August 12, 2024

Meta-analysis Finds Quality of Life Improvements Associated with ADHD Medications

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

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ADHD medication and risk of suicide

ADHD medication and risk of suicide

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 ..."

December 13, 2021

How Effective and Safe are Stimulant Medications for Older Adults?

How effective and safe are stimulant medications for older adults?

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"

December 21, 2021

How do Stimulants Modulate the Brain to Improve ADHD Symptoms?

How do Stimulants Modulate the Brain to Improve ADHD Symptoms?

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.

April 21, 2021

Study Finds Association Between Childhood ADHD and Poor Dental Health

The Spanish National Health Survey tracks health care outcomes through representative samples of the Spanish population. 

A Spanish research team used survey data to explore the relationship between ADHD symptoms and dental and gum health in a representative sample of 3,402 Spanish children aged 6 to 14.

While previous studies have found associations between ADHD and poor dental health, they have not fully accounted for such important determinants of poor oral health as socioeconomic status, dental hygiene, or diet. 

The team therefore adjusted for sociodemographic factors, lifestyle variables, and oral hygiene behaviors. More specifically, they adjusted for sex, age, social class, parental education, exposure to tobacco smoke, consumption of sweets, consumption of sugary drinks, use of asthma or allergy medication, adequate oral hygiene behavior of children, adherence to regular dental visits, parental adequate oral hygiene behavior, and parental adherence to regular dental visits.

With those adjustments, children with ADHD symptoms had over twice the incidence of dental caries (cavities) as their counterparts without ADHD symptoms.

Tooth extractions and dental restorations also occurred with over 40% greater frequency in children with ADHD symptoms.

Gum bleeding, a sign of gum disease, was more than 60% more common among children with ADHD symptoms than among their non-ADHD peers.

Importantly, excluding children with daily sugar consumption, which left 1,693 children in the sample, made no difference in the outcome for cavities.

Excluding children with poor oral hygiene habits, which left 1,657 children in the sample, those with ADHD had 2.5-fold more caries than their non-ADHD counterparts.

Excluding children of low social class, which left 1,827 children in the sample, those with ADHD had 2.6-fold more caries than their non-ADHD counterparts.

Turning to a different method to address potential confounding factors, the team used nearest-neighbor propensity score matching to create virtual controls. This compared 461 children with ADHD to 461 carefully matched children without ADHD.

This time, children with ADHD symptoms had just under twice the incidence of cavities as their counterparts without ADHD symptoms, but 60% more tooth extractions and about 75% more dental restorations. The difference in gum bleeding became nonsignificant.

Noting that “The increased risk of caries was maintained when the analyses were restricted to middle/high social class families and children with low sugar intake, good oral hygiene behaviors and regular dental visits,” the team concluded, “Children with ADHD symptoms in Spain had worse oral health indicators than those without ADHD symptoms. Our results suggest that the association of ADHD symptoms with caries was independent of socioeconomic level, cariogenic diet, frequency of toothbrushing, and dental visits.”

June 13, 2025

A Lesson in Correlation Versus Causation : Maternal Smoking and ADHD Risk in Children

Meta-analysis Finds Strong Link Between Maternal Smoking During Pregnancy and Increased Risk of ADHD in Children

This new meta-analysis confirms what other meta-analysis have already shown, i.e, that there exists in the population an association between maternal smoking during pregnancy and ADHD in their offspring.  But reader beware, association does not mean causation.

The team identified 55 studies with quantitative data suitable for meta-analysis, including 11 case-control, 13 cross-sectional, and 31 retrospective/prospective cohort studies. 

Altogether they combined more than four million persons in countries spanning six continents, including the United States, Finland, Sweden, Brazil, the Netherlands, Japan, the UK, Spain, China, Australia, New Zealand, Norway, Canada, France, Sweden, South Korea, Turkey, Romania, Bulgaria, Lithuania, Germany, Denmark, Egypt, and India.

Meta-analysis of all 55 studies found that offspring of mothers who smoked tobacco during pregnancy were about 70% more likely to develop ADHD than offspring of mothers who did not smoke during pregnancy.

Because variation in outcomes across studies was very high, the team performed subgroup analyses to explore potential sources of this heterogeneity. 

Comparing study designs, cohort studies reported roughly 50% greater odds of ADHD among children of mothers who smoked during pregnancy, whereas case-control studies reported roughly 70% greater odds and cross-sectional studies 2.3-fold greater odds.

Studies using the most reliable method of determining ADHD – clinical interview/professional diagnosis – reported 90% greater odds, contrasting with 66% through medical records/databases and 58% through self-report by child/parent or through teacher report.

Good quality studies reported roughly 75% greater odds. 

Studies with sample sizes above two thousand similarly found 70% greater odds.

There was no sign of publication bias using the more commonly used Egger’s test, but a marginal indication of publication bias using Begg’s test. Performing a standard correction reduced the effect size, indicating that the offspring of mothers who smoked tobacco during pregnancy were over 50% more likely to develop ADHD than the offspring of mothers who did not smoke during pregnancy.

The team concluded, “This systematic review and meta-analysis of 55 studies, encompassing over four million participants, provides compelling evidence that maternal tobacco smoking during pregnancy significantly increases the odds of ADHD in children … These findings underscore the critical need for public health interventions aimed at reducing tobacco smoking during pregnancy.”

However, we disagree with this conclusion; The authors ignore substantial evidence showing that maternal smoking during pregnancy is confounded by maternal ADHD. These mothers transmit ADHD via genetics, not via their smoking. This study should be seen not as "...[further evidence that smoking during pregnancy causes ADHD.] ", but as a lesson in how easy it can be to see correlation as causation.

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June 10, 2025

Meta-analysis Finds Little Evidence of Efficacy for Animal-Assisted Interventions for Treating Childhood ADHD

Study Background:

Animal-assisted interventions (AAIs) involve structured interactions with animals, designed and carried out by mental health teams assisted by trained human–animal professionals, to achieve specific therapeutic or educational goals. While a wide variety of animals may be used, horses and dogs tend to predominate. These interventions often involve physical contact, imitation, and play aimed at reducing stress and generating affection. Previous research has suggested that AAI to those with a range of developmental and mental health conditions.

Just how effective are they for treating ADHD in children and adolescents? Recent years have seen an increase in studies into AAIs for children with ADHD, but previous systematic reviews have not included quantitative meta-analysis to evaluate efficacy.

The Study:

A Chinese study team based in Nanjing set out to remedy that with a systematic search of the peer-reviewed published medical literature aimed at performing meta-analyses of efficacy.

The team limited its search to randomized controlled trials (RCTs) and pre–post single-group studies involving children and adolescents diagnosed with ADHD.

Meta-analysis of five studies with a combined total of 95 participants reported no significant effect of AAIs on ADHD symptom severity. There was negligible variation (heterogeneity) in outcomes among the studies.

Similarly, meta-analysis of the six studies encompassing 323 individuals found no significant improvements in social behavior. There was no heterogeneity and no sign of publication bias. Breaking that down into subcategories of social interaction (4 studies, 190 persons), social skill (3 studies, 53 persons), and problem behavior (4 studies, 80 participants) made no difference.

Likewise, meta-analysis of the three studies encompassing 61 individuals found no significant improvements in emotional control. Again, there was no heterogeneity and no sign of publication bias.

Three studies combining 56 participants reported no significant reductions in anxiety and depression, again with no heterogeneity and no sign of publication bias.

However, meta-analyses of five studies encompassing 194 individuals found a medium effect size association between AAIs and declines in attention problems, and a medium-to-large effect size improvement in learning and cognition. Heterogeneity was negligible to low.

Finally, meta-analysis of three studies combining 95 participants reported a large effect size improvement in motor proficiency, with moderate heterogeneity.

The Conclusion:

The team concluded, “As an ADHD management strategy complementary to gold-standard approaches, such as medication or multimodal interventions, AAIs did not appear to be more effective in improving the majority of core ADHD outcomes in children. Future studies should incorporate rigorous study designs with large sample sizes and a standard protocol to achieve more valid and reliable conclusions.”

June 5, 2025