July 25, 2024

Meta-analysis Associates Dasotraline with Some Reduction in ADHD Symptoms

Dasotraline is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that had been under development by Sunovion for treating ADHD and binge eating disorder.  

An Indian research team conducted a systematic search of the peer-reviewed medical literature to perform meta-analyses of the quantitative outcomes of clinical trials. 

Meta-analysis of five double-blinded randomized clinical trials (RCTs) with a combined total of 1,498 participants reported a small-to-medium effect size reduction in ADHD symptoms in patients given dasotraline as opposed to those given placebo. 

There were, however, strong indications of publication bias. Using the trim-and-fill procedure to correct for that bias yielded a small effect size reduction in ADHD symptoms in patients given dasotraline compared with those given placebo. 

Insomnia were more than four times more frequent among patients given dasotraline than among those given placebo. There was no evidence of the frequency of insomnia being dose-dependent. 

Similarly, patients given dasotraline were more than four times more likely to report decreased appetite than those receiving placebo. In this case, however, the effect was clearly dose-dependent, rising from 3x for 2mg to 4x for 4mg to 5x for 6mg and almost 8x for 8mg. 

The authors concluded, “dasotraline can reduce the core symptoms of ADHD, that is, hyperactivity/impulsivity and inattentiveness, leading to an overall improvement of ADHD compared to placebo. Dasotraline can also improve clinician-determined patients’ global functioning compared to the placebo. The most common adverse drug reactions related to dasotraline were insomnia and decreased appetite. However, to fill the knowledge gap, multicentric randomized active-controlled clinical trials are warranted in this domain for a successful translation into clinical practice.” 

Weighing these less than impressive initial results against the cost of further RCTs, Sunovion withdrew its application for approval by the Food and Drug Administration, stating, “while Sunovion considers dasotraline to be a promising, novel treatment for binge eating disorder and ADHD, we believe that further clinical studies would be needed to support a regulatory approval for dasotraline in these indications.” 

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Rituparna Maiti, Archana Mishra, Monalisa Jena, Shampa Maji, Milan Padhan, Biswa R. Mishra, “Efficacy and safety of dasotraline in attention‐deficit hyperactivity disorder: A systematic review and meta‐analysis,” Indian Journal of Psychiatry (2024), https://doi.org/10.4103/indianjpsychiatry.indianjpsychiatry_3_24. 

Brian Park, “Dasotraline Development for ADHD, Binge Eating Disorder Halted, NDAs Withdrawn,” Medica Professionals Reference, May 14, 2020, https://www.empr.com/home/news/drugs-in-the-pipeline/sunovion-withdraws-nda-dasotraline-development-binge-eating-adhd/.  

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Nationwide population study suggests ADHD medication may reduce child abuse

Nationwide Population Study Suggests ADHD Medication May Reduce Child Abuse

Child abuse includes any of the following inflicted on a minor under 18 years old: physical or emotional harm, sexual abuse, or neglect.

It is known to be associated with environmental factors such as poverty, parents or neighbors with a history of violence, and gender inequality.

Chronic mental disorders in minors are also associated with child abuse. To what extent, if any, might that be true of ADHD?

Taiwan has a single-payer national health insurance system that covers more than 99.6% of all residents, enabling nationwide population studies.

A local research team used data from almost two million Taiwanese in their country’s National Health Insurance Research Database (NHIRD) spanning 15 years (2000-2015) to carry out a matched-cohort study. 

All diagnoses of ADHD were made by board-certified specialists such as psychiatrists, pediatricians, neurologists, or physiatrists with a specialty in child and adolescent development.

3,540 children and adolescents between 6 and 18 years old with a diagnosis of ADHD were matched on a one-to-three basis with 10,620 peers from the NHIRD without an ADHD diagnosis.

The team adjusted for age, gender, location of residence (Northern, Central, Southern, and Eastern Taiwan), urbanization level of residence, level of hospitals as medical centers, and monthly insured premium. They further adjusted for comorbid conditions: intellectual disability, autistic disorder/pervasive developmental disorder, conduct disorder (CD)/oppositional defiant disorder (ODD), other developmental disorders, childhood emotional disorder, Tourette syndrome/tics disorders, and involuntary urination and defecation.

Overall, children and adolescents with an ADHD diagnosis were 1.8 times as likely to be abused as those without an ADHD diagnosis.

Unmedicated children and adolescents with an ADHD diagnosis were three times more likely to be abused. ADHD medication cut that risk in half.

That held true whether the medication used was methylphenidate or atomoxetine. Methylphenidate appeared to be slightly more effective than atomoxetine, and the combination of methylphenidate and atomoxetine slightly more effective yet, but these differences were not statistically significant.

The team concluded, “The results support that pharmacotherapy may attenuate the risk of child abuse in ADHD patients.”

March 5, 2024

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

Liquid Medication Options for ADHD Adults with Autism Spectrum Disorder

Long-Acting Liquid Methylphenidate for Treating ADHD in Intellectually Capable Adults with Autism Spectrum Disorder

A team from Harvard Medical School and Massachusetts General Hospital conducted a six-week open-label trial of liquid-formulation extended-release methylphenidate (MPH-ER) to treat ADHD in adults with high-functioning autism spectrum disorder (HF-ASD). ASD is a lifelong disorder with deficits in social communication and interaction and restricted, repetitive behaviors. Roughly half of those diagnosed with ASD also are diagnosed with ADHD.

This was the first stimulant trial in adults with both ASD and ADHD. There were twelve males and three female participants, all with moderate to severe ADHD, and in their twenties, with IQ scores of at least 85.

The use of a liquid formulation enabled doses to be raised very gradually, starting with a daily dose of 5 mg(1mL) and titrating up to 60 mg over the first three weeks, then maintaining that level through the sixth week. Participants were reevaluated for ADHD symptoms every week during the six-week trial. The severity of ASD was assessed at the start, midpoint, and conclusion of the trial, as were other psychiatric symptoms.

Before the trial, researchers agreed on a combination of targets on two clinician-rated scoring systems that would have to be reached for treatment to be considered successful. One is a score of 2 or less on the CGI-S, a measure of illness severity, with scores ranging from 1 (normal, not at all ill) to 7 (most extremely ill). The other is a reduction of at least 30 percent in the AIS RS score, which combines each of 18 symptoms of ADHD on a severity grid (0=not present; 3=severe; overall minimum score: 0; overall maximum score: 54).

After the trial, twelve of the fifteen patients (80 percent) met the preset conditions for success. Fully fourteen (93 percent) saw a ≥ 30 percent reduction in their AISRS score, while twelve scored ≤ 2 on illness severity.

However, when using the patient-rated ASRS scoring system, only five (33 percent) saw a ≥ 30 percent reduction in ADHD severity.

Thirteen participants (87percent) reported at least one adverse event, and nine (60 percent) reported two or more. One reported a serious adverse event (attempted suicide) in a patient with multiple prior attempts. Because the attempt was not deemed due to medication, they continued and completed the trial. Seven participants experienced titration-limiting adverse events (headaches, palpitations, jaw pain, and insomnia). Headache was most frequent (53%), followed by insomnia and anxiety(33% each), and decreased appetite (27%).

During the trial, weight significantly decreased, while pulse significantly increased. There were no significant differences in other vital and cardiovascular measurements.

The authors concluded, "this OLT of short-term MPH-ER therapy documents that acute treatment with MPH-ER in young adults with ASD was associated with significant improvement in ADHD symptoms, mirroring the typically-expected magnitude of response observed in adults with only ADHD. Treatment with MPH-ER was well-tolerated, though associated with a higher than expected frequency of adverse events."

They also cautioned, "The results of this study need to be considered in light of some methodological limitations. This was an open-label study; therefore, assessments were not blind to treatment. We did not employ a placebo control group and, therefore, cannot separate the effects of treatment from time or placebo effects. ... firmer conclusions regarding the safety and efficacy of MPH-ER for the treatment of ADHD in HF-ASD populations await results from larger, randomized, placebo-controlled clinical trials."

August 7, 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.

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‍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.

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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. 

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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.  

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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.” 

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