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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."
For centuries, we’ve called the eyes the "windows to the soul," but for modern neurologists, they are quite literally a window into the brain. The retina and the central nervous system share the same embryonic origins, developing from the same neural tissue in the womb. Because of this deep biological connection, the back of your eye acts as a non-invasive map of your brain's health, displaying a complex web of nerves and blood vessels that can (theoretically!) mirror certain neurodevelopmental conditions.
Recently, a buzz rippled through the mental health community when a study published in partnership with Seoul National University Bundang Hospital claimed a massive breakthrough. Researchers developed an Artificial Intelligence (AI) model that could screen children for Attention-Deficit/Hyperactivity Disorder (ADHD) using nothing more than a simple retinal photograph. The study, which prospectively recruited children from Severance Hospital and Eunpyeong St. Mary’s Hospital, produced results that were staggering: the AI reportedly achieved an accuracy rate of 96.9%!
In the world of medical testing, scientists use a metric called AUROC (Area Under the Receiver Operating Characteristic) to measure how well a test works.
An AUROC of 96.9% is a near-perfect score, suggesting a tool is ready for immediate, real-world deployment. While headlines promised a revolution in mental health screening, a deeper look into this research and the study’s design has exposed that this 96.9% AUROC was more likely evidence of a flawed methodology rather than a biological reality.
To build their screening tool, researchers analyzed over 1,100 retinal images using a digital pipeline called AutoMorph and a machine-learning model known as XGBoost. The AI was trained to hunt for physical signals of the "Dopamine Connection." Dopamine is the primary neurotransmitter involved in ADHD, but it is also essential to the eye. It regulates synaptic formation, retinal blood flow, and vascular endothelial regulation. Because dopamine dysregulation influences how blood vessels grow and remodel, the study hypothesized that an ADHD brain would leave a unique "fingerprint" on the retinal vasculature, resulting in denser, thicker vessel structures.
On paper, the logic was sound: use AI to spot the subtle vascular remodeling caused by dopaminergic shifts. But a closer look at the investigation revealed that the AI wasn't just spotting ADHD; it was over-indexing on technical noise.
The most significant "smoking gun" flagged by critics is a massive temporal mismatch. In other words, there was a severe disparity in the timeframes and conditions under which the retinal images for the two comparison groups were collected. For an AI to learn a biological condition, it must compare groups under identical technical conditions. Instead, this study created a time-traveling dataset:
A scientific study is only as reliable as its control group. The control in any experiment acts as a baseline against which the study group is compared. In this case, the control group should be composed of children without any neurodevelopmental disorders, or of “typically developing” children.
In this study, the control group wasn't composed of healthy children from the community. Instead, they were patients visiting a tertiary ophthalmology clinic. Children visiting a specialist eye hospital are rarely "typical." They are there because they have symptomatic eye issues. This introduced a massive selection bias involving three major confounders:
When training AI, you must never allow the "test questions" to leak into the "study material." The researchers, however, committed a fundamental violation of machine learning hygiene known as Eye-to-Eye Data Leakage. The study split the data by the eye rather than by the participant.
Human eyes are highly correlated; the left eye is a near-mirror of the right. If a child's left eye was used for training and their right eye was used for testing, the AI was effectively "cheating." Instead of learning the general traits of ADHD, the model was potentially memorizing individuals. This error artificially balloons accuracy metrics.
The true test of medical AI is diagnostic specificity, or differential diagnosis. This refers to the ability to tell one condition apart from another. While the model claimed 96.9% accuracy against a flawed control group, its performance collapsed when faced with real-world complexity.
When the researchers asked the AI to differentiate between ADHD and Autism Spectrum Disorder (ASD), the accuracy plummeted to a poor 63% AUROC. In real-world clinical settings, an accuracy of 63% is dangerously close to a 50% coin flip. Since ADHD frequently co-occurs with ASD, anxiety, or intellectual disabilities, an AI that cannot handle these "clinical differentials" is functionally useless in a doctor's office. The failure at this stage proves the model was likely detecting technical quirks of the dataset rather than a unique biological marker for ADHD.
To move from the lab to the clinic, we must establish a foundation built on rigor rather than high-speed data scraping. Moving forward, we must demand these 3 Pillars of Trusted Medical AI :
The dream of a quick eye scan to diagnose ADHD is not dead, but it must be rescued from "fast science" shortcuts and buzzy headlines.
Background:
One of the more persistent concerns among parents of children with ADHD is whether stimulant medications will stunt their child's growth. A large Israeli cohort study now offers some of the most rigorous reassurance to date, and its methodology sets it apart from earlier research.
The question has long been complicated by a more fundamental uncertainty: do growth differences in children with ADHD stem from the condition itself, from stimulant treatment, or from factors present before any medication is ever prescribed? Without a clear answer, clinicians and families have faced a genuine dilemma when weighing the benefits of stimulant therapy against potential long-term physical costs.
Most previous studies compounded this difficulty by comparing group-average heights, which ignores the crucial variable of genetic potential. A child who is short relative to the general population may simply have short parents. Failing to account for this introduces systematic bias and can make medications appear more harmful than they are.
The Study:
The Israeli research team addressed this directly. Using health records from a nationwide provider, they assembled a retrospective cohort of children born between 1995 and 2003, following them through 2023. This amount of time was long enough for all participants to have reached adult stature (defined as 17 or older for females, 19 or older for males). Their sample included 5,671 children with untreated ADHD, 11,846 who received stimulant treatment, and 47,258 non-ADHD controls. Children who took stimulants for only one to two months, or who had chronic medical conditions requiring long-term medication, were excluded to avoid confounding the results.
Crucially, adult height was evaluated not against population norms but against each individual's expected height, calculated from parental heights using the Tanner-Goldstein-Whitehouse method, a standard approach for estimating genetic height potential via mid-parental height.
When the researchers compared adult heights across the three groups using analysis of variance (ANOVA), they did find statistically significant differences. But statistical significance, particularly in studies with tens of thousands of participants, does not automatically translate into clinical significance. The effect sizes were consistently very small, and the absolute differences were under one centimeter, which is a margin considered clinically negligible.
Their conclusion is measured but clear: after accounting for genetic growth potential, neither an ADHD diagnosis nor stimulant treatment was associated with meaningful reductions in adult height. The findings, they argue, support prioritizing behavioral and functional outcomes when making treatment decisions, since the risk of clinically significant height loss appears to be minimal.
The Take-Away:
For families navigating ADHD treatment, the practical implication is significant: concerns about permanent growth suppression, while understandable, should not be the primary driver of whether or how long a child receives stimulant therapy.
A recent meta-analysis examined how well cognitive behavioral therapy (CBT) improves not just symptoms, but everyday functioning and quality of life in adults with ADHD.
The Background:
ADHD in adults affects far more than attention or impulsivity. It often disrupts key areas of life:
These broad impacts highlight a key issue: reducing symptoms does not automatically translate into better day-to-day functioning.
CBT is a structured, skills-based therapy that helps people:
While both medication (especially stimulants) and CBT improve core ADHD symptoms, CBT is particularly aimed at improving real-world functioning.
The Study:
The researchers analyzed studies involving adults diagnosed with ADHD (or showing clinically significant symptoms). They included:
They focused specifically on outcomes beyond symptoms:
The Results:
1. Strongest Effects: Occupational functioning
CBT showed consistently strong improvements in work-related functioning compared to control groups, both immediately after treatment and at follow-up. This was the most robust finding across domains.
2. Moderate Improvement: Global Functional Impairment
CBT led to moderate improvements in overall daily functioning, with some evidence that gains persist over time. In studies tracking individuals over time, improvements were even stronger at follow-up.
3. Modest Gains: Social Relationships
CBT produced small to moderate improvements in social functioning. Benefits were present both after treatment and at follow-up, but were less pronounced than in work-related outcomes.
4. Limited Effects: Academic Functioning
There were moderate short-term gains when CBT was compared to control groups, but these did not persist at follow-up. Within-subject studies showed only small improvements overall.
5. Modest and Inconsistent Effects: Quality of Life
Improvements in quality of life were small when compared to control groups and often did not last. However, studies tracking individuals over time showed moderate improvements, suggesting some benefit that may not always show up clearly in between-group comparisons.
Overall, the findings suggest:
One notable nuance: CBT did not always outperform other active treatments (like medication or other therapies). This suggests that while CBT is effective, its benefits may partly overlap with broader therapeutic or support effects rather than relying on a single, unique mechanism.
The Take-Away:
CBT is a valuable, evidence-based treatment for adults with ADHD, especially for improving work functioning and overall daily life management. However, its impact on relationships, academic outcomes, and quality of life is more limited and less consistent, pointing to the need for more targeted or combined approaches in those areas.
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