Amid the push to identify biomarkers in psychiatry, psychiatrists Awais Aftab and Manu Sharma call for the field to pause and reflect on some of the problematic assumptions and contradictions that are often built into biomarker research.
In their new paper, published in the Biomarkers in Neuropsychiatry, they lay out some conceptual considerations that can encourage a more thoughtful understanding of what biomarkers can really tell us about psychological distress. The article, titled “How not to think about biomarkers in psychiatry,” also warns against reductionist assumptions and approaches. Aftab and Sharma write:
“We…examine some of the ways in which diagnostic biomarkers may prompt erroneous assumptions regarding etiology and reductionism, and we illustrate ways in which biomarkers can be approached in a more conceptually robust manner.”
A central aim across the medical sciences has been to identify and classify experiences of distress. The hope is that a greater understanding of different types of afflictions can lead to increased precision and sophistication when it comes to personalizing effective treatments. Psychiatry has followed suit in the quest for biomarkers.
In recent decades, biomarkers have been a booming topic in the psychiatry research literature. A biomarker is “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions,” according to the FDA-NIH Biomarker Working Group.
In this case, biomarkers include biological processes that underpin or indicate psychological distress.
Thus, biomarkers in psychiatry are sought out to:
- Determine individuals’ susceptibility or risk to developing a disorder
- Diagnose disorder
- Monitor treatment responses
- Predict the likely course or onset of the disorder
- Predict response to treatment
Aftab and Sharma focus on diagnostic biomarkers in psychiatry and describe several challenges that emerge in this research.
First, the authors call attention to the conceptual pitfalls associated with diagnostic constructs in psychiatry. Diagnostic biomarkers are inherently tied to their referent diagnosis (e.g., depression) and, thereby, the logic of the psychiatric classification systems that define them (e.g., the DSM, ICD). Critiques and limitations of these diagnostic constructs and classification systems abound. For instance, Aftab and Sharma discuss how clinical descriptions of psychiatric disorders can be inconsistent with the research:
“Research findings do not validate the boundaries of DSM constructs in a way we would expect if these constructs represented distinct disease processes. All this suggests that the DSM categories are unlikely to capture fundamental mechanisms of dysfunction and etiology.”
Distress might be better understood as dimensional rather than as categorized into discrete concepts of disorder. Moreover, many people experiencing distress are likely to meet the criteria for multiple disorders. Taken together, these criticisms of existing classification systems challenge the utility of diagnostic biomarkers by exposing their limitations.
The authors write:
“All these considerations necessitate that we should be mindful of the limits of diagnostic biomarkers when it comes to conventional descriptive diagnoses, and that diagnostic markers will need to be continually revisited as our nosology evolves.”
Aftab and Sharma also point out that identifying a diagnostic biomarker does not necessarily equate to locating the physical cause of a disorder. Alternatively, a biomarker may represent the consequence of a disease process. Aftab and Sharma provide an example of how electroencephalogram (EEG) patterns may aid the identification of individuals experiencing Major Depressive Disorder (MDD). Still, they do not necessarily point to an underlying physical cause of MDD.
Although a biomarker could be causally informative, “the default explanation for diagnostic biomarkers should not be in causal terms, and great caution is needed before a causal role is assumed.”
Aftab and Sharma describe another conceptual pitfall pertaining to diagnostic biomarkers—the tendency to believe that biomarkers reify psychiatric diagnoses. “There is a tendency,” the authors write, “to think that a diagnostic biomarker validates the disorder as a discrete disease entity or establishes the disorder as more ‘real.’”
For example, machine learning algorithms can be trained to differentiate between individuals based on their EEG patterns. The successful differentiation of an individual whose EEG patterns reflect depression does not validate that pre-defined construct of depression. Observing and identifying biomarkers does not necessarily demonstrate that the category being applied is valid.
The authors challenge these assumptions:
“If such thinking is left unchecked, a biomarker can lead to a false sense of validity of the construct under study and in the context of psychiatric nosology may further contribute to the already rampant reification of DSM diagnoses.”
Finally, Aftab and Sharma discuss how biomarkers can be related to the effects of medication. They identified studies conducted to explore biomarkers associated with obsessive-compulsive disorder (OCD) and schizophrenia that more accurately captured the effects of the intervention or medication.
“Most biomarker studies are conducted in medicated individuals; however, psychiatric medications have effects of their own on brain functioning, and it is quite possible that we may interpret a biomarker association as evidence of association with the disorder when in fact it may simply be an association with the biological effects of the intervention.”
For example, there has been evidence to indicate that a reduction in brain volume occurring in individuals diagnosed with schizophrenia is an effect of antipsychotic medications rather than indicative of a disease process.
In recognizing possible confounds, such as medications, Aftab and Sharma consider what other confounds might be observed through biomarkers, such as the effects of social isolation or marginalization. They highlight “the need to understand biomarkers from an integrative perspective that also includes psychosocial variables and their interactions with biological variables.”
In other words, the effects of a phenomenon, such as social marginalization, can be observed at a biological level, but this does not mean that social marginalization can neatly be confined to and exclusively explained biologically.
This integrative perspective serves to debunk faulty assumptions of causality. The authors give examples of how the intersection of a psychosocial variable and a biological variable might mistakenly be interpreted through a causal lens. Resting amygdala activity is associated with individuals’ perceived stress, but this is not to say that a person is experiencing distress because of increased activity in this part of their brain.
Aftab and Sharma describe numerous additional examples of integrated and complex phenomena, such as experiences of chronic stress and accelerated aging, that may be identifiable through biomarkers but are not necessarily reducible to an exclusively biological explanation.
“It is to be expected that majority of psychiatric biomarkers will exist within causal networks that span the biological, psychological, and social domains. In other words, biomarker associations should not be seen as evidence of bioreductionism.”
Understanding distress and brain functions in the context of environmental interactions is key, they conclude. Aftab and Sharm’s work “guard[s] against overly simplified reductionist approaches, the reification of psychiatric diagnoses, and uncritical assumptions of causality.”
Aftab, A., & Sharma, M. (2021). How not to think about biomarkers in psychiatry: Challenges and conceptual pitfalls. Biomarkers in Neuropsychiatry, 4. https://doi.org/10.1016/j.bionps.2021.100031
To be clear, none of the following critique reflects on the author here, nor directly about Dr Aftab, but is a reflection of current medical and psychiatric diagnosis generally. I am reflecting on the pitfalls of reifying reliance on biomarkers for diagnosis in both psychiatry as well as general medicine (pertaining specifically to inflammatory disorders in this case).
The funny thing is that medicine generally relies on biomarkers even though many of the tests are only reliable for a fraction of the patients for most inflammatory illnesses. (SLE) Lupus is an outlier with a test that is 95% reliable for diagnosis. Almost all of the other inflammatory diseases have tests which are either only positive in a small minority of cases or as in rheumatoid arthritis are less than 70% reliable for diagnosis. MS has no reliable test. PSA relies on a history of Psoriasis for accurate diagnosis despite there being no correlation between severity of skin disease and severity of arthritis and only 80% of PSA patients have skin disease first. Only a portion of Sjogren’s Syndrome patients will have anti-Ro, anti-ANA, or anti-SSA antibodies. Lyme disease tests are 40-80% unreliable depending on which stage of the illness you are tested at. The initial period after infection will test negative even if the patient has clinical features such as the bullseye rash, and between the 6 week to 3 month mark, the initial IGM antibodies will wane and IGG antibodies will begin to show up in the test. You can test negative during this period as well. Ironically, the sickest patients in late disease can also test negative because of the way the lyme bacteria suppresses the immune response as a survival mechanism.
I read a pop science article recently that declared that 70% of depressed patients in a study had an elevated CRP level and that this could potentially be used as a biomarker test for depression. It’s funny to me because I have never in 20 years of multiple rounds of testing for inflammatory disorders ever once had a raised CRP. I have never had a raised anything indicating inflammation despite the fact that I have several chronically inflamed joints. I’ve been tested so thoroughly and I have had NO elevated results ever. And so I get no treatment. No raised interleukins, CRP, anti-ANA/SSA/RO/LA, no RF, and these are just the ones I can rattle off the top of my head. The ONLY positive result I’ve ever had was a single positive lyme test showing 7 of 10 bands for a CDC positive result, which even the CDC says right on it’s own website shouldn’t be used for diagnosis, and yet if you don’t test positive with at least 5 of these specific bands it’s almost impossible to get even a little treatment. Many of us still don’t get better with the little treatment we do receive. I have personally begun having again the symptoms that led to my initial diagnosis. And it’s almost impossible to get further treatment in this “post treatment” phase outside of a clinical research lab or seeing an LLMD who generally don’t take insurance. So yay me!
And this is what I find so hypocritical about both the argument that “mental illness” doesn’t have a biomarker test to begin with! What if there was a test? Would this go on to mean that people who are experiencing severe emotional distress would be treated the way people in physical pain with obvious physical evidence of inflammation are currently being treated when their tests are otherwise negative? And what would become of psychiatric treatment, since that is the mainstay for those who are physically ill and don’t test positive with any of the currently used tests? Would doctors begin telling *those* patients sorry there’s no indication anything is wrong so we can’t help you? (Obviously of course not, because psychiatry is a tool of behavioral control and not actual medicine.) However it is clear that Western Medicine is actually attempting to paint itself into a corner. And with the rate of medical error, the real answer seems to be to stay away from doctors unless you are literally bleeding out or about to expire otherwise.
Western Medicine is in a state of crisis where it has forgotten the ART of clinical diagnosis. The reliance on specialists, each seeing a different body part, and the inability of most doctors to form an integrative view of the patient as a whole, along with an over reliance on technology, increasing errors in medical charts, and a tendency to turn to surgery when all else fails, is leaving more and more of us sick, depressed, and deformed. And that’s just those of us who don’t die from their treatments.
Biomarkers correlating to a depressed or mentally altered state aren’t going to change anything substantially for the patients being treated probably ever, but at least not until such time when doctors begin seeing the whole patient again, preferably over a long period of time, if not from birth.
And to boot these articles are just fluff.
It keeps giving psychiatry and medicine an out, mumbling about “biomarkers”
they seem to equate that with a need for bad treatment, harmful treatments,
that really have zero to do with what the issues are.
Sam, you are correct but we have to dig deeper to understand what’s going on. Remember, first, that we have two (if not more) overlapping systems to contend with when it comes to the advancement of medical knowledge and treatment. You have the pure research wing – those rare medical researchers who have the freedom at their institutions to do research that doesn’t seem immediately relevant to disease but which has resulted in breakthroughs in medical/physiological knowledge. And you have BigPharma, who funds an awful lot of research on treatments for understood pathophysiology. Pharma isn’t largely interested in developing cures. It’s basis is treatments, hopefully for life, at the most profit. As Pharma has increasingly infiltrated medical schools and popular science, medical advancement has stagnated in the arena of understanding and addressing the underlying mechanisms of disease and moved toward a treatment model.
The goal of Pharma in developing biomarkers is pharmceutical treatments (mostly, but also sometimes implanted devices) that can counter those biomarkers. So to go back to inflammatory disorders, that model identifies the inflammatory biomarker that they’ve identified as the cause of the symptom and develops a drug to counter that symptom, but it does not ultimately address the cause of the underlying illness, which in most cases, continues to progress even if it has been slowed.
This is exemplified in diabetes treatment. Diabetes (let’s stick with type 2) isn’t just a lack of insulin, it’s also insulin insensitivity, it’s metabolic imbalance (hormones and fat), it’s inflammation. We have a range of drugs to address the symptoms. But there is very little research targeted at the root causes of the disease and cures. One, they are not profitable. Two, the root causes often point to changes in lifestyles that our culture is not ready to make. May not ever be ready to make. And for many groups, are simply unable to make.
The psychiatric domain is no different in terms of going after symptoms rather than causes. In fact, I’d venture to say that psychiatry has followed general medicine in this pursuit, rather than the other way around. Despite a lot of complaint to the contrary, there really is no difference between physical healthcare and psychiatric care. This line of argument is ineffective because it is fundamentally not evidence-based. Western medicine treats symptoms and sometimes (as in cases of infection), it manages to accidentally eliminate the cause. And even then, it’s a temporary situation where one individual is rid of the pathogen but the pathogen still exists and is constantly evolving to become resistant to these developed treatments. This is where the hubris of this approach becomes readily apparent. This is what has led to the crisis of antimicrobial resistance.
The root causes are of course our lifestyles in the west. The belief that we can dominate the environment rather than living in harmony with it. And to many people, the solutions sound counter productive. The notion of going back to nature, ditching our sheltered and air-conditioned indoor environments, our technology, our forms of transport and entertainment, our nuclear families and careers and many of our individual freedoms. All of it has to go.
The sad part of it all is that those peoples who never deviated from traditional agrarian tribal lifestyles are as doomed as the rest of us as that way of life shrinks further and further as “civilization” encroaches and as global warming threatens our planet’s ability to maintain homeostasis (actually already gone).
Of course, the surest way to sound like a crazy person is to tell people who are still striving to get what the privileged take for granted that actually none of us should be striving for such! So into the proverbial hand basket we all go…
The bottom line is: nearly all medical treatments are bandaids to ease the pain inflicted by the existential crisis we are facing on a global scale. Psychiatry does not deviate from accepted western medical approaches in this sense, regardless of its failed hypotheses.
Completely agree and you articulate it well.
Well said, Kindred. I never thought about it this way before.
At a screening of the film “Is Anybody Listening?” about veteran trauma, someone got up and talked excitedly about research at (as I recall) NYU Langone that was supposedly close to finding a biomarker for PTSD. My first thought was, if the person’s blood sample tests negative, does that mean they don’t actually suffer from war trauma even though their lived experience would obviously suggest they do?
Nonetheless, I appreciated Aftab et al.’s paper, though I find it disturbing that someone felt a need to explain to psychiatrists that they must be wary of confusing cause and effect:
“Aftab and Sharma also point out that identifying a diagnostic biomarker does not necessarily equate to locating the physical cause of a disorder. Alternatively, a biomarker may represent the consequence of a disease process.”
It would be grandiose thinking that biomarkers point to where the thing went faulty. And what if that thing you think is faulty, never was it. 🙂
I think many researchers get a chuckle out of people putting any significance to their research.
Psychiatry simply uses researchers chatter as some kind of evidence.
Gotta give it to psychiatrists. They are quite patient. Decades of fruitless search would have caused most people to conclude that there’s nothing to find.
Yes well it is a luxury to use oneself to distinguish between brain defected and not brain defected, and boy it would be easy to believe it if psychiatry was not causing immense damage and disability and death.
And since mental illness is tied to being of odd beliefs or habits, and to repeat, rinse and repeat, then we might say psychiatry is thus.
Simple, all they have to do is start being honest.
Yeah, how many times to you have to try and fail to prove something before you have disproven it? That’s kind of central to science – failed efforts to support a hypothesis means the hypothesis is regarded as false. Apparently, these rules don’t apply to psychiatric research?
Psychiatric research isn’t going anywhere soon, because, for one, shrinks seem to believe their “diagnoses” are of real ailments. Kryptopyrolle (“mauve factor”) isn’t regarded as a biomarker because the positive results fall into different “diagnostic categories”, even though all the “categories” respond to the same B6+ zinc treatment.
I’ve long said that the DSM categories make scientific research impossible, because they group together totally heterogeneous groupings of people, particularly if you’re studying physiology. Why would anyone assume that all people who feel depressed have the same problem??? Even if we assumed there WERE some physiological cause to ‘depression,’ which of course is also a ridiculous assumption, it’s like saying everyone with a rash has the same cause, or everyone with a sore knee should be diagnosed with “knee pain disorder.” (Of course, medicine IS moving in that direction, with things like “high blood pressure” and “obesity” being now accepted as “diagnoses.”) Naturally, if you studied people with “knee pain disorder,” you’d find that most did not respond to any single treatment, with only 20% responding to arthritis treatments, 15% responding to chiropractic adjustments, 20% responding to treatment for strained ligaments, 15% to orthotic shoe inserts, etc. All of these treatments would be dismissed because they only helped a small percentage of the “KPD” patients, and the only thing that would “help” the majority of them (temporarily) would, of course, be pain killers. So we’d decide that “KPD” is a chronic, untreatable condition, but that we can “manage symptoms” with pain killers for life. Works great for Big Pharma, but not so good for the person who could function fine in a few weeks or months if they got the correct treatment for their actual underlying problem!
Strictly speaking you don’t disprove a hypothesis, you either find evidence to reject the null hypothesis or you don’t.
That is a good way to put it. The error that many make, especially those with conflicts of interest, is that they try to find evidence to support their preferred theory, and despite never finding evidence to reject the null hypothesis, they continue to believe that their hypothesis will eventually be proven true. At a certain point, failure to disprove the null hypothesis repeatedly proves the null hypothesis true.
Exactly, Steve and beokay. Defenders of psychiatry have got themselves into a winning position …. there is no possible way of disproving the hypothesis that someone, somewhere, sometime, will stumble across the holy grail of primary biological causal factors in what they persist in describing as ‘mental illness.’ But Aftab is playing a slightly different game here. He admits all the logical errors in the arguments about biomarkers BUT then uses this to create a position that we need to understand biomarkers in a much broader way, which will allow the hunt to continue. He has a similar strategy in relation to psychiatric diagnosis. No longer need we be stuck in the naive view that terms such as ‘diagnosis’ and ‘disorder’ denote medical conditions… they simply suggest that the person is SUFFERING in some way. Any ill-informed person who interprets these terms differently has simply not kept up with the sophisticated new philosophy of psychiatry. He doesn’t explain the existence of all those rather concrete manifestations of the failed ‘medical illness’ paradigm… you know, things like doctors, and nurses, and hospitals, and lots and lots of drugs (‘medications.’) Are these too based on a fundamental misunderstanding of current philosophical thinking, and if so, should we not be getting rid of them? Or does that not, in fact, follow? Very strange indeed.
Oh, it IS based on a misunderstanding of their philosophy – anything that minimizes discomfort and maximizes profits for the “clinician” is good! Anything that increases discomfort or dilutes profit is “bad.” If people understood the REAL philosophy behind this “model,” they’d have a lot easier time deciding what to do with the “recommendations” it generates!
One helpful way to promote “clear thinking about biomarkers in psychiatry to avoid bioreductionism” is to STOP calling them “deficits” and “impairments.” These loaded terms are frequently used by researchers to describe biomarkers. They have obvious causal implications – a deficit/impairment is a biological abnormality caused by the “illness.” But with psychiatric biomarkers we have 2 big problems – the “illnesses” are not real and the biomarkers are mere correlates.
Biomedical researchers use such terms without apparently understanding or caring about their misleading nature. I’ve called out my fellow psychological scientists on this practice a few times and the response I’ve received from top-level, highly published, full professor psychological scientists is best described as a blank stare followed by the annoyance one demonstrates while swatting away a fly.
It is clear to me that the scientific community generally has no idea how to think properly about biomarkers, the nature of DSM diagnoses, and about reductionism. For starters, I wish professionals who work in this area would read this blog, “The Mereological Fallacy and representational Theories of Mind”: https://andersonbrownphilosophy.blogspot.com/2011/10/mereological-fallacy-and.html. To quote:
“Stomachs don’t eat lunch. Eating lunch is something that a whole, embodied person does. We understand the role that stomachs play in the lunch-eating process; we appreciate that people can’t eat lunch without them. Brains don’t think. They don’t learn, imagine, solve problems, calculate, dream, remember, hallucinate or perceive. To think that they do is to commit the same fallacy as someone who thought that people can eat lunch because they have little people inside them (stomachs) that eat lunch. This is the mereological fallacy: the fallacy of confusing the part with the whole (or of confusing the function of the part with the telos, or aim, of the whole, as Aristotle, who as usual beat us to the crux of the problem, would say).”
Thank you Brett – as a Wittgenstein inspired psychologist I am very aware of the mereological fallacy. Neural patterns are called ‘neural signatures’ by the enactivists (a movement which is sweeping the planet in cognitive science, as we get to understand what Wittgenstein was on about), as neural signatures are but a small part of the “mind” (or mental circuit) which includes the larger brain-body-world dynamic (which is the whole). (See Gallagher – 2017 ‘Enactivist interventions). Enactivists Hutto & Kirchhoff (2015) have been quick to point out that there are few neural networks (signatures) in play throughout development – at different ages different signatures – especially for social functioning. Wittgenstein once said with regards this debate: “The best prophylactic against this is the thought that I don’t know at all whether the humans I am acquainted with actually have a nervous system”.
So, does this also apply to the idea of sex-specific trait and biomarkers?
You mean like having facial hair?
Would that count? Or even things like genes, reproductive systems, etc?