Drug or psychological interventions for preventing depression in people with long-term physical conditions

Why is this review important?

People with long-term illness or other physical health conditions have a higher risk than other people of developing depression. This can reduce their quality of life. Depression is characterised by symptoms such as low mood, feelings of hopelessness, loss of interest in things that once gave pleasure, and other symptoms, as well as sleep disturbances. People with long-term physical conditions who develop depression are more likely to worsen in their illnesses and are more likely to die. Therefore, preventing depression in people with long-term physical conditions should be an important goal in healthcare.

What questions does this review aim to answer?

We wanted to know whether standard interventions for treating depression (i.e. psychological treatments and antidepressant drugs) can also safely be used to prevent the onset of an depressive episode in those adults at high risk for depression due to their long-term physical condition, but who do not yet show depressive symptoms. We also wanted to know whether these interventions worked in preventing recurrent depression, in those patients with long-term physical conditions who had a history of depression.

How did we identify and evaluate the evidence?

First, we searched the medical literature for randomised controlled studies (clinical studies where people are randomly put into one of two or more treatment groups). This type of study provides the most robust evidence about the effects of a treatment. We then compared the results, and summarised the evidence from all the studies. Finally, we assessed how certain the evidence was. To do this, we considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we categorised the evidence as being of very low, low, moderate or high certainty.

Who will be interested in this review?

Medical and mental health care providers (including physicians and psychologists) and pharmacists, as well as adults with long-term physical conditions, their relatives and care-givers.

Which studies were included in the review?

This review includes 11 trials comparing a psychological intervention (problem-solving therapy) to treatment as usual; or comparing pharmacological antidepressant interventions (citalopram, escitalopram, sertraline, fluoxetine/nortriptyline, milnacipran, or melatonin) to placebo. For the psychological intervention, we found only one trial, including 194 people with age-related macular degeneration (an eye disease). For pharmacological interventions, we included 10 trials comprising 1009 people. Due to some participants not completing the studies, we could only analyse data for 837 participants.

What does the evidence from the review tell us?

Our analyses show that people with long-term physical conditions may be less likely to develop depression during treatment with problem solving therapy, or with different types of antidepressants. However, these interventions appear to be beneficial only during treatment. Three to 12 months after treatment, there was no significant difference in onset of depression between the groups that had the interventions and those that did not. Therefore, preventive interventions might be effective in preventing depression onset only for the duration of the intervention. Our conclusions are based on evidence of very low certainty. In addition, there is not enough adequate information on the tolerability (unpleasant but generally medically less important adverse events due to the intervention, e.g. dry mouth) and acceptability (willingness to go through with the intervention even in the presence of adverse events) of these treatments. The interventions may be unsafe, irrespective of their potential to prevent depression.

How-up-to date is this review?

The evidence in this Cochrane Review is current to 6 February 2020.

Authors' conclusions: 

Based on evidence of very low certainty, our results may indicate the benefit of pharmacological interventions, during or directly after preventive treatment. Few trials examined short-term outcomes up to six months, nor the follow-up effects at six to 12 months, with studies suffering from great numbers of drop-outs and inconclusive results. Generalisation of results is limited as study populations and treatment regimes were very heterogeneous.

Based on the results of this review, we conclude that for adults with long-term physical conditions, there is only very uncertain evidence regarding the implementation of any primary preventive interventions (psychological/pharmacological) for depression.

Read the full abstract...

Major depression is one of the world’s leading causes of disability in adults with long-term physical conditions compared to those without physical illness. This co-morbidity is associated with a negative prognosis in terms of increased morbidity and mortality rates, increased healthcare costs, decreased adherence to treatment regimens, and a substantial decline in quality of life. Therefore, preventing the onset of depressive episodes in adults with long-term physical conditions should be a global healthcare aim.

In this review, primary or tertiary (in cases of preventing recurrences in those with a history of depression) prevention are the focus. While primary prevention aims at preventing the onset of depression, tertiary prevention comprises both preventing recurrences and prohibiting relapses. Tertiary prevention aims to address a depressive episode that might still be present, is about to subside, or has recently resolved. We included tertiary prevention in the case where the focus was preventing the onset of depression in those with a history of depression (preventing recurrences) but excluded it if it specifically focused on maintaining an condition or implementing rehabilitation services (relapse prevention). Secondary prevention of depression seeks to prevent the progression of depressive symptoms by early detection and treatment and may therefore be considered a 'treatment,' rather than prevention. We therefore exclude the whole spectrum of secondary prevention.


To assess the effectiveness, acceptability and tolerability of psychological or pharmacological interventions, in comparison to control conditions, in preventing depression in adults with long-term physical conditions; either before first ever onset of depressive symptoms (i.e. primary prevention) or before first onset of depressive symptoms in patients with a history of depression (i.e. tertiary prevention).

Search strategy: 

We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO and two trials registries, up to 6 February 2020.

Selection criteria: 

We included randomised controlled trials (RCTs) of preventive psychological or pharmacological interventions, specifically targeting incidence of depression in comparison to treatment as usual (TAU), waiting list, attention/psychological placebo, or placebo. Participants had to be age 18 years or older, with at least one long-term physical condition, and no diagnosis of major depression at baseline (primary prevention). In addition, we included studies comprising mixed samples of patients with and without a history of depression, which explored tertiary prevention of recurrent depression. We excluded other tertiary prevention studies. We also excluded secondary preventive interventions. Primary outcomes included incidence of depression, tolerability, and acceptability. Secondary outcomes included severity of depression, cost-effectiveness and cost-utility.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included 11 RCTs, with one trial on psychological interventions, and 10 trials on pharmacological interventions. Data analyses on the psychological intervention (problem-solving therapy compared to TAU) included 194 participants with age-related macular degeneration.

Data analyses on pharmacological interventions included 837 participants comparing citalopram (one trial), escitalopram (three trials), a mixed sample of fluoxetine/nortriptyline (one trial), melatonin (one trial), milnacipran (one trial), and sertraline (three trials), each to placebo. Included types of long-term physical conditions were acute coronary syndrome (one trial), breast cancer (one trial), head and neck cancer (two trials), stroke (five trials), and traumatic brain injury (one trial).

Psychological interventions

Very low-certainty evidence of one study suggests that problem solving therapy may be slightly more effective than TAU in preventing the incidence of depression, immediately post-intervention (odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20 to 0.95; 194 participants). However, there may be little to no difference between groups at six months follow-up (OR 0.71, 95% CI 0.36 to 1.38; 190 participants; one study; very low-certainty evidence). No data were available regarding incidence of depression after six months. Regarding acceptability (drop-outs due to any cause), slightly fewer drop-outs occurred in the TAU group immediately post-intervention (OR 5.21, 95% CI 1.11 to 24.40; 206 participants; low-certainty evidence). After six months, however, the groups did not differ (OR 1.67, 95% CI 0.58 to 4.77; 206 participants; low-certainty evidence). This study did not measure tolerability.

Pharmacological interventions

Post-intervention, compared to placebo, antidepressants may be beneficial in preventing depression in adults with different types of long-term physical conditions, but the evidence is very uncertain (OR 0.31, 95% CI 0.20 to 0.49; 814 participants; nine studies; I2 =0%; very low-certainty evidence). There may be little to no difference between groups both immediately and at six months follow-up (OR 0.44, 95% CI 0.08 to 2.46; 23 participants; one study; very low-certainty evidence) as well as at six to 12 months follow-up (OR 0.81, 95% CI 0.23 to 2.82; 233 participants; three studies; I2 = 49%; very low-certainty evidence). There was very low-certainty evidence from five studies regarding the tolerability of the pharmacological intervention. A total of 669 adverse events were observed in 316 participants from the pharmacological intervention group, and 610 adverse events from 311 participants in the placebo group. There was very low-certainty evidence that drop-outs due to adverse events may be less frequent in the placebo group (OR 2.05, 95% CI 1.07 to 3.89; 561 participants; five studies; I2 = 0%). There was also very low-certainty evidence that drop-outs due to any cause may not differ between groups either post-intervention (OR 1.13, 95% CI 0.73 to 1.73; 962 participants; nine studies; I2 = 28%), or at six to 12 months (OR 1.13, 95% CI 0.69 to 1.86; 327 participants; three studies; I2 = 0%).