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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."
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Language is powerful. The words we choose not only reflect our understanding of the world but also actively shape it. Recently, this truth has been at the center of a growing debate in the mental health field regarding how we talk about ADHD.
In a recent paper published in The Lancet Psychiatry titled “The Power of Words: Respectful Language in ADHD Research,” French and colleagues advocated for a shift toward "neurodiversity-affirmative language”. Rooted in the social model of disability, their proposal encourages researchers to abandon traditional medical terminology, e.g., words like disorder and deficit, in favor of more neutral terms such as condition and challenge.
My colleague, Dr. Michael Miller, and I read this with great interest. We completely agree that revising language is essential to good science and that, both as researchers and as human beings, we are ethically bound to speak respectfully. However, we felt compelled to write a response. In our new paper, we argue that while language must evolve, it must do so scientifically.
The Two Prerequisites for Language Change
If we are going to fundamentally shift our scientific lexicon, two requirements must be met:
Currently, the proposal by French and colleagues meets neither requirement. While they claim consensus is accumulating that certain terms are disrespectful, they provide zero empirical evidence that this view is shared by the community of individuals living with ADHD. Even proponents of patient-centered language admit there is surprisingly little data supporting specific language changes.
More alarmingly, the recommended changes severely dilute the scientific accuracy of our field. Let’s look at two examples.
Why a "Deficit" is Not Just a “Challenge"
French and colleagues suggest replacing the term deficit with challenge. On the surface, challenge sounds softer and more affirming. But scientifically, these words are not interchangeable.
For decades, the term deficit has been defined by a specific performance metric that falls substantially below an expected level. It is a measurable reality. A challenge, on the other hand, refers to a new or difficult task that tests someone's ability.
Every single human being is "challenged" by complex neuropsychological tests, but only some individuals who face that challenge demonstrate scientifically significant deficits. If we relabel measurable deficits as universal challenges, we sacrifice the exactness required to communicate scientific findings and accurately measure the effects of life-changing treatments.
ADHD is a Disorder, Not Just a "Condition"
Another proposal is to replace the word disorder with condition.
In mainstream psychiatry, a disorder is a clinically significant disturbance that causes distress or disability. The word purposefully separates natural human variation from the suffering (pathos) that gives pathology its meaning.
Condition is a completely neutral term. Pregnancy is a condition. Being tall is a condition. Calling ADHD a condition distances the diagnosis from the profound suffering it can cause.
French et al. argue against framing ADHD as a disorder because it exists on a spectrum without a clear cutoff, its manifestation is context-dependent, and its definition evolves. But if we apply that logic across all of medicine, the concept of disease unravels:
The Real-World Danger of Imprecise Language
This is not merely an academic debate over semantics. The language we use has real-world implications. In the United States and across the globe, our healthcare, educational, and legal systems run on precise medical language. Terms like impairment, dysfunction, and disorder are legally and administratively required to justify support services, workplace accommodations, specialized educational therapies, and medications. The language of pathology in diagnostic manuals regulates the flow of these resources.
If we reclassify ADHD as a neutral condition characterized only by challenges, we risk erecting massive bureaucratic barriers. Imprecise language could easily be used by institutions or insurance companies to deny vital care to the people who need it most.
The Need for Lexical Discipline
Attempting to characterize a clinical disorder entirely through its strengths happens in a scientific vacuum. We cannot ignore the vast body of rigorous evidence confirming that ADHD meets the long-standing criteria used by mental health science to identify clinical disorders.
As professionals, our respect for the ADHD community demands a commitment to language that is clear, correct, and evidence-based. To build genuine consensus about how we talk about ADHD, we need meaningful, collaborative dialogue that integrates compelling empirical data and rigorous theory.
This standard of "lexical discipline" is not just a technical preference. It is a vital mechanism through which science and the mental health professions uphold their duty to society.
For many ADHD patients, getting properly diagnosed and starting meds is only half the battle. The next step is figuring out the exact right dose. Historically, clinical guidelines have provided scant guidance on this critical step. This lack of direction can inadvertently foster two extremes in clinical practice: therapeutic inertia (settling for a subtherapeutic dose that leaves symptoms undertreated) or uncritical escalation (driving doses higher and higher beyond licensed limits without meaningful benefit).
To clear up this pharmacological gray area, an international team of researchers published the first comprehensive dose-effect network meta-analysis of ADHD medications in The Lancet Psychiatry. By pulling together a massive vault of clinical trial data, they mapped out exactly how efficacy and tolerability shift as doses increase.
Traditional meta-analyses evaluate head-to-head, pairwise data, comparing one drug at a specific dose directly against a placebo. However, this study utilized an advanced Bayesian hierarchical network model using restricted cubic splines.
This mathematical framework allowed the researchers to combine both direct trial data and indirect evidence simultaneously across 113 double-blind randomized controlled trials (RCTs). In total, the study evaluated data from 14,138 children/adolescents and 11,016 adults. By standardizing various formulations into basic equivalents (e.g., converting amphetamines to dextroamphetamine equivalents), they created a clear, unified map of dose ranges.
The study yielded distinct dose-response curves depending on the patient's age and the specific medication class. Rather than a linear trend in which "more medicine equals more benefit," most treatments reach a clear statistical plateau or ceiling.
For Children and Adolescents (under 18)
In the pediatric population, medications hit clear peak efficacy boundaries:
For both amphetamines and guanfacine, escalating the dosage past these points resulted in U-shaped curves, meaning further dose hikes yielded diminishing group-level symptom reduction.
For Adults (18 and older)
Adult profiles showed slightly different trajectories:
The ultimate goal of this landmark analysis is to guide shared decision-making between clinicians, patients, and families. The results send a dual message to the medical community:
A medication's true efficacy hinges on its tolerability, typically measured by how often patients discontinue treatment due to severe side effects. For amphetamines, this dropout risk scales linearly with dosage, notably exceeding placebo in children above 25 mg/day and becoming prominent in adults past 50 mg/day. In contrast, methylphenidate shows no clear dose-dependent dropout risk in pediatric patients, whereas adults face a steep risk curve: increasing the dose from 60 mg/day to 90 mg/day raises the dropout risk from 7.3% to 10.0% for only modest symptom relief. Finally, youth taking guanfacine experience a sharp climb in discontinuation risks, reaching a 9.8% median risk at 4 mg/day before data limitations obscure further trends.
The authors strongly emphasize that these findings represent group averages. Because individual metabolism, genetics, and comorbidities vary widely, some specific patients may legitimately require and tolerate higher off-label doses. However, if an unusually high dose is needed, the study suggests it should prompt a careful clinical pause, either to reassess for co-occurring conditions (like anxiety, autism, or sleep disorders) or to manage realistic expectations regarding what the medication can achieve.
The persistent shortage of ADHD medications has been more than a simple annoyance for patients at the pharmacy; the inconsistent availability of these medications has had deep impacts on the daily lives of those struggling without them. While public discourse has pointed fingers at over-prescribing or at restrictive DEA quotas, a recent economic evaluation in JAMA Health Forum suggests we’ve been looking in the wrong direction for an answer to what is causing this.
The reality of the shortage is less about increased demand and more about a fragile, globalized supply chain that snapped at a critical link.
Debunking the "Quota Myth":
The prevailing narrative suggested that the Drug Enforcement Administration (DEA) was stifling production by refusing to raise quotas. However, the data tells a different story. In 2022, manufacturers collectively met only about 70% of their allotted production quotas.
So we know that the problem wasn't that this DEA quota ceiling was too low. In fact, most manufacturers couldn't even reach it. Even when accounting for exports and domestic retail, production remained significantly below the legal limit. Even if the DEA had doubled its quotas, these medications still likely wouldn't have magically appeared on pharmacy shelves.
The most striking finding in the study is the correlation between the shortage and a sharp decline in the import of raw Active Pharmaceutical Ingredients (APIs). For the past decade, Germany has accounted for over 85% of US amphetamine imports. In 2022, these imports dropped by approximately 36.7%. When the API doesn't arrive at the factory, production for medium and small manufacturers grinds to a halt. Unlike larger pharmaceutical giants, these smaller players often lack the inventory cushion or flexibility to quickly pivot to a new supplier.
When the primary supply of amphetamine-based stimulants (like Adderall) faltered, it triggered a secondary crisis. Patients and clinicians, seeking alternatives, shifted toward lisdexamfetamine (Vyvanse) and methylphenidate (Ritalin/Concerta).
If we view this shortage purely through a regulatory or clinical lens, we miss the underlying cause of the crisis. The pharmaceutical industry has become a victim of its reliance on "just-in-time manufacturing” and highly concentrated sourcing. Because over 30% of APIs for the US market are produced in just one or two facilities globally, the system isn't just inefficient; it’s brittle. We are, in a sense, trapped in a system that prioritizes cost-reduction over the resilience required for public health.
The researchers suggest several policy shifts to prevent a repeat of this supply chain failure:
The ADHD medication shortage wasn't a failure of clinical oversight or a sudden surge in "TikTok-driven diagnoses”, as many have suggested. It was a failure of logistics. It reminds us that the path from a lab in Germany to a patient's hand in the US is far more precarious than we realized.
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