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October 18, 2023
Modified release (MR) formulations of ADHD stimulant medications simplify adherence over immediate-release (IR) formulations, by only requiring a single dosing per day. They are also intended to reduce diversion to nonmedical usage and the development of drug abuse or dependency. Is there evidence they deliver on this promise?
There are 55 poison control centers distributed throughout the United States, and they all report through the National Poison Data System (NPDS).
A pair of researchers used the NPDS to obtain all 15,796 single-substance MR ingestion and single-substance 23,418 IR ingestion reported to poison control centers over the eleven years from January 1, 2007, through December 31, 2017. The medications were either amphetamine or methylphenidate-based.
IR ingestion was more commonly associated with more serious outcomes than were MR ingestion. No deaths were reported from MR stimulant ingestion, versus three deaths (a rate of one in 7,800 reports) from IR stimulant ingestion. While there were no observed differences between youth MR and IR ingestion about admission to critical care units, adult IR ingestion was more commonly admitted to a critical care unit than was adult MR ingestion. Moreover, adults were more commonly admitted to critical care units for both MR and IR ingestion than were youths.
Among youths, the vast majority of MR ingestion was unintentional, with only one in eleven attributed to intentions of suicide. Among adults, however, almost half were intentional, with just over a quarter attributed to intentions of suicide, and another one in six to intentional misuse.
Turning to IR ingestion, the vast majority were again unintentional among youths, with less than one in twelve attributed to suspected suicide attempts. But among adults, the majority were intentional, with almost one in three attributed to suspected suicide attempts, plus another one in five to intentional misuse.
More than four out of five IR ingestion among both youths and adults were of amphetamine medications. For MR ingestion, methylphenidate was most common in youths and amphetamine medications in adults, but only by slight margins.
The most commonly reported symptoms in adults and youths alike for both IR and MR ingestion were agitation, abnormally rapid heart rates, and high blood pressure.
The authors concluded, "More serious outcomes were associated with advancing age, intentional ingestion, and IR preparations. Higher rates of hyperadrenergic symptoms (tachycardia, agitation, and hypertension) were observed with IR ingestion."
On balance, this suggests MR formulations are safer, but both formulations are subject to abuse by a small minority of users.
Michael A. Darracq and Stephen L. Thornton, "Sustainedstimulation? Characteristics of modified release and immediate releasestimulant exposures reported to the national poison data system," ClinicalToxicology (2020), https://doi.org/10.1080/15563650.2020.1787428.
Counting umbilical cord vessels is standard in prenatal ultrasounds and confirmed at birth. Single umbilical artery (SUA) occurs in about 1 in 200 cases, with roughly 10% associated with anomalies, including central nervous system defects. Isolated SUA (iSUA) means one artery is missing without other structural issues.
Research on SUA, especially isolated iSUA, and childhood neurodevelopmental disorders (NDD) is limited and inconclusive. iSUA is linked to preterm birth and small-for-gestational age (SGA), both of which are NDD risk factors.
This Norwegian nationwide population study aimed to assess NDD risk in children with iSUA at birth, the influence of sex, and how preterm birth and SGA mediate this relationship.
The nation’s universal single-payer health insurance and comprehensive population registries made it possible to analyze all 858,397 single births occurring from 1999 to 2013, with follow-up continuing through 2019. Among these cases, 3,532 involved iSUA.
After adjusting for confounders such as parental age, education, and maternal health factors, no overall link was found between iSUA and later ADHD diagnosis. However, females with iSUA had about a 40% higher risk of subsequent ADHD compared to those without iSUA, even after adjustment.
The authors concluded, “The present study indicates that iSUA is weakly associated with ID [intellectual disability] and ADHD, and these associations are influenced by sex. This association is mediated negligibly through preterm birth and SGA. The associations were not clinically significant, and the absence of associations of iSUA with other NDD is reassuring. This finding can be useful in the counseling of expectant parents of fetuses diagnosed with iSUA.”
Refractive errors, such as myopia (nearsightedness), hyperopia (farsightedness), and astigmatism (distorted vision due to irregular curvature of the eye or lens), are common worldwide. These conditions affect 12%, 5%, and 15% of children, and rise significantly in adults to 26.5%, 31%, and 40%. Additionally, strabismus (misalignment of the eyes) and amblyopia (reduced vision in one eye from uneven image formation, often linked to strabismus) occur globally at rates of 2% and 1.4%, respectively.
Visual impairment can affect children’s concentration in school, and studies suggest a link between eye disorders and ADHD.
To investigate this relationship, two researchers – one based in the US and the other in Israel –carried out a nationwide retrospective cohort study using electronic medical records of all insured individuals aged 5 to 30 who were part of Maccabi Health Services, Israel’s second largest health maintenance organization, between 2010 and 2022.
Of over 1.6 million insured members (2010–2020), inclusion/exclusion criteria and propensity score matching for age and sex were applied, along with a one-year wash-out period between the first eye diagnosis and ADHD diagnosis. In total, 221,707 cases were matched with controls without eye disorders at a 1:2 ratio, resulting in a cohort of 665,121 participants.
Overall, those with any previous eye diagnosis were 40% more likely to have a subsequent ADHD diagnosis. This was slightly higher for females (45%) than for males (35%). It was also slightly higher for children and adolescents (42%) than for adults (37%).
More specifically:
The authors concluded that eye disorders are associated with ADHD. They noted these associations were more marked in females and children and adolescents, although, as noted above, those differences were small. They recommended that primary care providers and neurologists consider risk stratification for early screening, and that ophthalmologists refer high-risk patients for ADHD evaluation.
Acid-suppressive medications, including proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists, are often prescribed during pregnancy to treat heartburn and gastroesophageal reflux disease.
Research shows changes in the gut microbiome can negatively affect neurodevelopment. Since acid-suppressive medications alter gut microbiota, maternal use during pregnancy may impact offspring’s neurodevelopment. Because PPIs and H2 receptor antagonists readily cross the placental barrier, they could potentially influence fetal neurodevelopment.
The link between prenatal exposure to acid-suppressive medications and major neuropsychiatric disorders is not well understood. With the use of these medications during pregnancy rising, it is important to assess their impact on children's long-term neurodevelopment. This study examined whether maternal use of acid-suppressive drugs is associated with increased risk of neuropsychiatric disorders in children, using a large, nationwide birth cohort from South Korea.
South Korea operates a single-payer health insurance system, providing coverage for over 97% of its citizens. The National Health Insurance Service (NHIS) maintains a comprehensive database with sociodemographic details, medical diagnoses, procedures, prescriptions, health examinations, and vital statistics for all insured individuals.
A Korean research team analyzed data from over three million mother-child pairs (2010–2017) to assess the risks of prenatal exposure to acid-suppressing medications. They applied propensity scoring to adjust for maternal age, number of children, medical history, and outpatient visits before pregnancy, to minimize confounding factors. That narrowed the cohort to just over 800,000 pairs, with half in the exposed group.
With these adjustments, prenatal exposure to acid-suppressing medications was associated with 14% greater likelihood of being subsequently diagnosed with ADHD.
Yet, when 151,737 exposed births were compared to the same number of sibling controls, no association was found between prenatal exposure and subsequent ADHD, which suggests unaccounted familial and genetic factors influenced the preceding results.
The Take-Away:
Evidence of these medications negatively affecting pregnancies is mixed, mostly observational, and generally reassuring when these medications are used appropriately. Untreated GERD and gastritis, however, have known risks and associations with the development of various cancers. With no evidence of an association with ADHD (or for that matter any other neuropsychiatric disorder), there is no current evidence-based reason for expectant mothers to discontinue use of acid-suppressing medications.
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