Psychological therapies for treatment-resistant depression in adults

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Antidepressants are a first-line treatment for adults with moderate to severe major depression. However, many people prescribed antidepressants for depression don't respond fully to such medication, and little evidence is available to inform the most appropriate 'next step' treatment for such patients, who may be referred to as having treatment-resistant depression (TRD). National Institute for Health and Care Excellence (NICE) guidance suggests that the 'next step' for those who do not respond to antidepressants may include a change in the dose or type of antidepressant medication, the addition of another medication, or the start of psychotherapy. Different types of psychotherapies may be used for TRD; evidence on these treatments is available but has not been collated to date.

Along with the sister review of pharmacological therapies for TRD, this review summarises available evidence for the effectiveness of psychotherapies for adults (18 to 74 years) with TRD with the goal of establishing the best 'next step' for this group.


To assess the effectiveness of psychotherapies for adults with TRD.

Search methods

We searched the Cochrane Common Mental Disorders Controlled Trials Register (until May 2016), along with CENTRAL, MEDLINE, Embase, and PsycINFO via OVID (until 16 May 2017). We also searched the World Health Organization (WHO) trials portal (ICTRP) and to identify unpublished and ongoing studies. There were no date or language restrictions.

Selection criteria

We included randomised controlled trials (RCTs) with participants aged 18 to 74 years diagnosed with unipolar depression that had not responded to minimum four weeks of antidepressant treatment at a recommended dose. We excluded studies of drug intolerance. Acceptable diagnoses of unipolar depression were based onthe Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria, or Research Diagnostic Criteria. We included the following comparisons.

1. Any psychological therapy versus antidepressant treatment alone, or another psychological therapy.

2. Any psychological therapy given in addition to antidepressant medication versus antidepressant treatment alone, or a psychological therapy alone.

Primary outcomes required were change in depressive symptoms and number of dropouts from study or treatment (as a measure of acceptability).

Data collection and analysis

We extracted data, assessed risk of bias in duplicate, and resolved disagreements through discussion or consultation with a third person. We conducted random-effects meta-analyses when appropriate. We summarised continuous outcomes using mean differences (MDs) or standardised mean differences (SMDs), and dichotomous outcomes using risk ratios (RRs).

Main results

We included six trials (n = 698; most participants were women approximately 40 years of age). All studies evaluated psychotherapy plus usual care (with antidepressants) versus usual care (with antidepressants). Three studies addressed the addition of cognitive-behavioural therapy (CBT) to usual care (n = 522), and one each evaluated intensive short-term dynamic psychotherapy (ISTDP) (n = 60), interpersonal therapy (IPT) (n = 34), or group dialectical behavioural therapy (DBT) (n = 19) as the intervention. Most studies were small (except one trial of CBT was large), and all studies were at high risk of detection bias for the main outcome of self-reported depressive symptoms.

A random-effects meta-analysis of five trials (n = 575) showed that psychotherapy given in addition to usual care (vs usual care alone) produced improvement in self-reported depressive symptoms (MD -4.07 points, 95% confidence interval (CI) -7.07 to -1.07 on the Beck Depression Inventory (BDI) scale) over the short term (up to six months). Effects were similar when data from all six studies were combined for self-reported depressive symptoms (SMD -0.40, 95% CI -0.65 to -0.14; n = 635). The quality of this evidence was moderate. Similar moderate-quality evidence of benefit was seen on the Patient Health Questionnaire-9 Scale (PHQ-9) from two studies (MD -4.66, 95% CI 8.72 to -0.59; n = 482) and on the Hamilton Depression Rating Scale (HAMD) from four studies (MD -3.28, 95% CI -5.71 to -0.85; n = 193).

High-quality evidence shows no differential dropout (a measure of acceptability) between intervention and comparator groups over the short term (RR 0.85, 95% CI 0.58 to 1.24; six studies; n = 698).

Moderate-quality evidence for remission from six studies (RR 1.92, 95% CI 1.46 to 2.52; n = 635) and low-quality evidence for response from four studies (RR 1.80, 95% CI 1.2 to 2.7; n = 556) indicate that psychotherapy was beneficial as an adjunct to usual care over the short term.

With the addition of CBT, low-quality evidence suggests lower depression scores on the BDI scale over the medium term (12 months) (RR -3.40, 95% CI -7.21 to 0.40; two studies; n = 475) and over the long term (46 months) (RR -1.90, 95% CI -3.22 to -0.58; one study; n = 248). Moderate-quality evidence for adjunctive CBT suggests no difference in acceptability (dropout) over the medium term (RR 0.98, 95% CI 0.66 to 1.47; two studies; n = 549) and lower dropout over long term (RR 0.80, 95% CI 0.66 to 0.97; one study; n = 248).

Two studies reported serious adverse events (one suicide, two hospitalisations, and two exacerbations of depression) in 4.2% of the total sample, which occurred only in the usual care group (no events in the intervention group).

An economic analysis (conducted as part of an included study) from the UK healthcare perspective (National Health Service (NHS)) revealed that adjunctive CBT was cost-effective over nearly four years.

Authors' conclusions

Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with TRD. Medium- and long-term effects seem similarly beneficial, although most evidence was derived from a single large trial. Psychotherapy added to usual care seems as acceptable as usual care alone.

Further evidence is needed on the effectiveness of different types of psychotherapies for patients with TRD. No evidence currently shows whether switching to a psychotherapy is more beneficial for this patient group than continuing an antidepressant medication regimen. Addressing this evidence gap is an important goal for researchers.

Plain language summary

Are psychological therapies effective in treating depression that did not get better with previous treatment?

Review question

Is psychological therapy an effective treatment for adults with treatment-resistant depression (TRD)?


Depression is a common problem often treated with antidepressant medication. However, many people do not get better with antidepressants. These patients may be said to have TRD. For these people, several different treatments can be tried - such as increasing the dose of medicine being taken, adding another medicine, or switching to a new one. Another option is to add or switch to a psychotherapy. Evidence indicates that psychotherapies can help in depression. What we don't know is whether psychotherapies work in people with TRD. This review aimed to answer this question.

Search date

Searches are current up to May 2017.

Study characteristics

We included six randomised trials (studies in which participants are allocated at random (by chance) to receive one of the treatments being compared). These trials included 698 people and tested three different types of psychotherapy. All studies looked at whether adding psychotherapy to current medical treatment leads to improvement in depression.

Study funding sources

All studies were funded by public research grants.

Key results

We found that patients who receive psychotherapy as well as usual care with antidepressants had fewer depressive symptoms and were more often depression-free six months later compared with patients who continued with usual care alone. We are moderately confident of these findings, which means that the true effect of adding CBT may be different from what we found, although findings are likely to be close. We also found that added psychotherapy was as acceptable to patients as usual care alone. Two studies noted similar beneficial effects after 12 months, and one study at 46 months.

Two studies reported harmful effects in people receiving usual care alone (one suicide, two people hospitalised) but none in people receiving psychotherapy in addition to usual care.

Quality of the evidence

Because participants were aware of the treatment they had received, and because we identified only a small number of studies, we graded the evidence as moderate in quality for findings at six months and low in quality for long-term results. This assessment might change in the future, if higher-quality research results become available.