Long-term treatment for people with persistent depression

Why is this review important?

Depressive disorders that persist for at least two years cause considerable problems. Even after successful treatment, they frequently recur. Common treatments are antidepressant medicines and psychological treatments (talking therapies), or a combination of both. Long-term treatments should prevent the recurrence of depressive symptoms.

Who will be interested in this review?

- People with persisting depression (longer than two years), friends, families, and carers.

- General practitioners, psychiatrists, clinical psychologists, psychological therapists, and pharmacists.

What questions does this review aim to answer?

In adults with persistent depression who improved with acute (short-term) treatment:

- Is receiving continued antidepressant medicine, psychological treatment, or a combination of both more effective in preventing recurrence of depression compared to placebo (a pretended treatment) or care as usual?

- Is receiving continued antidepressant medicine, psychological treatment, or a combination of both equally accepted as receiving placebo or usual care?

- Is one treatment more effective or more accepted than another?

Which studies does the review include?

We searched medical databases and other sources to find all relevant studies completed up to September 2018. The studies had to compare antidepressant treatment, psychological treatment, or a combination of both, with each other, with placebo, or with care as usual for preventing recurrence of depression in adults diagnosed with persistent depression. We included 10 studies involving 840 participants. Five studies compared antidepressant medicine with placebo.

One study compared psychological therapies versus attention placebo/non-specific control. One study compared psychotherapy with medication. Three studies compared combined psychological and pharmacological therapies with pharmacological therapies alone. One study compared combined psychological and pharmacological therapies with psychotherapeutic therapies alone.

Two studies compared two different antidepressants with each other.

Overall, the included studies were at low-to-moderate risk of bias.

What does the evidence from the review tell us?

According to GRADE, there was moderate quality evidence that participants taking medication treatment probably had less relapses/recurrences and may have lower dropouts than those taking placebo. The risk of depression returning in participants receiving a placebo (instead of antidepressant medicine) was 34%. In comparison, participants who remained on antidepressant medicines had a lower risk for recurrence of 13%. The continued treatment lasted between four months and two years. Antidepressant were as well accepted as placebo. However, as most of the included studies showed risk of bias and there were some inconsistent results between the different studies, it cannot be concluded with certainty whether continued or maintained pharmacotherapy (or both) is a convincing treatment for people with PDD. Additionally, as studies on the long-term effects of medication are lacking, recommendations on the necessary duration of medication treatment cannot be drawn.

The benefits of psychological therapies or combined treatment remained unclear, due to the small number of studies.

What should happen next?

This review cannot provide clear, certain evidence regarding whether continued antidepressant medication (compared to placebo tablet) reduces the risk of depression recurring in adults with persistent depression. However, only a few studies have been done. Further studies should especially address psychological and combined long-term treatments.

Authors' conclusions: 

Currently, it is uncertain whether continued or maintained pharmacotherapy (or both) with the reviewed antidepressant agents is a robust treatment for preventing relapse and recurrence in people with PDD, due to moderate or high risk of bias as well as clinical heterogeneity in the analyzed studies.

For all other comparisons, the body of evidence was too small to draw any final conclusions, although continued or maintained psychotherapy might be effective compared to no treatment. There is need for more high quality trials of psychological interventions. Further studies should address health-related quality of life and adverse events more precisely, as well as assessing follow-up data.

Read the full abstract...
Background: 

Persistent depressive disorder (PDD) is defined as a depressive disorder with a minimum illness duration of two years, including four diagnostic subgroups (dysthymia, chronic major depression, recurrent major depression with incomplete remission between episodes, and double depression). Persistent forms of depression represent a substantial proportion of depressive disorders, with a lifetime prevalence ranging from 3% to 6% in the Western world. Growing evidence indicates that PDD responds well to several acute interventions, such as combined psychological and pharmacological treatments. Yet, given the high rates of relapse and recurrences of depression following response to acute treatment, long-term continuation and maintenance therapy are of great importance. To date, there has been no evidence synthesis available on continuation and maintenance treatments of PDDs.

Objectives: 

To assess the effects of pharmacological and psychological (either alone or combined) continuation and maintenance treatments for persistent depressive disorder, in comparison with each other, placebo (drug/attention placebo/non-specific treatment control), and treatment as usual (TAU). Continuation treatments are defined as treatments given to currently remitted people (remission is defined as depressive symptoms dropping below case level) or to people who previously responded to an antidepressant treatment. Maintenance therapy is given during recovery (which is defined as remission lasting longer than six months).

Search strategy: 

We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 28 September 2018. An earlier search of these databases was also conducted for RCTs via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 Dec 2015). In addition we searched grey literature resources as well as the international trial registers ClinicalTrials.gov and ICTRP to 28 September 2018. We screened reference lists of included studies and contacted the first author of all included studies.

Selection criteria: 

We included randomized (RCTs) and non-randomized controlled trials (NRCTs) in adults with formally diagnosed PDD, receiving pharmacological, psychological, or combined continuation and maintenance interventions.

Data collection and analysis: 

Two review authors independently selected studies and extracted and analyzed data. The primary efficacy outcome was relapse/recurrence rate of depression. The primary acceptance outcome was dropout due to any reason other than relapse/recurrence. We performed random-effects meta-analyses using risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).

Main results: 

We included 10 studies (seven RCTs, three NRCTs) involving 840 participants in this review, from which five studies investigated continuation treatments and five studies investigated maintenance treatments. Overall, the included studies were at low-to-moderate risk of bias. For the three NRCTs, the most common source of risk of bias was selection of reported results. For the seven RCTs, the most common sources of risk of bias was non-blinding of outcome assessment and other bias (especially conflict of interest due to pharmaceutical sponsoring).

Pharmacological continuation and maintenance therapies

The most common comparison was antidepressant medication versus tablet placebo (five studies). Participants taking antidepressant medication were probably less likely to relapse or to experience a recurrent episode compared to participants in the placebo group at the end of the intervention (13.9% versus 33.8%, RR 0.41, 95% CI 0.21 to 0.79; participants = 383; studies = 4; I² = 54%, moderate quality evidence). Overall dropout rates may be similar between participants in the medication and placebo group (23.0% versus 25.5%, RR 0.90, 95% CI 0.39 to 2.11; RCTs = 4; participants = 386; I² = 64%, low quality evidence). However, sensitivity analyses showed that the primary outcome (rate of relapse/recurrence) showed no evidence of a difference between groups when only including studies with low risk of bias.

None of the studies compared pharmacological or psychological treatments versus TAU.

Psychological continuation and maintenance therapies

One study compared psychological therapies versus attention placebo/non-specific control. One study compared psychotherapy with medication. The results of the studies including psychotherapy might indicate that continued or maintained psychotherapy could be a useful intervention compared to no treatment or antidepressant medication. However, the body of evidence for these comparisons was too small and uncertain to draw any high quality conclusions.

Combined psychological and pharmacological continuation and maintenance therapies

Three studies compared combined psychological and pharmacological therapies with pharmacological therapies alone. One study compared combined psychological and pharmacological therapies with psychotherapeutic therapies alone. However, the body of evidence for these comparisons was too small and uncertain to draw any high quality conclusions

Comparison of different antidepressant medications

Two studies reported data on the direct comparison of two antidepressants. However, the body of evidence for this comparison was too small and uncertain to draw any high quality conclusions.

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