August 19, 2021

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."

Russell A. Barkley, Karen Müller Smith, and Mariellen Fischer, ADHD risk genes involved in dopamine signaling and metabolism are associated with reduced estimated life expectancy at young adult follow-up in hyperactive and control children, American Journal of Medical Genetics(2019), DOI:10.1002/aiming.b.32711.

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Swedish Population Study Confirms Association Between ADHD and Height

Nationwide population study in Sweden confirms association between ADHD and shorter height in children and adolescents, suggests stimulant medications are not a factor

A commonly reported risk associated with ADHD medication is reduced growth in height. But studies to date have generally not adequately described or measured possible confounders, such as genetic factors, prenatal factors, or socioeconomic factors. What if ADHD were associated with reduced height even in the absence of medications? 

An international study team explored this question by performing a nationwide population study comparing data from before (1968-1991) and after (1992-2020) the adoption of stimulant therapy for ADHD in Sweden. 

The country’s single-payer health insurance system that connects patient records with all other national registers through unique personal identification numbers makes such analysis possible. Sweden also has military service conscription, which records the heights of 18-year-old males.

The participants were all 14,268 Swedish males with a diagnosis of ADHD who were drafted into military service at any time from 1968 through 2020. 

Up to five non-ADHD controls were identified for each ADHD case, matched by sex (they had to be male), birth year, and county. The total number of controls was 71,339.

Among 34,586 participants in the period before adoption of stimulant medications (1968-1991), those diagnosed with ADHD had roughly 30% greater odds of being shorter than normal (166-172 vs. 173-185 cm) than typically developing controls. That dropped to 20% greater odds among the 34,714 participants in the cohort following adoption of stimulant medications.

The odds of those diagnosed with ADHD being much shorter than normal (150-165 vs. 173-185 cm) remained identical (about 55% greater) among the almost 30,000 participants in both cohorts.

In other words, there was no increase in the odds of ADHD individuals being shorter than normal after adoption of stimulant therapy in Sweden compared with before such adoption.

Furthermore, after adjusting for known confounders, including birth weight, inflammatory bowel disease, celiac disease, hypothyroidism, anxiety disorders, depression, substance use disorder, and highest parental education, the odds of those diagnosed with ADHD being shorter than normal or much shorter than normal in the 1992-2020 cohort dropped to roughly 10% and 30% greater, respectively.

Could it be the disorder itself rather than stimulant treatment that is associated with reduced height in individuals diagnosed with ADHD?

To address effects of environmental and familial/genetic confounding, the team then compared the entire cohort of males diagnosed with ADHD from 1968 through 2020 with typically developing male relatives, ranging from first cousins to full siblings.

Among full siblings, the odds of those with ADHD diagnoses being shorter (over 90,000 participants) or much shorter (over 77,000 participants) were a statistically significant 14% and 18%, respectively.

The authors concluded, “Our findings suggest that ADHD is associated with shorter height. On a population level, this association was present both before and after ADHD-medications were available in Sweden. The association between ADHD and height was partly explained by prenatal factors, psychiatric comorbidity, low SES [socioeconomic status] and a shared familial liability for ADHD.”

January 9, 2024

Swedish nationwide population study finds mothers with ADHD have elevated risk of depression and anxiety disorders after childbirth

Swedish nationwide population study finds mothers with ADHD have elevated risk of depression and anxiety disorders after childbirth

In the general population, most mothers experience mood disturbances right after childbirth, commonly known as postpartum blues, baby blues, or maternity blues. Yet only about one in six develop symptoms with a duration and magnitude that require treatment for depressive disorder, and one in ten for anxiety disorder.

To what extent does ADHD contribute to the risk of such disorders following childbirth? A Swedish study team used the country’s single-payer health insurance database and other national registers to conduct the first nationwide population study to explore this question.

They used the medical birth register to identify all 420,513 women above 15 years of age who gave birth to their first child, and all 352,534 who gave birth to their second child, between 2005 and 2013. They excluded miscarriages. They then looked for diagnoses of depression and/or anxiety disorders up to a year following childbirth.

In the study population, 3,515 mothers had been diagnosed with ADHD, and the other 769,532 had no such diagnosis. 

Following childbirth, depression disorders were five times more prevalent among mothers with ADHD than among their non-ADHD peers. Excluding individuals with a prior history of depression made little difference, lowering the prevalence ratio to just under 5. Among women under 25, the prevalence ratio was still above 3, while for those 25 and older it was above 6.

Similarly, anxiety disorders were over five times more prevalent among mothers with ADHD than among their non-ADHD peers. Once again, excluding individuals with a prior history of depression made little difference, lowering the prevalence ratio to just under 5. Among women under 25, the prevalence ratio was still above 3, while for those 25 and older it was above 6.

The team cautioned, “There is a potential risk of surveillance bias as women diagnosed with ADHD are more likely to have repeated visits to psychiatric care and might have an enhanced likelihood of also being diagnosed with depression and anxiety disorders postpartum, compared to women without ADHD.”

Nevertheless, they concluded, “ADHD is an important risk factor for both depression and anxiety disorders in the postpartum period and should be considered in the post- pregnancy maternal care, regardless of sociodemographic factors and the presence of other psychiatric disorders. Parental education prior to conception, psychological surveillance during, and social support after childbirth should be provided to women diagnosed with ADHD.”

December 22, 2023

Meta-analysis suggests acupuncture might offer effective treatment for ADHD, but suffers from methodological flaws

Meta-analysis suggests acupuncture might offer effective treatment for ADHD, but suffers from methodological flaws

Noting that previous “systematic reviews concluded that currently available data on the clinical effectiveness of acupuncture for treating ADHD are yet to be sufficient to support its routine use,” a South Korean study team conducted an updated systematic search of the medical literature for randomized controlled trials (RCTs) comparing acupuncture with drug treatment for children and adolescents with ADHD. There were no restrictions on language or publication type.

Only two of the meta-analyses involved more than two RCTs. 

One of them, of six RCTs with a combined 541 participants, reported total treatment efficacy of acupuncture to be at least equal to that of conventional treatment with ADHD medicines. 

Another, of five RCTs with a total of 351 participants, reported total treatment efficacy of combined acupuncture and ADHD drugs to be at least equal to that of conventional treatment with ADHD medicines.

Two RCTs with a Noting that previous “systematic reviews concluded that currently available data on the clinical effectiveness of acupuncture for treating ADHD are yet to be sufficient to support its routine use,” a South Korean study team conducted an updated systematic search of the medical literature for randomized controlled trials (RCTs) comparing acupuncture with drug treatment for children and adolescents with ADHD. There were no restrictions on language or publication type.

Only two of the meta-analyses involved more than two RCTs. 

One of them, of six RCTs with a combined 541 participants, reported total treatment efficacy of acupuncture to be at least equal to that of conventional treatment with ADHD medicines. 

Another, of five RCTs with a total of 351 participants, reported total treatment efficacy of combined acupuncture and ADHD drugs to be at least equal to that of conventional treatment with ADHD medicines.

Two RCTs with a combined 152 participants reported a large effect size improvement in hyperactivity/impulsivity symptoms from acupuncture treatment versus conventional drug treatment.

From this one could superficially conclude that acupuncture is at least as effective for treating ADHD as the medicines currently considered to be the standard of care, and that there is no need to combine acupuncture with drug treatment.

However, there were numerous methodological shortcomings:

  • No effort was made to look for publication bias.
  • There were few RCTs, and the combined number of participants was relatively small.
  • Only one of the six RCTs in the first meta-analysis and none of the five RCTs in the second meta-analysis was rated “low risk of bias.”
  • Though nowhere stated in the journal article, there may have been cultural bias as well. All studies included in the meta-analyses were conducted in China. As China has emerged as a global superpower, it has been eager to portray its traditional medicine as at least equal if not superior to forms of medicine originating elsewhere.
  • The authors noted, “the quality of the studies included in this systematic review was poor. Assessing the blinding of studies is a major aspect in determining the risk of bias of a study, but most of the studies did not provide any relevant information.” 

The authors concluded, “The current evidence on AT [acupuncture treatment] is still too limited to support its routine use in treating ADHD.”

152 participants reported a large effect size improvement in hyperactivity/impulsivity symptoms from acupuncture treatment versus conventional drug treatment.

From this one could superficially conclude that acupuncture is at least as effective for treating ADHD as the medicines currently considered to be the standard of care, and furthermore that there is no need to combine acupuncture with drug treatment.

However, there were numerous methodological shortcomings:

  • No effort was made to look for publication bias.
  • There were few RCTs, and the combined number of participants was relatively small.
  • Only one of the six RCTs in the first meta-analysis and none of the five RCTs in the second meta-analysis was rated “low risk of bias.”
  • Though nowhere stated in the journal article, there may have been cultural bias as well. All studies included in the meta-analyses were conducted in China. As China has emerged as a global superpower, it has been eager to portray its traditional medicine as at least equal if not superior to forms of medicine originating elsewhere.
  • The authors noted, “the quality of the studies included in this systematic review was poor. Assessing the blinding of studies is a major aspect in determining the risk of bias of a study, but most of the studies did not provide any relevant information.” 

The authors concluded, “The current evidence on AT [acupuncture treatment] is still too limited to support its routine use in treating ADHD.”

January 4, 2024