Who is the average patient with ADHD?

Is there an ‘average ADHD brain’? Our research group (from the Radboudumc in Nijmegen) shows that the average patient with ADHD does not exist biologically. These findings were recently published in the journal. Psychological Medicine.

Most biological psychiatry research heavily relies on so-called case-control comparisons. In this approach a group of patients with for instance ADHD is compared against a group of healthy individuals on a number of biological variables. If significant group effects are observed those are related to for instance the diagnosis ADHD. This often results in statements such as individuals with ADHD show differences in certain brain structures. While our results are in line with those earlier detected group effects, we clearly show that a simple comparison of these effects disguises individual differences between patients with the same mental disorder.

Modelling individual brains

In order to show this, we developed a technique called ‘normative modelling’ which allows us to map the brain of each individual patient against typical development. In this way we can see that individual differences in brain structure across individuals with ADHD are far greater than previously anticipated. In future, we hope that this approach provides important insights and sound evidence for an individualized approach to mental healthcare for ADHD and other mental disorders.

Individual differences in ADHD

When we studied the brain scans of individual patients, the differences between those were substantial. Only a few identical abnormalities in the brain occurred in more than two percent of patients. Marquand: “The brains of individuals with ADHD deviate so much from the average that the average has little to say about what might be occurring in the brain of an individual.”

Personalized diagnosis of ADHD

The research shows that almost every patient with ADHD has her or his own biological profile. The current method of making a diagnosis of psychiatric disorders based on symptoms is therefore not sufficient, the authors say: “Variation between patients is reflected in the brain, but despite this enormous variation all these people get the same diagnosis. Thus, we cannot achieve a better understanding of the biology behind ADHD by studying the average patient. We need to understand for each individual what the causes of a disorder may be. Insights based on research at group level say little about the individual patient.”

Re-conceptualize mental disorders

The researchers want to make a fingerprint of individual brains on the basis of differences in relation to the healthy range. Wolfers: “Psychiatrists and psychologists know very well that each patient is an individual with her or his own tale, history and biology. Nevertheless, we use diagnostic models that largely ignore these differences. Here, we raise this issue by showing that the average patient has limited informative value and by including biological, symptomatic and demographic information into our models. In future we hope that this kinds of models will help us to re-conceptualize mental disorders such as ADHD.”

Further reading

Wolfers, T., Beckmann, C.F., Hoogman, M., Buitelaar, J.K., Franke, B., Marquand, A.F. (2019). Individual differences v. the average patient: mapping the heterogeneity in ADHD using normative models. Psychological Medicine, https://doi.org/10.1017/S0033291719000084 .

This blog was written by Thomas Wolfers and Andre Marquand from the Radboudumc and Donders Institute for Brain, Cognition and Behaviour in Nijmegen, The Netherlands. On 15 March 2019 Thomas Wolfers will defend his doctoral thesis entitled ‘Towards precision medicine in psychiatry’ at the Radboud university in Nijmegen. You can find his thesis at http://www.thomaswolfers.com

ADHD Is A Risk Factor For Type Two Diabetes And High Blood Pressure, As Well As Other Psychiatric Disorders

All Swedish residents have their health records tracked through unique personal identity numbers. That makes it possible to identify psychiatric and medical disorders with great accuracy across an entire population, in this case encompassing more than five and a half million adults aged 18 to 64. A subgroup of more than 1.6 million persons between the ages of 50 and 64 enabled a separate examination of disorders in older adults.

Slightly over one percent of the entire population (about 61,000) were diagnosed with ADHD at some point as an adult. Individuals with ADHD were nine times as likely to suffer from depression as were adults not diagnosed with ADHD. They were also more than nine times as likely to suffer from anxiety or a substance use disorder, and twenty times as likely to be diagnosed with bipolar disorder.  These findings are very consistent with reports from clinical samples in the USA and Europe.

Adults with ADHD also had elevated levels of metabolic disorders, being almost twice as likely to have high blood pressure, and more than twice as likely to have type 2 diabetes. Persons with ADHD but without psychiatric comorbidities were also almost twice as likely to have high blood pressure, and more than twice as likely to have type 2 diabetes.

Similar patterns were found in men and women with ADHD, although comorbid depression, bipolar disorder, and anxiety were moderately more prevalent in females than in males, whereas substance use disorder, type 2 diabetes, and hypertension were more prevalent in males than in females.

ADHD was less than a third as prevalent in the over-50 population as in the general adult population. Nevertheless, individuals in this older group with ADHD were twelve times as likely to suffer from depression, anxiety, or substance use disorders, and more than 23 times as likely to be diagnosed with bipolar disorder as their non-ADHD peers. They were also 63% more likely to have high blood pressure, and 72% more likely to have type 2 diabetes.

The authors noted, “Although the mechanisms underlying these associations are not well understood, we know from both epidemiologic and molecular genetic studies that a shared genetic predisposition might account for the co­existence of two or more psychiatric conditions. In addition, individuals with ADHD may experience increased difficulties as the demands of life increase, which may contribute to the development of depression and anxiety.” As for associations with hypertension and type 2 diabetes, these “might reflect health ­risk behaviors among adult patients with comorbid ADHD in addition to a shared biological substrate. As others have noted, inattention, disinhibition, and disorganization associated with ADHD could make it difficult for patients to adhere to treatment regimens for metabolic disorders.” They concluded that “Clinicians should remain vigilant for a wide range of psychiatric and metabolic problems in ADHD affected adults of all ages and both sexes.”

Stephen Faraone is distinguished Professor of Psychiatry and of Neuroscience and Physiology at SUNY Upstate Medical University and is working on the H2020-funded project CoCA. 

REFERENCES

Qi Chen, Catharina A. Hartman, Jan Haavik, Jaanus Harro, Kari Klungsøyr, Tor­Arne Hegvik, Rob Wanders, Cæcilie Ottosen, Søren Dalsgaard, Stephen V. Faraone, Henrik Larsson, “Common psychiatric and metabolic comorbidity of adult attention-deficit/hyperactivity disorder: A population-based cross-sectional study,” PLoS ONE (2018), 13(9): e0204516. https://doi.org/10.1371/journal.pone.0204516.

Ghost busters: why even high ranking psychotherapy studies might be lousy

img_4358The last half year saw two high ranking psychotherapy studies in depression, published in the most prestigious journals of our profession. While in principle this is laudable, in these specific cases it is not doing any good as the studies fall short to prove what they are actually claiming and also, because they sack medical care for the sake of cost. Let’s have a closer look.

The first paper (https://www.ncbi.nlm.nih.gov/pubmed/27461440), on the “COBRA” study, was published in Lancet (!!!) and compared „behavioral activation” delivered by „junior mental health workers“ (i.e. relatively untrained and, first and foremost, receiving relatively small wages) is just as effective as routine CBT delivered by trained psychologist (which is the gold standard psychotherapy treatment in depression). So depression treatment can be quite unspecific and cheap! Yay!

Not.

The most important drawback is the that the primary endpoint was set at twelve months. As the average length of a depressive episode is six to eight month without treatment, this makes no sense at all. Imagine that a study on two treatments aimed at relieving common cold would set its primary endpoint at 4 weeks. Would you buy this? As neither a survival plot (Kaplan-Meier-Plot) nor any other time course are shown, being suspicious is appropriate.

A further, unfortunately quite common, drawback is the lack of a sham psychotherapy group (i.e., this study is not placebo controlled). Given the year-long course, it may quite well have shown that it is as effective as the two other groups.

This is made even worse by the fact that 80% of participants in both groups received anti-depressant drug treatment. Likely, a ceiling effect is effective, further obscuring any effect of whatever psychotherapy is done.

This is not a non-inferiority trial. This is a failed trail.

Another study published in JAMA Psychiatry (https://www.ncbi.nlm.nih.gov/pubmed/27487573) echoes the COBRA study, although changing the flavor. Here, psychodynamic (not behavioral activation) was compared against CBT in depression. I don’t want to nag about the underpowered sample for a non-inferiority trial (especially when looking at how many patients attended more than five sessions (116 in total). Again, we have an endpoint which is rather late (5 month) without any description of time courses, and again sham psychotherapy is lacking. Even worse, that average Hamilton score (HAM-D, likely HAM-D 17) was 21±6 points. This is quite low and barely reaches the border to moderate depression; the usual cut-off for study inclusion in pharma trials lies between 20 and 22. This means that many patients with mild depression were included, that usually are not the target population for depression studies. Any differences to placebo/sham are hard to demonstrate due to floor effects, especially when considering the low number of patients adhering to therapy and the measured effect size of 0.6 (Cohen’s d, corresponding to a medium effect size). Considering all this, watchful waiting, mere psychoeducation or having a beer every week or so would have had the same effect, namely, a reduction of five points on the HAM-D 17, as this is just the naturalistic course of mild to medium depression. An indicator of this are the significantly overlapping SD measurements pre- and post-treatment (wisely enough, the authors did not go for graphical display of their data). The most parsimonious interpretation of the data thus is that both treatments are equally ineffective!

You may ask about antidepressant use here as well. There is a simple answer: we don’t know. The numbers of patients on antidepressants are not given at all! That they were there, we know, as there is a small subclause: „We found no statistically significant interaction between the use of psychotropic medication and treatment group on the rate of change in the HAM-D”.

This is another failed trail. Although it was highly published…

Unsurprisingly, the rate of recidivism (which is a major effect of psychotherapy) is not given in any of the studies.

It is very surprising however that these studies were published so well, despite of these obvious flaws. I can only speculate on the reasons for this. Regarding the Lancet paper (COBRA), I assume that economic reasons play a major role. Cheap BA treatment by “juniors” (did not we just learn to abandon that word from our vocabulary?) is as effective as CBT by expensive, greedy psychologist. That makes treatment less expensive, which however is somewhat tainted by the fact that it is ineffective (notwithstanding the commonsense experience that unspecific BA especially in early stage depression by be quite helpful). Never mind. The psychodynamic study might have undergone a “wishful thinking” review process – so many people are out there who desperately wish that psychodynamic therapy works as well as CBT… so this one came in quite handy. However, no favor was done to the field, on contrary. We do not need so badly designed (or at least presented) studies; what we do need are psychotherapy trials adhering to the highest standards in analogy to drug trials: i.e. presenting time courses, studying severe cases, being well powered with low attrition rates, and – most important – including a sham (=placebo) condition.