A recent article in JAMA: Psychiatry:
Sun Y, Farzan F, Mulsant BH, Rajji TK, Fitzgerald PB, Barr MS, Downar J, Wong W, Blumberger DM, Daskalakis ZJ. Indicators for remission of suicidal ideation following magnetic seizure therapy in patients with treatment-resistant depression. JAMA Psychiatry. 2016 Mar 16.
Was accompanied by an editorial commentary:
Camprodon JA, Pascual-Leone A. Multimodal Applications of Transcranial Magnetic Stimulation for Circuit-Based Psychiatry. JAMA: Psychiatry. 2016 Mar 16.
Together both the article and commentary can be studied as:
- An effort by the authors and the journal itself to promote prematurely a treatment for reducing suicide.
- A pay back to sources of financial support for the authors. Both groups have industry ties that provide them with consulting fees, equipment, grants, and other unspecified rewards. One author has a patent that should increase in value as result of this article and commentary.
- A bid for successful applications to new grant initiatives with a pledge of allegiance to the NIMH Research Domain Criteria (RDoC).
After considering just how bad the science and reporting:
We have sufficient reason to ask how did this promotional campaign come about? Why was this article accepted by JAMA:Psychiatry? Why was it deemed worthy of comment?
I think a skeptical look at this article would lead to a warning label:
As we will see, the article is seriously flawed as a contribution to neuroscience, identification of biomarkers, treatment development, and suicidology, but we can nonetheless learn a lot from it in terms of how to detect such flaws when they are more subtle. If nothing else, your skepticism will be raised about articles accompanied by commentaries in prestigious journals and you will learn tools for probing such pairs of articles.
This article involves intimidating technical details and awe-inspiring figures.
Yet, as in some past blog posts concerning neuroscience and the NIMH RDoC, we will gloss over some technical details, which would be readily interpreted by experts. I would welcome the comments and critiques from experts.
I nonetheless expect readers to agree when they have finished this blog post that I have demonstrated that you don’t have to be an expert to detect neurononsense and crass publishing of articles that fit vested interests.
The larger trial from which these patients is registered as:
ClinicalTrials.gov. Magnetic Seizure Therapy (MST) for Treatment Resistant Depression, Schizophrenia, and Obsessive Compulsive Disorder. NCT01596608.
Because this article is strikingly lacking in crucial details or details in places where we would expect to find them, it will be useful at times to refer to the trial registration.
The title and abstract of the article
As we will soon see, the title, Indicators for remission of suicidal ideation following MST in patients with treatment-resistant depression is misleading. The article has too small sample and too inappropriate a design to establish anything as a reproducible “indicator.”
That the article is going to fail to deliver is already apparent in the abstract.
The abstract states:
Objective To identify a biomarker that may serve as an indicator of remission of suicidal ideation following a course of MST by using cortical inhibition measures from interleaved transcranial magnetic stimulation and electroencephalography (TMS-EEG).
Design, Setting, and Participants Thirty-three patients with TRD were part of an open-label clinical trial of MST treatment. Data from 27 patients (82%) were available for analysis in this study. Baseline TMS-EEG measures were assessed within 1 week before the initiation of MST treatment using the TMS-EEG measures of cortical inhibition (ie, N100 and long-interval cortical inhibition [LICI]) from the left dorsolateral prefrontal cortex and the left motor cortex, with the latter acting as a control site.
Interventions The MST treatments were administered under general anesthesia, and a stimulator coil consisting of 2 individual cone-shaped coils was used.
Main Outcomes and Measures Suicidal ideation was evaluated before initiation and after completion of MST using the Scale for Suicide Ideation (SSI). Measures of cortical inhibition (ie, N100 and LICI) from the left dorsolateral prefrontal cortex were selected. N100 was quantified as the amplitude of the negative peak around 100 milliseconds in the TMS-evoked potential (TEP) after a single TMS pulse. LICI was quantified as the amount of suppression in the double-pulse TEP relative to the single-pulse TEP.
Results Of the 27 patients included in the analyses, 15 (56%) were women; mean (SD) age of the sample was 46.0 (15.3) years. At baseline, patients had a mean SSI score of 9.0 (6.8), with 8 of 27 patients (30%) having a score of 0. After completion of MST, patients had a mean SSI score of 4.2 (6.3) (pre-post treatment mean difference, 4.8 [6.7]; paired t26 = 3.72; P = .001), and 18 of 27 individuals (67%) had a score of 0 for a remission rate of 53%. The N100 and LICI in the frontal cortex—but not in the motor cortex—were indicators of remission of suicidal ideation with 89% accuracy, 90% sensitivity, and 89% specificity (area under the curve, 0.90; P = .003).
Conclusions and Relevance These results suggest that cortical inhibition may be used to identify patients with TRD who are most likely to experience remission of suicidal ideation following a course of MST. Stronger inhibitory neurotransmission at baseline may reflect the integrity of transsynaptic networks that are targeted by MST for optimal therapeutic response.
Even viewing the abstract alone, we can see this article is in trouble. It claims to identify a biomarker following a course of magnet seizure therapy (MST) ]. That is an extraordinary claim when a study only started with 33 patients of whom only 27 remain for analysis. Furthermore, at the initial assessment of suicidal ideation, eight of the 27 patients did not have any and so could show no benefit of treatment.
Any results could be substantially changed with any of the four excluded patients being recovered for analysis and any of the 27 included patients being dropped from analyses as an outlier. Statistical controls to control for potential confounds will produce spurious results because of overfit equations ] with even one confound. We also know well that in situation requiring control of possible confounding factors, control of only one is really sufficient and often produces worse results than leaving variables unadjusted.
Identification of any biomarkers is unlikely to be reproducible in larger more representative samples. Any claims of performance characteristics of the biomarkers (accuracy, sensitivity, specificity, area under the curve) are likely to capitalize on sampling and chance in ways that are unlikely to be reproducible.
Nonetheless, the accompanying figures are dazzling, even if not readily interpretable or representative of what would be found in another sample.
Comparison of the article to the trial registration.
According to the trial registration, the study started in February 2012 and the registration was received in May 2012. There were unspecified changes as recently as this month (March 2016), and the study is expected to and final collection of primary outcome data is in December 2016.
The registration indicates that patients will have been diagnosed with severe major depression, schizophrenia or obsessive compulsive disorder. The primary outcome will depend on diagnosis. For depression it is the Hamilton Rating Scale for Depression.
There is no mention of suicidal ideation as either a primary or secondary outcome.
According to the registration, outcomes include (1) cognitive functioning as measured by episodic memory and non-memory cognitive functions; (2) changes in neuroimaging measures of brain structure and activity derived from fMRI and MRI from baseline to 24th treatment or 12 weeks, whichever comes sooner.
Comparison to the article suggests some important neuroimaging assessment proposed in the registration were compromised. (1) only baseline measures were obtained and without MRI or fMRI; and (2) the article states
Although magnetic resonance imaging (MRI)–guided TMS-EEG is more accurate than non–MRI-guided methods, the added step of obtaining an MRI for every participant would have significantly slowed recruitment for this study owing to the pressing
need to begin treatment in acutely ill patients, many of whom were experiencing suicidal ideation. As such, we proceeded with non–MRI-guided TMS-EEG using EEG-guided methods according to a previously published study.
The MST treatments were administered under general anesthesia using a stimulator machine (MagPro MST; MagVenture) with a twin coil. Methohexital sodium (n = 14), methohexital with remifentanil hydrochloride (n = 18), and ketamine hydrochloride (n = 1) were used as the anesthetic agents. Succinylcholine chloride was used as the neuromuscular blocker. Patients had a mean (SD) seizure duration of 45.1 (21.4) seconds. The twin coil consists of 2 individual cone-shaped coils. Stimulation was delivered over the frontal cortex at the midline position directly over the electrode Fz according to the international 10-20 system.36 Placing the twin coil symmetrically over electrode Fz results in the centers of the 2 coils being over F3 and F4. Based on finite element modeling, this configuration produces a maximum induced electric field between the 2 coils, which is over electrode Fz in this case.37 Patients were treated for 24 sessions or until remission of depressive symptoms based on the 24-item Hamilton Rating Scale for Depression (HRSD) (defined as an HRSD-24 score ≤10 and 60% reduction in symptoms for at least 2 days after the last treatment).38 These remission criteria were standardized from previous ECT depression trials.39,40 Further details of the treatment protocol are available,30 and comprehensive clinical and neurophysiologic trial results will be reported separately.
The article intended to refer the reader to the trial registration for further description of treatment, but the superscript citation in the article is inaccurate. Regardless, given other deviations from registration, readers can’t tell whether any deviations from what was proposed. In in the registration, seizure therapy was described as involving:
100% machine output at between 25 and 100 Hz, with coil directed over frontal brain regions, until adequate seizure achieved. Six treatment sessions, at a frequency of two or three times per week will be administered. If subjects fail to achieve the pre-defined criteria of remission at that point, the dose will be increased to the maximal stimulator output and 3 additional treatment sessions will be provided. This will be repeated a total of 5 times (i.e., maximum treatment number is 24). 24 treatments is typically longer that a conventional ECT treatment course.
One important implication is for this treatment being proposed as resolving suicidal ideation. It takes place over a considerable period of time. Patients who die by suicide notoriously break contact before doing so. It would seem that a required 24 treatments delivered on an outpatient basis would provide ample opportunities for breaks – including demoralization because so many treatments are needed in some cases – and therefore death by suicide
But a protocol that involves continuing treatment until a prespecified reduction in the Hamilton Depression Rating Scale is achieved assures that there will be a drop in suicidal ideation. The interview-based Hamilton depression rating scales and suicidal ideation are highly correlated.
There is no randomization or even adequate description of patient accrual in terms of the population from which the patients came. There is no control group and therefore no control for nonspecific factors. The patients are being subject to an elaborate, intrusive ritual In terms of nonspecific effects. The treatment involves patients in an elaborate ritual, starting with electroencephalographic (EEG) assessment [http://www.mayoclinic.org/tests-procedures/eeg/basics/definition/prc-20014093].
The ritual will undoubtedly will undoubtedly have strong nonspecific factors associated with it – instilling a positive expectations and considerable personal attention.
The article’s discussion of results
The discussion opens with some strong claims, unjustified by the modesty of the study and the likelihood that its specific results are not reproducible:
We found that TMS-EEG measures of cortical inhibition (ie, the N100 and LICI) in the frontal cortex, but not in the motor cortex, were strongly correlated with changes in suicidal ideation in patients with TRD who were treated with MST. These findings suggest that patients who benefitted the most from MST demonstrated the greatest cortical inhibition at baseline. More important, when patients were divided into remitters and nonremitters based on their SSI score, our results show that these measures can indicate remission of suicidal ideation from a course of MST with 90% sensitivity and 89% specificity.
The discussion contains a Pledge of Allegiance to the research domain criteria approach that is not actually a reflection of the results at hand. Among the many things that we knew before the study was done and that was not shown by the study, is to suicidal ideation is so hopelessly linked to hopelessness, negative affect, and attentional biases, that in such a situation is best seen as a surrogate measure of depression, rather than a marker for risk of suicidal acts or death by suicide.
Wave that RDoC flag and maybe you will attract money from NIMH.
Our results also support the research domain criteria approach, that is, that suicidal ideation represents a homogeneous symptom construct in TRD that is targeted by MST. Suicidal ideation has been shown to be linked to hopelessness, negative affect, and attentional biases. These maladaptive behaviors all fall under the domain of negative valence systems and are associated with the specific constructs of loss, sustained threat, and frustrative nonreward. Suicidal ideation may represent a better phenotype through which to understand the neurobiologic features of mental illnesses.In this case, variations in GABAergic-mediated inhibition before MST treatment explained much of the variance for improvements in suicidal ideation across individuals with TRD.
Debunking ‘a better phenotype through which to understand the neurobiologic features of mental illnesses.’
- Suicide is not a disorder or a symptom, but an infrequent, difficult to predict and complex act that varies greatly in nature and circumstances.
- While some features of a brain or brain functioning may be correlated with eventual death by suicide, most identifications they provide of persons at risk to eventually die by suicide will be false positives.
- In the United States, access to a firearm is a reliable proximal cause of suicide and is likely to be more so than anything in the brain. However, this basic observation is not consistent with American politics and can lead to grant applications not being funded.
In an important sense,
- It’s not what’s going on in the brain, but what’s going in the interpersonal context of the brain, in terms of modifiable risk for death by suicide.
The editorial commentary
On the JAMA: Psychiatry website, both the article and the editorial commentary contain sidebar links to each other. Is only in the last two paragraphs of a 14 paragraph commentary that the target article is mentioned. However, the commentary ends with a resounding celebration of the innovation this article represents [emphasis added]:
Sun and colleagues10 report that 2 different EEG measures of cortical inhibition (a negative evoked potential in the EEG that happens approximately 100 milliseconds after a stimulus or event of interest and long-interval cortical inhibition) evoked by TMS to the left dorsolateral prefrontal cortex, but not to the left motor cortex, predicted remission of suicidal ideation with great sensitivity and specificity. This study10 illustrates the potential of multimodal TMS to study physiological properties of relevant circuits in neuropsychiatric populations. Significantly, it also highlights the anatomical specificity of these measures because the predictive value was exclusive to the inhibitory properties of prefrontal circuits but not motor systems.
Multimodal TMS applications allow us to study the physiology of human brain circuitry noninvasively and with causal resolution, expanding previous motor applications to cognitive, behavioral, and affective systems. These innovations can significantly affect psychiatry at multiple levels, by studying disease-relevant circuits to further develop systems for neuroscience models of disease and by developing tools that could be integrated into clinical practice, as they are in clinical neurophysiology clinics, to inform decision making, the differential diagnosis, or treatment planning.
Disclosures of conflicts of interest
The article’s disclosure of conflicts of interest statement is longer than the abstract.
The disclosure for the conflicts of interest for the editorial commentary is much shorter but nonetheless impressive:
How did this article get into JAMA: Psychiatry with an editorial comment?
Editorial commentaries are often provided by reviewers who either simply check the box on the reviewers’ form indicating their willingness to provide a comment. For reviewers who already have a conflict of interest, this provides an additional one: a non-peer-reviewed paper in which they can promote their interest.
Alternatively, commentators are simply picked by an editor who judges an article to be noteworthy of special recognition. It’s noteworthy that at least one of the associate editors of JAMA: Psychiatry is actively campaigning for a particular direction to suicide research funded by NIMH as seen in an editorial comment of his own that I recently discussed. One of the authors of this paper currently under discussion was until recently a senior member of this associate editor’s department, before departing to become Chair of the Department of Psychiatry at University of Toronto.
Essentially the authors of the paper and the authors of the commentary of providing carefully constructed advertisers for themselves and their agenda. The opportunity for them to do so is because of consistency with the agenda of at least one of the editors, if not the journal itself.
The Committee on Publication Ethics (COPE) requires that non-peer-reviewed material in ostensibly peer reviewed journals be labeled as such. This requirement is seldom met.
The journal further promoted this article by providing 10 free continuing medical education credits for reading it.
I could go on much longer identifying other flaws in this paper and its editorial commentary. I could raise other objections to the article being published in JAMA:Psychiatry. But out of mercy for the authors, the editor, and my readers, I’ll stop here.
I would welcome comments about other flaws.
Special thanks to Bernard “Barney” Carroll for his helpful comments and encouragement, but all opinions expressed and all factual errors are my own responsibility.