While depression is a highly debilitating condition, there is evidence that psychotherapy, most notably cognitive behavioural therapy (CBT), can be an effective treatment option. However, while CBT remains the most studied psychotherapy for depression, other therapies have also been proven effective.

One such therapy is behavioural activation (BA), an easier to implement therapy that can also be applied by mental health workers with no professional psychotherapy training and hence is potentially cheaper and more accessible.

Given that the evidence for the comparative effectiveness of CBT and BA has been limited, Richards and colleagues designed and implemented a large comparative randomised controlled trial (RCT), recently published in The Lancet (Richards et al., 2016).

The COBRA trial was a large non-inferiority RCT with the goal of establishing the efficacy and cost-effectiveness of behavioural activation (BA) compared to cognitive behavioural therapy (CBT) for depression in adults.

In brief, in a non-inferiority trial, the objective is to prove that a new or less established intervention is not worse than another established one. Read this previous Mental Elf blog if you want more detail about the differences between a superiority trial and an equivalence or non-inferiority trial.

Methods

The authors conducted a two-arm multi-centre non-inferiority RCT. The trial was registered (ISRCTN27473954) and the study protocol was published beforehand (Rhodes et al., 2014).

Patients were recruited from primary care and psychological therapy services in three UK locations (Devon, Durham, Leeds) between September 2012 and April 2014. Patients could take part in the trial if they were adults meeting criteria for a major depressive disorder (MDD) as assessed with the Structured Clinical Interview (SCID) for DSM-IV.

Exclusion criteria

Patients already receiving psychological therapy, who had drug or alcohol dependence, were acutely suicidal or had attempted suicide in the previous 2 months were excluded. Also cognitive impairment, bipolar or psychotic symptoms were reasons for exclusion.

Manualised behavioural activation and CBT

Therapies were both manualised and delivered for a maximum of 20 1-hour face to face sessions over 16 weeks, with the option of four additional booster sessions if these were requested by patients. For both CBT and BA, the manuals specified that core components were delivered by session 8, which was considered to represent a minimally sufficient dose of therapy. While CBT was delivered by professional psychotherapists, specialised in CBT, BA was delivered by junior mental health workers, with no formal psychotherapy training. Both sets of therapists received 5 days training before embarking on the study.

Outcomes

The primary outcome measure was depression severity at 12 months, measured with the Patient Health Questionnaire-9 (PHQ-9).

Secondary outcome measures were depression severity at 6 and 12 months measured with the same instrument (PHQ-9), as well as DSM-IV diagnostic status for MDD and anxiety disorder, number of depression-free days between follow-ups, anxiety (measured with a self-report scale: The Generalized Anxiety Disorder 7), and health-related quality of life at 6, 12 and respectively 18 months.

Adverse effects were defined as deaths from whatever cause and all self-harm and suicide attempts.

Statistical analysis included both modified intent-to-treat/ (mITT; all participants included in random allocation with complete date) and per protocol analyses (PP; mITT participants that received at least 8 treatment sessions). As we explained previously, a major difference between non-inferiority and superiority trials is that for the former, per protocol and not ITT analyses are more conservative. Consequently, both should be reported and non-inferiority proven for both (Christensen, 2007).

For calculating the non-inferiority margin, the authors used a previous meta-analysis  comparing BA with treatment as usual (Ekers et al., 2008) and determined the non-inferiority margin as 1.9 PHQ-9 points. To conclude non-inferiority, the upper margin of the one-sided 97.5% CI (the maximum difference between groups within this 97.5% CI) had to be within the non-inferiority margin of -1.9 PHQ-9. Power calculations, using these parameters and allowing for a 20% attrition rate due to drop-outs and protocol violators, indicated a total of 440 participants would be needed.

Results

• 440 participants were randomised:
  • 221 to behavioural activation
  • 219 to CBT
• Adherence to treatment was similar in the two groups (8 sessions of therapy were completed by):
  • 147 patients (67%) in the BA group
  • 158 (72%) in the CBT group
• Out of these, numbers assessable in PP analysis were:
  • 135 patients for BA
  • 151 for CBT
• In both mITT and PP samples, BA was non-inferior to CBT. For the primary outcome measure (PHQ-9 scores at 12 months) the lower bound of the one-sided 97.5% CI was -1.3 for mITT analysis and, respectively, -1.5 for BA, in both cases exceeding the non-inferiority margin of -1.9
• No differences between BA and CBT were found on any of the secondary outcomes
• The results remained similar when sensitivity analyses were conducted with missing data imputed for primary and secondary outcomes at 12 months, though the proportion of missing data was significantly higher in the BA (21%) than in the CBT group (14%)
• The inference of non-inferiority also held across sensitivity analysis for the primary outcome at 12 months stratified by baseline depression severity, use of antidepressant medication or recruitment site for both mITT and PP populations.

• Adverse effects were two non-trial related deaths (1 in the BA and 1 in the CBT group) and 15 depression-related serious adverse effects (3 in the BA and 12 in CBT group)
• Economic analyses at 18 months found a significant difference in mean intervention costs between BA and CBT, but no differences in other categories of costs or in total cost.

Conclusions

The authors concluded that:

BA for depression is not inferior to CBT in terms of reduction of depression symptoms and is more cost-effective than is CBT against commonly applied decision maker willingness to pay thresholds.

Strengths and limitations

As the author note, a main strength of this trial is that it is adequately powered, being the largest trial of BA to date and one of the largest trials for psychological treatments for depression. It is also methodologically sound in aspects of design and implementation, with potential sources of bias minimised as much as possible, and transparently reported.

There are several important limitations:

• Most participants in both groups were also using antidepressants (around 80%). The authors argue most patients had been using antidepressants for a while before entering the trial, but the fact still remains that generalised antidepressant use could have contributed to levelling out differences between therapies.
• Patient with more serious depression related problems (like alcohol or drug dependence) or with acute suicide risk were excluded. This is also evident in the large number of patients that were deemed as non-eligible for the trial (312 after telephone screening and 222 after baseline interviews). As such, results may not be applicable in the population of more seriously depressed individuals, which is exactly where effective treatments are direly needed.
• Adherence to treatment was problematic and attrition was higher than what the authors anticipated. Roughly one third in both groups attended less than 8 therapy sessions, so both therapies seem equally ineffective for this sub-category.
• There is a referencing error in both the protocol and the article. The authors cite a previously published trial (Ekers et al., 2011) as basis for their calculations of the non-inferiority margin, when in fact they used a meta-analysis (Ekers et al., 2008). The problem that remains however is that this meta-analysis was based on 12 small under-powered studies (the largest trial had 43 participants per arm, half of the studies had less than 10), with moderate to high heterogeneity for depression outcomes and so the effect size estimation it produced are most likely unreliable. This also raises questions about the acceptability of the authors calculation of the non-inferiority margin.

Summary

The largest head to head trial so far found behavioural activation administered by junior mental health workers with no specific psychotherapy training as not inferior to CBT, suggesting it might be an effective alternative at least for a certain segment of the depressed population.

Conflict of interest

I collaborate on a number of professional projects with one of the authors of this paper (Hollon SD). However, I had no involvement whatsoever in the study described or in the paper.

Links

Primary paper

Richards DA, Ekers D, McMillan D, Taylor RS, Byford S, Warren FC, Barrett B, Farrand PA, Gilbody S, Kuyken W, O’Mahen H, Watkins ER, Wright KA, Hollon SD, Reed N, Rhodes S, Fletcher E, Finning K. (2016) Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial. Published Online: 22 July 2016 http://dx.doi.org/10.1016/S0140-6736(16)31140-0

Other references

Christensen E. (2007) Methodology of superiority vs. equivalence trials and non-inferiority trials. J. Hepatol. 46, 947–954. doi:10.1016/j.jhep.2007.02.015

Ekers D, Richards D, Gilbody S. (2008) A meta-analysis of randomized trials of behavioural treatment of depression. Psychol. Med. 38, 611–623. doi:10.1017/S0033291707001614

Ekers D, Richards D, McMillan D, Bland JM, Gilbody S. (2011) Behavioural activation delivered by the non-specialist: phase II randomised controlled trial. Br. J. Psychiatry J. Ment. Sci. 198, 66–72. doi:10.1192/bjp.bp.110.079111

Rhodes S, Richards DA, Ekers D, McMillan D, Byford S, Farrand PA, Gilbody S, Hollon SD, Kuyken W, Martell C, O’Mahen HA, O’Neill E, Reed N, Taylor RS, Watkins ER, Wright KA. (2014) Cost and outcome of behavioural activation versus cognitive behaviour therapy for depression (COBRA): study protocol for a randomised controlled trial. Trials 15, 29. doi:10.1186/1745-6215-15-29

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