDS) greater than 41; HAM‐D‐17 greater than 16. Two studies included individuals with 'mild to moderate depression' as measured with the HAM‐D‐17 rating scale (Liu 2021; Wang 2020). One study included people 'with major depression and/or anxiety disorder' diagnosed by an expert psychiatrist (Tavakoli Ardakani 2019). In these individuals "the severity of depression was evaluated via the Hospital Anxiety and Depression Scale (HADS) questionnaire." Finally, Cankurtaran 2008 recruited a mix of individuals with a diagnosis of major depressive disorder, adjustment disorder, anxiety disorders such as generalised anxiety disorder and panic disorder (or a combination of these) according to the DSM‐IV criteria. This study was excluded from the previous update; however, we re‐evaluated this and included it in the current update since the severity of the depressive symptoms as measured by the HADS at baseline was consistent with moderate depression (mean score at HADS scale 22.8).

With regards to the cancer type and stage, four studies had mixed populations (Cankurtaran 2008; Costa 1985; Holland 1998; Razavi 1996), but the majority of participants had a diagnosis of breast cancer. In Fisch 2003, the population was quite equally distributed between breast, thoracic, genitourinary and other types of cancer. Five studies included only women with breast cancer (Liu 2021; Musselman 2006; Navari 2008; Pezzella 2001; Van Heeringen 1996). One study included only people with head and neck cancer (EUCTR2008‐002159‐25‐FR), while Tavakoli Ardakani 2019 included only individuals with haematological cancer, Wang 2020 included only people with cervical carcinoma and NCT00387348 included only people with lung or gastrointestinal cancer. In three studies, the cancer stage was not clearly reported (Cankurtaran 2008; Fisch 2003; Razavi 1996). Three studies included only people with early stages ("localised" or "early locally advanced" disease) (Navari 2008; Van Heeringen 1996; Wang 2020), while all other studies also recruited people with late‐stage disease (Costa 1985; EUCTR2008‐002159‐25‐FR; Holland 1998; Liu 2021; Musselman 2006; Pezzella 2001; Tavakoli Ardakani 2019). One study included only people with late locally advanced or metastasised disease (NCT00387348).

Outcomes

For efficacy outcomes, most included studies provided continuous data such as mean score or mean change on standardised rating scales, including those considered reliable for the aims of this review, such as HAM‐D (Cankurtaran 2008; Costa 1985; Liu 2021; Musselman 2006; NCT00387348; Tavakoli Ardakani 2019; Van Heeringen 1996; Wang 2020), MADRS (EUCTR2008‐002159‐25‐FR; Razavi 1996), or other scales (Fisch 2003; Pezzella 2001). One study provided only dichotomous data (Navari 2008), defining "responders" as those who achieved a certain improvement in the rating scale score. This study provided these data only for the six‐month assessment and thus could not be included in the meta‐analysis.

For secondary outcomes, most studies provided complete data on total dropouts, due to inefficacy and adverse effects. Three studies provided only partial data on dropouts (Fisch 2003; Navari 2008; NCT00387348; Tavakoli Ardakani 2019). Very few studies reported data on other secondary outcomes, such as social adjustment (Pezzella 2001) and quality of life (Fisch 2003; Pezzella 2001).

We included 773 people in the efficacy analysis on a continuous outcome between six and 12 weeks (primary outcome) and 886 on a dichotomous outcome; 175 in the analysis of social adjustment, 305 in the quality of life analysis and 1159 in the analysis of dropouts.

Excluded studies

Of the 100 articles selected for a full‐text evaluation, we excluded 80, which did not meet one or more inclusion criteria (mostly a wrong diagnostic status), while two are awaiting classification and four were ongoing studies (Figure 1).

In particular, two studies did not enrol participants with cancer, while in 41 studies participants were not depressed when enroled or the studies enroled a population with mixed psychiatric symptoms. Eleven studies were not randomised, one was a review of other studies, eight studies compared placebo with a drug that was not approved for the treatment of depression (psylocybin, methylphenidate). For 11 studies, the comparison group was not reliable because there was no placebo or active comparator. For seven studies, for which there was only the abstract or protocol available, we contacted the authors who informed us that these studies had been withdrawn or changed in their design. Details are reported in Characteristics of excluded studies table.

Studies awaiting classification

Two studies are awaiting classification (N0405078066; UMIN000008768) (see Characteristics of studies awaiting classification table). We contacted the study authors, but received no reply.

Ongoing studies

Four studies are ongoing (IRCT20210425051075N1; NCT04303325; NCT04763135; NCT04818099) (see Characteristics of ongoing studies table).

Risk of bias in included studies

We performed ROB 2 assessment for three outcomes:

efficacy measured as a continuous outcome at six to 12 weeks;
efficacy measured as a dichotomous outcome at six to 12 weeks;
acceptability.

For the main outcome (efficacy at six to 12 weeks, continuous data), no studies had an overall low risk of bias according to the RoB 2 tool algorithm (Liu 2021; Tavakoli Ardakani 2019), and six studies (60%) had an overall high risk of bias (Cankurtaran 2008; Costa 1985; EUCTR2008‐002159‐25‐FR; Fisch 2003; Musselman 2006; Van Heeringen 1996). The RoB 2 assessment of the secondary outcome 'efficacy at six to 12 weeks', dichotomous data was substantially similar to the assessment of the main outcome, while for the outcome 'acceptability' we found the overall quality of the studies was better, with three studies with an overall low risk of bias (Fisch 2003; Liu 2021; Wang 2020). No studies had a high overall risk of bias for this outcome.

We found the overall methodological quality of the included trials to be low.

Effects of interventions

See: Table 1; Table 2; Table 3

Primary outcome

1. Efficacy at six to 12 weeks (continuous outcome)

1.1 Antidepressants versus placebo

We found a potential beneficial effect of antidepressants as a class versus placebo in efficacy at six to 12 weeks (SMD −0.52, 95% CI −0.92 to −0.12; 7 studies, 511 participants; very low‐certainty evidence; Analysis 1.1; Figure 2).

1.1 — Comparison 1: Depression: efficacy as a continuous outcome at 6–12 weeks, Outcome 1: Antidepressants vs placebo

Forest plot of comparison: 1 Depression: efficacy at six to 12 weeks (continuous outcome), outcome: 1.1 Antidepressants versus placebo.

1.2 Antidepressants versus antidepressants

We found no difference between SSRIs and TCAs as classes in efficacy at six to 12 weeks (SMD −0.08, 95% CI −0.34 to 0.18; 3 studies, 237 participants; very low‐certainty evidence; Analysis 1.2; Figure 3). There was no difference between mirtazapine and TCAs (MD −4.80, 95% CI −9.70 to 0.10; 1 study, 25 participants; Analysis 1.3).

1.2 — Comparison 1: Depression: efficacy as a continuous outcome at 6–12 weeks, Outcome 2: SSRIs vs TCAs

Forest plot of comparison: 1 Depression: efficacy at six to 12 weeks (continuous outcome), outcome: 1.2 Antidepressants versus antidepressants.

1.3 — Comparison 1: Depression: efficacy as a continuous outcome at 6–12 weeks, Outcome 3: Mirtazapine vs TCA

Secondary outcomes

2 Efficacy at one to four weeks (continuous outcome)

2.1 Antidepressants versus placebo

We found a potential beneficial effect of antidepressants as a class versus placebo in efficacy at one to four weeks (SMD −0.48, 95% CI −0.87 to −0.10; 8 studies, 764 participants; Analysis 2.1).

2.1 — Comparison 2: Depression: efficacy as a continuous outcome at 1–4 weeks, Outcome 1: Antidepressants vs placebo

For antidepressants versus other antidepressants (mirtazapine versus imipramine), there was no difference between groups in efficacy at one to four weeks (MD −5.00, 95% CI −10.63 to 0.63; 1 study, 32 participants; Analysis 2.2).

2.2 — Comparison 2: Depression: efficacy as a continuous outcome at 1–4 weeks, Outcome 2: Mirtazapine vs TCA

3 Efficacy at six to 12 weeks (dichotomous outcome)

3.1 Antidepressants versus placebo

We found a potential beneficial effect of antidepressants as a class versus placebo in terms of response rate at six to 12 weeks (RR 0.74, 95% CI 0.57 to 0.96; 7 studies, 662 participants; very low‐certainty evidence; Analysis 3.1).

3.1 — Comparison 3: Depression: efficacy as a dichotomous outcome at 6–12 weeks, Outcome 1: Antidepressants vs placebo

3.2 Antidepressants versus antidepressants

We found no difference between SSRIs and TCAs as classes in efficacy at six to 12 weeks (RR 1.10, 95% CI 0.78 to 1.53; 2 studies, 199 participants; very low‐certainty evidence). We found no difference between mirtazapine and TCAs in efficacy at six to 12 weeks (RR 0.81, 95% CI 0.60 to 1.09; 1 study, 33 participants; very low‐certainty evidence; Analysis 3.2).

3.2 — Comparison 3: Depression: efficacy as a dichotomous outcome at 6–12 weeks, Outcome 2: SSRI vs TCA

4 Social adjustment at six to 12 weeks

4.1 Antidepressants versus antidepressants

We found no studies comparing antidepressants versus placebo reporting social adjustment at six to 12 weeks.

There was no difference between paroxetine and amitriptyline in social adjustment at six to 12 weeks (MD 0.10, 95% CI −0.38 to 0.58; 1 study, 175 participants; negative values favour paroxetine on the MADRS rating scale; Analysis 4.1).

4.1 — Comparison 4: Social adjustment at 6–12 weeks, Outcome 1: Antidepressants vs antidepressants

5 Health‐related quality of life at six to 12 weeks

5.1 Antidepressants versus placebo

We found no difference between antidepressants as a class and placebo in quality of life at six to 12 weeks (SMD 0.05, 95% CI −0.27 to 0.37; 2 studies, 152 participants; Analysis 5.1).

5.1 — Comparison 5: Quality of life at 6–12 weeks, Outcome 1: Antidepressants vs placebo

5.2 Antidepressants versus antidepressants

There was no difference between paroxetine and amitriptyline in quality of life at six to 12 weeks (MD 6.50, 95% CI 0.21 to 12.79; 1 study, 153 participants; negative values favour paroxetine on the MADRS rating scale; Analysis 5.2).

5.2 — Comparison 5: Quality of life at 6–12 weeks, Outcome 2: Antidepressants vs antidepressants

6 Dropouts due to any cause (acceptability)

6.1 Antidepressants versus placebo

We found no difference between antidepressants as a class and placebo in dropouts due to any cause (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low‐certainty evidence; Analysis 6.1).

6.1 — Comparison 6: Dropouts due to any cause (acceptability), Outcome 1: Antidepressants vs placebo

6.2 Antidepressants versus antidepressants

We found no difference between SSRIs versus TCAs as classes in dropouts due to any cause (RR 0.83, 95% CI 0.53 to 1.30; 3 studies, 237 participants; very low‐certainty evidence; Analysis 6.2). We found no difference between mirtazapine and TCAs as classes in dropouts due to any cause (RR 0.65, 95% CI 0.20 to 2.15; 1 RCT, 33 participants; Analysis 6.2).

6.2 — Comparison 6: Dropouts due to any cause (acceptability), Outcome 2: SSRI vs TCA

7 Dropouts due to inefficacy

7.1 Antidepressants versus placebo

We found no difference between antidepressants as a class and placebo in dropouts due to inefficiency (RR 0.41, 95% CI 0.13 to 1.32; 6 studies, 455 participants; Analysis 7.1).

7.1 — Comparison 7: Dropouts due to inefficacy, Outcome 1: Antidepressants vs placebo

7.2 Antidepressants versus antidepressants

We found no difference between SSRIs and TCAs as classes in dropouts due to inefficiency (RR 0.85, 95% CI 0.14 to 5.06; 3 studies, 237 participants; Analysis 7.2).

7.2 — Comparison 7: Dropouts due to inefficacy, Outcome 2: Antidepressants vs antidepressants

8 Dropouts due to adverse effects (tolerability)

8.1 Antidepressants versus placebo

We found no difference between antidepressants as a class and placebo in dropouts due to adverse effects (RR 1.19, 95% CI 0.54 to 2.62; 9 studies, 889 participants; Analysis 8.1). Among the nine studies included in the analysis, two studies did not contribute to the analyses since there were no events reported in both intervention groups (Liu 2021; Wang 2020).

8.1 — Comparison 8: Dropouts due to adverse effects (tolerability), Outcome 1: Antidepressants vs placebo

8.2 Antidepressants versus antidepressants

We found no difference between SSRIs and TCAs as classes in dropouts due to adverse effects (RR 1.04, 95% CI 0.55 to 1.99; 3 studies, 237 participants; Analysis 8.2).

8.2 — Comparison 8: Dropouts due to adverse effects (tolerability), Outcome 2: Antidepressants vs antidepressants

Subgroup analyses

Psychiatric diagnosis

Results from this subgroup analysis found no differences in the subgroups of people with major depressive disorder versus people with adjustment disorder, dysthymic disorder or depressive symptoms. This is true for both the 'antidepressant‐placebo' and the 'head‐to‐head' comparisons (Analysis 9.1; Analysis 9.2). However, for the comparison of antidepressants versus placebo, the subgroup analysis seems to confirm the trend of the primary outcome, suggesting a positive effect of antidepressants rather than placebo in both populations (participants with major depressive disorder: RR −0.53, 95% CI −1.38 to 0.32; 3 studies, 291 participants; participants with adjustment disorder, dysthymic disorder and depressive symptoms: RR −0.28, 95% CI −0.67 to 0.10; 2 studies, 107 participants; Analysis 9.1).

9.1 — Comparison 9: Subgroup analysis: psychiatric diagnosis, Outcome 1: Antidepressants vs placebo

9.2 — Comparison 9: Subgroup analysis: psychiatric diagnosis, Outcome 2: SSRI vs TCA

Previous history of depressive conditions

We did not perform this analysis since the data provided were not sufficient to measure the primary outcome in this subgroup of participants.

Antidepressant class

In the main analysis, we pooled data separating the SSRIs, TCAs and other antidepressants classes of antidepressants. Considering the 'antidepressant‐placebo' comparison, we found a potential beneficial effect for SSRIs versus placebo (SMD −0.40, 95% CI −0.79 to −0.01; 5 studies, 238 participants). There was no difference to support the efficacy of TCAs versus placebo (MD 0.04, 95% CI −0.95 to 1.04; 1 study, 17 participants). We included in the 'other antidepressants' class two atypical antidepressants with different mechanisms of action: esketamine and mianserin. There were no differences between this drug class and placebo, although there was a trend indicating a potential beneficial effect for both treatments (SMD −1.01, 95% CI −2.44 to 0.41; 2 studies, 256 participants). The 'head‐to‐head' comparison found no differences between SSRIs and TCAs as classes (SMD −0.08, 95% CI −0.34 to 0.18; 3 studies, 237 participants; Analysis 1.2) or between mirtazapine and TCAs (SMD −4.80, 85% CI −9.70 to 0.10; 1 study, 25 participants; Analysis 1.3).

Cancer site

Results from this subgroup analysis did not change the main findings for the primary outcome. There was no effect when pooling studies that enroled only women with breast cancer (Analysis 10.1; Analysis 10.2). It was technically feasible to separate these two subgroups; however, the 'other sites' subgroup could not be considered a reliable comparison with the 'breast cancer' subgroup because, even if these studies enroled people with different types of cancer, the vast majority of them actually had breast cancer.

10.1 — Comparison 10: Subgroup analysis: cancer site, Outcome 1: Antidepressants vs placebo

10.2 — Comparison 10: Subgroup analysis: cancer site, Outcome 2: Antidepressants vs antidepressants

Cancer stage

Results from this subgroup analysis did not change the main findings for the primary outcome (Analysis 11.1; Analysis 11.2). Two studies amongst those comparing antidepressants versus placebo enroled only people with late‐stage disease (Costa 1985; Holland 1998); however, Costa 1985 did not provide data for the primary outcome (efficacy at six to 12 weeks) and was not included in the analysis. Other studies had a mixed population in terms of cancer stage, except for Razavi 1996, which enroled only people with stage 0 (carcinoma in situ, early form). Considering the 'head‐to‐head' comparison, only one study enroled people with early‐stage disease, showing no differences between SSRIs and TCAs as classes (MD 0.69, 95% CI −1.61 to 2.99; 1 trial, 38 participants), while other studies had a mixed population (Holland 1998).

11.1 — Comparison 11: Subgroup analysis: cancer stage, Outcome 1: Antidepressants vs placebo

11.2 — Comparison 11: Subgroup analysis: cancer stage, Outcome 2: Antidepressants vs antidepressants

Gender

This analysis is encompassed in the 'cancer site' analysis, because the 'female participant' subgroup matched with the 'breast cancer' subgroup (see Analysis 10.1). A subgroup analysis for men only was not feasible, since other studies enroled both male and female participants.

Sensitivity analyses

Excluding trials in which the randomisation process was not clearly reported

We did not perform this sensitivity analysis because only Fisch 2003 reported clear details on random sequence generation and concealment of random allocation.

Excluding trials with unclear concealment of random allocation

We did not perform this sensitivity analysis because only Fisch 2003 reported clear details on random sequence generation and concealment of random allocation.

Excluding trials that did not employ adequate blinding of participants, healthcare providers and outcome assessors

We did not perform this sensitivity analysis because no studies reported clear details on the procedures for ensuring blinding.

Excluding trials that did not employ depressive symptoms as their primary outcome

Three studies assessed depressive symptoms as a secondary outcome (Cankurtaran 2008; Fisch 2003; Tavakoli Ardakani 2019), with two contributing to the 'antidepressants versus placebo' analysis and Cankurtaran 2008 comparing mirtazapine versus imipramine. Results from this sensitivity analysis did not change the main findings for the primary outcome (Analysis 12.1).

12.1 — Comparison 12: Sensitivity analysis: excluding trials that did not employ depressive symptoms as their primary outcome, Outcome 1: Antidepressants vs placebo

Excluding trials with imputed data

Seven studies did not impute missing data, applying a 'per protocol', an 'as treated' or a 'modified Intent‐to‐treat' analysis (Cankurtaran 2008; EUCTR2008‐002159‐25‐FR; Fisch 2003; Navari 2008; Razavi 1996; Tavakoli Ardakani 2019; Van Heeringen 1996). These studies contributed only to the 'antidepressants versus placebo' analysis. After removing studies with imputed data the meta‐analysis showed a small superiority of antidepressants over placebo confirming substantially the main findings of the meta‐analysis (SMD −0.65, 95% CI −1.10 to −0.20; 6 studies, 476 participants; Analysis 13.1).

13.1 — Comparison 13: Sensitivity analysis: excluding trials with imputed data, Outcome 1: Antidepressants vs placebo

Discussion

Summary of main results

We included 14 RCTs involving 1364 participants in this review update. The updated electronic search and handsearch for new studies trials (and for new data on studies previously awaiting classification), allowed us to identify four new studies (Cankurtaran 2008; Liu 2021; Tavakoli Ardakani 2019; Wang 2020). Two studies assessed the efficacy of intravenous injection of esketamine against placebo (normal saline) (Liu 2021; Wang 2020). Tavakoli Ardakani 2019 assessed the efficacy of sertraline against placebo and Cankurtaran 2008 assessed the efficacy of mirtazapine against imipramine. Three studies contributed to the primary outcome (efficacy as a continuous outcome at six to 12 weeks) (Cankurtaran 2008; Liu 2021; Tavakoli Ardakani 2019).

The included studies did not report all the outcomes that were prespecified in the original protocol. Ten studies provided continuous data, which contributed to the meta‐analysis for the primary outcome of efficacy as a continuous outcome at six to 12 weeks (Analysis 1.1; Analysis 1.2). Only one study did not provide data suitable for any of the meta‐analyses (Navari 2008). Most studies provided detailed data on dropouts, while for some other secondary outcomes, such as social adjustment and quality of life, very few studies provided data (Analysis 4.1; Analysis 5.1; Analysis 5.2).

Overall, we detected a small beneficial effect between antidepressants as a class and placebo in terms of efficacy, in both continuous and dichotomous outcomes. There was no evidence of difference concerning acceptability (dropouts due to any cause), and tolerability (dropouts due to adverse events). For the primary outcome (efficacy as a continuous outcome at six to 12 weeks) we found mianserin, sertraline and esketamine to be effective over placebo. For the primary outcome, the sensitivity analysis excluding studies with imputed data gave similar results. Our study suggested a small benefit of antidepressants versus placebo in the early response phase (one to four weeks), but this analysis was limited by substantial statistical heterogeneity. No studies assessed follow‐up response after more than 12 weeks. In head‐to‐head comparisons, we retrieved data for SSRIs versus TCAs and we added in this update one small study comparing mirtazapine versus imipramine (Cankurtaran 2008). For both head‐to‐head comparisons, we found no difference between the classes of antidepressants.

For the secondary outcome 'remission rate at six to 12 weeks', we found a small beneficial effect in the antidepressant‐placebo comparison, in favour of antidepressants, while there was no difference in the head‐to‐head comparisons. Very few studies contributed to the secondary outcomes 'social adjustment' and 'quality of life', and, therefore, no relevant findings emerged. For the secondary outcome 'acceptability', we found only mianserin had lower dropouts due to inefficacy and dropouts due to any cause compared with placebo. In head‐to‐head comparisons, we retrieved data for SSRIs versus TCAs and mirtazapine versus TCAs. There were no differences between these classes in terms of dropout due to inefficacy and tolerability.

Overall completeness and applicability of evidence

Most participants had a diagnosis of breast cancer. There was some degree of heterogeneity in terms of stage of cancer, anticancer treatments and psychiatric diagnosis, including different depressive conditions. The overall number of participants was very low, and this population could hardly reflect the complexity of people with cancer from a 'real world' setting. Furthermore, it is worth noting that there were no studies conducted on older people only, despite this population representing a relevant portion of the oncological population.

Most studies enroled a very small number of participants and did not provide data for all the outcomes specified in the protocol. For these reasons, most of the analyses were underpowered and this limits the overall completeness of the evidence. In particular, we chose to consider efficacy as a continuous outcome at six to 12 weeks as the primary outcome, this being, in our opinion, a more reliable outcome for clinical practice. However, we had to exclude some studies from this analysis because they did not report continuous outcomes or they performed the assessment at a different time point.

Another important issue was retrieving data from unpublished studies. Even though we found a relatively consistent number of unpublished studies in the online registers, reliable data that we could include in the meta‐analysis were not available. Very few authors replied to our request for information or data and we included only two unpublished studies (EUCTR2008‐002159‐25‐FR; NCT00387348). Three studies were ongoing and we classified two studies as awaiting classification, as they were eligible according to the protocol or the abstract, but did not provide any data for meta‐analysis. Considering the overall small number of studies included and the uncertainty of the evidence, it is plausible that these studies could have made a relevant difference to our analysis.

We chose to consider only the dropout rate due to adverse events as a proxy of the tolerability of treatments because in this particular population the most common adverse effects of antidepressants (e.g. asthenia, sedation, headache, nausea and gastrointestinal problems) are very likely to be caused also by other anticancer therapies, pain syndromes or the direct effects of cancer. We know from previous literature that antidepressants are generally well tolerated by people with medical illnesses (Rayner 2010), even when very complex and advanced (including people with cancer) (Rayner 2011a). However, some authors showed possible toxicities of antidepressants in this population (Stockler 2007), and the issue of possible cardiac effects of citalopram and escitalopram (Nosé 2016; Sarganas 2014) may be particularly relevant for people with cancer. For this reason, further analysis may be relevant for assessing the occurrence of adverse effects likely linked to antidepressants. It is worth noting that two studies newly included in this update compared the efficacy of intravenous esketamine versus placebo (Liu 2021; Wang 2020). These studies could not measure tolerability and acceptability of the treatment since participants received the treatment in a single administration while undergoing surgery, therefore there was no possibility for the individuals to withdraw the assigned treatment.

It has been suggested that the efficacy of tamoxifen, a drug broadly used for the prevention and treatment of breast cancer, could be lessened by some antidepressants that act on CYP2D6 inhibitors. Therefore, this would worsen the prognosis of these people over a five‐year period (Kelly 2010). The most relevant effect has been shown for paroxetine, however other drugs, such as fluoxetine, bupropion and duloxetine, could theoretically have a similar effect, and should be therefore avoided in this population (Andrade 2012). This possible effect is unlikely to have affected our analysis, since two studies used paroxetine (Musselman 2006; Pezzella 2001), and only one included participants possibly taking tamoxifen (Musselman 2006), and the follow‐up period was relatively short to appreciate this potentially harmful effect.

Quality of the evidence

The overall methodological quality of the included studies was poor (Figure 2; Figure 2). For the primary outcome of efficacy at six to 12 weeks as a continuous outcome only two studies showed an overall low risk of bias (Liu 2021; Tavakoli Ardakani 2019). Most studies had poor methodological quality, as out of the 10 studies that contributed to the primary outcome, five (50%) were at high risk of bias. This was mainly due to four studies having a very high dropout rate and high risk for bias due to missing outcome data. Furthermore, in some cases, the poor quality of the study seemed to reflect the lack of exhaustive reporting rather than clear evidence of bias, especially for the older studies. This is consistent with the finding of general suboptimal reporting of studies in medical journals despite the large number of instruments designed to help transparent reporting, such as the CONSORT Statement (Turner 2012).

We used GRADEpro GDT to provide outcome‐specific information concerning the overall certainty of the evidence from each included study in the comparison and the magnitude of the effect of the interventions examined. Our overall confidence in the estimate of effect was very low for all main outcomes assessed (i.e. efficacy as a continuous outcome, efficacy as a dichotomous outcome and dropout due to any cause; see Table 1; Table 2; Table 3). This judgement reflects some issues in the included studies, namely the high risk of bias (due to poor methodological quality and high dropout rates), inconsistency (due to the high degree of heterogeneity between RCTs) and imprecision (due to the low number of participants in each study and wide CIs). In accordance with this, any estimate of effect in this review should be considered very uncertain, and further research is very likely to change the estimate of effect and thus the degree of confidence for its applicability in routine clinical practice.

Potential biases in the review process

There are several possible limitations of this review, and thus the interpretation of results should remain provisional and tentative.

Some limitations are intrinsically related to the actual process of retrieving, collecting, selecting and extracting data. In order to reduce the potential bias of this complex process, two review authors independently worked on each of these steps. With regards to the selection of relevant studies, the degree of agreement between the two review authors was evaluated with the calculation of 'simple kappa statistics,' which confirmed the reliability of the selection process (see Results of the search). It has been highlighted that data extraction performed by two extractors independently is, overall, more reliable than the extraction performed by a single author followed by verification by a second author (Buscemi 2006). We applied the same process for the risk of bias assessment. Furthermore, we discussed disagreements with a third review author, who also checked the data extracted from studies when the analysis was performed. Another relevant problem concerns the 'systematic' nature of the search. We chose to include only RCTs as they provide the strongest level of evidence available. In this type of review, there is some risk of publication bias, which means that negative studies may have not been published. Some authors of this review are experts in the field, thus it is unlikely that significant studies were overlooked. However, whilst the search was thorough, it is possible that there are still unpublished studies that have not been identified, considering that there are no shared procedures to perform this type of search (Chan 2012). The impact of unpublished literature on the results of this review is uncertain; however, it is expected that the analysis of only published literature would lead to an overestimation of the efficacy of a given intervention (Turner 2008). Moreover, the search date is November 2022 and there are two studies classified as 'awaiting classification,' the eligibility of which is yet to be determined. At the end of this process, we identified very few studies and the data of interest obtained were relatively limited.

It is important to consider that some of the included studies were funded by the pharmaceutical industry, and this may again introduce an overestimation of the efficacy of interventions.

To assess efficacy, we gave preference to rating scales administered by clinicians or expert assessors (HAM‐D, MADRS, CGI). Even though they are standardised tools commonly used in studies of antidepressants, they are all potentially prone to observer bias. Three studies used self‐administered questionnaires (EUCTR2008‐002159‐25‐FR; Fisch 2003; Navari 2008). We noted some heterogeneity in terms of outcome measurement, and this might represent a limitation in interpreting the effect of interventions. For instance, in Analysis 1.1, Analysis 2.1, Analysis 7.1, and Analysis 6.1, Van Heeringen 1996 showed a notably higher beneficial effect of the antidepressant (in this case, mianserin) over placebo compared to other studies, and this affects the final result of the meta‐analyses. In general, the positive effect shown in the mianserin studies had a relevant impact on overall results (Costa 1985; Van Heeringen 1996) (Analysis 2.1; Analysis 3.1). Another limitation is the use of non‐specific rating scales, designed for assessing specific psychiatric symptoms and domains, rather than mood disorders in medically ill people.

One important limitation of the included studies (and consequently of the present review) was that not all studies reported a continuous outcome for the chosen time points, underpowering the analyses and undermining the possibility of finding differences between comparisons.

The studies rarely reported quality of life and social functioning. This possibly limits our interpretation of the efficacy of intervention, which should not be focused only on depression, considering that comorbid depressive symptoms deeply impact the overall burden of disease alongside quality of life and functioning (Arrieta 2013). Some authors also described a relevant impact of comorbid depression on cancer mortality (Lloyd‐Williams 2009; Pinquart 2010; Satin 2009). The included studies did not describe this outcome due to relatively short periods of follow‐up.

The dropout rate due to any cause is considered a consistent measure for the acceptability of treatment, as it encompasses dropouts due to adverse events and dropouts due to inefficacy and any other cause. However, this is only a proxy measure for this outcome since it comprises very heterogeneous reasons for leaving the study early, a detailed description of which was beyond the aim of this review.

For one three‐armed study which compared paroxetine versus desipramine versus placebo (Musselman 2006), we chose to split the 'shared' group (in this case the placebo group) into two groups with smaller sample sizes, in order to avoid reporting the same subpopulation of participants in the analysis. These smaller groups contributed to one comparison each (namely paroxetine versus placebo and desipramine versus placebo). In the analysis of dichotomous outcomes, the number of events was also split between the two comparisons. This method, although considered reliable according to the Cochrane Handbook for Systematic Reviews of Interventions is not the most recommended since it only partially overcomes the unit of analysis error (because the resulting comparisons remain correlated) (Higgins 2022).

Finally, it is very relevant to note that people with different types and stages of cancer cannot be considered a homogeneous group, considering there are differences in genetic, biological and immunological mechanisms, as well as in physical and psychosocial impairment. Due to the paucity of data, several subgroup analyses that would have investigated these characteristics were not feasible. We interpreted the results from these analyses cautiously, since multiple calculations may risk producing a result that is statistically significant by chance alone.

Agreements and disagreements with other studies or reviews

Analyses from this study draw different conclusions with respect to previous reviews and meta‐analyses. Results from the meta‐analyses by Hart 2012 and Walker 2014 are not comparable to the present study since they enroled only people with elevated depressive symptoms (Hart 2012) and a formal diagnosis of major depression (Walker 2014). Conversely, the meta‐analysis by Laoutidis 2013 included the same studies as our review, with the difference of two (rather small) unpublished studies (EUCTR2008‐002159‐25‐FR; NCT00387348). In Laoutidis 2013, there was a superiority of antidepressants versus placebo in terms of 'therapeutic response' (as a dichotomous outcome) (RR 1.56, 95% CI 1.07 to 2.28; P = 0.021). Their analysis slightly differed from the one performed in the present systematic review, where we found no difference (Analysis 3.1). In contrast with the meta‐analysis by Laoutidis 2013, the study carried out by Navari 2008 was not eligible for our analysis as our focus was the 'acute phase treatment response' (between six and 12 weeks), while this study reported the number of responders at week 24. Other differences referred to different approaches employed in the definition of some ITT populations. Moreover, Laoutidis 2013 performed no analyses of continuous outcomes and, similarly to our analysis, there were no differences between SSRIs and TCAs. Additionally, the review and meta‐analysis by Riblet 2014 was difficult to compare with our review, as it included some studies that were excluded from our analysis, in particular one quasi‐randomised study (Wang 2011), and two studies where participants were not depressed at baseline (Del Carmen 1990; Roscoe 2005).

In a review published by Grassi 2018, the authors concluded that the weight of evidence currently available supports the efﬁcacy of antidepressants for more severe major depression in people with cancer and as an adjuvant treatment in cancer‐related symptoms, although the methodological limitations of reported RCTs do not permit definite conclusions. Data also indicate that there should be caution in the use of antidepressants in people with cancer in terms of their safety profile and potential clinically significant interactions with other prescribed medications. This particular study takes into consideration other pharmacological treatments for depression that we did not include in this current review since they are not approved to treat depression (methylphenidate, ketamine, modafinil, psilocybin).

The use of antidepressants in people with cancer has been studied in many ways in the scientific literature, focusing not only on treating depressive symptoms or disorders, but also on preventing depression (e.g. Morrow 2003, in which antidepressants appeared effective in a population of 549 participants), or treating some cancer‐related symptoms, such as hot flushes, fatigue, insomnia, hyporexia and weigh loss. Most studies enroled people on the basis of medical symptoms and a proper assessment of concomitant depressive conditions was not always performed. These studies were not included in the present review, however they may contribute to broaden the discussion about the clinical suitability of antidepressants in people with cancer, since it has been claimed that a continuum of depressive experiences, ranging from distressing cancer‐related symptoms to proper depressive symptoms or disorders, can be detected in this population (Brenne 2013; Mitchell 2011; Raison 2003), and can be effectively treated with antidepressants (Ostuzzi 2015a).

One systematic review and meta‐analysis by Zahid 2020 focused on preventing depression in participants with cancer. The work included three groups of intervention (pharmacological, psychological and other type of interventions). Amongst the pharmacological group only three studies contributed to the results of the meta‐analysis and in one of them the pharmacological treatment was melatonin (not included in the current review). In spite of the small number of included studies, the results showed a significant impact of pharmacological treatment in preventing depression in people with cancer (RR 0.34, 95% CI 0.18 to 0.63). However, the authors concluded that "no convincing evidence for any specific intervention is present."

Further, another recently published systematic review focused on the pharmacological treatment of depression in older people (aged over 65 years) with cancer (Rabin 2022). Similarly to what we observed, the study authors concluded that there is currently a lack of evidence concerning the management of depression in this specific population, despite the fact that older adults represent most new cancer diagnoses and are specifically vulnerable to develop depressive‐like symptoms. Given its clinical relevance, new research on this topic is critically needed. Some non‐randomised studies were retrieved (Biglia 2005; Caldera 2009; Evans 1988; KCT0000076; NCT00234195; NCT01725048; Tondlova 1997); however, for most of these only conference procedures or protocols were available. Moreover, results from the remaining studies did not provide a relevant contribution to the discussion, since they were performed on very small numbers of participants (Biglia 2005; Evans 1988).

We retrieved four ongoing studies (NCT04303325; NCT04763135; NCT04818099, IRCT20210425051075N1), and two studies are awaiting classification (N0405078066; UMIN000008768). Data from these studies, even partial or provisional, were not available, thus their possible impact remains unclear.

Authors' conclusions

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 (Figure 2).

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 (Figure 3).

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.

What's new

Date	Event	Description
31 March 2023	New search has been performed	We updated the literature searches and revised the flow‐chart describing study selection according to the additional search performed.
31 March 2023	New citation required and conclusions have changed	We included 4 additional RCTs, slightly changing the conclusions for some of the main outcomes of the review.

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History

Protocol first published: Issue 3, 2014 Review first published: Issue 6, 2015

Risk of bias

Risk of bias for analysis 1.1 Antidepressants vs placebo.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Subgroup 1.1.1 SSRIs

EUCTR2008‐002159‐25‐FR

Some concerns

Study described as randomized, however no detail is provided concerning the generation of the allocation sequence nor whether it was concealed or not until participants were enrolled (unpublished study). No major imbalances between intervention groups according to the results posted on clinicaltrials.gov

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure (unpublished study). A mITT approach has been used to measure the outcome, excluding from the analysis those patients who were unable to follow up. Completers were analyzed as randomized

Some concerns

8/20 patients in the escitalopram group (40%) and 6/18 in the placebo group (33%) were unable to follow up, hence their outcome wasn't available. No evidence is provided to justify the fact that the result was not biased by missing outcome data. Missingness in the outcome could depend on its true value, however specific reasons are provided for those drop‐outs that occurred and seem balanced between the two intervention groups, making it unlikely that this missingness of the outcome might depend on its true value

Some concerns

The Montgomery‐Asberg Depression Rating Scale (MADRS) is a validated tool to measure the outcome in question. No information is available concerning the frequency and way the outcome was measured in the two intervention groups. Concomitant medications for insomnia and nausea were allowed in both groups according to the study protocol. No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

High risk of bias

On the study protocol HADS scale was listed as the main tool to evaluate efficacy. However only results of the assessment with the MADRS and CES‐D scales are available.

High risk of bias

The overall risk of bias is high. The study is unpublished. Important information on the way the outcome was measured are indeed missing (no detail on randomization/ concealment of the allocation sequence, no clear detail on how the outcome was measured in the two study groups). Moreover the attrition rates are high in both group and the way the main outcome was measured was not coherent with the study protocol.

Fisch 2003

Low risk of bias

Quote: "[...] randomly assigned in a double‐blind manner to receive either fluoxetine (20‐mg tablets) or an identical placebo tablet. The randomisation was performed centrally through a preprinted randomisation table, and the study drug was sent by overnight mail directly to the patient". It is safe to assume that this method of randomization might have ensured concealment of the allocation sequence. No major imbalances between intervention groups

Low risk of bias

Study described as double blind. Fluoxetine and placebo pills were identical in appearance. No further detail is provided concerning the blinding procedure. A mITT approach has been used to measure the outcome, excluding from the analysis those patients who were unable to follow up. The other patients were analyzed as randomized

High risk of bias

26/64 patients in the fluoxetine group (40%) and 21/65 in the placebo group (32,3%) were unable to follow up, hence their outcome wasn't available. No evidence is provided to justify the fact that the result was not biased by missing outcome data. Missingness in the outcome could depend on its true value, drop out to adverse events are reported in the paper constitute only a small percentage of the total drop‐out rates and are well distributed among the two intervention groups. However other reasons for drop‐outs are not described in enough detail to estimate how likely it is that the missingness in the outcome might have depended on its true value

Low risk of bias

The BZSDS (Brief Zung Self‐Rating Depression Scale) is a validated tool to measure the outcome in question. According to study authors "The mean interval between visits (in weeks) was similar for patients in each treatment arm" and "Longitudinal assessments were performed at baseline and every 3 to 6 weeks thereafter and included the measurement of QOL and depression. The visit interval varied among patients and often depended on the schedule for anticancer therapy. Patients were assessed for 12 weeks, and complete assessment involved three to five sessions of data collection (depending on the individual patient’s visit intervals)." No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

Some concerns

No protocol or pre‐specified analysis plan is available for the study in question. However relevant data for the pre‐specified (methods) outcomes are well‐reported (results). The way the outcome was measured seems coherent with the prespecified plan (methods). It is however possible that the study authors measured other outcomes and/or conducted multiple analyses, but did not report them.

High risk of bias

We considered the measurement of the outcome to be at high risk of bias for the high attrition rates of study participants in both groups (40% in the fluoxetine group, 32,3% in the fluoxetine group). Furthermore reasons for drop‐outs are not described in enough detail.

Musselman 2006

Some concerns

Study described as randomized, however no detail is provided concerning the randomization of the allocation sequence nor whether it was concealed or not until participants were enrolled. No major imbalances between intervention groups (with the exception of stage, being less advanced in the placebo‐treated group, and previous chemotherapy, being less frequent in the placebo‐treated group)

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure. Patients were analyzed as randomized.

High risk of bias

5 out of 13 patients in the paroxetine group (40%), 4 out of 11 patients in the desipramine group (36%) and 5 out of 11 patients in the placebo group (45%) were unable to follow up, hence their outcome wasn't available. No evidence is provided to justify the fact that the result was not biased by missing outcome data. Reason for leaving the study are well described and overall balanced between groups, however dropout rates are relevant. Moreover, a relevant portion of missing data are possibly related to the true outcome (2 patients in the paroxetine group versus 2 in the desipramine group versus 0 patients in the placebo group dropped due to inefficacy)

Low risk of bias

the Hamilton Depression Rating Scale (HAM‐D) is a validated tool to measure the outcome in question. Patients in both groups were assessed for both efficacy and adverse events at baseline, weekly during weeks 1 through 6 and on a monthly basis thereafter for a total of 5 months of double‐blind, randomized treatment. No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

Some concerns

No protocol or pre‐specified analysos plan is available for the study in question. However prespecified outcomes are reported for the endpoint assessment (week 6) in the methods section. The way the outcome was measured seems coherent with the prespecified plan (methods). It is however possible that the study authors measured other outcomes and/or conducted multiple analyses, but did not report them.

High risk of bias

Although the overall quality of the study was acceptable, we considered the way the outcome was measured to be at high risk of bias for the high attrition rates. Moreover the reasons for the dropouts among the three groups are not well balanced enough and they may be related to the true outcome

Razavi 1996

Some concerns

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure. A mITT approach has been used to measure the outcome, excluding from the analysis those patients who were unable to follow up. The other patients were analyzed as randomized

High risk of bias

15/45 patients in the tluoxetine group (33%) and 7/46 patients in the placebo group (15,2%) were unable to follow up, hence their outcome wasn't available. No evidence is provided to justify the fact that the result was not biased by missing outcome data. Missingness in the outcome it's likely to depend on its true value. Indeed, there is imbalance between the two groups, even though reasons for dropping out from the study are well described.

Low risk of bias

The Hospital Anxiety and Depression scale is a validated tool to measure the outcome in question. The outcome was measured at regular follow up visits in both intervention groups. No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

Some concerns

No protocol or pre‐specified analysis plan is available for the study in question. Outcomes are not clearly pre‐specified in the method section (quote: "[...] evaluate, in a double‐blind placebo‐controlled design, the effectiveness of fluoxetine to treat and/or to control anxiety and depression [...]"). For relevant outcomes mean scores on rating scales are reported for 'visit 1' (but it is not clearly explained if it matches with the baseline point) and for 'visit 5'.

High risk of bias

We judged the measurement of this outcome to be at high risk of bias. The randomization process is not described in enough detail and the attrition rates are quite high and not well balanced between the two groups (although the reasons for the drop‐outs are described ). The way the outcomes were measured and analyzed were not pre‐specified in enough detail in the method section

Tavakoli Ardakani 2019

Low risk of bias

Study described as randomized. Generation of the allocation sequence was random and it was concealed until participants were enrolled and assigned to interventions. Quote: "Both placebo and sertraline tablets were prepared and packaged by the same manufacturer (SobhanTM Pharmaceutical Company, Rasht, Iran), were visually identical and labelled with a code number from the random list. At inclusion, general practitioners gave the code number from the drug unit to the patient and all patient related data." No major imbalances between intervention groups

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure; A mITT approach has been used to measure the outcome, excluding from the analysis those patients who were unable to follow up. The other patients were analyzed as randomized

Low risk of bias

9 patients out of 56 (16%) were lost to follow‐up and their outcome wasn't available. Of the 9 patients who were lost to follow up 5 belonged to the sertraline group and 4 to the placebo group. The number of patients with missing outcome data is inferior to 20% and this can be considered acceptable considered the type of population and the trial intervention

Low risk of bias

The Hospital Anxiety and Depression scale is a validated tool to measure the outcome in question; The outcome was measured at 3 and 6 weeks in both intervention groups; No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

Some concerns

No protocol or pre‐specified analysis plan is available for the study in question. Relevant data for the pre‐specified (methods) outcomes are well‐reported (results). It is however possible that the study authors measured other outcomes and/or conducted multiple analyses, but did not report them.

Some concerns

The overall assessment of the outcome had some concerns for a risk of bias, mainly due to the lack of a registered protocol or a pre specified analysis plan

Subgroup 1.1.2 TCAs

Musselman 2006

Some concerns

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure. Patients were analyzed as randomized.

High risk of bias

Low risk of bias

Some concerns

High risk of bias

Subgroup 1.1.3 Other antidepressants

Liu 2021

Low risk of bias

Quote: "patients were randomized into different groups through a computer‐generated randomized list using the SPSS software (SPSS Inc., Chicago, USA)". No detail is provided concerning the concealment of the allocation sequence". No major imbalances between intervention groups. No further detail is provided concerning the concealment of the allocation sequence, however, although information on the sequence generation and the allocation concealment are poorly reported, we considered that, given the overall good methodological quality of the study, major issues of the randomization process are unlikely to have occurred.

Low risk of bias

Study described as double blind. No further detail is provided concerning the blinding procedure. Patients were analyzed as randomized

Low risk of bias

According to study authors "No patients were lost to follow up"

Low risk of bias

The Hospital Anxiety and Depression scale is a validated tool to measure the outcome in question. The outcome was measured at day 1,3,7, at 1 month and 3 months in both intervention groups. No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study.

Some concerns

We considered the measurement of the outcome to have some concerns of risk of bias. The overall methodology was good, all patients were randomized as analyzed and no drop‐out occurred. The way the outcome was measured is appropriate, however no protocol or pre‐specified analysis plan was available for the study in question

Van Heeringen 1996

Some concerns

Low risk of bias

Study described as double blind. Placebo and mianserin pills were identical in appearance. No further detail is provided concerning the blinding procedure. A mITT analysis has been conducted, including in the final analysis all patients who had at least 1 post‐baseline follow‐up assessment.

High risk of bias

6/28 patients in the tluoxetine group (33%) and 15/27 patients in the placebo group (55%) were unable to follow up, hence their outcome wasn't available. No evidence is provided to justify the fact that the result was not biased by missing outcome data. Quote: "Significantly more placebo‐treated patients (n = 15) than mianserin‐treated patients (n = 6) prematurely terminated the study (Fishers' exact test P,=0.014). When withdrawals because of lack of efficacy were analysed, the difference was again significant and in favour of mianserin (2 and 11 patients in the mianserin and placebo treatment group, respec tively; Fisher's exact test, P= 0.006)." Missing of the outcome can indeed be explained by lack of efficacy in the placebo group.

Low risk of bias

The Hospital Anxiety and Depression scale is a validated tool to measure the outcome in question. The outcome was measured at regular follow up visits in both intervention groups at week 2, 4 and 6. No other reason to suspect that this kind of bias might have occurred. No detail is provided concerning the blinding of the assessors, however it seems implied in the double‐blind design of the study

Some concerns

No protocol or pre‐specified analysos plan is available for the study in question. Outcomes are not clearly prespecified (quote: "The aim of our study was to evaluate the efficacy and safety of mianserin in patients with breast cancer [...]"). However, mean change scores on HDRS, response rates and rates of relevant adverse events are reported.

High risk of bias

We considered the measurement of the outcome to be at high risk of bias. The attrition rates are high in both groups, with a significant imbalance between the two arms for the droupouts due to lack of efficacy (2 in the mianserin group vs 11 in the placebo group). The potential bias due to missing of outcome data favors placebo over comparator

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Acknowledgements

The authors thank Robin Grant and Alasdair Rooney for their clinical expertise, Gail Quinn and Clare Jess (Managing Editors), Tracey Harrison (Assistant Managing Editor), Joanne Platt (Cochrane Information Specialist) from Cochrane Gynaecological, Neuro‐oncology and Orphan Cancers. They also thank Dr Chin‐Kuo Chan (BPH, MS, PhD, King's College London) and Dr Irina Telegina (MD, Astrakhan State Medical Academy) for having kindly provided their help with translating from Chinese and Russian respectively. Finally, they thank Dr Tavakoli and Dr Ardakani for having provided them unpublished data concerning their work "Sertraline treatment decreased the serum levels of interleukin‐6 and high‐sensitivity C‐reactive protein in hematopoietic stem cell transplantation patients with depression; a randomized double‐blind, placebo‐controlled clinical trial."

The review authors would also like to thank Sarah Dauchy and Matthew Hotopf for their contribution to the previous version of this review.

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure to the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancers Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service or the Department of Health.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Neoplasms] explode all trees #2 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or choriocrcinoma* or leukemia* or leukaemia* or metastat* or sarcoma* or teratoma* ) #3 #1 or #2 #4 MeSH descriptor: [Depression] explode all trees #5 MeSH descriptor: [Depressive Disorder] explode all trees #6 MeSH descriptor: [Adjustment Disorders] explode all trees #7 (depress* or melanchol* or ((adjustment or reactive or dysthymic) near/5 disorder*)) #8 #4 or #5 or #6 or #7 #9 Any MeSH descriptor with qualifier(s): [Drug therapy ‐ DT] #10 MeSH descriptor: [Antidepressive Agents] explode all trees #11 MeSH descriptor: [Heterocyclic Compounds] explode all trees #12 MeSH descriptor: [Serotonin Uptake Inhibitors] explode all trees #13 MeSH descriptor: [Adrenergic Uptake Inhibitors] explode all trees #14 MeSH descriptor: [Monoamine Oxidase Inhibitors] explode all trees #15 (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*) #16 (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*) #17 #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 #18 #3 and #8 and #17

Appendix 2. MEDLINE (Ovid) 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 3. Embase (Ovid) search strategy

1 exp neoplasm/ 2 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or choriocrcinoma* or leukemia* or leukaemia* or metastat* or sarcoma* or teratoma*).ti,ab. 3 1 or 2 4 exp depression/ 5 adjustment disorder/ 6 (depress* or melanchol* or ((adjustment or reactive or dysthymic) adj3 disorder*)).ti,ab. 7 4 or 5 or 6 8 exp antidepressant agent/ 9 exp heterocyclic compound/ 10 exp serotonin uptake inhibitor/ 11 exp adrenergic receptor affecting agent/ 12 exp monoamine oxidase inhibitor/ 13 (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*).ti,ab. 14 (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*).ti,ab. 15 8 or 9 or 10 or 11 or 12 or 13 or 14 16 3 and 7 and 15 17 crossover procedure/ 18 double‐blind procedure/ 19 randomized controlled trial/ 20 single‐blind procedure/ 21 random*.mp. 22 factorial*.mp. 23 (crossover* or cross over* or cross‐over*).mp. 24 placebo*.mp. 25 (double* adj blind*).mp. 26 (singl* adj blind*).mp. 27 assign*.mp. 28 allocat*.mp. 29 volunteer*.mp. 30 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 31 16 and 30 32 (exp animal/ or nonhuman/ or exp animal experiment/) not human/ 33 31 not 32

key: [mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

Appendix 4. PsycINFO search strategy

1 exp Neoplasms/ 2 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or adenocarcinoma* or choriocrcinoma* or leukemia* or leukaemia* or metastat* or sarcoma* or teratoma*).ti,ab. 3 1 or 2 4 "depression (emotion)"/ 5 exp major depression/ 6 (depress* or melanchol* or ((adjustment or reactive or dysthymic) adj3 disorder*)).ti,ab. 7 4 or 5 or 6 8 exp antidepressant drugs/ 9 exp neurotransmitter uptake inhibitors/ 10 exp monoamine oxidase inhibitors/ 11 exp Drug Therapy/ 12 (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*).ti,ab. 13 (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*).ti,ab. 14 8 or 9 or 10 or 11 or 12 or 13 15 3 and 7 and 14 16 clinical trials/ 17 (random* or trial* or group* or placebo*).ti,ab. 18 16 or 17 19 15 and 18

Appendix 5. 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*

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* The total number of dropout patients might not be the sum of dropouts for inefficacy and side effects, because in some studies patients drop out 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

Appendix 6. Risk of bias

Domain 1: bias arising from the randomisation process

Signalling questions

1.1 Was the allocation sequence random? (Yes, Probably Yes, No, Probably No, No information)

1.2 Was the allocation sequence concealed until participants were recruited and assigned to interventions? Yes, Probably Yes, No, Probably No, No information

1.3 Were there baseline imbalances that suggest a problem with the randomisation process? Yes, Probably Yes, No, Probably No, No information

Domain 2: risk of bias due to deviations from the intended interventions (effect of assignment to intervention)

Signalling questions

2.1. Were participants aware of their assigned intervention during the trial? (Yes, Probably Yes, No, Probably No, No information)

2.2. Were carers and trial personnel aware of participants' assigned intervention during the trial? (Yes, Probably Yes, No, Probably No, No information)

2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention beyond what would be expected in usual practice? (Yes, Probably Yes, No, Probably No, No information)

2.4. If Y/PY to 2.3: Were these deviations from intended intervention unbalanced between groups and likely to have affected the outcome? (Yes, Probably Yes, No, Probably No, No information)

2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups? (Yes, Probably Yes, No, Probably No, No information)

2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention? (Yes, Probably Yes, No, Probably No, No information)

2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomised? (Yes, Probably Yes, No, Probably No, No information)

Domain 3: bias arising from missing outcome data

Signalling questions

3.1 Were data for this outcome available for all, or nearly all, participants randomised? (Yes, Probably Yes, No, Probably No, No information)

3.2 If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data? (Yes, Probably Yes, No, Probably No, No information)

3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value? (Yes, Probably Yes, No, Probably No, No information)

3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value? (Yes, Probably Yes, No, Probably No, No information)

Domain 4: bias arising from measurement of the outcome

Signalling questions

4.1 Was the method of measuring the outcome inappropriate? (Yes, Probably Yes, No, Probably No, No information)

4.2 Could measurement or ascertainment of the outcome have differed between intervention groups? (Yes, Probably Yes, No, Probably No, No information)

4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants? (Yes, Probably Yes, No, Probably No, No information)

4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received? (Yes, Probably Yes, No, Probably No, No information)

4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received? (Yes, Probably Yes, No, Probably No, No information)

Domain 5: bias arising from the selection of the reported results

Signalling questions

5.1 Were the data that produced this result analysed in accordance with a pre‐specified analysis plan that was finalised before unblinded outcome data were available for analysis? (Yes, Probably Yes, No, Probably No, No information)

5.2 Is the numerical result being assessed likely to have been assessed, on the basis of the results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain? (Yes, Probably Yes, No, Probably No, No information)

5.3 Is the numerical result being assessed likely to have been assessed, on the basis of the results, from multiple eligible analyses of the data? (Yes, Probably Yes, No, Probably No, No information)

Data and analyses

Comparison 1. Depression: efficacy as a continuous outcome at 6–12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Antidepressants vs placebo	7	511	Std. Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.92, ‐0.12]
1.1.1 SSRIs	5	238	Std. Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.79, ‐0.01]
1.1.2 TCAs	1	17	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.95, 1.04]
1.1.3 Other antidepressants	2	256	Std. Mean Difference (IV, Random, 95% CI)	‐1.01 [‐2.44, 0.41]
1.2 SSRIs vs TCAs	3	237	Std. Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.34, 0.18]
1.2.1 Paroxetine vs desipramine	1	24	Std. Mean Difference (IV, Random, 95% CI)	0.08 [‐0.73, 0.88]
1.2.2 Paroxetine vs amitriptyline	1	175	Std. Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.46, 0.14]
1.2.3 Fluoxetine vs desipramine	1	38	Std. Mean Difference (IV, Random, 95% CI)	0.19 [‐0.45, 0.83]
1.3 Mirtazapine vs TCA	1	25	Mean Difference (IV, Fixed, 95% CI)	‐4.80 [‐9.70, 0.10]

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Comparison 2. Depression: efficacy as a continuous outcome at 1–4 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Antidepressants vs placebo	8	764	Std. Mean Difference (IV, Random, 95% CI)	‐0.48 [‐0.87, ‐0.10]
2.1.1 SSRIs	4	226	Std. Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.62, 0.26]
2.1.2 Other antidepressants	4	538	Std. Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.26, ‐0.21]
2.2 Mirtazapine vs TCA	1	32	Mean Difference (IV, Fixed, 95% CI)	‐5.00 [‐10.63, 0.63]

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Comparison 3. Depression: efficacy as a dichotomous outcome at 6–12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Antidepressants vs placebo	7	662	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.57, 0.96]
3.1.1 SSRIs	4	316	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.58, 1.17]
3.1.2 TCAs	1	17	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.42, 2.86]
3.1.3 Other antidepressants	3	329	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.42, 0.87]
3.2 SSRI vs TCA	2	199	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.78, 1.53]
3.2.1 Paroxetine vs amitriptyline	1	175	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.79, 1.63]
3.2.2 Paroxetine vs desipramine	1	24	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.33, 2.18]
3.3 Mirtazapine vs TCA	1	33	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.60, 1.09]

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3.3 — Comparison 3: Depression: efficacy as a dichotomous outcome at 6–12 weeks, Outcome 3: Mirtazapine vs TCA

Comparison 4. Social adjustment at 6–12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Antidepressants vs antidepressants	1	175	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.38, 0.58]
4.1.1 Paroxetine vs amitriptyline	1	175	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.38, 0.58]

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Comparison 5. Quality of life at 6–12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Antidepressants vs placebo	2	152	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.27, 0.37]
5.1.1 SSRIs	2	152	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.27, 0.37]
5.2 Antidepressants vs antidepressants	1	153	Mean Difference (IV, Random, 95% CI)	6.50 [0.21, 12.79]
5.2.1 Paroxetine vs amitriptyline	1	153	Mean Difference (IV, Random, 95% CI)	6.50 [0.21, 12.79]

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Comparison 6. Dropouts due to any cause (acceptability).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Antidepressants vs placebo	9	889	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.52, 1.38]
6.1.1 SSRIs	5	334	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.84, 2.24]
6.1.2 TCAs	1	17	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.24, 2.23]
6.1.3 Other antidepressants	4	538	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.25, 0.75]
6.2 SSRI vs TCA	3	237	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.53, 1.30]
6.2.1 Fluoxetine vs desipramine	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.29, 1.68]
6.2.2 Paroxetine vs amitriptyline	1	175	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.46, 1.51]
6.2.3 Paroxetine vs desipramine	1	24	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.37, 3.00]
6.3 Mirtazapine vs TCA	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.20, 2.15]

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6.3 — Comparison 6: Dropouts due to any cause (acceptability), Outcome 3: Mirtazapine vs TCA

Comparison 7. Dropouts due to inefficacy.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Antidepressants vs placebo	6	455	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.13, 1.32]
7.1.1 SSRIs	4	310	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.10, 7.31]
7.1.2 TCAs	1	17	Risk Ratio (M‐H, Random, 95% CI)	2.92 [0.16, 52.47]
7.1.3 Other antidepressants	2	128	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.05, 0.65]
7.2 Antidepressants vs antidepressants	3	237	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.14, 5.06]
7.2.1 Fluoxetine vs desipramine	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
7.2.2 Paroxetine vs amitriptyline	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
7.2.3 Paroxetine vs desipramine	1	24	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.14, 5.06]

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Comparison 8. Dropouts due to adverse effects (tolerability).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Antidepressants vs placebo	9	889	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.54, 2.62]
8.1.1 SSRIs	5	334	Risk Ratio (M‐H, Random, 95% CI)	1.99 [0.71, 5.57]
8.1.2 Tricyclic antidepressants	1	17	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.04, 7.25]
8.1.3 Other antidepressants	4	538	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.15, 2.35]
8.2 Antidepressants vs antidepressants	3	237	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.55, 1.99]
8.2.1 Fluoxetine vs desipramine	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.41, 3.62]
8.2.2 Paroxetine vs amitriptyline	1	175	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.38, 2.08]
8.2.3 Paroxetine vs desipramine	1	24	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.18, 16.25]

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Comparison 9. Subgroup analysis: psychiatric diagnosis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Antidepressants vs placebo	5	398	Std. Mean Difference (IV, Random, 95% CI)	‐0.48 [‐0.98, 0.02]
9.1.1 Participants with major depressive disorder	3	291	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐1.38, 0.32]
9.1.2 Participants with adjustment disorder, dysthymic disorder, depressive symptoms	2	107	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.67, 0.10]
9.2 SSRI vs TCA	2	199	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.41, 0.15]
9.2.1 Participants with major depressive disorder	2	199	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.41, 0.15]
9.3 Mirtazapine vs TCA	1	25	Mean Difference (IV, Fixed, 95% CI)	‐4.80 [‐9.70, 0.10]

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9.3 — Comparison 9: Subgroup analysis: psychiatric diagnosis, Outcome 3: Mirtazapine vs TCA

Comparison 10. Subgroup analysis: cancer site.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Antidepressants vs placebo	7	511	Std. Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.92, ‐0.12]
10.1.1 Participants with breast cancer	3	291	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐1.38, 0.32]
10.1.2 Participants with other cancer types	4	220	Std. Mean Difference (IV, Random, 95% CI)	‐0.46 [‐0.90, ‐0.03]
10.2 Antidepressants vs antidepressants	4	262	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.41, 0.14]
10.2.1 Participants with breast cancer	2	199	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.41, 0.15]
10.2.2 Participants with other cancer types	2	63	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐1.15, 0.68]

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Comparison 11. Subgroup analysis: cancer stage.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Antidepressants vs placebo	2	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.66, 0.16]
11.1.1 Participants with an early‐stage cancer	1	69	Std. Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.65, 0.31]
11.1.2 Participants with late‐stage cancer	1	24	Std. Mean Difference (IV, Random, 95% CI)	‐0.48 [‐1.30, 0.33]
11.2 Antidepressants vs antidepressants	1	38	Mean Difference (IV, Random, 95% CI)	0.69 [‐1.61, 2.99]
11.2.1 Participants with early‐stage cancer	1	38	Mean Difference (IV, Random, 95% CI)	0.69 [‐1.61, 2.99]

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Comparison 12. Sensitivity analysis: excluding trials that did not employ depressive symptoms as their primary outcome.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Antidepressants vs placebo	5	384	Std. Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.98, 0.04]
12.1.1 SSRIs	3	111	Std. Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.58, 0.18]
12.1.2 TCAs	1	17	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.95, 1.04]
12.1.3 Other antidepressants	2	256	Std. Mean Difference (IV, Random, 95% CI)	‐1.01 [‐2.44, 0.41]

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Comparison 13. Sensitivity analysis: excluding trials with imputed data.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Antidepressants vs placebo	6	476	Std. Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.10, ‐0.20]
13.1.1 SSRIs	4	220	Std. Mean Difference (IV, Random, 95% CI)	‐0.46 [‐0.90, ‐0.03]
13.1.2 Other antidepressants	2	256	Std. Mean Difference (IV, Random, 95% CI)	‐1.01 [‐2.44, 0.41]
13.2 Mirtazapine vs TCA	1	36	Mean Difference (IV, Fixed, 95% CI)	‐4.80 [‐8.85, ‐0.75]

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13.2 — Comparison 13: Sensitivity analysis: excluding trials with imputed data, Outcome 2: Mirtazapine vs TCA

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cankurtaran 2008.

*Study characteristics*
Methods	6‐week randomised study
Participants	Inclusion criteria: white blood cell count ≥ 3000/μL at beginning of study and being able to stay in contact with their doctors for ≥ 6 weeks Exclusion criteria: unable to fill out the self‐report instruments for any reason such as any serious neurological illness, eye problems, mental retardation or illiteracy; any serious chronic physical illness other than cancer that could cause a conflict regarding the reason for somatic symptoms such as pain, nausea and vomiting; any psychiatric diagnoses other than major depressive disorder, anxiety disorders such as generalised anxiety disorder and panic disorder or adjustment disorder assessed with SCID‐I/CV; using any psychotropic drugs for pain management or sleep disturbance.
Interventions	Mirtazapine (20 participants) Imipramine (13 participants) Control (no placebo, not included in the meta‐analysis): 20 participants
Outcomes	Efficacy of mirtazapine and imipramine measured using HADS scale. Assessment of pain, nausea, vomiting and appetite
Notes

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Costa 1985.

*Study characteristics*
Methods	8‐week, randomised study
Participants	Female participants age ≥ 18 years affected by cancer and depression Inclusion criteria: cancer (mixed sites, including breast, ovary, uterine cervix and others) at any stage, diagnosed with depression; low mood and loss of interest for ≥ 3 weeks; ≥ 4 of: difficulty in concentration or memory problems, irritability, feelings of worthlessness or hopelessness, fear of losing one's mind, lack of initiative, frequent crying or wanting to die, suicide attempt; social impairment at work, home etc.; anorexia, sleep disturbance, fatigue, motor retardation; depression succeeding or paralleling development of cancer; ZSRDS score > 41; HAM‐D items 1–17 score > 16; informed consent of the participant. Participants were mostly inpatients, but rates of inpatients and outpatients were not reported.
Interventions	Mianserin: flexible dose starting from 10 mg, 1 tablet per day in first week and 2 tablets per day from second week (range not reported; mean dose between weeks 1 and 4 was 44.5 mg/day) (36 participants) Placebo (37 participants)
Outcomes	Efficacy and tolerability assessed using ZSRDS; HAM‐D‐17; CGI‐S; CGI‐I; Efficacy Index and a checklist for somatic findings and adverse effects
Notes

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EUCTR2008‐002159‐25‐FR.

*Study characteristics*
Methods	12‐week, randomised, double‐blind, placebo‐controlled study
Participants	Inclusion criteria: people with cancer of the upper aerodigestive tract (buccal cavity, larynx, oropharynx, hypopharynx), solitary or multiple synchronous localisations, stage I to IVb, to be treated by surgery or radiotherapy or chemotherapy (or a combination of these) (first‐line curative treatment); HADS > 11 (excluded those with a diagnosis of major depressive episode with severity criteria or suicidal thoughts); aged 18–75 years, having signed an informed consent form
Interventions	Escitalopram (20 participants) Placebo (18 participants)
Outcomes	Primary outcome: subscore depression of the HADS, W12 Secondary outcomes: CES‐D; MADRS; CGI; SCL‐90‐R; health‐related quality of life (EORTC QLQ‐C30, H‐N 35), alcohol or tobacco consumption (carbon monoxide, carbohydrate‐deficient transferrin)
Notes	Data were partially provided by the authors before the publication of the study.

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Fisch 2003.

*Study characteristics*
Methods	Randomised, placebo‐controlled, multicentre (15 centres) study
Participants	Ambulatory people of either sex with advanced cancer (mixed sites) and depressive symptoms, as assessed with a TQSS score ≥ 2, excluding people with major depression diagnosed by a psychiatrist in the past 6 months. All participants gave informed consent
Interventions	Fluoxetine: 20 mg/day, fixed (83 participants) Placebo (80 participants)
Outcomes	Primary outcome: quality‐of‐life assessed using the FACT‐G, version 3. Secondary outcome: depressive symptoms assessed using the 11‐item BZSDS
Notes

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Holland 1998.

*Study characteristics*
Methods	6‐week, prospective, randomised, double‐blind, multicentric (6 investigative sites) study
Participants	Women affected by cancer (mostly breast cancer stages II, II, IV) and major depressive disorder (for ≥ 30 days before entering study) or adjustment disorder with depressed mood (for ≥ 60 days before entering study), according to DSM‐III‐R criteria and score > 14 on the first 17 items of the HAM‐D. Participants gave signed informed consent.
Interventions	Fluoxetine: 20 mg/day for first month, thereafter dose was flexible. Maximum dose allowed was not reported (17 participants) Desipramine: starting dose 25 mg/day and titrated in 25 mg/week increments to 100 mg/day at week 4. Thereafter, dose was flexible to a maximum of 150 mg/day (21 participants) There was no placebo arm, but all participants received placebo + active drug (alternated during the day) in order to maintain the blindness ('double‐dummy' approach).
Outcomes	Safety and efficacy; depression and anxiety assessed using HAM‐D‐17, HAM‐A, CGI and PGI; quality of life assessed using FLIC, MPAC and SF‐36; adverse events were self‐reported and evaluated weekly through clinical assessment
Notes

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Liu 2021.

*Study characteristics*
Methods	3‐month randomised study
Participants	People with breast cancer who received modified radical mastectomy. Inclusion criteria: HAM‐D‐17 score measured before surgery of 8–24; aged 18–65 years; American Society of Anesthesiologists score I–II Exclusion criteria: HAM‐D‐17 scores > 24 or < 7 before surgery; other mental diseases, such as schizophrenia and mania, or with a psychiatric history before study; other severe system diseases, including severe heart, renal and liver diseases
Interventions	S‐ketamine: intravenous injection of 0.125 mg/kg in 2 mL after analgesia induction (101 participants) Placebo: intravenous injection of 2 mL of normal saline after analgesia induction (placebo) (100 participants)
Outcomes	Efficacy measured through HAM‐D score at 3 days, 1 week, 1 month and 3 months; brain‐derived neurotrophic factor and serotonin levels measured
Notes

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Musselman 2006.

*Study characteristics*
Methods	6‐week, randomised, double‐blind, placebo‐controlled, multicentric (2 centres), parallel‐group study
Participants	Inclusion criteria: female outpatients aged 18–75 years with a current diagnosis of breast carcinoma (stage I–IV); DSM‐III‐R criteria for major depression or adjustment disorder with depressed mood for ≥ 2 months; score ≥ 14 on the first 17 items of the 21‐items HAM‐D; last cancer treatment within the last 5 years
Interventions	Paroxetine: flexible dose, starting with 20 mg/day for first 4 weeks, thereafter it could be increased at 40 mg/day (13 participants) Desipramine: flexible dose, starting with 25 mg/day and gradually titrated to 125 mg/day within the fourth week; thereafter it could be increased by 25 mg/day every 3 days up to 200 mg/day as maximum dose (11 participants) Placebo (11 participants)
Outcomes	Primary outcome: efficacy and tolerability assessed with 21‐item HAM‐D, 14‐item observer‐rated HAM‐A, CGI‐S, routine adverse event monitoring and vital assessment for exploring tolerability Secondary outcome: mean change from baseline in the CGI‐S score
Notes

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Navari 2008.

*Study characteristics*
Methods	24‐week, randomised, double‐blind, placebo‐controlled study
Participants	Inclusion criteria: women with early‐stage breast cancer (stages I, II) who were candidates for adjuvant hormonal therapy, local radiation, adjuvant chemotherapy treatment (or a combination) and had depressive symptoms, as indicated by TQSS score ≥ 2 Exclusion criteria: "clinically depressed"
Interventions	Fluoxetine: 20 mg/day (not clearly reported if it was a fixed dose) (number of participants not reported) Placebo (number of participants not reported)
Outcomes	Efficacy on depressive symptoms assessed with 11‐item BZSDS; quality of life assessed with FACT‐G, version 3; completion of adjuvant treatment
Notes

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NCT00387348.

*Study characteristics*
Methods	Interventional, randomised, cross‐over, 8‐week, double‐blind study. Randomisation stratified according to stage of disease (stage IIIB with effusions vs stage IV) and current treatment (radiation vs chemotherapy vs novel agent)
Participants	Inclusion criteria: diagnosed with advanced lung or gastrointestinal cancer and major depressive disorder (according to DSM‐IV and Endicott criteria); aged 35–85 years
Interventions	Study had a cross‐over design (the switch from 1 to the other took place after 4 weeks) Placebo then escitalopram Escitalopram then placebo Placebo then placebo In the first phase of the trial, 11 participants received escitalopram 10 mg/day and 13 participants received placebo.
Outcomes	Primary outcomes: response rate, defined as a 50% reduction in HAM‐D scores over 4 weeks; change in HAM‐D scores at week 4 Secondary outcome: adverse effect burden, defined as the total score of the UKU Side Effects Rating Scale
Notes	According to the protocol, the study started in March 2006 and was supposed to be completed in April 2011. Results for primary and secondary outcomes for the first 4 weeks of treatment were made available at ClinicalTrials.gov.

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Pezzella 2001.

*Study characteristics*
Methods	8‐week, multicentric (25 centres), double‐blind, parallel‐group, randomised study
Participants	Inclusion criteria: women aged 18–65 years (according to data reported in tables, older participants were also analysed), with a diagnosis of breast cancer (at any stage, but without cerebral metastases), with a rating < 2 on the WHO Performance Status scale and a life expectancy > 3 months; who had received chemotherapy and were scheduled to receive further cycles during study period, and had received tamoxifen or paclitaxel and were scheduled to receive further treatment during study. Participants had to be diagnosed with a mild, moderate or severe depressive episode, according to ICD‐10 and have MADRS score > 16. All participants gave written informed consent
Interventions	Paroxetine: flexible dose, starting with 20 mg/day for first 3 weeks. Thereafter, dose could be increased to 30 mg/day (after week 3) and to 40 mg/day (after week 5) if clinically indicated (88 participants) Amitriptyline: flexible dose, titrating up to 75 mg/day within the first 3 weeks. Thereafter, the dose could be increased to 100 mg/day (after week 3) and to 150 mg/day (after week 5) if clinically indicated (87 participants) Placebo capsules were administered in order to maintain blinding.
Outcomes	Efficacy assessed using MADRS, CGI‐S, FLIC and Patient's Global Evaluation at endpoint; tolerability assessed by recording adverse events and evaluating vital signs and laboratory parameters
Notes

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Razavi 1996.

*Study characteristics*
Methods	5‐week, double‐blind, placebo‐controlled, randomised, multicentric trial (14 centres)
Participants	People (mostly females) aged over 18 years, diagnosed with an adjustment disorder (with a depressive mood or with mixed features) or from a major depressive disorder (excluding major depressive disorder with melancholic features) as defined by the DSM‐III‐R "in relation to" a cancer disease that had been diagnosed for between 6 weeks and 7 years; HADS score > 13 before and after the 1‐week placebo treatment; Karnofsky Performance Scale ≥ 60; had to provide written informed consent
Interventions	Fluoxetine: 20 mg/day, 1 tablet (45 participants) Placebo (46 participants)
Outcomes	Effectiveness assessed using HADS, MADRS, HAM‐A, SCL‐90‐R, and the Spitzer Quality of Life Index. Main assessment criterion was success rate defined by HADS score < 8 after 5 weeks of treatment. Tolerance assessed using AMDP5, weight, blood pressure, pulse, biochemical and haematological tests, and spontaneous adverse effect reports.
Notes

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Tavakoli Ardakani 2019.

*Study characteristics*
Methods	8‐week randomised study
Participants	Participants aged 18–60 years who were candidates for autologous or allogeneic HSCT with major depression or anxiety disorder (or both) diagnosed by an expert psychiatrist. Severity of depression evaluated using the HADS questionnaire. Exclusion criteria: documented hepatic or kidney dysfunction; active infection; autoimmune diseases; severe or uncontrolled mental illness (or both) or cognitive dysfunction; history of receiving antidepressants, antianxiety, immunosuppressive, anti‐inflammatory agents or a combination of these within last month; history of documented hypersensitivity to sertraline or unable to tolerate oral intake
Interventions	Sertraline: 50 mg/day for first week and then 100 mg/day (25 participants) Placebo: visually identical to sertraline tablets (22 participants)
Outcomes	Assessment of efficacy of sertraline with HADS scale, assessment of post‐HSCT complications
Notes

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Van Heeringen 1996.

*Study characteristics*
Methods	6‐week, randomised, double‐blind, placebo‐controlled, single‐centre study
Participants	Women aged > 18 years with breast cancer at stage I or II, without metastases, not qualifying for primary surgical treatment, treated with radiotherapy, and depression, diagnosed according to DSM‐III criteria, and 21‐item HAM‐D score ≥ 16
Interventions	Mianserin: fixed dose at 30 mg/day for first week and 60 mg/day thereafter (28 participants) Placebo (27 participants)
Outcomes	Efficacy and safety; depression assessed using 21‐item HAM‐D after 2, 4 and 6 weeks; tolerability assessed using the Record of Symptoms Emerging and clinical evaluation of vital signs and laboratory measurements
Notes

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Wang 2020.

*Study characteristics*
Methods	1‐week randomised study
Participants	Women with cervical carcinoma who received laparoscopic modified radical hysterectomy from April 2015 to July 2018. All were at TNM I–II stage. Evaluated using HAM‐D‐17 score Inclusion criteria: HAM‐D‐17 score 8–24 and American Society of Anesthesiologists score I–II before surgery Exclusion criteria: HAM‐D score ≤ 7 or ≥ 24 before study; psychiatric disorders such as mania and schizophrenia; and severe liver, renal, cardiovascular or systematic inflammatory diseases. Written informed consent was obtained
Interventions	S‐Ketamine (high dose): 0.5 mg/kg in 50 mL (104 participants) Placebo: 50 mL normal saline by intravenous injection after 1 hour of analgesia (105 participants) Racemic ketamine: 0.5 mg/kg in 50 mL (not included in analysis) (104 participants) S‐ketamine (low dose): 0.25 mg/kg in 50 mL (not included in analysis) (104 participants)
Outcomes	Efficacy using HAM‐D score; brain‐derived neurotrophic factor and serotonin levels
Notes

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AMDP5: Association for Methodology and Documentation in Psychiatry adverse event scale; BZSDS: Brief Zung Self‐Rating Depression Scale; CDT: carbohydrate‐deficient transferrin; CES‐D: Center for Epidemiologic Studies Depression Scale; CGI: Clinical Global Impression scale; CGI‐I: Clinical Global Impression – Improvement; CGI‐S: Clinical Global Impression – Severity; DSM‐III: Diagnostic and Statistical Manual of Mental Disorders, Third Edition; DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revision; EI: Efficacy Index; EORTC QLQ‐C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐30; FACT‐G: Functional Assessment of Cancer Therapy – General; FLIC: Functional Living Index for Cancer; HADS: Hospital Anxiety and Depression Scale; HAM‐A: Hamilton Rating Scale for Anxiety; HAM‐D‐17: 17‐item Hamilton Rating Scale for Depression; HAM‐D: Hamilton Rating Scale for Depression; HSCT: haematopoietic stem‐cell transplantation; ITT: intention‐to‐treat; LOCF: last observation carried forward; MADRS: Montgomery Åsberg Depression Rating Scale; MDD: major depressive disorder; MPAC: Memorial Pain Assessment Card; PGI: Patient's Global Impression; SCID‐I/CV: Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV), Clinical Version; SCL‐90‐R: Symptom Checklist‐90‐Revised; SF‐36: 36‐item Short Form Health Survey; TQSS: Two‐Question Screening Survey; WHO: World Health Organization; ZSRDS: Zung Self‐Rating Depression Scale.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Amodeo 2012	Wrong comparison: participants in the 2 arms received the same drug at different doses.
Ashrafi 2018	Wrong condition: participants not depressed at enrolment
Biglia 2005	Wrong design: not randomised
Biglia 2009	Wrong comparison: control group without placebo
Biglia 2018	Wrong condition: participants not depressed at enrolment
Boekhout 2011	Wrong condition: participants not depressed at enrolment
Caldera 2009	Wrong design: not randomised
Capriglione 2016	Wrong condition: participants not depressed at enrolment.
Capuron 2002	Wrong condition: participants not depressed at enrolment
Capuron 2003	Wrong condition: participants not depressed at enrolment
Dai 2017	Wrong comparison: no placebo in the control group
Del Carmen 1990	Wrong condition: participants not depressed at enrolment
Di 2019	Wrong comparison: control group without placebo
Durand 2012	Wrong condition: participants not depressed at enrolment
Ell 2010	Wrong design: review referring to 3 studies, none of which are eligible
Evans 1988	Wrong design: not randomised
Griffiths 2016	Wrong drug: psilocybin
Heras 2013	Wrong condition: participants not depressed at enrolment
Hua 2009	Wrong comparison: control group without placebo
Hunter 2021	Wrong condition: participants not depressed at enrolment
ISRCTN51232664	Study eligible according to the protocol, however no published or unpublished data were retrieved. We contacted the authors and they stated that the study never started due to concerns around drug interactions and cancer symptoms. No further clarifications provided.
JPRN‐UMIN000003383	Wrong design: not randomised
Kalso 1996	Wrong condition: participants not depressed at enrolment
Kamath 2010	Only the abstract of the study was available. Study eligible according to the abstract, but the author's feedback was negative: study was concluded due to recruitment issues.
Kautio 2008	Wrong condition: participants not depressed at enrolment
KCT0000076	Wrong design: not randomised
Kimmick 2006	Wrong condition: participants not depressed at enrolment
Loibl 2007	Wrong condition: participants not depressed at enrolment
Lydiatt 2008	Wrong condition: participants not depressed at enrolment
Marasanov 2013	Wrong condition: participants not depressed at enrolment
Morrow 2003	Wrong condition: participants not depressed at enrolment
Musselman 2013	Wrong condition: participants not depressed at enrolment
NCT00005805	Wrong condition: participants not depressed at enrolment
NCT00066859	According to information provided by the author (Prof EG Shaw), the study closed due to the low number of participants enroled (only 8).
NCT00129467	Wrong comparison: the experimental arm received methylphenidate plus SSRI, the control arm received placebo plus SSRI
NCT00234195	Wrong design: not randomised
NCT00302744	Wrong population: participants not depressed at enrolment
NCT00352885	Wrong condition: participants not depressed at enrolment
NCT00488072	Wrong condition: participants not depressed at enrolment
NCT00536172	Wrong condition: participants not depressed at enrolment
NCT00740571	Wrong comparison: no placebo or antidepressant in the control group
NCT00832520	Wrong condition: participants not depressed at enrolment
NCT00957359	Wrong drug: psylocibin. Wrong condition: participants not depressed
NCT01219673	Wrong condition: participants not depressed at enrolment
NCT01256008	Study was eligible according to the protocol. We contacted the authors and they provided negative feedback; the design of the study had been changed and the antidepressant arm was removed.
NCT01497548	Wrong drug: methylphenidate
NCT01501396	Wrong condition: participants not depressed at enrolment
NCT01598584	According to information provided by the author (Dr Yi Ba), the study was withdrawn before enrolment.
NCT01719861	Wrong design: not randomised
NCT01725048	Wrong design: not randomised
NCT02443194	Wrong condition: participants not depressed at enrolment
NCT02637466	Withdrawn study (funding not received)
NCT02650544	Wrong condition: participants not depressed at enrolment
NCT03086148	Wrong intervention: ketamine not included amongst antidepressants according to WHO/defined daily dose
NCT03254173	Wrong population: participants not depressed at enrolment
NCT03935685	Wrong design: not randomised
NCT03996265	Wrong population: participants not depressed at enrolment
NCT04253678	Wrong comparison: no placebo
Ng 2014	Wrong comparison: control group without placebo
Nunez 2013	Wrong condition: participants not depressed at enrolment
Palesh 2012	Wrong condition: participants not depressed at enrolment
Panerai 1990	Wrong condition: recruited participants with conditions other than cancer
Panwar 2018	Wrong condition: participants not depressed at baseline
Peng 2021	Wrong comparison: no placebo in control group
Rodríguez 2011	Wrong comparison: control group without placebo
Roscoe 2005	Wrong condition: participants not depressed at enrolment
Ross 2016	Wrong drug: psilocybin
Ross 2021	Wrong drug: psilocybin
Stockler 2007	Wrong condition: mixed population was enroled, also included participants with fatigue and symptoms of anxiety
Sullivan 2017	Wrong drug: methylphenidate
Taraz 2013	Wrong condition: participants not affected by cancer
Theobald 2002	Wrong condition: participants not depressed at enrolment
Tondlova 1997	Wrong design: not randomised
Tondlova 2002	Wrong condition: participants not depressed at enrolment
UKCCCR	Wrong condition: participants not depressed at enrolment
Vitolins 2013	Wrong population: participants not depressed at enrolment.
Zhang 2003	Wrong design: the study described as "randomised," but the treatment received by the comparison arm was not clearly reported
Zhang 2011	Wrong comparison: control group without placebo
Zimmerman 2016	Wrong population: participants not depressed at enrolment
Zvukova 2010	Wrong condition: recruited participants with thyroid cancer and benign thyroid tumour, and not only participants with depression

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SSRI: selective serotonin reuptake inhibitor; WHO: World Health Organization.

Characteristics of studies awaiting classification [ordered by study ID]

N0405078066.

Methods	Randomised controlled trial
Participants	People with lung cancer
Interventions	Venlafaxine versus placebo
Outcomes	Effects on symptom profiles after 12 weeks (not clearly specified)
Notes	According to the protocol the study has been completed, but no published or unpublished data have been retrieved. Unclear if the study is eligible. Authors did not reply to our request for clarification or data.

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UMIN000008768.

Methods	Parallel, randomised, open‐label study
Participants	Men and women with cancer, diagnosed with major depression; aged > 20 years
Interventions	Mirtazapine versus duloxetine hydrochloride
Outcomes	Primary outcome: change in HAM‐D scores between pretreatment baseline and 6‐week treatment
Notes	The study is eligible according to the abstract, but results were not available. Authors did not reply to our request for data.

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HAM‐D: Hamilton Rating Scale for Depression.

Characteristics of ongoing studies [ordered by study ID]

IRCT20210425051075N1.

Study name	IRCT20220406054440N1
Methods	RCT
Participants	People with breast cancer
Interventions	Mirtazapine/escitalopram
Outcomes	Quality of life
Starting date	2022
Contact information
Notes

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NCT04303325.

Study name	Effect of Esketamine on Postoperative Depression, Gut Microbiota Bispectral Index data of depression patients undergoing breast cancer operation (ESPOD‐BI) (ESPOD‐BI)
Methods
Participants
Interventions	Esketamine vs placebo
Outcomes
Starting date	2020
Contact information
Notes

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NCT04763135.

Study name	Mirtazapine in cancer‐related poly‐symptomatology (MIR‐P)
Methods
Participants
Interventions
Outcomes
Starting date	2021
Contact information
Notes

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NCT04818099.

Study name	Vortioxetine in the treatment of depression associated with head and neck cancers undergoing radiotherapy
Methods
Participants
Interventions	Vortioxetine 10 mg vs placebo
Outcomes
Starting date	10 October 2020
Contact information
Notes

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RCT: randomised controlled trial.

Differences between protocol and review

Under Types of participants, we explained that we included studies where, although a formal diagnosis of depression was not reported, the mean baseline score of validated rating scales measuring depression was consistent with depression of at least moderate severity.

We amended the Selection of studies paragraph to report that only the Endnote software was used.

In the paragraph Subgroup analysis and investigation of heterogeneity, we clarified that the subgroup analyses were performed only for the primary outcome. We further specified which subgroups we considered.

We updated the Description of the intervention section with a brief discussion of a review and meta‐analysis (Riblet 2014).

In the Objectives section we replaced the term 'people' with 'adults (aged 18 years or older)'.

We used the RoB 2 tool rather than RoB 1 tool (see Assessment of risk of bias in included studies).

In the Data extraction and management section, we made clear that the endpoint response rate and dropout rate were calculated on a strict intention‐to‐treat (ITT) basis.

In the Measures of treatment effect section, we described which measures for the continuous and dichotomous outcomes were retrieved for the analyses. We moved the methodology for pooling these data from this section to the Data synthesis section, where we also specified the use of the Mantel‐Haenszel methods for the analysis.

We moved the discussion on multiple intervention groups from the Unit of analysis issues section to the Data synthesis section.

In the Data synthesis section, we removed the list of comparisons performed, namely antidepressants versus placebo and antidepressants versus antidepressants, as it was already reported in the paragraph Types of interventions. In this section, we added a more detailed description on how data were managed and entered in the analysis, including the use of a random‐effects model.

Contributions of authors

GO, CB and MH planned the study.

GV and BC retrieved and selected the studies, extracted the data and performed the quality assessment.

GO and GV ran the analysis.

GV drafted the manuscript.

GO, FM and CB critically revised the text.

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 researcher and doctor and receives salary support from the University of Verona. GV is a resident doctor and receives salary support in the form of a public grant from the Italian Ministry of Education, University and Research
School of Psychology, University of Sussex, Brighton, UK, UK

FM receives salary support from "School of Psychology, University of Sussex, Brighton, UK"

External sources

No sources of support provided

Declarations of interest

GV: none.

BC: none.

FM: none.

CB: none.

GO: none.

New search for studies and content updated (conclusions changed)

References

References to studies included in this review

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JPRN‐UMIN000003383 {unpublished data only}

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NCT00005805 {unpublished data only}

NCT00005805. St. John's Wort in relieving fatigue in patients undergoing chemotherapy or hormone therapy for cancer. clinicaltrials.gov/ct2/show/NCT00005805 (first received 26 July 2004).

NCT00066859 {unpublished data only}

NCT00066859. Sertraline compared with Hypericum perforatum (St. John's wort) in treating depression. clinicaltrials.gov/ct2/show/NCT00066859 (first received 7 August 2003).

NCT00129467 {unpublished data only}

NCT00129467. Methylphenidate for depressed cancer patients receiving palliative care. clinicaltrials.gov/ct2/show/NCT00129467 (first received 11 August 2005).

NCT00234195 {unpublished data only}

NCT00234195. Wellbutrin XL, major depressive disorder and breast cancer. clinicaltrials.gov/ct2/show/NCT00234195 (first received 6 October 2005).

NCT00302744 {published data only}

NCT00302744. Effects of psilocybin in advanced-stage cancer patients with anxiety. clinicaltrials.gov/ct2/show/NCT00302744 (first received 14 March 2006). [CLINICALTRIALS.GOV: NCT00302744]

NCT00352885 {unpublished data only}

NCT00352885. Evaluating the effectiveness of escitalopram in preventing or reducing depressive symptoms in people receiving interleukin-2 treatment. clinicaltrials.gov/ct2/show/NCT00352885 (first received 17 July 2006).

NCT00488072 {unpublished data only}

NCT00488072. Effects of mirtazapine on appetite in advanced cancer patients. clinicaltrials.gov/ct2/show/NCT00488072 (first received 19 June 2007).

NCT00536172 {unpublished data only}

NCT00536172. Evaluating the effectiveness of escitalopram to prevent depression in head and neck cancer patients receiving treatment (PROTECT). clinicaltrials.gov/ct2/show/NCT00536172 (first received 27 September 2007).

NCT00740571 {published data only}

NCT00740571. Amitriptyline or pregabalin to treat neuropathic pain in incurable cancer (Off-label). clinicaltrials.gov/ct2/show/NCT00740571 (first received 25 August 2008). [NCT00740571]

NCT00832520 {unpublished data only}

NCT00832520. Phase II study of Remeron for cancer patients losing more than 10% of their body weight. clinicaltrials.gov/ct2/show/NCT00832520 (first received 18 December 2012).

NCT00957359 {published data only}

NCT00957359. Psilocybin cancer anxiety study. clinicaltrials.gov/ct2/show/NCT00957359 (first received 12 August 2009). [CLINICALTRIALS.GOV: NCT00957359]

NCT01219673 {unpublished data only}

NCT01219673. Symptom burden in head and neck cancer. clinicaltrials.gov/ct2/show/NCT01219673 (first received 13 October 2010).

NCT01256008 {published data only}

NCT01256008. Intervention study of depression in breast cancer patients. clinicaltrials.gov/ct2/show/NCT01256008 (first received 8 December 2010). [NCT01256008]

NCT01497548 {published data only}

NCT01497548. Study of methylphenidate as add on therapy in depressed cancer patients. clinicaltrials.gov/ct2/show/NCT01497548 (first received 22 December 2011). [CLINICALTRIALS.GOV: NCT01497548]

NCT01501396 {unpublished data only}

NCT01501396. Megestrol acetate with or without mirtazapine in treating cancer patients with weight loss or loss of appetite. clinicaltrials.gov/ct2/show/NCT01501396 (first received 29 December 2011).

NCT01598584 {unpublished data only}

NCT01598584. Mirtazapine plus gemcitabine versus gemcitabine in metastasis pancreatic cancer. clinicaltrials.gov/ct2/show/NCT01598584 (first received 15 May 2012). [NCT01598584]

NCT01719861 {published data only}

NCT01719861. Phase 2a desipramine in small cell lung cancer and other high-grade neuroendocrine tumors. clinicaltrials.gov/ct2/show/NCT01719861 (first received 1 November 2012). [NCT01719861]

NCT01725048 {unpublished data only}

NCT01725048. Pilot study to evaluate individualized choice of antidepressants in patients with cancer. clinicaltrials.gov/ct2/show/NCT01725048 (first received 12 November 2012).

NCT02443194 {published data only}

NCT02443194. The effect of duloxetine on mood, quality of life and cognitive functioning in glioblastoma patients. clinicaltrials.gov/ct2/show/NCT02443194 (first received 13 May 2015). [NCT02443194]

NCT02637466 {published data only}

NCT02637466. Vortioxetine for MDD, cognition, and systemic inflammatory biomarkers. clinicaltrials.gov/ct2/show/NCT02637466 (first received 22 December 2015). [CLINICALTRIALS.GOV: NCT02637466]

NCT02650544 {published data only}

NCT02650544. Efficacy and safety analyses of mirtazapine in NSCLC patients with depression. clinicaltrials.gov/ct2/show/NCT02650544 (first received 8 January 2016). [NCT02650544]

NCT03086148 {published data only}

NCT03086148. Ketamine and postoperative depressive symptom. clinicaltrials.gov/ct2/show/NCT03086148 (first received 22 March 2017). [NCT03086148]

NCT03254173 {published data only}

NCT03254173. Mirtazapine for treatment of cancer associated anorexia-cachexia (MCACS100). clinicaltrials.gov/ct2/show/NCT03254173 (first received 18 August 2017). [CLINICALTRIALS.GOV: NCT03254173]

NCT03935685 {published data only}

NCT03935685. Pilot study of mirtazapine for the dual Tx of depression and CINV in high-grade glioma Pts on TMZ. clinicaltrials.gov/ct2/show/NCT03935685 (first received 2 May 2019). [CLINICALTRIALS.GOV: NCT03935685]

NCT03996265 {published data only}

NCT03996265. Bupropion in Reducing Cancer Related Fatigue in Stage I-III Breast Cancer Survivors. clinicaltrials.gov/ct2/show/NCT03996265 (first received 24 June 2019). [CLINICALTRIALS.GOV: NCT03996265]

NCT04253678 {published data only}

NCT04253678. Vortioxetine for Cancer Patients With Depression: An Observational Study. clinicaltrials.gov/ct2/show/NCT04253678 (first received 5 February 2020). [CLINICALTRIALS.GOV: 04253678]

Ng 2014 {published data only}

Ng CG, Boks MP, Roes KC, Zainal NZ, Sulaiman AH, Tan SB, et al. Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study. European Neuropsychopharmacology 2014;24:491-8. [DOI: 10.1016/j.euroneuro.2014.01.016] [DOI] [PubMed] [Google Scholar]

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UMIN000008768. A randomized comparative study of efficacy and safety between mirtazapine and duloxetine hydrochloride in patients with cancer. UMIN Clinical Trials Registry 2012. [UMIN000008768]

References to ongoing studies

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NCT04303325. Effect of esketamine on postoperative depression, gut microbiota, Bispectral Index data of depression patients undergoing breast cancer operation (ESPOD-BI) (ESPOD-BI). clinicaltrials.gov/ct2/show/record/NCT04303325 (first received 11 March 2020). [CLINICALTRIALS.GOV: NCT04303325]

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PERMALINK

Antidepressants for the treatment of depression in people with cancer

Giovanni Vita

Beatrice Compri

Faith Matcham

Corrado Barbui

Giovanni Ostuzzi

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Antidepressants compared to placebo for people with cancer and depression.

Summary of findings 2. Selective serotonin reuptake inhibitors (SSRIs) compared to tricyclic antidepressants (TCAs) for people with cancer and depression.

Summary of findings 3. Mirtazapine compared to tricyclic antidepressants (TCA) for people with cancer and depression.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Efficacy as a continuous outcome

Secondary outcomes

Efficacy as a dichotomous outcome

Social adjustment

Health‐related quality of life

Dropouts

Search methods for identification of studies

Electronic searches

Searching other resources

Handsearches

Personal communication

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Continuous data

Dichotomous data

Unit of analysis issues

Cross‐over trials

Cluster‐randomised trials

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Design and interventions

Sample sizes

Setting

Participants

Outcomes

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

Effects of interventions

Primary outcome

1. Efficacy at six to 12 weeks (continuous outcome)

1.1 Antidepressants versus placebo

1.1. Analysis.