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November 21, 2021
The Comparison of Methylphenidate and Psychotherapy in adult ADHD Study (COMPAS) was a prospective, randomized multicenter clinical trial, comparing methylphenidate (MPH) with placebo in combination with cognitive-behavioral group psychotherapy or (GPT) individual clinical management (CM), the latter two being active controls. This was a year-long trial.
The German study team randomly assigned 433 participants with adult ADHD to each of the four study groups. As this was a 2 x 2 matrix trial, each study group included both one pharmacological intervention (MPH or placebo) and one psychological intervention (GPT or CM).
GPT included mindfulness training, skills for stress management, emotion regulation, and time management as well as behavioral analyses. CM sessions focused on participants' current concerns and medication.
As is usual in such trials, the number of participants decreased throughout the study as some individuals dropped out. At 13 weeks, 337 participants were still taking their study medication.
Both MPH and placebo were started at 10 mg doses, then up-titrated depending on clinical response. After 13 weeks, the mean MPH dose had risen to 50 mg, and the mean dose of placebo to 58 mg.
Safety
Among those taking MPH, 96 percent of participants reported at least one adverse event. Among those on placebo, the equivalent figure was 88 percent.
The principal adverse events occurring significantly more frequently in the MPH group were decreased appetite (22 vs. 3.8 %), dry mouth (15 vs. 4.8 %), palpitations (13 vs. 3.3 %), gastrointestinal infection (11 vs. 4.8 %), agitation (11 vs. 3.3 %), restlessness (10 vs. 2.9 %), excessive sweating, rapid heartbeat, and weight decrease (all 6.3 vs. 1.9 %).
The only adverse event that occurred significantly more frequently in the placebo group was a temporary loss of consciousness caused by a fall in blood pressure (2.4 vs. 0%).
Serious adverse events were infrequent in both groups, affecting 7.3 percent of those in the MPH group and 4.3 percent of those in the placebo group. The difference between groups was not statistically significant. There were no deaths.
While patients on MPH lost an average of 1.2 Kg during the year, those on placebo remained constant (gained 0.3 Kg). Changes in blood pressure were negligible in both groups. Average heart rate rose by 3 beats per minute in the MPH group, versus a 1 beat per minute decline in the placebo group. There were no significant differences in clinically relevant electrocardiogram abnormalities between the two treatment groups.
Turning to psychological interventions, 90 percent of participants in the GPT group and 94 percent in the CM group experienced at least one adverse event. Differences between the two groups were not statistically significant. Serious adverse events occurred in 3.9% of the GPT participants and 7.7 percent of the CN participants, but again the difference between groups was not statistically significant. There were no clinically relevant changes in weight, blood pressure, or heart rates in these groups throughout the study.
The study team found no modulating effects of either form of psychological treatment on the distribution of adverse events under MPH and placebo treatment.
The authors concluded, "adverse events were found more frequently in patients receiving MPH compared to placebo and were mostly attributable to the centrally stimulating and sympathomimetic action of MPH, including agitation, restlessness, dry mouth, decreased appetite, palpitations, tachycardia [rapid heartbeat], and hyperhidrosis [excessive sweating]. About these adverse events, a causal relationship with MPH seems likely, supported by both the pharmacological effects of MPH as well as previous safety data. ... It is important to note that patients receiving MPH in COMPAS significantly profited from the medication about the reduction of ADHD symptom load, thus the risks of adverse events have to be weighed against the clear benefits. ... Premature termination of MPH due to an adverse event as major reason occurred in less than 10 % of patients and was not statistically significantly different from placebo."
Bernhard Kis, Caroline Lücke, Mona Abdel-Hamid, Philipp Heßmann, Erika Graf, Mathias Berger, Swantje Matthies, Patricia Borel, Esther Sobanski, Barbara Alm, Michael Rösler, Wolfgang Retz, Christian Jacob, Michael Colla, Michael Huss, Thomas Jans, Ludger Tebartz van Elst, Helge H. O. Müller, Alexandra Philipsen, "Safety Profile of Methylphenidate Under Long-Term Treatment in Adult ADHD Patients - Results of the COMPAS Study," Pharmacopsychiatry (2020), https://doi.org/10.1055/a-1207-9851.
Vitamins play important roles in metabolism, immune regulation, and neurodevelopment. Recent studies show that deficiencies in vitamins like D, B6, B12, and folate are common in people with ADHD and ASD (autism spectrum disorder), and are associated with behavioral, cognitive, and brain development issues.
The Study:
A study team based in China has just performed a systematic search of the peer-reviewed medical literature to perform meta-analyses of clinical trials exploring vitamin interventions in the treatment of ADHD and ASD.
ADHD trials included participants with an official diagnosis. The primary intervention was vitamin supplements, while other treatments, including medications, remained unchanged or were excluded during the study period. ADHD outcomes included measurable changes in ADHD symptoms using validated rating scales and executive function measures.
Eligible studies included standard or sham control groups, crossover, parallel, or other clinical trial designs. In crossover studies, only first-phase data were analyzed to prevent carryover effects.
Ten trials with 852 participants met the standards, but meta-analysis showed no significant results. The outcomes varied widely, suggesting a need to distinguish among vitamins.
Results:
Of the five trials involving 347 participants that specifically evaluated vitamin D supplementation, results indicated a large effect size improvement in ADHD symptoms and executive function measures. The other five studies did not show any observable improvement.
Key limitations include:
The team concluded, “This meta-analysis supports the use of vitamin supplementation as a promising adjunctive treatment for ASD and ADHD. Vitamin B showed greater benefits in improving symptoms of ASD, while vitamin D was more effective in managing ADHD-related behaviors. These findings suggest that specific vitamins may target disorder-specific symptoms. Despite limitations such as the lack of trials on other vitamins and limited understanding of underlying mechanisms, vitamin therapy remains a low-cost, accessible option.”
An important limitation of this work is that the positive results for vitamin D were due to two studies from Iran. So far, no positive study has emerged from a non-Iranian study.
Interpretation:
The vitamin D findings are intriguing and could be important if replicated outside of Iran. Since supplementation is already widely recommended to those with limited sunlight exposure, clinicians may want to consider monitoring their patients’ vitamin D intake, especially in the winter months. It should be noted, however, that due to the limitations of this study, the results are by no means conclusive, and vitamin D should not be taken as a stand-alone treatment for ADHD.
Claims-based real-world data can reveal population-level trends in health among people with neurodevelopmental disorders. This new study examined the prevalence, demographics, and chronic comorbidities of adults and of children and adolescents with ADHD in a large national health plan. It also compared healthcare use and costs between those with and without ADHD.
A research team in the United States conducted an observational cohort study using claims data from more than 1.9 million adults and nearly 500,000 children and adolescents, comparing individuals diagnosed with ADHD to those without the diagnosis.
ADHD was diagnosed in 4% of adults and in 5% of children and adolescents.
Comorbidities By The Numbers:
Disruptive childhood disorders are behavioral problems marked by ongoing defiance, uncooperativeness, and aggression that affect a child's daily life and relationships. The main types, oppositional defiant disorder (ODD) and conduct disorder (CD), involve persistent anger and argumentativeness in ODD, and more severe actions like aggression, cruelty, and criminal behavior in CD. Without treatment, these common childhood disorders can continue into adulthood and raise the risks of substance use, violence, incarceration, and early death.
Disruptive childhood disorders were twenty times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and fifteen times more frequent among adults with ADHD.
Bipolar disorder was twelve times more common among children and adolescents with ADHD than those without ADHD, and seven times more common among adults with ADHD.
Schizophrenia was eleven times more prevalent among children and adolescents with ADHD than those without ADHD, and three-and-a-half times more common among adults with ADHD.
Anxiety was nine times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and more than five times more frequent among adults with ADHD.
Depression was eight times more common among children and adolescents with ADHD than those without ADHD, and more than five times more common among adults with ADHD.
Suicidal ideation was eight times more prevalent, and suicide attempt seven times more prevalent, among children and adolescents with ADHD than those without ADHD. Both suicidal ideation and suicide attempt were five times more common among adults with ADHD.
Gender dysphoria was almost six times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and five times more frequent among adults with ADHD.
Eating disorders were over four times more common among children and adolescents with ADHD than those without ADHD, and five times more common among adults with ADHD.
Substance-related disorders were over six times more prevalent, and alcohol use disorder was six times more prevalent among children and adolescents with ADHD than those without ADHD, and four and three times more prevalent among adults with ADHD.
Increased Costs of Medical Care:
These comorbidities and ADHD led to higher medical costs. Children and adolescents with ADHD spent $610 more annually on healthcare than those without, while adults with ADHD had $1,684 higher average yearly expenditures than non-ADHD adults.
The Take-Away:
This large claims-based analysis of a national commercial insurer found ADHD diagnoses in roughly 4% of adults and 5% of children. It documented substantially higher rates of co-occurring behavioral-health conditions and markedly greater healthcare utilization and expenditures among those with ADHD. The authors report increased odds for several co-occurring diagnoses, as well as higher per-member-per-month (PMPM) spending and per-thousand-per-month (PTPM) utilization, largely driven by greater use of behavioral health services.
Importantly, these results come from cross-sectional, claims data within a commercially insured population: they describe associations, not causal relationships, and may not generalize to uninsured, publicly insured, or otherwise different populations. These findings, therefore, warrant cautious interpretation and highlight the need for longitudinal and more representative studies to clarify drivers of the increased burden and to inform care and policy.
Background:
Since the first in vitro fertilization (IVF) in 1978, assisted reproductive technology (ART) has led to over 10 million births worldwide.
There are four types of embryo transfers, depending on whether they are fresh or frozen, and on their developmental stage.
Fresh cleavage stage embryos are transferred on day 2 or 3 following fertilization and typically contain four to eight relatively large, undifferentiated cells. Fresh blastocyst embryos are transferred on day 5 or 6 after fertilization. At this point, they have developed over a hundred cells and have differentiated into two types: the inner cell mass, which develops into the fetus, and the outer cell layer, which forms the placenta.
Globally, more children are now born through assisted reproductive technology using frozen-thawed embryo transfer than fresh embryo transfer.
Research suggests that ART-conceived offspring may face increased risks of cardiovascular, musculoskeletal, chromosomal, urogenital diseases, and cancers. Might they also be at increased risk for ADHD?
Study:
Taiwan’s single-payer health insurance covers over 99% of people and records all their healthcare activity. Since 1998, it has kept an ART database for all couples registered for IVF treatment.
A Taiwanese research team reviewed all records for the five-year period from 2013 through 2017, ultimately analyzing 3,125 live singleton births from fresh cleavage stages, 1,332 from fresh blastocysts, 1,465 from frozen cleavage stages, and 4,708 from frozen blastocysts, alongside 878,643 naturally conceived singleton births.
The team controlled for the following potential confounders: pregnancy-induced hypertension, chronic hypertension, diabetes mellitus, gestational diabetes mellitus, unhealthy lifestyle, placenta previa, placenta abruption, preterm premature rupture of membrane, and postpartum hemorrhage.
Results:
With these adjustments, cleavage stage embryo transfers, whether fresh or frozen, were associated with a seven-fold higher rate of ADHD diagnosis in offspring than natural conception.
Frozen blastocyst embryo transfers were likewise linked to a seven-fold increase in ADHD diagnoses in offspring compared to natural conception. Notably, fresh blastocyst transfers showed a 19-fold increase, likely due to the smaller number of cases in this category.
The team concluded, “Compared to natural conception, ART is associated with higher risks, particularly for preterm birth, ADHD, and developmental delay.”
Conclusion:
This large national cohort suggests that ART-conceived singletons face higher rates of several adverse outcomes, including preterm birth, ADHD, and developmental delay. Clinicians and prospective parents should therefore weigh these potential associations when counseling and planning care, prioritize optimized ART protocols and perinatal management, and ensure early developmental surveillance for ART-conceived children so concerns can be identified and addressed promptly.
It is important to note that the findings also point to the likely contribution of underlying parental infertility in these developmental outcomes. Future research should aim to disentangle parental- versus procedure-related risks to clarify absolute risk magnitudes. As always, associations of this time should not be interpreted as causal due to the inability of observational studies to rule out all possible confounding factors.
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