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.
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.
The aim of behavioral parent training is to improve the child’s behavior through improved parenting. Noting that “it is unknown which of its components are most effective,†a Dutch team of researchers conducted a systematic search of the peer-reviewed medical literature to identify randomized controlled trials (RCTs) suitable for meta-analysis.
Twenty-nine RCTs with a combined total of 2,345 participants met the criteria.
The team explored five types of outcome variables:
· Positive parenting: behaviors such as reinforcement, monitoring, stimulating, and guiding the child.
· Negative parenting: behaviors such as corporal punishment, harsh discipline, inconsistent parenting, and poor monitoring.
· Parenting sense of competence: the extent to which parents perceive themselves as competent or effective in raising their child.
· quality of the parent-child relationship: signs of affection, support, sensitivity, and responsiveness.
Behavioral parent training aims
· Parental mental health: measures included parenting stress and several indices of parental psychopathologies, such as depression and anxiety.
A meta-analysis of 19 RCTs with 1,070 participants found a medium effect size improvement in positive parenting. Evidence of publication bias was borderline, but a trim-and-fill adjustment still reported a medium effect size reduction in ADHD symptoms. Similarly, limiting the meta-analysis to the 12 RCTs that were probably blinded made no difference in the outcome.
A second meta-analysis, of 15 RCTs with 878 participants, found a small-to-medium effect size reduction in negative parenting, after adjusting for publication bias. Limiting the meta-analysis to the six RCTs that were probably blinded modestly increased the effect size.
After adjusting for publication bias, a meta-analysis of 13RCTs with a combined total of 783 participants reported a small-to-medium effect size improvement in the quality of parent-child relationships. Limiting the meta-analysis to the six RCTs that were probably blinded made no difference in the outcome.
After adjusting for publication bias, a meta-analysis of 17 RCTs with a combined total of 1,083 participants reported a medium effect size improvement in parent sense of competency.
Finally, with no sign of publication bias, 23 RCTs with a combined total of 1,191 participants found a small-to-medium effect size improvement in parental mental health.
The team concluded, “Parent training had robust small- medium-sized positive effects on all parental outcomes relative to control conditions, both for unblinded and probably blinded measures. … A reassuring finding was that effect sizes on positive parenting, negative parenting, and the parent-child relationship did not differ between probably blinded and unblinded measures, indicating that effects are not merely attributable to parents' investment affecting their assessment of outcome measures.â€
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 23,418IR 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.â€
On balance, this suggests MR formulations are safer, but both formulations are subject to abuse by a small minority of users.
Youths with disabilities face varying degrees of social exclusion and mental, physical, and sexual violence.
A Danish researcher used the country’s extensive national registers to explore reported sexual crimes against youths across the entire population. Of 679,683 youths born from 1984to 1994 and between the ages of seven and eighteen, 8,039 (1.2 percent) were victims of at least one reported sex crime.
The sexual offenses in question included rape, sexual assault, sexual exploitation, incest, and indecent exposure. Sexual assault encompassed both intercourse/penetration without consent or engaged in with a youth not old enough to consent (statutory rape).
The study examined numerous disabilities, including ADHD, which was the most common one. It also performed a regression analysis to tease out other covariants, such as parental violence, parental inpatient mental illness, parental suicidal behavior or alcohol abuse, parental long-term unemployment, family separation, and child in public care outside the family.
In the raw data, youths with ADHD were 3.7 times more likely to be a victim of sexual crimes than normally developing youths. That was roughly equal to the odds for youths with an autism spectrum disorder or mental retardation, but considerably higher than for blindness, stuttering, dyslexia, and epilepsy (all roughly twice as likely to be victims of such crimes), and even higher than for the loss of hearing, brain injury, or speech or physical disabilities.
Looking at covariate, family separation, having a teenage mother, or being in public care almost doubled the risk of being a victim of sexual crimes. Parental violence or parental substance abuse increased the risk by 40 percent, and parental unemployment for over 21 weeks increased the risk by 30 percent. Girls were nine times more likely to be victimized than boys. Living in a disadvantaged neighborhood made no difference, and living in immigrant neighborhoods actually reduced the odds of being victimized by about 30 percent.
After adjusting for other risk factors, youths with ADHD were still almost twice as likely to be victims of reported sex crimes than normally developing youths. All other youths with disabilities registered significantly lower levels of risk after adjusting for other risk factors: for those who were blind, 60 percent higher risk; for those with autism, hearing loss, or epilepsy, 40 percent higher risk. Communicative disabilities – speech disability, stuttering, and dyslexia – actually turned out to have protective effects.
This points to a need to be particularly vigilant for signs of sexual abuse among youths with ADHD.
Strabismus is a condition in which the eyes do not properly align with each other. It affects 1 to 5 percent of children worldwide. Exotropia, and outward deviation, are more common in Asian populations. Isotropic, an inward deviation, predominates in European and North American populations.
Besides deviated gaze, strabismus can lead to a lack of depth perception or to lazy eye (amblyopia), in which the brain favors inputs from one eye over the other). It can also impair learning performance and lead to social rejection and low self-esteem.
Two nationwide population studies published this year – one in South Korea, the other in Taiwan – explored the relationship between strabismus and ADHD. Both countries have mandatory single-payer health insurance systems. That makes it easy to conduct nationwide population studies, because virtually every resident is covered, and records are maintained consistently.
Using data from the National Health Claims Database, a Korean research team obtained a nationwide cohort of 327,076 strabismus patients who were 1 to19 year old between 2011 and 2017. They matched these by age and sex with an equal number of randomly selected controls without strabismus.
Among those with strabismus, ADHD was detected in 3.4%, whereas among those without strabismus, ADHD was detected in 2.75%.
After adjusting for continuous age, preterm birth, cerebral palsy, and mental retardation, youths with strabismus were found to be 14% more likely to be diagnosed with ADHD. This outcome was highly statistically significant (p < .0001).
There was a much stronger association with some other neurological disorders, however. Motor disorders were 3.3 times more likely among strabismus patients than controls. Language disorders were 74% more likely, learning disorders 41% more likely, and autism 36% more likely.
On the other hand, there was no significant association between the schizophrenia spectrum and other psychotic disorders, bipolar disorder, depression, or anxiety.
Like South Korea, Taiwan has a mandatory single-payer health insurance system. Almost all (99%) of the island’s more than 23 million inhabitants are tracked in the Taiwan National Health Insurance Research Database (NHIRD). A subset of this database, the Longitudinal Health Insurance Database, randomly selects a million persons from the larger database.
A local study team used the Longitudinal Health Insurance Database to identify every person 18 and under with exotropia or esotropia between 2000 and 2010. The team excluded anyone with a previous diagnosis of ADHD. For each case of exotropia or esotropia, they matched four strabismus-free controls by age and sex.
The case group totaled 2,049 youths, 404 with esotropia, and the other 1,645 with exotropia. There were 8,196 controls, for a combined total sample size of 10,245.
During the decade under observation, ADHD was diagnosed in 29 patients with esotropia, 43 patients with exotropia, and 173 patients in the control group. After further adjustment for known confounders – autism, delayed development, intellectual disability, lower respiratory tract infection, paralysis, and premature birth – strabismus patients were 64% more likely to be diagnosed with ADHD than were controls. The subset of patients with exotropia were44% more likely to be diagnosed with ADHD, and the subset with esotropia was more than twice as likely. The outcomes were highly statistically significant (p< .0001) for strabismus and for esotropia and statistically significant for exotropia (p < .01).
By way of comparison, in the Korean study which found an overall 14% increased risk of ADHD in strabismus patients, esotropia increased the risk by 20% and exotropia by 17%.[1]All outcomes were highly statistically significant (p < .0001).
Both nationwide population cohorts thus revealed highly statistically significant associations between strabismus and ADHD, and between both esotropia and exotropia on the one hand, and ADHD on the other.
Nevertheless, the magnitude of the associations with ADHD was far greater in Taiwan than in South Korea – more than four times the observed risk from strabismus overall, well over twice the risk from exotropia, and over five times the risk from esotropia. Also, whereas the Korean study indicated only a marginally higher risk of ADHD from esotropia than from exotropia, the Taiwanese study found the risk of ADHD from esotropia to be well over double the risk from exotropia. Differences in the adjustment of confounders may explain some differences.
The Taiwanese team concluded, “Our study found a higher cumulative incidence of ADHD in patients with strabismus in a large nationwide database with an average of 6.5 ± 2.9 years of follow-up. The relative risk of ADHD was higher in children with esotropia than in those with exotropia and without strabismus. Further neuroimaging or field survey studies are required to understand the underlying pathomechanisms.â€
[1] There are other subsets of strabismus, which explains why both the esotropia and exotropia risk could be marginally higher than the overall strabismus risk.
Folic acid, also known as folate, is an essential vitamin(B-9). Inadequate dietary folate has been associated with abnormal fetal brain development. That suggests a deficiency could contribute to neurodevelopmental disorders, including ADHD.
If so, could folic acid supplementation for pregnant mothers help avoid ADHD in offspring?
A Chinese study team conducted a systematic search of the peer-reviewed medical journal literature looking for studies exploring neurodevelopmental effects associated with such supplementation.
It identified six studies that specifically looked for associations with offspring ADHD. A meta-analysis of these studies encompassing a total of 29,634 participants found a 14% (one in seven) reduction in the odds of ADHD in the offspring of mothers taking folate supplementation as opposed to children of mothers not doing so.
There was no sign of either publication bias or between-study heterogeneity.
The authors concluded, “Our meta-analysis indicated that appropriate maternal FA supplementation may have positive effects on offspring's neurodevelopmental outcomes, including improved intellectual development and reduced risk of autism traits, ADHD, behavioral, and language problems.â€
Given that folate is an essential vitamin in the first place, this suggests ensuring that pregnant women supplement their diet with folic acid. The authors further counseled, “However, further high-quality studies on this topic are needed to confirm the optimal dosage and the right time of FA supplementation and to investigate the underlying mechanisms.â€
A team of Taiwanese researchers conducted a comprehensive search of the peer-reviewed literature to identify all randomized controlled trials (RCTs) performed to date exploring the efficacy of acupuncture treatment (AT) in reducing ADHD symptoms. They found ten studies with a combined total of 876 participants that met their search criteria. Seven were performed in China, one in South Korea, one in Iran, and one in the U.S. All involved youths, ranging from ages 3 to 18. All required either a DSM-IV or DSM-V diagnosis of ADHD for inclusion. The controls varied. One used waitlist. Eight compared acupuncture treatment with methylphenidate treatment, with dosages varying from as little as 10-20 mg/day to 1,020 mg/day and 1,854 mg/day. Only one study was double-blind, meaning that both participants and investigators were blinded as to who was getting which treatment. It is of course essentially impossible to blind participants in RCTs involving AT unless sham-At is used as a control. Only one RCT compared AT with sham-AT, and it was not used in either meta-analysis. Keeping these limitations in mind, a meta-analysis of the eight studies with 716 participants that compared AT with MPH found AT to be more than twice as effective in reducing ADHD symptoms as MPH. Heterogeneity between studies was low, with no sign of publication bias. However, none of these studies reported ADHD rating scale scores, an additional major limitation. Instead, because outcome measurements varied across RCTs, the authors relied on “effective rate†(ER): The evaluation was divided into cured, markedly effective, effective, and ineffective. We merged the number of “cured,†“markedly effective,†and “effective†patients to be divided by the sample size to calculate the proportion of subjects who experienced at least some improvement in their ADHD symptoms in the ER. On the other hand, a meta-analysis of three studies with 232 participants compared the effects of AT and MPH on actual hyperactivity scores and found MPH was much more effective than AT. Homogeneity was moderate, again with no sign of publication bias. The author cautioned, “The quality of the evidence was low for the ER assessment because of the selection, performance, and detection biases. For hyperactivity scores, the quality of evidence was very low because of the selection and performance biases and significant heterogeneity.†Due to the various limitations, they concluded, “AT may be more effective than methylphenidate for the treatment of ADHD in children and adolescents,†but “firm conclusions still can not be drawn.â€
Youths with ADHD are at higher risk of suicide, burn injuries, road injuries, and more generally all-cause mortality than normally developing children. Methylphenidate (MPH) is known to be effective in reducing ADHD symptoms. Can it also reduce the risk of all-cause mortality? A team of Taiwanese researchers, collaborating with two British researchers, explored that question by looking at a nationwide population cohort. Taiwan has a single-payer national health insurance system that includes the entire population (99.6 percent coverage). Using the National Health Insurance Research Database (NHIRD), the team identified over 183,000 youths under 18 with an ADHD diagnosis. Of these, just over 68,000 had been prescribed to MPH. The team matched them with an equal number of ADHD youths who were not prescribed MPH. All records were anonymized and checked against the National Mortality Register. All-cause mortality was split into two subcategories. Unnatural-cause mortality consisted of homicide, suicide, and motor vehicle fatalities. Natural-cause mortality encompassed all other premature deaths. In the raw data, ADHD youths on MPH had half the all-cause mortality of those not on MPH. Natural-cause mortality was down about 40 percent and unnatural-cause mortality was by almost two-thirds. In the non-MPH group, 32 committed suicide in the follow-up year, versus only a single individual in the MPH group. There were seven homicide victims in the non-MPH group, versus none at all in the MPH group. These staggering reductions, however, were almost exclusively among males. The team then adjusted for potential confounding variables – gender, age, residence, insurance premium, out-patient visits, and pre-existing diagnoses. In the adjusted model, the risk for all-cause mortality was still reduced – by about 20 percent – for those on MPH and remained statistically significant. Virtually identical reductions were found for males and for children first diagnosed with ADHD between 4 and 7 years old. But all other risk estimates became statistically non-significant, due in large measure to the rarity of mortality events. The authors concluded, “This is the first study reporting that a longer interval between first ADHD diagnosis and first prescription of MPH is associated with a higher risk of all-cause mortality. In addition, we also found that participants receiving longer-duration MPH treatment had a lower risk of all-cause mortality. … an implication is that receiving a diagnosis earlier and receiving medication earlier may reduce the risk of later adverse consequences.†They nevertheless cautioned, “although we adjusted for multiple covariant, information lacking in the database precluded the measurement of other possible confounders, such as family history, psychosocial stressors, the effect of behavioral therapy or severity of comorbidities. Therefore, as with all observational data, it is not possible to be conclusive about whether the association with lower mortality is related to an effect of MPH treatment itself or whether other characteristics of the children receiving MPH may account for the lower risk (i.e. confounding by indication). Finally, although the cohort sizes were large, the number of deaths was small, and this limited statistical power, particularly for the investigation of cause-specific mortality and of subgroup differences. Because of the relatively low number of deaths and limited follow-up duration, longer-term studies with larger samples are warranted …â€
Children with ADHD are at higher risk of getting severe burns than normally developing children. Burn injuries can be traumatic, imposing physical, psychological, and economic burdens on children, their families, and society. Methylphenidate is known to be effective in reducing ADHD symptoms. Can it also reduce the risk of burn injuries? A team of Taiwanese researchers collaborating with two British researchers explored that question by looking at a nationwide population cohort. Taiwan has a single-payer national health insurance system that includes the entire population (99.6percent coverage). Using Taiwan’s National Health Insurance Research Database(NHIRD), they identified over 90,000 youths under 18 years old with a diagnosis of ADHD. Youths who had burned injuries before diagnosis were excluded. ADHD youths were further divided into three groups: those not prescribed methylphenidate (over 22,000), those prescribed methylphenidate for less than90 days (over 17,500), and those prescribed methylphenidates for 90 days or more(over 50,000). Because methylphenidate is the only approved stimulant in Taiwan, it was the only stimulant analyzed in this study. Atomoxetine, a non-stimulant, is also approved in Taiwan, but only for those whose, outcomes with methylphenidate are suboptimal. It was only used by 4percent of those on ADHD medication, and generally after prior use of methylphenidate, so there was no way to evaluate its effectiveness. Among ADHD youths, not on methylphenidate, the proportion who got burn injuries was 6.7 percent. That dropped to 4.5 percent for those medicated for under 90 days, and to 2.9percent for those on longer-term medication. Calculations indicated that half of all burn injuries could have been prevented if all youths had been on methylphenidate. After adjusting for multiple confounders – seizure, intellectual disability, autism, conduct disorder, opposition defiant disorder, anxiety, depression, and psychotropic use(benzodiazepine, Z-drugs, antipsychotics, and antidepressants) – that taking methylphenidate for any length of time was 38 percent less likely to suffer burn injuries. Moreover, longer-term medication had a greater beneficial effect. Those taking methylphenidate for under 90 days were 30 percent less likely to get burn injuries, whereas those taking it for90 or more days were less than half as likely to get burn injuries, as those not on methylphenidate. The authors emphasized, “This nation-wide population-based study has several strengths. First, the nationally-representative sample was substantial and minimized selection bias. Second, patients with ADHD were identified through physician-based diagnoses. Third, all MPH [methylphenidate] prescriptions are recorded in the NHIRD, avoiding misclassification bias. Also, by excluding burn injuries before ADHD diagnosis, the reverse causal relationship between ADHD and burn injury was eliminated.â€
A team of Canadian researchers recently published the first meta-analysis of studies estimating the prevalence of ADHD in the Black population in the U.S. The overall meta-analysis combined 21 studies encompassing over 154,000 individuals of all ages, and produced an estimated prevalence of 14.5 percent. Only two studies with 1,534 individuals, a relatively small sample size, looked at adults. Moreover, three youth samples were obtained in the juvenile justice system. Because the prevalence of ADHD in the juvenile justice system is well above that in the general population (Beau dry), this would tend to bias estimates upward. Removing these studies and samples still leaves 19 studies with about 150,000 individuals. Performing a meta-analysis of these yielded a slightly lower prevalence estimate of 14percent for U.S. Black youths under 18. The authors concluded, “Contrary to what is stated in the DSM-5, the results of this systematic review and meta-analysis suggest that Black individuals are at higher risk for ADHD diagnoses than the general US population. These results highlight a need to increase AHD assessment and monitoring among Black individuals from different social backgrounds. They also highlight the importance of establishing accurate diagnoses and culturally appropriate care.â€