Research: “No Promising Biomarkers” Identified for ADHD

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A new study reviews all the various possible biomarkers for identifying ADHD—and comes up empty-handed.

A new study reviewed all types of possible biomarkers for ADHD, including those from genetics, brain volume and connectivity, and levels of various brain chemicals, among others. The researchers found that there is no biological difference that can be used to differentiate people with an ADHD diagnosis from those without it.

“Despite the large number of studies and variety of techniques used, no promising biomarkers have been identified so far,” the researchers write.

Valeria Parlatini at King’s College London, UK, and Alessio Bellato at the University of Southampton, UK, led the study, which was overseen by Samuele Cortese at the University of Southampton, UK. The paper was published in Expert Review of Molecular Diagnostics.

For each type of possible biomarker, the researchers found early, positive studies that they describe as “promising.” However, in each case, they conclude that these have either failed to replicate in later studies, never been tested for potential use as a biomarker, emerged only in studies with major methodological problems, or failed to have sensitivity, specificity, or predictive values that are sufficiently above chance. In most cases, even if they aren’t false positives, the slight average differences found between those with ADHD and those without indicate huge overlap—meaning that the biomarker doesn’t actually distinguish between cases and controls on the individual level.

As one example, the researchers note that using the polygenic risk score (PGS)—a way of calculating a person’s risk for ADHD based on their entire genome—was able to account for “up to 4% of the variance” in whether or not a person met criteria for ADHD. That is, 96% of whether a person gets the diagnosis or not remains unexplained by genetics, even when their entire genome is considered.

Ultimately, for each type of possible biomarker, the researchers conclude that initial results appear “promising,” but they all need to be validated and, in most cases, replicated in larger studies before it is possible to argue that they support the diagnosis. Moreover, many of the studies exhibit major methodological limitations.

The researchers’ conclusions:

Genetic and epigenetic biomarkers: “In sum, these results are promising but studies are still in their early stages, thus findings need to be confirmed in larger studies and tested as potential biomarkers.”

Biochemical markers: “In sum, several potential biochemical markers have been investigated, ranging from inflammatory and oxidative stress markers to minerals and gut micro/myco-biota. Although promising, the predictive ability of these biomarkers needs to be confirmed.”

Neuroimaging biomarkers: “In sum, although some neuroimaging findings appear promising, they have not been replicated in independent external samples. Further, study quality may be limited where design does not include robust power calculations, information on data source, or adjustment for confounders.”

Neurophysiological biomarkers: “Overall, although neurophysiological measures appear promising, studies did not consistently report information on power calculation, sampling frame, and participation rate, which may affect study quality, and metrics necessary to port the use of the investigated metrics as biomarkers.”

Neuropsychological biomarkers: “Overall, although neuropsychological characteristics appear to be promising in theory, studies did not consistently report metrics, such as sensitivity and specificity, to support their use as biomarkers. Further, the quality data assessment based on BIOCROSS highlighted limitations, especially in terms of lack of information on power calculation, sampling frame, and participation rate.”

The ADHD Explosion

According to the researchers, one limitation is that the diagnosis of ADHD largely overlaps with other psychiatric and neurodevelopmental diagnoses, including autism, and thus they suggest that any biomarkers may be transdiagnostic—showing up in various different disorders. However, the authors cite their own systematic review of last year, in which they found no evidence for transdiagnostic biomarkers except for one: memory difficulties, which was shared by those with ADHD and those with autism. In that study, they also found no independent biomarkers for ADHD.

Another limitation, according to the researchers, may be that the diagnosis of ADHD is extremely broad, with over 100,000 different ways to meet the DSM-5 criteria for the diagnosis. Thus, any two individuals with an ADHD diagnosis may have extremely different traits. Indeed, the construct of ADHD has been criticized for being so all-encompassing that it lacks clinical meaning, including by the very psychiatrists who were responsible for its proliferation, Keith Conners and Allen Frances.

Frances, who was the Chair of the DSM-IV task force—essentially, the man responsible for creating the diagnostic categories—has written extensive critiques of ADHD. According to Frances, the research demonstrates the “inescapable finding that we are turning immaturity into disease.” He has criticised the impact of massive drug industry marketing in expanding psychiatric disorders. In a Tweet, he called adult ADHD “a fake diagnosis helping to trigger an explosive growth of stimulant drug prescription.”

Conners gives his namesake to one of the primary means of diagnosing ADHD. He led the initial studies on the use of methylphenidate (Ritalin) for the then-rare diagnosis of “minimal brain dysfunction” and was one of the scientists responsible for the evolution and broadening of that category into “ADHD.” But later, he began to change his opinion, noting that “It seems obvious to me that the steady increases over time in the apparent high prevalence of ADHD is due to doctor practices fueled by the shoddy science and allure of the big numbers, without the only meaningful ingredient of a comprehensive clinical history.”

Other researchers have argued that the measures used to diagnose ADHD are creating huge numbers of false positives—people diagnosed with ADHD who don’t even meet the very broad DSM-5 criteria for the diagnosis. As these researchers write, “Most [of the measures] had less than a 10% chance of accurate diagnosis given a positive test score.”

Studies have consistently found that younger children in the classroom are much more likely to receive a diagnosis of ADHD and be medicated with stimulant drugs. Aspects of the ADHD diagnosis, like being able to sit still in a classroom, are extremely relative, and it makes sense that kids who are almost a year younger than their peers are less able to control themselves through boring lectures.

And there is evidence that the diagnosis and treatment of ADHD are creating worse outcomes, not better. A recent study compared kids with the same symptoms, some of whom received the diagnosis and some of whom did not. Those who were diagnosed with ADHD had worse quality of life, not better—and were more than twice as likely to self-harm—than kids with the same symptoms who went undiagnosed. The researchers write that “the harms associated with an ADHD label (such as stigma, prejudice, deflection from other problems, or the perceived inability to change) may not be offset by benefits associated with the diagnosis or treatment.”

The large, NIMH-funded MTA study is often cited as evidence that stimulant drugs work. Indeed, the short-term results appeared positive. However, by the 22-month mark, the benefit of stimulant drugs vanished. The authors wrote that “the MTA medication algorithm was associated with deterioration rather than a further benefit.” Ultimately, they added, “extended use of medication was associated with suppression of adult height but not with reduction of symptom severity.”

Other studies have contradicted the notion that stimulants can improve academic performance and even support the notion that kids are more likely to drop out of school after taking the drugs. One study noted that Ritalin was associated with an 18-fold increase in depression, which returned to baseline once kids stopped taking the drug. Another study found that 62.5% of kids may experience hallucinations and other psychotic experiences after taking stimulant drugs.

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Peter Simons was an academic researcher in psychology. Now, as a science writer, he tries to provide the layperson with a view into the sometimes inscrutable world of psychiatric research. As an editor for blogs and personal stories at Mad in America, he prizes the accounts of those with lived experience of the psychiatric system and shares alternatives to the biomedical model.

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