From a Woodland perspective we are often interested in the overlap between physical and mental health. In November 2014 this little elf wrote a blog summarising the work published across the Lancet journals on the prevalence of depression in a variety of cancers and the effects of integrated collaborative care.

The work being done in Oxford and Edinburgh included a new integrated treatment programme called ‘Depression Care for People with Cancer’ (DCPC). DCPC is delivered by a team of specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment programme that includes both antidepressants and psychological therapy. I am pleased to say that the results were very positive.

At the Liaison Psychiatry Conference in May this year I enjoyed hearing Drs Michael Sharpe and Jane Walker talk in person about the studies; looking at care for depression within cancer and also palliative care. I was therefore very interested to see that earlier this year Cochrane published their review on the evidence for use of antidepressants for the treatment of depression in people with cancer. The reviewing team included representation from Verona, Paris and London (Ostuzzi G et al, 2015).

Depressive symptoms (including subthreshold manifestations) can be difficult to detect in clinical practice; especially in patients affected by serious medical conditions, due to the overlap between medical and psychiatric symptoms. For example; fatigue, weight loss and sleep disturbances. However, as I have mentioned previously, all good Liaison Services will be able to tell you that patients with cancer and comorbid depression have worse anxiety, pain, fatigue, and functioning than do other patients with cancer. They are also more likely to have suicidal thoughts, and to have more difficulties with adherence to cancer treatments with ultimately a potential higher rate of mortality.

Randomised controlled trials (RCTs) on the efficacy and tolerability of antidepressants in this population group are few and often report conflicting results and whilst Cochrane reviews are available on the efficacy of psychotherapy (Akechi 2008) and psychosocial interventions (Galway 2012), no Cochrane review has been performed on the efficacy of antidepressants in this patient population.

The objective of this new Cochrane systematic review (Ostuzzi G et al, 2015) was to assess the effects and acceptability of antidepressants for treating depressive symptoms in adults (18 years or older) with cancer (any site and stage).

Methods

Searches were done across multiple electronic bibliographic databases: the Cochrane Central Register of Controlled Trials, MEDLINE Ovid, EMBASE Ovid and PsycINFO Ovid. Additionally, there was a hand search of the trial databases of the most relevant national, international and pharmaceutical company trial registers and drug-approving agencies for published, unpublished and ongoing control led trials.

Selection criteria

They included RCTs allocating adults (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) comparing antidepressants versus placebo, or antidepressants versus other antidepressants.

Outcomes

Primary outcomes: efficacy as a continuous outcome

• Early response: between one and four weeks,
• Acute phase treatment response: between 6 and 12 weeks,
• Follow-up response: after 12 weeks

The acute phase treatment response (between 6 and 12 weeks) was the primary outcome of interest.

Secondary outcomes

• Efficacy as a dichotomous outcome; proportion of patients showing a 50% reduction in symptoms
• Social adjustment
• Health-related quality of life
• Acceptability (dropouts)

Results

The review looked at a total of nine studies with 861 participants.

Primary outcome (7 studies included)

• 4 compared antidepressants and placebo
• 2 compared two antidepressants and
• 1-three armed study compared two antidepressants and a placebo arm

Acute phase treatment response (6 to 12 weeks)

• Efficacy as a continuous outcome: mean efficacy 0.45 standard deviations lower than placebo (95% CI -1.01 to 0.11) 5 RCTs, 266 participants = no clear evidence of effect.
• No trials reported data on the follow-up response (more than 12 weeks)
• In head-to-head comparisons there was only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, providing very low quality evidence for the difference between these two classes (SMD -0.08, 95% CI -0.34 to 0.18) 3 RCTs, 237 participants.

Secondary outcomes

Efficacy as a dichotomous outcome

Proportion of people who had depression:

• 358/1,000 Placebo
• 294/1,000 Antidepressants (95% CI 222 to 387)
• Risk ratio 0.82, (95% CI 0.62 to 1.08)

5 RCTs, 417 participants

No clear evidence of an effect of antidepressants versus either placebo or other antidepressants emerged from the analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low quality evidence).

Social Adjustment (6 to 12 weeks)

• Only one study provided data for this outcome, showing no statistically significant difference between paroxetine and amitriptyline, with a mean difference (MD) of 0.10 (95% CI -0.38 to 0.58, 175 participants)
• For antidepressants versus placebo, no studies provided data for this outcome.

Quality of life (6 to 12 weeks)

• No statistically significant difference between antidepressants as a class and placebo (SMD of 0.05 (95% CI – 0.27 to 0.37) 1 RCTs, 152 participants)
• No statistically significant difference between paroxetine and amitriptyline (SMD of 6.50 (95% CI 0.21 to 12.79) 1 RCT, 153 participants)

Acceptability

• No statistically significant difference in the effect of antidepressants as a class compared with placebo (RR 0.87, 95% CI 0.49 to 1.53) six RCTs, 455 participants
• No statistically significant difference in the effect between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30) three RCTs, 237 participants

Quality of the evidence

A Cochrane review can only ever be as good as the evidence it is reviewing. Overall the quality of the evidence was deemed very low because the included studies were at an unclear or high risk of bias due to poor reporting, risk of sponsorship bias, imprecision arising from small sample sizes (fewer than 100 individuals in treatment arm) and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity.

This is reported as being consistent with the finding of a general sub-optimal reporting of RCTs in medical journals, despite the large diffusion of instruments designed to help transparent reporting, such as the CONSORT.

The GRADE methodology is a tool to provide outcome-specific information concerning the overall quality of evidence from each included study in the comparison and the magnitude of effect of the interventions examined.

The overall confidence in the estimate of effect appeared to be ’very low’ for all of the main outcomes assessed.

This judgement reflects some issues of 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 studies) and
• ‘imprecision‘ (due to the low number of participants in each trial and wide confidence intervals).

In accordance with that, any estimate of effect 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.

Authors’ conclusions

Despite the impact of depression on people with cancer, available studies for the use if antidepressants were very few and of low quality. This review found very low quality evidence for the effects of these drugs compared with placebo.

On the basis of these results clear implications for practice cannot be made.

The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggests a positive safety profile for the SSRIs.

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.

In order to increase the evidence base on this compelling issue the Cochrane team argue that large, simple, randomised, pragmatic RCTs comparing commonly used antidepressants (SSRIs, serotonin- norepinephrine reuptake inhibitor (SNRIs), mirtazapine) versus placebo should be conducted in individuals with cancer and depressive symptoms, with or without a formal diagnosis of a depressive disorder.

I would also add that this should also be in comparison with integrated treatments, such as the DCPC. In real life, we seldom work in treatment silos and in my opinion research should be able to reflect this also.

Well, who’s to say what’s impossible…there’s no stopping curiosity.

Links

Primary paper

Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. (2015) Antidepressants for the treatment of depression in people with cancer. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD011006. DOI:10.1002/14651858.CD011006.pub2.

Other references

Lawson K. Depression and cancer: Lancet papers on prevalence and integrated collaborative care. The Mental Elf, 3 Nov 2014.

Akechi T, Okuyama T, Onishi J, Morita T, Furukawa TA. (2008) Psychotherapy for depression Among incurable cancer patients. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No .: CD005537. DOI: 10.1002 / 14651858.CD005537.pub2.

Galway K, Black A, Cantwell M, Cardwell CR, Mills M, Donnelly M. (2012) Psychosocial interventions to improve quality of life and emotional wellbeing for recently diagnosed cancer patients. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD007064. DOI: 10.1002/14651858.CD007064.pub2.