May 31, 2021
To what extent are ADHD medications insufficiently used to address properly diagnosed ADHD? To what extent are they misused by persons who are either undiagnosed or improperly diagnosed? In search of answers, an international team of researchers from Brazil, the United Kingdom, and the United States conducted a systematic review of the peer-reviewed literature and a meta-analysis of studies from four continents - South America, North America, Europe, and Australia.
The benchmarks set for proper ADHD diagnosis were any of the following:
· Criteria established in the Diagnostic and Statistical Manual of Mental Disorders (DSM)or the International Statistical Classification of Diseases and Related Health Problems (ICD), confirmed by validated diagnostic instruments or clinical interviews.
· Use of validated ADHD symptom scales with pre-specified thresholds.
· Participants or caregivers affirming ADHD diagnosis by a physician.
Medications reviewed were those recommended by the majority of the international guidelines-both stimulant(methylphenidate, dexmethylphenidate, amphetamines), and non-stimulant (atomoxetine).
The team excluded studies relying on the insurance health system and third-party reimbursement datasets because the focus was on rates of ADHD medication use in the entire population rather than among individuals searching for treatment.
A meta-analysis of 18 studies with a total of 3,311 children and adolescents properly diagnosed with ADHD in seven countries on four continents (Canada, United States, Australia, Brazil, Netherlands, England, Venezuela) found an overall pharmacological treatment rate of only 19%. There was considerable variation, with the highest treatment rates in the United States (frequently over 40%) and the lowest treatment rates in Brazil, Venezuela, and Canada (under 10%). There was no sign of publication bias.
A second meta-analysis pooled 14 studies with a total of 29,559 children and adolescents without a proper diagnosis of ADHD in five countries on four continents (United States, Canada, Venezuela, Australia, Netherlands). Roughly 1% were using ADHD medications. Again, there was considerable variation, with the highest rates of medication misuse being reported in the United States and Venezuela (3-7%). Again, there was no sign of publication bias.
The authors cautioned, "it is important to note that even though the data collected constitute the most comprehensive evidence available in the literature and response/completion rates observed are acceptable, it does not constitute a world representative sample." Also, the predominance of samples from prosperous countries "most certainly inflates the treatment rates due to the exclusion of a large proportion of the world population with significant financial, cultural, and health access barriers to ADHD treatment."
They concluded, "Despite these limitations, our meta-analysis provides evidence for substantial under-treatment of children and adolescents affected by ADHD in different countries. This is a relevant public health issue worldwide since ADHD under treatment is associated with known negative outcomes in education, healthcare, and productivity systems. At the same time, we found evidence of overtreatment/misuse in individuals without a formal ADHD diagnosis. This practice might expose individuals to undesirable side effects of medications, increased risk of medication misuse, and unmeasured costs for the health care system."
RafaelMassuti, Carlos RenatoMoreira-Maia, FaustoCampani, MárcioSônego, JuliaAmaro, GláuciaChiyokoAkutagava-Martins, LucaTessari, Guilherme V.Polanczyk, SamueleCortese, Luis Augusto Rohde, “Assessing undertreatment and overtreatment/misuse of ADHD medications in children and adolescents across continents: A systematic review and meta-analysis,” Neuroscience &Biobehavioral Reviews(2021), Vol. 128, 64-73, published online ahead of print, https://doi.org/10.1016/j.neubiorev.2021.06.001.
A Chinese research team performed two types of meta-analyses to compare the risk of suicide for ADHD patients taking ADHD medication as opposed to those not taking medication.
The first type of meta-analysis combined six large population studies with a total of over 4.7 million participants. These were located on three continents - Europe, Asia, and North America - and more specifically Sweden, England, Taiwan, and the United States.
The risk of suicide among those taking medication was found to be about a quarter less than for unmediated individuals, though the results were barely significant at the 95 percent confidence level (p = 0.49, just a sliver below the p = 0.5 cutoff point). There were no significant differences between males and females, except that looking only at males or females reduced sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications produced divergent outcomes. A meta-analysis of four population studies covering almost 900,000 individuals found stimulant medications to be associated with a 28 percent reduced risk of suicide. On the other hand, a meta-analysis of three studies with over 62,000 individuals found no significant difference in suicide risk for non-stimulant medications. The benefit, therefore, seems limited to stimulant medication.
The second type of meta-analysis combined three within-individual studies with over 3.9 million persons in the United States, China, and Sweden. The risk of suicide among those taking medication was found to be almost a third less than for unmediated individuals, though the results were again barely significant at the 95 percent confidence level (p =0.49, just a sliver below the p = 0.5 cutoff point). Once again, there were no significant differences between males and females, except that looking only at males or females reduced the sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications once again produced divergent outcomes. Meta-analysis of the same three studies found a 25 percent reduced risk of suicide among those taking stimulant medications. But as in the population studies, a meta-analysis of two studies with over 3.9 million persons found no reduction in risk among those taking non-stimulant medications.
A further meta-analysis of two studies with 3.9 million persons found no reduction in suicide risk among persons taking ADHD medications for 90 days or less, "revealing the importance of duration and adherence to medication in all individuals prescribed stimulants for ADHD."
The authors concluded, "exposure to non-stimulants is not associated with a higher risk of suicide attempts. However, a lower risk of suicide attempts was observed for stimulant drugs. However, the results must be interpreted with caution due to the evidence of heterogeneity ..."
With the growth of the Internet, we are flooded with information about attention deficit hyperactivity disorder from many sources, most of which aim to provide useful and compelling "facts" about the disorder. But, for the cautious reader, separating fact from opinion can be difficult when writers have not spelled out how they have come to decide that the information they present is factual.
My blog has several guidelines to reassure readers that the information they read about ADHD is up-to-date and dependable. They are as follows:
Nearly all the information presented is based on peer-reviewed publications in the scientific literature about ADHD. "Peer-reviewed" means that other scientists read the article and made suggestions for changes and approved that it was of sufficient quality for publication. I say "nearly all" because in some cases I've used books or other information published by colleagues who have a reputation for high-quality science.
When expressing certainty about putative facts, I am guided by the principles of evidence-based medicine, which recognizes that the degree to which we can be certain about the truth of scientific statements depends on several features of the scientific papers used to justify the statements, such as the number of studies available and the quality of the individual studies. For example, compare these two types of studies. One study gives drug X to 10 ADHD patients and reported that 7 improved. Another gave drug Y to 100 patients and a placebo to 100 other patients and used statistics to show that the rate of improvement was significantly greater in the drug-treated group. The second study is much better and much larger, so we should be more confident in its conclusions. The rules of evidence are fairly complex and can be viewed at the Oxford Center for Evidenced Based Medicine (OCEBM;http://www.cebm.net/).
The evidenced-based approach incorporates two types of information: a) the quality of the evidence and b) the magnitude of the treatment effect. The OCEBM levels of evidence quality are defined as follows (higher numbers are better:
Non-randomized, controlled studies. In these studies, the treatment group is compared to a group that receives a placebo treatment, which is a fake treatment not expected to work.
It is possible to have high-quality evidence proving that a treatment works but the treatment might not work very well. So it is important to consider the magnitude of the treatment effect, also called the "effect size" by statisticians. For ADHD, it is easiest to think about ranking treatments on a ten-point scale. The stimulant medications have a quality rating of 5 and also have the strongest magnitude of effect, about 9 or 10.Omega-3 fatty acid supplementation 'works' with a quality rating of 5, but the score for the magnitude of the effect is only 2, so it doesn't work very well. We have to take into account patient or parent preferences, comorbid conditions, prior response to treatment, and other issues when choosing a treatment for a specific patient, but we can only use an evidence-based approach when deciding which treatments are well-supported as helpful for a disorder.
Older adults are at greater risk for cardiovascular disease. Psychostimulants may contribute to that risk through side effects, such as elevation of systolic blood pressure, diastolic blood pressure, and heart rate.
On the other hand, smoking, substance abuse, obesity, and chronic sleep loss - all of which are associated with ADHD - are known to increase cardiovascular risk, and stimulant medications are an effective treatment for ADHD.
So how does this all shake out? A Dutch team of researchers sets out to explore this. Using electronic health records, they compared all 139 patients 55 years and older at PsyQ outpatient clinic, Program Adult ADHD, in The Hague. Because a principal aim of the study was to evaluate the effect of medication on cardiovascular functioning after first medication use, the 26 patients who had previously been prescribed ADHD medication were excluded from the study, leaving a sample size of 113.
The ages of participants ranged from 55 from 79, with a mean of 61. Slightly over half were women. At the outset, 13 percent had elevated systolic and/or diastolic blood pressure, 2 percent had an irregular heart rate, 15 percent had an abnormal electrocardiogram, and 29 percent had some combination of these (a "cardiovascular risk profile"), and 21 percent used antihypertensive medication.
Three out of four participants had at least e comorbid disorder. The most common are sleep disorders, affecting a quarter of participants, and unipolar mood disorders (depressive or more rarely manic episodes, but not both), also affecting a quarter of participants.
Twenty-four patients did not initiate pharmacological treatment. Of the 89 who received ADHD medication, 58 (65%) reported positive effects, and five experienced no effect. Thirty-eight (43%) discontinued ADHD medication while at the clinic due to lack of effect or to side effects. The most commonly reported positive effects were enhanced concentration, more overview, less restlessness, more stable mood, and having more energy. The principal reasons for discontinuing medication were anxiety/depression, cardiovascular complaints, and lack of effect.
Methylphenidate raised heart rate and lowered weight, but had no significant effect on systolic and diastolic blood pressure. Moreover, there was no significant correlation between methylphenidate dosage and any of these variables, nor between methylphenidate users taking hypertensive medication and those not taking such medication. There was no significant difference in systolic or diastolic blood pressure and heart rate before and after the use of methylphenidate among patients with the cardiovascular risk profiles.
Systolic blood pressure rose in ten out of 64 patients, with two experiencing an increase of at least 20 mmHg. It descended in five patients, with three having a decrease of at least 20 mmHg. Diastolic blood pressure rose by at least 10 mmHg in four patients, while dropping at least 10 mmHg in five others.
The authors concluded "that the use of a low dose of ADHD-medication is well tolerated and does not cause clinically significant cardiovascular changes among older adults with ADHD, even among those with an increased cardiovascular risk profile. Furthermore, our older patients experienced significant and clinically relevant improvement of their ADHD symptoms using stimulants, comparable with what is found among the younger age group," and that "the use of methylphenidate may be a relatively safe and effective treatment for older adults with ADHD, under the condition that all somatic complaints and especially cardiovascular parameters are monitored before and during pharmacological treatment."
Yet they cautioned that "due to the observational nature of the study and the lack of a control group, no firm conclusions can be drawn as to the effectiveness of the stimulants used. ... Important factors that were not systematically reported were the presence of other risk factors, such as smoking, substance (ab)use, aspirin use, and level of physical activity. In addition, the response to medication was not systematically measured"
Background:
Noting that “the results of previous investigations into the therapeutic benefits of probiotics in the treatment of ADHD symptoms remain inconsistent,” a Taiwanese study team conducted a systematic search of the peer-reviewed medical literature to perform a meta-analysis.
The Study:
The team identified seven randomized controlled trials (RCTs) that met criteria for inclusion: focusing on children and adolescents under 18, with ADHD diagnoses, comparing probiotic interventions with placebo, and using standardized behavioral rating scales to assess ADHD symptoms.
Meta-analysis of these seven RCTs with a combined total of 342 participants found no significant improvement in ADHD symptoms. In fact, six of the seven RCTs clustered tightly around zero effect, while the seventh – a small sample (38) outlier – reported a very large effect size improvement.
Meta-analysis of the three RCTs with a combined 154 individuals that used probiotics with single strains of microorganisms showed absolutely no improvement in ADHD symptoms with no between-study variation (heterogeneity).
Meta-analysis of the four RCTs with a total of 188 participants that used multiple strains pointed to a medium – but statistically nonsignificant – effect size improvement, with high heterogeneity. Removing the previously mentioned outlier RCT collapsed the effect size to zero.
Two of the RCTs (with 72 total individuals), including the outlier, offered probiotics in conjunction with methylphenidate treatment. Meta-analysis of the other five RCTs with 270 persons that were structured around pure supplementation yielded absolutely no improvement in ADHD symptoms with no heterogeneity.
Meta-analyses of the four RCTs with a combined total of 238 participants that examined ADHD subtypes reported no effect on either inattention symptoms or hyperactivity/impulsivity symptoms.
Trivially, given the lack of efficacy, probiotic regimens were tolerated as well as placebo.
The Take-Away:
Ultimately, this meta-analysis found no evidence that probiotics improve ADHD symptoms in children and adolescents. Across seven randomized controlled trials, results consistently showed no significant benefit compared to a placebo. While probiotics were well-tolerated, they did not meaningfully impact inattention, hyperactivity, or impulsivity. These findings suggest that probiotics, whether single or multi-strain, are not an effective treatment for ADHD.
Background:
Noting that “Previous research has demonstrated that attention significantly influences various domains such as language, literacy, and mathematics, making it a crucial determinant of academic achievement,” an international study team performed a comprehensive search of the peer-reviewed medical literature for studies evaluating effects of physical activity on attention.
The Study:
The team’s meta-analysis of ten studies with a combined total of 474 participants found moderate reductions in attention problems following physical activity. They found no significant evidence of publication bias, but there was considerable variation in outcomes between studies (heterogeneity).
To tease out the reasons for this variability, the team looked at specific attributes of the physical activity regimens used in the studies.
The seven studies with 168 participants that involved mentally engaging physical activity reported large reductions in attention problems, whereas the three studies with 306 persons that used aerobic exercise found no reduction whatsoever. Heterogeneity in the former was reduced, in the latter all but disappearing.
Comparing studies with other interventions as control groups (6 studies, 393 participants) with those with no intervention as control (4 studies, 81 participants), the former reported only small improvements in attention problems, while the latter reported large improvements.
Duration of physical activity made little difference. The four studies with physical activity of an hour or more reported better outcomes than the six with less than an hour, but the difference was not significant.
Greater frequency did make a difference, but in a counterintuitive way. The seven studies with one or two physical activity interventions per week (162 participants) reported large reductions in attention problems, whereas the three studies with three or more interventions per week (312 participants) showed no improvement.
Conclusion:
The authors concluded, “Our study suggests that cognitively engaging exercise is more effective in improving attention problems in school-aged children with ADHD.” Moreover, “the benefits of improved attention in school-age children with ADHD are not necessarily positively correlated with higher frequency and longer duration of physical activity.” Also keep in mind that exercise, while important for all children, should not replace medical and psychological treatments for the disorder.
The National Health Interview Survey (NHIS) is conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. The NHIS is done primarily through face-to-face computer-assisted interviews in the homes of respondents. But telephone interviews are substituted on request, or where travel distances make in-home visits impractical.
For each interviewed family, only one sample child is randomly selected by a computer program.
The total number of households with a child or adolescent aged 3-17 for the years 2018 through 2021 was 26,422.
Based on responses from family members, 9.5% of the children and adolescents randomly surveyed throughout the United States had ADHD.
This proportion varied significantly based on age, rising from 1.5% for ages 3-5 to 9.6% for ages 6-11 and to 13.4% for ages 12-17.
There was an almost two-to-one gap between the 12.4% prevalence among males and the 6.6% prevalence among females.
There was significant variation by race/ethnicity. While rates among non-Hispanic whites (11.1%) and non-Hispanic blacks (10.5%) did not differ significantly, these two groups differed significantly from Hispanics (7.2%) and Others (6.6%).
There were no significant variations in ADHD prevalence based on highest education level of family members.
But family income had a significant relationship with ADHD prevalence, especially at lower incomes. For family incomes under the poverty line, the prevalence was 12.7%. That dropped to 10.3% for family incomes above the poverty level but less than twice that level. For all others it dropped further to about 8.5%. Although that might seem like poverty causes ADHD, we cannot draw that conclusion. Other data indicate that adults with ADHD have lower incomes. That would lead to more ADHD in kids from lower income families.
There was also significant geographic variation in reported prevalence rates. It was highest in the South, at 11.3%, then the Midwest at 10%, the Northeast at 9.1%, with a jump down to 6.9% in the West.
Overall ADHD prevalence did not vary significantly by year over the four years covered by this study.
This study highlights a consistently high prevalence of developmental disabilities among U.S. children and adolescents, with notable increases in other developmental delays and co-occurring learning and intellectual disabilities from 2018 to 2021. While the overall prevalence remained stable, these findings emphasize the need for continued research into potential risk factors and targeted interventions to address developmental challenges in youth.
It is also important to note that this study assessed the prevalence of ADHD being diagnosed by healthcare professionals. Due to variations in healthcare accessibility across the country, the true prevalence of ADHD may differ still.
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