Background About one-third of patients who are depressed do not respond to antidepressant medication (ADM) and traditional psychotherapy shows limited benefits. However, most randomised trials have excluded the most sick patients, especially with comorbid personality disorder. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting emotionally overcontrolled personality, which is common in refractory depression. Objective To evaluate the efficacy, cost-effectiveness and therapeutic mechanisms of RO DBT for patients with refractory depression. Design The Refractory depression: Mechanisms and Efficacy of RO DBT (RefraMED) trial was a multicentre, parallel-group, randomised trial in which participants were randomised to receive either RO DBT plus treatment as usual (TAU) or TAU alone. Participants were assessed at 7, 12 and 18 months after randomisation. Therapeutic mechanisms were explored in causal analyses. Setting Participants were recruited from three secondary care NHS organisations in the UK: Dorset, Hampshire and North Wales. Participants Patients were eligible if they were aged ≥ 18 years, had a Hamilton Rating Scale for Depression (HRSD) score of at least 15, had a current diagnosis of major depressive disorder in the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I, were suffering either refractory or chronic depression and, in their current episode, had taken an adequate dose of ADM for at least 6 weeks without relief. Patients who met criteria for dramatic-erratic personality disorder (Cluster B), bipolar disorder or psychosis or who had a primary diagnosis of substance dependence or abuse were excluded. Interventions The intervention, RO DBT, comprised 29 weekly individual sessions lasting 1 hour and 27 weekly skills classes lasting 2.5 hours. Participants allocated to TAU could access any treatment offered by the NHS or privately. Main outcome measures The reported HRSD score 12 months after randomisation and cost per quality-adjusted life-year (QALY). Results A total of 250 participants were allocated at random: 162 (65%) participants were randomised to RO DBT plus TAU and 88 (35%) were randomised to TAU. The difference between RO DBT and TAU in the primary outcome at 12 months was not statistically significant. Nevertheless, after 7 months, participants randomised to RO DBT had substantially, and significantly, reduced depressive symptoms, relative to TAU, by 5.40 HRSD points [standardised mean difference 1.03 points, 95% confidence interval (CI) 0.94 to 9.85 points; p = 0.02]. Thereafter, RO DBT remained the better treatment with net, but non-significant, reductions of 2.15 HRSD points (standardised mean difference 0.41 points, 95% CI –2.28 to 6.59 points; p = 0.29) after 12 months and 1.69 points (standardised mean difference 0.32 points, 95% CI –2.84 to 6.22 points; p = 0.42) after 18 months. Participants allocated to TAU could access any treatment offered by the NHS or privately. Participants randomised to RO DBT reported significantly better psychological flexibility and emotional coping than TAU participants; these differences increased over time. From the perspective of the NHS and personal social services, RO DBT was not cost-effective; the incremental cost-effectiveness ratio was £220,000 per QALY, which is considerably above the willingness-to-pay threshold of £30,000 set by the National Institute for Health and Care Excellence (NICE). RO DBT participants reported eight possible serious adverse reactions compared with none by TAU participants; however, we believe that this imbalance was a result of major differences in reporting opportunities. The Data Monitoring and Ethics Committee agreed that there was no reason to suspect that RO DBT was harmful. Conclusions Although RO DBT achieved the target effect size (Cohen’s d) with a d of 0.4 at the primary end point of 12 months, this was not significant. RO DBT was not cost-effective by NICE criteria. Nevertheless, RO DBT enhanced psychological flexibility and emotional coping, which are potential mechanisms of change. Limitations Analysing only 190 participants, instead of the target of 245, reduced the statistical power of the trial. Future work Future studies should aim to refine RO DBT, by maintaining clinical effectiveness while reducing costs, and to evaluate it for a wider range of overcontrolled disorders over a longer period. Trial registration Current controlled trials ISRCTN85784627. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 5, No. 7. See the NIHR Journals Library website for further project information.



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