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
Given the persistence of ADHD and its adverse effects on children and adolescents, one might expect caregivers to face greater parenting challenges, with potential effects on their own mental health.
To what extent do parenting stress, depression, and – at the extreme – even suicidal ideation manifest themselves among caregivers of ADHD patients as opposed to caregivers of children and adolescents without ADHD?
A pair of Korean researchers made use of their country’s single-payer health insurance system, which maintains records on virtually the entire population, to perform a nationwide population study. They used data from the Korean National Health and Nutrition Examination Surveys (KNHANES) covering the decade from 2011 to 2020. KNHANES is an annual survey using a sophisticated sampling design conducted by the Korean Ministry of Health and Welfare to represent the entire population of South Korea.
The analysis included 14,428 individuals who had children younger than 19 at the time of participation. All were asked whether their child had ever been diagnosed with ADHD by a physician. The mental health problems of the parents were assessed in terms of perceived stress, depressive symptoms, and suicidality.
Of the 14,428 participants, 8,298 (57.5 %) were mothers and 6,130 (42.5 %) were fathers. Of the mothers, 116 (1.4 %) had a child with ADHD, and of the fathers, 86 (1.4 %) had a child with ADHD.
The researchers adjusted for the following confounders: age of caregiver, education level, household income, area of residence, employment status, alcohol consumption, smoking status, cohabitation status, number of children, and child’s age.
After adjustment, mothers of ADHD patients fared significantly worse than mothers of typically developing children on all three categories of mental health problems. They were 67% more likely to report higher stress, three times as likely to report symptoms of depression, and 2.5 times more likely to report suicidal ideation.
Yet that pattern did not carry over to fathers, where there was no significant difference in mental health indicators between fathers of children with ADHD and fathers of children without ADHD.
The authors concluded, “Parents of children with ADHD, especially mothers, need community support and public health attention to help alleviate their mental health problems.”
Background:
ADHD is commonly accompanied by psychiatric comorbidities that complicate its diagnosis and treatment. Roughly two out of three affected children and adolescents have one or more comorbid psychiatric disorder.
Because the peak age of ADHD onset is typically a decade or more earlier than those for schizophrenia, depressive disorder, or bipolar disorder, it is essential to explore these comorbidities over an extended period. Populations studies help researchers identify broader patterns and trends within an entire population and includes adults as well as children. This type of study provides unique insights into the population at large, rather than a sample group.
In earlier studies the maximum follow-up period was twelve years, insufficient in view of the roughly ten years between onset of ADHD and onset of major psychiatric disorders. Also, previous nationwide population studies have included less than 150,000 participants.
This study, relying on data from South Korea’s universal single-payer health insurance system, included over one and a half million individuals. Persons previously diagnosed with depression, bipolar disorder, tic disorder, or schizophrenia were excluded.
382,434 individuals had been diagnosed with ADHD, while 1,169,279 were without an ADHD diagnosis.
Propensity score matching ensured that potential confounders, both sociodemographic and clinical, were equalized for the ADHD and control groups. After matching, there were 353,898 individuals in each group.
After these adjustments, individuals in the ADHD group were at least an order of magnitude more likely to subsequently be diagnosed with psychiatric disorders than their peers without an ADHD diagnosis:
Conclusion:
The Korean study team concluded, “Overall, our findings suggest that upon prolonged examination, the risk of subsequent diagnoses of other psychiatric disorders in individuals with ADHD appears to be higher than that reported previously. … Therefore, patients with ADHD should be carefully screened for the presence of other psychiatric symptoms on a regular basis from an earlier age … It is advisable to have a follow-up period extending beyond 10 years to sufficiently identify the occurrence of comorbid disorders in patients with ADHD.”
Children with ADHD often face challenges in social interactions, leading to long-term consequences if not properly addressed. While various interventions exist, many fail to consider the broader social context in which these children interact. A recent study conducted in Bergen, Norway, explored how primary school teachers perceive their role in supporting children with ADHD who struggle socially and the strategies they use to assist them.
Researchers conducted semi-structured interviews with five focus groups of primary school teachers. Using reflexive thematic analysis, they identified two major themes:
Rather than relying on standardized interventions, teachers tailored their strategies to foster an inclusive and supportive social environment. Their methods included both active participation in social situations and behind-the-scenes efforts to encourage peer inclusion and understanding.
This study underscores the need to move beyond labels and recognize children with ADHD as individuals with distinct social needs. Teachers play a crucial role in shaping these children’s experiences, using flexible and personalized approaches to promote positive social interactions. By integrating social context and individualized support, educators can help children with ADHD build meaningful connections and navigate their social world more effectively.
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