Nationwide population studies: atomoxetine not associated with birth defects

Nationwide population studies: atomoxetine not associated with birth defects

Treatment for ADHD among women of reproductive age is increasingly common. That means we need to know whether ADHD medications have any tendency to increase the risk of birth defects.

Treatment for ADHD among women of reproductive age is increasingly common. 

That means we need to know whether ADHD medications have any tendency to increase the risk of birth defects. Previous studies have looked mostly at ADHD medications that are central nervous system stimulants, especially methylphenidate and amphetamines.

Atomoxetine is the most widely prescribed non-stimulant for treating ADHD. It acts indirectly, by selectively inhibiting the removal of norepinephrine, a neurotransmitter that mobilizes the brain and body for action. 

To explore whether atomoxetine might be associated with any higher risk of birth defects, an international study team examined nationwide population data from four Nordic countries with universal single-payer health insurance systems – Denmark, Norway, Sweden, and Iceland – along with nationwide data from the U.S. Medicaid system, which is likewise single-payer, and covers roughly half of all births in the U.S.

They compared the prevalence of major birth defects among infants born to women exposed to atomoxetine in the first trimester (three months) of pregnancy to the prevalence among infants born to women not exposed to any ADHD drug during the period beginning three months before their last menstrual period and concluding at the end of the first trimester.

The team adjusted for maternal characteristics such as maternal age, calendar year of delivery, childbirth and medical characteristics, psychiatric conditions, high blood pressure, diabetes, kidney disease, obesity, and smoking.

In more than 2.4 million births in the four Nordic countries, and almost 1.8 million births in the U.S., there was absolutely no sign of increased prevalence of major infant malformations among infants born to mothers taking atomoxetine. 

More specifically looking at heart defects, there was again no significant association with maternal atomoxetine use, either in the Nordic population, the U.S. population, or the combined populations.

For limb malformations, there was again no significant association between maternal atomoxetine use and birth defects in the combined populations. There was an appearance of a significant association in the Nordic population, but that was based on only 5 instances, and because there were zero instances in the U.S. population, there was no net association at all in the combined population of more than 4.2 million.

The team concluded, “We found no increased prevalence of major congenital malformations overall associated with atomoxetine use in early pregnancy. The increased prevalence of limb malformations in the Nordic countries was not observed in the US. … Given the low absolute risk of both of these outcomes, these results are reassuring from a public health perspective and provide important information in the consideration of whether to continue treatment with atomoxetine during pregnancy.”

January 15, 2024

Danish population study: Sex chromosome abnormalities increase risk of ADHD

Danish population study: Sex chromosome abnormalities increase risk of ADHD

Sex chromosome abnormalities are replication errors that produce an atypical number of sex chromosomes relative to the typical 46,XY and 46,XX arrangements.

Sex chromosome abnormalities are replication errors that produce an atypical number of sex chromosomes.  Most people have 23 pairs of chromosomes for a total of 46.  One pair is called the sex chromosome pair.  It is either XX (for biological females) or XY (for biological males).  The term 46,XY refers to a typical biological male and the term 46,XX refers to the typical biological female.  

In rare cases a person may have only 45 chromosomes due to having only one sex chromosome, the X chromosome (45,X).  Some people, rarely, have an extra sex chromosome and are designated: 47,XXX, 47,XXY, and 47,XYY.  These rare sex chromosome differences occur in between 0.5 and 1.3 per 1,000 livebirths. 

These differences have physical manifestations. For example, 45,X is associated with shorter height and abnormal development of the ovaries. The other three are associated with greater height. 47,XXX is associated with premature ovarian failure and 47,XXY with low testosterone.

A Danish and U.S. team used data from Denmark’s single-payer universal health insurance system to assess the association of these sex chromosome differences with the prevalence of ADHD.

They performed a case-cohort study. The source population was all 1,657,449 singleton births in Denmark between May 1, 1981, and Dec 31, 2008. The cases consisted of all 93,608 individuals in this population who were diagnosed with any of five psychiatric disorders, including ADHD. These were compared with a cohort consisting of 50,615 individuals randomly selected from the source population.

The combined population prevalence of these four sex chromosome differences was 1.45 per 1,000. 47,XXY was the most common, at 1.23 per 1,000, followed by 47,XYY at .82 per 1,000, then 47,XXX at .66 per 1,000. 45,X was by far the least common, at less than .23 per 1,000.

All four conditions were associated with significantly increased risk of ADHD:

  • 47,XXY roughly doubled the risk. 
  • 47,XXX increased the risk 2.5-fold.
  • 47,XYY more than quadrupled the risk.
  • 45,X more than sextupled the risk.

These data are intriguing because we know there  are sex differences in the prevalence of ADHD but the causes of those differences are unknown.  

Given that ADHD is more common in boys than girls, one would have predicted that having an extra Y chromosome would increase risk for ADHD.  That is the case here but we also see that having an extra X chromosome also increases risk, which means that the impact of sex chromosomes on ADHD is not straightforward.

January 10, 2023

Hong Kong population study finds methylphenidate use is associated with reduced risk of fractures among persons with ADHD

Hong Kong Population Study Finds Methylphenidate Use is Associated With Reduced Risk of Fractures Among Persons with ADHD

Some animal studies and laboratory experiments have suggested that methylphenidate, the most widely prescribed pharmaceutical to treat ADHD, may weaken bones. On the other hand, other studies have indicated that methylphenidate is associated with lower risk of injury.

Some animal studies and laboratory experiments have suggested that methylphenidate, the most widely prescribed pharmaceutical to treat ADHD, may weaken bones. On the other hand, other studies have indicated that methylphenidate is associated with lower risk of injury.

What, then, is the overall effect? 

The Hong Kong Hospital Authority is the sole public health provider for the city’s 7.3 million residents. Using the Clinical Data Analysis and Reporting System, the Authority’s electronic database, an international study team set out to explore this question.

Among 43,841 individuals with ADHD medication, the team identified 2,023 children and youths 5 through 24 years old with both methylphenidate prescription and a fracture between January 2001 and December 2020. 

In the six months following prescription, individuals were found to be roughly 40% less likely to be treated for a fracture than in the six months prior to prescription. The same held true when comparing the period 7 to 12 months after prescription with the six months prior to prescription. 

As a control, the team also looked at the effect of methylphenidate prescription on a completely unrelated condition – diseases of the esophagus, stomach, and duodenum. 

In this case, there was absolutely no difference in disease incidence for equal periods of time before and after initiation of methylphenidate treatment.

The team concluded, “for all-cause fractures, the results of the … within-individual comparison demonstrated that the use of methylphenidate is associated with lower risk … compared with the … period before the treatment initiation.”

January 30, 2024

Combined meta-analysis and nationwide population study indicates ADHD by itself has negligible effect on risk of type 2 diabetes

Study Indicates ADHD By Itself Has Negligible Effect on Risk of Type 2 Diabetes

Noting that “evidence on the association between ADHD and a physical condition associated with obesity, namely type 2 diabetes mellitus (T2D), is sparse and has not been meta-analysed yet,” a European study team performed a systematic search of the peer-reviewed medical literature followed by a meta-analysis, and then a nationwide population study.

Noting that “evidence on the association between ADHD and a physical condition associated with obesity, namely type 2 diabetes mellitus (T2D), is sparse and has not been meta-analysed yet,” a European study team performed a systematic search of the peer-reviewed medical literature followed by a meta-analysis, and then a nationwide population study.

Unlike type 1 diabetes, which is an auto-immune disease, type 2 diabetes is believed to be primarily related to lifestyle, associated with insufficient exercise, overconsumption of highly processed foods, and especially with large amounts of refined sugar. This leads to insulin resistance and excessively high blood glucose levels that damage the body and greatly lower life expectancy.

Because difficulty with impulse control is a symptom of ADHD, one might hypothesize that individuals with ADHD would be more likely to develop type-2 diabetes. 

The meta-analysis of four cohort studies encompassing more than 5.7 million persons of all ages spread over three continents (in the U.S., Taiwan, and Sweden) seemed to point in that direction. It found that individuals with ADHD had more than twice the odds of developing type 2 diabetes than normally developing peers. There was no sign of publication bias, but between-study variability (heterogeneity) was moderately high.

The nationwide population study of over 4.2 million Swedish adults came up with the same result when adjusting only for sex and birth year. 

Within the Swedish cohort there were 1.3 million families with at least two full siblings. Comparisons among siblings with and without ADHD again showed those with ADHD having more than twice the odds of developing type 2 diabetes. That indicated there was little in the way of familial confounding.

However, further adjusting for education, psychiatric comorbidity, and antipsychotic drugs dropped those higher odds among those with ADHD in the overall population to negligible (13% higher) and barely significant levels. 

The drops were particularly pronounced for psychiatric comorbidities, especially anxiety, depression, and substance use disorders, all of which had equal impacts.

The authors concluded, “This study revealed a significant association between ADHD and T2D [type 2 diabetes] that was largely due to psychiatric comorbidities, in particular SUD [substance use disorders], depression, and anxiety. Our findings suggest that clinicians need to be aware of the increased risk of developing T2D in individuals with ADHD and that psychiatric comorbidities may be the main driver of this association. Appropriate identification and treatment of these psychiatric comorbidities may reduce the risk for developing T2D in ADHD, together with efforts to intervene on other modifiable T2D risk factors (e.g., unhealthy lifestyle habits and use of antipsychotics, which are common in ADHD), and to devise individual programs to increase physical activity. Considering the significant economic burden of ADHD and T2D, a better understanding of this relationship is essential for targeted interventions or prevention programs with the potential for a positive impact on both public health and the lives of persons living with ADHD.”

Norwegian nationwide population study finds no association between maternal organophosphate pesticide exposure and offspring ADHD

Population Study Finds No Association Between Maternal Organophosphate Exposure and Offspring ADHD

Organophosphate pesticides were originally developed as nerve agents for chemical warfare, then used in lower doses as insecticides.

Organophosphate pesticides were originally developed as nerve agents for chemical warfare, then used in lower doses as insecticides. 

Their neurotoxicity raises the possibility of effects on development of the nervous system at lower doses, including psychiatric disorders.

Previous studies have found mixed results for any association with ADHD.

Norway has a single-payer health insurance system that covers virtually the entire population, facilitating nationwide population studies. 

A primarily Norwegian study team used the Norwegian Mother, Father, and Child Cohort Study, a prospective population-based cohort that enrolled participants between 1999 and 2008 to explore possible associations. The study invited all 227,702 pregnant mothers to enroll, of which 112,908 (41%) actually enrolled.

Children were eligible for the present study if they were born after 2002, did not have Down’s syndrome or cerebral palsy, had available maternal biospecimens, were the result of a singleton pregnancy, and lived near Oslo (the location of the clinic). That left a sample of 24,035.

The team used the Norwegian Patient Registry (NPR) to identify diagnosed cases of ADHD. 

From the final eligible population, the team randomly selected 552 mother-child pairs to represent the exposure distribution in the population of pregnancies that gave rise to the cases of ADHD.

At about 17 weeks into pregnancy, maternal spot urine samples were collected at the mother’s first ultrasound appointment. These samples were then tested for concentrations of organophosphate metabolites (breakdown chemicals). 

Adjustments were made for a variety of possible confounding variables: season, birth year, maternal education, vegetable intake, fruit intake, maternal self-reported ADHD, financial status, other organophosphorus pesticides, and sex.

Comparing higher versus lower maternal exposures to organophosphates, no significant differences emerged in rates of ADHD diagnosis among offspring.

February 5, 2024

Nationwide population study finds cancer survivors have much higher risk of ADHD

Nationwide Population Study Finds Cancer Survivors Have Much Higher Risk of ADHD

Thanks to improvements in cancer treatment, there is a growing population of childhood and adolescent cancer survivors (CACSs). CACSs are at an increased risk of chronic physical, psychological, and social problems because of their cancer experiences and intensive cancer treatments.

Thanks to improvements in cancer treatment, there is a growing population of childhood and adolescent cancer survivors (CACSs). CACSs are at an increased risk of chronic physical, psychological, and social problems because of their cancer experiences and intensive cancer treatments. These include depression, anxiety, suicidal ideation, and post-traumatic stress disorder (PTSD). 

To what extent, if at all, does this also apply to ADHD? Noting that “previous studies … have reported inconsistent findings,” a local research team took advantage of Taiwan’s mandatory single-payer National Health Insurance that covers over 99% of the island’s population. More specifically, the National Health Insurance Research Database (NHIRD) maintains data on the insured population available on formal request for study purposes.

Linking the catastrophic illness database, mental disorders database, and longitudinal health insurance database, they tracked children age younger than 10 years and adolescents aged 11-17 years who were diagnosed with any malignancy (cancer) between 2002 and 2011 with no history of major psychiatric disorders (including ADHD). Parental history of major psychiatric disorders was likewise controlled as a potential confounder.

The team identified 5,121 CACSs, which they matched one to ten with 51,210 age-, sex-, income-, and residence-matched cancer-free controls.

ADHD diagnoses were made by board-certified psychiatrists during the study follow-up period (from enrollment through 2011) based on a comprehensive clinical interview and clinical judgment. 

Cancer survivors were diagnosed with ADHD at more than six times the rate of matched controls. Survival duration made no significant difference in this outcome. 

Cancers of bone, connective tissue, skin, and breast were associated with a more than threefold increase in risk of an ADHD diagnosis. For cancers of the circulatory system, there was a more than sixfold increased risk of ADHD, and for those of the genitourinary organs, more than sevenfold increased risk. 

For brain cancer survivors, the increased risk of ADHD was more than twelvefold. That may be at least in part because the brain itself was targeted for treatment in these instances, which plausibly could cause damage resulting in psychiatric disorders.

The team concluded, “we observed a comparatively higher risk of MPDs [major psychiatric disorders] among CACSs than among controls and likewise found that such risks varied across different cancer types. Survivors of both CNS [central nervous system] and non-CNS cancers have increased risks of MPD diagnoses. Among the enrolled CACSs, ASD [autism spectrum disorder] and ADHD were associated with most types/categories of cancers. Long-term care of this vulnerable population must include psychosocial interventions for patients and their families. Physicians need to be aware of early signs of mental health problems in this high-risk subpopulation and arrange early interventions accordingly.”

February 9, 2024

Study of U.S. 12th grade public and private school students finds no link between stimulant use for ADHD and subsequent cocaine or methamphetamine use

Large Scale Study of U.S. High Schoolers Finds No Link Between Stimulant Use for ADHD and Subsequent Cocaine or Methamphetamine Use

Monitoring the Future is a multicohort U.S. national longitudinal study of adolescents followed up into young adulthood.

Monitoring the Future is a multicohort U.S. national longitudinal study of adolescents followed up into young adulthood. 

The U.S. research team used data from this study to follow 5,034 twelfth graders over a period of six years, until they were 23 and 24 years of age.

Prescription stimulant misuse was assessed at baseline and each follow-up survey year by asking how often they used prescription stimulants without a physician’s orders. They were similarly asked about cocaine and methamphetamine use.

The study team adjusted for the following confounding variables: sex, race and ethnicity, parents’ level of education, urbanicity, U.S. region, cohort year, grade point average during high school, past-30-day cigarette use (at 18 years of age), past-2-week binge drinking (at 18), past-year marijuana use (at 18), past-year prescription opioid misuse (at 18), past-year prescription stimulant misuse (at 18), lifetime cocaine use (at 18), lifetime methamphetamine use (at 18), lifetime use of nonstimulant therapy for ADHD (at 18), and discontinued use of stimulant therapy for ADHD (at 18).

With these adjustments, they found that stimulant use for ADHD was in no way associated with subsequent cocaine use. In fact, it was associated with lesser odds of subsequent cocaine use, though the association was not statistically significant.

Likewise, they reported that stimulant use for ADHD was in no way associated with subsequent methamphetamine use.

On the other hand, those who used prescription stimulants without a physician’s orders were 2.6 times more likely to subsequently use either cocaine or methamphetamine.

The team concluded, “In this multicohort study of adolescents exposed to prescription stimulants, adolescents who used stimulant therapy for ADHD did not differ from population controls in initiation of illicit stimulant (cocaine or methamphetamine) use, which suggested a potential protective effect, given evidence of elevated illicit stimulant use among those with ADHD. In contrast, monitoring adolescents for PSM is warranted because this behavior offered a strong signal for transitioning to later cocaine or methamphetamine initiation and use during young adulthood.”

February 15, 2024

Cohort Study Finds Association Between Parkinson’s Disease and ADHD

Nationwide cohort study finds association between Parkinson’s disease and ADHD

Parkinson’s disease is a chronic, progressive neurological disease, characterized by the drastic reduction of dopamine transporters and the dopaminergic neurons upon which they are expressed.

Parkinson’s disease is a chronic, progressive neurological disease, characterized by the drastic reduction of dopamine transporters and the dopaminergic neurons upon which they are expressed. The resulting symptoms include bradykinesia (slowness of initiation of voluntary movements), tremors, rigidity, and postural instability.

Taiwan’s National Health Service covers about 99 percent of its 24 million inhabitants and maintains complete records in its National Health Insurance Research Database. The Longitudinal Health Insurance Database2000 (LHID 2000) is a nationally representative subset of the latter.

Using the LHID 2000, a Taiwanese research team identified 10,726 patients with Parkinson’s disease. It paired them with an identical number of randomly selected non-Parkinson’s controls, matched by age, gender, and index date (first date of diagnosis of Parkinson’s disease).

The team then looked retroactively through the database to determine which of the 21,452 individuals had previously been diagnosed with ADHD. Fourteen of the 10,726 Parkinson’s patients had been diagnosed with ADHD, versus five of the 10,726 in the control group.

Parkinson’s patients were thus 2.8 times as likely to have had a previous diagnosis of ADHD as the controls. When adjusted for age, gender, and Carlson Comorbidity Index scores, they were 3.6 times as likely to have had a previous ADHD diagnosis.

The authors cautioned that this association between prior ADHD diagnosis and subsequent Parkinson’s diagnosis is not causal.

Only one in 766 of Parkinson’s patients (a seventh of one percent) had previously been diagnosed with ADHD. So even if there were any causal relationship, it would be extremely weak.

November 9, 2023

Daytime Sleepiness, Cognitive Function, and Adult ADHD

What’s the relationship between daytime sleepiness and cognitive functioning in adults with ADHD?

Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them.

Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them. A team of British researchers set out to see whether this association could be further confirmed with objective sleep measures, using cognitive function tests and electroencephalography (EEG).

Measured as theta/beta ratio, EEG slowing is a widely used indicator in ADHD research. While it occurs normally in non-ADHD adults at the conclusion of a day, during the day it signals excessive sleepiness, whether from obstructive sleep apnea or neurodegenerative and neurodevelopmental disorders. Coffee reverses EEG slowing, as do ADHD stimulant medications.

Study participants were either on stable treatment with ADHD medication (stimulant or non-stimulant medication) or on no medication. Participants had to refrain from taking any stimulant medications for at least 48 hours prior to taking the tests. Persons with IQ below 80 or with recurrent depression or undergoing a depressive episode were excluded.

The team administered a cognitive function test, The Sustained Attention to Response Task (SART). Observers rated on-task sleepiness using videos from the cognitive testing sessions. They wired participants for EEG monitoring.

Observer-rated sleepiness was found to be moderately higher in the ADHD group than in controls. Although sleep quality was slightly lower in the sleepy group than in the ADHD group, and symptom severity slightly greater in the ADHD group than the sleepy group, neither difference was statistically significant, indicating extensive overlap.

Omission errors in the SART were strongly correlated with sleepiness level, and the strength of this correlation was independent of ADHD symptom severity. EEG slowing in all regions of the brain was more than 50 percent higher in the ADHD group than in the control group and was highest in the frontal cortex.

Treating the sleepy group as a third group, EEG slowing was highest for the ADHD group, followed closely by the sleepy group, and more distantly by the neurotypical group. The gaps between the ADHD and sleepy groups on the one hand, and the neurotypical group on the other, were both large and statistically significant, whereas the gap between the ADHD and sleepy groups was not. EEG slowing was both a significant predictor of ADHD and of ADHD symptom severity.

The authors concluded, “These findings indicate that the cognitive performance deficits routinely attributed to ADHD … are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. … we would like to propose a simple working hypothesis that daytime sleepiness plays a major role in cognitive functioning of adults with ADHD. … As adults with ADHD are more severely sleep deprived compared to neurotypical control subjects and are more vulnerable to sleep deprivation, in various neurocognitive tasks they should manifest larger sleepiness-related reductions in cognitive performance. … One clear testable prediction of the working hypothesis would be that carefully controlling for sleepiness, time of day, and/or individual circadian rhythms would result in a substantial reduction in the neurocognitive deficits in replications of classic ADHD studies.”

March 31, 2022

Study Finds Significant Association Between Allergies and ADHD

Nationally representative sample of almost 200,000 U.S. youths finds association between allergies and ADHD

After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.

A growing body of studies suggests a link between inflammation and autoimmune diseases on the one hand and ADHD on the other. It has been hypothesized that excessive release of cytokines (small signaling proteins that regulate immune response and inflammation and repair) and keratinocytes (skin cells) under allergic conditions may cause structural and functional changes to the nervous system and brain, which can contribute to psychiatric disorders, including ADHD.

Noting that previous studies have focused primarily on associations between ADHD and respiratory allergies(asthma) and skin allergies, a joint Chinese and American study team set out to see what, if any, association there might be with food allergies.

To this end, they turned to the national health Interview Survey (NHIS), conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. This survey relies on a very large, nationally representative sample of the U.S. population.

The study encompassed 192,573 youths aged 4 through 17 years old. Of these, 15,376 had an ADHD diagnosis, 8,603 had food allergies, 24,218 had respiratory allergies, and 18,703 had skin allergies.

After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.

How did that compare with respiratory and skin allergies? In the same study population, making identical adjustments for potential confounders, youths with respiratory allergies were 50% more likely to be diagnosed with ADHD than those without such allergies. Those with skin allergies were 65% more likely to be diagnosed with ADHD. After further mutual adjustment for other allergic conditions, those with respiratory allergies were still over a third more likely to be diagnosed with ADHD, and those with skin allergies were 50% more likely to be diagnosed with ADHD.

The authors concluded, "The current study found a significant and positive association between common allergic conditions, including food allergy, respiratory allergy, skin allergy, and ADHD in children. Although the detailed mechanisms linking food allergy and other allergic conditions to ADHD remain to be understood, physicians should be aware of the increased risk of ADHD as a comorbidity of children with allergic conditions".

March 29, 2022

Siblings of Those With ADHD at Higher Risk for ADHD & Other Disorders

Israel-wide population study:siblings of individuals with ADHD have highly elevated risk of ADHD, slightly elevated risk of anxiety and personality disorders, no greater risk for other disorders or low IQ

Israel has a military draft that applies to males and females alike, except orthodox women and orthodox male seminary(yeshiva) students, who are exempt. Upon turning 17 every Israeli undergoes a medical review, including both a physical and psychiatric assessment, in preparation for the draft. The Draft Board Registry maintains comprehensive health information on all unselected Israelis until they turn 21. The registry also tracks all family members of draft registrants, including full siblings.

An Israeli study team used registry records from 1998 through2014 to obtain data for a total of over a million individuals (1,085,388). Because of the exemption for orthodox women, 59% were male.

The team identified 903,690 full siblings in the study population (58% males), including 166,359 male-male sibling pairs, 104,494 female-female sibling pairs, and 197,571 opposite-sex sibling pairs.

Next, the team identified all cases in the study population with a diagnosis of a psychiatric disorder, low IQ (≥2 standard deviations below the population mean), Type-1 diabetes, hernia, or hematological malignancies. It matched each case with ten age- and sex-matched controls selected at random from the study population. Then, for each case and case-matched controls, it identified all siblings.

There were 3,272 cases receiving treatment for ADHD, 2,128 with autistic spectrum disorder, 9,572 with severe/profound intellectual disability, 7,902 with psychotic disorders, 9,704 with mood disorders, 10,606with anxiety disorders, 24,815 with personality disorders, 791 with substance abuse disorders, 31,186 with low IQ, 2,770 with Type-1 diabetes, 30,199 with a hernia, and 931 with hematological malignancies.

Draftees with ADHD were five and a half times more likely to have a sibling with ADHD than controls.

There were no significant associations between ADHD and any of the somatic disorders - Type-1 diabetes, hernia, or hematological malignancies - nor between ADHD and low IQ.

There were also no significant associations between ADHD and autism spectrum disorder, severe/profound intellectual disability, mood disorders, and substance use disorders.

On the other hand, draftees with ADHD were more than 40% more likely to have siblings with anxiety or personality disorders than controls.

Surprisingly, draftees with ADHD were less than half as likely to have siblings with psychotic disorders than controls.

There were some limitations. The psychiatric classification system used by the Israeli military did not permit assessing the risk of bipolar disorder and depression separately. That meant having to use a broader category of mood disorders, including both disorders. In addition, the military diagnostic system does not allow diagnosis of comorbid psychiatric disorders in the same individual, instead of assigning only the most severe diagnosis.

March 27, 2022

Strong Association Between Low Birth Weight and ADHD Discovered

South Korean nationwide population study finds strong association between low birth weight and subsequent ADHD

Since 1989, South Korea has had a single-payer healthcare insurance system, the Korean National Health Insurance Service. This facilitates nationwide population studies.

A South Korean study team used the national health claims database to retroactively examine the relationship between birth weight and subsequent diagnosis of ADHD for all 2.36 million children born in the country between 2008 and 2012. After excluding children who had since died, who had missing birth weight records, missing income information, or who weighed under400 grams at birth, 2,143,652 children remained in the study cohort.

Gestational age at birth was not available, so could not be taken into consideration.

To reduce the impact of confounding factors, odds ratios were adjusted for sex, history of congenital or perinatal diseases, income, and birth year.

Children with more normal birth weights in the range of 2.5 to 4 kilograms were used as the reference group.

Children with birth weights greater than this reference group were found to be no more likely to develop ADHD than those in the reference group.

At the other end of the spectrum, children with birth weights under a kilogram were 2.2 times more likely to be diagnosed with ADHD than those in the reference group.

That dropped to 1.7 times more likely for those with birth weights from 1 to 1.5 kilograms; 1.5 times more likely in the 1.5-to-2-kilogram range, and 1.4 times more likely in the 2-to-2.5-kilogram range. This dose-response curve, accelerating steeply with lower birth weights, points to a strong association.

For autism spectrum disorder (ASD), the association was even stronger. Again, there was no significant association with higher-than-normal birth weight. But children in the 2-to-2.5-kilogram range were 1.9 times as likely to be diagnosed with ASD; those in the 1.5-to-2 kilogram tranche over three times as likely; those in the 1 to 1.5-kilogram tranche five and halftime as likely, and those under 1 kilogram over ten times as likely.

The authors concluded, "In this national cohort, infants with birth weights of < 2.5 kg were associated with ADHD and ASD, regardless of perinatal history. Children born with LBW [low birth weight] need detailed clinical follow-up."

March 25, 2022

Significant Association Found Between Type 1 Diabetes and ADHD

Nationwide population-based cohort study finds very strong association between type 1 diabetes and ADHD

Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic.

Taiwan has a mandatory single-payer universal health insurance system, the National Health Insurance (NHI), that records diagnoses and prescriptions across virtually the entire resident population. Out of the roughly 28 million residents covered by NHI, a randomly assigned sample of 3 million is tracked in the Taiwan National Health Insurance Research Database(NHIRD).

Expert panels have to confirm all diagnoses of severe systemic autoimmune diseases, ensuring a high level of accuracy.

A Taiwanese study team availed itself of these records to explore the link between type 1 diabetes mellitus (T1DM) and ADHD. ADHD diagnoses were made by board-certified psychiatrists, based on comprehensive interviews and clinical judgment.

The team found a total of 6,226 cases diagnosed with T1DM in the decade from 2001 through 2010 and followed them through the end of 2001. It matched each case with ten age- and sex-matched non-T1DM controls from the same database, for a total of 62,260 controls.

Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic. There was no difference in the risk ratio between youth and adults. The risk of ADHD among females with T1DM was only slightly lower than among males: sevenfold greater, rather than 8.5 times greater.

The authors concluded, "Our findings indicate the importance of the close monitoring of the mental health condition of patients with T1DM by clinicians ... The exact path of mechanisms between T1DM and major psychiatric disorders should be elucidated in future studies."

March 19, 2022

Risk of Unnatural Death Tripled in Those with ADHD

Meta-analysis finds no significant increase in natural mortality, but almost tripled risk of unnatural death, in persons with ADHD

A meta-analysis of eight studies with a combined total of over 396,000 persons with ADHD reported a twofold greater risk of premature death in persons with ADHD as compared with the general population. There was no significant difference in mortality between males and females with ADHD.

But when natural causes of death, primarily disease, were distinguished from unnatural causes, such as injuries and poisoning, virtually all the increased risk was attributable to the latter.

A meta-analysis of four studies with a combined total of over 394,000 participants with ADHD found no significant increase in natural mortality among persons with ADHD. This held for both males and females.

But a meta-analysis of ten studies with over 430,000 persons with ADHD found a nearly threefold increase in unnatural mortality (injuries, poisoning, etc.) in persons with ADHD. Among females (five studies, over 110,000 participants) the increase was threefold. Males with ADHD (five studies, over 310,000 participants) were 2.5 times more susceptible to premature death.

An important caution: in all of these meta-analyses, between-study heterogeneity was extreme, meaning there was little consistency from one study to the next. Moreover, no effort was made to evaluate the likelihood of publication bias.

The largest study, with over 275,000 participants with ADHD, found a negligible and only marginally significant 7% increased all-cause risk of death. It found no increase in natural causes of mortality, but a 50% increase in unnatural causes of premature mortality.

The authors described these results as "suggestive," but emphasized that "the evidence was judged as only low confidence," in line with "inconsistent" evidence from previous nationwide population studies: in Denmark, a twofold increase in all-cause mortality; in Sweden, a fourfold increase; but in Taiwan, a tiny 7% increase that was at the limit of statistical significance, once the data was fully adjusted for confounding factors.

That led the authors to suggest "that all relevant potential confounders should be accounted for" in "future studies."

March 15, 2022

Association Found: Maternal PCOS and ADHD

Meta-analysis with over 1.3 million participants finds clear association between maternal polycystic ovary syndrome and ADHD in offspring

Meta-analysis discovers clear link between mothers with PCOS and children with ADHD.

Polycystic ovary syndrome (PCOS) affects somewhere between 6 and 20% of women of reproductive age. Typical effects include:

·  failure to ovulate;

·      high levels of male hormones (androgens), which can lead to acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation;

·       metabolic disruption, including obesity and insulin resistance.

In pregnancy, PCOS is also known to increase the chances of birth complications.

Previous studies have suggested a link between maternal PCOS and ADHD.

A team of Arabian (Saudi and United Arab Emirates) researchers conducted a systematic review of the peer-reviewed medical literature and were able to identify four studies with a total of 1,354,182 participants that could be combined into a meta-analysis.

The meta-analysis found that children born to mothers with PCOS were 43% more likely to develop ADHD. The 95% confidence interval stretched from 35% to 51%, indicating a highly reliable finding.

Moreover, there was between-study variation: They all produced essentially identical results. There was also no sign of publication bias.

"However,"the authors noted, "the reported results do not necessarily provide definitive findings of a causal inference due to the randomized study design. All the included studies were observational in design." With this caution, they could only conclude that "the results of this meta-analysis showed that there might be a link between maternal PCOS and the risk of developing ASD and ADHD in the offspring."

March 11, 2022

New Study Finds C-Section Delivery is Not A Risk Factor For ADHD

Nationwide cohort study finds Cesarean delivery does not appear to be a risk factor for ADHD after adjusting for familial confounding

After adjusting for genetic and environmental risk factors, meta-analysis shows Caesarean delivery does not appear to be an ADHD risk factor.

Previous meta-analyses have found an association between cesarean delivery (CD) and subsequent ADHD in children delivered in that manner. Some have theorized that by bypassing the birth canal, children delivered via CD may acquire their first microbiota from the hospital environment rather than from their mothers, which could disturb the normal development of the nervous system, including the brain.

Nevertheless, earlier studies have not fully explored the role of confounding factors.

A team of Swedish researchers availed themselves of the country's all-encompassing system of national population and health care registers to examine a cohort of over a 1.1 million single births from 1990 through 2003 and followed up through 2013.

They distinguished between planned CD and intrapartum (i.e., during the act of birth) CD. The latter is performed in response to complications with childbirth. This distinction could matter both because of different levels of exposure to the maternal gut microbiota, and because "intrapartum CD is often the result of complications during pregnancy (e.g., preeclampsia) or delivery (e.g., fetal distress), which could affect brain development."

Of 1,179,341 individuals, 1,048,838 were delivered vaginally, 59,514 were delivered by planned CD, and 70,989 were delivered by intrapartum CD.

After adjusting for the child's year of birth, gestational age, age of mother and father at birth, parity, mother's highest education level at birth, maternal smoking during pregnancy, maternal and paternal history of psychiatric disorders, maternal hypertension, maternal diabetes, maternal infections during pregnancy, fetal MAL presentation, large for gestational age, polyhydramnios, oligohydramnios, preeclampsia, and pelvic disproportion, children born by planned CD were 17% more likely to have ADHD.

After adjusting for all previously listed variables plus placenta disorders, dystocia failed induction, and fetal distress, children born by intrapartum CD were 10% more likely to have ADHD.

So far, the analysis confirmed results from previous meta-analyses.

But by exploring such a large cohort, it also became possible to compare ADHD prevalence, not only among unrelated individuals, but also among siblings and cousins, and thereby assess the role of confounders arising from genetics or shared environment.

Whether between full siblings or full maternal cousins, the associations between both types of CD and subsequent ADHD became weak and statistically non-significant.

The authors concluded, "The findings of this study suggest that the association between CD and increased risk of neurodevelopmental disorders in the children was most likely explained by unmeasured familial confounding."

March 9, 2022

Population Study Finds Association Between ADHD and Dementia

Nationwide population study finds association between ADHD and dementia, declining with decreasing genetic relatedness

ADHD aggregates with Alzheimer's disease and any dementia within families

Alzheimer's disease is characterized by an aging-related progressive deterioration in cognition and ability for independent living. It is the most common form of dementia. Few studies, with limited sample sizes, have probed the relationship between ADHD and dementia, with conflicting results.

A Swedish study team used the country's universal system of population and health registers' linked through unique personal identification numbers - to examine patterns among the more than 2.1 million Swedes born between 1980 and 2001.

Each of these individuals was then linked to their biological relatives, parents, grandparents, uncles, and aunts through the Medical Birth Register and Multi-generation Register.

This generated three cohorts of relatives representing different levels of genetic relatedness: parents sharing half of their genes; grandparents sharing a quarter of their genes; and uncles and aunts who also share a quarter of their genes with index persons. After linking index persons to their biological relatives, the study cohorts contained more than 2.2 million parents, over 2.5 million grandparents, and almost a million uncles/aunts.

By the end of follow-up, 3,042 (0.13%) parents, 171,732 (6.82%) grandparents, and 1,369 (0.15%) uncles/aunts had a diagnosis of Alzheimer's. The numbers for any dementia were 3,792 (0.17%) for parents, 197,843 (7.86%) for grandparents, and 1,697 (0.18%) for uncles/aunts.

Parents of persons with ADHD were 34% more likely to have any dementia, and 55% more likely to have Alzheimer's. Among grandparents of persons with ADHD, the association dropped to 10-11% more likely for any kind of dementia. Among aunts and uncles, it dropped to a 14% greater likelihood of Alzheimer's(similar to grandparents) and a 4% greater chance of any dementia. In this case, however, the results were not statistically significant, probably due in part to the much smaller sample size

Both with parents and grandparents of persons with ADHD, the risk of early onset of any kind of dementia was well over twice as high as the risk of late-onset.

"We found that ADHD aggregated with AD [Alzheimer's disease] and any dementia within families, and the strength of association attenuated with decreasing degree of genetic relatedness," the authors concluded, and called for further studies to identify genetic variants and family-wide environmental risk factors contributing to both conditions. If verified by such studies, that would indicate a need for "investigation of early-life psychiatric prevention on the development of neurodegenerative diseases in older age."

March 7, 2022

Meta-analysis: No Association Between Childhood Antibiotic Use and ADHD

Meta-analysis finds no association between childhood antibiotic exposure and ADHD

Childhood antibiotic use is not found to be associated with development of ADHD

A Chinese research team recently conducted a systematic search of the peer-reviewed medical journal literature for studies exploring the association between childhood antibiotic exposure and subsequent diagnosis of ADHD in youths 18 years and younger.

A meta-analysis of six studies with a combined total of over 1.5 million participants found that children exposed to antibiotics were 18% more likely to later be diagnosed with ADHD.

There was absolutely no indication of publication bias. Between-study heterogeneity, on the other hand, was extremely high.

With such large cohorts, one can often tease out whether an association is causal, or due to genetic and familial confounding, by looking at matched close relatives.

Three of the studies, with a combined total of well over half a million participants, also compared matched siblings.

Significantly, the meta-analysis among matched siblings found no association whatsoever between childhood exposure to antibiotics and subsequent ADHD. Between-study heterogeneity was virtually nonexistent.

The team concluded, "Our meta-analysis indicated that early-life antibiotic exposure was associated with a subsequent increased risk of ASD or ADHD. However, such association was not found in the sibling-matched analysis, indicating that genetic and familial confounding factors may largely explain the observed association."

March 3, 2022

Maternal Anti-Seizure Meds May Affect Offspring Chances of Developing ADHD

Nationwide cohort study indicates choice of maternal antiseizure medication during pregnancy has implications for offspring ADHD

Although all potential confounding factors have not been ruled out, these findings add to a growing body of evidence that suggests that certain ASMs (i.e., lamotrigine) may be safer than others in pregnancy.

Roughly five of every thousand women (0.5%) have epilepsy, a neurological disorder characterized by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. Primary treatment consists of anti-seizure medications (ASMs).

Yet, research has shown that ASMs cross the human placenta. In rodents, ASMs have been shown to lead to abnormal neuronal development, and some research has pointed to the risk of adverse birth outcomes and neurodevelopmental disorders in humans. But samples have been too small for reliable conclusions, and in most cases confounding factors are not addressed.

For a more comprehensive evaluation of risk from ASMs, an international team of researchers examined a nationwide cohort using Swedish national registers that track health outcomes for virtually the entire population.

Using the Medical Birth Register, the National Patient Register, and the Multi-Generation Register, they were able to identify 14,614 children born from 1996-to 2011 to mothers with epilepsy.

Through the prescribed Drug Register, they also examined the first-trimester use of anti-seizure medications (ASMs) by these mothers. The three most frequently used ASMs "frequent enough to yield useful data“ were valproic acid, lamotrigine, and carbamazepine.

The researchers identified ADHD in offspring in one of two ways: ICD-10 (international classification of Diseases, 10th Revision) diagnoses, or filled prescriptions of ADHD medication.

Finally, they consulted the Integrated Database for Labor Market Research and the Education Register to explore potential confounding variables. These included maternal and paternal age at birth, the highest education, cohabitation status, and country of origin. They also included maternal and paternal disposable income in the year of birth and a measure of neighborhood deprivation.

Using the medical registers, they considered parental psychiatric and behavioral problems diagnosed before pregnancy, including bipolar disorder, suicide attempt, schizophrenia diagnosis, substance use disorder, and criminal convictions. They adjusted for inpatient diagnosis of seizures in the year before pregnancy to capture and adjust for indication severity.

Other covariates explored included year of birth, birth order, child sex, maternal-reported smoking during pregnancy, and use of other psychotropic medications.

After fully adjusting for all these confounders, children of mothers who were taking valproic acid were more than 70% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy. The sample size was 699, and the 95% confidence interval stretched from 28% to 138% more likely to develop ADHD.

By contrast, children of mothers who were taking lamotrigine were at absolutely no greater risk(Hazard Ratio = 1) of developing ADHD than those of mothers not taking an anti-seizure medicine during pregnancy.

Finally, children of mothers who were taking carbamazepine were 18% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy, but this result was not statistically significant (the 95% confidence interval ranged from 9% less likely to 52% more likely).

The authors concluded, "The present study did not find support for a causal association between maternal use of lamotrigine in pregnancy and ASD [Autism Spectrum Disorder] and ADHD in children. We observed an elevated risk of ASD and ADHD related to maternal use of valproic acid, while associations with carbamazepine were weak and not statistically significant. Although we could not rule out all potential confounding factors, our findings add to a growing body of evidence that suggests that certain ASMs (i.e., lamotrigine) may be safer than others in pregnancy."

February 17, 2022

Nationwide cohort study finds association between miscarriage and ADHD

Nationwide cohort study finds association between miscarriage and ADHD

Statistically significant exposure-response trend found linking miscarriage and ADHD

Spontaneous abortion is the medical term used for what is more commonly known as miscarriage. It means the unintended loss of an embryo or fetus before the 20th week of pregnancy. This must not be confused in any way with induced abortion, which is a deliberate and intentional act to terminate a pregnancy.

Most miscarriages occur when the fetus is not developing properly. Among the major causes of miscarriage are chromosomal abnormalities, birth defects, abnormal hormonal imbalances, infections, and exposure to toxins.

A team of Chinese researchers used the Danish national registers to explore a nationwide cohort for associations between previous miscarriage and ADHD in subsequent offspring. They included all 1.1 million births in Denmark over the 17 years from 1995 through 2012. They excluded all children with chromosomal abnormalities, those born either extremely early (after less than 22 weeks gestation) or extremely late (greater than 45 weeks), and those for whom this information was missing. That left over one million children in the study cohort.

The team classified children as having ADHD either based on a recorded hospital diagnosis or after receiving ADHD medication prescriptions at least twice after the age of 3 years. A total of 25,747 children were identified as ADHD individuals (554 mothers having at least two miscarriages, 3,087 mothers having one miscarriage, and 22,106 mothers without miscarriage). The average age of the first ADHD diagnosis was 10 years.

Just over 130,000 children (12.2%) were born to mothers who had at least one miscarriage. Of these, just under 113,000 (10.6%) were born to mothers with a single miscarriage before birth, and just over 17,000 to mothers with more than one prior miscarriage.

Based on previous research, the team identified potential confounders, including sex, preterm birth (less than 37 weeks), low birth weight, small for gestational age, low Agar score (performed right after birth to assess the risk of infant mortality), maternal and paternal ages at birth, maternal diabetes, maternal hypothyroidism, maternal smoking during pregnancy, maternal education level, maternal and paternal psychiatric disorders before birth.

After adjusting for these possible confounders, children of mothers with a single prior miscarriage were 9% more likely to develop ADHD than those of mothers without any miscarriage. Children of mothers with two or more prior miscarriages were 22% more likely to be diagnosed with ADHD. This upward exposure-response trend was statistically significant.

Preterm birth was found to be the strongest confounding mediator of this trend but accounted for under 4% of the association. The authors concluded, "the observed associations were independent of several factors, such as maternal socioeconomic status, type of spontaneous abortion, parental history of psychiatric disorders, pregnancy characteristics (maternal smoking status, infection, diabetes and hypothyroidism status during pregnancy)and birth outcomes (low birth weight, preterm birth, low Agar score, and small for gestational age)."

They also noted that given the frequency of miscarriages, affecting more than one in eight women, "a small increase of neurodevelopmental problems in offspring could have major public health implications."

February 13, 2022

Childhood Enterovirus Infection May Be a Risk Factor for ADHD

Taiwanese population study finds childhood enterovirus infection is associated with higher risk of ADHD

Population study finds that early enterovirus infection can put those individuals at a 25% higher risk for later ADHD diagnosis.

Enteroviruses (EV) are a class of RNA viruses. This group of viruses includes some no-longer endemic forms such as polio and some serious but rare forms that cause encephalitis and meningitis. The most common virus in this population and period (1999-2003) was EV71, which can have complications, sometimes fatal, especially for children under five years old. It has also been linked to various chronic diseases, many of them neurological.

Is it associated with the subsequent diagnosis of ADHD and, if so, to what extent?


Taiwan offers an excellent opportunity to study this in an entire population. This is because of its single-payer health care system. Its database "the National Health Insurance research database" covers 99.5 percent of the population.


The Taiwanese study team used a sub-database, the Longitudinal Health Insurance Database 2000, containing claims data from a million persons randomly sampled from the parent database.
From this database, the researchers identified over 49,000 EV patients. They excluded all who were 18 and older, were missing essential data or had been diagnosed with ADHD, epilepsy, topic diseases, coronary artery disease, stroke, rheumatoid arthritis, or systemic lupus erythematosus before being diagnosed with enterovirus. That left an EV cohort of 14,168,  who were matched with an equal number of non-EV individuals matched by age and sex.


After adjusting for age, sex, paternal occupation, and urbanization level of the residence, the EV cohort group was found to have a 25 percent greater risk for ADHD than the control group.

February 7, 2022

Assessing Co-occuring Disorders in Relatives of Those With ADHD

Taiwan Population Study Assesses Comorbidity of Psychiatric Disorders among First-degree Relatives of Those with ADHD

ADHD patients were found to be seven times more likely than controls to have first-degree relatives with ADHD.

Taiwan's National Health Insurance program is a single-payer system that covers 99.6% of the island's 23 million residents. It includes family relationships.

This enabled a Taiwanese study team to examine the comorbidity of psychiatric disorders among close relatives in the entire population over eleven years, beginning at the start of 2001 and concluding at the end of2011.

For greater certainty of diagnosis, only persons twice diagnosed with the same psychiatric disorder were included as index individuals. There were 431,887 index patients, 152,443 of whom were ADHD index patients.

These index patients were then compared with all of their first-degree relatives (FDRs): parents, children, siblings, and twins. This produced 1,017,430 patient-FDR pairs, of which 401,301 were ADHD patient-FDR pairs.

Next, four controls were matched by age, gender, and type relative to each case, resulting in 4,069,720 control pairs.

After adjusting for age, gender, urbanization, and income level, ADHD patients were seven times more likely than controls to have first-degree relatives with ADHD. They were also seven times more likely to have FDRs with major depressive disorder, four times more likely to have FDRs with autism spectrum disorder, twice as likely to have FDRs with bipolar disorder, and 80%more likely to have FDRs with schizophrenia.

February 3, 2023

Is Oxytocin During Childbirth an ADHD Risk Factor Later in Life?

Danish-Finnish countrywide population studies conclude that administration of oxytocin during childbirth is not a risk factor for ADHD

Oxytocin is a hormone released by the pituitary gland that stimulates the contraction of the uterus during labor. Synthetic oxytocin is widely administered during labor to supplement a birthing parent's supply and facilitate childbirth.

Previous studies have found an association between synthetic oxytocin and increased odds of ADHD in offspring.

A joint Danish and Finnish team used their countries' national registers to obtain countrywide cohorts encompassing over 577,000 Danes and over 945,000 Finns. Oxytocin had been administered in 31% of the Danish deliveries and 46% of the Finnish ones. Any children either diagnosed with ADHD or who received prescriptions for ADHD drugs were categorized as having ADHD.

As in previous studies, unadjusted results found a significant association with ADHD. Combining the two populations, children whose mothers had received oxytocin during labor were 16% more likely to later develop ADHD.

After adjusting for a series of confounders such as birth year, maternal age, education, marital status, parity, smoking in pregnancy, labor induction, gestational age, and intrauterine growth, the association dropped markedly, to an increased likelihood of barely 3%.

Looking at Denmark alone, the unadjusted risk was 9% greater, vanishing altogether after adjusting for confounders. In Finland, the unadjusted risk was 20% greater, declining to 4% after adjusting for confounders.

The authors noted that "Exposure to obstetric oxytocin is not a random process, and it is likely that other factors than the ones included here vary systematically between women treated vs not treated with oxytocin. ... Therefore, we find it most likely that the minor elevations in risk are due to uncontrolled and residual confounding, and thereby our results underscore the lack of a causal association between obstetric oxytocin exposure and ADHD."

February 1, 2022

Breastfeeding associated with an almost 2/3 reduction in risk of ADHD

Breastfeeding associated with an almost 2/3 reduction in risk of ADHD

Preschool children who were never breastfed as infants are much more likely to have a medical diagnosis of ADHD than are children who were exclusively breastfed as infants.

The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for the first six months of infancy and continuation of breastfeeding for at least a year thereafter. Yet less than a third of U.S. mothers are still breastfeeding their infants at 12 months.

Previous studies have suggested that breastfeeding is associated with a lower risk of ADHD. But sample sizes have been small, and have not sufficiently explored confounding factors.

Using the Centers for Disease Control and Prevention's 2011-2012 National Survey of Children's Health, a research team analyzed data from a representative U.S. sample of 12,793 three- to five-year-old children.

The team excluded children with autism, developmental delays, speech problems, Tourette syndrome, epilepsy or seizure disorder, hearing problems, non-correctable vision problems, bone/joint/muscle problems, brain injury/concussion, or any current behavioral/conduct problems other than ADHD.

The team also adjusted for potential confounders. Some were demographic: sex, age, race, household income, the number of adults older than 18 years of age living in the home, and the number of children younger than the age of 18 years living in the home. Other variables related to health care access and delivery: insurance type, consistency of health insurance in the past 12 months, and a composite variable reflecting having a primary care provider, getting needed referrals, and effective care coordination. Exposure to secondhand smoke and preterm births were other key variables.

In the fully adjusted results, children who had been breastfed for at least six months were 62% less likely to be diagnosed with ADHD than those who had not (p = .0483). Moreover, each month of breastfeeding duration was associated with a significant additional 8% reduction in the odds of an ADHD diagnosis (95% confidence interval from 1% to 14%).

The authors concluded, "Preschool children who were never breastfed as infants were much more likely to have a medical diagnosis of ADHD than were children who were exclusively breastfed. Moreover, there seems to be a continuum of neuroprotective benefits associated with breastfeeding duration. Although these analyses cannot establish a causal relationship, our findings add to a growing body of literature-including several longitudinal studies and a meta-analysis-that suggests breastfeeding may reduce the likelihood of a child having later problems with inattention and/or hyperactivity. Although follow-up studies are needed to further examine the relationship between infant feeding and ADHD, these findings provide evidence to support the neurodevelopmental benefits of breastfeeding."

January 28, 2022

Is Antibiotic Use in Infancy a Risk-Factor for ADHD? How Do We Know?

Nationwide twin cohorts in the Netherlands and Sweden suggest antibiotic use in infants is not a risk factor for ADHD

There was no association found between ADHD and ASD diagnoses and early antibiotic use when environmental and genetic family factors were taken into account.

Proper development of the gut biota is important for the health of the brain and nervous system. It has been hypothesized that disturbances of gut bacteria by antibiotics could contribute to the development of neurodevelopmental disorders, including ADHD.

In the case of ADHD, studies to date have produced conflicting results. To tease out any familial confounding reflecting shared environment and genetics, a joint Dutch-Swedish team of researchers further tested the hypothesis through 7- to 12-year-old twins in the Netherlands Twin Register (25,781 twins) and 9-year-old twins in the Swedish Twin Registry (7,946 twins).

ADHD symptoms in the Netherlands cohort were derived from mothers' answers to the short Conners' Parental Rating Scale-Revised. For the Swedish cohort, ADHD was determined through the International Classification of Diseases codes for ADHD in the cross-linked National Patient Register.

Exposure to antibiotics during the first two years of childhood was determined by parent reports for the Netherlands twin cohort, and by prescription claims for antibiotics in the Swedish twin cohort.

Covariates were explored in both twin cohorts including educational attainment of parents, gender of the infant, birth weight, delivery mode, and asthma. Breastfeeding was also explored in the Dutch cohort.

In the unmatched analysis, comparing children with ADHD with non-related children without ADHD, early-life antibiotic use was associated with a significant 8% greater odds of ADHD in the Netherlands cohort and a significant 14% greater odds of ADHD in the Swedish cohort.

However, when limiting the analysis to matched monozygotic twins, the association disappeared altogether in both the Dutch and Swedish cohorts. Pooling both cohorts resulted in the same outcome. In all three cases, the odds flipped into a mildly negative association, but with no statistical significance.

Using higher cutoff values for ADHD symptoms made no difference.

The authors concluded, "In this large co-twin study performed in two countries, early-life antibiotic use was associated with increased risk of ADHD and ASD, but the results suggest that the association disappeared when controlled for shared familial environment and genetics, indicating that this association may be susceptible to confounding. Our results indicate that there is no association between ADHD and ASD diagnoses and early antibiotic use when environmental and genetic family factors are taken into account."

January 24, 2022

Connection Found Between Air Pollution and ADHD

Large longitudinal cohort study finds association between nitric oxide in air pollution and ADHD (hyperactivity)

Strong association found between gestational exposure to high levels of nitrogen oxide and later ADHD-hyperactive symptoms.

Taiwan's National Birth Registration database tracks every birth. Using all entries from 2005, random sampling was used to create the Taiwan Birth Cohort Study of 24,200 mother-infant pairs, which were geographically distributed and represented 12 percent of all births.

As this was an eight-year longitudinal study, there were dropouts, and 17,256 pairs completed the study. After excluding cases with fetal distress, smoking or alcohol use during pregnancy, and missing information on covariates, the final study population was 16,376.

Participants' addresses during gestation were geocoded to the township level, and local air pollution data was retrieved for the years 2004 to 2006 from air quality monitoring stations administered by Taiwan's Environmental Protection Administration. Every hour, each station records levels of nitric oxide (NO), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulfur dioxide (SO2), carbon monoxide (CO), and particulate matter of diameter 10 μm or less (PM10).

The Taiwanese research team addressed several potential confounding factors: sex, maternal age, delivery method (cesarean section or not), birth in summer (June-August), urban or rural residence, and annual household income.

Because ADHD is primarily observable as hyperactivity rather than inattention among young children, the team focused on relating symptoms of hyperactivity to levels of air pollutants.

After adjusting for covariates, the team found no significant association between PM10 and SO2 levels and hyperactivity disorder. Nitrogen oxide levels, on the other hand, were associated with more than 25 percent higher odds of hyperactivity.

Breaking that down further, they found no significant association with NO2, and that the 25 percent higher odds were exclusive with nitric oxide (NO), a pollutant emitted by internal combustion engines in cars, trucks, and busses. NO is a free radical, meaning it has an unpaired electron that can damage the body because of its strong chemical reactivity.

The authors noted, "Our study has some limitations. First, hyperactivity was diagnosed based on a parent-reported physician or specialist diagnosis. Although we did not inquire which specialists made these diagnoses, they must have been a pediatrician, psychiatrist, or special education teacher. ... Second, the calculated exposure to ambient air pollutants was not an accurate personal exposure because it did not take indoor air pollutant levels and time-activity patterns into consideration. Applying personal environmental monitoring in such a large sample is impractical, especially when the subjects are pregnant."

Nevertheless, they emphasized, "this is the first study attempting to discover which component of NOx is more critical to the development of hyperactivity in offspring."

January 20, 2022

The Use of EEGs in Diagnosing Various Levels of Adult ADHD

Adult ADHD: How do those with the full syndrome compare with those who are subthreshold on executive functioning, and are EEGs of any use in diagnosis?

German researchers study how useful EEG markers may or may not be in the treatment of full-spectrum ADHD as compared to sub-threshold ADHD.

Noting that to date, no study investigated potential behavioral and neural markers in adults with subthreshold ADHD as compared to adults with full syndrome ADHD and healthy controls, the German team of researchers at the University of Tübingen out to do just that, recruiting volunteers through flyers and advertisements.

Their ADHD sample consisted of 113 adults between 18 and 60 years of age (mean age 38) who fulfilled the DSM-IV-TR criteria of ADHD and were either not on medication or a steady dose of medication over the prior two months.

Another 46 participants (also mean age 38), whose symptoms did not reach the DSM-IV-TR criteria, were assigned to the group with subthreshold ADHD.

The control sample was comprised of 42 healthy participants (mean age 37).

Individuals with schizophrenia, bipolar disorder, borderline personality disorder, epilepsy, or traumatic brain injury were excluded from the sample, as were those with current substance abuse or dependence.

All participants were German-speaking Caucasians. There were no significant differences in gender, age, education, or verbal/nonverbal intelligence among the three groups.

Participants first completed an online pre-screening, which was followed up with an interview to confirm the ADHD diagnosis.

ADHD impairs executive functions, "defined as the 'top-down' cognitive abilities for maintaining problem-solving skills to achieve future goals." The researchers explored three categories of executive functioning: 1) capacity for inhibition, "the ability to inhibit dominant, automatic, or prepotent responses when necessary- 2) ability to shift, enabling smooth switching between tasks or mental sets; and 3) ability to update, "updating and monitoring of working memory representations." Participants took a battery of neuropsychological tests to assess performance in each category.

Significant differences emerged between the group with ADHD and healthy controls in all measures except one: the STROOP Reading test. But there were no significant differences between participants suffering from subthreshold and full-syndrome ADHD. Nor were there any significant differences between those with subthreshold ADHD and healthy controls.

The researchers also recorded electroencephalograms(EEGs) for each participant. In healthy individuals, there is little to no association between resting-state EEG spectral power measures and executive functions. In individuals with ADHD, some studies have indicated increased theta-to-beta ratios, while others have found no significant differences. This study found no significant differences between the three groups.

The authors concluded, "The main results of the study can be summarized as follows: First, increased executive function deficits (in updating, inhibition, and shifting functions) could be observed in the full syndrome ADHD as compared to the healthy control group while, on the electrophysiological level, no differences in the theta to the beta ratio between these groups were found. Second, we observed only slightly impaired neuropsychological functions and no abnormal electrophysiological activity in the subthreshold ADHD sample. Taken together, our data suggest some practical uses of the assessment of objective cognitive markers but no additional value of examining electrophysiological characteristics in the diagnosis of subthreshold and full syndrome ADHD in adulthood."

They added, "These findings deeply question the value of including resting EEG markers into the diagnostic procedure and also have implications for standard neurofeedback protocols frequently used in the treatment of ADHD, where patients are trained to reduce their theta power while simultaneously increasing beta activity."

January 12, 2022

Population Study Finds Association Between ADHD and Obesity in Adolescents

Israeli nationwide population study finds association between ADHD and obesity in adolescents

After noting that the association between ADHD and obesity has been called into question because of small sample sizes, wide age ranges, self-reported assessments, and inadequate attention to potential confounders, an Israeli study team set out "to assess the association between board-certified psychiatrist diagnoses of ADHD and measured adolescent BMI [body mass index] in a nationally represented sample of over one million adolescents who were medically evaluated before mandatory military service."

The team distinguished between severe and mild ADHD. It also focused on a single age group.

All Israelis are subject to compulsory military service. In preparation for that service, military physicians perform a thorough medical evaluation. Trained paramedics recorded every conscript's height and weight.

The study cohort was divided into five BMI percentile groups according to the U.S. Centers for Disease Control and Prevention's BMI percentiles for 17-year-olds, and further divided by sex: <5th percentile (underweight), 5th-49th percentile (low-normal), 50th-84th percentile (high normal), 85th-94th percentile (overweight) and ≥95th (obese). Low-normal was used as the reference group.

Adjustments were made for sex, birth year, age at examination, height, country of birth (Israeli or other), socioeconomic status, and education level.

In the fully adjusted results, those with severe ADHD were 32% more likely to be overweight and 84% more likely to be obese than their typically developing peers. Limiting results to Israeli-born conscripts made a no difference.

Male adolescents with mild ADHD were 24% more likely to be overweight, and 42% more likely to be obese. Females with mild ADHD are 33% more likely to be overweight, and 42% more likely to be obese. Again, the country of birth made no difference.

The authors concluded, that both severe and mild ADHD was associated with an increased risk for obesity in adolescents at the age of 17 years. The increasing recognition of the persistence of ADHD into adulthood suggests that this dual morbidity may have a significant impact on the long-term health of individuals with ADHD, thus early preventive measures should be taken.

January 6, 2022

Are There Short-term Effects of Air Pollution on Severity of ADHD symptoms?

Is there a short-term relationship between air pollution and severity of ADHD symptoms?

A South Korean research group studies associations between ADHD-related healthcare visits and short-term exposure to specific air pollutants.

Certain air pollutants can produce free radicals and inflammatory cytokines that can penetrate the central nervous system and affect behavior. Long-term exposure to air pollution has been associated with a higher risk of developing ADHD.

There has, however, been little focus on the short-term effects of exposure. Might there be any correlation between levels of air contaminants and subsequent healthcare visits of adolescents for severe spikes in ADHD symptoms (frequently but not always associated with comorbid conduct disorder, oppositional defiance disorder, or mood disorder), such as extreme hyperactivity, serious rule violations, theft, or aggression to people or animals?

A South Korean (Republic of Korea) research team explored this question through a nationwide cohort study using the database of the National Health Insurance Service, a single-payer system, that covers the entire population.

Using a time-series approach, they compared measured levels of three airborne pollutants - particulate matter with a diameter ≤ 10 μm (PM10), nitrogen oxide (NO2), produced by vehicular traffic, and sulfur dioxide (SO2), produced by manufacturing industries- with healthcare visits with a principal diagnosis of ADHD. They chose these three contaminants because they have been associated with ADHD in long-term studies. What made this approach feasible is that healthcare visits are typically unscheduled in Korea, making it possible to get quick medical attention.

The team divided the country into sixteen regions, looked at boys and girls separately, and also split adolescents into two age groups (10 to 14 years and 15 to 19 years). They estimated region-specific daily concentrations of the three pollutants from 318 government-run monitoring sites, located according to population density and distribution.

The researchers next calculated zero(same day) to five-day lag figures for ADHD-related healthcare visits in each region and ran meta-analyses on the time-series data.

There were 7,200 ADHD-related healthcare visits in the 2013-2015 study period. Major increases in PM10 levels were associated with increased ADHD-related healthcare visits from the day of the spike to three days later, peaking the day after the upturn. Major increases in SO2 levels were associated with increased ADHD-related healthcare visits from one to four days later, peaking the day following the upturn. Major increases in NO2 levels were associated with increased ADHD-related healthcare visits from one to four days later, peaking three days after the spike.

There were no significant differences between male and female adolescents, and between younger and older adolescents.

The strongest increased risk for ADHD-related healthcare visits was for NO2 spikes (up 47 percent), followed by SO2 spikes (up 27 percent), with PM10 spikes coming in last (up 12 percent).

Among the limitations, the authors were unable to evaluate the most hazardous types of particulate emissions, because the smaller-diameter PM2.5 particles (≤2.5 μm) have only been measured partially in South Korea since 2015. On the other hand, they pointed out that this was the first study to investigate associations between short-term air pollution exposure and ADHD-related healthcare visits, and that it included all ADHD-related healthcare visits in South Korea, making the possibility of selection bias negligible. They recommended conducting similar studies on other national populations.

December 31, 2021

Is There a Link Between Polycystic Ovary Syndrome and ADHD?

Is there a link between polycystic ovary syndrome and ADHD?

Meta-analysis shows clear correlation between maternal PCOS and offspring ADHD.

Polycystic ovary syndrome (PCOS) is a disorder affecting women of reproductive age, characterized by elevated levels of male hormones (androgens). The name is derived from the presence of cysts surrounding the ovum, which cause enlargement of the ovaries. Its cause remains unknown. There is speculation that high androgen levels could affect brain development in the fetus.

A team of Iranian researchers (Maleki et al.) published a twofold meta-analysis earlier this year exploring the relationship between PCOS and offspring ADHD. A systematic search of the peer-reviewed medical literature came up with six studies, consisting of three cohort studies, and three case-control studies.

A meta-analysis of the three case-control studies with a combined total of 79,978 participants found that children of mothers with PCOS were 42 percent more likely to develop ADHD.

A separate meta-analysis of the three cohort studies with a combined total of 325,435 participants produced essentially identical outcomes: children of mothers with PCOS were 43 percent more likely to develop ADHD.

There was no indication of publication bias in either meta-analysis and virtually no heterogeneity. Except for one case-control study, all studies were considered to be of high quality.

The authors concluded, "Our study showed that maternal PCOS is a risk factor for ADHD. Therefore, Screening for ADHD among children of these women should be considered as part of the comprehensive clinical care for women with PCOS."

More recently, a second-team (Dubey et al.), based in Texas, published a meta-analysis on the same subject. Their systematic search produced the same studies, but classified one study described as case-control by Malekiet al. as a cohort study.

Their meta-analysis of four cohort studies with a combined total of over two million participants (they counted participants differently than Maleki et al.) found that children of mothers with PCOS were 43 percent more likely to develop ADHD. Adjusting for confounders made no difference.

Again, there was no indication of publication bias, and between-study heterogeneity was virtually nil.

Considering they relied on the same studies, the fact that both teams reported identical outcomes is unsurprising, confirming there's a clear association between maternal PCOS and ADHD in offspring.

December 19, 2021

ADHD and Poor Blood Sugar Management in Type-1 Childhood-onset Diabetes

Nationwide population study finds association between ADHD and poor blood sugar management in type-1 childhood onset diabetes

It is difficult enough for a typical child to manage type-1 diabetes. For a child that also has ADHD, with learning difficulties, attention and memory problems, and limitations in social communication, it can be all the more challenging to carry out the complex tasks necessary to maintain glycemic control (control of blood sugar levels) and avoid diabetic harm.

To explore the additional risk associated with ADHD among children with type-1 diabetes, an international research team used the Swedish national registers to conduct a nationwide population study. Sweden has a single-payer national health insurance system, and assigns unique personal identification numbers to all residents, making it easy to cross-reference through various population and health registers.

The team used the Swedish Diabetes Register to identify all individuals born in Sweden from 1973 onwards with childhood-onset type 1 diabetes diagnosed before age 18. They then restricted the cohort to those who had no diabetic complications at diagnosis and whose HbA1c values had been recorded within 5 years of diagnosis.

Also known as the glycated hemoglobin test, HbA1c is an indicator of the average blood sugar (glucose) level over the past three months. When glucose builds up in the blood, it binds to the hemoglobin in red blood cells. The HbA1ctest measures bound glucose. Since red blood cells live for about 3 months, the test shows the average blood glucose over that period.

The team also searched for records of diabetes-related kidney damage (nephropathy) and damage to the retina (retinopathy). Diabetic retinopathy is the leading cause of blindness among working-age adults.

The nationwide cohort consisted of 11,326 Swedish youths diagnosed with type-1 diabetes, of whom 415 (3.7%) were also diagnosed with ADHD.

Poor glycemic control, defined as mean HbA1c greater than 8.5%, was found in 38% of those with ADHD, twice the 19% found in those without neurodevelopmental disorders. After adjusting for confounders(sex, age at diabetes diagnosis, year of birth and year of diabetes diagnosis, another psychiatric morbidity, parental highest education level, parental psychiatric morbidity, smoking status, mean BMI [body mass index], and mean systolic and diastolic blood pressure), those with ADHD were 2.3 times as likely to have poor glycemic control.

Patients with ADHD were also almost twice as likely to suffer kidney damage, after adjusting for sex, age at diabetes diagnosis, year of birth, year of diabetes diagnosis, another psychiatric morbidity, parental highest education level, parental psychiatric morbidity, mean HbA1c levels, mean BMI, systolic and diastolic blood pressure, and smoking status.

After the same adjustments, patients with ADHD were found to be a third (33%) more likely to suffer retinal damage.

The team concluded, "childhood-onset type 1 diabetes patients with neurodevelopmental disorders, especially those with ADHD or intellectual disability, are more prone to poor glycemic control and a higher risk of chronic diabetic complications compared with those without neurodevelopmental disorders.

Further longitudinal studies with a more comprehensive evaluation of diabetes management and molecular data are needed to provide insight into potential mediators in the association between comorbid neurodevelopmental disorder and diabetes complications in type 1 diabetes."

December 9, 2021

Swedish Twin Study Finds Association Between Diet and ADHD

Associations between diet and ADHD emerge from Swedish population-based twin study

Sweden has a national single-payer health insurance system that includes virtually the entire population. It also has a system of national registers that track every resident from birth to death. That makes it possible to conduct nationwide population studies with a very high degree of precision and reliability.

In addition, one of the national registers is the Swedish Twin Register. Tracking all twins in the population enables studies to evaluate the degree to which observed associations may be attributable to genetic influences and to familial confounding. The twin method relies on the different levels of genetic relatedness between monozygotic ("identical") twins, who are genetically identical, and dizygotic ("fraternal") twins, who share on average half of their genetic variation (as do ordinary full siblings).

A Swedish team of researchers identified 42,582 Swedish twins born between 1959 and 1985, and who were, therefore, adults by the time of the study (20-47 years old). Of these, 24,872 (three out of five) completed a web-based survey with 1,300 questions covering lifestyle and mental and physical health. Out of this group, 17,999 provided information on ADHD symptoms and food frequency.

Self-reported ADHD symptoms came from nine inattention components and nine hyperactivity/impulsivity components, covering the 18 DSM- IV symptoms of ADHD.

The food frequency questionnaire included 94 food items, with the following frequency categories: never, 1-3 times/month, 1-2 times/week, 3-4 times/week, 5-6 times/week, 1 time/day, 2 times/day, 3 times/day.

In the raw data, the two subtypes of ADHD exhibited very similar associations. Both had significant associations with unhealthy diets. Both were more likely to be eating foods high in added sugar, and neglecting fruits and vegetables while eating more meat and fats.

After adjusting for the degree of relatedness of twins (whether monozygotic or dizygotic) and controlling for the other ADHD subtype, the associations remained statistically significant for inattention, but diminished to negligible levels or became statistically non-significant for hyperactivity/impulsivity.

Even for persons with inattention symptoms, adjusted correlations were small (never exceeding r = 0.10), with the strongest associations being for overall unhealthy eating habits (r = 0.09), eating foods high in added sugar (r = 0.10) or high in fat (r = 0.05), and neglecting fruits and vegetables (r = 0.06). All other associations became statistically non-significant.

For persons with hyperactivity/impulsivity symptoms, the only associations that remained statistically significant ­- but at tiny effect sizes - were unhealthy dietary patterns (r = 0.04) and consumption of foods high in added sugar (r = 0.03).

The further genetic analysis, therefore, focused on the strongest associations, between ADHD subtypes on the one hand, and unhealthy dietary patterns and eating foods high in added sugar on the other hand. The heritability estimates (the fraction of phenotypic covariance explained by genetic influences) were 44%, 40%, and 37% for inattention and high-sugar food, inattention and unhealthy dietary patterns, and hyperactivity/impulsivity and high-sugar food, respectively.

 When examining only differences between pairs of monozygotic("identical") twins, the correlations became stronger for inattention, rising to r = 0.12 for unhealthy eating habits and r = 0.13 for consumption of foods high in added sugar. For hyperactivity/impulsivity symptoms, the association with unhealthy eating habits was weaker, and the association with consumption of foods high in added sugar became statistically insignificant.

The authors concluded, "we identified positive associations between self-reported trait dimensions of ADHD and intake of seafood, high-fat food, high-sugar food, high-protein food, and an unhealthy dietary pattern, and negative associations with consumption of fruits, vegetables, and a healthy dietary pattern. However, all the associations are small in magnitude. These associations were stronger for inattention compared to hyperactivity/ impulsivity. This pattern of associations was also reflected at the etiological level, where we found a slightly stronger genetic correlation between inattention with dietary habits and hyperactivity/impulsivity with dietary habits. Non-shared environmental influences also contributed to the overlap between ADHD symptom dimensions and consumption of high-sugar food and unhealthy dietary pattern. However, shared environmental influences probably contributed relatively little to the associations between ADHD symptoms and dietary habits. ... significant MZ twin intraplate differences also provided support for a potential causal link between inattention and dietary habits.

November 29, 2021

Swedish countrywide population study concludes that neonatal jaundice is not tied to ADHD

Swedish countrywide population study concludes that neonatal jaundice is not tied to ADHD

Bilirubin is an orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted in bile. Elevated levels in blood serum can cause jaundice, a yellowing of the skin, or whites of the eyes.

More than one in twenty Swedish newborns are treated for neonatal jaundice, which is particularly common among preterm babies. It is usually benign.

A team of Swedish researchers used e Swedish Medical Birth Register, which contains information on all children born in the country, to identify all 814,420 single births without birth defects between 1992 and 2000, and followed them until 2009. They then identified instances of neonatal jaundice and of ADHD through linked nationwide medical registers.

The team also identified a sub-sample of full siblings (384,290 children from 181,354 families) in order to control for shared familial traits.

In the unadjusted results, children with any kind of neonatal jaundice were 38% more likely to be diagnosed with ADHD. After adjustment for known confounding variables, two-thirds of the association disappeared, with a residual increased risk of 13%.

There are, however, two types of neonatal jaundice: hemolytic and non-hemolytic. Hemolytic jaundice is typically caused by the mother's immune system mistaking the fetus' red blood cells as a threat, and responding by attacking with antibodies, rupturing and destroying the cells.

The study found no association between hemolytic jaundice and ADHD, either in the raw results or after adjusting for known confounders. Unsurprisingly, there was also no association in the sibling comparison.

That meant that all the association was concentrated among children born with non-hemolytic jaundice, who in the crude results were 43% more likely to subsequently develop ADHD. Adjusting for known confounders again reduced the association by two-thirds, to 14%. But among siblings, that association vanished altogether. Children born with non-hemolytic jaundice were no more likely than their non-jaundiced siblings to develop ADHD.

The authors concluded that "neonatal jaundice is not likely a causal risk factor for ADHD."

December 14, 2023

How social disadvantages affect risk of ADHD

How social disadvantages affect risk of ADHD

Danish health care is universal and free. That means there is very complete data available that covers the entire population. The health registers are linked to other national registers that provide access to socioeconomic information. That offers unusual opportunities to research correlations across an entire national population.

Moreover, the health care system requires a high standard for diagnosis of ADHD - evaluation by specialist doctors or psychiatrists rather than a general practitioner. An exception is when parents seek a diagnosis from a private practicing child psychiatrist, in which case diagnostic registration is not mandatory and data is therefore incomplete.

A trio of Danish researchers used the country' national registers to conduct a nationwide population cohort study to explore the cumulative effects of social disadvantages as risk factors for being diagnosed with ADHD.

They looked at all 632,725 children born in Denmark during the 1990s, of which 23,287 (3.7 percent) either had a registered diagnosis in the Patient Registry or else were undergoing ADHD treatment before age 18. Of these, 12,610 children had a registered ADHD diagnosis and entered medical treatment, 4,049 children had a registered diagnosis with no medical treatment, and 6,628 children entered medical treatment with no registered diagnosis. The latter were presumably diagnosed by private practicing psychiatrists. Adjustments were made for gender, immigrant status, birth characteristics (weight, gestational age), single-parenthood, parent ADHD diagnosis, and the number of children in the household.

The study determined that parental educational attainment had the largest effect on the risk of ADHD. Having parents who completed no more than the minimum compulsory education was associated with a 3.5 percentage point higher risk of getting an ADHD diagnosis. Completing no more than upper secondary education was associated with a 1.3 percent higher risk. But there was a sharp bifurcation in the two alternative components of upper secondary education. Children of parents who completed a vocational track faced a 1.7 percent increase in risk, whereas those whose parents completed a college preparatory track faced a negligible 0.17 percent increase.

Parental unemployment also had a significant effect. Youths whose parents were unemployed most of the year faced a 2.1 percent higher risk of ADHD, whereas those whose parents were unemployed less than half the year faced a 1.3 percent higher risk.

Relative income poverty had a comparable impact. Children of parents in the lowest income quintile faced a 2.3 percent higher risk of ADHD than those of parents in the uppermost income quintile. Those in the second-lowest quintile faced a 1.9 percent higher risk than those in the uppermost quintile; those in the middle quintile a 1.3 percent higher risk, and those in the second-highest quintile a 0.8 percent higher risk.

All three cases showed a dose-response relationship, in which higher gradations of social disadvantage were associated with higher levels of risk.

Since these social disadvantages often overlap, the researchers looked at combinations as well and found them to be roughly additive in effect. Parental unemployment plus relative income poverty was associated with a 1.9 percent higher risk of offspring ADHD. Parental unemployment plus completion of no more than compulsory education was associated with a 3.2 percent higher risk. Parental relative income poverty plus completion of no more than compulsory education produced a 4.2 percent higher risk. Finally, Parental relative income poverty plus completion of no more than compulsory education plus unemployment was associated with a 4.9 percent higher risk.

The authors concluded, "This study shows that specific and well-measured parental social disadvantages in terms of unemployment, relative income poverty, and low educational attainment independently affect the risk of ADHD."

November 19, 2021

Meta-analysis Finds Narrative Language Impairment in Youths with ADHD

Meta-analysis Finds Narrative Language Impairment in Youths with ADHD

Youths with ADHD are known to be more prone to language problems when compared with typically developing peers. To what extent does that affect their ability to share a narrative with others?

A Danish research team conducted a systematic review and meta-analysis of the peer-reviewed medical literature to explore this question. They stressed that this ability is important because "a narrative is a genre of discourse - a form of social communication used to derive meaning from experiences and to construct a shared understanding of events. In other words, it is the fundamental ability of orally producing a coherent story." They focused on the production of narratives rather than comprehension.

Studies had to have a minimum of 10 participants. They had to compare aspects of oral narrative production in children and adolescents with either a formal ADHD diagnosis or a score above a clinical cut-off on a validated ADHD rating scale to a control group of typically developing youths. Youths with confirmed autism spectrum disorder (ASD) or language impairment diagnoses were excluded. There were no constraints on IQ.

The team found sixteen studies with a combined total of 1,015 youths that met these criteria and were suitable for meta-analysis.

They examined seven aspects of oral narrative production:

·        Coherence: A story structure that is logical and easy to follow in cause and sequence. There is a clear beginning, middle, and end. There are goals, attempts, and outcomes. A meta-analysis of nine studies with a combined total of 750 participants found youths with ADHD less coherent than their typically developing peers, with a medium effect size. There was virtually no between-study heterogeneity and no sign of publication bias.
·        Cohesion: This ensures referencing of events and characters in a manner that enables the listener to grasp how characters, events, and ideas in a story are related. Ambiguous or contradictory references get in the way of this. A meta-analysis of eight studies with a combined total of 501 participants found youths with ADHD showed less cohesion than their typically developing peers, with a medium effect size. Again, with virtually no between-study heterogeneity, and no sign of publication bias.
·        Disruptions: These can be sequence errors, misinterpretations, embellishments, or confabulations - fabricating imaginary experiences as compensation for loss of memory. A meta-analysis of six studies with 389 participants found youths with ADHD had more disruptions than their typically developing peers, with a small-to-medium effect size. There was virtually no between-study heterogeneity and no sign of publication bias.
·        Fluency: Best explained in terms of errors that interfere with this quality, such as false starts, repeating words or sentences, and abandoning sentences without completing them. A meta-analysis of four studies with 220 participants found no difference in fluency between youths with ADHD and their typically developing peers.
·        Production: This is a measure of output -overall length of the story, number of sentences, number of words. After adjusting for evidence of publication bias, a meta-analysis of twelve studies with 645 participants found no difference here.
·        Syntactic complexity: This includes the extent of vocabulary and the use of proper grammar. A meta-analysis of six studies with 272 participants found youths with ADHD displayed less syntactic complexity than their typically developing peers, with a small-to-medium effect size. There was virtually no between-study heterogeneity and no sign of publication bi
·        Internal state language: References to perceptions, thoughts, beliefs, and feelings. There were only two studies with 130 participants, so no meta-analysis was performed.

The authors concluded, "the results from the current meta-analysis suggest that children with ADHD have impairments in their narrative language. In particular, children with ADHD produce narratives that are less coherent, less cohesive, less syntactically complex, and include more disruptive errors than typically developing children do."

December 4, 2023

Meta-analysis Finds Association Between Postnatal Secondhand Smoke and ADHD

Meta-analysis finds association between postnatal secondhand smoke and ADHD

Secondhand smoke (SHS) is tobacco smoke inhaled by nonsmokers sharing enclosed spaces with smokers. It contains well over two hundred toxic chemicals, including some toxic metals known to cause serious harm to humans. It is among the most common indoor air pollutants worldwide, with roughly two in five children exposed.

Until now, studies have focused primarily on maternal smoking before childbirth. A Chinese research team set out to explore what, if any, association there might be between childhood exposure to SHS and ADHD. They conducted a comprehensive search of the peer-reviewed literature and identified nine studies with a combined total of over a hundred thousand participants that looked for such effects. The studies were carried out in the United States, Germany, Spain, and the Republic of Korea.

Merging these studies into a meta-analysis, the team found that children exposed to secondhand smoke were 60 percent more likely to develop ADHD. The same overall pattern held true on all three continents.

A further meta-analysis of four of the studies with over 12,000 participants found children exposed to secondhand smoke were 33% more likely to exhibit conduct problems.

The authors concluded, "The results of our meta-analysis suggest that postnatal exposure to SHS may be associated with ADHD in children. Exposure to SHS can also lead to a variety of adverse behavioral outcomes in children. Therefore, parents should stop smoking to create a good growing environment for their children. Further prospective studies should fully adjust for potential confounding factors to determine whether there is a causal relationship between SHS and ADHD."

December 4, 2023

Study Finds Montelukast Treatment for Asthma is Not a Risk Factor for ADHD

Nationwide cohort study indicates montelukast treatment for asthma not a risk factor for ADHD

Montelukast is a leukotriene receptor antagonist that binds to the cysteinyl leukotriene type 1 receptor. It thereby blocks the action of leukotriene, an inflammatory mediator produced by white blood cells. By binding with the receptors, montelukast decreases the inflammation associated with asthma, relaxing smooth muscles and dilating air passages. Though used as an alternative to inhaled corticosteroids for mild persistent asthma, it is not suitable for acute attacks.

Previous smaller studies have produced inconsistent results on whether montelukast treatment is a risk factor for ADHD. That led a Taiwanese research team to conduct a nationwide cohort study. They used the Nationwide Health Insurance Research Database (NHIRD), consisting of a million randomly selected participants drawn from the Taiwan's universal single-payer health insurance system.

The team identified a total of 53,645 children 12 years old and under-diagnosed with asthma. Of these, 17,773 were treated with montelukast, and 35,912 were not. The two groups were then matched on a 1:1 ratio for age, sex, geographic region of residence, comorbidities including allergic rhinitis and atopic dermatitis, admission or emergency department visits due to an asthma attack, and index date. That yielded a montelukast group of 12,806 and an identically sized control group.

Both in the crude and adjusted results, children treated with montelukast were found to be no more likely to develop ADHD than those not treated with montelukast (p = .5). Longer treatment with montelukast (over 90 days) had no effect, with an adjusted hazard ratio of exactly 1.00 (p = .95).

The authors concluded, "Our current findings indicate that exposure to montelukast among pediatric asthma patients poses no increased risk of attention-deficit/hyperactivity disorder. Montelukast therapy, which may be necessary for pediatric patients with asthma, is a safe therapy for such patients."

October 31, 2023

A Norwegian nationwide cohort study finds link between prescribed drugs widely used as sleeping aids and subsequent ADHD

A Norwegian nationwide cohort study finds link between prescribed drugs widely used as sleeping aids and subsequent ADHD

There have been indications that infants who have difficulty sleeping are more likely to later develop ADHD in childhood. Would this hold up in a large nationwide cohort study?

Noting that "Norway has several national health registries with compulsory and automatically collected information," and "registries can be linked on an individual level, making it possible to conduct large cohort studies," a Norwegian team of researchers studied the association between sleep-inducing medications prescribed to infants under three years old and diagnoses of ADHD between the ages of five and eleven.

Norway has a national health insurance system that covers all residents, and pays in full for youths under 16 years old. Norwegian pharmacies must register all dispensed prescriptions into a national register as a prerequisite for reimbursement.

The study included all children born in Norway from 2004 through 2010, minus those who died or emigrated, leaving a total of 410,555 children.

In addition to traditional hypnotic and sedative drugs and melatonin, the study looked at antihistamines, which though intended for respiratory use, are frequently used for gentle sedation.

The two most frequently prescribed drugs were found to be dexchlorpheniramine (girls 7%, boys 8%) and trimeprazine(girls 3%, boys 4%), both of which are antihistamines.

After adjusting for parental education as an indicator of family socioeconomic status, and parental ADHD as indicated by prescription of ADHD medications, girls who had been prescribed sleeping medications on at least two occasions were twice as likely to subsequently develop ADHD, and boys about 60 percent more likely. For, dexchlorpheniramine equivalent associations were not statistically significant for either boys or girls. But girls prescribed trimeprazine on at least two occasions were almost three times as likely to subsequently develop ADHD, and boys were well over twice as likely.

A limitation of the study was that there was no direct data for sleep diagnosis. The authors noted, "The Norwegian prescription database does not contain diagnosis unless medications are reimbursed and hypnotics are not reimbursed for insomnia or sleep disturbances in general. Sleep diagnoses were also not available from the Norwegian Patient Registry, as there seems to be a clinical tradition for not using the ICD- 10G47 Sleep Disorders diagnosis for children."

The authors concluded, "It has previously been shown that infant regulation problems, including sleep problems, are associated with ADHD diagnosis. We replicate this finding in a large cohort, where continuous data collection ensures no recall bias and no loss to follow-up. We find that the use of hypnotic drugs before 3 years of age, signifying substantial sleeping problems, increases the risk of a later ADHD diagnosis. This was especially true for the antihistaminic drug, trimeprazine."

September 25, 2023

Genetic Co-Aggregation: The Possible Link Between Autoimmune Disease and ADHD?

Two nationwide population studies on opposite sides of the world confirm links between autoimmune diseases and ADHD, suggest they are from genetic co-aggregation

Both Taiwan and Sweden have universal single-payer health insurance systems that in effect track their entire national populations. With detailed health and other records on millions of individuals, with no significant exclusions, one can essentially eliminate sampling error, and also explore how associations vary by degree of familial/genetic relationship.

A Taiwanese research team used the Taiwan National Health Insurance Research Database to follow 708,517 family triads (father-mother-child) from 2001 through 2011. That's a total of over 2.1 million persons. The database covers over 99% of Taiwan's population.

Noting that previous studies had found links between maternal autoimmune diseases and ADHD in their offspring and that research on associations with paternal autoimmune diseases had been inconclusive, they were particularly interested in exploring the latter.

Children born from 2001 through 2008 were enrolled in the study. The investigators then noted the presence or absence of any autoimmune disease in their parents from 1996 through childbirth.

In Taiwan, expert panels review diagnostic information of severe systemic autoimmune diseases to confirm the diagnosis. Once confirmed, patient co-payments are waived. ADHD diagnoses are by board-certified psychiatrists.

To reduce the effect of confounding variables, adjustments were made for family demographic data (income level and residence), parental ages, parental mental disorders, and sex of children.

The presence of any maternal autoimmune diseases was associated with a 60% greater risk of ADHD in offspring. The risk was especially elevated for inflammatory bowel diseases (2.4 times the risk) and ankylosing spondylitis (twice the risk).

The presence of any paternal autoimmune diseases was also associated with an elevated risk of ADHD in offspring, although only about half as much as for maternal autoimmune diseases, with a 33% greater risk overall. The association was especially pronounced for psoriasis and ankylosing spondylitis, both doubling the risk of ADHD in offspring.

Meanwhile, half a world away, a joint Swedish, Norwegian, and U.S. team used the Swedish national registries to dig further into these associations. They did this by examining data not only from mothers and fathers, but from full siblings, aunts, uncles, and cousins as well, to probe genetic links.

The team used the Swedish registers to identify 5,178,225 individuals born in Sweden between 1960 and 2010 for whom the identity of the biological mother was known, excluding all who died or emigrated before age 10. They then used the registers to identify the aforementioned relatives.

The researchers only included autoimmune diseases with at least two thousand diagnosed individuals in the cohort, to avoid small sample effects.

They adjusted for sex and year of birth, but not "for another covariate that is often adjusted for (e.g. maternal education, family income, parental psychiatric disorder, parental AD [autoimmune disease] as these are likely not true confounders of the association between ADHD and ADD, but may rather represent either mediator between ADHD and AD's, or proxies of ADHD and/or AD risk or alternatively proxies for the associations we aim to measure."

The team found statistically significant associations between ADHD and autoimmune diseases in all categories of relatives. Mothers of children with ADHD were 29% more likely to have an autoimmune disease than those of typically developing children; fathers were 14% more likely to have an autoimmune disease; full siblings 19% more likely; aunts 12% more likely; uncles 7% more likely; and cousins 4% more likely.

Quantitative genetic modeling produced a significant genetic correlation, but no significant environmental correlation. Genetic correlation explained most, if not all, the covariance between ADHD and any autoimmune disease.

The authors concluded, "ADHD was to some degree more strongly associated with maternal than paternal AD's, but by using aunts and uncles in a genetically informative study design, we demonstrate that this difference cannot be readily explained by AD-mediated maternal effects. Quantitative genetic modeling further indicates that the familial co-aggregation of ADHD and ADs is partly due to shared genetic factors. In addition, biological aunts, uncles, and cousins must be assumed to share the little environment with the index individuals, in further support of shared genetic factors underlying the familial co-aggregation. Moreover, both epidemiological and molecular genetics studies have demonstrated positive genetic correlations between ADHD and ADs, in agreement with our findings."

The authors emphasize that these results do not warrant screening for autoimmune diseases among asymptomatic individuals with ADHD.

November 1, 2021

Possible Connection: Maternal Thyroid Dysfunction and ADHD in Offspring

Is there an association between maternal thyroid dysfunction during pregnancy and ADHD in offspring?

Hyperthyroidism, an overactive thyroid gland, occurs in about one in five hundred women. It has been tied to adverse effects in both mother and fetus, including pre-eclampsia (a condition in pregnancy characterized by high blood pressure, sometimes with fluid retention and excessive protein in the urine, which can indicate kidney damage), preterm delivery, heart failure, and in uteri retardation of growth.

In hypothyroidism, on the other hand, thyroid activity is abnormally low, which retards growth and mental development. It is particularly common in regions with widespread iodine deficiency. Depending on the region, it affects one in three hundred to one in thirty women. Maternal hypothyroidism is associated with an increased risk of pre-eclampsia, premature separation of the placenta from the wall of the uterus, miscarriage, in uteri growth retardation, and fetal death.

The fetus relies on maternal thyroid hormones until its own thyroid function initiates halfway through pregnancy. As we have just seen, this direct link in the early stages of pregnancy has serious consequences described above. Does it also affect the risk of developing ADHD in offspring?

A team of researchers based in Hong Kong reformed a comprehensive search of the peer-reviewed medical literature on this subject. It then conducted two meta-analyses, one examining maternal hyperthyroidism during pregnancy, the other on maternal hypothyroidism.

The meta-analysis for maternal hyperthyroidism during pregnancy combined two nationwide cohort studies with a total of over 3.1 million persons, using the Danish and Norwegian medical registries. It found a slight but significant association with ADHD in offspring.

The meta-analysis for maternal hypothyroidism during pregnancy included the same two nationwide cohort studies, plus an Israeli nationwide cohort study (along with a tiny U.S. cohort study), with a total of over 3.4 million persons. It likewise found a slight but significant association with ADHD in offspring.

Though the component studies did some assessment of confounders, the authors of the meta-analyses noted, "By including a more comprehensive range of confounding factors and biologically relevant covariate (e.g. thyroxine treatment), future studies are warranted to re-visit the association between maternal thyroid dysfunction and various health outcomes in offspring."

December 8, 2023

Is There an Association Between Perfluoroalkyl Substances (PFAS)-exposure in Infancy and ADHD?

Is There an Association Between Perfluoroalkyl Substances (PFAS)-Exposure in Infancy and ADHD?

Although there are numerous kinds of perfluoroalkyl substances (PFAS), the primary ones used in the manufacture of fluoropolymers are perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Because of their strong water-repelling properties, fluoropolymers are used in stain repellents, polishes, paints, and other coatings, as well as in water-resistant outdoor clothing. They are long-lasting and therefore both pervasive in the home and environment and subject to accumulation in our bodies, especially in urbanized and industrialized areas. These substances can be passed from mother to child both through the placenta and through breastfeeding.

With support from the European Union, a large international team of European and North American researchers set out to investigate possible associations between early-life exposure to PFOS and PFOA and subsequent ADHD. They performed a meta-analysis on nine European population studies encompassing 4,826 mother-child pairs.

Participants were restricted to live-born single births with data on concentrations of PFOS and/or PFOA, and available information on ADHD diagnosis or symptoms.

Because a) some studies looked at maternal serum/plasma, others at maternal breast milk; b) timing of sample collection varied (first trimester, delivery); and c) children's levels during the first two years of life were unavailable (ethical constraints limit drawing blood samples from infants), the team used a validated pharmacokinetic model of pregnancy and lactation to estimate pre-and postnatal concentrations of PFASs in offspring.

The team adjusted for seven potential confounders: maternal pre-pregnancy body mass index, maternal age at delivery, maternal education, maternal smoking, number of previous children, duration of breastfeeding, and child sex.

With these adjustments, no association was found between estimated exposures to either PFOS or PFOA at birth, at three months, and at two years and subsequent diagnosis or symptoms of ADHD. While the raw data showed slightly higher odds for girls than for boys to develop ADHD with identical exposures, the differences were statistically non-significant.

November 27, 2023

Does Sugar Actually Worsen ADHD Symptoms? A Meta-Analysis

Meta-analysis finds no association between sugar consumption and ADHD, but a possible link with sugar-sweetened beverages

There's a widespread, but so far unsupported, popular belief that sugar consumption, and sugar-sweetened beverages, in particular, trigger symptoms, especially hyperactivity, in youth.

Given the steep rise of sugar consumption by youth, what evidence is there of a link to ADHD?  

An Iranian team of researchers carried out a comprehensive search of the peer-reviewed literature on this subject. It identified seven studies - two cross-sectional, two case-control, and three prospective " with a combined total of over 25,000 participants that were amenable to meta-analysis. The studies spanned the globe, including the United States, Brazil, Taiwan, the U. K., Spain, and Norway.

Using a fixed-effects model, they found a tiny 7.5% increase in ADHD associated with sugar consumption. With a random-effects model, that rose to a 22% increase. But correcting for publication bias with a trim-and-fill adjustment removed any evidence of an association (p = 0.8).

Even without adjusting for publication bias, subgroup analysis found no evidence of an association with sugar consumption per se.

On the other hand, two studies that looked exclusively at sugar-sweetened beverages reported an 80% increase in the odds of ADHD. There was no way to evaluate publication bias for just two studies. Furthermore, two studies are insufficient for a proper meta-analysis.

There are two conclusions to be drawn from this meta-analysis: 1) It reinforces previous findings of no significant association between sugar consumption and ADHD; 2) It suggests it would be worth conducting more studies, specifically focusing on sugar-sweetened beverages.

November 13, 2023

Systematic review finds association between ADHD and gaming disorder

Systematic review finds association between ADHD and gaming disorder

The specific type of gaming disorder (GD) that is the focus of this review is "disordered video-gaming," or more precisely the addictive potential of interactive video games played on mobile phones, gaming consoles, individual computers, and over networks. Certain characteristics of such games, including structured rewards and multi-modal sensory stimulation, contribute to that addictive potential. Networked games also allow for direct social engagement through role playing and cooperation with others. They also lead to further opportunities for participation in a wider community of players on forums outside gameplay, such as discussion platforms, video play-through analyses, or live-streaming.

The authors performed a systematic search of the peer-review literature, and identified 29 studies exploring the relationship between Addend GD.

All studies found a positive association between ADHD and GD. Of studies reporting effect sizes, seven reported small effect sizes, three reported medium ones, and three reported large ones. There was a similarly wide variety of reported effect sizes among studies that reported correlations between ADHD scales and GD scales. These ranged from r = .12 (small) to r = .45(large).

Three studies examined longitudinal outcomes. One reported that lower ADHD scores at baseline predicted positive long-term recovery. Another noted that GD was more likely to develop into significant psychiatric symptoms and poorer educational outcomes two years later. The third study found that higher ADHD and GD scores were associated with higher incidences of delinquent or aggressive behaviors and externalizing problems, as compared to a sample with ADHD but not GD. All three studies reported that ADHD was a risk factor for the development of problematic gaming behavior. There was no clear indication of the reverse relationship - GD predicting ADHD.

The authors concluded, "This review found a consistent positive association between ADHD and GD, particularly for the inattention subscale. The strength of the association between ADHD and GD was variable. On symptom severity ratings, there was a positive relationship between scores measuring GD and ADHD pathology in some studies. Fewer studies in this review showed hyperactivity was commonly associated with GD. It is well known that hyperactivity in ADHD tends to improve significantly with age. It is possible that the natural progression of the disorder resulted in lower rates of hyperactivity. Such a hypothesis is strengthened by findings of a stronger association with hyperactivity among children aged between 4 and 8."

Ideas for policy interventions to address disordered video gaming include:

·        Parental controls on games.
·        Warning messages similar to those on cigarette packaging.
·        Organizing help services for gamers.

The authors called for further study on:

·        Effectiveness of intervention strategies.
·        The contribution of GD to the dysfunction associated with ADHD.
·        The relationship between the content of play (e.g., violence) and motivation to play (e.g., escapism) and ADHD symptoms.
role-playin·        The role of depression, anxiety, and another comorbidity in mediating the relationship between ADHD and GD

"Clinicians should beware that ADHD is common in GD," the authors emphasized, "and we, therefore, recommend that ADHD is screened for when evaluating GD as part of routine practice. This would ensure interventions aimed at ADHD can be successfully combined with GD treatment, potentially improving patient outcomes."

October 20, 2021

Nationwide Study: Threatened Miscarriage Not a Risk Factor for ADHD

Nationwide population study: threatened spontaneous abortions not a risk factor for ADHD

Threatened spontaneous abortion is defined as vaginal bleeding without cervix dilation within 20 weeks of the onset of pregnancy.

Risk factors include advanced age, obesity, lifestyle (e.g., caffeine intake, lack of physical exercise, stress, cigarette smoking, and alcohol intake), socioeconomic variables, and low serum progesterone. Progesterone is a female hormone that plays a key role in the implantation of the fertilized egg, formation of the placenta, and sustaining a pregnancy.

Threatened spontaneous abortion affects roughly a fifth of pregnancies in the first trimester (first three months). Up to 11 weeks into pregnancy, it seldom leads to spontaneous abortion, but after 11 weeks the likelihood shoots up to as high as half of the affected pregnancies.

Denmark has universal single-payer health insurance. A team of researchers at Aarhus University used their country's comprehensive administrative and healthcare registries to explore any possible association between threatened spontaneous abortion and subsequent ADHD.

That enabled them to analyze a nationwide population of 1,864,221 singletons (as opposed to multiple births such as twins or triplets) live-born from 1979 to 2010. Of these children,59,134 (3.2%) experienced threatened spontaneous abortion within 20 weeks of gestation.

The team adjusted for a series of covariants that could confound outcomes: characteristics of mothers [age at childbirth, pre-pregnancy co-morbidities (somatic, neurologic, psychiatric), healthcare use, medication use, income, education, and employment]; fathers (age on the date of the child's birth, psychiatric co-morbidities a history of epilepsy, cerebral palsy, and ADHD); and children (birth year, birth order).

With these adjustments, they found that children who had experienced threatened spontaneous abortion were a fifth (21%) more likely to have ADHD. But it's exceedingly difficult to account for all confounding variables.

Because of the enormous size of the sample, however, the team was also able to compare 15,875 individuals who experienced threatened spontaneous abortions with an equal number of their paired full siblings who did not, to examine the effect of residual confounding variables. This time, they found no significant differences in the likelihood of ADHD between full siblings.

The authors observed that "controlling for family-shared factors, including genetic makeup and other factors remaining constant between pregnancies and in children's early environments, removed family-shared confounding." They concluded, "After removal, by the sibling design, of time-invariant family-shared confounding, there was no evidence of an increased risk of epilepsy or ADHD among TAB [Threatened Abortion]-affected children."

November 6, 2023

Swedish nationwide population study explores links between ADHD and physical ailments

Swedish nationwide population study explores links between ADHD and physical ailments

What are the links between ADHD and physical ailments in adults? And, where such links exist, how can we tease out where they are due to genetics, shared environment, or unshared environmental influences?

An international research team used the Swedish population and health registers to explore these links in an entire national population. They were able to do this because Sweden has a single-payer national health insurance system, cross-referenced with the population and other national registries through personal identification numbers.

This study identified full-sibling and maternal half-sibling pairs born from 1932 through 1995, through the Population and Multi-Generation Registers. This yielded a total of 4,789,799 individuals - consisting of 3,819,207 full-sibling pairs and 469,244 maternal half-sibling pairs, and 1,841,303family clusters (siblings, parents, cousins, spouses). Roughly half were men, the other half women.

After adjusting for sex and birth year, those with ADHD were at significantly higher risk of a wide range of physical ailments, when compared with individuals without ADHD:

·        Over four times as likely to have sleep disorders or develop alcohol-related liver disease;
·        Roughly three times as likely to develop the chronic obstructive pulmonary disease, epilepsy, and fatty liver disease;

·        Over two and a half times more likely to become obese.

Overall, ADHD was significantly associated with 34 of the 35 physical diseases studied, rheumatoid arthritis being the only exception.

Comparing men with women, women with ADHD were at significantly greater risk of atrial fibrillation, urolithiasis, sleep disorders, and asthma than men with ADHD. Conversely, men with ADHD faced a greater risk of thyroid disorder than women with ADHD.

Between-sibling analyses showed that full siblings of individuals with ADHD were at significantly increased risk for 27 of the 35 physical ailments, suggesting that shared familial factors contributed to the co-occurrence of the conditions. This remained true even after adjusting for the occurrence of ADHD in full siblings.

These associations were generally reduced in maternal half-siblings of individuals with ADHD. The associations between full-siblings were significantly stronger than between maternal half-siblings for type 1 diabetes, obesity, kidney infections, back or spine pain, migraine, sleep disorders, asthma, and chronic obstructive pulmonary disease.

Keep in mind that full-siblings on average share half of their genes, whereas maternal half-siblings share only a quarter of their genes. Maternal (as opposed to paternal) half-siblings were chosen as a basis for comparison because they are typically brought up together in the same family setting, and thus are similar to full-siblings in having a shared family environment. Reduced risk in maternal half-siblings would therefore signal a genetic component to the risk.

Given that ADHD is itself a nervous system disorder, it is unsurprising that it correlated most strongly with other nervous system disorders, with a medium effect size (r=.23). Genetic factors explained over a quarter of the correlation, shared environmental factors over a seventh, and non-shared environmental factors the other three-fifths. The latter could point to environmental risk factors that influence both ADHD and nervous system diseases.

Small-to-medium correlations were found with metabolic, respiratory, and musculoskeletal disease groups, with genetic factors explaining roughly two-thirds of the correlation, and non-shared environmental factors most of the rest.

The authors concluded that "adults with ADHD are at increased risk of a range of physical conditions, across circulatory, metabolic, gastrointestinal, genitourinary, musculoskeletal, nervous system, respiratory, and skin diseases. Most physical conditions showed familial associations with ADHD (mainly from genetic factors). Our findings highlight the need for rigorous medical assessment and care in adult patients with ADHD, and suggest long-term consequences of age-related diseases."

October 16, 2021

Maternal Folic Acid Supplementation Reduces Risk of ADHD in Offspring

Meta-Analysis: Maternal Folic Acid Supplementation Reduces Risk of ADHD in Offspring

Folic acid, also known as folate, is an essential vitamin(B-9). Inadequate dietary folate has been associated with abnormal fetal brain development. That suggests a deficiency could contribute to neurodevelopmental disorders, including ADHD.

If so, could folic acid supplementation for pregnant mothers help avoid ADHD in offspring?

A Chinese study team conducted a systematic search of the peer-reviewed medical journal literature looking for studies exploring neurodevelopmental effects associated with such supplementation.

It identified six studies that specifically looked for associations with offspring ADHD. A meta-analysis of these studies encompassing a total of 29,634 participants found a 14% (one in seven) reduction in the odds of ADHD in the offspring of mothers taking folate supplementation as opposed to children of mothers not doing so.

There was no sign of either publication bias or between-study heterogeneity.

The authors concluded, "Our meta-analysis indicated that appropriate maternal FA supplementation may have positive effects on offspring's neurodevelopmental outcomes, including improved intellectual development and reduced risk of autism traits, ADHD, behavioral, and language problems."

Given that folate is an essential vitamin in the first place, this suggests ensuring that pregnant women supplement their diet with folic acid. The authors further counseled, "However, further high-quality studies on this topic are needed to confirm the optimal dosage and the right time of FA supplementation and to investigate the underlying mechanisms."

November 28, 2023

Sex Differences in ADHD Symptoms and Related Cognitive Deficits in Youths

Sex Differences in ADHD Symptoms and Related Cognitive Deficits in Youths

To what extent does sex matter in the expression of ADHD symptoms and associated cognitive deficits among youths with ADHD?

A recently published meta-analysis of 54 studies by a Canadian team of researchers at the University of Quebec at Montreal suggests it makes little to no difference. A meta-analysis of 26 studies with over 5,900 youths found no significant difference in inattention symptoms, and a meta-analysis of 24 studies with over 5,500 youths likewise found no difference in hyperactivity-impulsivity symptoms. Separating out hyperactivity and impulsivity made no difference.

Given these results, it's no surprise that a meta-analysis of 15 studies with over 3,500 youths again found no significant divergence between the sexes for total ADHD symptoms. Parents and teachers differed, however, in their ratings of symptoms. Whereas parents observed no differences, teachers reported boys had slightly more inattention and hyperactive-impulsive behaviors than girls. Turning to cognitive functions, a series of meta-analyses found no significant sex differences for interference control, working memory, and planning scores. But boys performed slightly worse on inhibition and motor response inhibition. While the raw data also showed boys slightly under-performing girls on cognitive flexibility, strong evidence of publication bias made this unreliable.

The team also compared youths with ADHD and youths without ADHD. Both for females and for males, those differences in ADHD symptoms were - as would be expected - extremely large, whether for total symptoms, inattention, or hyperactivity-impulsivity. All cognitive function scores were moderately better for normally developing boys compared with boys with ADHD, and for normally developing girls compared with girls with ADHD. Yet once again, when comparing these effect sizes between girls and boys, there were no significant differences for any of the symptom and cognitive function effects.

"In other words," the authors wrote, "boys and girls with ADHD presented significantly more primary symptoms and executive and attention deficits than did their peers without ADHD, and effect sizes were not significantly different between the sexes." They concluded, "girls with ADHD do not differ from boys with ADHD in many domains of cognitive functioning, and they have significantly more severe difficulties across the executive and attentional functions measured relative to girls without ADHD. This meta-analysis is the first to examine sex differences in cognitive flexibility, working memory, and planning."

December 11, 2023

Hypertensive Disorders of Pregnancy and Offspring ADHD: An Exploration

Two nationwide population studies explore relationship between maternal hypertensive disorders of pregnancy and ADHD in offspring

Two new studies, examining entire nationwide populations on opposite sides of the world, have just reported findings on the association between hypertensive disorders of pregnancy (HDP) and subsequent ADHD in off spring. HDP includes chronic hypertension, pre-eclampsia, pre-eclampsia superimposed on chronic hypertension, and gestational hypertension.

According to the Mayo Clinic, Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys. Preeclampsia usually begins after 20 weeks of pregnancy in women whose blood pressure had been normal. Left untreated, it can lead to serious complications for both mother and baby and can be fatal. This range of conditions affects more than one in twenty pregnancies worldwide. HDP hampers permeability of the placenta, which may reduce delivery of blood-borne oxygen and nutrients to the fetus, potentially affecting brain development. ADHD could thus theoretically emerge as a neurodevelopmental outcome.

To what extent is this borne out in national-wide population studies? Both Taiwan and Sweden have single-payer national health insurance systems that systematically track virtually every resident. One study team used the Taiwan National Health Insurance research database to examine a cohort of 877,233 children born between 2004 and 2008. The other study team used the Swedish national registers to explore a cohort of 1,085,024 individuals born between 1987 and 1996.

The Taiwanese study adjusted for the following covariate/confounders: year of birth, fetal sex, paternal age, maternal age, family income, urbanization level, maternal diabetes diagnosis, preterm birth, small for gestational age, and parental psychiatric disorders. The Swedish study adjusted for the calendar year of birth, offspring sex, maternal age, parity, height, body mass index, smoking, presentational diabetes, parental educational level, occupation, and marital status. In the Taiwanese population, children of mothers with hypertensive disorders during pregnancy were about 20% more likely to develop ADHD than those of mothers without such disorders. There was no significant difference between chronic hypertension and pregnancy-induced hypertension/pre-eclampsia.

In the Swedish population, children of mothers with hypertensive disorders during pregnancy were about 10% more likely to develop ADHD than those of mothers without such disorders. But the Swedish study also went a step further. It is incredibly difficult to identify all significant confounding variables. But if you have a large enough study population, one can examine the effect of restricting the analysis to siblings within the same families. In that way, one can control in large measure for familial confounding “ shared environment and heredity. In the subsample of siblings “ 1,279 exposed to HDP versus 1,607 not exposed “ those exposed to outerwear were 9% more likely to develop ADHD, but this outcome was not statistically significant.

Noting the reduced statistical power of the subsample, the authors nonetheless concluded, the magnitude of these associations might be too weak(for ADHD in particular) to be considered an important risk factor at the level of the general population  Moreover, in a separate cohort of 285,901 Swedish men born between 1982 and 1992 who attended assessments for military conscription, mildly lower cognitive scores among those exposed to HDP in uteri vanished altogether (mean difference = 0) when limited to comparisons between full siblings (1,917 exposed versus 2,044 not exposed).

November 14, 2023

Comorbidities and Risk of Premature Death in Individuals With ADHD

How do psychiatric comorbidities affect risk of premature death among children and adults with ADHD?

Comorbidities contribute substantially to premature mortality risks in ADHD patients, but even those with ADHD alone are at a 40% greater risk.


The Nordic countries maintain detailed registers of their inhabitants. This enables researchers to examine patterns over entire nations. An international research team used the Swedish national registers for a prospective cohort study of 2,675,615 persons in the Medical Birth Register born in Sweden over 27 years from January 1, 1983, through December 31, 2009. Follow-up was completed in December 2013, with the oldest cohort member aged 31. The mean age at study entry was 6, and the mean at follow-up was 11.

Using personal identification numbers, researchers were able to cross-reference with the National Patient Register and the National Drug Register. From this, they determined that 86,670 members of the cohort (3.2 percent) had ADHD, based either on records of clinical diagnosis or of prescription of ADHD drugs. Psychiatric comorbidities were likewise identified in the National Patient Register.

These comorbidities were significantly more prevalent in the ADHD population than in the rest of the cohort. For example, whereas only 2.2% of the non-ADHD group was diagnosed with substance use disorder (SUD), 13.3% of the ADHD group also had SUD, a six-fold difference. For depression, it was a seven-fold difference; for schizophrenia a nine-fold difference.

The ADHD group had a significantly higher risk of premature death from all causes than the non-ADHD group, with an adjusted hazard ratio(HR) of 3.94 (95% CI 3.51-4.43). Unintentional injury (36%) and suicide (31%)were the leading causes of death in the ADHD group. Those with ADHD were more than eight times more likely to die by suicide than non-ADHD individuals and roughly four times more likely to die from unintentional injury.

The vast majority of the increased risk appears to be associated with comorbid psychiatric conditions. Those with ADHD but no diagnosed comorbidities had an adjusted HR of 1.41 (95% CI 1.01-1.97). With a single comorbidity, the HR more than doubled to 3.71 (95% CI 2.88-4.78). With four or more comorbidities, it rose to a staggering 25.22 (95% CI 19.6-32.46).

The comorbid condition with the greatest impact was SUD, which increased the risk eight-fold by comparison with those with only ADHD (HR= 8.01, 95% CI 6.16-10.41). Anxiety disorder, schizophrenia, and personality disorder increased the risk about fourfold. Bipolar disorder, depression, and eating disorders increased risk by roughly two and a half times.

The co-variate analysis helped tease out what portion of the risk was associated with ADHD alone versus comorbid conditions. Adjusting for the year of birth, sex, birth weight, maternal age at birth, parental educational level, and parental employment status, those with ADHD (including comorbid conditions)were 2.7 times more likely to prematurely die of natural causes than those without. Adjusting for comorbid psychiatric conditions completely eliminated the risk from ADHD alone (HR = 1.01, 95% CI.72-1.42).

Likewise, those with ADHD (including comorbid conditions)were six times as likely to die of unnatural causes. Adjusting for early-onset comorbid disorders (such as conduct disorders, autism spectrum disorder, and intellectual disability) only modestly reduced the HR to 5.3, but further adjusting for later-onset comorbid disorders(including substance use disorder, depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, personality disorder, and eating disorders)reduced the HR to 1.57 (95% CI 1.35-1.83), and reduced it to insignificance in the case of suicide (HR = 1.13, 95% CI .88-1.45).

Summing up, the lion's share of the greater risk of premature death in persons with ADHD is attributable to psychiatric comorbidities. Nevertheless, those with ADHD alone still face a 40 percent greater risk than those without ADHD.

The study did not examine the effects of ADHD medication, which the authors state should be analyzed because of documented potential benefits on ADHD symptoms and comorbid disorders.

The authors concluded, Among adults, early-onset psychiatric comorbidity contributed substantially to the premature mortality risks due to natural causes. On the other hand, later-onset psychiatric comorbidity, especially SUD, explained a substantial part of the risk for unnatural deaths, including all the risk of suicide deaths and most of the deaths due to unintentional injuries. These results suggest that overall health conditions and risk of psychiatric comorbidity should be evaluated clinically to identify high-risk groups among individuals with ADHD.

September 8, 2021

Link Found Between ADHD Risk Genes and Reduced Estimated Life Expectancy

Association found between ADHD risk genes involved in dopamine signaling and reduced estimated life expectancy

Behavioral disinhibition is a trait associated with both ADHD and several genes that affect dopamine signaling. A new study by three American medical researchers set out to examine how these ADHD risk genes - DRD4 (dopamine 4 receptor density), DAT1 (dopamine 1 transporter), and DBH(dopamine beta-hydroxylase) - affect estimated life expectancy in young adulthood.

The method used was a longitudinal study of 131 hyperactive children and 71 matched controls through early adulthood. The original evaluations were done in 1979-1980, when both groups were children in the 4 to 12 age range. They were reevaluated in1987-1988 as adolescents aged 12 to 20. The next follow-up was in 1992-1996 in early adulthood, aged 19 to 25. The final follow-up was in 1998-2004, for adults aged 24 to 32. All agreed to physical examinations that formed the basis for calculating estimated life expectancy using actuarial tables that factor in the effects of smoking, body mass index, alcohol, and other risk factors of on expected longevity. Participants also provided blood samples that enabled gene typing.

For the DAT1 gene, participants who had the homozygous-repeat allele (9/9) had a five-year reduction in estimated life expectancy relative to those with the ten-repeat allele (10/10). Those with the intermediate (9/10) configuration had a three-year reduction in estimated life expectancy.

For the DBH Taq1 gene, those with a heterozygous (A1/A2) combination had almost a three-year reduction in estimated life expectancy relative to those with homozygous (A1/A1 or A2/A2)configurations.

For DRD4, on the other hand, no significant differences were found in estimated life expectancy.

In a related study, several background traits were found to be significantly predictive of variance estimated life expectancy. The largest of these was behavioral disinhibition, followed by verbal IQ, self-rated hostility, and a nonverbal fluency test. But no significant differences were found between any of the gene polymorphisms on any of these four measures, indicating that the present gene associations were independent of the background traits.

The researchers next sought to determine which variables used in the estimated life expectancy calculations were associated with the two significant genes. For DBH, one variable stood out. Those with the A1/A2 heterozygous pairings had almost twice the alcohol consumption of those with homozygous pairings (p = 0.023).

For DAT1, two variables stood out. Overall, the 9/9 pairings smoked two and a half times as much as the 10/10pairings, with the 9/10 pairings midway between the extremes (p = 0.036). They were also 73 percent more likely to be smokers relative to the 10/10 pairings, and 61 percent more likely relative to the 9/10 pairings. They also had significantly less education than the 10/10 pairings, with the 9/10 pairings again being intermediate (p = 0.027).

An obvious limitation of the study was its small sample size. The authors cautioned, our findings should be considered quite preliminary and in need of much greater research before being given much weight in the literature or public policy.

"With these limitations in mind, they concluded, the present study demonstrated that two ADHD risk genes (DB Hand DAT1) independently contributed to a reduction in ELE [estimated life expectancy] beyond the second-order variables of behavioral disinhibition, IQ, hostility, and nonverbal fluency that contributed in the related study to variation in ELE. The gene polymorphisms seemed to be influencing ELE through their affiliation with first-order or more proximal factors related to ELE such as education, smoking, alcohol use, and possibly exercise."

August 19, 2021

Are Low Vitamin D Levels a Risk Factor for ADHD?

Are low Vitamin D levels a risk factor for ADHD?

A team of Iranian researchers recently published a meta-analysis seeking to determine what, if any, association there may be between low vitamin D levels and ADHD in children and adolescents.
Combining the results from thirteen studies with 10,334participants, they found that youth with ADHD had "modest but significant" lower serum concentrations of 25-hydroxyvitamin D than normally developing children. The weighted mean difference was just under 7 nanograms per milliliter. The odds of obtaining such a result by chance would be less than one in a thousand(p < .001). There was little to no sign of publication bias. Between-study heterogeneity, however, was very high (I2 = 94).
These results suggest an association. But are low serum levels of vitamin D a cause or effect of ADHD? Causation is vastly more difficult to establish than an association. To begin to tease this out, the researchers identified four prospective studies that compared maternal vitamin D levels with the subsequent development of ADHD symptoms in their children. Two of these used maternal serum levels, and two used umbilical cord serum levels. Together, these studies found that low maternal vitamin D levels were associated with a 40% higher risk of ADHD in their children. Whether maternal serum or umbilical cord serum measurements were used had little or no effect on the outcome. Study heterogeneity was negligible. But the authors noted that this result "should be considered with caution" because it was heavily dependent on one of the prospective studies included in the analysis. All of which suggest a need for further prospective studies
In the meantime, the authors suggest it would be prudent to increase sun exposure and vitamin D supplementation, given the prevalence of vitamin D deficiency.

July 30, 2021

Is There a Relationship Between ADHD and Migraines?

Is there a relationship between ADHD and migraines?

A Danish team recruited 29,489 participants from 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 a migraine?" and "Have you ever had visual disturbances lasting 5-60 min followed by a 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 near twice the risk for others. The (odds)'s 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 is of the p-values, and should not be misinterpreted as an indication of a strong association, as the odds ratios point variably tweak, 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.

July 14, 2021

Is prenatal antidepressant exposure a risk factor for ADHD?

Is prenatal antidepressant exposure a risk factor for ADHD?

A systematic review of the literature found seven studies examining this question. Significantly, six were large cohort studies with a combined total of almost three million individuals. The other was a large case-control study with 7,874 participants.
The largest cohort study, with more than a million and a half children, found that prenatal antidepressant exposure increased the risk for ADHD.  The adjusted odds ratio was 1.6forany antidepressant and for selective serotonin reuptake inhibitors (SSRI). But sibling comparison models, which better adjust for confounds shared by siblings(e.g., poverty, stress in the home), this study found no increased risk of ADHD.
The second-largest cohort study, with over 875 thousand children, found a small adjusted risk of 1.2 for all antidepressants, with little variation by class of antidepressant. The fourth-largest study, with over 140 thousand children, likewise found a small adjusted risk of 1.2, which barely achieved statistical significance (95% CI 1.0-1.4).
The third-largest study, with over 190 thousand children, obtained an adjusted risk of 1.4 for all antidepressants. But it also pointed to a possible explanation for the small association found in this and other studies, suggesting that the apparent association with antidepressant use was due to ADHD's known genetic association with psychiatric conditions treated by antidepressants.
The fifth-largest study, with more than 55 thousand children, similarly found an adjusted risk of 1.7 for SSRIs and an adjusted risk of 1.7 for an unmediated maternal psychiatric disorder. Again, the underlying psychiatric disorder appears to be confounding the effect of antidepressants.
The sixth-largest study, with over 38 thousand children, found no evidence of any effect from SSRIs. Yet it found evidence of a large effect from bupropion, with an odds ratio of 3.6, and only one in 50 odds of obtaining such a result by chance (p = 0.02). However, it offered no comparison with untreated depression and made no adjustments for potential confounders.
The case-control study found an odds ratio of 2.3 for maternal use of any antidepressant, which dropped to a statistically non-significant 1.6 when adjusted for a maternal psychiatric disorder (95% CI0.66-3.71).

July 10, 2021

Researchers Have Found the First Risk Genes for ADHD

Researchers have found the first risk genes for ADHD

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 psych 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 genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning.
Our study used the genome-wide 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 ADHDvs. 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:

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.  
B) we found a significant polygenic etiology in our data, which means that there must be many loci(perhaps thousands) having variants that increase the 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 tells us that many of the genetic variants which increase the risk for ADHD also make it more likely that a person 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.

July 4, 2021

Bad eating habits in adults with ADHD

Bad eating habits in adults with ADHD

An Israeli team compared eating habits and body mass index(BMI) in adults with and without ADHD. They recruited 60 students from Hebrew University in Jerusalem between 20 and 30 years old. To avoid bias due to particular diets, the authors excluded vegetarians and vegans, as well as persons with chronic diseases that require altered diets, such as diabetes, inflammatory bowel diseases, and chronic kidney disease. Twenty-nine of the participants had been diagnosed with ADHD.
All participants filled out the Food Frequency Questionnaire, a semi-quantitative scale querying about 119 food items. Based on World Health Organization guidelines, it distinguished between "healthy" items (such as vegetables, fruits, whole grains, and minimally processed foods)and "unhealthy" ones (such as cookies, processed meats, and other processed foods). The data obtained from the questionnaires were linked to a nutrient database to estimate daily nutrient intake. BMI was calculated from heights and weights reported by the students.
No significant differences were found between the two groups for servings, calories, fats, carbohydrates, and proteins. Yet, the ratio of healthy to unhealthy portions was significantly higher among controls than among those with ADHD. Those without ADHD consumed about a quarter more servings of healthy food and about a quarter fewer servings of unhealthy food.
On average, BMI levels were about 13 percent higher in participants with ADHD than among those without, meaning they were significantly more likely to be overweight. This finding is consistent with many prior studies.
The authors concluded, "Although participants in both groups consumed similar amounts of servings, calories, and nutrients, students with ADHD reported eating lower amounts of healthy food and higher amounts of unhealthy food. The results suggest that ADHD is not associated with general overeating, but with a biased proportion of unhealthy versus healthy food consumption."
They also recognized limitations to their study. One was a relatively small sample size and the fact that all participants were recruited from a single university. Another is that they did not try to fully evaluate the effects of medication, other than to note the absence of significant differences in food choices between those who used medication regularly and those who used it only occasionally. An unrecognized limitation was the exclusive reliance on self-reporting, both for food consumption, weight, and height.
Despite these limitations, this study is an important first step toward understanding the eating habits of people with ADHD.  It suggests to me that those treating ADHD should promote healthy lifestyles, as that should reduce ADHD's known risks of obesity and adverse medical outcomes.

July 2, 2021

ADHD, High Blood Pressure, and Diabetes

ADHDIs 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) was 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 type2 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."

June 30, 2021

Is Prenatal Exposure to Bisphenol A (BPA) Associated with Childhood ADHD?

Is prenatal exposure to bisphenol A (BPA) associated with childhood ADHD?

A team of U.S. endocrinologists recently published the results of a meta-analysis examining a possible association between bisphenol A(BPA) and childhood ADHD. BPA is used in a variety of consumer products, including plastic bottles for food and drink, epoxy resins used to line cans of food, dental sealants, and the thermal receipts issued by stores.
A review of the literature found 29 rodent studies, but only three with humans. The human studies were too different from each other to be suitable for meta-analysis. One found no association between prenatal exposure and ADHD. A second found prenatal BPA exposure to be associated with teacher-reported hyperactivity in 4-year-old boys, but not girls. The third found is to be associated with hyperactivity scores in 3-year-old girls.
As the authors note, "Often, there is little human data available, particularly in the environmental toxicology/health fields, due to the time and expense of conducting epidemiological studies and the ethical barriers for human-controlled trials that involve human exposure to potentially hazardous chemicals. Thus, it is important to have methods for using animal data to inform human health hazard conclusions; indeed, animal models are traditionally used to study human health."
Twelve of the mice and rat studies, with a total of 709 rodents, were suitable for meta-analysis.
Overall these pointed to a tiny SMD effect size of 0.09, but it was not significant, with the odds of such a result being obtained by chance being almost one in four (p = 0.237). But when results from the 356 males and353 females were looked at separately, a significant sex difference emerged. There was essentially no effect on female rodents, with an effect size of -0.07and a 95% confidence interval of -0.27 to 0.14, widely spanning the zero mark, rendering the result statistically non-significant. Among male rodents, however, there was a small but statistically significant effect size (0.24), with a 95%confidence interval from 0.04 to 0.45. The odds of obtaining this outcome by chance were only one in 50 (p = .02).
This result must be viewed with caution, as rodent physiology often differs substantially from that of humans. The authors, therefore, conclude, "early BPA exposure is associated with a presumed hazard of hyperactivity in humans. Our conclusion is based on 'moderate' levels of evidence for the human and 'high' levels of evidence for animal literature."

June 26, 2021

Associations between ADHD and autoimmune diseases

Associations between ADHD and autoimmune diseases

A Norwegian team based at the University of Bergen recently performed a population study using the country's detailed national health registries. With records from more than two and a half million Norwegians, the team examined what, if any, associations could be found between ADHD and nine autoimmune diseases: ankylosing spondylitis, Crohn's disease, iridocyclitis, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis.

After adjusting for age and maternal education, the team found no association between ADHD and five of the nine autoimmune disorders: type 1 diabetes, rheumatoid arthritis, iridocyclitis, systemic lupus erythematosus, and multiple sclerosis. In the case of ankylosing spondylitis, it found no association with males with ADHD, but a negative association with females. Females with ADHD were less likely to have ankylosing spondylitis. The adjusted odds ratio (AOR) was 0.56 (95% CI 0.32-0.96).

Positive associations were found for only three autoimmune diseases. The strongest was for psoriasis, with adjusted odds ratios of 1.6(95% CI 1.5-1.7) for females and 1.3 (95% CI 1.2-1.4) for males. When further adjusted for education, smoking, and body mass index (BMI), however, the adjusted odds ratio for females with ADHD dropped to 1.3 (95% CI 1.0-1.6).

The second-strongest association was with Crohn's disease. But here it was only among women. The odds ratio, in this case, was 1.4 (95% CI 1.2-1.8). Males with ADHD were less likely to have Crohn's disease, with an odds ratio of 0.71 (95% CI 0.54-0.92).

Finally, females with ADHD were slightly more likely to have ulcerative colitis, with a barely significant odds ratio of 1.3 (95% CI 1.1-1.5), while no such association was found for males with ADHD, whose odds ratio was a statistically non-significant 0.9.

Given the large sample size of over two and a half million, this is no underpowered study. It found no association between ADHD and the generic category of autoimmune disorders. Furthermore, it is a stretch to argue that there are any clear and clinically meaningful links between ADHD and any of the specific disorders that were analyzed in this study. The small and often opposite effect sizes may simply reflect limitations with the data (presumed autoimmune disorders were identified based on drugs prescribed), or other unidentified confounding factors.

June 24, 2021

Is There Any Relationship Between Artificial Food Colors and ADHD?

Is there any relationship between artificial food colors and ADHD?

Several meta-analyses have assessed this question by computing the standardized mean difference or SMD statistic.  The SMD is a measure that allows us to compare different studies. For context, the effect of stimulant medication for treating ADHD is about 0.9.  SMDs less than 0.3 are considered low, between 0.3 to 0.6 medium, and anything greater than high.
A 2004 meta-analysis by Schab and Trinh combined the results of fifteen studies with a total of 219 participants and found a small association(SMD = .28, 95% CI .08-.49) between consumption of artificial food colors by children and increased hyperactivity. Excluding the smallest and lowest quality studies further reduced the SMD to .21, and a lower confidence limit of .007 also made it barely statistically significant. Publication bias was indicated by an asymmetric funnel plot. No effort was made to correct the bias.
A 2012 meta-analysis by Nigg et al. combined twenty studies with a total of 794 participants and again found a small effect size (SMD =.18, 95% CI .08-.29). It likewise found evidence of publication bias. Correcting for the bias led to a tiny effect size at the outer margin of statistical significance (SMD = .12, 95% CI .01-.23). Restricting the pool to eleven high-quality studies with 619 participants led to a similarly tiny effect size that fell just outside the 95% confidence interval (SMD = .13, CI =0-.25, p = .053). The authors concluded, "Overall, a mixed conclusion must be drawn. Although the evidence is too weak to justify action recommendations absent a strong precautionary stance, it is too substantial to dismiss."
In 2013 a European ADHD Guidelines Group consisting of 21 researchers (Sonuga-Barke et al.) performed a meta-analysis of eight studies involving 294 participants that examined the efficacy of excluding artificial colors from the diets of children and adolescents as a treatment for ADHD. It found a small-to-medium effect size (SMD = .32, 95% CI .06-.58), with less than one in fifty probability that such a result would occur by chance. Yet "Restricting the probably blinded assessment analysis to the four no/low medication trials reduced the standardized mean difference (0.32) to non-significant levels (95%CI=-0.13, 0.77)."
On balance, the research to date suggests a small effect of artificial food colors in aggravating symptoms of hyperactivity in children, and a small beneficial effect of excluding these substances from the diets of children and adolescents, but the evidence is not very robust. More studies with greater numbers of participants, and better control for the effects of ADHD medications, will be required for a more definitive finding.
In the meantime, given that artificial food colors are not an essential part of the diet, parents should consider excluding them from their children's meals, since doing so is risk-free, and the cost (reading labels) negligible.

June 22, 2021

How To Best Manage ADHD During Pregnancy to Minimize Risk to Offspring

How can women best manage ADHD during pregnancy to minimize risk to their babies?

Roughly one in thirty adult women have ADHD. Research results indicate that psychostimulants (methylphenidate and amphetamines) offer the most effective course of treatment in most instances. But during pregnancy, such treatment also exposes the fetus to these drugs. Several studies have set out to determine whether such exposure is harmful.

The largest comparison was 5,571 infants exposed to amphetamines and 2,072 exposed to methylphenidate with unexposed infants. It found no increased risks for adverse outcomes due to amphetamine or methylphenidate exposures. Another study studied 3,331 infants exposed to amphetamines, 1,515 exposed to methylphenidate, and 453 to atomoxetine. Comparing these infants to unexposed infants, it found a slightly increased risk of preeclampsia, with an adjusted risk ratio of 1.29 (95% CI 1.11-1.49), but no statistically significant effect for placental abruption, small gestational age, and preterm birth. When assessing the two stimulants, amphetamine, and methylphenidate, together, it found a small increased risk of preterm birth, with an adjusted risk ratio of 1.3 (95% CI 1.10-1.55). There was a statistically significant effect for preeclampsia, placental abruption, or small gestational age. Atomoxetine use was free of any indication of increased risk.

Another study involving 1,591 infants exposed to ADHD medication (mostly methylphenidate) during pregnancy, reported increased risks associated with exposure. The adjusted odds ratio for admission to a neonatal intensive care unit was 1.5 (95% CI 1.3-1.7), and for the central nervous system, disorders were 1.9 (95% CI 1.1-3.1). There was no increased risk for congenital malformations or perinatal death.

Six studies focused on methylphenidate exposure. Two, with a combined total of 402 exposed infants, found no increased risk for malformations. Another, with 208 exposed infants, found a slightly greater risk of cardiovascular malformations, but it was not statistically significant. A fourth, with 186 exposed infants, found no increased risk of malformations but did find a higher rate of miscarriage, with an adjusted hazard ratio of 1.98(95% CI 1.23-3.20). A fifth, with 480 exposed infants, also found a higher rate of miscarriage, with an odds ratio of 2.07 (95% CI 1.51-2.84). But although the sixth, with 382 exposed infants, likewise found an increased risk of miscarriage (adjusted relative risk 1.55 with 95% CI1.03-2.06), it also found an identical risk for women with ADHD who were not on medication during their pregnancies (adjusted relative risk 1.56with 95% CI 1.11-2.20). That finding suggests that all women with ADHD have a higher risk of miscarriage, and that methylphenidate exposure is not the causal factor.

Summing up, while some studies have shown increased adverse effects among infants exposed to maternal ADHD medications, most have not. There are indications that higher rates of miscarriage are associated with maternal ADHD rather than fetal exposure to psychostimulant medications. One study did find a small increased risk of central nervous system disorders and admission to a neonatal intensive care unit. But, again, we do not know whether that was due to exposure to psychostimulant medication or associated with maternal ADHD. If there is a risk, it appears to be a small one.

The question then becomes how to balance that as yet uncertain risk against the disadvantage of discontinuing the effective psychostimulant medication. As the authors of this review conclude. It [ADHD] is associated with significant psychiatric comorbidities for women, including depression, anxiety, substance use disorders, driving safety impairment, and occupational impairment. The gold standard treatment includes behavioral therapy and stimulant medication, namely methylphenidate and amphetamine derivatives. Psychostimulant use during pregnancy continues to increase and has been associated with a small increased relative risk of a range of obstetric concerns. However, the absolute increases in risks are small, and many of the best studies to date are confounded by other medication use and medical comorbidities.

Thus, women with moderate-to-severe ADHD should not necessarily be counseled to suspend their ADHD treatment based on these findings. They advise that when functional impairment from ADHD is moderate to severe, the benefits of stimulant medications may outweigh the small known and unknown risks of medication exposure, and that "If a decision is made to take ADHD medication, women should be informed of the known risks and benefits of the medication use in pregnancy, and take the lowest therapeutic dose possible."

June 18, 2021

What Are The Barriers To Understanding ADHD in Primary Care?

What are the barriers to understanding ADHD in primary care?

A newly-published systematic review by a British team identified48 qualitative and quantitative studies that explored "ADHD in primary care, including beliefs, understanding, attitudes, and experiences." The studies described primary care experiences in the U.S., Canada, Europe, Australia, Singapore, Iran, Pakistan, Brazil, and South Africa.

More than three out of four studies identified deficits in education about ADHD. Of particular concern was the training of primary care providers (PCPs), most of whom received no specific training on ADHD. In most places, a quarter or less of PCPs received such training. Even when such training was provided, PCPs often rated it as inadequate and said they did not feel they could adequately evaluate children with ADHD.

There was even less training for adult ADHD. A 2009 survey of 194 PCPs in Pakistan found that ADHD was not included at all in medical training there and that most learned from colleagues. Half readily admitted to having no competence, and less than one in five were shown to have adequate knowledge about ADHD. In a 2009 survey of 229South African PCPs, only 7 percent reported adequate training in childhood ADHD, and a scant one percent in adult ADHD.

These problems were by no means limited to fewer developed countries. A 2001 U.K. survey of 150 general practitioners found that only 6percent of them had received formal ADHD training. In a 2002 study of 499Finnish PCPs, only half felt confident in their ability to diagnose ADHD. A2005 survey of 405 Canadian PCPs likewise found that only half reported skill and comfort in diagnosis. In a 2009 survey of 400 U.S. primary care physicians, only 13 percent said they had received adequate training. A 2017 study of Swiss PCPs found that only five of the 75 physicians in the sample expressed competence in diagnosis.

Eight studies explored knowledge of DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria and clinical guidelines among PCPs. Only a quarter of PCPs were using DSM criteria, and only one in five were using published guidelines. In a 1999 survey of 401 pediatricians in the U.S.and Canada, only 38 percent reported using DSM criteria. A 2004 survey of 723U. S. PCPs found only 44 percent used DSM criteria. In a 2006 UK study of 40general practitioners, only 22 percent were aware of ADHD criteria. In the same year, a survey of 235 U.S. physicians found that only 22 percent were familiar with ADHD guidelines, and 70 percent used child behavior in the office to make a diagnosis. More encouragingly, a 2010 U.S. study reported that the use of APA (American Psychological Association) guidelines by PCPs had expanded markedly between1999 and 2005, from one in eight to one in two.

Given these facts, it is unsurprising that many PCPs expressed a lack of confidence in treating ADHD. In a 2003 survey of 143 South African general practitioners, two-thirds thought it was difficult to diagnose ADHD in college students. A 2012 U.S. study of 1,216 PCPs found that roughly a third lacked confidence in diagnosis and treatment. More than a third said they did not know how to manage adult ADHD. In a 2015 survey of 59 physicians and138 nurses in the U.S., half lacked confidence in their ability to recognize ADHD symptoms. This was especially pronounced among the nurses. A 2001 U.K.survey of 150 general practitioners found that nine out of ten wanted further training on drug treatment, and more than one out of ten were unwilling to prescribe due to insufficient knowledge.

Misconceptions about ADHD were widespread. In a survey of380 U.S. PCPs, almost half thought ADHD medications were addictive, one in five thought ADHD was "caused by poor diet," more than one in seven thought "the child does it on purpose," and one in ten thought medications can cure ADHD. Some studies reported that many PCPs believed ADHD was related to the consumption of sugary food and drink. Others reported a gender bias. A 2002 U.S. study of395 PCPs found that when presented with boys and girls with parent-reported problems, they were significantly more likely to diagnose ADHD in boys.

A 2010 Iranian study of 665 PCPs found that 82 percent believed children adopted ADHD behavior patterns as a strategy to avoid obeying rules and doing assignments. One-third believed sugary food and drink contributed to ADHD. Only 6 percent believed it could be a lifelong condition. Half blamed dysfunctional families. The aforementioned large 2012 U.S. study similarly found that almost half of PCPs believed ADHD was caused by absent or bad parenting. More than half of 399 Australian PCPs surveyed in 2002 believed inadequate parenting played a key role. In a 2003 study of 48 general practitioners in Singapore, a quarter blamed sugar for ADHD. A 2014 survey of 57French pediatricians found that a quarter thought ADHD was a foreign construct imported into France, and 15 percent attributed it to bad parenting. In all, ten studies reported a widespread belief that ADHD was due to bad parenting, with ratios varying from over one in seven PCPs to more than half. They were particularly likely to attribute hyperactivity to dysfunctional families and to dismiss parents' views of hyperactivity as a medical problem as a way to deflect attention from inadequate parenting. While a third of the studies reported on stigma, the surprise was that it did not seem to play as big a role as expected. A 2012study in the Netherlands found that 74 physicians and 154 non-medical professionals matched by age, sex, and education showed no differences in the level of stigmatization toward ADHD.

On the other hand, the studies identified significant resource constraints limiting more effective understanding, diagnosis, and treatment. Given the complex nature of ADHD, the time required to gain relevant information, especially in the context of competing demands on the attention of PCPs, was a limiting factor. Many studies identified a need for better assessment tools, especially for adults.

Another major constraint was PCP's uneasiness about medication. Studies found a widespread lack of knowledge about treatment options, and more specifically the pros and cons of medication relative to other options. This often led to an unwillingness to prescribe.

Yet another limitation was the difficulties PCPs had in communicating with mental health specialists. One study found that less than one in six PCPs received communications from psychiatrists. Much of this was ascribed to "system failure": discontinuity of care, no central accountability, limited resources, buck-passing. Many PCPs were unsure who to turn to. Another problem is often faulty interactions between schools, parents, children, and providers. Parents often fail to keep appointments. Schools and parents often are less than cooperative in providing information. In a 2004 survey of 786 U.S. school nurses, less than half reported good levels of communication between schools and physicians. Schools and parents often apply pressure on PCPs to issue a diagnosis. In the U.S. survey of 723 PCPs, more than half reported strong pressure from teachers to diagnose ADHD, and more than two-thirds said they were under pressure to prescribe medication.

The authors noted, "The need for education was the most highly endorsed factor overall, with PCPs reporting a general lack of education on ADHD. This need for education was observed on a worldwide scale; this factor was discussed in over 75% of our studies, in 12 different countries, suggesting that lack of education and inadequate education was the main barrier to the understanding of ADHD in primary care.

"In addition, "time and financial constraints affect the opportunities for PCPs to seek extra training and education but also affect the communication with other professionals such as secondary care workers, teachers, and parents." The authors cautioned that only eleven of the 48 studies were published since 2010. Also, because it was a systematic review and not a meta-analysis, there was no way to evaluate publication bias.

They concluded, "Better training of PCPs on ADHD is, therefore, necessary but to facilitate this, dedicated time and resources towards education needs to be put in place by the service providers and local authorities."

June 16, 2021

Is there an association between asthma and ADHD?

Is there an association between asthma and ADHD?

An international team of researchers has carefully examined the best current evidence and found strong evidence for an association between asthma and ADHD by combining a meta-analysis of prior data with a new analysis of the Swedish population.

The meta-analysis identified 46 datasets with a total of more than 3.3 million persons.  It computed an unadjusted (odds)'s ratio (OR) of 1.7, which indicates that ADHD patients have about twice the risk of developing asthma compared with people without ADHD. Limiting the meta-analysis to studies that adjusted for confounding factors, 30 datasets with more than a third of a million participants still led to an adjusted (odds)' ratio of 1.5 (95% CI 1.4 - 1.7). The likelihood of obtaining this result by chance in such a large sample would be less than one in ten thousand.

When the team further checked this result against the results for the Swedish population of more than one and a half million persons, the (odds)  ratio was almost identical to 1.6. Adjusting for confounding factors reduced it to 1.5 (95% CI 1.41 - 1.48). That means the findings are very robust: asthma and ADHD are associated, with an (odds)'ratio of 1.5, after adjusting for confounding factors.

What does this small but statistically very reliable association between asthma and ADHD mean? For researchers, it suggests that the two disorders may have common risk factors and that the search for these shared risk factors might lead to improved treatments.  These risk factors might also be shared with two other somatic conditions for which ADHD patients are at increased risk: obesity and eczema.  Common inflammatory processes may account for this overlap among disorders.  Clinicians should be aware that children with asthma have an increased risk for ADHD, although, given the small association, systematic screening may not be warranted.  But given that ADHD might interfere with asthma medication compliance, the disorder should be considered among noncompliant youth, especially among those who show other evidence of inattention, poor memory, or disorganization.

June 12, 2021

The State of the Art on Identifying and Treating Persons with Comorbid ADHD and Substance Use Disorders

The State of the Art on Identifying and Treating Persons with Comorbid ADHD and Substance Use Disorders

An international group of twelve experts recently published a consensus report examining the state of the evidence and offering recommendations to guide the screening, diagnosis, and treatment of individuals with ADHD-SUD comorbidity.[1]

In a clear sign that we are still in the early stages of understanding this relationship, five of the thirteen recommendations received the lowest recommendation grade (D), eight received the next-lowest (C), and none received the highest (A and B). The lower grades reflected the absence of the highest level of evidence, obtained from meta-analyses or systematic reviews of relevant randomized controlled trials (RCTs).

Nevertheless, with these limitations in mind, the experts agreed on the following points:

Diagnosis

  •  The strongest recommendation, the only one based on a 2+ level of evidence (well-conducted case-control or cohort studies with allowing risk of confounding or bias and a moderate probability that the relationship is causal) is that the "Short Version of the Adult ADHD Self-Report Scale (ASRS-SV) screener is currently the most widely used and investigated screening tool in individuals with ADHD and comorbid SUD, with good sensitivity and specificity across studies."
  • Two other recommendations were graded C: The diagnostic process should include current and past substance abuse, and seek to involve partners and relatives in evaluating symptoms and functional impairments.
  • Four recommendations got the lowest grade, D. The experts suggested starting the diagnostic process as soon as possible and focusing on drug- and alcohol-free periods in the patient's life during history taking. They also recommended that physicians and clinical psychologists should only make diagnoses if they have extensive training in diagnosing ADHD, as well as experience with adults with ADHD and with addiction care, and that they should consider treating adults with sufficiently severe ADHD symptoms.

Treatmen

  •  In general, evidence was stronger in this area, and only one of the six recommendations was graded D. The other five recommendations were graded C, with the highest level of evidence being 2(cohort or case and control studies with undetermined risk of bias), although in three cases it was level 3 (non-analytical studies, such as case reports and case series).
  • The grade D recommendation was to always consider a combination of psychotherapy and pharmacotherapy.

The grade C recommendations included considering adequate medical treatment of both ADHD and SUD; integrating ADHD treatment with SUD treatment as soon as possible;

June 2, 2021

Eight Pictures Describe Brain Mechanisms in ADHD

Eight Pictures Describe Brain Mechanisms in ADHD

When my colleagues and I wrote our "Primer" about ADHD, the topic of brain mechanisms was a top priority. Because so much has been written about the ADHD brain, it is difficult to summarize. Yet we did it with the eight pictures reproduced here in one figure.

A quick overview of this figure shows you the complexity of ADHD's pathophysiology. There is no single brain region or neural circuit that is affected.

Figures (a) and (b) show you the main regions implicated by structural and functional neuroimaging studies.

As (c) shows, these regions are united by neural networks rich in noradrenalin (aka, norepinephrine) and dopamine, two neurotransmitters whose activity is regulated by medications that treat ADHD.

Figure (d) describes two functional networks.

The executive control network is, perhaps, the best-described network in ADHD. This network regulates behavior by linking the dorsal striatum with the dorsolateral prefrontal cortex. This network is essential for inhibitory control, self-regulation, working memory, and attention.

The Corticocerebellar network is a well-known regulator of complex motor skills. Data also suggest it plays a role in the regulation of cognitive functions.

Figure (d) describes the Reward Networks of the brain that link the ventral striatum with the prefrontal cortex. This network regulates how we experience and value rewards and punishments. In addition to its involvement in ADHD, this network has also been implicated in substance use disorders, for which ADHD persons are at high risk.

Figures (f)(g) and (h) complete the puzzle with additional regions implicated in ADHD whose role is less well understood. One role for these regions is in the regulation of the Default Mode Network, which controls what the brain does when it is not focused on any specific task (e.g., daydreaming, mind wandering).

People differ in the degree to which they shift between the default mode network and networks like Reward or Executive Control, which are active when we engage the world. Recent data suggest that the brains of ADHD people may be in 'default mode' when they ought to be engaged in the world.

May 21, 2021

Myths About The Cause of ADHD

MYTHS ABOUT THE CAUSES OF ADHD

Myth: ADHD is caused by poor parenting or teaching.
Parents and teachers are popular targets for those who misunderstand ADHD.  This myth posits that ADHD would not exist if parents and teachers were more effective at disciplining and teaching children.  From this perspective, ADHD is a failure of society, not a brain disease.

Fact: ADHD occurs when genes and toxic environments harm the brain.
Blaming parents and teachers for ADHD is wrong.  We know from research studies that many parents of ADHD children have normal parenting skills and even when we train parents to be better parents, ADHD does not disappear.  Many parents of ADHD children have an anon-ADHD child that they raised with the same discipline methods.  If bad parenting causes ADHD, all the children in the family should have ADHD. Equally important, decades of research studies have shown that genes and toxic environments cause ADHD by harming the brain.  I'm not saying that all parents and teachers are perfect.  Teaching parents and teachers, special methods for dealing with ADHD can help children with ADHD.  

Myth: Watching Television causes ADHD.
This myth hit the media in 2004 when a research group published a paper suggesting that toddlers who watched too much TV were at risk for attentional problems later in life.

Fact: The study was wrong.
Sometimes researchers get it wrong. But fortunately, science is self-correcting; if an incorrect result is published, subsequent studies will show that it is wrong. That's what happened with the ADHD television study.  After the first study made such a media splash, several other researchers did similar studies.  They found out that the original study had errors and that watching too much TV does not cause ADHD.  But, because the popular media did not pick up the later studies, the myth persists. I'm not recommending that toddlers watch a lot of television, but rest assured that, if they do, it will not cause ADHD.

Myth: Too much sugar causes ADHD.
This idea is based on common sense.  Many parents know that when their children and their friends have too much sugary food, they can get very active and out of control.

Fact: Sometimes, common sense is wrong.
As a parent, I thought there was some truth to the sugar myth.   But when a colleague, Dr. Wolraich, reviewed the world literature on the topic, he found that there have been many studies on the effect of sugar on children.  These studies show that sugar does not affect either the behavior or the thinking patterns of children.  Having too much sugar is bad for other reasons, but it does not cause ADHD.

May 11, 2021

Is ADHD a Serious Condition?

Is ADHD a Serious Condition?

In the popular media, ADHD has sometimes been portrayed as a minor condition or not a disorder at all. It is easy to find websites claiming that ADHD is an invention of the medical profession and that the symptoms used to diagnose the disorder are simply normal behaviors that have been "medicalized". These claims are wrong. They miss the main point of any psychiatric diagnostic process, which is to identify people who experience distress or disability due to a set of well-defined symptoms. So, does ADHD cause serious distress and disability? It is a serious psychiatric condition? To illustrate the strong evidence base for the "Yes" answer to that question, my colleagues and I constructed this infographic for our "Primer" about ADHD,http://rdcu.be/gYyV.It describes the many ways in which the symptoms of ADHD impact and impair the lives of children, adolescents, and adults with the disorder. We divided these 'impacts' into four categories: other disorders (both psychiatric and medical), psychological dysfunction, academic and occupational failure, social disability, and risky behaviors. Let's start with other health problems. We know from many studies that have followed ADHD children into adolescence and adulthood that having the disorder puts patients at risk for several psychiatric disorders, addictions, criminality, learning disabilities, and speech/language disorders. ADHD even increases the risk for-psychiatric diseases such as obesity, hypertension, and diabetes. Perhaps most worrisome is that people with ADHD have a small increased risk for premature death. This increased risk is due in part to their having other psychiatric and medical conditions and also to their risky behaviors which, as research documents, lead to accidents and traumatic brain injuries. In the category of psychological dysfunction,' we highlighted emotional dysregulation, which makes ADHD people quick to anger or fail to tame extreme emotions. Other serious psychological issues are low self-esteem and increased thoughts of suicide, which lead to more suicide attempts than for people without ADHD. This increased risk for suicide is small, but it is real. A more prevalent impact of ADHD is the broad category of social disability, which includes marital discord, poor parenting, legal problems, arrests, and incarceration. This typically starts in youth with poor social adjustment and conflict with parents, siblings, and friends. Another common impact of ADHD is on academic and vocational pursuits. ADHD youth are at risk for underachievement in school, repeating grades, and dropping out. As adults, they are more likely to be unemployed or underemployed, which leads to them having lower incomes than expected for their level of school achievement. So, don't believe anyone who claims that ADHD is not a disorder or is only a mild one. To be sure, there is a wide range of impairments among people with ADHD but, in the absence of treatment, they are at risk for adverse outcomes. Fortunately, the medications that treat ADHD have been documented to reduce this risk, which is why they are typically the first-line treatment for most people with ADHD.

May 3, 2021

Is ADHD A Serious Conidtion?

How Serious is ADHD?

The US Center for Disease Control's (CDC)review of ADHD starts with the statement: "Attention-deficit/hyperactivity disorder (ADHD) is a serious public health problem affecting many children and adults" (http://www.cdc.gov/ncbddd/adhd/research.html). My colleagues and I recently reviewed the ADHD literature. That let us describe ADHD as "... a seriously impairing, often persistent neurobiological disorder of high prevalence..." (Faraone et al., 2015). The figure 1, which comes from that paper, provides an overview of the lifetime trajectory of ADHD-associated morbidity.

Especially compelling data about ADHD and injuries comes from a recent paper, in Lancet Psychiatry, which used the Danish national registers to follow a cohort of 710,120 children (Dalsgaard et al., 2015a).   Compared with children not having ADHD, those with ADHD were 30% more likely to sustain injuries than other children.  Pharmacotherapy for ADHD reduced the risk for injuries by 32% from 5 to 10 years of age. Pharmacotherapy for ADHD reduced emergency room visits by 28.2% at age 10and 45.7% at age 12.    

These results are shown in Figure 2, taken from the publication.

Especially compelling data about ADHD and injuries comes from a recent paper, in Lancet Psychiatry, which used the Danish national registers to follow a cohort of 710,120 children (Dalsgaard et al., 2015a).   Compared with children not having ADHD, those with ADHD were 30% more likely to sustain injuries than other children.  Pharmacotherapy for ADHD reduced the risk for injuries by 32% from 5 to 10 years of age. Pharmacotherapy for ADHD reduced emergency room visits by 28.2%at age 10and 45.7% at age 12.    

These results are shown in Figure2, taken from the publication.  The Figure compares the prevalence of injuries among three groups.  ADHD children treated with medication, ADHD children not treated with medication, and children without ADHD.  The Figure shows how ADHD risk for injuries occurs for all age groups. It also shows how the risk for injuries drops with treatment so that by age 12, the prevalence of injuries among treated ADHD children is the same as the prevalence of injuries for children without ADHD.

Documented examples of ADHD-associated injuries which impact day-to-day functioning include severe burns (Fritz and Butz, 2007), dental injuries (Sabuncuoglu, 2007), penetrating eye injuries (Bayar et al., 2015), the hospital treated injuries (Hurtig et al., 2013), and head injuries (DiScala et al., 1998).  In one study (DiScala et al., 1998), when compared to other children admitted to the hospital for injuries, ADHD children were more likely to sustain injuries in multiple body regions (57.1% vs 43%), sustain head injuries (53% vs 41%), and to be severely injured as measured by the Injury Severity Score (12.5% vs5.4%) and the Glasgow Coma Scale (7.5% vs 3.4%).

Injuries are a substantial cause of ADHD-associated premature death.  This assertion comes from the work of Dalsgaard et al. (2015b)based on the same Danish registry discussed above.   In this second study, ADHD was associated with an increased risk for premature death and 53% of those deaths were due to injuries.  They reported the risk for premature death in three age groups: 1-5, 6-17, and >17.  For all three age groups, they found a greater risk for death in the ADHD group. For ages 6 to 17 and greater than 17. The ADHD-associated risk for mortality remained significant after excluding individuals with antisocial or substance use disorders.

There are currently no data about the effect of ADHD treatment on ADHD-associated premature death.  We do, however, know from the data reviewed above that ADHD treatment reduces injuries and that half the deaths in the ADHD group were due to injuries.  From this, we infer that ADHD treatments could reduce the risk of ADHD-associated premature death.

Two other ADHD-associated mobilities, obesity and cigarette smoking, have clear medical consequences.  In a meta-analysis of 42 cross-sectional studies comprising 48,161 people with ADHD and 679,975 controls, my colleagues and I reported that the pooled prevalence of obesity was increased by about 40% in ADHD children compared with non-ADHD children and by about 70% in ADHD adults compared with non-ADHD adults(Cortese et al.,2015). The association between ADHD and obesity was significant for ADHD medication-naïve subjects but not for those medicated for ADHD, which suggests that medication reduces the risk for obesity.  

Likewise, a meta-analysis of 27 longitudinal studies assessed the risk for several addictive disorders with sample sizes ranging from 4142 to 4175 for ADHD and 6835 to 6880 for non-ADHD controls (Lee et al., 2011).  Children with ADHD were at higher risk for disorders of abuse or dependence on nicotine, alcohol, marijuana, cocaine, and other unspecified substances.  Another meta-analysis (42 studies totaling, 2360 participants) showed that medications for ADHD reduced the ADHD-associated risk for smoking (Schoenfelder et al., 2014).   The authors concluded that, for ADHD patients, "Consistent stimulant treatment for ADHD may reduce the risk of smoking". This finding is especially notable given that, for ADHD youth, cigarette smoking is a gateway drug to more serious addictions (Biederman et al., 2006).

 Yes, ADHD is a serious disorder.  Although most ADHD people will be spared the worst of these outcomes, they must be considered by parents and patients when weighing the pros and cons of treatment options.

November 16, 2023

Adult Onset ADHD: Does it Exist? Is it Distinct from Youth Onset ADHD?

Adult Onset ADHD: Does it Exist? Is it Distinct from Youth Onset ADHD?

There is a growing interest (and controversy) in 'adult-onset ADHD. No current diagnostic system allows for the diagnosis of ADHD in adulthood, yet clinicians sometimes face adults who meet all criteria for ADHD, except for age at onset. Although many of these clinically referred adult-onset cases may reflect poor recall, several recent longitudinal population studies have claimed to detect cases of adult-onset ADHD that showed no signs of ADHD as a youth (Agnew-Blais, Polanczyk et al. 2016, Caye, Rocha, et al. 2016). They conclude, not only that ADHD can onset in adulthood, but that childhood-onset and adult-onset ADHD may be distinct syndromes(Moffitt, Houts, et al. 2015)

In each study, the prevalence of adult-onset ADHD was much larger than the prevalence of childhood-onset adult ADHD). These estimates should be viewed with caution.  The adults in two of the studies were 18-19 years old.  That is too small a slice of adulthood to draw firm conclusions. As discussed elsewhere (Faraone and Biederman 2016), the claims for adult-onset ADHD are all based on population as opposed to clinical studies.
Population studies are plagued by the "false positive paradox", which states that, even when false positive rates are low, many or even most diagnoses in a population study can be false.  

Another problem is that the false positive rate is sensitive to the method of diagnosis. The child diagnoses in the studies claiming the existence of adult-onset ADHDused reports from parents and/or teachers but the adult diagnoses were based on self-report. Self-reports of ADHD in adults are less reliable than informant reports, which raises concerns about measurement error.   Another longitudinal study found that current symptoms of ADHD were under-reported by adults who had had ADHD in childhood and over-reported by adults who did not have ADHD in childhood(Sibley, Pelham, et al. 2012).   These issues strongly suggest that the studies claiming the existence of adult-onset ADHD underestimated the prevalence of persistent ADHD and overestimated the prevalence of adult-onset ADHD.  Thus, we cannot yet accept the conclusion that most adults referred to clinicians with ADHD symptoms will not have a history of ADHD in youth.

The new papers conclude that child and adult ADHD are "distinct syndromes", "that adult ADHD is more complex than a straightforward continuation of the childhood disorder" and that adult ADHD is "not a neurodevelopmental disorder". These conclusions are provocative, suggesting a paradigm shift in how we view adulthood and childhood ADHD.   Yet they seem premature.  In these studies, people were categorized as adult-onset ADHD if full-threshold add had not been diagnosed in childhood.  Yet, in all of these population studies, there was substantial evidence that the adult-onset cases were not neurotypical in adulthood (Faraone and Biederman 2016).  Notably, in a study of referred cases, one-third of late adolescent and adult-onset cases had childhood histories of ODD, CD, and school failure(Chandra, Biederman, et al. 2016).   Thus, many of the "adult onsets" of ADHD appear to have had neurodevelopmental roots. 

Looking through a more parsimonious lens, Faraone and Biederman(2016)proposed that the putative cases of adult-onset ADHD reflect the existence of subthreshold childhood ADHD that emerges with full threshold diagnostic criteria in adulthood.   Other work shows that subthreshold ADHD in childhood predicts onsets of full-threshold ADHD in adolescence(Lecendreux, Konofal, et al. 2015).   Why is onset delayed in subthreshold cases? One possibility is that intellectual and social supports help subthreshold ADHD youth compensate in early life, with decompensation occurring when supports are removed in adulthood or the challenges of life increase.  A related possibility is that the subthreshold cases are at the lower end of a dimensional liability spectrum that indexes risk for onset of ADHD symptoms and impairments.  This is consistent with the idea that ADHD is an extreme form of a dimensional trait, which is supported by twin and molecular genetic studies(Larsson, Anckarsater, et al. 2012, Lee, Ripke, et al. 2013).  These data suggest that disorders emerge when risk factors accumulate over time to exceed a threshold.  Those with lower levels of risk at birth will take longer to accumulate sufficient risk factors and longer to onset.

In conclusion, it is premature to accept the idea that there exists an adult-onset form of ADHD that does not have its roots in neurodevelopment and is not expressed in childhood.   It is, however, the right time to carefully study apparent cases of adult-onset ADHD to test the idea that they are late manifestations of a subthreshold childhood condition.

April 7, 2021

ADHD Treatment Decision Tree

ADHD Treatment Decision Tree

If you've ever wondered how experts make treatment recommendations for patients with ADHD, take a look at this ADHD treatment decision tree that my colleagues and I constructed for our "Primer" about ADHD,http://rdcu.be/gYyV.  

Although a picture is worth a thousand words, keep in mind that this infographic only gives the bare bones of a complex process. That said, it is telling that one of the first questions an expert asks is if the patient has a comorbid condition that is more severe than ADHD. The general rule is to treat the more severe disorder first and after that condition has been stabilized plan a treatment approach for the other condition. Stimulants are typically the first-line treatment due to their greater efficacy compared with non-stimulants.

When considering any medication treatment for ADHD safety is the first concern, which is why medical contraindications to stimulants, such as cardiovascular issues or concerns about substance abuse, must be considered. For very young children (preschoolers) family behavior therapy is typically used before medication. Clinicians also must deal with personal preferences.  Some parents and some adolescents and adults with ADHD simply don't want to take stimulant medications for the disorder. When that happens, clinicians should do their best to educate them about the costs and benefits of stimulant treatment.

If, as is the case for most patients, the doctor takes the stimulant arm of the decision tree, he or she must next decide if methylphenidate or amphetamine is more appropriate. Here there is very little guidance for doctors. Amphetamine compounds are a bit more effective, but can lead to greater side effects.  Genetic studies suggest that a person's genetic background provides some information about who will respond well to methylphenidate, but we are not yet able to make very accurate predictions. After choosing the type of stimulant, the doctor must next consider what duration of action is appropriate for each patient.

There is no simple rule here; the choice will depend upon the specific needs of each patient. Many children benefit from longer-acting medications to get them through school, homework, and late afternoon/evening social activities. Likewise for adults. But many patients prefer shorter-acting medications, especially as these can be used to target specific times of day and can also lower the burden of side effects.  

For patients taking down the non-stimulant arm of the decision tree, duration is not an issue but the patient and doctor must choose from among two classes of medications norepinephrine reuptake inhibitors or alpha-2-agonists. There are not a lot of good data to guide this decision but, again, genetics can be useful in some cases. Regardless of whether the first treatment is a stimulant or a non-stimulant, the patient's response must be closely monitored as there is no guarantee that the first choice of medication will work out well. In some cases, efficacy is low, or adverse events are high. Sometimes this can be fixed by changing the dose, and sometimes a trial of a new medication is indicated.

If you are a parent of a child with ADHD or an adult with ADHD, this trial-and-error approach can be frustrating. But don't lose hope. In the end, most ADHD patients find a dose and a medication that works for them. Last but not least, when medication leads to a partial response, even after adjusting doses and trying different medication types, doctors should consider referring the patient for a non-pharmacologic ADHD treatment.

You can read details about these in my other blogs, but here the main point is to find an evidence-based treatment. For children, the biggest evidence base is for behavioral family therapy. For adults, cognitive behavior therapy (CBT) is the best choice.  Except for preschoolers, the experts I worked with on this infographic did not recommend these therapies before medication treatment. The reason is that the medications are much more effective, and many non-pharmacologic treatments (such as CBT) have no data indicating they work well in the absence of medication.

April 3, 2021

Adult ADHD is a Risk Factor for Broken Bones

Adult ADHD is a Risk Factor for Broken Bones

Although some people view the impulsivity and inattentiveness of ADHD adults as a normal trait, these symptoms have adverse consequences, which is why doctors consider ADHD to be a disorder. The list of adverse consequences is long and now we can add another: broken bones.  

A recent study by Komurcu and colleagues examined 40 patients who were seen by doctors because of broken bones and forty people who had not broken a bone. After measuring ADHD symptoms in these patients, the study found that the patients with broken bones were more impulsive and inattentive than those without broken bones. This data suggest that, compared with others, adults with ADHD symptoms put themselves in situations that lead to broken bones. What could those situations be?  

Well, we know for starters that ADHD adults are more likely to have traffic accidents. They are also more likely to get into fights due to their impulsivity. As a general observation, it makes sense that inattentive people are more likely to have accidents that lead to injuries.


When we don't pay attention, we can put ourselves in dangerous situations. So, who should care about these results?  ADHD patients need to know about this so that they understand the potential consequences of their disorder. They are exposed to so much media attention to the dangers of drug treatment that it can be easy to forget that non-treatment also has consequences. Cognitive behavior therapy is also useful for helping patients learn how to avoid situations that might lead to accidents and broken bones.    

This study also has an important message for administrators on how to make decisions about subsidizing or reimbursing treatment for ADHD. They need to know that treating ADHD can prevent outcomes that are costly to the healthcare system, such as broken bones.  For example, in a study of children and adolescents, Leibson and colleagues showed that healthcare costs for ADHD patients were twice the cost for other youth, partly due to more hospitalizations and more emergency room visits.

Does this data mean that every ADHD patient is doomed to a life of injury and hospital visits? Certainly not.

But they do mean that patients and their loved ones need to be cautious and need to seek treatments that can limit the possibility of accidents and injury.

March 18, 2021

Does Obesity Directly Contribute to Risk of ADHD in Offspring?

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 painkillers, 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 (http://www.ncbi.nlm.nih.gov/pubmed/25251831), which also showed that the 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. 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 aweak, yet real, the 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 usecausedtheir 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 for risks to make an informed decision.

Find more evidence-based blogs at www.adhdinaduls.com.

March 14, 2021

Everything You Need to Know About ADHD

Everything You Need to Know About ADHD

You've heard all sorts of misinformation about Attention-Deficit/Hyperactivity Disorder(ADHD), whether from friends, the internet, or uninformed press articles:

"ADHD is not real."

"Pharmaceutical companies invented ADHD to make money."

"I'm just a little ADD."

"Natural solutions are the best for ADHD treatment."

ADHD symptoms were first described in the late 1700s, primarily among hyperactive boys. It was described variously over 200 years as "fidgeting," "defects of moral control," "hyperkinetic reaction," "minimal brain damage" and eventually ADD (Attention Deficit Disorder) in the 1980s and ADHD today.

Because the natural tendency toward hyperactivity decreased with age, ADHD was originally thought to be a developmental disorder that disappeared in mid-to-late adolescence. When medicines were developed and used in ADHD treatment for young boys, physicians stopped prescribing them around mid-adolescence, because it was presumed the condition had been remediated. They were wrong. We know now that ADHD persists into adulthood for about two-thirds of ADHD youth.

ADHD was not widely recognized in girls until the mid-1990s when it became clear that girls with ADHD were less disruptive than boys with ADHD and were not being appropriately diagnosed. Girls with ADHD show less of the physical hyperactivity of boys, but suffer from "dreaminess," "lack of focus" and "lack of follow-through."

It was also in the 1990s that ADHD' pervasive comorbidity with depression, anxiety, mood, and autism spectrum disorders was established. At the same time, researchers were beginning to describe deficits in executive functioning and emotional dysregulation that became targets of substantial research in the 21st century.

Even with the 1990s recognition that ADHD is a lifetime disorder, equally present (in different forms) in both men and women, medical schools and continuing medical education courses (required for realizing sure of health professionals) have only begun to teach the most up-to-date evidence-based knowledge to the medical community. There still is much misinformation and a lack of knowledge among primary care professionals and the public.

ADHD Throughout the Lifespan
Most cases of ADHD start in Otero before the child is born. As a fetus, the future ADHD person carries versions of genes that increase the risk for the disorder. At the same time, they are exposed to toxic environments. These genetic and environmental risks change the developing brain, setting the foundation for the future emergence of ADHD.

In preschool, early signs of ADHD are seen in emotional lability, hyperactivity, disinhibited behavior and speech, and language and coordination problems. The full-blown ADHD syndrome typically occurs in early childhood, but can be delayed until adolescence. In some cases, the future ADHD person is temporarily protected from the emergence of ADHD due to factors such as high intelligence or especially supportive family and/or school environments. But, as the challenges of life increase, this social, emotional, and intellectual scaffolding is no longer sufficient to control the emergence of disabling ADHD symptoms.

Throughout childhood and adolescence, the emergence and persistence of the disorder are regulated by additional environmental risk factors such as family chaos, as well as the age-dependent expression of risk genes that exert different effects at different stages of development. During adolescence, most cases of ADHD persist and by the teenage years, many youths with ADHD have onset with a mood, anxiety, or substance use disorder. Indeed, parents and clinicians need to monitor ADHD youth for early signs of these disorders. Prompt treatment can prevent years of distress and disability.

By adulthood, the number of comorbid conditions increases, including obesity, which likely impacts future medical outcomes. Emerging data shows people with ADHD to be at increased risk for hypertension and diabetes. ADHD adults tend to be very inattentive but show fewer symptoms of hyperactivity and impulsivity. They remain at risk for substance abuse, low self-esteem, injuries due to accidents, occupational failure, and social disability, especially if they are not treated for the disorder.

Seven Important Concepts About ADHD


There are approximately 10 million U.S. adults with ADHD, 9 million of whom are undiagnosed. But with diligent research by the medical profession, we have learned seven important concepts about ADHD:
1.    ADHD has been documented worldwide in 5% of the population.
2.    Sixty-seven percent of ADHD children grow into ADHD adults and seniors. ADHD is heritable, runs in families, and is impacted by the physical environment and familial lifestyle.
3.    In youth, rates of ADHD are higher in males than females as males, but these rates even out by adulthood.
4.    ADHD coexists and is often masked by several other disorders: anxiety, depression, spectrum bipolar and autism disorder, substance abuse, alcoholism, obesity, risky behaviors, disorganized lives, working memory deficits, and significant executive dysfunctions that affect personal, social, and work success.
5.    ADHD medications(stimulants and non-stimulants) are the most effective treatments for ADHD symptoms. Psychological support/training designed for ADHD, and lifestyle modifications, are important adjuncts to medicine.
6.    ADHD costs the U.S. economy more than $100 million annually in lost productivity, accidents, hospitalizations with comorbidities, and family and professional support for ADHD patients.
7.    ADHD is diagnosable and safely treatable in trained primary care practices.

How do you know if you or someone you love has ADHD? Evaluate your life against the seven concepts above. Then get screened and diagnosed by a health care professional. The diagnosis of ADHD should be done only by a licensed clinician who has been trained in ADHD. That clinician should have one goal in mind: to plan a safe and effective course of evidence-based treatment.

When diagnosing adults, it is also useful to collect information from a significant other, which can be a parent for young adults or a spouse for older adults. But when such individuals are not available, diagnosing ADHD based on the patient's self-report is valid. Just remember that personal, work, and family lives are improved with treatment. Research and technology related to ADHD improve all the time.

ADHD in Adults is a great resource for anyone interested in learning more about ADHD, with evidence-based information and education for both healthcare professionals and the public. The website also features a new ADHD screener for predicting the presence of ADHD in adults.

Stephen V. Faraone, Ph.D., is a Distinguished Professor of Psychiatry and Neuroscience & Physiology at SUNY Update Medical University and a global expert on Adult ADHD.

March 12, 2021

Comorbidities and Risk of Premature Death in Individuals With ADHD

How do psychiatric comorbidities affect risk of premature death among children and adults with ADHD?

The Nordic countries maintain detailed registers of their inhabitants. This enables researchers to examine patterns over entire nations. An international research team used the Swedish national registers for a prospective cohort study of 2,675,615 persons in the Medical Birth Register born in Sweden over a 27-year period from January 1, 1983, through December 31, 2009. Follow-up was completed in December 2013, with the oldest cohort member aged 31. The mean age at study entry was 6, and the mean at follow-up was 11.

Using personal identification numbers, researchers were able to cross-reference with the National Patient Register and the National Drug Register. From this, they determined that 86,670 members of the cohort (3.2 percent) had ADHD, based either on records of clinical diagnosis or of prescription of ADHD drugs. Psychiatric comorbidities were likewise identified in the National Patient Register.

These comorbidities were significantly more prevalent in the ADHD population than in the rest of the cohort. For example, whereas only 2.2% of the non-ADHD group was diagnosed with substance use disorder (SUD), 13.3% of the ADHD group also had SUD, a six-fold difference. For depression, it was a seven-fold difference, for schizophrenia a nine-fold difference.

The ADHD group had a significantly higher risk of premature death from all causes than the non-ADHD group, with an adjusted hazard ratio (HR) of 3.94 (95% CI 3.51-4.43). Unintentional injury(36%) and suicide (31%) were the leading causes of death in the ADHD group. Those with ADHD were more than eight times more likely to die by suicide than non-ADHD individuals, and roughly four times more likely to die from unintentional injury.

The vast majority of the increased risk appears to be associated with comorbid psychiatric conditions. Those with ADHD but no diagnosed comorbidities had an adjusted HR of 1.41 (95% CI 1.01-1.97). With a single comorbidity, the HR more than doubled to 3.71 (95% CI 2.88-4.78). With four or more comorbidities, it rose to a staggering 25.22 (95% CI 19.6-32.46).

The comorbid condition with the greatest impact was SUD, which increased the risk eight-fold by comparison with those with only ADHD (HR = 8.01, 95% CI 6.16-10.41). Anxiety disorder, schizophrenia, and personality disorder increased the risk about fourfold. Bipolar disorder, depression, and eating disorder increased risk by roughly two and a half times.

Co variate analysis helped tease out what portion of the risk was associated with ADHD alone versus comorbid conditions. Adjusting for the year of birth, sex, birth weight, maternal age at birth, parental educational level, and parental employment status, those with ADHD (including comorbid conditions) were 2.7 times more likely to prematurely die of natural causes than those without. Adjusting for comorbid psychiatric conditions completely eliminated the risk from ADHD alone (HR = 1.01, 95% CI .72-1.42).

Likewise, those with ADHD (including comorbid conditions) were six times as likely to die of unnatural causes. Adjusting for early-onset comorbid disorders(such as conduct disorders, autism spectrum disorder, and intellectual disability) only modestly reduced the HR to 5.3, but further adjusting for later-onset comorbid disorders (including substance use disorder, depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, personality disorder, and eating disorders) reduced the HR to 1.57 (95% CI 1.35-1.83), and reduced it to insignificance in the case of suicide (HR = 1.13, 95% CI.88-1.45).

Summing up, the lion’s share of the greater risk of premature death in persons with ADHD is attributable to psychiatric comorbidities. Nevertheless, those with ADHD alone still face a 40 percent greater risk than those without ADHD.

The study did not examine effects of ADHD medication, which the authors state “should be analyzed because of documented potential benefits on ADHD symptoms and comorbid disorders.”

The authors concluded, “Among adults, early-onset psychiatric comorbidity contributed substantially to the premature mortality risks due to natural causes. On the other hand, later-onset psychiatric comorbidity, especially SUD, explained a substantial part of the risk for unnatural deaths, including all the risk of suicide deaths and most of the deaths due to unintentional injuries. These results suggest that overall health conditions and risk of psychiatric comorbidity should be evaluated clinically to identify high-risk groups among individuals with ADHD.”

November 10, 2023

Link Found Between ADHD Risk Genes and Reduced Estimated Life Expectancy

Association found between ADHD risk genes involved in dopamine signaling and reduced estimated life expectancy

Behavioral disinhibition is a trait associated with both ADHD and several genes that affect dopamine signaling. Anew study by three American medical researchers set out to examine how threaded risk genes – DRD4 (dopamine 4 receptor density), DAT1 (dopamine 1transporter), and DBH (dopamine beta-hydroxylase) – affect estimated life expectancy in young adulthood.

The method used was a longitudinal study of 131 hyperactive children and 71 matched controls through early adulthood. The original evaluations were done in 1979-1980, when both groups were children in the 4 to 12 age range. They were reevaluated in1987-1988 as adolescents aged 12 to 20. The next follow-up was in 1992-1996 in early adulthood, aged 19 to 25. The final follow-up was in 1998-2004, as adults aged 24 to 32. All agreed to physical examinations that formed the basis for calculating estimated life expectancy using actuarial tables that factor in the effects of smoking, body mass index, alcohol, and other risk factors on expected longevity. Participants also provided blood samples that enabled gene typing.

For the DAT1gene, participants who had the homozygous nine-repeat allele (9/9) had an a five-year reduction in estimated life expectancy relative to those with the ten-repeat allele (10/10). Those with the intermediate (9/10) configuration had a three-year reduction in estimated life expectancy.

For the DBHTaq1 gene, those with a heterozygous (A1/A2) combination had almost a three-year reduction in estimated life expectancy relative to those with homozygous (A1/A1 or A2/A2) configurations.

For DRD4, on the other hand, no significant differences were found for estimated life expectancy.

In a related study, several background traits were found to be significantly predictive of variance in estimated life expectancy. The largest of these was behavioral disinhibition, followed by verbal IQ, self-rated hostility, and a nonverbal fluency test. But no significant differences were found between any of the gene polymorphisms on any of these four measures, indicating that the present gene associations were independent of the background traits.

The researchers next sought to determine which variables used in the estimated life expectancy calculations were associated with the two significant genes. For DBH, one variable stood out. Those with the A1/A2 heterozygous pairings had almost twice the alcohol consumption of those with homozygous pairings (p = 0.023).

For DAT1, two variables stood out. Overall, the 9/9 pairings smoked two and a half times as much as the 10/10 pairings, with the 9/10 pairings midway between the extremes(p = 0.036). They were also 73 percent more likely to be smokers relative to the 10/10 pairings, and 61 percent more likely relative to the 9/10 pairings. They also had significantly less education than the 10/10 pairings, with the 9/10pairings again being intermediate (p = 0.027).

An obvious limitation of the study was its small sample size. The authors cautioned, “our findings should be considered quite preliminary and in need of much greater research before being given much weight in the literature or in public policy.

“With these limitations in mind,” they concluded, “the present study demonstrated that two ADHD risk genes (DBH and DAT1) independently contributed to a reduction in ELE [estimated life expectancy] beyond the second order variables of behavioral disinhibition, IQ, hostility, and nonverbal fluency that contributed in the related study to variation in ELE. The gene polymorphisms seemed to be influencing ELE through their affiliation with first-order or more proximal factors related to ELE such as education, smoking, alcohol use, and possibly exercise.”

February 28, 2021

Sleep and ADHD?

Sleep and ADHD?

Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them. A team of British researchers set out to see whether this association could be further confirmed with objective sleep measures, using cognitive function tests and electroencephalography (EEG).

Measured as theta/beta ratio, EEG slowing is a widely used indicator in ADHD research. While it occurs normally in non-ADHD adults at the conclusion of a day, during the day it signals excessive sleepiness, whether from obstructive sleep apnea or from neurodegenerative and neurodevelopmental disorders. Coffee reverses EEG slowing, as do ADHD stimulant medications.

Study participants were either on stable treatment with ADHD medication (stimulant or non-stimulant medication), or on no medication. Participants had to refrain from taking any stimulant medications for at least 48 hours prior to taking the tests. Persons with IQ below 80 or with recurrent depression or undergoing a depressive episode were excluded.

The team administered a cognitive function test, The Sustained Attention to Response Task (SART). Observers rated on-task sleepiness using videos from the cognitive testing sessions. They wired participants for EEG monitoring.

Observer-rated sleepiness was found to be moderately higher in the ADHD group than in controls. Although sleep quality was slightly lower in the sleepy group than in the ADHD group, and symptom severity slightly greater in the ADHD group than the sleepy group, neither difference was statistically significant, indicating extensive overlap.

Omission errors in the SART were strongly correlated with sleepiness level, and the strength of this correlation was independent of ADHD symptom severity. EEG slowing in all regions of the brain was more than 50 percent higher in the ADHD group than in the control group and was highest in the frontal cortex.

Treating the sleepy group as a third group, EEG slowing was highest for the ADHD group, followed closely by the sleepy group, and more distantly by the neurotypical group. The gaps between the ADHD and sleepy groups on the one hand, and the neurotypical group on the other, were both large and statistically significant, whereas the gap between the ADHD and sleepy groups was not. EEG slowing was both a significant predictor of ADHD and of ADHD symptom severity.

The authors concluded, These findings indicate that the cognitive performance deficits routinely attributed to ADHD  are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. We would like to propose a simple working hypothesis that daytime sleepiness plays a major role in cognitive functioning of adults with ADHD. As adults with ADHD are more severely sleep deprived compared to neurotypical control subjects and are more vulnerable to sleep deprivation, in various neurocognitive tasks they should manifest larger sleepiness-related reductions in cognitive performance. One clear testable prediction of the working hypothesis would be that carefully controlling for sleepiness, time of day and/or individual circadian rhythms, would result in substantial reduction in the neurocognitive deficits in replications of classic ADHD studies.

November 1, 2023

ADHD May Be Underdiagnosed Based on Sociodemographics

ADHD is underdiagnosed, to varying degrees, among adults of different ethnicities, ages, and education levels in the U.S.

ADHD is underdiagnosed and most cases of ADHD in adults are not being diagnosed by clinicians.

A cohort study looked at over five million adults and over 850,000 children between the ages of five and eleven who received care at Kaiser Permanente Northern California during the ten-year period from the beginning of 2007 through the end of 2016. At any given time, KPNC serves roughly four million persons. It is representative of the population of the region, except for the highest and lowest income strata.

Among adults rates of ADHD diagnosis rose from 0.43% to 0.96%. Among children the diagnosis rates rose from 2.96% to 3.74%, ending up almost four times as high as for adults.

Non-Hispanic whites had the highest adult rates throughout, increasing from 0.67% in 2007 to 1.42% in 2016. American Indian or Alaska Native (AIAN) had the second highest rates, rising from 0.56% to 1.14%. Blacks and Hispanics had roughly comparable rates of diagnosis, the former rising from 0.22% to 0.69%, the latter from 0.25% to 0.65%. The lowest rates were among Asians (rising from 0.11% to 0.35%) and Native Hawaiian or other Pacific Islanders (increasing from 0.11% to 0.39%).

The odds of diagnosis dropped steeply with age among adults. Relative to 18-24-year-olds, 25-34-year-olds were 1/6th less likely to be diagnosed with ADHD, 35-44-year-olds 1/3rd less likely, 45-54-year-olds less than half as likely, 55-64-year-olds less than a quarter as likely, and those over 65 about a twentieth as likely.  This is consistent with other studies reporting an age-dependent decline in the diagnosis.

Adults with the highest levels of education were twice as likely to be diagnosed as those with the lowest levels. But variations in median household income had almost no effect. Women were marginally less likely to be diagnosed than men.

ADHD is associated with some other psychiatric disorders. Compared with normally developing adults, and adjusted for confounders, those with ADHD were five times as likely to have an eating disorder, over four times as likely to be diagnosed with bipolar disorder or depression, more than twice as likely to suffer from anxiety, but only slightly more likely to abuse drugs or alcohol.

The authors speculate that rising rates of diagnosis “could reflect increasing recognition of ADHD in adults by physicians and other clinicians as well as growing public awareness of ADHD during the decade under study.” Turning to the strong differences among ethnicities, they note, “Racial/ethnic differences could also reflect differential rates of treatment-seeking or access to care. … Racial/ethnic background is known to play an important role in opinions on mental health services, health care utilization, and physician preferences. In addition, rates of diagnosis- seeking to obtain stimulant medication for nonmedical use may be more common among white vs nonwhite patients.” They conclude, “greater consideration must be placed on cultural influences on health care seeking and delivery, along with an increased understanding of the various social, psychological, and biological differences among races/ethnicities as well as culturally sensitive approaches to identify and treat ADHD in the total population.”

But the main take-home message of this work is that most cases of ADHD in adults are not being diagnosed by clinicians.  We know from population studies, worldwide, that about three percent of adults suffer from the disorder.  This study found that less than 1 percent are diagnosed by their doctors.  Clearly, more education is needed to teach clinicians how to identify, diagnose and treat ADHD in adults.

February 2, 2021