ADHD, especially when untreated impairs patients and creates difficulties in families. Although these are the proximal targets of treatment, ADHD also burdens society due, for example, to underemployment and use of health resources. A recent study assessed economic burden using the Danish population registries, researchers, which link medical information with employment, education, crime, and social care registers while maintaining confidentiality. They identified 5,269 adults with adult ADHD who had not been diagnosed with ADHD in childhood and, we can assume, were probably not treated for the disorder. They excluded patients with other psychiatric diagnoses, and cases without a same sex sibling free of any diagnosed psychiatric diagnoses. That left 460 pairs of same-sex siblings, one with adult ADHD and the other with no psychiatric diagnosis. They selected the non-ADHD sibling closest in age to the ADHD sibling. Using siblings mitigated effects of genetics and upbringing between the ADHD group and normally developing controls.

Looking at personal income (combining work income and public transfers), adults with ADHD on average brought home about 12,000 Euros less – almost a third less – than their sibling counterparts. They also paid 40% less tax. Balancing that out, their after-tax income was roughly 7,500 Euros less than their siblings. With the additional personal cost of prescribed medication (prescriptions are relatively inexpensive in Denmark, and copayments even more so) the net personal cost to adults with ADHD was 7,700 Euros.

The net public costs were considerably greater. That was primarily due to the reduction in taxes paid (about 4,500 Euros) and increase in income replacement transfers (just over 5,500 Euros). The cost of additional crimes committed by adults with ADHD added another 1,000 Euros. Additional primary and secondary health care costs contributed another 1,000 Euros. Subsidies for prescribed medicines added 661 Euros, but that was partly counterbalanced by a reduction of 344 Euros in education costs. There were no significant differences in costs from traffic accidents or adult continuation of foster care. Overall, the net per capita public cost of adults with ADHD was just over 12,400 Euros each year.

Combining public and private costs, the per capita economic burden of adult ADHD was just over 20,000 Euros each year.

The study could not evaluate the extent to which ADHD treatment may reduce economic burden but given many studies that show treatment for ADHD reduces impairments, we would expect treatment to have a positive impact on economic burden. These results are extremely important for policy makers and for those who control the allocation of treatment in health care systems. Although treating ADHD incurs costs, not treating in incurs even greater costs in the long run

REFERENCES
D. Daley, R.H. Jacobsen, A.-M. Lange, A. Sørensen, J. Walldorf, “The economic burden of adult attention deficit hyperactivity disorder: A sibling comparison cost analysis,” European Psychiatry 61 (2019) 41–48.

A newly published meta-analysis of 57 studies encompassing almost a third of a million participants has uncovered a very strong association between ADHD and suicide, a strong association with suicidal ideation, and a small-to-medium association with suicide attempts.

The population examined included children, adolescents, and adults. Only persons formally diagnosed were considered to have ADHD. Studies that included self-injuries without suicidal intent were excluded. Most of the studies focused on European and American populations, with one in six from other locations, mostly Asian.

The most striking result was for actual suicides. The odds ratio (OR) for four datasets encompassing roughly one hundred forty thousand participants was 6.69 (95% CI 3.24 to 17.39, p < .0001). As a frame of reference, an OR of 1.5 is a small effect size, 2.5 a medium one, and 4.3 a large one. That means the effect size in this case is very large.

For suicidal ideation, 23 datasets with a combined total of just over 73,000 participants produced a medium-to-large OR of 3.5 (95% CI 2.94 to 4.25, p < .0001). In three datasets with more than nine thousand participants that adjusted for confounders, the adjusted OR was 4.5 (95% CI 1.72 to 11.63, p < .0001), indicating a large effect size.

For suicide attempts, 44 datasets encompassing over 228,000 participants produced an OR of 2.4 (95% CI 1.64 to 3.43, p < .0001). In six datasets with over 65,000 participants that adjusted for confounders, the adjusted OR dropped to 2.1 (95% CI 1.27 to 3.47, p = .005).

There was no evidence of publication bias for studies on suicides or suicidal ideation, but significant evidence of bias for studies on suicide attempts (Egger’s p = .03). This means that studies with positive findings were more likely to be published than negative studies.

There was, however, strong statistical evidence for differences between studies in the size of their ORs. This indicates that the pooled OR cannot summarize results from all datasets and more work is needed to clarify why the ORs differ among studies.

The authors appropriately caution that their meta-analysis is “not informative on cause-effect relationships,” but offer as a hypothesis that ADHD contributes to suicidal spectrum behaviors (SSBs) through “Impulsivity, a core symptom of ADHD, along with impaired decision-making and risk taking, that characterize a number of individuals with ADHD … Additionally, a sizeable portion of individuals with ADHD present with deficits in executive functions. As executive functions are implicated in the regulation of impulse control and emotions, executive dysfunctions may contribute to SSBs.”

In view of the large to very large effect sizes for suicide and suicidal ideation, the authors advise: “Awareness of this association should prompt practitioners to systematically screen for SSBs in patients with ADHD at the first assessment and at each follow-up, which in turns should contribute to decrease the risk of SSBs. This is particularly noteworthy considering that questionnaires/scales commonly used to screen/assess ADHD symptoms generally do not include suicide related items.”

REFERENCES
Septier M, Stordeur C, Zhang J, Delorme R, Cortese S, Association between suicidal spectrum behaviors and Attention-Deficit/Hyperactivity Disorder: A systematic review and meta-analysis, Neuroscience and Biobehavioral Reviews (2019), https://doi.org/10.1016/j.neubiorev.2019.05.022.

Yan He, Jian Chen, Li-Hua Zhu, Ling-Ling Hua, and Fang-Fang Ke

Journal of Attention Disorders 1 –11 , 2017 DOI: 10.1177/1087054717696766

This article describes a meta-analyses of studies which examined the potential effects of maternal smoking on the risk of childhood ADHD. A prior meta-analysis in 2005 (Langley, Rice, Van den Bree, & Thapar, 2005) found a strong association between maternal smoking and subsequent development of childhood ADHD in exposed offspring. Several recent individual studies also found an association be, tween maternal smoking and childhood ADHD, but one prospective study (Ball et al., 2010) did not find such an association. Therefore, given the length of time since the last meta-analysis and the one negative study noted above, highlighted the need for an updated meta-analysis. The authors employed fairly standard meta-analysis guidelines via the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement, which included a selection of studies, data extraction and assessment of study quality. The risk ratios (RRs) and 95% CIs reported in the individual studies were pooled across studies to examine the potential association of maternal smoking during pregnancy and childhood ADHD risk. The authors also examined for presence of publication bias and changing association over time. 265 studies were originally identified, with 12 meeting the stringent criteria to be included in the meta-analysis. The main finding of the analysis was the maternal smoking was modestly association with an increased risk of ADHD in children (pooled RR = 1.58, 95% CI = [1.33, 1.88]) and this association seemed to increase over time (by examining publication year); no significant publication bias was seen. The authors that the association they observed was not as robust as the one seen by Langley et al. for several reasons: their including a larger number of trials, which were limited to those with prospective and not case-controlled desi This meta-analysis is important for clinicians as it highlights the importance of the need to caution their patients as to potential risks of offspring developing ADHD in mothers who smoke during pregnancy.

REFERENCES:
Ball, S. W., Gilman, S. E., Mick, E., Fitzmaurice, G., Ganz, M. L., Seidman, L. J., & Buka, S. L. (2010). Revisiting the association between maternal smoking during pregnancy and ADHD. Journal of Psychiatric Research, 44, 1058-10

Langley, K., Rice, F., Van den Bree, M. B., & Thapar, A. (2005). Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review. Minerva Pediatrica, 57, 359-37

Our genes are very important for the development of mental disorders – including ADHD, where genetic factors capture up to 75% of the risk. Until now, the search for these genes had yet to deliver clear results. In the 1990s, many of us were searching for genes that increased the risk for ADHD because we know from twin studies that ADHD had a robust genetic component. Because I realized that solving this problem required many DNA samples from people with and without ADHD, I created the ADHD Molecular Genetics Network, funded by the US NIMH. We later joined forces with the Psychiatric Genomics Consortium (PTC) and the Danish iPSYCH group, which had access to many samples.

The result is a study of over 20,000 people with ADHD and 35,000 who do not suffer from it – finding twelve locations (loci) where people with a particular genetic variant have an increased risk of ADHD compared to those who do not have the variant. The results of the study have just been published in the scientific journal Nature Genetics, https://www.nature.com/articles/s41588-018-0269-7.

These genetic discoveries provide new insights into the biology behind developing ADHD. For example, some of the genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning.

We study used genomewide association study (GWAS) methodology because it allowed us to discover genetic loci anywhere on the genome. The method assays DNA variants throughout the genome and determines which variants are more common among ADHD vs. control participants. It also allowed for the discovery of loci having very small effects. That feature was essential because prior work suggested that, except for very rare cases, ADHD risk loci would individually have small effects.

The main findings are:

  1. A) we found 12 loci on the genome that we can be certain harbor DNA risk variants for ADHD. None of these loci were traditional ‘candidate genes’ for ADHD, i.e., genes involved in regulating neurotransmission systems that are affected by ADHD medications. Instead, these genes seem to be involved in the development of brain circuits.
  2. B) we found a significant polygenic etiology in our data, which means that there must be many loci (perhaps thousands) having variants that increase risk for ADHD. We will need to collect a much larger sample to find out which specific loci are involved;

We also compared the new results with those from a genetic study of continuous measures of ADHD symptoms in the general population. We found that the same genetic variants that give rise to an ADHD diagnosis also affect inattention and impulsivity in the general population. This supports prior clinical research suggesting that, like hypertension and hypercholesteremia, ADHD is a continuous trait in the population. These genetic data now show that the genetic susceptibility to ADHD is also a quantitative trait comprised of many, perhaps thousands, of DNA variants

The study also examined the genetic overlap with other disorders and traits in analyses that ask the questions: Do genetic risk variants for ADHD increase or decrease the likelihood a person will express other traits and disorders.  These analyses found a strong negative genetic correlation between ADHD and education. This tell us that many of the genetic variants which increase the risk for ADHD also make it more likely that persons will perform poorly in educational settings. The study also found a positive correlation between ADHD and obesity, increased BMI and type-2 diabetes, which is to say that variants that increase the risk of ADHD also increase the risk of overweight and type-2 diabetes in the population.

This work has laid the foundation for future work that will clarify how genetic risks combine with environmental risks to cause ADHD. When the pieces of that puzzle come together, researchers will be able to improve the diagnosis and treatment of ADHD.

 

 

A Danish team recruited 29,489 participants from among voluntary blood donors between the ages of 17 and 67, ensuring a large sample size. Participants were asked to complete two simple questionnaires on digital tablets. One asked two questions: “Have you ever had migraine?” and “Have you ever had visual disturbances lasting 5-60 min followed by headache?” A yes to either was considered positive for migraine. The other used the ADHD Self-Report Scale, with 18 ADHD symptoms evaluated on a five-point scale.

Excluding those who did not answer all questions left 26,456 participants. The risk for migraines among those with ADHD was nearly twice the risk for others. The odds ratio (OR) was 1.8, with a 95 percent confidence interval from 1.53 to 2.12 (p < 0.001). The OR was higher among females (2.01) than males (1.64). For those with visual disturbances, the OR was higher (1.98) than for those without (1.52). The association disappeared in those over 60, with an OR essentially equal to one (0.98, 95% CI = 0.84 – 1.15, p = 0.8).

Although the authors concluded, “We demonstrate a significant comorbidity between migraine and ADHD in adults, and this is most prominent for participants with migraine with visual disturbances,” the significance to which they refer are of the p-values, and should not be misinterpreted as an indication of a strong association, as the odds ratios point variably to weak, and weak-to-moderate associations, depending on subpopulations. The work is, however, important as it points to another somatic comorbidity of ADHD. That list is growing and now includes obesity, eczema and asthma.

REFERENCES
Thomas Folkmann Hansen, Louise K. Hoeffding, Lisette Kogelman, Thilde Marie Haspang, Henrik Ullum, Erik Sørensen, Christian Erikstrup, Ole Birger Pedersen, Kaspar René Nielsen, Henrik Hjalgrim, Helene M. Paarup, Thomas Werge, and Kristoffer Burgdorf, “Comorbidity of migraine with ADHD in adults,” BMC Neurology (2018), 18:147.

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 co¬existence 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.”

REFERENCES
Qi Chen, Catharina A. Hartman, Jan Haavik, Jaanus Harro, Kari Klungsøyr, Tor¬Arne 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.

Stephen_Faraone_PhD_ADHD_in_Adults
Does Acetaminophen use During Pregnancy Cause ADHD in Offspring?

Many media outlets have reported on a study suggesting that mothers who use acetaminophen during pregnancy may put their unborn child at risk for ADHD.   Given that acetaminophen is used in many over-the-counter pain killers, correctly reporting such information is crucial. 

As usual, rather than relying on one study, looking at the big picture using all available studies is best.  Because it is not possible to examine this issue with a randomized trial, we must rely on naturalistic studies.  

One registry study (http://www.ncbi.nlm.nih.gov/pubmed/24566677) reported that fetal exposure to acetaminophen predicted an increased risk of ADHD with a risk ratio of 1.37.  The risk was dose-dependent in the sense that it increased with increased maternal use of acetaminophen.  Of particular note, the authors made sure that their results were not accounted for by potential confounds (e.g., maternal fever, inflammation and infection). 

Similar results were reported by another group, which also showed that risk for ADHD was not predicted by maternal use of aspirin, antacids, or antibiotics.  But that study only found an increased risk at age 7 (risk ratio = 2.0) not at age 11. (http://www.ncbi.nlm.nih.gov/pubmed/25251831)

In a Spanish study, (http://www.ncbi.nlm.nih.gov/pubmed/27353198), children exposed prenatally to acetaminophen were more likely to show symptoms of hyperactivity and impulsivity later in life.  The risk ratio was small (1.1) but it increased with the frequency of prenatal acetaminophen use by their mothers. 

We can draw a few conclusions from these studies.  There does seem to be a weak, yet real, association between maternal use of acetaminophen while pregnant and subsequent ADHD or ADHD symptoms in the exposed child.  The association is weak in several ways: there are not many studies, they are all naturalistic and the risk ratios are small.  

So mothers that have used acetaminophen during pregnancy and have an ADHD child should not conclude that their acetaminophen use caused their child’s ADHD.  On the other hand, pregnant women who are considering the use of acetaminophen for fever or pain should discuss other options with their physician.  As with many medical decisions, one must balance competing risks to make an informed decision.