The ENIGMA-MDD Project: Searching for the Neuropathology of “Major Depressive Disorder”

There's an old saying in research: "garbage in; garbage out". Research based on invalid concepts or false assumptions will produce invalid conclusions.

INTRODUCTION

According to its About page,

“The ENIGMA consortium is an international effort by leaders worldwide. The Consortium brings together researchers in imaging genomics, neurology and psychiatry, to understand brain structure and function, based on MRI, DTI [Diffusion Tensor Imaging], fMRI, genetic data and many patient populations.

The best return on our research investments will come from combining our data to achieve the large samples necessary to detect the modest gene effect sizes that we now know are the rule rather [than] the exception for complex traits.

The ENIGMA Consortium has several goals:

to create a network of like-minded individuals, interested in pushing forward the field of imaging genetics

to ensure promising findings are replicated via member collaborations, in order to satisfy the mandates of most journals

to share ideas, algorithms, data, and information on promising findings or methods

to facilitate training, including workshops and conferences on key methods and emerging directions in imaging genetics.“

ENIGMA stands for Enhancing Neuro Imaging Genetics through Meta-Analysis.  Funding comes from many sources, mostly government departments from the various countries involved.

“Core funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided as part of the 2014 NIH Big Data to Knowledge (BD2K) Initiative under U54EB020403 (PI: Paul Thompson) to support big data analytics, management and distribution of programs.”

Here’s a quote from the Faculty page at USC (University of Southern California), where ENIGMA is based:

“Paul Thompson directs the ENIGMA Consortium, a global alliance of 307 scientists in 33 countries who conduct the largest studies of 10 major brain diseases – ranging from schizophrenia, depression, ADHD, bipolar illness and OCD, to HIV and addictions on the brain.”

Note the assumption that several of the loose collections of vaguely-defined thoughts, feelings, and behaviors that psychiatry calls mental illnesses are here referred to as brain illnesses.  I have no idea what the term “addictions on the brain” means.

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One of ENIGMA’s sub-groups is ENIGMA-MDD, whose “primary aim…is to identify imaging markers that robustly discriminate MDD [major depressive disorder] patients from healthy controls”.  To date, ENIGMA-MDD has published ten papers, all attempting to find the patterns of brain alterations associated with “MDD”.  The first paper, Schmaal, Veltman et al (2015), concluded:

“This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.”

So people who were “MDD patients” were found, on average, to have smaller hippocampal volumes than people who were not “MDD patients”.

This paper was published in Molecular Psychiatry (2016) 21, 806-812.  Title Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group, authors L Schmaal, DJ Veltman et al.

The group published nine more papers between 2016 and 2020.  Here are the hyperlinks:

Paper 2,  Schmaal, Hibar et al

Paper 3,  Frodl, Janowitz et al

Paper 4,  Renteria, Schmaal et al

Paper 5,  Tozzi, Garczarek et al

Paper 6,  VanVelzen, Kelly et al

Paper 7,  de Kovel, Aftanas et al

Paper 8, Han et al

Paper 9,  Ho, Gutman et al

Paper 10, Schmaal, Pozzi et al

I need to stress that the purpose of the international collaboration was to produce very large samples in order to maximize the chances of finding meaningful correlations between “having a diagnosis of MDD” and an identifiable and replicable brain aberration.  This has been psychiatry’s “Holy Grail” for decades.

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Paper 10 was published in Translational Psychiatry (2020) 10: 172.  Title is:  ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing.  Authors Lianne Schmaal, Elana Pozzi et al.  Towards the end of this paper (p 14), the authors identify a number of challenges that they faced, and continue to face, in their attempts to validate predictive models in multiple independent samples:

“A challenge in this respect is the relative unavailability of deeply characterized phenotypes and longitudinal data. To date, ENIGMA MDD has largely relied on existing data, which implies a degree of heterogeneity with respect to phenotyping including clinical assessments, limiting the analysis of sources of clinical heterogeneity.”

The last sentence quoted is a little unclear, but my best guess at the meaning is that the phenotypal heterogeneity inherent in a DSM “diagnosis of MDD” limits the researchers’ ability to identify genuine variations in how individuals actually manifest depression/despondency.

However, the phenotypal heterogeneity inherent in DSM “diagnoses” was deliberately included in DSM-III-R’s polythetic format (5 out of 9, 3 out of 4, etc.) and was specifically justified by the false assertion that this procedure was “likely to enhance diagnostic reliability” (p xxiv).  A “diagnosis” of MDD requires the presence of at least 5 out of 9 criterion items.  There are 256 such combinations, and even if we accept that some of these will be fairly similar, it is equally clear that other combinations will be very different.  It is also evident that this polythetic format, which is an integral part of the “diagnosis of MDD”, is the primary source of heterogeneity in the group of individuals to whom psychiatrists assign this “diagnosis”.

Given the obvious falseness of the “likely to enhance diagnostic reliability” claim, it is difficult to avoid the conclusion that the real reason for the polythetic format was to spread the net wider and capture more individuals as candidates for “diagnosis” and, of course, “treatment”.  The successive revisions of the DSM are, first and foremost, catalogs of billing codes.  The “diagnoses” were not discovered in nature.  Rather, they were invented by APA committees to serve psychiatry’s ardent desire to be considered real doctors, and to increase business.

The built-in heterogeneity of “major depressive disorder” was continued in DSM-IV:

“In DSM-IV, there is no assumption that each category of mental disorder is a completely discrete entity with absolute boundaries dividing it from other mental disorders or from no mental disorder. There is also no assumption that all individuals described as having the same mental disorder are alike in all important ways. The clinician using DSM-IV should therefore consider that individuals sharing a diagnosis are likely to be heterogeneous even in regard to the defining features of the diagnosis and that boundary cases will be difficult to diagnose in any but a probabilistic fashion. This outlook allows greater flexibility in the use of the system, encourages more specific attention to boundary cases, and emphasizes the need to capture additional clinical information that goes beyond diagnosis. In recognition of the heterogeneity of clinical presentations, DSM-IV often includes polythetic criteria sets, in which the individual need only present with a subset of items from a longer list (e.g., the diagnosis of Borderline Personality Disorder requires only five out of nine items).” (p xxii) [Emphasis added]

and in DSM-5:

“Indeed, the once plausible goal of identifying homogeneous populations for treatment and research resulted in narrow diagnostic categories that did not capture clinical reality, symptom heterogeneity within disorders, and significant sharing of symptoms across multiple disorders.” (p 12)

But how could the APA know that the “narrow diagnostic categories” did not “capture clinical reality”, since there’s no way to know what the “clinical reality” is except through making the “diagnostic” categories more valid and more reliable?  Which again, supports the notion that the object of the exercise was to widen the net and, thereby, increase business.

Note that even as late as DSM-5 (2013), the APA is still pushing the notion that built-in heterogeneity in their “diagnoses” is a good thing, which it clearly isn’t.  The fact is that if there are 256 different versions of “major depressive disorder”, the term has lost most of its denotative value, and has become little more than a bureaucratic instrument to justify (and bill for) the provision of psychiatric services.

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Paper 10 also contains a list of the study’s limitations (p 14-15).  Here’s the final limitation (p 15):

“Finally, it could be the case that certain findings regarding the neurobiology of MDD will not be obtained by ever larger meta-analyses of existing samples; we may need alternative methods of data collection or new data types that are sensitive to effects that are undetected today. We stress the need for a many-pronged approach using novel data collection and the coordinated analysis of the data already available, as well as the development of new approaches.” [Emphases added]

So having built an enormous international consortium “to achieve the large samples necessary to detect the modest gene effect sizes that we now know are the rule rather than the exception for complex traits”, they now tell us that “…it could be the case that certain findings regarding the neurobiology of MDD will not be obtained by ever larger meta-analyses of existing samples.”

After nine published studies over seven years using what are probably the largest samples ever used in this kind of quest, ENIGMA-MDD is acknowledging here that they need:

1. 1. new data types,
   2. alternative methods of data collection,
   3. a many-pronged approach, and
   4. a coordinated analysis of the data already available.

All of which, I had believed, were features of the last seven years of work.

And here’s the Conclusion of the tenth paper:

“Over the past 7 years since its initiation, ENIGMA MDD has brought together research groups across the world with broad expertize to work together to gain a better understanding of brain abnormalities associated with MDD.  By addressing issues of underpowered studies, our work has provided more reliable estimates of the extent of structural brain abnormalities in depression, showing that variability in structural brain alterations may only account for a small percentage of the depression phenotype. Future work is underway that aims to address the heterogeneity of depression and to integrate across data modalities to better understand the multi-causal nature of depression, with the ultimate goal to help develop or select more effective treatments for MDD.” (p 15) [Emphasis added]

And here are my thoughts on the matter:  Seven years of research dissipated, in yet another futile attempt on the part of psychiatrists to inflate their perceived esteem, and draw increasing numbers of new “patients” into their trap of drug-induced apathy.  Note the final phrase in the above quotation:  “to help develop or select more effective treatments for MDD.”   New and improved, no doubt.  Does this mean that we could soon expect to see anti-depressants that don’t need suicide warnings on the packaging?  The primary justification that psychiatrists stress for “treating” depression with drugs is to prevent suicide.  But the very drugs that they prescribe for this purpose are known to entail a significant risk of suicide!  And there’s no reliable way to tell which clients will fall victim to this risk.

FURTHERMORE

Elliot Valenstein, PhD, is Professor Emeritus of Psychology and Neuroscience at the University of Michigan.  Here are two quotes from his book Blaming the Brain, 1998:

“Contrary to what is often claimed, no biochemical, anatomical, or functional signs have been found that reliably distinguish the brains of mental patients.” (p 125)

and

“The now overwhelming evidence that experience can alter neuronal structure and function should make it clear that it is dangerous to assume that any distinctive anatomical or physiological characteristic found in the brains of people with mental disorders was the cause of that disorder.” (p 128)

Our experiences modify our brain structures.  Finding differences in the brains of people who have been evincing depressive thoughts, feelings, and behaviors, even for relatively short periods, is not surprising.  In fact, it would be surprising if no differences were found.  To conclude from any such findings that the differences caused the depression is a bit like visiting a tornado site and concluding that the high winds were caused by the simultaneous collapse of so many buildings!

To demonstrate that a difference in brain anatomy caused depressive behavior, one would need to elucidate the actual neural mechanism that caused this particular effect.  This is a very high bar that to the best of my knowledge has not been attained, which is why research papers that focus on these areas invariably contain a great many “mays”, “mights”, and “possiblys”.

AND, SOME ADVICE FOR PSYCHIATRISTS

If you want to know why a person is depressed, you don’t need a vast international research consortium.  You just need to do four things:

1. 1. Gain his/her trust (which can’t be done in a 15-minute med check).
   2. Gently ask why he/she is depressed. (Questioning needs to be done gently and respectfully, because anything that appears brusque or “third degree” can come across as threatening, and will likely attract defensive responses.  Gentle questioning on matters that are often deeply personal and private can’t be done in 15 minutes.)
   3. Shut up and listen (which also takes more than 15 minutes).
   4. Never say, or even imply, that he/she is mistaken, and the real reason for the depression is an illness just like diabetes which requires ongoing “treatment” with mood-altering drugs, that, by the way, just happen to have suicide warnings on the packaging.

And if you pursue these simple, respectful, validating procedures, be prepared to hear a very wide range of answers, because people become despondent for a very wide range of reasons, e.g. bereavement, job loss, poor housing, being a victim of crime, discrimination, violation, history of being betrayed, chronic illness, terminal illness, lost opportunities, general sense of purposelessness, empty nest, abandonment by a partner, educational failure, physical/emotional/sexual abuse, feeling generally valueless, job failure, threat of prosecution, sense of isolation, fear of aging, etc., etc.

The psychiatrically-inspired and widely accepted notion that these variegated sources of sadness and despondency can be reduced to a few simplistic “mental illnesses” is perhaps the saddest and most destructive tragedy of our times.  If you can’t or won’t help with the despondency as presented by the client, then get out of the way and refer the individual to someone who can and will.

GARBAGE IN, GARBAGE OUT

There’s an old saying in research:  “garbage in; garbage out”.  The essential meaning of this is that research that uses invalid concepts or false assumptions to identify and study populations will likely produce invalid and unsound conclusions.  There is no such entity as “MDD”.  It is nothing more than a loose collection of vaguely described thoughts, feelings, and behaviors, and any attempt to discover the underlying neuropathology of this hodge-podge is doomed to failure.  It’s a bit like looking for the neuropathology that causes people to ride off-road bicycles, or play the drums in a marching band.

CONFLICTS OF INTEREST

It is difficult to assess the extent to which conflicts of interest impact ENIGMA-MDD’s activities.  Each of the ten cited papers lists multiple authors.  The lists are not identical, but there is considerable overlap.

Here are the conflicts of interest disclosures for the first three studies.

Paper 1

“All authors have no conflicts of interest related to this study. Carsten Konrad received fees for an educational program from Esparma / Aristo Pharma, Lilly, Servier, and MagVenture, as well as travel support and speakers honoraria from Lundbeck and Servier. Wiro Niessen is co-founder, chief scientific officer, and shareholder of Quantib BV. Theodorus van Erp consulted for Roche Pharmaceuticals in 2013-2014.”

Paper 2

“The authors declare no conflict of interest. Jair Soares has participated in research funded by Forest, Merck, BMS, GSK and has been a speaker for Pfizer and Abbott.  Andrew McIntosh has received support from Lilly, Janssen, Pfizer and Saccade Diagnostics. Carsten Konrad received fees for an educational program from Aristo Pharma, Janssen-Cilag, Lilly, MagVenture, Servier, and Trommsdorff as well as travel support and speakers honoraria from Janssen, Lundbeck and Servier. Theo G.M. van Erp has consulted for Roche Pharmaceuticals Ltd., and has a contract with Otsuka Phamaceutical Co., Ltd (OPCJ). Knut Schnell has consulted for Roche Pharmaceuticals and Servier Pharmaceuticals. Henrik Walter has received a speaker honorarium from Servier, 9987.”

Paper 3

“All authors have no conflicts of interest related to this study. Dr. Stein has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun.  Professor Ian Hickie is a Commissioner in Australia’s new National Mental Health Commission from 2012. He is the Co-Director, Health and Policy at the Brain and Mind Centre which operates two early-intervention youth services under contract to headspace.  Professor Hickie has led a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs. He has led projects for health professionals and the community supported by governmental, community agency and pharmaceutical industry partners (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) for the identification and management of depression and anxiety. He has received honoraria for presentations of his own work at educational seminars supported by a number of nongovernment organisations and the pharmaceutical industry (including Servier, Pfizer, AstraZeneca, and Eli Lilly). He is a member of the Medical Advisory Panel for Medibank Private and also a Board Member of Psychosis Australia Trust. He leads an investigator-initiated study of the effects of agomelatine on circadian parameters (supported in part by Servier) and has participated in a multicentre clinical trial of the effects of agomelatine on sleep architecture in depression and a Servier-supported study of major depression and sleep disturbance in primary care settings.  Carsten Konrad received fees for an educational program from Aristo Pharma, Janssen-Cilag, Lilly, MagVenture, Servier, and Trommsdorff as well as travel support and speakers honoraria from Aristo Pharma, Janssen, Lundbeck and Servier. Professor Thomas Frodl received fees for presentations and scientific organisation of a conference from Janssen-Cilag, Lund-beck and Servier.  Dr. Van Erp has a contract with Otsuka Pharmaceutical, Inc.”

Similar acknowledgements are included in the other seven papers.  As mentioned earlier, the bulk of the funding for ENIGMA-MDD comes from governmental agencies in the various countries (e.g., The National Institutes of Health in the US), and most of the pharma money paid to various authors was not used in the ENIGMA-MDD studies.  In Paper 1 there is a statement:  “All authors have no conflicts of interest related to this study.”  Similar statements can be found in most of the other papers.

So, on the face of it, it looks like there was no industry contamination of the study’s procedures or results.

However, this issue is considerably more complex than is apparent at face value.  It’s difficult not to identify with the aims of a company that’s giving you, or your university lab, large sums of money on a regular basis.  Research careers are sometimes founded on precisely these expectations, and although pharma contamination may have been relatively low in the specific ENIGMA-MDD studies, many of the researchers who had taken pharma grants previously are well aware that their eligibility for further support will depend, at least to some extent, on how pharma-friendly their work is, even in studies that are not directly funded by pharma.

At the present time, the various psychiatric drugs that are in common use are under fire from many sources.  In particular, the fraudulent notion, heavily promoted by psychiatrists, that their drugs correct chemical imbalances in the brain, is thoroughly discredited.  Pharma is highly motivated by the need for “new and improved” psychiatric drugs, and every researcher and university lab in the world knows that this is the “mother lode”.

But first they need to find brain aberrations that cause depression, and then find a “cure” for those brain aberrations.  All of which requires researchers that are pharma friendly.  So, although there may have been a general policy to keep pharma money out of ENIGMA-MDD, it is likely that the researchers who had taken pharma support previously remain attuned to pharma’s goals, especially those goals that might bring them closer to the “mother lode”.

In brief, any researcher that brings proof that depression is caused by brain aberrations or, better still, a pharmaceutical cure for such aberrations, would be highly placed for a seat at the table when the profits were being distributed.

While I’m not suggesting that any impropriety has occurred, or is occurring, within the ENIGMA-MDD team, it is worth bearing in mind that large quantities of money constitute a grave temptation to put a pharma-favorable spin on the findings.

Given the critical nature of the issues, the large sums of money involved, and the history of widespread irregularities in this area, it would be really helpful if there were an opaque wall between pharma and the university research labs.