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July 25, 2024
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.”
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/.
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.”
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 ..."
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."
A new study in the respected journal PLOS One analyzes data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to examine trends in the incidence, prevalence, and disability-adjusted life-years associated with ADHD among adolescents and young adults aged 10 to 24 years between 1990 and 2021.
The GBD 2021, released by the Institute for Health Metrics and Evaluation (U.S.), is a comprehensive global analysis of 371 diseases, injuries, and risk factors – such as ADHD – across 204 countries from 1990 to 2021. Its open-source data are publicly available.
First, a distinction. Incidence measures the number of new cases of a disease that develop in a specific population each year. Prevalence measures the total number of existing cases – both new and pre-existing – in a population each year.
The estimated global incidence of ADHD declined marginally from 12.61 per 100,000 population in 1990 to 11.89 per 100,000 population in 2021, representing an average annual decrease of 0.6% in age-standardized incidence. The rates observed were comparable between males and females.
Regional trends varied: Western Europe had the highest rise in ADHD incidence (0.5% annually), while North Africa and the Middle East saw the largest drop (0.7% annually). Overall, a higher Socio-Demographic Index (SDI) is linked to a greater incidence, although it is far from a perfect fit. Nationally, showed the highest increase in ADHD incidence (1.15% annually), while Qatar showed the largest decrease with an annualized reduction of 1.77%.
The estimated global prevalence of ADHD declined marginally from 2.38% in 1990 to 2.17% in 2021. Again, the decline was similar for males and females, and across all age groups (10-14, 15-19, 20-24). Higher SDI was associated with higher prevalence, but inconsistently.
Disability-adjusted life-years (DALYs) combine years lost from early death and years lived with disability to measure disease burden. Globally, the age-standardized DALYs rate for ADHD decreased slightly from 30.3 per 100,000 population to 26.6 per 100,000 population, for an average annual decline of 0.6%. The decline occurred across age groups and was similar between males and females.
The authors concluded that ADHD rates and related health burdens have generally declined over the past quarter century, though recent patterns are less consistent due to factors like socioeconomic changes and evolving diagnostic standards. Continued research is needed to improve the accuracy and accessibility of ADHD diagnosis and treatment to further reduce its global impact.
Take-Away:
The broader takeaway is one of cautious reassurance. Despite rising public awareness and diagnosis rates in many Western countries, the global picture over 25 years shows a gentle decline in ADHD burden among young people — not a crisis of escalating proportions. That said, the variation between regions suggests that access to diagnosis, cultural factors, and reporting standards are shaping the numbers as much as underlying biology. Progress is real but uneven, and the work of improving equitable access to diagnosis and care is far from finished.
The first few weeks of life are the time when babies are most vulnerable to seizures (known as neonatal seizures). This is partly because of events that can occur during birth, and partly because the newborn brain is naturally in a more excitable state than a mature brain, making it more prone to seizure activity.
Seizures affect roughly 1 to 3 in every 1,000 full-term babies born, and the rate is considerably higher in premature babies, at around 11 to 14 per 1,000. In most cases, seizures at this age are triggered by a specific event or injury affecting the brain. In full-term newborns, the most common cause is a condition called hypoxic-ischemic encephalopathy (HIE), which occurs when the brain is deprived of adequate oxygen and blood flow around the time of birth. Other causes include genetic or metabolic conditions, stroke, bleeding in the brain, and structural abnormalities in how the brain developed. In very premature babies, bleeding into the fluid-filled spaces of the brain (known as intraventricular hemorrhage) is the leading culprit.
Diagnosing seizures in newborns is tricky because many normal or abnormal movements and behaviors in this age group can look like seizures without actually being them. For this reason, monitoring the baby’s brain activity using an electroencephalogram (EEG) – a test that records electrical signals in the brain – is essential to confirm whether a seizure is truly occurring.
Sweden’s single-payer health system provides universal coverage, with national registers linking healthcare and population data. Researchers tracked infants with EEG/aEEG-confirmed seizures born between 2009 and 2020 and compared them to controls without neonatal seizures.
Altogether, 1062 infants with neonatal seizures were matched with 5310 controls.
The team adjusted for birth, mode of delivery, sex, birth weight, and Apgar scores – quick, standardized assessments used to evaluate newborns’ health minutes after birth.
With these adjustments, infants who had neonatal seizures were twice as likely to subsequently be diagnosed with ADHD and three times as likely to be subsequently diagnosed with autism spectrum disorder.
The authors emphasized that because the study was observational, it cannot demonstrate a direct cause-and-effect relationship between neonatal seizures and outcomes. Factors like seizure frequency, genetics, and socioeconomic status are thought to significantly impact the prognosis of affected children, but these could not be included in this study due to data limitations.
Background:
There are currently few long-term treatment options for adult ADHD. Psychostimulants can help reduce symptoms, but their benefits rely on availability, continued use, and are not easily tolerated by some. Cognitive-behavioral therapies have also proven to be helpful, but access is limited because they must be provided by trained specialists. These challenges highlight the need to explore alternative interventions that could provide cognitive and behavioral improvements with fewer side effects.
Exercise has shown potential as a nonclinical intervention for ADHD. Previous research indicates that physical activity can increase cortical volume, enhance brain activation, and boost connectivity in cognitive regions, as well as raise dopamine and norepinephrine levels – effects similar to psychostimulants. Research in children and teens with ADHD has found that both regular exercise programs and even single workout sessions can improve executive functions (mental skills like planning and self-control) and reduce core ADHD symptoms. But whether exercise helps adults with ADHD has remained an open question.
Study:
A Chinese sports medicine research team set out to answer this by reviewing all available peer-reviewed studies on exercise and adult ADHD. They found so few studies on regular exercise programs – only four total, and three of those were small pilot studies just testing whether the approach was feasible – that they couldn’t draw firm conclusions about long-term exercise interventions.
However, they were able to analyze four moderate-to-high-quality studies involving 152 adults with ADHD that tested single exercise sessions. The combined results showed moderate improvements in inhibitory control (the ability to resist impulses and stay focused). Adults not taking medication showed large improvements.
When they looked at four studies involving 170 adults, they found small but consistent improvements in core ADHD symptoms after single exercise sessions. There was little to no variation (heterogeneity) in individual study outcomes, and no sign of publication bias.
Results:
The team concluded, “Overall, these findings offer preliminary evidence on the potential role of exercise as a helpful strategy in the management of adult ADHD,” but cautioned that more well-designed randomized controlled trials are needed to determine the efficacy of both acute and chronic exercise interventions for adult ADHD, with particular emphasis placed on determining the best “prescription” for exercise – what type, how intense, and how often.
They also noted that most existing research has focused narrowly on attention and impulse control, while other important mental abilities like working memory and mental flexibility remain largely unexplored.
Take-Away:
The takeaway here is practical and accessible: you don't need a long-term fitness program to get a cognitive bump from exercise if you have ADHD. Even a single session appears to help — particularly with impulse control. While the research base is still thin and we don't yet know the ideal exercise "prescription," the risk-benefit calculation is hard to argue with. For adults with ADHD who can't access medication or therapy, or who simply want an additional tool, breaking a sweat may be worth building into the routine.
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