Effect of a missing clinical trial on what we think about cognitive behavior therapy

  • Data collection for a large, well-resourced study of cognitive behavior therapy (CBT) for psychosis was completed years ago, but the study remains unpublished.
  • Its results could influence the overall evaluation of CBT versus alternative treatments if integrated with what is already known.
  • Political considerations can determine whether completed psychotherapy studies get published or remain lost.
  • This rich example demonstrates the strong influence of publication bias on how we assess psychotherapies.
  • What can be done to reduce the impact of this particular study having gone missing?

A few years ago Ben Goldacre suggested that we do a study of the registration of clinical trials.

lets'collaborate

I can’t remember the circumstances, but Goldacre and I did not pursue the idea further. I was already committed to studying psychological interventions, in which Goldacre was much less interested. Having battled to get American Psychological Association to fully accept and implement CONSORT in its journals, I was well aware how difficult it was getting the professional organizations offering the prime outlets for psychotherapy studies to accept needed reform. I wanted to stay focused on that.

I continue to follow Goldacre’s work closely and cite him often. I also pay particular attention to John Ioannidis’ follow up of his documentation that much of what we found in the biomedical literature is false or exaggerated, like:

Ioannidis JP. Clinical trials: what a waste. BMJ. 2014 Dec 10;349:g7089

Many trials are entirely lost, as they are not even registered. Substantial diversity probably exists across specialties, countries, and settings. Overall, in a survey conducted in 2012, only 30% of journal editors requested or encouraged trial registration.

In a seeming parallel world, I keep showing that in psychology the situation is worse. I had a simple explanation why that I now recognize was naïve: Needed reforms enforced by regulatory bodies like the US Food and Drug Administration (FDA) take longer to influence the psychotherapy literature, where there are no such pressures.

I think we now know that in both biomedicine and, again, psychology, that broad declarations of government and funding bodies and even journals’ of a commitment to disclose a conflict of interest, registering trials, sharing data, are insufficient to ensure that the literature gets cleaned up.

Statements were published across 14 major medical journals endorsing routine data sharing]. Editors of some of the top journals immediately took steps to undermine the implementation in their particular journals. Think of the specter of “research parasites, raised by the editors of New England Journal of Medicine (NEJM).

Another effort at reform

Following each demonstration that reforms are not being implemented, we get more pressures to do better. For instance, the 2015 World Health Organization (WHO) position paper:

Rationale for WHO’s New Position Calling for Prompt Reporting and Public Disclosure of Interventional Clinical Trial Results

WHO’s 2005 statement called for all interventional clinical trials to be registered. Subsequently, there has been an increase in clinical trial registration prior to the start of trials. This has enabled tracking of the completion and timeliness of clinical trial reporting. There is now a strong body of evidence showing failure to comply with results-reporting requirements across intervention classes, even in the case of large, randomised trials [37]. This applies to both industry and investigator-driven trials. In a study that analysed reporting from large clinical trials (over 500 participants) registered on clinicaltrials.gov and completed by 2009, 23% had no results reported even after a median of 60 months following trial completion; unpublished trials included nearly 300,000 participants [3]. Among randomised clinical trials (RCTs) of vaccines against five diseases registered in a variety of databases between 2006–2012, only 29% had been published in a peer-reviewed journal by 24 months following study completion [4]. At 48 months after completion, 18% of trials were not reported at all, which included over 24,000 participants. In another study, among 400 randomly selected clinical trials, nearly 30% did not publish the primary outcomes in a journal or post results to a clinical trial registry within four years of completion [5].

Why is this a problem?

  • It affects understanding of the scientific state of the art.

  • It leads to inefficiencies in resource allocation for both research and development and financing of health interventions.

  • It creates indirect costs for public and private entities, including patients themselves, who pay for suboptimal or harmful treatments.

  • It potentially distorts regulatory and public health decision making.

Furthermore, it is unethical to conduct human research without publication and dissemination of the results of that research. In particular, withholding results may subject future volunteers to unnecessary risk.

How the psychotherapy literature is different from a medical literature.

Unfortunately for the trustworthiness of the psychotherapy literature, the WHO statement is limited to medical interventions. We probably won’t see any direct effects on the psychotherapy literature anytime soon.

The psychotherapy literature has all the problems in implementing reforms that we see in biomedicine – and more. Professional organizations like the American Psychological Association and British Psychological Society publishing psychotherapy research have the other important function of ensuring their clinical membership developer’s employment opportunities. More opportunities for employment show the organizations are meeting their members’ needs this results in more dues-paying members.

The organizations don’t want to facilitate third-party payers citing research that particular interventions that their membership is already practicing are inferior and need to be abandoned. They want the branding of members practicing “evidence-based treatment” but not the burden of members having to make decisions based on what is evidence-based. More basically, psychologists’ professional organizations are cognizant of the need to demonstrate a place in providing services that are reimbursed because they improve mental and physical health. In this respect, they are competing with biomedical interventions for the same pot of money.

So, journals published by psychological organizations have vested interests and not stringently enforcing standards. The well-known questionable research practices of investigators are strengthened by questionable publication practices, like confirmation bias, that are tied to the organizations’ institutional agenda.

And the lower status journals that are not published by professional organizations may compromise their standards for publishing psychotherapy trials because of the status that having these articles confers.

Increasingly, medical journals like The Lancet and The Lancet Psychiatry are seen as more prestigious for publishing psychotherapy trials, but they take less seriously the need to enforce standards for psychotherapy studies the regulatory agencies require for biomedical interventions. Example: The Lancet violated its own policies and accepted publication Tony Morrison’s CBT for psychosis study  for publication when it wasn’t registered until after the trial and started. The declared outcomes were vague enough so they could be re-specified after results were known .

Bottom line, in the case of publishing all psychotherapy trials consistent with published protocols: the problem is taken less seriously than if it were a medical trial.

Overall, there is less requirement for psychotherapy trials be registered and less attention paid by editors and reviewers as to whether trials were registered, and whether outcomes are analytic plans were consistent between the registration in the published study.

In a recent blog post, I identified results of a trial that had been published with switched outcomes and then re-published in another paper with different outcomes, without the registration even being noted.

But for all the same reasons cited by the recent WHO statement, publication of all psychotherapy trials matters.

archaeologist digging for goldRecovering an important CBT trial gone missing

I am now going to review the impact of a large, well resourced study of CBT for psychosis remaining on published. I identified the study by a search of the ISRCTN:

The ISRCTN registry is a primary clinical trial registry recognised by WHO and ICMJE that accepts all clinical research studies (whether proposed, ongoing or completed), providing content validation and curation and the unique identification number necessary for publication. All study records in the database are freely accessible and searchable.

I then went back to the literature to see what it happened with it. Keep in mind that this step is not even possible for the many psychotherapy trials that are simply not registered at all.

Many trials are not registered because they are considered pilot and feasibility studies and therefore not suitable for entering effect sizes into the literature. Yet, if significant results are found, they will be exaggerated because they come from an underpowered study. And such results become the basis for entering results into the literature as if it were a planned clinical trial, with considerable likelihood of not being able to be replicated.

There are whole classes of clinical and health psychology interventions that are dominated by underpowered, poor quality studies that should have been flagged as for evidence or excluded altogether. So, in centering on this trial, I’m picking an important example because it was available to be discovered, but there is much of their there is not available to be discovered, because it was not registered.

CBT versus supportive therapy for persistent positive symptoms in psychotic disorders

The trial registration is:

Cognitive behavioural treatment for persistent positive symptoms in psychotic disorders SRCTN29242879DOI 10.1186/ISRCTN29242879

The trial registration indicates that recruitment started on January 1, 2007 and ended on December 31, 2008.

No publications are listed. I and others have sent repeated emails to the principal investigator inquiring about any publications and have failed to get a response. I even sent a German colleague to visit him and all he would say was that results were being written up. That was two years ago.

Google Scholar indicates the principal investigator continues to publish, but not the results of this trial.

A study to die for

The study protocol is available as a PDF

Klingberg S, Wittorf A, Meisner C, Wölwer W, Wiedemann G, Herrlich J, Bechdolf A, Müller BW, Sartory G, Wagner M, Kircher T. Cognitive behavioural therapy versus supportive therapy for persistent positive symptoms in psychotic disorders: The POSITIVE Study, a multicenter, prospective, single-blind, randomised controlled clinical trial. Trials. 2010 Dec 29;11(1):123.

The methods section makes it sound like a dream study with resources beyond what is usually encountered for psychotherapy research. If the protocol is followed, the study would be an innovative, large, methodologically superior study.

Methods/Design: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists.

The study was one of the rare ones providing for systematic assessments of adverse events and any harm to patients. Preumably if CBT is powerful enough to affect positive change, it can have negative effects as well. But these remain entirely a matter of speculation.

Ratings of outcome were blinded and steps were taken to preserve the blinding even if an adverse event occurred. This is important because blinded trials are less susceptible to investigator bias.

Another unusual feature is the use of a supportive therapy (ST) credible, but nonspecific condition as a control/comparison.

ST is thought as an active treatment with respect to the patient-therapist relationship and with respect to therapeutic commitment [21]. In the treatment of patients suffering from psychotic disorders these ingredients are viewed to be essential as it has been shown consistently that the social network of these patients is limited. To have at least one trustworthy person to talk to may be the most important ingredient in any kind of treatment. However, with respect to specific processes related to modification of psychotic beliefs, ST is not an active treatment. Strategies specifically designed to change misperceptions or reasoning biases are not part of ST.

Use of this control condition allows evaluation of the important question of whether any apparent effects of CBT are due to the active ingredients of that approach or to the supportive therapeutic relationship within which the active ingredients are delivered.

Being able to rule out the effects of CBT are due to nonspecific effects justifies the extra resources needed to provide specialized training in CBT, if equivalent effects are obtained in the ST group, it suggests that equivalent outcomes can be achieved simply by providing more support to patients, presumably by less trained and maybe even lay personnel.

It is a notorious feature of studies of CBT for psychosis that they lack comparison/control groups in any way equivalent to the CBT in terms of nonspecific intensity, support, encouragement, and positive expectations. Too often, the control group are ill-defined treatment as usual (TAU) that lacks regular contact and inspires any positive expectations. Basically CBT is being compared to inadequate treatment and sometimes no treatment and so any apparent effects that are observed are due to correcting these inadequacies, not any active ingredient.

The protocol hints in passing at the investigators’ agenda.

This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care.

Here we see an aim to justify implementation of CBT for psychosis in routine care in Germany. We have seen something similar with repeated efforts of German to demonstrate that long-term psychodynamic psychotherapy is more effective than shorter, less expensive treatments, despite the lack of credible data [ ].

And so, if the results would not contribute to getting psychotherapy implemented in routine care in Germany, do they get buried?

Science & Politics of CBT for Psychosis

A rollout of a CBT study for psychosis published in Lancet made strong claims in a BBC article and audiotape promotion.

morroson slide-page-0

 

 

 

The attention attracted critical scrutiny that these claims couldn’t sustain. After controversy on Twitter, the BBC headline was changed to a more modest claim.

Criticism mounted:

  • The study retained fewer participants receiving CBT at the end of the study than authors.
  • The comparison treatment was ill-defined, but for some patients meant no treatment because they were kicked out of routine care for refusing medication.
  • A substantial proportion of patients assigned to CBT began taking antipsychotic medication by the end of the study.
  • There was no evidence that the response to CBT was comparable to that achieved with antipsychotic medication alone in clinical trials.
  • No evidence that less intensive, nonspecific supportive therapy would not have achieved the same results as CBT.

And the authors ended up conceding in a letter to the editor that their trial had been registered after data collection had started and it did not produce evidence of equivalence to antipsychotic medication.

In a blog post containing the actual video of the presentation before his British Psychological Society, Keith Laws declares

Politics have overcome the science in CBT for psychosis

Recently the British Psychological Society invited me to give a public talk entitled CBT: The Science & Politics behind CBT for Psychosis. In this talk, which was filmed…, I highlight the unquestionable bias shown by the National Institute of Clinical Excellence (NICE) committee  (CG178) in their advocacy of CBT for psychosis.

The bias is not concealed, but unashamedly served-up by NICE as a dish that is high in ‘evidence-substitute’, uses data that are past their sell-by-date and is topped-off with some nicely picked cherries. I raise the question of whether committees – with such obvious vested interests – should be advocating on mental health interventions.

I present findings from our own recent meta-analysis (Jauhar et al 2014) showing that three-quarters of all RCTs have failed to find any reduction in the symptoms of psychosis following CBT. I also outline how trials which have used non-blind assessment of outcomes have inflated effect sizes by up to 600%. Finally, I give examples where CBT may have adverse consequences – both for the negative symptoms of psychosis and for relapse rates.

A pair of well-conducted and transparently reported Cochrane reviews suggest there is little evidence for the efficacy of CBT for psychosis (*)

cochrane slide-page-0                          cochrane2-page-0

 

These and other slides are available in a slideshow presentation of a talk I gave at the Edinburgh Royal  Infirmary.

Yet, even after having to be tempered in the face of criticism, the original claims of the Morrison study get echoed in the antipsychiatry Understanding Psychosis:

“Other forms of therapy can also be helpful, but so far it is CBTp that has been most intensively researched. There have now been several meta-analyses (studies using a statistical technique that allows findings from various trials to be averaged out) looking at its effectiveness. Although they each yield slightly different estimates, there is general consensus that on average, people gain around as much benefit from CBT as they do from taking psychiatric medication.”

Such misinformation can confuse patients making difficult decisions about whether to accept antipsychotic medication.

go on without mejpgIf the results from the missing CBT for psychosis study became available…

If the Klingberg study were available and integrated with existing data, it would be one of the largest and highest quality studies and it would provide insight into any advantage of CBT for psychosis. For those who can be convinced by data, a null finding from a large studythat added to mostly small and methodologically unsophisticated studies could be decisive.

A recent meta-analysis of CBT for prevention of psychosis by Hutton and Taylor includes six studies and mentions the trial protocol in passing:

Two recent trials of CBT for established psychosis provide examples of good practice for reporting harms (Klingberg et al. 20102012) and CONSORT (Consolidated Standards of Reporting Trials) provide a sensible set of recommendations (Ioannidis et al. 2004).

Yet, it does not provide indicate why it is missing and is not included in a list of completed but unpublished studies. Yet, the protocol indicates a study considerably larger than any of the studies that were included.

To communicate a better sense of the potential importance of this missing study and perhaps place more pressures on the investigators to release its results, I would suggest that future meta-analyses state:

The protocol for Klingberg et al. Cognitive behavioural treatment for persistent positive symptoms in psychotic disorders indicates that recruitment was completed in 2008. No publications have resulted. Emails to Professor Klingberg about the status of the study failed to get a response. If the study were completed consistent with its protocol, it would represent one of the largest studies of CBT for psychosis ever and one of the few with a fair comparison between CBT and supportive therapy. Inclusion of the results could potentially substantially modify the conclusions of the current meta-analysis.

 



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