Mindfulness-based interventions are moving more and more into the spotlight and we have been covering them extensively on the Mental Elf (for example, see our 2015 Mental Health Awareness Week blog for a review of the evidence).

Relapse prevention in depression appears to be one of the areas where mindfulness interventions, more precisely mindfulness-based cognitive therapy (MBCT), are particularly effective. In fact, a year ago we covered one of the largest randomised controlled trials (RCTs) comparing MBCT accompanied by support to taper or discontinue antidepressant medication (MBCT-TS) with maintenance antidepressants (mADM) for relapse prevention in depression – the PREVENT trial (Kuyken et al., 2015). The PREVENT trial found no differences between the two arms for time to relapse or recurrence of depression over 24 months.

However, a new large trial recently published in the British Journal of Psychiatry (BJP) casts a fresh view on this issue. Huijbers and co-authors (2016) set to investigate whether MBCT accompanied by discontinuation of antidepressant medication was non-inferior to MBCT plus mADM.

Before we move on to discussing the actual study, it is important we clarify the difference between a superiority trial and an equivalence trial or a non-inferiority trial. In the former, the objective is to determine a clinically relevant difference between two interventions. In this sense, the PREVENT study was a superiority trial because the authors set out to show that MBCT-TS would fare better than mADM for preventing relapse in depression. Conversely, in an equivalence or non-inferiority trial, the objective is to prove that a new intervention is neither worse nor better (equivalence) or simply non-inferior (non-inferiority) than another established intervention. This distinction is not just academic, but it involves important implications about how data are analyzed and interpreted.

Methods

The authors conducted a multi-centre non-inferiority RCT with the hypothesis that MBCT with discontinuation of mADM would be non-inferior, in other words would not lead to an unacceptably higher risk of relapse and recurrence, compared to the combination of MBCT and mADM.

The study protocol was registered beforehand (ClinicalTrials.gov: NCT00928980). Initially, the authors intended to conduct a three arm trial of MBCT alone, mADM alone and their combination. However, since this proved too difficult because of patients’ strong treatment preferences for mindfulness, the authors conducted two parallel trials. One was the non-inferiority trial published in the BJP and covered here. The other, reported elsewhere, was a superiority trial comparing MBCT+mADM versus mADM for patients who did not want to give up their medication (Huijbers et al., 2015).

Patients were recruited in 12 secondary and tertiary psychiatric outpatient clinics across the Netherlands between September 2009 and January 2012. Patients could take part in the trial if they were Dutch speaking adults with a history of at least three depressive episodes according to the DSM IV,  in partial or full remission (i.e., not currently meeting criteria for MDD), and currently treated with antidepressants for at least 6 months. Individuals with bipolar, psychotic or current alcohol and drug dependency were excluded, as were individuals undergoing recent electroconvulsive therapy, who had previous MBCT or extensive mindfulness practice or who were in psychological treatment more frequent than once every 3 weeks.

Outcome measures

• The primary outcome measure was relapse/recurrence as measured with the Structured Clinical Interview for the DSM-IV (SCID-I) by non-blinded trained research assistants at a frequency of 3 months during the 15 months follow-up period.
• Secondary outcome measures were:
  • Time to relapse/recurrence (calculated in weeks from the start of the study until the start of the first relapse),
  • Severity of residual depressive symptoms (measured with the Inventory of Depressive Symptomatology- Clinician Rated)
  • Quality of life.

Statistical analysis included both intent-to-treat/ (ITT; all randomised participants) and per protocol analyses (PP; only adherent participants defined as having attended four or more MBCT sessions). A major difference between non-inferiority and superiority trials is that for the former, per protocol analyses are more conservative, while for the latter, ITT analyses are more stringent. Consequently, it is recommended both are reported and non-inferiority is proven for both (Christensen, 2007). The authors calculated the one-sided 95% confidence interval (CI) of the difference in relapse/recurrence rates between the two groups. To conclude non-inferiority, the upper margin of the 95% CI (the maximum difference between groups within this 95% CI) should not exceed the non-inferiority margin of 25%.

Results

• 249 participants were randomised (128 to MBCT with discontinuation of mADM and 121 to MBCT+mADM)
• Adherence to MBCT was significantly higher (χ²= 6.26, p=0.01) in the MBCT + discontinuation (91%) than in the MBCT + mADM (79%)
• In the ITT sample, 54% of the participants in the MBCT + discontinuation group and 39% of the ones in the MBCT + mADM group experienced relapse during the 15 months follow-up. The upper margin of the one-sided 95% CI of the difference between groups was 3%, exceeding the non-inferiority margin of 25%.
• In the PP sample, 69% of participants randomised to the MBCT + discontinuation compared to 46% of the MBCT + mADM group relapsed. The upper margin of the one-sided 95% CI was 7%, which also exceeded the 25% non-inferiority margin.

• MBCT + discontinuation was associated with increased relapse/recurrence risk over the 15 month follow-up in both ITT (hazard ratio/HR=1.59, p=0.01) and PP analyses (HR=1.59, p=0.05)
• Severity of depressive symptoms did not differ between the two groups at 15 months follow-up, but the participants in the MBCT + discontinuation group had higher levels of depression than those in the MBCT + mADM at 3 months follow-up (p=0.02).

Conclusions

The authors concluded that:

The findings of this effectiveness study reflect an increased risk of relapse/recurrence for patients withdrawing from mADM after having participated in MBCT for recurrent depression.

They also speculated that the discrepancy between the results of this trial and PREVENT might be explained by the fact that in the latter the withdrawal process was part of the MBCT intervention in a more controlled way (i.e., at the same time for all participants) than in the current trial where mindfulness groups were mixed, so there may have been more support to use mindfulness skills to accept the symptoms accompanying discontinuation of medication.

Strengths and limitations

The main strengths of this trial include the fact that it was adequately powered, methodologically solid in terms of design, implementation and data analysis, as well as transparently reported. It was also delivered in a real-world setting, thus enhancing the practical relevance of its results.

One major limitation involves the lack of blinding of outcome assessors.

Summary

MBCT is not yet ready to replace maintenance antidepressant medication for relapse prevention in depression, at least not in real-life settings, which are really the ones that count.

Links

Primary paper

Huijbers MJ, Spinhoven P, Spijker J, Ruhé HG, Schaik DJF van, Oppen P van, Nolen WA, Ormel J, Kuyken W, Wilt GJ van der, Blom MBJ, Schene AH, Donders ART, Speckens AEM. (2016) Discontinuation of antidepressant medication after mindfulness-based cognitive therapy for recurrent depression: randomised controlled non-inferiority trial. The British Journal of Psychiatry Feb 2016, DOI: 10.1192/bjp.bp.115.168971 [Abstract]

Other papers

Christensen E. (2007) Methodology of superiority vs. equivalence trials and non-inferiority trials. J. Hepatol. 46, 947–954.

Huijbers MJ, Spinhoven P, Spijker J, Ruhé HG, Schaik DJF van, Oppen P van, Nolen WA, Ormel J, Kuyken W, Wilt GJ van der, Blom MBJ, Schene AH, Donders ART, Speckens AEM. (2015) Adding mindfulness-based cognitive therapy to maintenance antidepressant medication for prevention of relapse/recurrence in major depressive disorder: Randomised controlled trial. J. Affect. Disord. 187, 54–61. [PubMed abstract]

Kuyken W. et al (2015) Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial. The Lancet, published online 21 Apr 2015.

Tomlin A. (2015) Mindfulness-based cognitive therapy to prevent depression. The Mental Elf, 21 Apr 2015.

Tomlin A. (2015) The evidence for mindfulness: Mental Health Awareness Week #mhaw15. The Mental Elf, 11 May 2015.

Photo credits

• James West CC BY 2.0
• Jack Ricchiuto CC BY 2.0
• Rachael Parun CC BY 2.0
• Stewart Black CC BY 2.0