- A well-designed recent study found that patients with depression in remission who switch from maintenance antidepressants to mindfulness meditation without continuing medication had an increase in relapses.
- The study is better designed and more transparently reported than a recent British study, but will get none of the British study’s attention.
- The well-orchestrated promotion of mindfulness raises issues about the lack of checks and balances between investigators’ vested interest, supposedly independent evaluation, and the making of policy.
Huijbers MJ, Spinhoven P, Spijker J, Ruhé HG, van Schaik DJ, van Oppen P, Nolen WA, Ormel J, Kuyken W, van der Wilt GJ, Blom MB. Discontinuation of antidepressant medication after mindfulness-based cognitive therapy for recurrent depression: randomised controlled non-inferiority trial. The British Journal of Psychiatry. 2016 Feb 18:bjp-p.
The study is currently behind a pay wall and does not appear to have a press release. These two factors will not contribute to it getting the attention it deserves.
But the protocol for the study is available here.
Huijbers MJ, Spijker J, Donders AR, van Schaik DJ, van Oppen P, Ruhé HG, Blom MB, Nolen WA, Ormel J, van der Wilt GJ, Kuyken W. Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: trial design and protocol of the MOMENT study. BMC Psychiatry. 2012 Aug 27;12(1):1.
And the trial registration is here
Mindfulness Based Cognitive Therapy and Antidepressant Medication in Recurrent Depression. ClinicalTrials.gov: NCT00928980
Mindfulness-based cognitive therapy (MBCT) and maintenance antidepressant medication (mADM) both reduce the risk of relapse in recurrent depression, but their combination has not been studied.
To investigate whether MBCT with discontinuation of mADM is non-inferior to MBCT+mADM.
A multicentre randomised controlled non-inferiority trial (ClinicalTrials.gov: NCT00928980). Adults with recurrent depression in remission, using mADM for 6 months or longer (n = 249), were randomly allocated to either discontinue (n = 128) or continue (n = 121) mADM after MBCT. The primary outcome was depressive relapse/recurrence within 15 months. A confidence interval approach with a margin of 25% was used to test non-inferiority. Key secondary outcomes were time to relapse/recurrence and depression severity.
The difference in relapse/recurrence rates exceeded the non-inferiority margin and time to relapse/recurrence was significantly shorter after discontinuation of mADM. There were only minor differences in depression severity.
Our findings suggest an increased risk of relapse/recurrence in patients withdrawing from mADM after MBCT.
A comment by Deborah Apthorp suggested that the original title Switching from antidepressants to mindfulness meditation increases relapse was incorrect. Checking it I realized that the abstract provides the article was Confusing, but the study did indded show that mindfulness alone led to more relapses and continued medication plus mindfulness.
Here is what is said in the actual introduction to the article:
The main aim of this multicentre, noninferiority effectiveness trial was to examine whether patients who receive MBCT for recurrent depression in remission could safely withdraw from mADM, i.e. without increased relapse/recurrence risk, compared with the combination of these interventions. Patients were randomly allocated to MBCT followed by discontinuation of mADM or MBCT+mADM. The study had a follow-up of 15 months. Our primary hypothesis was that discontinuing mADM after MBCT would be non-inferior, i.e. would not lead to an unacceptably higher risk of relapse/ recurrence, compared with the combination of MBCT+mADM.
Here is what is said in the discussion:
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.
So, to be clear, the sequence was that patients were randomized either to MBCT without antidepressant or to MBCT with continuing antidepressants. Patients were then followed up for 15 months. Patients who received MBCT without the antidepressants have significantly more relapses/recurrences In the follow-up period than those who received MBCT with antidepressants.
The study addresses the question about whether patients with remitted depression on maintenance antidepressants who were randomized to receive mindfulness-based cognitive therapy (MBCT) have poorer outcomes than those randomized to remaining on their antidepressants.
The study found that poorer outcomes – more relapses – were experienced by patients switching to MBCT verses those remaining on antidepressants plus MBCT.
Strengths of the study
The patients were carefully assessed with validated semi structured interviews to verify they had recurrent past depression, were in current remission, and were taking their antidepressants. Assessment has an advantage over past studies that depended on less reliable primary-care physicians’ records to ascertain eligibility. There’s ample evidence that primary-care physicians often do not make systematic assessments deciding whether or not to preparation on antidepressants.
The control group. The comparison/control group continued on antidepressants after they were assessed by a psychiatrist who made specific recommendations.
Power analysis. Calculation of sample size for this study was based on a noninferiority design. That meant that the investigators wanted to establish that within particular limit (25%), whether switching to MBCT produce poor outcomes.
A conventional clinical trial is designed to see if the the null hypothesis can rejected of no differences between intervention and control group. As an noninferiority trial, this study tested the null hypothesis that the intervention, shifting patients to MBCT would not result in an unacceptable rise, set at 25% more relapses and recurrences. Noninferiority trials are explained here.
Change in plans for the study
The protocol for the study originally proposed a more complex design. Patients would be randomized to one of three conditions: (1) continuing antidepressants alone; (2) continuing antidepressants, but with MBCT; or (3) MBCT alone. The problem the investigators encountered was that many patients had a strong preference and did not want to be randomized. So, they conducted two separate randomized trials.
This change in plans was appropriately noted in a modification in the trial registration.
The companion study examined whether adding MBCT to maintenance antidepressants reduce relapses. The study was published first:
Huijbers MJ, Spinhoven P, Spijker J, Ruhé HG, van Schaik DJ, van Oppen P, Nolen WA, Ormel J, Kuyken W, van der Wilt GJ, Blom MB. Adding mindfulness-based cognitive therapy to maintenance antidepressant medication for prevention of relapse/recurrence in major depressive disorder: Randomised controlled trial. Journal of Affective Disorders. 2015 Nov 15;187:54-61.
A copy can be obtained from this depository.
It was a smaller study – 35 patients randomized to MBCT alone and 33 patients randomized to a combination of MBCT and continued antidepressants. There were no differences in relapse/recurrence in 15 months.
An important limitation on generalizability
The patients were recruited from university-based mental health settings. The minority of patients who move from treatment of depression in primary care to a specially mental health settings proportionately include more with moderate to severe depression and with a more defined history of past depression. In contrast, the patients being treated for depression in primary care include more who were mild to moderate and whose current depression and past history have not been systematically assessed. There is evidence that primary-care physicians do not make diagnoses of depression based on a structured assessment. Many patients deemed depressed and in need of treatment will have milder depression and only meet the vaguer, less validated diagnosis of Depression Not Otherwise Specified.
Declaration of interest
The authors indicated no conflicts of interest to declare for either study.
Added February 29: This may be a true statement for the core Dutch researchers who led in conducted the study. However, it is certainly not true for the British collaborator who may have served as a consultant and got authorship as result. He has extensive conflicts of interest and gains a lot personally and professionally from promotion of mindfulness in the UK. Read on.
The previous British study in The Lancet
Kuyken W, Hayes R, Barrett B, Byng R, Dalgleish T, Kessler D, Lewis G, Watkins E, Brejcha C, Cardy J, Causley A. 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. 2015 Jul 10;386(9988):63-73.
I provided my extended critique of this study in a previous blog post:
The study protocol claimed it was designed as a superiority trial, but the authors did not provide the added sample size needed to demonstrate superiority. And they spun null findings, starting in their abstract:
However, when considered in the context of the totality of randomised controlled data, we found evidence from this trial to support MBCT-TS as an alternative to maintenance antidepressants for prevention of depressive relapse or recurrence at similar costs.
What is wrong here? They are discussing null findings as if they had conducted a noninferiority trial with sufficient power to show that differences of a particular size could be ruled out. Lots of psychotherapy trials are underpowered, but should not be used to declare treatments can be substituted for each other.
Contrasting features of the previous study versus the present one
Spinning of null findings. According to the trial registration, the previous study was designed to show that MBCT was superior to maintenance antidepressant treatment and preventing relapse and recurrence. A superiority trial tests the hypothesis that an intervention is better than a control group by a pre-set margin. For a very cool slideshow comparing superiority to noninferiority trials, see here .
Rather than demonstrating that MBCT was superior to routine care with maintenance antidepressant treatment, The Lancet study failed to find significant differences between the two conditions. In an amazing feat of spin, the authors took to publicizing this has a success that MBCT was equivalent to maintenance antidepressants. Equivalence is a stricter criterion that requires more than null findings – that any differences be within pre-set (registered) margins. Many null findings represent low power to find significant differences, not equivalence.
Patient selection. Patients were recruited from primary care on the basis of records indicating they had been prescribed antidepressants two years ago. There was no ascertainment of whether the patients were currently adhering to the antidepressants or whether they were getting effective monitoring with feedback.
Poorly matched, nonequivalent comparison/control group. The guidelines that patients with recurrent depression should remain on antidepressants for two years when developed based on studies in tertiary care. It’s likely that many of these patients were never systematically assessed for the appropriateness of treatment with antidepressants, follow-up was spotty, and many patients were not even continuing to take their antidepressants with any regularit
So, MBCT was being compared to an ill-defined, unknown condition in which some proportion of patients do not need to be taken antidepressants and were not taking them. This routine care also lack the intensity, positive expectations, attention and support of the MBCT condition. If an advantage for MBCT had been found – and it was not – it might only a matter that there was nothing specific about MBCT, but only the benefits of providing nonspecific conditions that were lacking in routine care.
The unknowns. There was no assessment of whether the patients actually practiced MBCT, and so there was further doubt that anything specific to MBCT was relevant. But then again, in the absence of any differences between groups, we may not have anything to explain.
- Given we don’t know what proportion of patients were taking an adequate maintenance doses of antidepressants, we don’t know whether anything further treatment was needed for them – Or for what proportion.
- We don’t know whether it would have been more cost-effective simply to have a depression care manager recontact patients recontact patients, and determine whether they were still taking their antidepressants and whether they were interested in a supervised tapering.
- We’re not even given the answer of the extent to which primary care patients provided with an MBCT actually practiced.
A well orchestrated publicity campaign to misrepresent the findings. Rather than offering an independent critical evaluation of The Lancet study, press coverage offered the investigators’ preferred spin. As I noted in a previous blog
The headline of a Guardian column written by one of the Lancet article’s first author’s colleagues at Oxford misleadingly proclaimed that the study showed
And that misrepresentation was echoed in the Mental Health Foundation call for mindfulness to be offered through the UK National Health Service –
The Mental Health Foundation is offering a 10-session online course for £60 and is undoubtedly prepared for an expanded market
Declaration of interests
WK [the first author] and AE are co-directors of the Mindfulness Network Community Interest Company and teach nationally and internationally on MBCT. The other authors declare no competing interests.
Like most declarations of conflicts of interest, this one alerts us to something we might be concerned about but does not adequately inform us.
We are not told, for instance, something the authors were likely to know: Soon after all the hoopla about the study, The Oxford Mindfulness Centre, which is directed by the first author, but not mentioned in the declaration of interest publicize a massive effort by the Wellcome Trust to roll out its massive Mindfulness in the Schools project that provides mindfulness training to children, teachers, and parents.
A recent headline in the Times: US & America says it all.
A Confirmation bias in subsequent citing
It is generally understood that much of what we read in the scientific literature is false or exaggerated due to various Questionable Research Practices (QRP) leading to confirmation bias in what is reported in the literature. But there is another kind of confirmation bias associated with the creation of false authority through citation distortion. It’s well-documented that proponents of a particular view selectively cite papers in terms of whether the conclusions support of their position. Not only are positive findings claimed original reports exaggerated as they progress through citations, negative findings receie less attention or are simply lost.
Huijbers et al.transparently reported that switching to MBCT leads to more relapses in patients who have recovered from depression. I confidently predict that these findings will be cited less often than the poorer quality The Lancet study, which was spun to create the appearance that it showed MBCT had equivalent outcomes to remaining on antidepressants. I also predict that the Huijbers et al MBCT study will often be misrepresented when it is cited.
Added February 29: For whatever reason, perhaps because he served as a consultant, the author of The Lancet study is also an author on this paper, which describes a study conducted entirely in the Netherlands. Note however, when it comes to the British The Lancet study, this article cites it has replicating past work when it was a null trial. This is an example of creating a false authority by distorted citation in action. I can’t judge whether the Dutch authors simply accepted the the conclusions offered in the abstract and press coverage of The Lancet study, or whether The Lancet author influenced their interpretation of it.
I would be very curious and his outpouring of subsequent papers on MBCT, whether The author of The Lancet paper cites this paper and whether he cites it accurately. Skeptics, join me in watching.
What do I think is going on it in the study?
I think it is apparent that the authors have selected a group of patients who have remitted from their depression, but who are at risk for relapse and recurrence if they go without treatment. With such chronic, recurring depression, there is evidence that psychotherapy adds little to medication, particularly when patients are showing a clinical response to the antidepressants. However, psychotherapy benefits from antidepressants being added.
But a final point is important – MBCT was never designed as a primary cognitive behavioral therapy for depression. It was intended as a means of patients paying attention to themselves in terms of cues suggesting there are sliding back into depression and taking appropriate action. It’s unfortunate that been oversold as something more than this.