November 20, 2023
Celiac disease is an autoimmune disorder triggered by dietary gluten in genetically predisposed individuals. Gluten is a protein found in wheat and related grains such as barley and rye. The disease affects one to two percent of Western populations.
An international team of physicians conducted a nationwide cohort study of the Swedish population to explore the relationship between childhood celiac disease and subsequent psychiatric disorders, including ADHD, as well as suicide attempts and suicide.
With data from all 28 pathology departments in Sweden, they identified all 19,186 children with a diagnosis of biopsy-verified celiac disease from 1973 through 2016, and no previous history of psychiatric disorder. They then matched them with 94,249 children controls matched for age, sex, county, and calendar year from the Swedish national registers that encompass the entire resident population.
To address shared intrafamilial confounding, including genetic and early environmental factors, the team also compared 13,015 individuals with celiac disease with their 18,024 non-celiac siblings.
Additional Swedish national registers (Patient Register, Cause of Death Register) then made it possible to link the preceding data with data on subsequent psychiatric disorders and suicides for all the children in the study.
Celiac disease diagnosed in childhood was associated with a 19 percent higher risk of any subsequent psychiatric disorder at any time than for controls. The greatest spike in risk - 70 percent higher than for non-celiac controls - was in the first year following diagnosis of celiac disease. Restricting follow-up until the age of 18 years, celiac disease was linked to a 26 percent increased risk of any psychiatric disorder. For adults 18 and over, the increased risk declined to just 11 percent. So an initial sharp spike was followed by a steeply declining curve over time.
For ADHD, the increased risk at any time after the diagnosis of celiac disease was 29 percent. That compares with 47 percent for autism spectrum disorder, 34 percent for eating disorders, 20 percent for mood disorders, and 12 percent for anxiety disorders. There was no increased risk of psychotic disorders, behavioral disorders, personality disorders, psychoactive substance abuse, suicide attempts, or suicide. For adults 18 and over, however, the increased risk of ADHD rose to 39 percent, second only to autism spectrum disorder. For these two psychiatric conditions, there was an upward curve rather than a declining one.
The sibling analyses found a reduced but still significant 12 percent increased risk of psychiatric disorder following a diagnosis of celiac disease, again with the first-year spike of 48 percent increased risk declining to insignificance for the period beginning five years later. For ADHD, the increased risk also descended to 12 percent, but became non-significant, suggesting the increases were primarily attributable to confounding variables.
Among the 2,071 children with celiac disease who had a follow-up biopsy that showed mucosal healing of the small intestine in response to a gluten-free diet, the association with subsequent psychiatric disorders vanished.
The authors speculated that the spike in psychiatric diagnoses in the year following diagnosis of celiac disease could be because "the systemic inflammatory response is mediating this relationship," or could be due to "the psychosocial stress associated with adapting to the gluten-free diet." "However," they cautioned, "this risk is unlikely to be due to the gluten-free diet alone since we also observed an increased risk of psychiatric disorders preceding the diagnosis of celiac disease, possibly related to the systemic inflammatory response described above." We must also keep in mind that such studies cannot rule out all sources of confounding or the possibility that being diagnosed with celiac disease leads to more exposure to the healthcare system and more opportunities for a diagnosis of ADHD to be recognized.
Benjamin Lebwohl, MD, Linnea Haggård, MD, Louise Emilsson, MD, PhD, Jonas Söderling, PhD, Bjorn Roelstraete PhD, and Agnieszka Butwicka,MD, Peter HR Green, MD, Jonas F.
Ludvigsson, MD, Ph.D., "Psychiatric disorders in patients with a diagnosis of celiac disease during childhood from 1973 to 2016," Clinical Gastroenterology and Hepatology (2020), https://doi.org/10.1016/j.cgh.2020.08.018.
A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications.
However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life?
Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies.
A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD.
The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders.
With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants.
None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail.
Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect.
Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine.
Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.
The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect.
Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect.
The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.”
Noting that “Oxidative stress disrupts the structure and function of neurons in the prefrontal lobe of the brain,” and “Structural and functional impairments in the prefrontal cortex have been shown to be highly correlated with behavioral and emotional problems of ADHD,” a Chinese team at Dalian University set out to systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with ADHD.
The team’s systematic search of the peer-reviewed medical literature identified a total of 48 randomized controlled trials (RCTs) or prospective studies involving 12 antioxidant agents (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) that met criteria for inclusion:
Treatment efficacy was measured through ADHD symptom scores using Conners’ parent rating scale (CPRS), Conners’ teacher rating scale (CTRS), ADHD rating scale-parent (ADHD RS-Parent), and ADHD rating scale-teacher (ADHD RS-Teacher), as well as secondary outcome indicators such as the Clinical Global Impressions scale (CGI) and Continuous Performance Test (CPT), relative to controls.
None of the antioxidant therapies were significantly better than placebo.
One limitation is that no effort was made to assess publication bias.
These results indicate that antioxidants should not be used for treating ADHD.
A 2021 consensus statement by an international group of scientists and clinicians (Bauer et al.) recommended that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” due to the potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD).
A mostly Swedish research team, collaborating with a U.S. researcher, nevertheless noted that previous studies have been limited by:
Sweden has a single-payer health insurance system that includes virtually its entire population, and national registers that enable tracking the health history of mothers and their children, including their children’s siblings.
The team used the Swedish registers to identify the roughly two-and-a-half million children born in Sweden from mid-1995 through 2019. They were also able to identify all siblings to be able to control for otherwise unmeasured familial and genetic confounding.
Almost 186,000 of these children were exposed to acetaminophen during pregnancy.
After adjusting for available known confounders, including (but not limited to) child sex and birthdate, mother’s age and medical history, use of any other painkillers, use of any psychoactive medications, country of birth, residential region, smoking status, highest household education, and disposable income, children exposed to acetaminophen during pregnancy were 7% more likely to be diagnosed with ADHD subsequently than those who were not exposed.
However, roughly the same results were found for other painkillers, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antimigraine medication. High doses of acetaminophen did not produce any stronger association with subsequent ADHD than low dosage.
Moreover, when confining results to siblings – 8,526 children who were exposed versus 87,679 who were unexposed – the association between acetaminophen use during pregnancy and subsequent offspring ADHD vanished altogether (and, again, at every dose level). The associations similarly vanished with every other painkiller medication.
The Swedish team concluded, “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in models without sibling control may have been attributable to confounding.”
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