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August 12, 2024
Quality of life (QoL) is defined as a person’s satisfaction with their life, measured across several dimensions including psychological, social, health, biological, and economic well-being. For adults, these are usually self-reported. QoL for children and adolescents is usually reported by parents.
Medications for ADHD include stimulants (methylphenidate and amphetamines) and non-stimulants (e.g., atomoxetine, clonidine, guanfacine, viloxazine). As QoL is related to ADHD symptoms’ severity, management of ADHD via medication could improve not only core symptoms but also QoL in people with ADHD.
Noting the absence of meta-analytic evidence on the effects of ADHD medications on QoL, an international research team conducted a systematic review and meta-analysis of parallel or cross-over randomized clinical trials (RCTs) to estimate the effects of ADHD medication on QoL. They also performed secondary analyses to see if these effects differed in children and adolescents versus adults, as well as by class of medications, and if they were moderated by length of treatment.
Meta-analyses of four RCTs with a combined total of 950 participants with ADHD (45% adults) found a medium effect size improvement among those receiving amphetamines by comparison with those receiving placebo. There was no sign of publication bias, but there was wide variation (heterogeneity) in effect size estimated among the studies.
Meta-analysis of four RCTs with a combined total of 1,094 participants with ADHD (57% adults) found a small-to-medium effect size improvement among those receiving methylphenidate by comparison with those receiving placebo. Again, there was no sign of publication bias, but wide variation in effect sizes among the studies.
Due to lack of sufficient data, the team could not explore whether length of treatment affected the results, or if there were differences between children/adolescents and adults.
Finally, a meta-analysis of eleven RCTs with a combined total of 3,344 participants with ADHD (63% adults) likewise found a small effect size improvement among those taking atomoxetine compared with those receiving placebo. Once again, there was no sign of publication bias, but wide variation in effect sizes among the studies.
The team was able to establish that for atomoxetine treatment, length of intervention – the studies ranged from 6 to 24 weeks – had no significant moderating effect. Similarly, they found no significant differences in effect on children and adolescents versus adults.
A single RCT evaluating modafinil treatment in adults found no improvements at any dose, whereas a single RCT testing non-stimulant guanfacine reported a medium effect size improvement in QoL. Modafinil is not FDA approved for ADHD but is sometimes used as a last resort if other treatments fail.
The team concluded that the FDA approved medications for ADHD were significantly more efficacious than placebo in improving QoL in people with ADHD. The improvements in Q0L were, however, smaller than what has been found for improvements is the symptoms of ADHD (inattention, hyperactivity, impulsivity). More work is needed to detect differences by age and length of treatment.
Alessio Bellato, Nadia J. Perrott, Lucia Marzulli, Valeria Parlatini, David Coghill, and Samuele Cortese, “Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life,” Journal of the American Academy of Child & Adolescent Psychiatry (2024), https://doi.org/10.1016/j.jaac.2024.05.023.
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 ..."
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"
The stimulants methylphenidate and amphetamine are well known for their efficacy in treating symptoms of ADHD in both youth and adults. Although these medications have been used for several decades, relatively little is known about the mechanisms of action that lead to their therapeutic effect.
New data about the mechanism comes from a meta-analysis by Katya Rubia and colleagues. They analyzed 14 functional magnetic resonance imaging (fMRI) data sets comprising 212 youth with ADHD. Each of these data sets assessed the short-term effects of stimulants on fMRI-assessed brain activations. In the fMRI paradigm, ADHD and control participants are asked to do a neurocognitive task while the activity of their brains is being measured. Dr. Rubia and colleagues analyzed data from fMRI assessments of time discrimination, inhibition, and working memory, each of which is known to be deficient in ADHD patients.
The meta-analysis found that the most consistent brain activations were seen in a region comprising the right inferior frontal cortex(IFC) and insula, even when the analysis was limited to previously medication-naïve patients. The implicated region of the brain is known to mediate cognitive control, time estimation, and attention. Dr.Rubia also notes that other studies show that the IFC/Insula is needed for updating information and allocating attention to relevant stimuli.
Another region implicate by the meta-analysis was the right putamen, a region that is rich in dopamine transporters. This finding is consistent with the fact that the dopamine transporter is the main target of stimulant medications.
What is the potential clinical implication of these findings? As Dr. Rubia and colleagues note, it is possible that the fMRI anomalies they identified could be used as a biomarker for ADHD or a biomarker to select patients who should respond optimally to stimulant medication. Although fMRI cannot be used as a clinical tool at this time, research of this sort is opening up new horizons for how we understand the etiology of ADHD and the mechanisms whereby medications exert their effects.
Many news outlets have reported an increase – or surge – in attention-deficit/hyperactivity disorder, or ADHD, diagnoses in both children and adults. At the same time, health care providers, teachers and school systems have reported an uptick in requests for ADHD assessments.
These reports have led some experts and parents to wonder whether ADHD is being overdiagnosed and overtreated.
As researchers who have spent our careers studying neurodevelopmental disorders like ADHD, we are concerned that fears about widespread overdiagnosis are misplaced, perhaps based on a fundamental misunderstanding of the condition.
Discussions about overdiagnosis of ADHD imply that you either have it or you don’t.
However, when epidemiologists ask people in the general population about their symptoms of ADHD, some have a few symptoms, some have a moderate level, and a few have lots of symptoms. But there is no clear dividing line between those who are diagnosed with ADHD and those who are not, since ADHD – much like blood pressure – occurs on a spectrum.
Treating mild ADHD is similar to treating mild high blood pressure – it depends on the situation. Care can be helpful when a doctor considers the details of a person’s daily life and how much the symptoms are affecting them.
Not only can ADHD symptoms be very different from person to person, but research shows that ADHD symptoms can change within an individual. For example, symptoms become more severe when the challenges of life increase.
ADHD symptoms fluctuate depending on many factors, including whether the person is at school or home, whether they have had enough sleep, if they are under a great deal of stress or if they are taking medications or other substances. Someone who has mild ADHD may not experience many symptoms while they are on vacation and well rested, for example, but they may have impairing symptoms if they have a demanding job or school schedule and have not gotten enough sleep. These people may need treatment for ADHD in certain situations but may do just fine without treatment in other situations.
This is similar to what is seen in conditions like high blood pressure, which can change from day to day or from month to month, depending on a person’s diet, stress level and many other factors.
ADHD symptoms start in early childhood and typically are at their worst in mid-to late childhood. Thus, the average age of diagnosis is between 9 and 12 years old. This age is also the time when children are transitioning from elementary school to middle school and may also be experiencing changes in their environment that make their symptoms worse.
Classes can be more challenging beginning around fifth grade than in earlier grades. In addition, the transition to middle school typically means that children move from having all their subjects taught by one teacher in a single classroom to having to change classrooms with a different teacher for each class. These changes can exacerbate symptoms that were previously well-controlled. Symptoms can also wax and wane throughout life.
Psychiatric problems that often co-occur with ADHD, such as anxiety or depression, can worsen ADHD symptoms that are already present. These conditions can also mimic ADHD symptoms, making it difficult to know which to treat. High levels of stress leading to poorer sleep, and increased demands at work or school, can also exacerbate or cause ADHD-like symptoms.
Finally, the use of some substances, such as marijuana or sedatives, can worsen, or even cause, ADHD symptoms. In addition to making symptoms worse in someone who already has an ADHD diagnosis, these factors can also push someone who has mild symptoms into full-blown ADHD, at least for a short time.
The reverse is also true: Symptoms of ADHD can be minimized or reversed in people who do not meet full diagnostic criteria once the external cause is removed.
Clinicians diagnose ADHD based on symptoms of inattention, hyperactivity and impulsivity. To make an ADHD diagnosis in children, six or more symptoms in at least one of these three categories must be present. For adults, five or more symptoms are required, but they must begin in childhood. For all ages, the symptoms must cause serious problems in at least two areas of life, such as home, school or work.
Current estimates show that the strict prevalence of ADHD is about 5% in children. In young adults, the figure drops to 3%, and it is less than 1% after age 60. Researchers use the term “strict prevalence” to mean the percentage of people who meet all of the criteria for ADHD based on epidemiological studies. It is an important number because it provides clinicians and scientists with an estimate on how many people are expected to have ADHD in a given group of people.
In contrast, the “diagnosed prevalence” is the percentage of people who have been diagnosed with ADHD based on real-world assessments by health care professionals. The diagnosed prevalence in the U.S. and Canada ranges from 7.5% to 11.1% in children under age 18. These rates are quite a bit higher than the strict prevalence of 5%.
Some researchers claim that the difference between the diagnosed prevalence and the strict prevalence means that ADHD is overdiagnosed.
We disagree. In clinical practice, the diagnostic rules allow a patient to be diagnosed with ADHD if they have most of the symptoms that cause distress, impairment or both, even when they don’t meet the full criteria. And much evidence shows that increases in the diagnostic prevalence can be attributed to diagnosing milder cases that may have been missed previously. The validity of these mild diagnoses is well-documented.
Consider children who have five inattentive symptoms and five hyperactive-impulsive symptoms. These children would not meet strict diagnostic criteria for ADHD even though they clearly have a lot of ADHD symptoms. But in clinical practice, these children would be diagnosed with ADHD if they had marked distress, disability or both because of their symptoms – in other words, if the symptoms were interfering substantially with their everyday lives.
So it makes sense that the diagnosed prevalence of ADHD is substantially higher than the strict prevalence.
People who are concerned about overdiagnosis commonly worry that people are taking medications they don’t need or that they are diverting resources away from those who need it more. Other concerns are that people may experience side effects from the medications, or that they may be stigmatized by a diagnosis.
Those concerns are important. However, there is strong evidence that underdiagnosis and undertreatment of ADHD lead to serious negative outcomes in school, work, mental health and quality of life.
In other words, the risks of not treating ADHD are well-established. In contrast, the potential harms of overdiagnosis remain largely unproven.
It is important to consider how to manage the growing number of milder cases, however. Research suggests that children and adults with less severe ADHD symptoms may benefit less from medication than those with more severe symptoms.
This raises an important question: How much benefit is enough to justify treatment? These are decisions best made in conversations between clinicians, patients and caregivers.
Because ADHD symptoms can shift with age, stress, environment and other life circumstances, treatment needs to be flexible. For some, simple adjustments like classroom seating changes, better sleep or reduced stress may be enough. For others, medication, behavior therapy, or a combination of these interventions may be necessary. The key is a personalized approach that adapts as patients’ needs evolve over time.
Executive function impairment is a key feature of ADHD, with its severity linked to the intensity of ADHD symptoms. Executive function involves managing complex cognitive tasks for organized behavior and includes three main areas: inhibitory control (suppressing impulsive actions), working memory (holding information briefly), and cognitive flexibility (switching between different mental tasks). Improving executive functions is a critical objective in the management of ADHD.
Recent studies show that exercise interventions can enhance executive function in individuals with ADHD. Unlike traditional medications, which are costly and may cause side effects such as headaches, nausea, or growth issues, exercise can be incorporated into daily routines of children and adolescents without negative reactions.
Some studies report that aerobic exercise does not significantly improve executive function. However, most past reviews of aerobic exercise effects on executive function have focused on people without ADHD, with few examining interventions for children or adolescents with ADHD.
The Study:
A Chinese and South Korean study team conducted a systematic search of the peer-reviewed published literature to perform meta-analyses on randomized controlled trials (RCTs) specifically focused on aerobic exercise interventions for children and adolescents with ADHD.
All studies included were randomized controlled trials involving participants aged 6 to 18 years who had been clinically diagnosed with ADHD. The interventions consisted of various forms of aerobic exercise, while the control groups engaged in either non-exercise activities or daily routines. Each study was required to report at least one outcome measure with usable data for calculating the effect size on executive functioning.
The Results:
Meta-analysis of fifteen RCTs combining 653 children and adolescents with ADHD reported a medium to large effect size improvement in inhibitory control. There was no sign of publication bias, but wide heterogeneity (variation) in outcomes among studies.
Six to eight weeks of aerobic exercise produced modest improvements, with much greater gains seen after twelve weeks. Hour-long sessions were as effective as longer ones. Moderate intensity exercise proved more beneficial than vigorous intensity.
Meta-analysis of eight RCTs combining 399 children and adolescents with ADHD produced a medium effect size improvement in working memory. There was no sign of publication bias, and heterogeneity was moderate.
Once again, six to eight weeks of aerobic exercise produced modest improvements, with much greater gains seen after twelve weeks. Hour-long sessions were as effective as longer ones. But in this case moderate-to-vigorous intensity yielded the best results.
Meta-analysis of ten RCTs combining 443 children and adolescents with ADHD was associated with a medium to large effect size improvement in cognitive flexibility. There was no sign of either publication bias or heterogeneity. Neither the length of treatment, session time, or intensity affected the outcome.
The Take-Away:
The team concluded, “Our study indicates that aerobic exercise interventions have a positive impact with a moderate effect size on inhibitory control, working memory, and cognitive flexibility in children and adolescents with ADHD. However, the effectiveness of the intervention is influenced by factors such as the intervention period, frequency, session durations, intensity, and the choice between acute or chronic exercise. Specifically, chronic aerobic exercise interventions lasting 12 weeks or longer, with a frequency of 3 to 5 sessions per week, session durations of 60 min or more, and intensities that are moderate or moderate-to-vigorous, have the greatest overall effect… caution should be exercised when interpreting these findings due to the significant heterogeneity in inhibitory control and working memory.”
Vitamins play important roles in metabolism, immune regulation, and neurodevelopment. Recent studies show that deficiencies in vitamins like D, B6, B12, and folate are common in people with ADHD and ASD (autism spectrum disorder), and are associated with behavioral, cognitive, and brain development issues.
The Study:
A study team based in China has just performed a systematic search of the peer-reviewed medical literature to perform meta-analyses of clinical trials exploring vitamin interventions in the treatment of ADHD and ASD.
ADHD trials included participants with an official diagnosis. The primary intervention was vitamin supplements, while other treatments, including medications, remained unchanged or were excluded during the study period. ADHD outcomes included measurable changes in ADHD symptoms using validated rating scales and executive function measures.
Eligible studies included standard or sham control groups, crossover, parallel, or other clinical trial designs. In crossover studies, only first-phase data were analyzed to prevent carryover effects.
Ten trials with 852 participants met the standards, but meta-analysis showed no significant results. The outcomes varied widely, suggesting a need to distinguish among vitamins.
Results:
Of the five trials involving 347 participants that specifically evaluated vitamin D supplementation, results indicated a large effect size improvement in ADHD symptoms and executive function measures. The other five studies did not show any observable improvement.
Key limitations include:
The team concluded, “This meta-analysis supports the use of vitamin supplementation as a promising adjunctive treatment for ASD and ADHD. Vitamin B showed greater benefits in improving symptoms of ASD, while vitamin D was more effective in managing ADHD-related behaviors. These findings suggest that specific vitamins may target disorder-specific symptoms. Despite limitations such as the lack of trials on other vitamins and limited understanding of underlying mechanisms, vitamin therapy remains a low-cost, accessible option.”
An important limitation of this work is that the positive results for vitamin D were due to two studies from Iran. So far, no positive study has emerged from a non-Iranian study.
Interpretation:
The vitamin D findings are intriguing and could be important if replicated outside of Iran. Since supplementation is already widely recommended to those with limited sunlight exposure, clinicians may want to consider monitoring their patients’ vitamin D intake, especially in the winter months. It should be noted, however, that due to the limitations of this study, the results are by no means conclusive, and vitamin D should not be taken as a stand-alone treatment for ADHD.
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