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July 23, 2025

Exploring The Long-term Effects of Treating ADHD with Methylphenidate

Are There Adverse Effects to Long-Term Treatment of ADHD with Methylphenidate?

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; 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 dyskinesias. 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.”

·  Seizures or 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 non-comparative studies, with 118 and 289 participants, 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 other neuropsychiatric outcomes, 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 in the evidence base, it mainly supports prior conclusions of the US Food and Drug Administration) 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.

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Advanced Economy Outlier: Even in China’s largest cities, ADHD is seldom treated with ...

Advanced Economy Outlier: Even in China’s largest cities, ADHD is seldom treated with pharmaceuticals

China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has “experienced the fastest sustained expansion by a major economy in history – and has lifted more than 800 million people out of poverty.”

China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has “experienced the fastest sustained expansion by a major economy in history – and has lifted more than 800 million people out of poverty.”

That expansion has been accompanied by major investments in medical research, and medical treatment capability, especially in the major urban centers that have spearheaded the boom. Life expectancy has risen from 71 in 2000 to 77 in 2019, nearing the U.S. level of 79.

Yet when it comes to pharmaceutical treatment of ADHD, China is an outlier, as revealed by a new study exploring the data in the two main medical insurance programs for its urban population.

The Urban Employee Basic Medical Insurance(UEBMI) covers both employers and employees in public and private workplaces, while the Urban Residents Basic Medical Insurance (BMI) covers the unemployed. As of 2014, these programs cover over 97% of urban residents. The China Health Insurance Research Association (CHIRA) database is a random sampling database from the UEBMI and UBMI databases.

The study population consisted of residents of the 63 cities in the CHIRA database from 2013 through 2017. Prescription prevalence was calculated by dividing the total number of patients prescribed ADHD medications in the CH IRA database by the urban population of the included cities, which was two hundred million as of 2017.

Other studies have found the prevalence of ADHD among Chinese children and adolescents to be about 6.5%, comparable to North American and European countries. Yet, the prescription prevalence of ADHD medications was 0.036% among those aged 0–14 years in 2017 in China. In other words, only about one in every two hundred youths with ADHD were being prescribed pharmaceutical treatments.

For further context, among other economically prosperous countries in Asia, Australia, North America, and Europe, the lowest prescription prevalence of ADHD medications is 0.27% in France, which is still over seven times higher than the Chinese level.

Among Chinese urban dwellers from 15 through 64 years of age, ADHD prescription prevalence in 2017 dropped by a further order of magnitude (over tenfold) to 0.003%, and among those 65 and older, to a scant 0.001%.

The Chinese study team suggested several likely contributing factors:

  • Lack of training in ADHD treatment among clinical practitioners;
  • Government fears of addiction have led to strict control of stimulant medications;
  • Discontinuation of methylphenidate production by Chinese pharmaceutical enterprises in 2009 meant having to purchase more expensive imported ADHD medications;
  • Widespread parental belief that ADHD is just “bad behavior,” not a disease requiring medication;
  • Parental reliance on alternative treatments, such as Traditional Chinese Medicine (TCM) 

April 2, 2022
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Daytime Sleepiness, Cognitive Function, and Adult ADHD

What’s the relationship between daytime sleepiness and cognitive functioning in adults with ADHD?

Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them.

Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them. A team of British researchers set out to see whether this association could be further confirmed with objective sleep measures, using cognitive function tests and electroencephalography (EEG).

Measured as theta/beta ratio, EEG slowing is a widely used indicator in ADHD research. While it occurs normally in non-ADHD adults at the conclusion of a day, during the day it signals excessive sleepiness, whether from obstructive sleep apnea or neurodegenerative and neurodevelopmental disorders. Coffee reverses EEG slowing, as do ADHD stimulant medications.

Study participants were either on stable treatment with ADHD medication (stimulant or non-stimulant medication) or on no medication. Participants had to refrain from taking any stimulant medications for at least 48 hours prior to taking the tests. Persons with IQ below 80 or with recurrent depression or undergoing a depressive episode were excluded.

The team administered a cognitive function test, The Sustained Attention to Response Task (SART). Observers rated on-task sleepiness using videos from the cognitive testing sessions. They wired participants for EEG monitoring.

Observer-rated sleepiness was found to be moderately higher in the ADHD group than in controls. Although sleep quality was slightly lower in the sleepy group than in the ADHD group, and symptom severity slightly greater in the ADHD group than the sleepy group, neither difference was statistically significant, indicating extensive overlap.

Omission errors in the SART were strongly correlated with sleepiness level, and the strength of this correlation was independent of ADHD symptom severity. EEG slowing in all regions of the brain was more than 50 percent higher in the ADHD group than in the control group and was highest in the frontal cortex.

Treating the sleepy group as a third group, EEG slowing was highest for the ADHD group, followed closely by the sleepy group, and more distantly by the neurotypical group. The gaps between the ADHD and sleepy groups on the one hand, and the neurotypical group on the other, were both large and statistically significant, whereas the gap between the ADHD and sleepy groups was not. EEG slowing was both a significant predictor of ADHD and of ADHD symptom severity.

The authors concluded, “These findings indicate that the cognitive performance deficits routinely attributed to ADHD … are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. … we would like to propose a simple working hypothesis that daytime sleepiness plays a major role in cognitive functioning of adults with ADHD. … As adults with ADHD are more severely sleep deprived compared to neurotypical control subjects and are more vulnerable to sleep deprivation, in various neurocognitive tasks they should manifest larger sleepiness-related reductions in cognitive performance. … One clear testable prediction of the working hypothesis would be that carefully controlling for sleepiness, time of day, and/or individual circadian rhythms would result in a substantial reduction in the neurocognitive deficits in replications of classic ADHD studies.”

March 31, 2022
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Study Finds Significant Association Between Allergies and ADHD

Nationally representative sample of almost 200,000 U.S. youths finds association between allergies and ADHD

After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.

A growing body of studies suggests a link between inflammation and autoimmune diseases on the one hand and ADHD on the other. It has been hypothesized that excessive release of cytokines (small signaling proteins that regulate immune response and inflammation and repair) and keratinocytes (skin cells) under allergic conditions may cause structural and functional changes to the nervous system and brain, which can contribute to psychiatric disorders, including ADHD.

Noting that previous studies have focused primarily on associations between ADHD and respiratory allergies(asthma) and skin allergies, a joint Chinese and American study team set out to see what, if any, association there might be with food allergies.

To this end, they turned to the national health Interview Survey (NHIS), conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. This survey relies on a very large, nationally representative sample of the U.S. population.

The study encompassed 192,573 youths aged 4 through 17 years old. Of these, 15,376 had an ADHD diagnosis, 8,603 had food allergies, 24,218 had respiratory allergies, and 18,703 had skin allergies.

After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.

How did that compare with respiratory and skin allergies? In the same study population, making identical adjustments for potential confounders, youths with respiratory allergies were 50% more likely to be diagnosed with ADHD than those without such allergies. Those with skin allergies were 65% more likely to be diagnosed with ADHD. After further mutual adjustment for other allergic conditions, those with respiratory allergies were still over a third more likely to be diagnosed with ADHD, and those with skin allergies were 50% more likely to be diagnosed with ADHD.

The authors concluded, "The current study found a significant and positive association between common allergic conditions, including food allergy, respiratory allergy, skin allergy, and ADHD in children. Although the detailed mechanisms linking food allergy and other allergic conditions to ADHD remain to be understood, physicians should be aware of the increased risk of ADHD as a comorbidity of children with allergic conditions".

March 29, 2022
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Siblings of Those With ADHD at Higher Risk for ADHD & Other Disorders

Israel-wide population study:siblings of individuals with ADHD have highly elevated risk of ADHD, slightly elevated risk of anxiety and personality disorders, no greater risk for other disorders or low IQ

Israel has a military draft that applies to males and females alike, except orthodox women and orthodox male seminary(yeshiva) students, who are exempt. Upon turning 17 every Israeli undergoes a medical review, including both a physical and psychiatric assessment, in preparation for the draft. The Draft Board Registry maintains comprehensive health information on all unselected Israelis until they turn 21. The registry also tracks all family members of draft registrants, including full siblings.

An Israeli study team used registry records from 1998 through2014 to obtain data for a total of over a million individuals (1,085,388). Because of the exemption for orthodox women, 59% were male.

The team identified 903,690 full siblings in the study population (58% males), including 166,359 male-male sibling pairs, 104,494 female-female sibling pairs, and 197,571 opposite-sex sibling pairs.

Next, the team identified all cases in the study population with a diagnosis of a psychiatric disorder, low IQ (≥2 standard deviations below the population mean), Type-1 diabetes, hernia, or hematological malignancies. It matched each case with ten age- and sex-matched controls selected at random from the study population. Then, for each case and case-matched controls, it identified all siblings.

There were 3,272 cases receiving treatment for ADHD, 2,128 with autistic spectrum disorder, 9,572 with severe/profound intellectual disability, 7,902 with psychotic disorders, 9,704 with mood disorders, 10,606with anxiety disorders, 24,815 with personality disorders, 791 with substance abuse disorders, 31,186 with low IQ, 2,770 with Type-1 diabetes, 30,199 with a hernia, and 931 with hematological malignancies.

Draftees with ADHD were five and a half times more likely to have a sibling with ADHD than controls.

There were no significant associations between ADHD and any of the somatic disorders - Type-1 diabetes, hernia, or hematological malignancies - nor between ADHD and low IQ.

There were also no significant associations between ADHD and autism spectrum disorder, severe/profound intellectual disability, mood disorders, and substance use disorders.

On the other hand, draftees with ADHD were more than 40% more likely to have siblings with anxiety or personality disorders than controls.

Surprisingly, draftees with ADHD were less than half as likely to have siblings with psychotic disorders than controls.

There were some limitations. The psychiatric classification system used by the Israeli military did not permit assessing the risk of bipolar disorder and depression separately. That meant having to use a broader category of mood disorders, including both disorders. In addition, the military diagnostic system does not allow diagnosis of comorbid psychiatric disorders in the same individual, instead of assigning only the most severe diagnosis.

March 27, 2022
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Strong Association Between Low Birth Weight and ADHD Discovered

South Korean nationwide population study finds strong association between low birth weight and subsequent ADHD

Since 1989, South Korea has had a single-payer healthcare insurance system, the Korean National Health Insurance Service. This facilitates nationwide population studies.

A South Korean study team used the national health claims database to retroactively examine the relationship between birth weight and subsequent diagnosis of ADHD for all 2.36 million children born in the country between 2008 and 2012. After excluding children who had since died, who had missing birth weight records, missing income information, or who weighed under400 grams at birth, 2,143,652 children remained in the study cohort.

Gestational age at birth was not available, so could not be taken into consideration.

To reduce the impact of confounding factors, odds ratios were adjusted for sex, history of congenital or perinatal diseases, income, and birth year.

Children with more normal birth weights in the range of 2.5 to 4 kilograms were used as the reference group.

Children with birth weights greater than this reference group were found to be no more likely to develop ADHD than those in the reference group.

At the other end of the spectrum, children with birth weights under a kilogram were 2.2 times more likely to be diagnosed with ADHD than those in the reference group.

That dropped to 1.7 times more likely for those with birth weights from 1 to 1.5 kilograms; 1.5 times more likely in the 1.5-to-2-kilogram range, and 1.4 times more likely in the 2-to-2.5-kilogram range. This dose-response curve, accelerating steeply with lower birth weights, points to a strong association.

For autism spectrum disorder (ASD), the association was even stronger. Again, there was no significant association with higher-than-normal birth weight. But children in the 2-to-2.5-kilogram range were 1.9 times as likely to be diagnosed with ASD; those in the 1.5-to-2 kilogram tranche over three times as likely; those in the 1 to 1.5-kilogram tranche five and halftime as likely, and those under 1 kilogram over ten times as likely.

The authors concluded, "In this national cohort, infants with birth weights of < 2.5 kg were associated with ADHD and ASD, regardless of perinatal history. Children born with LBW [low birth weight] need detailed clinical follow-up."

March 25, 2022
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Meta-Analysis: Is Neurofeedback A Viable Treatment For ADHD?

New meta-analysis of 17 RCTs finds no evidence of efficacy for neurofeedback treatment of ADHD

Neurofeedback, also known as EEG (electroencephalogram)biofeedback, is a treatment that seeks to alleviate symptoms of various neurological and mental health disorders, including ADHD. It does this through immediate feedback from a computer program that tracks a client's brainwave activity, then uses sound or visual signals to retrain these brain signals. This in principle enables patients to learn to regulate and improve their brain function and reduce symptoms.

An Iranian study team recently performed a systematic search of the peer-reviewed medical literature. It identified seventeen randomized-controlled trials (RCTs) of neurofeedback treatment for children and adolescents with ADHD that could be aggregated for meta-analysis.

A meta-analysis of twelve RCTs with a combined total of 740 youths looked at parent ratings of changes in hyperactivity/impulsivity symptoms, and separately of changes in inattention symptoms. In both instances, the net pooled effect centered on zero.

A meta-analysis of nine RCTs with a combined total of 787 youths examined teacher ratings. Once again, the pooled change hyperactivity/impulsivity symptoms centered on zero. For inattention symptoms, the teacher ratings centered on a tiny improvement, but it did not approach statistical significance. The 95% confidence interval stretched well into negative territory.

There was no sign of publication bias. Between-study heterogeneity, on the other hand, was high, with some small sample size RCTs pointing to reduced symptoms, and other small sample size RCTs pointing to increased symptoms. However, the RCTs with the larger sample sizes clustered close around zero effect size.

The authors concluded,"The results provide preliminary evidence that neurofeedback treatment is not an efficacious clinical method for ADHD."

March 23, 2022
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"Time-Blindness" Found to Be a Consistent Feature of ADHD

Meta-analysis finds consistent time perception impairments in persons with ADHD

An international study team conducted the first meta-analysis of studies examining differences in time perception between persons with ADHD and normally developing controls. A systematic search of the peer-reviewed medical literature identified 55 studies that could be combined into various subgroups for meta-analysis.

A meta-analysis of 25 studies with a combined 1,633 participants looking at time discrimination found a medium effect size deficit among persons with ADHD in the number of correct comparisons between the length of two signals. There was little between-study heterogeneity and no sign of publication bias.

Turning to time estimation, a meta-analysis of eight studies with a combined 1,024 participants found a small-to-medium effect size increase in absolute errors (i.e., the absolute value of deviation between the specified and the estimated time interval, representing the absolute amount of error regardless of its direction) among persons with ADHD, compared to controls. Again, there was little between-study heterogeneity and no sign of publication bias.

A meta-analysis of seven studies with combined 380 participants looked at differences in time production, in which they had to produce a previously specified time interval by pressing and holding a button. In this case, those with ADHD manifested a small effect size increase in absolute error relative to their normally developing counterparts. There was moderate between-study heterogeneity and no sign of publication bias.

Finally, a meta-analysis of 26 studies with combined 2,364 participants examined differences in time reproduction, in which they had to reproduce the duration of a previously presented stimulus by pressing and holding a button. Here, those with ADHD exhibited a medium effect size increase in absolute error. There was moderate between-study heterogeneity and no indication of publication bias.

An acknowledged limitation of these meta-analyses was the inability to assess the effects of pharmacological treatment. In addition, 84% of the studies did not report the ethnicity of participants.

The team concluded, "We found meta-analytic evidence of significant deficits in individuals with ADHD across all timing paradigms ... individuals with ADHD have difficulties to discriminate stimuli that vary from each other for only several milliseconds, and they are more variable in their time estimates of several seconds irrespective of the paradigm examined, which may both be driven by their lowered alertness levels."

They suggested that this might eventually become a criterion to help diagnose ADHD: "Our findings have possible clinical implications, albeit not currently directly applicable to the clinical practice. As timing has been proposed as an independent neuropsychological pathway to ADHD, timing tasks should be considered in the clinical assessment of ADHD to better characterize the clinical profile of the patient... To characterize further the phenotype of the patient during the diagnostic process that may deserve clinical attention, we suggest developing a tool based on the time estimation paradigm. The time estimation accuracy score not only represents an intuitive score reflecting faster internal clock mechanisms in individuals with ADHD, but the paradigm also shows high internal consistency and test-retest reliability, allowing for a reliable assessment of developmental or interventional changes in timing abilities related to developmental factors or external interventions."

March 21, 2022
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Significant Association Found Between Type 1 Diabetes and ADHD

Nationwide population-based cohort study finds very strong association between type 1 diabetes and ADHD

Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic.

Taiwan has a mandatory single-payer universal health insurance system, the National Health Insurance (NHI), that records diagnoses and prescriptions across virtually the entire resident population. Out of the roughly 28 million residents covered by NHI, a randomly assigned sample of 3 million is tracked in the Taiwan National Health Insurance Research Database(NHIRD).

Expert panels have to confirm all diagnoses of severe systemic autoimmune diseases, ensuring a high level of accuracy.

A Taiwanese study team availed itself of these records to explore the link between type 1 diabetes mellitus (T1DM) and ADHD. ADHD diagnoses were made by board-certified psychiatrists, based on comprehensive interviews and clinical judgment.

The team found a total of 6,226 cases diagnosed with T1DM in the decade from 2001 through 2010 and followed them through the end of 2001. It matched each case with ten age- and sex-matched non-T1DM controls from the same database, for a total of 62,260 controls.

Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic. There was no difference in the risk ratio between youth and adults. The risk of ADHD among females with T1DM was only slightly lower than among males: sevenfold greater, rather than 8.5 times greater.

The authors concluded, "Our findings indicate the importance of the close monitoring of the mental health condition of patients with T1DM by clinicians ... The exact path of mechanisms between T1DM and major psychiatric disorders should be elucidated in future studies."

March 19, 2022
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Cognitive Treatment for ADHD Symtoms May Be Uneffective

Meta-analysis finds no significant effect of cognitive treatment on ADHD symptoms and executive functioning when randomized controlled trials are blinded

A Chinese study team performed a systematic search of peer-reviewed journal literature to identify randomized controlled trials (RCTs) examining the efficacy of cognitive training as a treatment for youths with ADHD.

Seventeen RCTs with a combined total of 1,075 participants met standards for inclusion in a series of meta-analyses. Seven RCTs used waitlist controls, seven used placebo training, two used treatment-as-usual, and one used active knowledge training. Participants were unmediated in four RCTs, with varying proportions of medicated participants in the remaining thirteen.

A meta-analysis of 15 RCTs, with a combined 789 participants, assessed changes in inattention symptoms following treatment, as rated by parents or clinicians. It found a small-to-medium effect size improvement in symptoms of inattention. There was no indication of publication bias, but between-study heterogeneity was very high.

But that gain vanished altogether when combining only the six RCTs that were blinded, meaning the symptom evaluators had no idea which participants had received cognitive treatment and which participants had not. There was zero difference between the treatment and control groups. Significantly, between-study heterogeneity also diminished markedly, becoming low to moderate.

A second meta-analysis, of 15 RCTs with a combined 723 participants, assessed changes in hyperactivity/impulsivity symptoms following treatment, as rated by parents or clinicians. It found no significant difference between participants who received cognitive training and controls. There was no sign of publication bias, and between-study heterogeneity was moderate-to-high.

The three remaining meta-analyses looked for improvements in executive functions, using the Behavior Rating Inventory of Executive Function (BRIEF).

A meta-analysis of 13 RCTs, with a combined 748 participants, found a small-to-medium effect size improvement in the global executive composite index of BRIEF, as evaluated by parents. There was no sign of publication bias, and between-study heterogeneity was moderate-to-high.

But that improvement again disappeared altogether when considering only the five RCTs that were blinded. Between-study heterogeneity also became insignificant.

A meta-analysis of 6 RCTs with 401 participants found no significant improvement in the behavioral regulation index of BRIEF. Heterogeneity was negligible.

Finally, a meta-analysis of 7 RCTs with 463 participants also found no significant improvement in the metacognition index of BRIEF. In this case, between-study heterogeneity was high.

While acknowledging that "when analyses were set in blinded measures, effect sizes were not statistically significant," the author nevertheless concluded, "In summary, multiple cognitive training alleviates the presentation of inattention and improves general executive function behaviors in children with ADHD." This suggests an underlying bias on the part of the study team in favor of treatment even when not supported by best (i.e., blinded) methodological practices.

March 17, 2022
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Risk of Unnatural Death Tripled in Those with ADHD

Meta-analysis finds no significant increase in natural mortality, but almost tripled risk of unnatural death, in persons with ADHD

A meta-analysis of eight studies with a combined total of over 396,000 persons with ADHD reported a twofold greater risk of premature death in persons with ADHD as compared with the general population. There was no significant difference in mortality between males and females with ADHD.

But when natural causes of death, primarily disease, were distinguished from unnatural causes, such as injuries and poisoning, virtually all the increased risk was attributable to the latter.

A meta-analysis of four studies with a combined total of over 394,000 participants with ADHD found no significant increase in natural mortality among persons with ADHD. This held for both males and females.

But a meta-analysis of ten studies with over 430,000 persons with ADHD found a nearly threefold increase in unnatural mortality (injuries, poisoning, etc.) in persons with ADHD. Among females (five studies, over 110,000 participants) the increase was threefold. Males with ADHD (five studies, over 310,000 participants) were 2.5 times more susceptible to premature death.

An important caution: in all of these meta-analyses, between-study heterogeneity was extreme, meaning there was little consistency from one study to the next. Moreover, no effort was made to evaluate the likelihood of publication bias.

The largest study, with over 275,000 participants with ADHD, found a negligible and only marginally significant 7% increased all-cause risk of death. It found no increase in natural causes of mortality, but a 50% increase in unnatural causes of premature mortality.

The authors described these results as "suggestive," but emphasized that "the evidence was judged as only low confidence," in line with "inconsistent" evidence from previous nationwide population studies: in Denmark, a twofold increase in all-cause mortality; in Sweden, a fourfold increase; but in Taiwan, a tiny 7% increase that was at the limit of statistical significance, once the data was fully adjusted for confounding factors.

That led the authors to suggest "that all relevant potential confounders should be accounted for" in "future studies."

March 15, 2022
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