August 25, 2021
Methylphenidate (MPH) is one of the most widely-prescribed medications for children. Given that ADHD frequently persists over a large part of an individual's lifespan, any side effects of medication initiated during childhood may well be compounded over time. With funding from the European Union, a recently released review of the evidence looked for possible adverse neurological and psychiatric outcomes.
From the outset, the international team recognized a challenge: ADHD severity may be an important potential confounder, as it may be associated with both the need for long-term MPH therapy and high levels of underlying neuropsychiatric comorbidity. Their searches found a highly heterogeneous evidence base, which made meta-analysis inadvisable. For example, only 25 of 39 group studies reported the presence or absence of comorbid psychiatric conditions, and even among those, only one excluded participants with comorbidities. Moreover, in only 24 of 67 studies was the type of MPH used (immediate or extended-release) specified. The team, therefore, focused on laying out an evidence map to help determine priorities for further research.
The team found the following breakdown for specific types of adverse events:
· Low mood/depression. All three non-comparative studies found MPH safe. Two large cohort studies, one with over 2,300 participants, and the other with 142,000, favored MPH over the non-stimulant atomoxetine. But many other studies, including a randomized controlled trial (RCT), had unclear results. Conclusion: the evidence base regarding mood outcomes from long-term MPH treatment is relatively strong, includes two well-powered comparative studies, and tends to favor MPH.
· Anxiety. Here again, all three non-comparative studies found MPH safe. But only two of seven comparative studies favored MPH, with the other five having unclear results. Conclusion: while the evidence about anxiety as an outcome of long-term MPH treatment tends to favor MPH, the evidence base is relatively weak.
· Irritability/emotional reactivity. A large cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: the evidence base is limited, although it includes one well-powered study that found in favor of MPH over atomoxetine.
· Suicidal behavior/ideation. There were no non-comparative studies, but all five comparative studies favored MPH. That included three large cohort studies, with a combined total of over a hundred thousand participants, that favored MPH over atomoxetine. Conclusion: the evidence base is relatively strong, and tends to favor MPH.
· Bipolar disorder. A very large cohort study, with well over a quarter-million participants, favored MPH over atomoxetine. A much smaller cohort study comparing MPH with atomoxetine, with less than a tenth the number of participants, pointed toward caution. Conclusion: the evidence base is limited and unclear, although it includes two well-powered studies.
· Psychosis/psychotic-like symptoms. By far the largest study, with over 145,000 participants, compared MPH with no treatment, and pointed toward caution. A cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: These findings indicate that more research is needed into the relationship between ADHD and psychosis, and into whether MPH moderates that risk, as well as research into individual risk factors for MPH-related psychosis in young people with ADHD.
· Substance use disorders. A cohort study with over 20,000 participants favored MPH over anti-depressants, anti-psychotics, and no medication. Other studies looking at dosages and durations of treatment, age at treatment initiation, or comparing with no treatment or alternative treatment, all favored MPH except a single study with unclear results. Conclusion: the evidence base is relatively strong, includes one well-powered study that compared MPH with antipsychotic and antidepressant treatment, and tends to favor MPH.
· Tics and other dyskinetic. Of four non-comparative studies, three favored MPH, the other, with the smallest sample size, urged caution. In studies comparing with dexamphetamine, pemoline, Adderall, or no active treatment, three had unclear results and two pointed towards caution. Conclusion: more research is needed regarding the safety and management of long-term MPH in those with comorbidities or tic disorder.
· Seizuresor EEG abnormalities. With one exception, the studies had small sample sizes. The largest, with over 2,300 participants, compared MPH with atomoxetine, with inconclusive results. Two small studies found MPH safe, one had unclear results, and two others pointed towards caution. Conclusion: While the evidence is limited and unclear, the studies do not indicate evidence for seizures as an AE of MPH treatment in children with no prior history more research is needed into the safety of long-term MPH in children and young people at risk of seizures.
· Sleep Disorders. All three non-comparative studies found MPH safe, but the largest cohort study, with over 2,300 participants, clearly favored atomoxetine. Conclusion: more research is needed into the relationship between ADHD, sleep, and long-term MPH treatment.
· Other notable psychiatric outcomes. Two noncomparative studies, with 118 and 289participants, found MPH safe. A cohort study with over 700 participants compared with atomoxetine, with inconclusive results. Conclusion: there is limited evidence regarding long-term MPH treatment and another neuropsychiatric outcome, and that further research may be needed into the relationship between long-term MPH treatment and aggression/hostility.
Although this landmark review points to several gaps sins in the evidence base, it mainly supports prior conclusions of the US Food antidrug Administration (FDA) and other regulatory agencies (based on short-term randomized controlled trials) that MPH is safe for the treatment of ADHD in children and adults. Given that MPH has been used for ADHD for over fifty years and that the FDA monitors the emergence of rare adverse events, patients, parents, and prescribers can feel confident that the medication is safe when used as prescribed.
Helga Krinzinger, Charlotte L Hall, Madeleine JGroom, Mohammed T Ansari, Tobias Banaschewski, Jan K Buitelaar, Sara CarucciDavid Coghill, Marina Danckaerts, Ralf W Dittmann, Bruno Falissard, PeterGaras, Sarah K Inglis, Hanna Kovshoff, Puja Kochhar, Suzanne McCarthy, PeterNagy, Antje Neubert, Samantha Roberts, Kapil Sayal, Edmund Sonuga-Barke , Ian CK Wong , Jun Xia, Alexander Zuddas, Chris Hollis, Kerstin Konrad, Elizabeth Biddle and the ADDUCE Consortium,Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence, Neuroscience and Biobehavioral Reviews(2019)DOI:https://doi.org/10.1016/j.neubiorev.2019.09.023
Maternal infections and inflammatory responses during pregnancy have been proposed as risk factors for neurodevelopmental disorders such as ADHD.
Taiwan has a single-payer health insurance system that covers virtually the entirety of its population. Its Ministry of Health and Welfare maintains the National Health Insurance Research Database (NHIRD), with detailed information on outpatient services, hospitalizations, and medical treatment for nearly 99% of all residents.
A Taiwanese study team used NHIRD to examine to examine the relationship between maternal hospitalization for infection, and early childhood infection, and subsequent ADHD in offspring. The study cohort originated with all 3,260,879 individuals born between 2001 and 2018.
The team excluded births from foreign mothers, still births, births with congenital defects, low birth weights, abnormally late births, twins, triplets, and other multiple births, culminating in a final population cohort of 2,885,662 live-born single infants across 1,893,171 families, and 1,864,660 individuals with full siblings from 872,169 families comprising the full sibling cohort.
Study participants were followed until diagnosis of a neurodevelopmental disorder, their death, or the end of 2021.
After adjusting for sex, birth year, paternal and maternal ages, birthweight, birth season, parity, delivery method, 1 minute APGAR score (evaluating baby’s appearance, pulse, grimace, activity and respiration at birth), gestational age, pregnancy and delivery complications, parental history of neurodevelopmental disorders, maternal asthma and diabetes, urbanization level of the residential area, and family’s insurance amount, offspring of mothers hospitalized for infections had 14% greater odds of being subsequently diagnosed with ADHD.
However, in the full sibling cohort of over 1.8 million, this association vanished. That held true for each of the three trimesters of pregnancy. It also held true for bacterial infections. Surprisingly, offspring of mothers hospitalized for viral infections were 24% less likely to be diagnosed with ADHD than their siblings not exposed to maternal viral infection. Because of that, they also had a 6% lower risk overall.
After the same adjustments, early childhood infection was associated with 16% greater odds of being diagnosed with ADHD.
Nevertheless, in the full sibling cohort of over 1.8 million, this association again vanished. That held true overall, as well as separately for childhood infections in months 1-6 and months 7-12. The association vanished altogether both for bacterial infections as well as for viral infections.
The authors concluded, “the results of this nationwide birth cohort study with population and sibling analyses suggest that the association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors.”
Most previous studies of suicide and self-harm risk among persons with ADHD have focused on adolescents and adults. They’ve also tended to be cross-sectional, analyzing data from a population at a specific point in time.
An Australian study team took a different approach, conducting a before-and-after study through the birth cohort of the Longitudinal Study of Australian Children (LSAC), comprising 5,107 children who have been followed up every two years since birth.
The diagnosis of ADHD was based on parents reporting that their child had received a diagnosis of ADHD at or before age ten.
Suicide and self-harm were defined as children’s self-report at age 14 of any thought or attempt of suicide and self-harm respectively over the past year.
The team adjusted for the following confounders: socioeconomic status, birth weight, ADHD medication history, maternal education level, maternal age at birth, experience in bullying victimization at age 12, and depression score based on Short Mood and Feelings Questionnaire (SMFQ).
Of the 5,107 participants, 3,696 had all the valid data required for analysis and were included in the final cohort. Of these, 3.6% were diagnosed with ADHD by age 10.
With diagnosis of ADHD at age 10 and all other factors held constant:
Both depression and exposure to bullying were statistically significant mediators for the relationship. Nevertheless, depression and exposure to bullying each accounted for well under 10% of the overall effect.
Neither socioeconomic status nor maternal factors had any significant mediating effect on outcomes.
Conclusion:
The authors concluded, “This study provides compelling evidence that children diagnosed with ADHD at the age of 10 years face significantly elevated risks of experiencing suicidal thoughts, planning, or attempts, as well as self-harm, by the age of 14 years, which underscores the critical importance of recognizing and addressing these heightened risks in children with ADHD.”
While factors like depression and bullying contribute, ADHD itself remains a key risk factor. Early intervention and strong mental health support are crucial to protecting these children’s well-being.
Noting that “Recent research has demonstrated that some gut bacteria can affect the nervous system,” and speculating that “dysregulation in the gut microbiota may increase the incidence of ADHD by overproducing reactive oxygen and nitrogen species, thereby causing neuroinflammation and oxidative stress”, a Taiwanese study team decided to explore whether early-life use of antibiotics – in the first two years – is associated with increased risk of subsequent diagnosis of ADHD.
Because Taiwan has a single-payer national health insurance system that covers 99.8% of the island’s population, they were able to use the system’s National Health Insurance Research Database (NHIRD) and Maternal and Child Health Database (TMCHD) to include all 1.6 million children born between 2004 and 2012.
Of these, a little over 1.1 million were given antibiotics before turning two years old, and just over 460,000 were not given antibiotics in the same time frame.
The mean follow-up period for records of subsequent ADHD diagnoses was seven years.
The team adjusted for confounding variables: sex, gestational age at birth (weeks), and birth weight (grams) of the children, and age at birth (years), insurance amount (New Taiwan Dollar (TWD)), insurance location, method of delivery, comorbidities, and medication used during pregnancy.
With these adjustments, early-life antibiotics use was associated with a 12% increase in likelihood of being subsequently diagnosed with ADHD.
However, looking at the effects of antibiotics as an undifferentiated grouping turned out to be misleading, because the association was limited to only some classes of antibiotics.
Penicillins were associated with a 22% increase in risk of subsequent ADHD diagnosis, cephalosporins with a 10% increase.
On the other hand, there was absolutely no such association for tetracyclines, macrolides, and quinolones.
The Take-Away:
This study found that children in Taiwan who took certain types of antibiotics before age 2 had a slightly higher risk of developing ADHD later in life. More work is needed to determine if this finding is due to unmeasured confounding before a causal link can be concluded.
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