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

Beyond Dopamine: How Serotonin Influences ADHD Symptoms

ADHD is usually framed as a dopamine-and-norepinephrine condition, but recent studies have revealed that serotonin may also play a significant role. To delve deeper into this, we conducted a systematic literature review of studies looking at serotonin, its receptors, and the serotonin transporter (SERT) in relation to ADHD. The result: serotonin appears to be an important piece of the puzzle, but the overall picture is quite complex.

An ADHD & Serotonin Literature Review:

The authors searched the literature without time limits and screened thousands of records to end up with 95 relevant publications. Those included animal/basic-science work, neuroimaging, pharmacodynamics, a couple of large genetic/transcriptomic studies (GWAS and a cortico-striatal TWAS), and a few clinical reports. Each paper was graded for quality: 17 high, 59 medium, and 19 low.

The Results:
  • Most studies support a serotonergic role. About 81% (77/95) of the papers reported altered serotonin production, binding, transport, or degradation linked to ADHD or ADHD-like behaviors.

  • Multiple lines of evidence: animal models frequently show that changing serotonin levels or receptor activity alters hyperactivity and impulsivity; human imaging and clinical studies provide supportive but smaller and sometimes mixed signals; genetic/transcriptomic work points to serotonin-related pathways among many implicated systems.

  • Receptors and SERT matter: Multiple serotonin receptor subtypes (5-HT1A, 1B, 2A, 2C, 7) and SERT show associations with impulsivity, hyperactivity, attention, or brain activity patterns in ADHD models and some human studies.

  • Mixed and conflicting data: Central measures (brain, CSF) more often show serotonin deficits, while peripheral measures (platelets, plasma) sometimes show higher serotonin — methodological differences likely explain some contradictions.

  • Drugs used for ADHD can affect serotonin: Stimulants and non-stimulant drugs approved by FDA for treating ADHD (e.g., methylphenidate, atomoxetine, extended release viloxazine) or under investigation (centafafadine) have direct or indirect effects on serotonin systems, supporting the idea that monoamines interact rather than acting separately.  Because drugs that mainly affect serotonin are not useful for ADHD it seems likely that a pathway forward for ADHD drug development would be drugs that target multiple neurotransmitter systems.  A complex treatment for an etiologically complex disorder.

The Role of Serotonin in ADHD: What's The Take-Away?

As the study points out, the idea that serotonin may play a role in the neurobiology of ADHD is not new, but this literature review “identified multiple individual strands of evidence gathered over several decades and brought them into a more coherent focus”. It concludes that serotonergic neurotransmission is implicated in ADHD.  This doesn’t mean variations in serotonin levels cause ADHD, but that serotonin may be a plausible target for future treatments and research.

ADHD is polygenic and multi-systemic. For now, clinicians and patients should view serotonin as part of a complex network that may contribute to ADHD symptoms.  More research is needed before making treatment decisions based on these findings. 

Registry-based Cohort Study Finds No Association Between Maternal Diabetes and Offspring ADHD

Background:

A previous meta-analysis found that children born to mothers with diabetes had a 34% higher risk of developing ADHD compared to those born to non-diabetic mothers.  

However, previous studies suffered methodological limitations, such as small sample sizes, case-control or cross-sectional designs, and insufficient adjustment for key confounders such as maternal socio-economic status, mental health conditions, obesity, and substance use disorders.  

Moreover, many studies relied on self-reported maternal diabetes, and on non-clinical ADHD assessments, such as parental reports or screening tools, which are prone to bias and inaccuracies.  

Furthermore, the role of maternal antidiabetic medication use in relation to ADHD risk has rarely been examined. Antidiabetic medications are effective in controlling high blood sugar during pregnancy, but many can cross the placenta and the blood-brain barrier, raising concerns about potential effects on fetal brain development.  

Study:

To address these gaps, an Australian study team used a large cohort of linked health administrative data from New South Wales to investigate both the association between maternal diabetes and the risk of ADHD and the independent effect of prenatal exposure to antidiabetic medications. 

The study encompassed all mother-child pairs born from 2003 through 2005, with follow-up conducted through 2018 to monitor hospital admissions related to ADHD. That yielded a final cohort of almost 230,000 mother-child pairs. 

The team adjusted for potential confounders including maternal age, socioeconomic status, previous children, pregnancy-related hypertension, caesarean delivery, birth order and plurality, maternal anxiety, depression, schizophrenia, bipolar disorder, substance use (alcohol, tobacco, stimulants, opioids, cannabis), and child factors such as Apgar score, sex, prematurity, and low birth weight. 

Results:

For maternal diabetes overall, there was no significant association with offspring ADHD. That was also true when broken down into pre-existing maternal diabetes and gestational (pregnancy-induced) diabetes.  

In a subset of 11,668 mother-child pairs, including 3,210 involving exposure to antidiabetic medications, there was likewise no significant association with offspring ADHD

Conclusion:

The team concluded, “Our findings did not support the hypothesis that maternal diabetes increases the risk of ADHD in children. Additionally, maternal use of antidiabetic medication was not associated with ADHD.” 

This study highlights the importance of high-quality research. A previous meta-analysis linking ADHD and maternal diabetes did not appropriately adjust for confounders and cited many small studies that may have included biased self-report scales. This large, registry-based cohort study of nearly 230,000 mother–child pairs found no evidence that maternal diabetes—whether pre-existing or gestational—or prenatal exposure to antidiabetic medications was associated with subsequent offspring ADHD as measured by hospital-recorded ADHD outcomes. The study’s strengths include its population scale, prolonged follow-up, and extensive adjustment for maternal and perinatal confounders (including maternal mental health and substance-use disorders), which address many limitations of earlier, smaller studies that reported elevated risks.  

September 8, 2025

Population Study Finds Association Between COVID-19 Infection and ADHD

Background: 

The COVID-19 pandemic brought environmental changes that may have influenced ADHD symptoms and contributed to higher diagnosis rates. School closures, the transition to remote learning, and restrictions on outdoor activities led to increased screen time and isolation, both of which can affect attention and behavioral regulation. Children and adolescents, who usually depend on social interactions and structured routines, experienced significant disruptions during this period.  

Method:

South Korea has a nationwide single-payer health insurance system that keeps detailed health records on virtually its entire population. To explore the impact of COVID-19 on ADHD, a Korean research team used a database established by the Korean government that tracked all patients with COVID-19 between 2020 and 2023, nationwide COVID vaccination records, and insurance claims. They included all participants aged 6 through 29 years old. 

The onset of ADHD was determined by diagnosis combined with the prescription of ADHD medication. 

Altogether, the study encompassed almost 1.2 million Koreans, including over 150,000 children (6-12), more than 220,000 adolescents (13-19), and almost 800,000 young adults (20-29). 

The team adjusted for age, sex, income, Charlson Comorbidity Index, and medical visits. The Charlson Comorbidity Index predicts the mortality for a patient who may have a range of 17 concurrent conditions, such as heart disease, AIDS, or cancer. 

Results:

With these adjustments, young adults known to be infected with COVID-19 were about 40% more likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection

Adolescents known to be infected with COVID-19 were about twice as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

Children known to be infected with COVID-19 were 2.4 times as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection

All these results were highly significant, and point to much greater impact on the youngest persons infected. 

Interpretation: 

The team concluded, “our nationwide study revealed that the COVID-19 pandemic significantly influenced ADHD incidence (raising incidence between 2020 and 2023), with SARS-CoV-2 infection identified as a critical risk factor,” and “In particular, early intervention and neurological evaluations are needed for children, adolescents, and young adults with a history of SARS-CoV-2 infection.”