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September 13, 2024
A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications.
However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life?
Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies.
A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD.
The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders.
With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants.
None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail.
Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect.
Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine.
Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.
The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect.
Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect.
The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.”
Heidi Taipale, Jakob Bergström, Katalin Gèmes, Antti Tanskanen, Lisa Ekselius, Ellenor Mittendorfer-Rutz, and Magnus Helgesson, “Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes,” JAMA Network Open (2024), 7(3):e242859, https://doi.org/10.1001/jamanetworkopen.2024.2859.
Cortese S, Adamo N, Del Giovane C, et al., “Comparative efficacy and tolerability of medications for attention- deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis,” Lancet Psychiatry (2018) 5(9):727-738, https://doi.org/10.1016/S2215-0366(18)30269-4.
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.
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 ..."
Raising children is not easy. I should know.
As a clinical psychologist, I've helped parents learn the skills they need to be better parents. And my experience raising three children confirmed my clinical experience.
Parenting is a tough job under the best of circumstances, but it is even harder if the parent has ADHD.
For example, an effective parent establishes rules and enforces them systematically. This requires attention to detail, self-control, and good organizational skills. Given these requirements, it is easy to see how ADHD symptoms interfere with parenting. These observations have led some of my colleagues to test the theory that treating ADHD adults with medication would improve their parenting skills. I know about two studies that tested this idea.
In 2008, Dr. Chronis-Toscano and colleagues published a study using a sustained-release form of methylphenidate for mothers with ADHD. As expected, the medication decreased their symptoms of inattention and hyperactivity/impulsivity. The medication also reduced the mother's use of inconsistent discipline and corporal punishment and improved their monitoring and supervision of their children.
In a 2014 study, Waxmonsky and colleagues observed ADHD adults and their children in a laboratory setting once when the adults were off medication and once when they were on medication. They used the same sustained-release form of amphetamine for all the patients. As expected, the medications reduced ADHD symptoms in the parents. This laboratory study is especially informative because the researchers made objective ratings of parent-child interactions, rather than relying on the parents' reports of those interactions. Twenty parents completed the study. The medication led to less negative talk and commands and more praise by parents. It also reduced negative and inappropriate behaviors in their children.
Both studies suggest that treating ADHD adults with medication will improve their parenting skills. That is good news. But they also found that not all parenting behaviors improved. That makes sense. Parenting is a skill that must be learned. Because ADHD interferes with learning, parents with the disorder need time to learn these skills. Medication can eliminate some of the worst behaviors, but doctors should also provide adjunct behavioral or cognitive-behavioral therapies that could help ADHD parents learn parenting skills and achieve their full potential as parents.
Background:
ADHD treatment includes medication, behavioral therapy, dietary changes, and special education. Stimulants are usually the first choice but may cause side effects like appetite loss and stomach discomfort, leading some to stop using them. Cognitive behavioral therapy (CBT) is effective but not always sufficient on its own. Research is increasingly exploring non-drug options, such as transcranial direct current stimulation (tDCS), which may boost medication effectiveness and improve results.
What is tDCS?
tDCS delivers a weak electric current (1.0–2.0 mA) via scalp electrodes to modulate brain activity, with current flowing from anode to cathode. Anodal stimulation increases neuronal activity, while cathodal stimulation generally inhibits it, though effects vary by region and neural circuitry. The impact of tDCS depends on factors such as current intensity, duration, and electrode shape. It targets cortical areas, often stimulating the dorsolateral prefrontal cortex for ADHD due to its role in cognitive control. Stimulation of the inferior frontal gyrus has also been shown to improve response inhibition, making it another target for ADHD therapy.
There is an ongoing debate about how effective tDCS is for individuals with ADHD. One study found that applying tDCS to the left dorsolateral prefrontal cortex can help reduce impulsivity symptoms in ADHD, whereas another study reported that several sessions of anodic tDCS did not lead to improvements in ADHD symptoms or cognitive abilities.
New Research:
Two recent meta-analyses have searched for a resolution to these conflicting findings. Both included only randomized controlled trials (RCTs) using either sham stimulation or a waitlist for controls.
Each team included seven studies in their respective meta-analyses, three of which appeared in both.
Both Wang et al. (three RCTs totaling 97 participants) and Wen et al. (three RCTs combining 121 participants) reported very large effect size reductions in inattention symptoms from tDCS versus controls. There was only one RCT overlap between them. Wang et al. had moderate to high variation (heterogeneity) in individual study outcomes, whereas Wen et al. had virtually none. There was no indication of publication bias.
Whereas Wen et al.’s same three RCTs found no significant reduction in hyperactivity/impulsivity symptoms, Wang et al. combined five RCTs with 221 total participants and reported a medium effect size reduction in impulsivity symptoms. This time, there was an overlap of two RCTs between the studies. Wen et al. had no heterogeneity, while Wang et al. had moderate heterogeneity. Neither showed signs of publication bias.
Turning to performance-based tasks, Wang et al. reported a medium effect size improvement in attentional performance from tDCS over controls (three RCTs totaling 136 participants), but no improvement in inhibitory control (five RCTs combining 234 persons).
Wang et al. found no significant difference in adverse events (four RCTs combining 161 participants) between tDCS and controls, with no heterogeneity. Wen et al. found no significant difference in dropout rates (4 RCTs totaling 143 individuals), again with no heterogeneity.
Wang et al. concluded, “tDCS may improve impulsive symptoms and inattentive symptoms among ADHD patients without increasing adverse effects, which is critical for clinical practice, especially when considering noninvasive brain stimulation, where patient safety is a key concern.”
Wen et al. further concluded, “Our study supported the use of tDCS for improving the self-reported symptoms of inattention and objective attentional performance in adults diagnosed with ADHD. However, the limited number of available trials hindered a robust investigation into the parameters required for establishing a standard protocol, such as the optimal location of electrode placement and treatment frequency in this setting. Further large-scale double-blind sham-controlled clinical trials that include assessments of self-reported symptoms and performance-based tasks both immediately after interventions and during follow-up periods, as well as comparisons of the efficacy of tDCS targeting different brain locations, are warranted to address these issues.”
The Take-Away:
Previous studies have shown mixed results on the benefits of this therapy on ADHD. These new findings suggest that tDCS may hold some real promise for adults with ADHD. While the technique didn’t meaningfully shift hyperactivity or impulsivity, it was well-tolerated and showed benefit, especially in self-reported symptoms. However, with only a handful of trials to draw from, it would be a mistake to suggest tDCS as a standard treatment protocol. Larger, well-designed studies are the next essential step to clarify where, how, and how often tDCS works best.
Background:
The development of ADHD is strongly associated with functional impairments in the prefrontal cortex, particularly the dorsolateral prefrontal cortex, which plays a key role in maintaining attention and controlling impulses. Moreover, imbalances in neurotransmitters like dopamine and norepinephrine are widely regarded as major neurobiological factors contributing to ADHD.
Executive functions are a group of higher-order cognitive skills that guide thoughts and actions toward goals. “Executive function” refers to three main components: inhibitory control, working memory, and cognitive flexibility. Inhibitory control helps curb impulsive actions to stay on track. Working memory allows temporary storage and manipulation of information for complex tasks. Cognitive flexibility enables switching attention and strategies in varied or demanding situations.
Research shows that about 89% of children with ADHD have specific executive function impairments. These difficulties in attention, self-control, and working memory often result in academic and social issues. Without timely intervention, these issues can lead to emotional disorders like depression, anxiety, and irritability, further affecting both physical health and social development.
Currently, primary treatments for executive function deficits in school-aged children with ADHD include medication and behavioral or psychological therapies, such as Cognitive Behavioral Therapy (CBT). While stimulant medications do improve executive function, not all patients are able to tolerate these medications. Behavioral interventions like neurofeedback provide customized care but show variable effectiveness and require specialized resources, making them hard to sustain. Safer, more practical, and long-lasting treatment options are urgently needed.
Exercise interventions are increasingly recognized as a safe, effective way to improve executive function in children with ADHD. However, systematic studies on school-aged children remain limited.
Moreover, there are two main scoring methods for assessing executive function: positive scoring (higher values mean better performance, such as accuracy) and reverse scoring (lower values mean better performance, such as reaction time). These different methods can affect how results are interpreted and compared across studies. This meta-analysis explored how different measurement and scoring methods might influence results, addressing important gaps in the research.
The Study:
Only randomized controlled trials (RCTs) involving school-aged children (6–13 years old) diagnosed with ADHD by DSM-IV, DSM-5, ICD-10, ICD-11, or the SNAP-IV scale were included. Studies were excluded if the experimental group received non-exercise interventions or exercise combined with other interventions.
Cognitive Flexibility
Using positive scoring, exercise interventions were associated with a narrowly non-significant small effect size improvement relative to controls (eight RCTs, 268 children). Using reverse scoring, however, they were associated with a medium effect size improvement (eleven RCTs, 452 children). Variation (heterogeneity) in individual RCT outcomes was moderate, with no sign of publication bias in both instances.
Inhibitory Control
Using positive scoring, exercise interventions were associated with a medium effect size improvement relative to controls (ten RCTs, 421 children). Using reverse scoring, there was an association with a medium effect size improvement (eight RCTs, 265 children). Heterogeneity was moderate with no sign of publication bias in either case.
Working Memory
Using positive scoring, exercise interventions were associated with a medium effect size improvement relative to controls (six RCTs, 321 children). Using reverse scoring, the exercise was associated with a medium effect size improvement (five RCTs, 143 children). Heterogeneity was low with no indication of publication bias in both instances.
Conclusion:
The team concluded, “Exercise interventions can effectively improve inhibitory control and working memory in school-aged children with ADHD, regardless of whether positive or reverse scoring methods are applied. However, the effects of exercise on cognitive flexibility appear to be limited, with significant improvements observed only under reverse scoring. Moreover, the effects of exercise interventions on inhibitory control, working memory, and cognitive flexibility vary across different measurement paradigms and scoring methods, indicating the importance of considering these methodological differences when interpreting results.”
Although this work is intriguing, it does not show that exercise significantly improves the symptoms of ADHD in children. This means that exercise, although beneficial for many reasons, should not be viewed as a replacement for evidence-based treatments for the disorder.
A recent Wall Street Journal article raised alarms by concluding that many children who start medication for ADHD will later end up on several psychiatric drugs. It’s an emotional topic that will make many parents, teachers, and even doctors worry: “Are we putting kids on a conveyor belt of medications?”
The article seeks to shine a light on the use of more than one psychiatric medication for children with ADHD. My biggest worry about the article is that it presents itself as a scientific study because they analyzed a database. It is not a scientific study. It is a journalistic investigation that does not meet the standards of a scientific report..
The WJS brings attention to several issues that parents and prescribers should think about. It documents that some kids with ADHD are on more than one psychiatric medication, and some are receiving drugs like antipsychotics, which have serious side effects. Is that appropriate? Access to good therapy, careful evaluation, and follow-up care can be lacking, especially for low-income families. Can that be improved? On that level, the article is doing something valuable: it’s shining a spotlight on potential problems.
It is, of course, fine for a journalist to raise questions, but it is not OK for them to pretend that they’ve done a scientific investigation that proves anything. Journalism pretending to be science is both bad science and bad journalism.
Journalism vs. Science: Why Peer Review Matters
Journalists can get big datasets, hire data journalists, and present numbers that look scientific. But consider the differences between Journalism and Science. These types of articles are usually checked by editors and fact-checkers. Their main goals are:
Is this fact basically correct?
Are we being fair?
Are we avoiding legal problems?
But editors are not qualified to evaluate scientific data analysis methods. Scientific reports are evaluated by experts who are not part of the project. They ask tough questions like:
Exactly how did you define ADHD?
How did you handle missing data?
Did you address confounding?
Did you confuse correlation with causation?
If the authors of the study cannot address these and other technical issues, the paper is rejected.
The WSJ article has the veneer of science but lacks its methodology.
Correlation vs. Causation: A Classic Trap
The article’s storyline goes something like this: A kid starts ADHD medication. She has additional problems or side effects caused by the ADHD medications. Because of that, the prescriber adds more drugs. That leads to the patient being put on several drugs. Although it is true that some ADHD youth are on multiple drugs, the WSJ is wrong to conclude that the medications for ADHD cause this to occur. That simply confuses correlation with causation, which only the most naïve scientist would do.
In science, this problem is called confounding. It means other factors (like how severe or complex a child’s condition is) explain the results, not just the thing we’re focused on (medication for ADHD).
The WSJ analyzed a database of prescriptions. They did not survey the prescribers who made the prescriptions of the patients who received them. So they cannot conclude that ADHD medication caused the later prescriptions, or that the later medications were unnecessary or inappropriate.
Other explanations are very likely. It has been well documented that youth with ADHD are at high risk for developing other disorders such as anxiety, depression, and substance use. The kids in the WSJ database might have developed these disorders and needed several medications. A peer-reviewed article in a scientific journal would be expected to adjust for other diagnoses. If that is not possible, as it is in the case of the WSJ’s database, a journal would not allow the author to make strong conclusions about cause-and-effect.
Powerful Stories Don’t Always Mean Typical Stories
The article includes emotional accounts of children who seemed harmed by being put on multiple psychiatric drugs. Strong, emotional stories can make rare events feel common. They also frighten parents and patients, which might lead some to decline appropriate care.
These stories matter. They remind us that each data point is a real person. But these stories are the weakest form of data. They can raise important questions and lead scientists to design definitive studies, but we cannot use them to draw conclusions about the experiences of other patients. These stories serve as a warning about the importance of finding a qualified provider, not as against the use of multiple medications. That decision should be made by the parent or adult patient based on an informed discussion with the prescriber.
Many children and adults with ADHD benefit from multiple medications. The WSJ does not tell those stories, which creates an unbalanced and misleading presentation.
Newspapers frequently publish stories that send the message: “Beware! Doctors are practicing medicine in a way that will harm you and your family.” They then use case studies to prove their point. The title of the article is, itself, emotional clickbait designed to get more readers and advertising revenue. Don’t be confused by such journalistic trickery.
What Should We Conclude?
Here’s a balanced way to read the article. It is true that some patients are prescribed more than one medication for mental health problems. But the article does not tell us whether this prescribing practice is or is not warranted for most patients. I agree that the use of antipsychotic medications needs careful justification and close monitoring. I also agree that patients on multiple medications should be monitored closely to see if some of the medications can be eliminated. Many prescribers do exactly that, but the WSJ did not tell their stories.
It is not appropriate to conclude that ADHD medications typically cause combined pharmacotherapy or to suggest that combined pharmacotherapy is usually bad. The data presented by the WSJ does not adequately address these concerns. It does not prove that medications for ADHD cause dangerous medication cascades.
We have to remember that even when a journalist analyzes data, that is not the same as a peer-reviewed scientific study. Journalism pretending to be science is both bad science and bad journalism.
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