Accessibility of psychology papers: Will you sign the More Open Access Pledge?

open accessIn an ideal world, our knowledge would be of high quality and it would be accessible to all.

This guest blogpost is about an initiative to speed up accessibility: the More Open Access Pledge. I’m hoping that you will sign up and encourage others to do so too.

Introducing Eva Alisic

evaOur guest blogger is a senior research fellow at Monash University, Australia, where she leads the Trauma Recovery Lab, and a visiting scholar at the University Children’s Hospital Zurich, Switzerland. Her team studies how children, young people, and families cope with traumatic experiences, and how professionals can support them. Parts of this blogpost have been published on the Trauma Recovery blog.  

Therapists cannot access therapy literature

We recently examined how open the literature on Posttraumatic Stress Disorder is. Unfortunately not very: 58% of the publications were behind a paywall.

It is worrying that practicing psychologists cannot access the latest research on therapy effectiveness. Or on how to deal with dropout from interventions. Or on clients’ perspectives.

The migration crisis and refugees are on my mind a lot these days. How can we justify that relevant knowledge is unavailable to support those in need?

Not only practitioners have little access to the latest evidence. The same applies to many scholars in low-resource settings, policy makers, and citizens in general. Much research is behind a paywall, even though it was funded with public money. This system is lucrative for the publishers of certain ‘traditional journals’, which charge extra-ordinary amounts of subscription money to university libraries.

Getting radical

I have decided to be radical about it: since last month, I submit my first-authored research papers to Open Access outlets only. I’m moving to reviewing exclusively for Open Access journals, reflecting on my citation practices and exploring my Open Data possibilities.

With Open Access outlets, I do not mean traditional journals that offer authors the option to make a single article available to everyone. That means paying the same publisher twice and does not change the system. I also do not mean falling into the hands of predatory publishers (see e.g. Beall’s list and ThinkCheckSubmit).

Several quality Open Access journals accept psychology articles. Examples are PLOS ONE, PLOS Medicine, PeerJ, and, in my specific field, the European Journal of Psychotraumatology. Some of them charge authors high amounts of money though, creating further inequality between researchers from high- and low-income settings. There are also interesting developments around pre-print platforms and overlay journals.

Many see my move as ‘career suicide’, as I will not submit my papers to top journals. Even colleagues with a strong commitment to Open Access feel they cannot take the risk.

It says a lot about how much we focus on reputation of journals in contrast to quality and accessibility of knowledge itself. And it reinforces why radical stances like mine are necessary to change the system.

Nevertheless, making a smaller move towards open access is much better than making no move at all. If many people do this, it will make a difference. That is why, together with members of the Global Young Academy, we recently launched the More Open Access pledge.

The More Open Access Pledge

The Global Young Academy is a 200-strong worldwide organization of early- and mid-career researchers. They are passionate about science communication, science advice, and science education. Open Science is a key interest, which led to statements on Open Data and Open Acces

Last week, 132 members and alumni pledged to submit at least 1 manuscript to an Open Access outlet in the remainder of 2016. The outlet can be either an Open Access journal or a well-recognized platform (e.g. ArXiv for physics), as long as the manuscript is peer-reviewed and shared without an embargo period.

The goal of the pledge to accelerate the move towards Open Access in a way that is feasible for most researchers, irrespective of discipline, seniority, or resources.

As one signatory commented: “It makes so much more sense to start with a low threshold self-commitment pledge rather than ‘I will publish most of my articles in OA’ and other manifestos out there that are unpractical for the majority of researchers.”

You can join the pledge

We hope that many people will join the pledge for More Open Access.

You can read more and sign up right away. And we hope that you will start conversations with colleagues and encourage them to get involved too.

 

A bad response to the crisis of untrustworthiness in clinical psychological science

surpriseA new Call for Papers establishes a place for failed replications and null findings in clinical psychology in an American Psychological Association journal. Unfortunately, the journal lacks an impact factor, despite the journal having been publishing for decades.

There are lots of reasons that establishing such a ghetto where failed replications and null findings can be herded and ignored is a bad idea. I provide nine. I’m sure there are more.

But the critical issue in the creation such ghettos is that they reduce pressure on the APA vanity journal,  Journal of Consulting and Clinical Psychology to reform questionable publication practices and routinely accept replications and null findings.

 Clinical psychology is different

  • The untrustworthiness in clinical psychological science is serious, but different than that of personality and social psychology, and the crisis it poses requires different solutions.
  • There is little harm to not been able to replicate personality and social psychology studies, beyond to the credibility of those fields and the investigators within them.
  • However, untrustworthy findings in clinical psychology – whether they are exaggerated or simply false – can translate into ineffective and even harmful services being delivered, along with poor commitment of scarce resources to where they are needed less.
  • Personality and social psychologists can look to organized mass replication efforts to assess the reproducibility of findings in their fields. However, such efforts are best undertaken with Internet-recruited and student samples using surveys and simple tasks.
  • Mass replication efforts are less suitable for key areas of clinical psychology research, which often depends on expensive clinical trials with patients and extended follow-up. Of course, research and clinical psychology benefits from independent replication, but it is unlikely to occur on a mass basis.

Efforts to improve the trustworthiness of clinical psychology should have progressed more, but they have not.

Clinical psychology has greater contact than personality and social psychology with the biomedical literature, where untrustworthy findings can have more serious implications for health and mortality.

In response to repeated demonstrations of untrustworthy findings, medical journals have mandated reforms such as preregistration, CONSORT checklists for reporting, transparency of methods and results using supplements, declarations of conflicts of interest, and requirements for the routine sharing of data.  Implementation of these reforms in medical journals is incomplete and enforcement is inconsistent, with clear signs of resistance from some prestigious journals. Note for instance, the editor of the New England Journal of Medicine warning that routine sharing of data from clinical trials would produce “research parasites” who would put the data to different purposes than intended by the original authors.

While many of these reforms have been nominally endorsed by specialty clinical psychology journals, they are largely ignored in the review and acceptance of manuscripts. For instance, a recent systematic review published in JCCP  of randomized trials published in the most prestigious clinical psychology journals in 2013 identified 165 RCTs. Of them,

  • 73 (44%) RCTs were registered.
  • 25 (15%) were registered prospectively.
  • Of registered RCTs, only 42 (58%) indicated registration status in the publication.
  • Only 2 (1% of all trials) were registered prospectively and defined primary outcomes completely.

Apparently not only are investigators failing to register their trials, editors and reviewers ignore whether registration has occurred and don’t bother to check whether what is reported in a manuscript is inconsistent with what is proposed in a registration.

Questionable research practices in clinical psychology

The crisis in clinical psychological science lies in its evidence base:

  • RCTs are underpowered, yet consistently obtain positive results by redefining the primary outcomes after results are known.
  • Typical RCTs are small, methodologically flawed study conducted by investigators with strong allegiances to one of the treatments being evaluated.
  • Treatment preferred by investigators are a better predictor of the outcome of RCTs than the specific treatment being evaluated.

Questionable publication practices in clinical psychology

Questionable research practices (QRPs) in clinical psychology are maintained and amplified by questionable publication practices (QPPs).

The premier psychology journal for publishing randomized trials is Journal of Consulting and Clinical Psychology. It is a vanity journal with a strong confirmation bias and a distinct aversion to publishing null findings and replications. Until recently, letters to the editor were not even allowed. When the ban was relaxed a few years ago, a high bar was set for accepting them. Statistics about the rate of acceptance of letters to the editor are not available, but accounts from colleagues suggest that criticisms of basic flaws in articles that have been published are suppressed. JCCP is not a journal hospitable to post-publication peer review.

Publication of flawed studies in JCCP go on detected and unannounced, except through alternative post publication peer review, outside the journal, such as PubMed Commons comments and blogging.

Although the term “Pink Floyd rejection” was originally developed by an outgoing editor of the Association for Psychological Science’s Psychological Science, it captures well the editorial practices of JCCP.

pink floyd study -page-0

Call for Brief Reports: Null Results and Failures to Replicate

An APA press release announced:

Journal of Psychotherapy Integration will start publishing a new recurring brief reports section titled, “Surprise, Surprise: Interesting Null Results and Failures to Replicate.”

In an era when findings from psychological science are called into question, it is especially important to publish carefully constructed studies that yield surprising null results and/or failures at replicating “known” effects.

The following 2012 article published in Journal of Psychotherapy Integration is a good example of a paper that would be appropriate for this section:

DeGeorge, J., & Constantino, M. (2012). Perceptions of analogue therapist empathy as a function of salient experience. Journal of Psychotherapy Integration, 22, 52-59.

Submitted manuscripts should not exceed 2500 words, including references. Manuscript should be submitted electronically through the journal’s submission portal under Instructions to Authors.

Please note in your cover letter that you are submitting for this brief reports section. We look forward to your submissions!

What’s wrong with this resting place for failures to replicate and null findings?

  1. Authors undertaking replications, regardless whether they succeed in confirming past findings, are entitled to a journal with an impact factor.
  2. The title Journal of Psychotherapy Integration adds nothing to electronic bibliographic searches because “psychotherapy integration” is not what failures to replicate and null findings necessarily represent. Locating particular articles in electronic bibliographic searches is often fortuitous. Readers’ decisions to click on a title   to examine the abstract  depend on their recognizing the relevance of the article from the title of the journal in which it is published.
  3. The title to this special section is demeaning. If it is a joke, it will soon wear thin.
  4. Failures to replicate and null findings are not necessarily “surprises” given the untrustworthiness of the clinical psychology literature.
  5. Reasons for the failure to replicate previously published clinical trials often lie in the conduct and reporting of the original studies themselves. Yet having been granted “peer-reviewed” status in a more prestigious journal, the original articles are automatically granted more credibility than the failure to replicate them.
  6. A word limit of 2500 is hardly adequate to describe methods and results, yet there is no provision for web-based supplements to present further details. The value in failures to replicate and null findings lies in part in the ability to make sense of the apparent discrepancy with past studies. Confining such papers to 2500 words reduces the likelihood that the discussion will be meaningful.
  7. The existence of such a ghetto to which these papers can be herded takes pressure off the vanity JCCP to reform its publication practices. Editors can perceive when studies are likely to be failed attempts at replications or null findings and issue desk rejections for manuscripts with a standard form letter suggesting resubmitting to the Journal of Psychotherapy Integration.
  8. pottery barn ruleProviding such a ghetto is APA’s alternative to acceptance of a Pottery Barn rule, whereby if JCCP publishes a clinical trial, it incurs an obligation to publish attempted replications, regardless of whether results are consistent with the study being replicated.
  9. Without journal reform, publication in JCCP represents a biased sampling of evidence for particular psychotherapies with a strong confirmation bias.

Clinical psychology doesn’t need such silliness

Initiatives such as this call for papers are a distraction from the urgent need to clean up the clinical psychology literature. We need to confront directly  JCCP‘s policy of limiting publication to articles that are newsworthy and that claim to be innovative, at the expense of being robust and solid clinical psychological science.

Some personality and social psychologists involved in the replication initiative have received recognition and endorsement from the two professional organizations competing for the highest impact factors in psychology, Association for Psychological Science and American Psychological Association. Those of us who’ve continue to call in the social media for reform of the vanity journals, are often met with a flurry of negative response from the replicators who praise the professional organizations for their commitment to open psychological science

Have the replicators sold out the movement to reform psychology by leaving the vanity journals intact? As I’ve argued elsewhere, compromises worked out for replicability project may adversely affect efforts to improve the trustworthiness of clinical  psychologicalscience, even if the stakes are higher.

 

 

 

Mindfulness-based stress reduction for improving sleep among cancer patients: A disappointing look

insomniawomansleepingContinuing to probe studies of mindfulness-based stress reduction (MBSR) for health problems, I turned to some contradictory claims that an investigator had made about her trial of MBSR for improving the sleep of cancer patients.

  • I noticed things in a CONSORT flowchart in the article that the editor and reviewers should have flagged as a serious limitation of the study and one noteworthy of acknowledgment and discussion.
  • What I saw undercut the validity of complicated statistical analyses on which the author’s claims depended, as well as any credibility to claims about efficacy of MBSR.
  • Promoters of MBSR desperately need to demonstrate that the treatment is as good as or better than alternatives. This study does not contribute credible, favorable evidence, despite being dressed up to do so.
  •  It is time to attach an expression of concern to MBSR studies:

warning Warning! Likely to contain exaggerations and distortions favoring MBSR. Not suitable as a basis for decision-making as to whether to seek, provide, or commit public resources to MBSR.

There’s a growing sense that claims about MBSR are overblown and based on spun and low-quality evidence largely generated by enthusiasts and promoters with undeclared conflicts of interest. I had thought, though, that someone who is motivated but not caught up in all the fanfare could come to an independent judgment of the available literature.  Well, it takes too much work.

I’m losing confidence that anyone can evaluate MBSR studies without a concerted effort to cut through hype and hokum,  probing to a level of detail that the quality of evidence ultimately does not justify.

Simply put, it takes too much effort for outsiders – researchers, clinicians, and patients – to grasp how they are being misled by the mindfulness literature.

What we don’t know about MBSR for sleep problems

A comprehensive systematic review and meta-analysis prepared for the US Agency for Healthcare Research and Quality (AHRQ):

Goyal M, Singh S. Sibinga EMS, et al. Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA Intern Med. Epub Jan 6 2014. doi:10.1001/jamainternmed.2013.13018.

Reviewed 18,753 citations, and found only 47 trials (3%) with 3515 participants that included an active control treatment.

The dismal conclusion:

 We found low evidence of no effect or insufficient evidence of any effect of meditation programs on positive mood, attention, substance use, eating habits, sleep, and weight.

The results of the study that I’m going be discussing became available after the systematic review. The primary outcome paper was published in a prestigious journal. Maybe, I had hoped, it could represent a sorely needed contribution to the limited evidence available for strong claims that MBSR is a cure for whatever ails you. No, it was not.

staying awakeBut why should we expect MBSR to improve sleep? A Buddhist neuroscientist expressed doubt.

Willoughby Britton, PhD is a clinical psychologist, neuroscience researcher, and Buddhist practitioner.  As Assistant Professor of Psychiatry and Human Behavior at Brown University Medical School, she specializes in research on meditation in education and as treatment for depression and sleep disorders. She was interviewed by Tricycle, a respected magazine of Buddhist thought that has been around since 1990. She was asked:Is the data better for some applications of meditation than others?”

I have done very careful reviews of the efficacy of meditation in two areas in which there are high levels of popular misconception about how much data we have: sleep and education. The data for sleep, for example, is really not that strong. And the AHRQ article concurs: it judges the level of evidence for meditation’s ability to improve sleep as “insufficient.”

What I found from my study was that meditation made people’s brains more awake. From a very basic brain point of view, what happens in your brain when you fall asleep? The frontal cortex deactivates. Nobody agrees what meditation does to the brain, but across the board, one of the most common findings is that meditation increases blood flow and activity in the prefrontal cortex. So how is that going to improve sleep? It doesn’t make any sense. It is completely incompatible with sleeping if you are doing it right. And we know that people stop sleeping when they go on retreats. That is never reported in scientific publications, even though it is well known among practitioners.

A tale of a study of MBSR and CBT to improve sleep problems in cancer patients thrice told.

 The primary report of the study appeared in the prestigious Journal of Clinical Oncology:

Garland, S. N., Carlson, L. E., Stephens, A. J., Antle, M. C., Samuels, C., & Campbell, T. S. (2014). Mindfulness-based stress reduction compared with cognitive behavioral therapy for the treatment of insomnia comorbid with cancer: A randomized, partially blinded, noninferiority trial. Journal of Clinical Oncology, JCO-2012.

The article concluded:

 Although MBSR produced a clinically significant change in sleep and psychological outcomes, CBT-I was associated with rapid and durable improvement and remains the best choice for the nonpharmacologic treatment of insomnia.

A conference abstract reporting the study published the same year concluded:

While both CBT-I and MBSR produced significant improvement in sleep and psychological outcomes, a more rapid change occurred in CBT-I.

The principal investigator’s review of her own work  published two years later concluded:

These findings indicated that while MBCR was slower to take effect, it could be as effective as the gold-standard treatment for insomnia in cancer survivors over time.

Delving into the details of the study

 From the abstract:

This was a randomized, partially blinded, noninferiority trial involving patients with cancer with insomnia recruited from a tertiary cancer center in Calgary, Alberta, Canada, from September 2008 to March 2011. Assessments were conducted at baseline, after the program, and after 3 months of follow-up. The noninferiority margin was 4 points measured by the Insomnia Severity Index. Sleep diaries and actigraphy measured sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency. Secondary outcomes included sleep quality, sleep beliefs, mood, and stress.

Results

Of 327 patients screened, 111 were randomly assigned (CBT-I, n _ 47; MBSR, n _ 64). MBSR was inferior to CBT-I for improving insomnia severity immediately after the program (P < .35), but MBSR demonstrated noninferiority at follow-up (P <.02). Sleep diary–measured SOL was reduced by 22 minutes in the CBT-I group and by 14 minutes in the MBSR group at follow-up. Similar reductions in WASO were observed for both groups. TST increased by 0.60 hours for CBT-I and 0.75 hours for MBSR. CBT-I improved sleep quality (P < .001) and dysfunctional sleep beliefs (P <.001), whereas both groups experienced reduced stress (P < .001) and mood disturbance (P< .001).

[For more information about a noninferiority  trial (NI), see here.]

Basically,

The objective of non-inferiority trials is to compare a novel treatment to an active treatment with a view of demonstrating that it is not clinically worse with regards to a specified endpoint.

Investigators commit themselves to a pre-set difference between the two interventions that would satisfy them that the treatment was inferior, if they found it. In an earlier blog post, I noted that NI RCTs have a reputation for methodological flaws and bias:

An NI RCT commits investigators and readers to accepting null results as support for a new treatment because it is no worse than an existing one. Suspicions are immediately raised as to why investigators might want to make that point.

The trial had no control group from which it could be determined whether the benefits of either intervention exceeded what would be obtained with a nonspecific treatment that had no active ingredient beyond positive expectations, support, and attention.

The results of the trial were analyzed both intent to treat and per protocol. The intent-to-treat analyses included all patients who where randomized, regardless of the extent to which they actually attended treatment. The per-protocol analyses included only patients who attended at least 5 sessions.

The description of the analyses are likely to dazzle most readers and impress them that the authors knew what they were doing in applying sophisticated techniques- that is, if readers are unfamiliar with these techniques and the assumptions they make.

For each of the models, the random effect was participant, and the fixed effects were group (MBSR or CBT-I), time, baseline value, and the group-time interaction. Time was also set as a repeated measure. The restricted maximum likelihood estimate method was used to estimate the model parameters and SEs with a compound symmetry covariance structure to account for the correlation between measurements. We used type III fixed effects (F and t) and set the statistical significance of P values at P<.05.

A skeptic would figure out that the authors probably had to contend with a lot of missing data.

Oops!

 This excerpt from the CONSORT flow chart tracks what happened after random assignment to either CBT or MBSR.

 consort flow attrition.PNG

Only half of the patients assigned to MBST actually attended the pre-set minimal number of sessions. Of 64 patients, 22 withdrew, another 2 attended no sessions, and 8 attended less than 5. CBT fared considerably better, with only 7 patients either not attending or withdrawing.

At 5 month follow up, the situation for MBSR worsened, only 27 patients – a minority of patients who had been randomized – were left to provide data for analysis.

The authors adopted their complex analytic strategy to compensate for missing data. The  strategy involves basically using all available data to guess what the results would have been for individual patients if their data had been available. Yup, they were inventing data based on a best guess.

These sophisticated techniques are only valid if most data for most patients remain available and the assumption can be made the loss of patients is random. But in this case, loss was not random, patients assigned to MBSR were less likely to stick around. We are not in position to know, but there is undoubtedly other nonrandom loss

So?

 Results that depend so much on guesstimates from so much missing data that are not reliable or generalizable.

The study started out small and got smaller because of patient attrition.

The study did not have a nonspecific  control group. Yet, judging from the rest of the literature, it is unlikely that a superiority of MBSR over nonspecific treatment could be demonstrated with such a small sample, and certainly with the sample left after attrition.

Most psychotherapy research experts would not expect such a small study to be able to detect a difference between two active treatments. So, calling this a “noinferiority trial” is a cop out that serves to hide the low likelihood of finding a difference.

Appreciate what the author is asking of us – that we revise our appraisal of  MBSR for insomnia from “weak or no evidence” to “equivalent to gold standard treatment” on the basis of this study. We are asked to do this based on what shrunk to an underpowered study in which most patients assigned to MBSR weren’t around for follow up and there is a heavy reliance on tortured , post hoc analyses of secondary outcomes. No, thank you.

To improve the credibility of their claims, MBSR desperately need to demonstrate that the treatment is as good or better than alternatives. This study is not a fair demonstration of that. The high rate of nonretention of patients after being assigned to MBSR should be quite troubling to anyone promoting MBSR for whatever ails you.

Are mindfulness and cognitive behavioral interventions for smoking cessation obsolete?

nosmokingA well-designed and conducted study raises issues whether cognitive behavioral therapy interventions (CBT), including mindfulness-based abstinence therapy (MBAT) are obsolete and no longer cost effective.

  • The study reported that intensive CBT and MBAT were no more effective than usual care consisting of 4 5-10 minute individual counseling sessions.
  •  The article in the study failed to note an obvious reason why the more intensive therapies were no more effective than the lighter usual care.
  •  Results were spun to create the impression that although MBAT was not more effective in achieving smoking cessation, it may be more effective than CBT or usual care in promoting recovery from relapse.
  •  Overall, the study raises important issues about whether cognitive behavioral interventions are now obsolete and represents another example of confirmation bias in the mindfulness literature.

The study is

Vidrine JI, Spears CA, Heppner WL, Reitzel LR, Marcus MT, Cinciripini PM, Waters AJ, Li Y, Nguyen NT, Cao Y, Tindle HA. Efficacy of Mindfulness-Based Addiction Treatment (MBAT) for Smoking Cessation and Lapse Recovery: A Randomized Clinical Trial. Journal of Consulting and Clinical Psychology. 2016 May.

The abstract is

 Objective: To compare the efficacy of Mindfulness-Based Addiction Treatment (MBAT) to a Cognitive Behavioral Treatment (CBT) that matched MBAT on treatment contact time, and a Usual Care (UC) condition that comprised brief individual counseling. Method: Participants (N _ 412) were 48.2% African American, 41.5% non-Latino White, 5.4% Latino, and 4.9% other, and 57.6% reported a total annual household income _ $30,000. The majority of participants were female (54.9%). Mean cigarettes per day was 19.9 (SD= 10.1). Following the baseline visit, participants were randomized to UC (n =103), CBT (n = 155), or MBAT (n = 154). All participants were given self-help materials and nicotine patch therapy. CBT and MBAT groups received 8 2-hr in-person group counseling sessions. UC participants received 4 brief individual counseling sessions. Biochemically verified smoking abstinence was assessed 4 and 26 weeks after the quit date. Results: Logistic random effects model analyses over time indicated no overall significant treatment effects (completers only: F(2, 236) = 0.29, p = .749; intent-to-treat: F(2, 401) = 0.9, p = .407). Among participants classified as smoking at the last treatment session, analyses examining the recovery of abstinence revealed a significant overall treatment effect, F(2, 103) = 4.41, p = .015 (MBAT vs. CBT: OR = 4.94, 95% CI: 1.47 to 16.59, p =.010, Effect Size = .88; MBAT vs. UC: OR = 4.18, 95% CI: 1.04 to 16.75, p =.043, Effect Size = .79). Conclusion: Although there were no overall significant effects of treatment on abstinence, MBAT may be more effective than CBT or UC in promoting recovery from lapses.

[Note how minimal and nonsignificant  the differences were between the treatments in this large N study. What critical detail in the abstract might explain this lack of differences? Are you impressed by the suggestion that MBAT could nonetheless be more effective than the other treatments?

A boxed statement in the article declares the public health implications of the study.

What is the public health significance of this article?

Although there were no significant differences in overall abstinence between Mindfulness-Based Addiction Treatment (MBAT) and traditional Guideline-based treatments within a diverse and relatively low SES sample of smokers, MBAT may be more efficacious than CBT or UC in facilitating lapse recovery.

 Exceptional strengths of the study.

The investigators recruited a large sample of low income participants with a strong minority representation.

Given the characteristics of the population, there were reasonably good retention rates. Analyses were conducted both intent-to-treat and for completers only, as seen in the chart below:

consort flowchart

Measurement of smoking cessation was by both self-report and an objective measure of abstinence, biologically confirmed carbon monoxide (CO) levels.

Self-reported use of mindfulness meditation before recruitment was assessed, along with actual practice of mindfulness techniques during treatment.

The CBT and MBAT treatments were carefully described in the frequency and intensity.

treatment schedule-page-0

 What the authors fail to note in their discussion of null results.

Although the usual care involved minimal contact and support, levels were far below the levels for the active CBT and MBAT treatments in frequency and intensity. In that sense, the UC group was not adequate as a control group. But it makes the lack of differences in results all the more impressive. All conditions involved distribution of nicotine patches and repeated presentation of instructions for use.

nicotine patchLack of differences between groups raises issues of whether more intensive cognitive behavioral treatments add anything to supplying nicotine patches with instructions. There have been no previous well powered and conducted studies providing patches across active treatment and control conditions.

Why I don’t put much weight in the authors’ claims about the superiority of MBAT facilitating relapse recovery.

The study involved randomizing patients to one of three treatments: CBT, MBAT or usual care. The analyses from which the authors claim facilitation of relapse were post-hoc subgroup analyses, which lost the benefits of having come from randomized trial. Such analyses are certainly not equivalent to randomizing patients who are smoking to one of these three conditions, which we know from primary analyses did not produce differences. Focusing on these patients introduces unknown biases.

Note also that there were differences across conditions in rates of patients still smoking at the end of the study.

Among participants classified as smoking on the last treatment session (completers only; n = 145), 14.7% in UC, 7.0% in CBT, and 27.8% in MBAT had recovered abstinence 1 week following the end of treatment.

In the subsample of participants still smoking, there were differences in those who recovered abstinence.

Among participants classified as smoking on the last treatment session (completers only; n = 145), 14.7% in UC,7.0% in CBT, and 27.8% in MBAT had recovered abstinence 1 week following the end of treatment.

Although the trial randomized patients to a particular treatment, the post-hoc subgroup analyses focused on the nonrandomized selection of patients still smoking in each group. Rates of such patients were four times higher in the MBAT versus the CBT group. These still-smoking patients are nonrandom (biased) selections from the original sample.   The results claimed to be significant for transitions from still smoking at the end of treatment to abstinence.

Let’s return to how these results were presented in the abstract:

Among participants classified as smoking at the last treatment session, analyses examining the recovery of abstinence revealed a significant overall treatment effect, F(2, 103) = 4.41, p = .015 (MBAT vs. CBT: OR = 4.94, 95% CI: 1.47 to 16.59, p =.010, Effect Size = .88; MBAT vs. UC: OR = 4.18, 95% CI: 1.04 to 16.75, p =.043, Effect Size = .79).

So, we are being asked to place a lot of confidence in post-hoc results to get past the impression that this was an utterly null trial. There were no differences in the primary outcome at the end of treatment, but these differences being emphasized emerged in a nonrandom selection of patients. The largest differences in recovery of abstinence was for participants who were sill smoking after MBAT versus CBT, but MBAT participants had the highest rates of still smoking at the end of treatment. As for MBAT versus usual care, I don’t think we should attach much practical importance to p= .043.

Are the authors persuasive in claiming that they have demonstrated a benefit for MBAT over CBT? Over Usual Care?

I think the most straightforward conclusion is that adding intensive CBT and mindfulness-based treatments to simple support of use of nicotine patches does not accomplish much, at least in this population.

Is mindfulness training the new “gateway drug” to quack breast cancer treatments?

Integrative oncology is but a smokescreen for quacks – Edzard Ernst

Yoga-for-Cancer-Care-1024x953Has mindfulness-based stress reduction (MBSR) treatment become the equivalent of a “gateway drug” in cancer patients who go on to access a full range of unproven and disproven cancer treatments? I discuss this possibility in this edition of Quick Thoughts.

Here’s my argument:

  • Mindfulness-based stress reduction (MBSR) is widely promoted as a nonpharmacological “wonder drug” changing the brain and improving immune function.
  • Belief in the power of MBSR over cancer has replaced discredited beliefs about psychotherapy and support groups bringing the power of the mind to bear in “fighting” cancer.
  • MBSR groups are now offered through newly renamed “integrative cancer centers” which offer a full range of unproven and discredited treatments.
  • The seeming scientific status of health claims of MBSR lends support to the claims of integrative cancer centers that they have a modern scientific basis for treatments developed on the basis of traditional Chinese medicine.
  • Patients’ acceptance of exaggerated claims about the science behind MBSR leads to false confidence in other claims of integrative cancer centers that unproven treatments are actually evidence-based.
  • Once engaged at integrative cancer centers, women with advanced breast cancer are particularly likely receive a full range of services, which can consume time and money, but also delay or become alternatives to proven treatments.
  • MBSR can thus be a nonpharmacological “gateway drug” into an alternative pathway of cancer care in which unproven treatments are adopted by patients and even come to replace conventional, proven medicine.

Who can remain skeptical about the powers of MBSR?

It is difficult for even educated nonspecialists to evaluate claims of seeming experts that MBSR uniquely changes the brain and improves the immune system.

Studies claiming to correlate changes in brain functioning and structure with practicing MBSR get lots of uncritical media attention. When the studies are given a closer look, they are typically too small to warrant the strength of the claims that they are making, often don’t replicate, and don’t establish that any correlates are specific to MBSR, rather than also found with other experiences. Consumers need to keep in mind that all experiences change the brain, and that finding such correlates usually have unclear significance, even when they can be replicated.

Claims that MBSR influences the immune system come from a body of particularly weak and inconsistent findings with unknown, if any medical significance. I’ll be devoting a future edition of Mind the Brain to a skeptical look at the literature concerning effects of MBSR on the immune functioning of cancer patients. Suffice to say for now, these same claims were until recently made for support and psychotherapy groups. They were discredited not only because of a lack of consistent effects on immune functioning, but a lack of evidence that such groups affect the course or outcome of cancer. Effects of support groups on the immune system had been a presumed mediator, but it is no use pursuing a mediator of an effect if there is no effect to explain.

It is unlikely that endocrinologists or oncologists would be impressed by the findings of these studies of the MBSR or support groups. They would likely be especially skeptical of the plausibility of the medical claims that are being made. The role of the immune system in cancer is poorly understood and complex, but far beyond the simplistic models taken for granted in psychoneuroimunological  studies.

 The rise and fall of psychotherapy and support groups as a means of mind control over cancer

The claim that psychotherapy and support groups could improve the outcome of cancer garnered excitement and scientific credibility with a small 1989 study in The Lancet by David Speigel. I have critiqued that study thoroughly elsewhere, noting that the study was not designed nor powered for observing an effect on survival and claims made about its results depend on statistical flaws. In the Although Spiegel has persisted in his claims, no one can replicate his earlier study, not even Spiegel, in larger, methodologically superior studies. There is a lack of evidence that psychotherapy or support groups can extend the lives or influence the course of cancer.

Perhaps the absence of evidence for an effect of psychotherapy and support groups does not establish the absence of an effect, but the evidence is quite consistent and there is a lack of evidence supporting any plausible mechanism. Large-scale epidemiologic studies suggest that any apparent association between psychological factors and incidence and outcome of cancer is small enough to be within the range to be attributable to uncontrolled confounds and certainly not of clinical significance.

Support groups can be recommended to cancer patients for the opportunity to express their feelings, receive validation and support from others, and be of help to others. They are valued and satisfying experiences for many patients. However, a key difficulty that support groups reduce distress demonstrating in clinical trials is that most patients attending them do not have clinically significant distress . Floor effects are consistently observed, whereby the modest elevations of psychological distress of the bulk of patients recruited to clinical trials preclude there been any demonstration that support groups reduce psychological distress. There has been a move in the psycho-oncology  literature to set clinically significant distress one of the entry criteria for enrollment in clinical trials of psychosocial interventions. However, it takes considerable effort to recruit an adequate sample size because many patients who have appropriate levels of psychological distress are already receiving services and not interested in obtaining any more more. Others want to deal on their with what they understand as normal reaction. Setting heightened distress as a requirement for enrolling in a clinical trial of psychological interventions also means that the resulting sample will not be representative of the larger population of cancer patients from which they were drawn.

At the height of enthusiasm for medical benefits of support groups, many cancer patients attended them because they believed that they were getting medical, as well as psychological benefits. Eventually the American Cancer Society had to issue a statement about the lack of evidence of any medical benefits.

The research is clear that support groups can affect quality of life, but the available scientific evidence does not support the idea that support groups or other forms of mental health therapy can by themselves help people with cancer live longer.

 Support groups are out of fashion, MBSR is in

 MBSR is tremendously popular in non-patient populations. When informed of a cancer diagnosis, patients may view MBSR as a tool with which they already have experience or are familiar. Furthermore, surveys find that cancer patients believe that stress is an important cause of both the onset of cancer and recurrence. Thus, MBSR is readily acceptable as a familiar tool with added benefits in overcoming cancer as a physical disease, not just a psychological threat. The problem is, of course, a lack of evidence for such role of psychological factors in the implausibility of mechanisms by which psychological intervention might conceivably influence disease processes.

 Cancer center ads more emotional than informative 

 As seen in billboard and TV advertising campaigns, providing care for cancer is a lucrative and competitive business even among non-for-profit cancer centers. There is seldom evidence for the claims made in advertising campaigns they particular cancer center gets better outcomes. But advertisements typically back up the claims with moving patient testimonials about the outcomes they received.

Reputations for providing better care than rival centers attracts not only patient volume, but donor contributions. Most large cancer centers have fund raising departments ,  which routinely document the wealth of patients and the extent of effort that would be justified in obtaining a donation. I once worked at cancer center that had a large yacht bequeathed to it, which was kept and used to entertain potential donors of known wealth. There was also a fund for female oncologists to buy expensive fashionable clothes in order to make a pitch for funds at charitable events.

Cancer centers have established fees with hefty administrative costs by which donors can attach their name to the bench in the waiting area for tens of thousands of dollars or millions for naming a whole cancer center.

Effective marketing requires the cancer centers advertise that they treat the whole person, not just the tumor. Wealthy donors often specify that particular amenities be available. For instance, at the cancer center where I worked, a donor had insisted that friendly greeters welcome arriving cancer patients, just had been done for her at a world-renowned spa where she went for recuperation.

do you have

 A name change: from complementary and alternative medicine to integrative medicine centers

better respectful insolenceSuch amenities and services requested by donors become available for all patients and can improve their treatment experiences. But in the past decade, many cancer centers found competitive advantage in offering a full range of unproven and disproven alternative treatments. Sometimes donors specifically requested that such services be established. The availability of complementary alternative medicine (CAM) became a selling point. But then, a name change was required. As the pseudonymous cancer surgeon blogger Orac noted:

 

It was not long before the problem with the term CAM became apparent. It had the word “complementary” in it. The implication of that word, of course, is that what they were doing was still somehow not real medicine. It was complementary to real medicine, the icing on the cake, if you will. Real medicine could do without it, and having that implication in the very name that their evolving specialty had taken on was offensive to the quacks.

So they changed it.

Thus was born “integrative medicine.”

 Breast Cancer Integrative Oncology Care and Its Costs

 A recent article in Integrative Cancer Therapies documented the cost of integrative cancer care and contained some surprising revelations:

 Standish LJ, Dowd F, Sweet E, Dale L, Weaver M, Osborne B, Andersen MR. Breast Cancer Integrative Oncology Care and Its Costs. Integrative Cancer Therapies. 2016 May 26:1534735416649034.

More and more people diagnosed with cancer are choosing to supplement their conventional oncology treatment with complementary care provided by licensed complementary and alternative medicine (CAM) providers, including doctors of osteopathy, doctors of traditional Chinese medicine (TCM), and oncology board certified naturopathic oncologists (Fellows of the American Board of Naturopathic Oncology or FABNOs; http://www.fabno.org/), some of whom are co-licensed as acupuncturists. This growing field of medicine is increasingly being referred to as integrative oncology (IO). ND, FABNO consultations and some procedures are reimbursed by medical insurance companies in some states in the United States.

The article reported results of a study of 324 women who

Sought care at 1 of 6 naturopathic oncology clinics in Washington State were asked to enroll in a prospective 5 year observational outcomes study.

The findings:

More than 72 oral or topical, nutritional, botanical, fungal and bacterial-based medicines were prescribed to the cohort during their first year of IO care. Trametes versicolor was prescribed to 63% of the women. Mind-body therapy was recommended to 45% of patients, and 49% received acupuncture. Also, 26% were prescribed injectable therapy, including mistletoe, vitamin B complex (12%), IV ascorbate (12%), IV artesunate (7%), and IV nutrition and hydration (4%). Costs ranged from $1594/year for early-stage breast cancer to $6200/year for stage 4 breast cancer patients. Of the total amount billed for IO care for 1 year for breast cancer patients, 21% was out-of-pocket.

However:

A comprehensive protocol for stage 4 breast cancer includes IV nutrients and botanicals plus oral and topical natural medicine and costs approximately $32 000/year.

The article describes these services as all “evidence-based” but if they were evidence-based, they would be conventional, not complementary and alternative medicine.

 Is MBSR the gateway drug to quack treatments?

 Confrontation with a diagnosis of cancer, particularly when it is advanced and life-threatening, often leads to a search for information that inevitably includes unproven treatments. Patient’s susceptibility to misleading information is increased by the offering of unproven treatments and their labeling as “evidence-based” by prestigious cancer centers associated with medical schools lends credibility to unwarranted claims.

Almost half of the patients going to integrative medicine centers receive mind-body therapies, and undoubtedly MBSR figures prominently. MBSR is familiar, widely promoted as evidence-based, and use of it is consistent with patient believes about the role of stress in cancer. The acceptance of unwarranted claims of MBSR can be a step on the path of accepting claims of unproven and quack treatments as being evidence-based. In that sense, MBSR is the gateway drug for cancer patients to quack treatment.

 What is our responsibility to patients?

 There are always ethical issues with exaggerating the effectiveness of treatments or their evidence base for particular claims. But with vulnerable and often desperate cancer patients, ethical responsibilities become more pronounced. It’s incumbent on promoters of MBSR as a cure for all that ails should be clear that effects of MBSR on the immune system and the course and outcome of cancer are not established. Further, there is a lack of plausible biological mechanisms by which such effects would occur. Just as acknowledgment is now being done for support groups, it should be done for MBSR, particularly because of its likely place as a step on the way to unproven and quack treatments.

See also

skeptic north

Why patients should not enroll in a clinical trial of video gaming treatment for chronic fatigue syndrome

xboxIf I were a patient with with chronic fatigue syndrome/myalgic Encephalomyelitis (CFS/ME), I would not consent to be in a clinical trial of active video gaming for adults. I would consider withdrawing my consent if I had already provided it.

Either decision would be within my rights. I would be acting for myself, but also out of concern for the patient community.

But then again, saying no would mean I would miss dancin’ up with storm with Kinect Dance Central or being all I can be in the endless competition of  Sports Rivals.

  • Enrollment has begun for a clinical trial evaluating a treatment for chronic fatigue syndrome, but important details that should have been set remained ill-defined.
  • The trial is scientifically unsound, likely to contribute misinformation to the existing scientific literature, and has unresolved safety concerns. Recruitment began without patients having had an adequate say.
  • Participation in a clinical trial is not a responsibility that patients must accept. It’s a choice, a gift from them. Consenting to being in a clinical trial often involves patients assuming considerable burden with the hope that their participation will benefit others. Under the Declaration of Helsinki, patients can only be enrolled in clinical trials with their fully informed consent based on full consideration of risks and benefits.
  • Patients need to understand their basic rights and insist on active participation in the planning and design of clinical trials, as well as the analysis, interpretation and dissemination of results. Patients need to be prepared to refuse to consent to a clinical trial or to leave one when these conditions are not met.

An interview with the trial’s principal investigator is here. It raised serious concerns.

Thanks to Sasha Nimmo [I recommend following@sashanimmo on Twitter] for blogging about the opening of enrollment for this trial, interviewing the principal investigator, and providing some invaluable links.

The trial as summarized in the published registration:

Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is characterised by profound and debilitating exhaustion, resulting in chronic physical inactivity. The detrimental effects of physical inactivity, potentially related to inflammatory pathways (allostatic load) and the body’s ability to cope with stress, further compound the health risk of the disease. The aetiology of CFS/ME is unclear, and recent research has focussed unsuccessfully on individual inflammatory and immune biomarkers. Cumulative biomarkers such as the allostatic load index have stronger predictive power; enhancing our understanding of factors related to CFS/ME. To improve the health of people with CFS/ME and fill these knowledge gaps, this project will conduct a novel intervention using active video gaming to explore the relationships between allostatic load and physical activity in people with CFS/ME.
Aims
1. To investigate if active video gaming is an effective management strategy to increase the physical activity levels of adults with CFS/ME
2. To investigate the relationship between allostatic load and physical activity in people with CFS/ME
3. To determine the feasibility and acceptability of active video gaming as a management strategy to increase physical activity levels in adults with CFS/ME

The registration does not specify the video game patients to which patients will be randomized. However, in the interview with Sasha Nimmo, the investigator described it as:

A dance-based game called Kinect Dance Central and a sports game called Sports Rivals. These were chosen for pragmatic reasons, they are off-the-shelf easily available games, and after informal consultation with some adults of varying ages and genders with CFS, a preference to sporting and dance-type games was indicated.

Kinect-Demokinect sports rivalsHmm, I would love to see a record of the deliberations out of which this choice of games emerged, how many patients were involved and with what say.

It boggles my mind to imagine patients who actually suffers from ME dancing up a storm with Kinect Direct Center or becoming the “champion they were meant to be in an ever-evolving sports competition”  of Sports Rivals.

Why trial registration is important.

 Trial registrations commits investigators in advance of recruiting for a trial to particular details of the trial, including entry and exclusion criteria, procedures, sample size, primary and secondary outcomes, and key data analyses.

An adequate registration requires all these elements to be clearly specified. When they are not, or when the investigators subsequently ignore the registration, there is heightened risk of selective reporting, bias, and the dumping of misleading information into the scientific literature. Poorly defined trial registrations or their simply ignored by investigators contribute to an untrustworthy literature that communicates an exaggerations of the effectiveness of interventions that would be obtained in clinical practice.

When investigators do not adhere to a well-defined trial registration, they put patients, providers, and policymakers at risk of bad decisions based on poor quality data. Patients may be harmed by what they thought had been established scientifically as a safe, effective treatment.

Scientific Concerns.

The investigators have an inadequate idea of who will participate and how they will be described for clinical and scientific purposes.

 The trial registration does not provide scientifically and clinically useful inclusion criteria. What the principal investigator said in an interview worried me:

 The inclusion criteria for the study stipulate participants will need to have been diagnosed with CFS by a medical specialist and they will be requested to report which criteria were used for their diagnosis. Diagnostic uncertainty is an issue that has surrounded CFS research for some time, and unfortunately there still does not seem to be any consensus agreement. The inclusion criteria were designed to take a pragmatic approach which would provide the opportunity for sub-group analyses at the end of the study to determine whether diagnostic criteria were related to intervention outcomes.

This leaves basic entry criteria undefined. This being left open gives investigators an opportunity to exaggerate the effectiveness of their intervention at the end by making decisions about lumping and splitting of patients after they have already seen their outcome data and picking what works best.

 This looseness in describing entry criteria occurs against the backdrop of considerable confusion in Australia and misdiagnosis of persons suspected of having chronic fatigue syndrome/ myalgic encephalomyelitis. As many as two in five patients who are diagnosed by clinicians do not actually meeting the Fukuda chronic fatigue syndrome definition (CFS) or the International Consensus Criteria for Myalgic Encephalomyelitis (ICC ME).

 A recent article in the journal Clinical Epidemiology  reported:

A total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. Of these, 30.28% met Fukuda criteria. A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress. Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified.

Such a mixed bag of patients with unvalidated diagnoses will pose serious problems for any generalizing beyond the immediate sample. A sample collected elsewhere would very likely have a different case mix. Conclusions from this study would not hold.

Any generalizations about the whole sample would represent inaccurate portrayals of the patients within particular subgroups that are defined by specific diagnostic criteria.

No power analysis  [What is that?] is given for the particular recruitment goal of 30 patients stated in the trial registration. A sample of 30 means that 15 patients would be randomized to immediate receipt of the intervention and 15 would be placed on a waiting list. This would be a grossly underpowered trial, which some would argue in itself poses serious scientific and ethical problems.

The investigators’ post-hoc sorting of patients into subgroups would mean much smaller groups than the already small total sample of 30 would be examined, producing statistically meaningless results.

This trial would be a waste of resources and the invalidity of the results would mean that the efforts of patients who had consented to participate were squandered.

Data will be analyzed for a 12 month follow-up, but the study is randomized only for six months.

The principal investigator said in the interview:

The pilot study is designed so that there is a 6 months comparison of the intervention to control and after that time the waitlisted control group will then participate in the intervention for the final six months.

The principal investigator described the clinical trial as only a pilot study, but it is not described that way in the trial registration. Instead, it is clearly aiming to introduce an estimate of the efficacy of the intervention into the literature.

The primary outcome will be assessed at 12 months. However, there is no control group at that point, and so interpretation will be made without the benefit of a comparison. The difficulty that this poses is that any change from 6 to 12 months will be attributed to the intervention, whereas some or all of it of it might be due to changes that would occur in the absence of intervention or by patients remaining in routine care.

Safety concerns.

 The principal investigator seems unaware of the dangers posed to patients by overexertion.

 The principal investigator stated:

 Unfortunately, the issues surrounding the PACE trial have clouded some people’s thoughts regarding the benefit of physical activity for people with chronic conditions such as people with CFS. This is potentially detrimental given the indisputable research surrounding the health benefits of physical activity.

“Indisputable?” I worry what the investigator means by issues surrounding the PACE trial being ‘clouding some people’s thoughts’. If the investigator rejects the serious criticisms that have been leveled against the PACE trial and its investigators, I don’t think they should expect much patient participation.

The investigator group does not grasp the understandable concerns that patients share with researchers like myself and many others about the results of the PACE trial being fatally flawed.

 Moreover, the statements concerning “indisputable research concerning the health benefits of physical activity” is a general statement that is misleading when applied to chronic fatigue syndrome/ myalgic Encephalomyelitis.

The investigator may not be sufficiently medically informed about the condition to anticipate and respond to likely serious adverse events.

The trial registration had conveyed a bias against construing CFS/ME as a physical health condition, rather than a mental health condition. Maybe that bias is now coming home to roost.

The aetiology of CFS/ME is unclear, and recent research has focussed unsuccessfully on individual inflammatory and immune biomarkers.

“Unsuccessfully?” How about the ineffectiveness and harm of treating CFS/ME as a mental disorder with cognitive behavioral therapy and graded exercise therapy?

If I were a patient with ME, I would worry about being harmed by the exercise required for participation in the trial and for the trial team being ill-prepared to respond appropriately. Given the statements that were made in the interview by the principal investigator, I’ve wonder if the consenting process for patients involves accurate portrayal of the potential risks of participating.

 Will the data be shared after the study is completed?

The principal investigator’s answer  evaded revealing whether the data would be shared, with whom, and under what conditions.

Patient should not consent to participation in a trial where data are not publicly shared. The data should be available for reanalysis, checks on the interpretations made by the investigators, and integration with other data in a transparent fashion.

Notoriously, investigators in the PACE trial of cognitive behavior therapy and graded exercise for chronic fatigue syndrome continue to refuse to share their data – even when they published in PLOS One, a journal where making the data available was required. They have attacked the character of anyone seeking access to the data, particularly patients. They have even barred a professional from obtaining access to the data on the grounds she has visited patient websites.

The PACE investigators even argue that the possibility of damage to their interpretations of the trial and their reputations is sufficient to require a noncritical attitude toward them as a condition for receipt of the data. But they readily share their data with colleagues who accept and promote their distorted interpretations.

 The failure to specify that data will be made publicly available without restrictions would alone be sufficient for me to refuse participation in the trial.

An already misleading literature concerning treatment of adults with ME/CFS.

 The scientific literature concerning treatment of chronic fatigue syndrome is dominated by investigators who consistently misrepresent their findings; refuse to share their data; and have financial conflicts of interests that are served by inflated estimates of the efficacy of psychological interventions for ME/CFS.

The financial interests of  investigators have also intruded upon a systematic summary of the effectiveness of intervention, providing misinformation in a recent Cochrane review, so that the review is neither objective nor trustworthy.

 Patient involvement should be from the start of the planning of a trial.

 The “stakeholder advisory group” for this trial has not even met yet, despite recruitment already having begun. The diverse advisory group seems heavy on researcher and professional involvement, and weak on patient representation. Only two patient representatives are indicated.

The principal investigator stated in the interview:

Part of the project involves forming a Stakeholder Advisory Group which will include rheumatologists, exercise physiologists and the research team, but more importantly several people from the general public who are managing CFS and at least two representatives from the SA ME/CFS Society and Bridges and Pathways; all of whom will help finalise the finer points of the intervention before it commences. The Stakeholder Advisory Group is soon to convene to finalise details. I acknowledge that perhaps some members of the ME and CFS community may not agree with all components of the study design, and I welcome any discussions with them in order to improve the proposed project.

Peter Mitchell, Secretary, responded on behalf of the Management Committee of ME/CFS Australia (SA) Inc:

We have no input into the design of the trial.

We are cognizant of the many faults in the PACE trial which claims, incorrectly, to demonstrate the value of GET [graded exercise therapy] for people with ME/CFS.  We are also aware of the survey indicating the harm experienced by patients who have attempted GET.

Our organisation is therefore unequivocally opposed to the practice of GET for patients with ME/CFS, and we would not lend our support to any study that had that intention.

The Bridges and Pathways ME/CFS Multidisciplinary Clinical and Research Centre responded to the question Did you raise any objections about this study?”:

We did not know about it until it was on the [South Australian] ME/CFS Society’s website.

To the question: “What is Bridges and Pathways position on graded exercise therapy?”:

B&P uses a biomedical model of ME/CFS and have a recognition that many people have mitochondrial (energy making) faults or immune system faults that can be increased with physical exercise and stress. These pathways can now be measured and identified using laboratory tests. We do not include graded exercise therapy as one of our recommended treatments.

What patients should require before consenting to participate in research…

An editorial in The BMJ has taken a bold stand about greater patient involvement in all phases of research:

Working with other journals, research funders, and ethics committees, we hope that at some time in the future only research in which patients have been fully involved will be considered acceptable.

In their instructions to authors, The BMJ now includes a section Reporting patients’ involvement in research which states:

As part of its patient partnership strategy, The BMJ is encouraging active patient involvement in setting the research agenda.

We appreciate that not all authors of research papers will have done this, and we will still consider your paper if you did not involve patients at an early stage. We do, however, request that all authors provide a statement in the methods section under the subheading Patient involvement.

This should provide a brief response to the following questions:

How was the development of the research question and outcome measures informed by patients’ priorities, experience, and preferences?

How did you involve patients in the design of this study?

Were patients involved in the recruitment to and conduct of the study?

How will the results be disseminated to study participants?

For randomised controlled trials, was the burden of the intervention assessed by patients themselves?

Patient advisers should also be thanked in the contributorship statement/acknowledgements.

If patients were not involved please state this.

If this information is not in the submitted manuscript we will ask you to provide it during the peer review process.

Please also note also note that The BMJ now sends randomised controlled trials and other relevant studies for peer review by patients.

Will the Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients of Australia rise up and inspire the parents of child and teen CFS/ME patients of the UK?

Australian patients face a clear challenge and a clear choice whether to participate in this clinical trial. Maybe they can act in a way that inspires the parents of CFS/ME children in the UK to similarly demand involvement before consenting to their children to participate in a clinical trial. Principal Investigator Esther Crawley has given no indication that she will share her data from a new trial of an Internet-based CBT program for adolescents with CFS.

Esther Crawley has a bad history with the patient community. Through the NHS, she inflicted a quack Lightning Process treatment on children and adolescents with CFS/ME in the SMILE trial. Yet, three years after completing the trial, she still has not published the results. But her friend Phil Parker has profited handsomely. Although the UK’s Advertising Standards Authority (ASA) has forbidden him from advertising the Lightning Process as a medical treatment, Parker has received payment for training and providing treatment in a clinical trial. Parker even implied on his promotional website that his treatment was being used in the Northern Ireland NHS – that is, until I alerted a member of the Northern Irish National Assembly Health Committee and the NHS insignia was removed.

If Esther Crawley won’t commit to publishing the data from her new trial and sharing it in a timely matter, why should parents consent for their children to enroll? Parents should demand greater say in all phases of the trial as a condition for consenting for their children or for keeping their children in the trial. Taking their children out of the trial is their right.

 

A systematic review of mindfulness-based stress reduction for fibromyalgia that I really like

melbourneI am preparing a keynote address, Mindfulness Training for Physical Health Problems, to deliver at the World Congress of Behavioural and Cognitive Therapies in Melbourne on Friday, June 24, 2016. I have been despairing about the quality of both the clinical trials and systematic reviews of mindfulness treatments that I have been encountering.

Mindfulness training, mindfulness-based cognitive therapy, and mindfulness-based stress reduction (MBSR) are hot topics. That means that studies get published with obvious methodological problems ignored,  and premature and exaggerated claims are rewarded. Articles are  prone to spin and confirmation bias, not only in the reporting the results of a particular study, but also in what past studies get cited or are buried,  depending on whether they support all the enthusiasm.

bandwagon1_original_original_original_crop_northIt is difficult to get a fair evidence-based appraisal of MBSR for clinicians, patients, and policy makers.  There is a bandwagon rushing far ahead of what best evidence supports. Aside from all the other problems, the literature is being hijacked by enthusiastic promoters with undisclosed conflicts of interest who hype what they don’t tell us they are offering for sale elsewhere. Clear declarations of conflicts of interest, please.

We know that MBSR is better than no treatment. But there is only weak and inconsistent evidence telling us whether MBSR is better than other active treatments delivered with the same intensity and the same positive expectations.

Most often, MBSR is compared to a waitlist control or treatment as usual. Depending on the context, we don’t know if these control groups are actually the opposite of placebos,  nocebos Patients agreed to participate in a study that gave them a chance to get MBSR. Left in the (unblinded) control condition, they got nothing except having to be assessed repeatedly. They are going to be disappointed and this reaction is going to register in the self-report outcome data received from them.

Also, the ill-described routine care or treatment as usual as being provided may be so inadequate that we are only witnessing MBSR compensating for poor quality treatment, rather than making an active contribution of its own. This was particularly true when mindfulness training was used to taper patients from antidepressants. Patients receiving MBSR and tapering were compared to patients remaining in the routine care in primary care in which they had placed on antidepressants some time ago. At the time of recruitment, many patients were simply being ignored with minimal or no monitoring of theyor whe were taking their medication or they were even still depressed. It’s not clear whether reassessing whether the medication is still being of any benefit and providing support for tapering would’ve accomplished as much or than MBSR accomplished, without requiring daily practice or a full day retreat.

Data describing treatment as usual or routine care control conditions are readily available, but almost never reported in studies of evaluating MSB are.

To take another example, when patients with chronic back pain are being recruited  from primary care, their long term routine care eventually lacks support, positive expectations, or encouragement and may become iatrogenic  because guidelines requiring escalating futile interventions. Here too, putting back in some support and realistic expectations may work as well as more complicated n interventions.

Some members of the audience in Melbourne surely anticipate a relentlessly critical perspective on mindfulness from me. They will be surprised when I present limitations of current literature, but also positive recommendations for how future studies can be improved.

We need less research evaluating MBSR, but of a better quality.

There is far too much bad mindfulness research being done and uncritically cited and being put into systematic reviews. A meta-analysis cannot overcome the limitations of individual trials, if the bulk of the studies being integrated share the same problems. Garbage in, garbage out is a bit too harsh, but communicates a valid concern.

I think it is very important that meta analysis  with a hot topic like MBSR not become overly focused on summary effect sizes. Such effect sizes are inevitably inflated because of a dependence on at best a few small studies with a high risk of bias, which includes the allegiance of overenthusiastic investigators. These effect sizes are best ignored. It is better instead to identify the gaps and limitations in the existing literature, and how they can be corrected.

Stumbling on a quality review of MBSR for fibromyalgia.

I was quite pleased to stumble upon a review and meta-analysis of MBSR for fibromyalgia. Although it is published in a pay walled journal, a PDF is available at ResearchGate.

 Lauche R, Cramer H, Dobos G, Langhorst J, Schmidt S. A systematic review and meta-analysis of mindfulness-based stress reduction for the fibromyalgia syndrome. Journal of Psychosomatic Research. 2013 Dec 31;75(6):500-10.

Here’s the abstract:

Objectives: This paper presents a systematic review and meta-analysis of the effectiveness of mindfulness-based stress reduction (MBSR) for FMS.

Methods: The PubMed/MEDLINE, Cochrane Library, EMBASE, PsychINFO and CAMBASE databases were screened in September 2013 to identify randomized and non-randomized controlled trials comparing MBSR to control interventions. Major outcome measures were quality of life and pain; secondary outcomes included sleep quality, fatigue, depression and safety. Standardized mean differences and 95% confidence intervals were calculated.

Results: Six trials were located with a total of 674 FMS patients. Analyses revealed low quality evidence for shortterm improvement of quality of life (SMD=−0.35; 95% CI−0.57 to−0.12; P=0.002) and pain (SMD=−0.23; 95% CI −0.46 to −0.01; P=0.04) after MBSR, when compared to usual care; and for short-term improvement of quality of life (SMD=−0.32; 95% CI −0.59 to −0.04; P=0.02) and pain (SMD=−0.44; 95% CI −0.73 to −0.16; P=0.002) after MBSR, when compared to active control interventions. Effects were not robust against bias. No evidence was further found for secondary outcomes or long-term effects of MBSR. Safety data were not reported in any trial.

Conclusions: This systematic review found that MBSR might be a useful approach for FMS patients. According to the quality of evidence only a weak recommendation for MBSR can be made at this point. Further high quality RCTs are required for a conclusive judgment of its effects.

I will be blogging about MBSR for fibromyalgia in the future, but now I simply want to show off the systematic review and meta-analysis and point to some of its unusual strengths.

fibromyeliaA digression: What is fibromyalgia?

Fibromyalgia syndrome is a common and chronic disorder characterized by widespread pain, diffuse tenderness, and a number of other symptoms. The word “fibromyalgia” comes from the Latin term for fibrous tissue (fibro) and the Greek ones for muscle (myo) and pain (algia).

Although fibromyalgia is often considered an arthritis-related condition, it is not truly a form of arthritis (a disease of the joints) because it does not cause inflammation or damage to the joints, muscles, or other tissues. Like arthritis, however, fibromyalgia can cause significant pain and fatigue, and it can interfere with a person’s ability to carry on daily activities. Also like arthritis, fibromyalgia is considered a rheumatic condition, a medical condition that impairs the joints and/or soft tissues and causes chronic pain.

criteria fibromyalgiaYou can find out more about fibromyalgia from a fact sheet from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD)  that is only minimally contaminated by outdated notions of fibromyalgia being a psychosomatic condition, i.e., all in the head, or recommendations for unproven complementary and alternative medicines.

 What I like about this systematic review and meta-analysis.

 The authors convey familiarity with the standards for conducting and reporting systematic reviews and meta-analyses, recommendations for the grading of evidence, and guidelines specific to the particular topic, fibromyalgia. They also admit that they had not registered their protocol. No one is perfect, and it is important for authors to indicate that they are aware of standards, even when they do not meet them. Readers can decide for themselves how to take this into account.

This review was planned and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. guidelines (PRISMA) [15], the recommendations of the Cochrane Musculoskeletal Group [16,17] and the GRADE recommendations (Grading of Recommendations Assessment, Development and Evaluation) [18]. The protocol was not registered in any database.

The authors also laid out key features of systematic review and meta-analyses where you would expect to find them with explicit headings: eligibility criteria, search strategy, study selection and data collection including risk of bias in individual studies, etc.

Designation of primary and secondary outcomes.

Fibromyalgia causes pain and fatigue, disrupting quality of life. These are the outcomes in which patients and their healthcare providers will be most interested. Improvement in pain should be given the priority. However, in clinical trials of MBSR for fibromyalgia ,investigators often administer a full battery of measures, and select the ones that are positive, even if they’re not the outcomes that will be most important to patients and providers. For instance, the first report from one trial focused on depressive symptoms . Designating depressive symptoms as the primary outcome ignored that  not all patients with fibromyalgia have heightened depressive symptoms, and depression is not their primary concern. Moreover, the paper reporting this clinical trial is inconsistent with  its regiistration, where a full range of other outcomes were designated as primary. Ugh, such papers defeat the purpose of having their protocols registered.

In the review under discussion, depressive symptoms were designated as a secondary outcome, along with sleep and fatigue.

 Compared to what?

The review clearly distinguished waitlist/routine care from active comparison treatments and provide separate effect sizes.

The review also indicated whether the patients had been randomized to MBSR versus comparison treatment, and explicitly indicated that any significant effects for MBSR are disappeared when only randomized trials were considered.

 Strength of recommendation.

The review took into account the small number of studies (4 randomized and 2 non-randomized trials  with a total of 674 patients) and the low quality of evidence in grading the recommendation that it was making:

According to GRADE, only a weak recommendation could be made for the use of MBSR for FMS, mainly due to the small number of studies and low quality of evidence.

 Summary of main results.

The article produces a series of forest plots [How to read one ] that graphically display the unambiguous results showing weak effects of mindfulness in the short-term but none in the long term. For instance:

pain short and long

This meta-analysis found low quality evidence for small effects of MBSR on quality of life and pain intensity in patients with fibromyalgia syndrome, when compared to usual care control groups or active control groups. Effects however were not robust against bias. Finally, data on safety were not reported in any study.

 Agreements and disagreements with other systematic reviews.

The few other reviews of MBSR fibromyalgia are of poor quality. So, the authors of  this review discusses results in the context of the larger literature of MBSR for physical health problems.

 Implication for further research.

Too often, reviews of fashionable psychological interventions for health problems end with an obligatory positive assessment and, of course, “further research is needed.”

Enthusiasts assume MSBR is that it is good for whatever ails you. MBSR training can help you cope, if it doesn’t actually address your physical health problem. I really liked that this review gave pause and reflected on why MBSR should be expected to be the treatment of choice and to make sure that relevant process and outcome variables are being assessed.

Patients with fibromyalgia are seek to relieve their debilitating pain and accompanying fatigue, or at least resume some semblance of a normal life they have lost their condition. It is important that results of MBSR research allow informed decisions about whether it is worth the effort to patients and providers to get involved in MBSR or whether it would simply be more more burden with uncertain  results.

One major implication for future research is that researchers should bear in mind that MBSR primarily aims to establish a mindful and accepting pain coping style rather than to reduce the intensity of pain or other complaints. Therefore researchers are encouraged to select custom outcomes such as awareness, acceptance or coping rather than intensity of symptom which might not reflect the intention of the intervention. Only two trials measured coping, however, only one of them actually reported results and the other one [47] did not provid data but stated that besides catastrophizing there were no significant group differences. Results of the trial by Grossmann et al. [49] on the other hand indicated significant improvements on several subscales, which could be worth further investigations.

Further high quality RCTs comparing MBSR to established therapies
(e.g. defined drug treatment, cognitive behavioral therapy) are also required
for the conclusive judgment.

Conclusion.

This systematic review found low quality evidence for a small short term improvement of pain and quality of life after MBSR for fibromyalgia, when compared to usual care or active control interventions. No evidence was found for long-term effects.

Not much spin here or basis for yet recommending MBSR for fibromyalgia  as ready for  implementing in routine care.

 

No, irritable bowel syndrome is not all in your head.

Updated May 22, 2016. I have added an opening summary, as well as a few links for readers who may want to learn more about IBS as a physical health problem about which we are learning a lot, not a mental health issue.

Irritable bowel syndrome (IBS) has symptoms in common with other physical conditions. IBS ranges in severity from mild and infrequent episodes to more frequent,severe, longer, and more debilitating episodes. It is thus a  recurrent, episodic condition. For many patients in many healthcare contexts, IBS remains an undiagnosed pattern of recurrent, but different symptoms that are presented without much relief.

Often IBS is effectively managed in primary care with lifestyle management and monitoring and identifying of triggers. However, when IBS is not effectively dealt with in primary care, a patient may need a referral to a specialist. This article argues that first specialist who  is considered should be a gastroenterologist, not a mental health professional.

Evidence is accumulating that IBS is often a disturbance in the gut-brain relationship. In that sense, it has a psychological component. But it is important to recognize that it is a matter of the gut influencing the brain by way of well-documented pathways.

IBS is increasingly seen as a  disturbance in the microbiota or microbiome (I explain what that means below) of the gut. President Obama has directed the NIH to study the human microbiota or microbiome as part of a larger initiative studying these phenomena in other ecological systems, including soil. There is a lot of enthusiasm for this broad initiative, but also some caution that the enthusiasm should not get too far ahead of the data. I have added some links about this.

Anxiety and depression often accompany IBS. The symptoms may reflect the uncertainty and discomfort of trying to managing an ill-defined condition. But this distress also may be a direct effect of the gut on the brain, again through increasingly known pathways.

Patients with undiagnosed IBS challenge and ultimately frustrate physicians. When physicians cannot resolve their complaints, patients sometimes get mistreated and blamed for their condition.

Previous explanations for IBS focused on it being an expression of unconscious conflicts. Psychoanalytically oriented explanations suggest anal conflicts in which the patient struggles with hostility that she cannot express directly. IBS can been seen as a conflict between retaining in expelling fecal contents. Diarrhea or loose bowel movements can be seen as symbolically crapping on somebody in a situation where anger cannot be directly expressed. Such explanations are creative and  even literary, but they are  testable hypotheses about an individual patient. Such ideas just do not hold up in research studies, often because the hypotheses cannot be coherently expressed with key variables  assessed with validated measures.

I’m not a physician and I’m not a position to offer advice to individual sufferers from IBS. But if I or a family member developed what looked like IBS, and it could not be brought under control in primary care. I would not recommend referral not to a mental health professional as the next step.

In the UK, IBS is considered a medically unexplained symptom (MUS). IBS patients are likely to be referred to psychological interventions for which there is only weak evidence. Patients with IBS may have to get educated on their own about the condition and fend for themselves in a medical system that is unresponsive to them.

Finally, some readers have attempted to leave comments on this blog post discussing benefits they sincerely believe they have received from treatments, including dietary supplements for which there is not scientific evidence. I have not accepted those comments for posting. I’m very skeptical of alternative and complementary medicine which is basically  unproven medicine. I also see suffers from IBS vulnerable to exploitation by all sorts of deliberate or innocent quackery.

A segment of CBS This Morning Saturday News showed the view of Irritable Bowel Syndrome (IBS) as  “all in your head” is outmoded. Placing the source of IBS as “all in the head” is unlikely to lead to improvement in a chronic, intermittent condition affecting millions of people, and disproportionately women.

Jonathan LaPookThe Host Was CBS News Chief Medical Correspondent, Jonathan LaPook.

 

 

 

 

 

 

Mark Pimental

Mark Pimentel MD (@MarkPimentelMD) on Twitter

He was interviewing Mark Pimental, MD, Associate Professor of Medicine, and Director of the G.I. Motility Program of Cedars-Sinai in Los Angeles.

 

 

 

 

 

 

 

At one point, Dr. LaPook poked fun at the obsolete approach to IBS in which physicians patted women on the head and told them that their condition was result of anxiety and depression.

pat on the head.PNGDr. Pimentel offered a view of IBS coming out of his research and specialty practice:

Irritable Bowel Syndrome (IBS) is one of the most common chronic medical conditions, affecting 10%-15% of the population in the United States and worldwide. Work on two distinct fronts has suggested that the pathophysiology of IBS may have microbial origins. First, a series of studies and meta-analyses over the last decade suggests that IBS can develop after a single episode of acute bacterial gastroenteritis (referred to as post-infectious IBS (PI-IBS). While these subjects exhibit characteristic gut immunologic changes (in the mucosa and myenteric ganglia), the mechanisms underlying the transition to an IBS phenotype remain unknown. Second, subjects with IBS have been shown to have specific changes in luminal bacterial contents, the most common of which is small intestinal bacterial overgrowth (SIBO), a condition whereby coliform bacterial counts in the small bowel become excessive. The presence of SIBO in IBS subjects has recently been confirmed by both small bowel culture and by quantitative PCR (qPCR) of duodenal contents.

Dr. LaPook advised sufferers of IBS to work with their primary care physicians to determine whether lifestyle changes could avoid episodes of IBS or at least make them less frequent and severe. If these efforts were not successful, Dr. LaPook recommended that they consult a specialist – a gastroenterologist, not a mental health professional!

More resources about contemporary views of IBS

Here’s a link to a US National Institute of Health webpage about Symptoms and Causes of Irritable Bowel Syndrome:

What causes IBS?

Doctors aren’t sure what causes IBS. Experts think that a combination of problems can lead to IBS.

Physical Problems

Brain-Gut Signal Problems

Signals between your brain and the nerves of your gut, or small and large intestines, control how your gut works. Problems with brain-gut signals may cause IBS symptoms.

GI Motility Problems

If you have IBS, you may not have normal motility in your colon. Slow motility can lead to constipation and fast motility can lead to diarrhea. Spasms can cause abdominal pain. If you have IBS, you may also experience hyperreactivity—a dramatic increase in bowel contractions when you feel stress or after you eat.

Pain Sensitivity

If you have IBS, the nerves in your gut may be extra sensitive, causing you to feel more pain or discomfort than normal when gas or stool is in your gut. Your brain may process pain signals from your bowel differently if you have IBS.

Infections

A bacterial infection in the GI tract may cause some people to develop IBS. Researchers don’t know why infections in the GI tract lead to IBS in some people and not others, although abnormalities of the GI tract lining and mental health problems may play a role.

Small Intestinal Bacterial Overgrowth

Normally, few bacteria live in your small intestine. Small intestinal bacterial overgrowth is an increase in the number or a change in the type of bacteria in your small intestine. These bacteria can produce extra gas and may also cause diarrhea and weight loss. Some experts think small intestinal bacterial overgrowth may lead to IBS. Research continues to explore a possible link between the two conditions.

Neurotransmitters (Body Chemicals)

People with IBS have altered levels of neurotransmitters—chemicals in the body that transmit nerve signals—and GI hormones. The role these chemicals play in IBS is unclear.

Younger women with IBS often have more symptoms during their menstrual periods. Post-menopausal women have fewer symptoms compared with women who are still menstruating. These findings suggest that reproductive hormones can worsen IBS problems.

Only at the bottom of the page is any reference to the traditional view that IBS somehow expresses psychological conflicts.

The dominant theme of the fact sheet is that IBS is often a disorder of the brain-gut signaling. However, the signaling problem originates in the gut which influences the brain.

Here is a link to a freely available  article in JAMA, the Journal of the American Medical Association, Small Intestinal Bacterial Overgrowth: A Framework for Understanding Irritable Bowel Syndrome.

IBS as a disorder of the microbiota or microbiome.

A microbiota is “the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space”.[1][2] Joshua Lederberg coined the term, emphasising the importance of microorganisms inhabiting the human body in health and disease. Many scientific articles distinguish microbiome and microbiota to describe either the collective genomes of the microorganisms that reside in an environmental niche or the microorganisms themselves, respectively.[3][4][5] However, by the original definitions these terms are largely synonymous There are trillions of microbes in the human microbiome, although the entire microbiome only accounts for about for 1-3% total body mass,[6] with some weight-estimates ranging as high as 3 pounds (approximately 48 ounces or 1,400 grams).[n 1] Research into the role that microbiota in the gut might play in the human immune system started in the late 1990s.[9] The microbiome of the gut has been characterised as a “forgotten organ”,[10] and the possibility has been raised that “the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms”.[11] The human microbiome may have a role in auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, fibromyalgia, and perhaps some cancers.[12] A poor mix of microbes in the gut may also aggravate common obesity.[13][14][15] Since some of the microbes in the human body can modify the regulation of some neurotransmitters, it may be possible to use certain microorganisms to supplement treatments for depression, bipolar disorder and other stress-related psychiatric disorders.[16]

BMC Medicine is assembling a new article collection “The Microbiome and Man,” guest edited by Dr Omry Koren.

But I warn you it is heavy going and highly technical.

Here’s a more accessible link describing President Barack Obama’s National Microbiome Initiative:

Microbiomes are the communities of microorganisms that live on or in people, plants, soil, oceans, and the atmosphere. Microbiomes maintain healthy function of these diverse ecosystems, influencing human health, climate change, food security, and other factors. Dysfunctional microbiomes are associated with issues including human chronic diseases such as obesity, diabetes, and asthma; local ecological disruptions such as the hypoxic zone in the Gulf of Mexico; and reductions in agricultural productivity.

Here is an interesting link to an account of a participant in a citizen scientist effort to map the human microbiota, Some of My Best Friends Are Germs:

 Microbiomes are the communities of microorganisms that live on or in people, plants, soil, oceans, and the atmosphere. Microbiomes maintain healthy function of these diverse ecosystems, influencing human health, climate change, food security, and other factors. Dysfunctional microbiomes are associated with issues including human chronic diseases such as obesity, diabetes, and asthma; local ecological disruptions such as the hypoxic zone in the Gulf of Mexico; and reductions in agricultural productivity.

This article from USA Today is reasonably well-informed:There’s 10 trillion microbes on you; the White House wants to figure them out.

This freely available article from Nature expresses enthusiasm about the US initiative, but indicates that there are some challenges ahead that require an international effort. It’s balanced: Microbiology: Create a global microbiome effort.

The outmoded view of IBS is dominant in the UK

Suzanne O’Sullivan’s  “It’s All in Your Head “is a collection of obsolete and simply wrong ideas about “psychosomatic conditions” in itself an outmoded term, but still in circulation in the UK. She specifically mentions IBS in an editorial based on the book in The Lancet:

 Some 20% of people in the UK have irritable bowel syndrome. This is one of the most common reasons for people to present to a gastroenterology clinic. It is also a condition that is affected by psychological distress and where no organic bowel disease is evident. And yet, to convince patients that psychosomatic disorders are an everyday problem that could affect any sort of person is very difficult. To tell somebody that their medical complaint might have an emotional cause is often met with anger. It is hard to believe that we can lose control of our bodies so completely and without our knowledge. And if our subconscious has chosen to mask our psychological distress and express it in a way more palatable to us then it follows that to remove the mask will be painful.

Suzanne O’Sullivan suggests the role of the physician in the UK is to convince the patient that IBS is all in her head. The notion that “our subconscious is choosing to mask psychological distress” is at the root of the problem would be considered rubbish by informed American professionals. It’s one of many neo-crypto-psychoanalytic ideas that of have crept into CBT in the UK, despite lacking empirical evidence and being untestable with the individual patient.

O’Sullivan doesn’t tell us, but she’s referring to the old psychoanalytic literature that considers IBS as expressing unresolved anal issues acquired in potty training. Then she expresses confusion why some patients are offended by this.

Stay tuned for a blog post in Mind the Brain that traces this idea to the fraudulent data of Hans Eysenck.

Simon Wessely has praised Suzanne O’Sullivan’s book.  It was picked for Wellcome book award as a ‘thoughtful, humane and heartfelt’ study” by Baroness Joan Bakewall. The  Baroness  closed her Twitter account and fled social media after making uninformed comments blaming sufferers of anorexia for their condition:

Bakewell, 82, said: “I am alarmed by anorexia among young people, which arises presumably because they are preoccupied with being beautiful and healthy and thin.

“No one has anorexia in societies where there is not enough food. They do not have anorexia in the camps in Syria. I think it’s possible anorexia could be about narcissism.”

She added: “To be unhappy because you are the wrong weight is a sign of the overindulgence of our society, over-introspection, narcissism, really.”

It’s all in your head”is also the view of IBS promoted by Trudie Chalder and her co-investigator Simon Wessely in a King’s College, London slide presentation aimed at getting primary-care physicians to refer patients to their PRINCE Project. PRINCE is an clumsy acronym for Persistent physical symptoms Reduction INtervention:  a system Change & Evaluation in Primary and Secondary Care.

first slide MUS presentation 2015-2-page-0

second slide MUS presentation 2015-2-page-0

third slide MUS presentation 2015-2-page-0

As can be seen, the brain-gut connection is portrayed as running from the controlling brain  down to the gut.

An article about CBT for medically unexplained symptoms is recommended for the GP’s self-study.

fourth slide MUS presentation 2015-2-page-0.jpg

The preferred treatment for IBS is CBT.

fifth slide-page-0.jpg

As an American, I can’t make a positive identification of this, but I strongly suspect a British attempt at humor. However, I find it quite revealing of how psychoanalysis intrudes into what passes for CBT in the UK. This is associated with lots of patient-blaming notions about somatic conditions expressing hidden conflicts about sex and aggression and dependency.

Participation in clinical trials should be based on patients being fully informed about alternatives. I don’t know if modern treatment of IBS is available in the UK. But if I had a friend who was approached by their GP in the UK about participating in PRINCE, I would recommend that the friend become acquainted with the contemporary view of IBS in the rest of the world, and if necessary, educate their GP.

The undoing of Pharma’s promotion of antidepressants as safe and effective for young people

The treasure trove: Annotated links to some relevant materials.

treasure troveMy recent post at Mind the Brain, Study protocol violations, outcomes switching, adverse events misreporting: A peek under the hood  concerns a must-read IJRSM article:

Jureidini, JN, Amsterdam, JD, McHenry, LB. The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance. International Journal of Risk & Safety in Medicine, vol. 28, no. 1, pp. 33-43, 2016

Which offers a detailed critique and re-analysis of:

Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry. 2004 Jun 1;161(6):1079-83.

Letters to the Editor concerning the AJP article

 Shortly after the original article appeared in AJP, there was a series of letters to the editor commenting on the article and the authors responded:

RÉMY P. BARBE, M.D.,  Child Psychopharmacology, Effect Sizes, and the Big Bang

ANDRÉS MARTIN, M.D., M.P.H., WALTER S. GILLIAM, Ph.D., New Haven, Conn., JEFFREY Q. BOSTIC, M.D., Ed.D., Boston, Mass., and JOSEPH M. REY, M.D., Sydney, Australia. Child Psychopharmacology, Effect Sizes, and the Big Bang

MAJU MATHEWS, M.D., M.R.C.Psych., BABATUNDE ADETUNJI, M.D., F.A.S.A.M., JOANNE MATHEWS, M.D., BIJU BASIL, M.D., VINU GEORGE, M.D., MANU MATHEWS, M.D., KUMAR BUDUR, M.D., and SHINY ABRAHAM, M.D., Kottayam, Child Psychopharmacology, Effect Sizes, and the Big Bang

KAREN DINEEN WAGNER, M.D., Ph.D., ADELAIDE S. ROBB, M.D., ROBERT L. FINDLING, M.D., and JIANQING JIN, Ph.D., Dr. Wagner and Colleagues Reply

Additional Background Notes for the IJRSM article posted by JM Nardo

Here are links to more rich material, including documents that were received from Forest Laboratories and a history of attempts to get this article published. For these and other materials, I am grateful to John M Nardo, MD. I’ve included some other links to his relevant blog post as well

In addition to detailing the history of the IJ RSM article, Dr. Nardo provides:

Other relevant blog posts from JM Nardo

In this series of blog posts, Nardo comments on both the deconstruction of citalopram CIT-MD-18, but also a reanalysis in which he was involved that was published in The BMJ, Restoring Study 329.  Links to that important paper and relevant materials will be presented in the section below this one on his blog posts.

the jewel in the crown… Posted on Thursday 5 May 20

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
In our paper, we were able to obtain the raw data as the result of over a decade of work coming from multiple foci. Analyzing the data using the manufacturer’s own a priori protocol we found that the reported efficacy of the drug disappeared and that the safety of the drug had been exaggerated.

Having been intimately involved in one of these articles and knowing the authors of the other, I can attest to the herculean effort required to produce them. Both are the result of unfunded research. There were no Conflicts of Interest and they were largely done by senior people with no need for further credentialing. Unfortunately, the primary articles they analyzed are not exceptions. And at least in the domain of industry funded RCTs of CNS drugs, they’re the rule. Even worse, both studies involved medications for vulnerable youth. The mandate for change is clear as a bell…

the obvious irony… Posted on Thursday 12 May 2016

Having been intimately involved in one of these articles and knowing the authors of the other, I can attest to the herculean effort required to produce them. Both are the result of unfunded research. There were no Conflicts of Interest and they were largely done by senior people with no need for further credentialing. Unfortunately, the primary articles they analyzed are not exceptions. And at least in the domain of industry funded RCTs of CNS drugs, they’re the rule. Even worse, both studies involved medications for vulnerable youth. The mandate for change is clear as a bell…

this tawdry era… Posted on Saturday 14 May 2016

While this is only one example of many similarly misreported Clinical Trials, the access to the internal industry documents allowed these authors to leave nothing to our imagination. They prove that it’s ghost written; that it was framed by the industry executives for commercial gain before any academic author got near the data; that it was deceitfully written to hide its failings, on purpose; and that it was a negative Clinical Trial presented as positive and subsequently used to gain FDA Approval. Those points and more are abundantly clear in this easy-reading article…

I think it’s now our job to insure that all this dedicated work is rewarded with a wide readership, one that helps us move closer to putting this tawdry era behind us…

Dr. Nardo’s article in The BMJ:

Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, Abi-Jaoude E. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015; 351: h4320

 

The article from which data were re-analyzed:

Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry. 2001 Jul 31;40(7):762-72.

30 Rapid responses to the BMJ article

The BMJ article by Le Noury, Nardo and colleagues has so far received 30 Rapid Responses Including a 18 January 2016  response from Martin Keller and the authors of the original Study 329, as well as the 03 February 2016 reply from Jon N Jureidini and the authors. Click here for the links.

Guilty pleas from Forest Laboratories and GlaxoSmithKline

The two pharmaceutical companies that produced ghost authored papers were subject to criminal and civil proceedings. They both pleaded guilty. Some excerpts from these proceedings are summarized in another blog post, When the US government cracked down on drug companies promoting antidepressants for children and teens. Other links to the proceedings are below:

Justice Department Files Suit Against Forest Laboratories for Illegally Marketing Celexa, Lexapro for Children

The actual filing

Drug Maker Forest Pleads Guilty; To Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations

Complaint: United States ex rel. Greg Thorpe et at [Consolidated] Plaintiffs vs GlaxoSmithKline PLC, and GlaxoSmithKline LLC Defendents

GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data: Largest Health Care Fraud Settlement in U.S. History

When the US government cracked down on drug companies promoting antidepressants for children and teens

One in a series of three blog posts about Pharma’s promotion of medication for treatment of depression in young children and teens.

antidepressantsThis post concerns legal action by the US federal government in which two pharmaceutical companies pleaded guilty and had to pay large sums of money because of their promotion of misleading claims about about the efficacy and safety of antidepressants for children and adolescents.

This post is part of a three-part series exploring The discrepancy between Pharma’s promotion of antidepressants to children and adolescents and the evidence generated by clinical trials. The series is intended to be useful to anyone who wants to acquire a more in-depth understanding of how the pharmaceutical industry has misled professionals and mental health consumers about the efficacy and risk of antidepressant treatment for children and adolescents. I pay particular attention to re-analyses of data  from previously published in major psychiatric journals that showed claims in these journals about the effectiveness and safety of these medications for young people were exaggerated.

 Examination of other things I’ve written about antidepressants should establish that I don’t have an ax to grind and I certainly don’t consider myself anti-medication or antipsychiatry.

 One of my previous blog posts  discussed a study I had done with colleagues examining how psychotherapy compared with pill placebo, the standard comparator for antidepressants. We found that psychotherapy and antidepressants had modest, but comparable advantages over pill placebo.

Another of my blog posts discussed a study I had done with colleagues examining in 29 countries whether trends over time in the prescription of antidepressants were associated with trends in rates of suicide. We found it rather consistently that increases in prescription of antidepressants were associated with decreases in rates of suicide.

The present series was prompted by the publication of an article that described how previously confidential documents revealed that professionals employed by Forest Laboratories had ghostwritten an article in American Journal of Psychiatry. Authorship was then attributed to prominent mental health professionals, some of whom were paid for additional consultation and promotional activities. This particular AJP article was pivotal in convincing professionals and the public to accept the antidepressant citalopram (Celexa) for children and adolescents.

antidepressants-2Part one, the first blog in the series will soon be posted at Mind the Brain. It  provides a detailed “deconstruction” of the ghostwritten article claiming to demonstrate the citalopram was effective and safe for children and adolescents. The authors of this article relied on access to company documents released in a lawsuit and reanalysis of the data from the study. The re-analyses suggested that the drug was ineffective for both children and adolescents and its use was associated with significant adverse effects, including suicidal thoughts and behavior in some patients. The documents clearly demonstrated that Forest Laboratories were aware of the lack of benefits and the existence of risks with these medications, but suppressed and distorted findings in a ghostwritten article.

The second blog post will also be soon posted here at Quick Thoughts. It provides a rich set of links to other materials related to the American Journal of Psychiatry article that was systematically “deconstructed” in the new article, as well as the actual legal documents obtained in a civil action.

Additionally, the second blog post has links to materials related to another reanalysis reported in The BMJ of data from an article in Journal of the American Academy of Child & Adolescent Psychiatry and the controversies around both the original article and the re-analyses.

As with the deconstruction of the article concerning citalopram in American Journal of Psychiatry, the reanalysis reported in The BMJ failed to show that paroxetine (marketed as Paxil in the US and Seroxat in the UK) was safe and effective as claimed for children and adolescents.

This blog post summarizes two key legal actions resulting in the pharmaceutical companies Forest Laboratories and GlaxoSmithKline paying large fines for exaggerating benefits and hiding risks of antidepressants for young people. These misrepresentations involved publishing misleading articles in major medical journals and promoting off-label (unapproved) use in children and adolescents, when efficacy and safety had only been established for adults.

For what follows, it’s important to know that the antidepressant citalopram is a selective serotonin reuptake inhibitor (SSRI) that is actually a mixture of two enantiomers, molecules that are almost identical but are actual mirror images of each other, R-citalopram and S-citalopram. Forest laboratories claimed that that the S enantiomer, or S-citalopram was the more active antidepressant and began marketing it as Lexapro. Critics noted that Forest Laboratories’ tradename patent was expiring for citalopram 2003 and so other companies could have soon been in a position to market a generic citalopram. Isolation and approval of S-citalopram (Lexapro) would mean another patent would be effective until 2012. Evidence that Lexapro is actually more effective or has a mild or side effect profile is mixed.

Forest Laboratories and citalopram

In 2010, Forest Laboratories agreed to pay $313 million and plead guilty to “one criminal felony count of obstructing justice, one criminal misdemeanor count of distributing an unapproved drug in interstate commerce, and one criminal misdemeanor count of distributing a misbranded drug in interstate commerce.” The settlement was for three drugs, including the two antidepressants, Celexa and Lexapro.

Regarding Celexa, the criminal information and the False Claims Act complaint filed by the United States allege that Forest Pharmaceuticals promoted the drug for unapproved pediatric use. Despite a limited approval only for adult depression, Forest Pharmaceuticals promoted Celexa for use in treating children and adolescents suffering from depression. The government alleges that Forest Pharmaceuticals publicized and circulated the positive results of a double-blind, placebo-controlled Forest study on the use of Celexa in adolescents while, at the same time, Forest Pharmaceuticals failed to discuss the negative results of a contemporaneous double-blind, placebo-controlled European study on the use of Celexa in adolescents.

The government further alleges that Forest Pharmaceuticals’ off-label promotion consisted of various sales techniques, including directing its sales representatives to promote pediatric use of Celexa in sales calls to physicians who treated children and adolescents, and hiring outside speakers to talk to pediatric specialists about the benefits of prescribing Celexa to children and teens.

The False Claims Act complaint also alleges that Forest engaged in such marketing conduct in connection with Lexapro, which, at that time, also lacked any approvals for pediatric use. The civil complaint further alleges that Forest used illegal kickbacks to induce physicians and others to prescribe Celexa and Lexapro. Kickbacks allegedly included cash payments disguised as grants or consulting fees, expensive meals and lavish entertainment. The civil complaint alleges that as a result of the foregoing conduct, Forest caused false claims to be submitted to federal health care programs.

Lexapro was approved for use for acute and maintenance treatment of Major Depressive Disorder in adolescents, 12 – 17 years of age, on March 19, 2009.

Anyone who had purchased Celexa for someone under 18 from 1998 to 2013 or Lexapro from 2002 to 2013 became eligible for partial to full refunds.

GlaxoSmithKline and paroxetine

In the largest health care fraud settlement to date, GlaxoSmithKline agreed in 2012 to plead guilty and pay $3 billion to resolve allegations of fraud and failure to report safety data for a number of drugs, including paroxetine for depression in teenagers and adolescents. The settlement specifically said about paroxetine:

In the criminal information, the government alleges that, from April 1998 to August 2003, GSK unlawfully promoted Paxil for treating depression in patients under age 18, even though the FDA has never approved it for pediatric use. The United States alleges that, among other things, GSK participated in preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy. At the same time, the United States alleges, GSK did not make available data from two other studies in which Paxil also failed to demonstrate efficacy in treating depression in patients under 18. The United States further alleges that GSK sponsored dinner programs, lunch programs, spa programs and similar activities to promote the use of Paxil in children and adolescents. GSK paid a speaker to talk to an audience of doctors and paid for the meal or spa treatment for the doctors who attended. Since 2004, Paxil, like other antidepressants, included on its label a “black box warning” stating that antidepressants may increase the risk of suicidal thinking and behavior in short-term studies in patients under age 18. GSK agreed to plead guilty to misbranding Paxil in that its labeling was false and misleading regarding the use of Paxil for patients under 18.