COBRA study would have shown homeopathy can be substituted for cognitive behavior therapy for depression

If The Lancet COBRA study had evaluated homeopathy rather than behavioural activation (BA), homeopathy would likely have similarly been found “non-inferior” to cognitive behavior therapy.

This is not an argument for treating depression with homeopathy, but an argument that the 14 talented authors of The Lancet COBRA study stacked the deck for their conclusion that BA could be substituted for CBT in routine care for depression without loss of effectiveness. Conflict of interest and catering to politics intruded on science in the COBRA trial.

If a study like COBRA produces phenomenally similar results with treatments based on distinct mechanisms of change, one possibility is that background nonspecific factors are dominating the results. Insert homeopathy, a bogus treatment with strong nonspecific effects, in place of BA, and a non-inferiority may well be shown.

Why homeopathy?

Homeopathy involves diluting a substance so thoroughly that no molecules are likely to be present in what is administered to patients. The original substance is first diluted to one part per 10,000 part alcohol or distilled water. This process is repeated six times, ending up with the original material diluted by a factor of 100−6=10−12 .

Nonetheless, a super diluted and essentially inert substance is selected and delivered within a complex ritual.  The choice of the particular substance being diluted and the extent of its dilution is determined with detailed questioning of patients about their background, life style, and personal functioning. Naïve and unskeptical patients are likely to perceive themselves as receiving exceptionally personalized medicine delivered by a sympathetic and caring provider. Homeopathy thus has potentially strong nonspecific (placebo) elements that may be lacking in the briefer and less attentive encounters of routine medical care.

As an academic editor at PLOS One, I received considerable criticism for having accepted a failed trial of homeopathy for depression. The study had been funded by the German government and had fallen miserably short in efforts to recruit the intended sample size. I felt the study should be published in PLOS One  to provide evidence whether such and worthless studies should be undertaken in the future. But I also wanted readers to have the opportunity to see what I had learned from the article about just how ritualized homeopathy can be, with a strong potential for placebo effects.

Presumably, readers would then be better equipped to evaluate when authors claim in other contexts that homeopathy is effective from clinical trials with it was inadequate control of nonspecific effects. But that is also a pervasive problem in psychotherapy trials [ 1,  2 ]  that do not have a suitable comparison/control group.

I have tried to reinforce this message in the evaluation of complementary or integrative treatments in Relaxing vs Stimulating Acupressure for Fatigue Among Breast Cancer Patients: Lessons to be Learned.

The Lancet COBRA study

The Lancet COBRA study has received extraordinary promotion as evidence for the cost-effectiveness of substituting behavioural activation therapy (BA) delivered by minimally trained professionals for cognitive behaviour therapy (CBT) for depression. The study  is serving as the basis for proposals to cut costs in the UK National Health Service by replacing more expensive clinical psychologists with less trained and experienced providers.

Coached by the Science Media Centre, the authors of The Lancet study focused our attention on their finding no inferiority of BA to CBT. They are distracting us from the more important question of whether either treatment had any advantage over nonspecific interventions in the unusual context in which they were evaluated.

The editorial accompanying the COBRA study suggest a BA involves a simple message delivered by providers with very little training:

“Life will inevitably throw obstacles at you, and you will feel down. When you do, stay active. Do not quit. I will help you get active again.”

I encourage readers to stop and think how depressed persons suffering substantial impairment, including reduced ability to experience pleasure, would respond to such suggestions. It sounds all too much like the “Snap out of it, Debbie” they may have already heard from people around them or in their own self-blame.

Snap out of it, Debbie (from South Park)

 BA by any other name…

Actually, this kind of activation is routinely provided in in primary care in some countries as a first stage treatment in a stepped care approach to depression.

In such a system, when emergent mild to moderate depressive symptoms are uncovered in a primary medical care setting, providers are encouraged neither to initiate an active treatment nor even make a formal psychiatric diagnosis of a condition that could prove self-limiting with a brief passage of time. Rather, providers are encouraged to defer diagnosis and schedule a follow-up appointment. This is more than simple watchful waiting. Until the next appointment, providers encourage patients to undertake some guided self-help, including engagement in pleasant activities of their choice, much as apparently done in the BA condition in the COBRA study. Increasingly, they may encourage Internet-based therapy.

In a few parts of the UK, general practitioners may refer patients to a green gym.

green gym

It’s now appreciated that to have any effectiveness, such prescriptions have to be made in a relationship of supportive accountability. For patients to adhere adequately to such prescriptions and not feel they are simply being dismissed by the provider and sent away. Patients need to have a sense that the prescription is occurring within the context of a relationship with someone who cares with whether they carry out and benefit from the prescription.

Used in this way, this BA component of stepped care could possibly be part of reducing unnecessary medication and the need for more intensive treatment. However, evaluation of cost effectiveness is complicated by the need for a support structure in which treatment can be monitored, including any antidepressant medication that is subsequently prescribed. Otherwise, the needs of a substantial number of patients needing more intensive, quality care for depression would be neglected.

The shortcomings of COBRA as an evaluation of BA in context

COBRA does not provide an evaluation of any system offering BA to the large pool of patients who do not require more intensive treatment in a system where they would be provided appropriate timely evaluation and referral onwards.

It is the nature of mild to moderate depressive symptoms being presented in primary care, especially when patients are not specifically seeking mental health treatment, that the threshold for a formal diagnosis of major depression is often met by the minimum or only one more than the five required symptoms. Diagnoses are of necessity unreliable, in part because the judgment of particular symptoms meeting a minimal threshold of severity is unreliable. After a brief passage of time and in the absence of formal treatment, a substantial proportion of patients will no longer meet diagnostic criteria.

COBRA also does not evaluate BA versus CBT in the more select population that participates in clinical trials of treatment for depression. Sir David Goldberg is credited  with first describing the filters that operate on the pathway of patients from presenting a complex combination of problems in living and psychiatric symptoms in primary medical care to treatment in specialty settings.

Results of the COBRA study cannot be meaningfully integrated into the existing literature concerning BA as a component of stepped care or treatment for depression that is sufficient in itself.

More recently, I reviewed in detail The Lancet COBRA study, highlighting how one of the most ambitious and heavily promoted psychotherapy studies ever – was noninformative.  The authors’ claim was unwarranted that it would be wise to substitute BA delivered by minimally trained providers for cognitive behavior therapy delivered by clinical psychologists.

I refer readers to that blog post for further elaboration of some points I will be making here. For instance, some readers might want to refresh their sense of how a noninferiority trial differs from a conventional comparison of two treatments.

Risk of bias in noninferiority trial

 Published reports of clinical trials are notoriously unreliable and biased in terms of the authors’ favored conclusions.

With the typical evaluation of an active treatment versus a control condition, the risk of bias is that reported results will favor the active treatment. However, the issue of bias in a noninferiority trial is more complex. The investigators’ interest is in demonstrating that within certain limits, there are no significant differences between two treatments. Yet, although it is not always tested directly, the intention is to show that this lack of difference is due them both being effective, rather than ineffective.

In COBRA, the authors’ clear intention was to show that less expensive BA was not inferior to CBT, with the assumption that both were effective. Biases can emerge from building in features of the design, analysis, and interpretation of the study that minimized differences between these two treatments. But bias can also arise from a study design in which nonspecific effects are distributed across interventions so that any difference in active ingredients is obscured by shared features of the circumstances in which the interventions are delivered. As in Alice in Wonderland [https://en.wikipedia.org/wiki/Dodo_bird_verdict ], the race is rigged so that almost everybody can get a prize.

Why COBRA could have shown almost any treatment with nonspecific effects was noninferior to CBT for depression

 1.The investigators chose a population and a recruitment strategy that increase the likelihood that patients participating in the trial would likely get better with minimal support and contact available in either of the two conditions – BA versus CBT.

The recruited patients were not actively seeking treatment. They were identified from records of GPs has having had a diagnosis of depression, but were required to not currently being in psychotherapy.

GP recording of a diagnosis of depression has poor concordance with a formal, structured interview-based diagnosis, with considerable overdiagnosis and overtreatment.

A recent Dutch study found that persons meeting interview-based criteria for major depression in the community who do not have a past history of treatment mostly are not found to be depressed upon re-interview.

To be eligible for participation in the study, the patients also had to meet criteria for major depression in a semi structured research interview with (Structured Clinical Interview for the Diagnostic and Statistical Manual of  Mental Disorders, Fourth Edition [SCID]. Diagnoses with the SCID obtained under these circumstances are also likely to have a considerable proportion of false positives.

A dirty secret from someone who has supervised thousands of SCID interviews of medical patients. The developers of the SCID recognized that it yielded a lot of false positives and inflated rates of disorder among patients who are not seeking mental health care.

They attempted to compensate by requiring that respondents not only endorse symptoms, but indicate that the symptoms are a source of impairment. This is the so-called clinical significance criterion. Respondents automatically meet the criterion if they are seeking mental health treatment. Those who are not seeking treatment are asked directly whether the symptoms impair them. This is a particularly on validated aspect of the SCID in patients typically do not endorse their symptoms as a source of impairment.

When we asked breast cancer patients who otherwise met criteria for depression with the SCID whether the depressive symptoms impaired them, they uniformly said something like ‘No, my cancer impairs me.’ When we conducted a systematic study of the clinical significance criterion, we found that whether or not it was endorsed substantially affected individual in overall rates of diagnosis. Robert Spitzer, who developed the SCID interview along with his wife Janet Williams, conceded to me in a symposium that application of the clinical significance criterion was a failure.

What is the relevance in a discussion of the COBRA study? I would wager that the authors, like most investigators who use the SCID, did not inquire about the clinical significance criterion, and as a result they had a lot of false positives.

The population being sampled in the recruitment strategy used in COBRA is likely to yield a sample unrepresentative of patients participating in the usual trials of psychotherapy and medication for depression.

2. Most patients participating in COBRA reported already receiving antidepressants at baseline, but adherence and follow-up are unknown, but likely to be inadequate.

Notoriously, patients receiving a prescription for an antidepressant in primary care actually take the medication inconsistently and for only a short time, if at all. They receive inadequate follow-up and reassessment. Their depression outcomes may actually be poorer than for patients receiving a pill placebo in the context of a clinical trial, where there is blinding and a high degree of positive expectations, attention and support.

Studies, including one by an author of the COBRA study suggests that augmenting adequately managed treatment with antidepressants with psychotherapy is unlikely to improve outcomes.

We’re stumbling upon one of the more messy features of COBRA. Most patients had already been prescribed medication at baseline, but their adherence and follow-up is left unreported, but is likely to be poor. The prescription is likely to have been made up to two years before baseline.

It would not be cost-effective to introduce psychotherapy to such a sample without reassessing whether they were adequately receiving medication. Such a sample would also be highly susceptible to nonspecific interventions providing positive expectations, support, and attention that they are not receiving in their antidepressant treatment. There are multiple ways in which nonspecific effects could improve outcomes – perhaps by improving adherence, but perhaps because of the healing effects of support on mild depressive symptoms.

3. The COBRA authors’ way of dealing with co-treatment with antidepressants blocked readers ability to independently evaluate main effects and interactions with BA versus CBT.

 The authors used antidepressant treatment as a stratification factor, insuring that the 70% of patients receiving them were evenly distributed the BA in CBT conditions. This strategy made it more difficult to separate effects of antidepressants. However, the problem is compounded by the authors failure to provide subgroup analyses based on whether patients had received an antidepressant prescription, as well as the authors failure to provide any descriptions of the extent to which patients received management of their antidepressants at baseline or during active psychotherapy and follow-up. The authors incorporated data concerning the cost of medication into their economic analyses, but did not report the data in a way that could be scrutinized.

I anticipate requesting these data from the authors to find out more, although they have not responded to my previous query concerning anomalies in the reporting of how long since patients had first received a prescription for antidepressants.

4. The 12 month assessment designated as the primary outcomes capitalized on natural recovery patterns, unreliability of initial diagnosis, and simple regression to the mean.

Depression identified in the community and in primary care patient populations is variable in the course, but typically resolves in nine months. Making reassessment of primary outcomes at 12 months increases the likelihood that effects of active ingredients of the two treatments would be lost in a natural recovery process.

5. The intensity of treatment (allowable number of 20 sessions plus for additional sessions) offered in the study exceeded what is available in typical psychotherapy trials and exceeded what was actually accessed by patients.

Allowing this level of intensity of treatment generates a lot of noise in any interpretation of the resulting data. Offering so much treatment encourages patients dropping out, with the loss of their follow-up data. We can’t tell if they simply dropped out because they had received what they perceived as sufficient treatment or if they were dissatisfied. This intensity of offered treatment reduces generalizability to what actually occurs in routine care and comparing and contrasting results of the COBRA study to the existing literature.

 6. The low rate of actual uptake of psychotherapy and retention of patients for follow-up present serious problems for interpreting the results of the COBRA study.

Intent to treat analyses with imputation of missing data are simply voodoo statistics with so much missing data. Imputation and other multivariate techniques make the assumption that data are missing at random, but as I just noted, this is an improbable assumption. [I refer readers back to my previous blog post who want to learn more about intent to treat versus per-protocol analyses].

The authors cite past literature in their choice to emphasize the per-protocol analyses. That means that they based their interpretation of the results on 135 of 221 patients originally assigned to the BA and in the 151 of 219 patients originally signed to CBT. This is a messy approach and precludes generalizing back to original assignment. That’s why that intent to treat analyses are emphasized in conventional evaluations of psychotherapy.

A skeptical view of what will be done with the COBRA data

 The authors clear intent was to produce data supporting an argument that more expensive clinical psychologists could be replaced by less trained clinicians providing a simplified treatment. The striking lack of differences between BA and CBT might be seen as strong evidence that BA could replace CBT. Yet, I am suggesting that the striking lack of differences could also indicate features built into the design that swamped any differences in limited any generalizability to what would happen if all depressed patients were referred to BA delivered by clinicians with little training versus CBT. I’m arguing that homeopathy would have done as well.

BA is already being implemented in the UK and elsewhere as part of stepped care initiatives for depression. Inclusion of BA is inadequately evaluated, as is the overall strategy of stepped care. See here for an excellent review of stepped care initiatives and a tentative conclusion that they are moderately effective, but that many questions remain.

If the COBRA authors were most committed to improving the quality of depression care in the UK, they would’ve either designed their study as a fairer test of substituting BA for CBT or they would have tackled the more urgent task of evaluating rigorously whether stepped care initiatives work.

Years ago, collaborative care programs for depression were touted as reducing overall costs. These programs, which were found to be robustly effective in many contexts, involved placing depression managers in primary care to assist the GPs in improved monitoring and management of treatment. Often the most immediate and effective improvement was that patients got adequate follow-up, where previously they were simply being ignored. Collaborative care programs did not prove to be cheaper, and not surprising, because better care is often more expensive than ineptly provided inadequate care.

We should be extremely skeptical of experienced investigators who claim that they demonstrate that they can cut costs and maintain quality with a wholesale reduction in the level of training of providers treating depression, a complex and heterogeneous disorder, especially when their expensive study fails to deal with this complexity and heterogeneity.

 



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