October 23, 2023
Guanfacine extended-release(GXR) is a non-stimulant α2A-adrenergic receptor agonist, approved worldwide for ADHD in children and adolescents.
A Japanese research team set out to explore the long-term administration of once-daily GXR in adults with ADHD over a year of treatment. Their primary objective was to evaluate the safety, and the secondary objective was to evaluate efficacy.
This was an open-label trial. Open-label trials are the opposite of double-blind trials. In a double-blind trial, neither the researchers nor the participants know what treatment they participants are receiving. In an open-label trial, on the other hand, both the researchers and participants know what treatment the participant is receiving, which can introduce significant bias. These studies are therefore at the lowest rung in the evidentiary base.
It is worth noting, however, that the risk of bias would be primarily for efficacy, and the primary aim of the trial was to evaluate safety.
The trial was funded by the manufacturer, but preregistered, a way of assuring that results would be released regardless of the outcome.
The study population consisted of 191 ADHD patients 18 and older at 71 locations in Japan. There was no control population. The 50-week flexible titrated dosing treatment period was followed by a 2-week period over which doses were gradually reduced, and then a one-week follow-up period. That means the trial covered an entire year. Of the enrolled patients, 67 dropped out, mostly due to adverse events, leaving 124 patients after the trial.
A total of 830 treatment-emergent adverse events (TEAEs) were reported by 180 patients. One in five patients (34)discontinued treatment due to adverse events. The most commonly reported adverse events were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia (abnormally slow heartbeat), malaise, constipation, and dizziness. Except for nasopharyngitis, all were considered related to the medication. There were two serious adverse events, one unrelated to the medication, the other a supraventricular tachycardia (abnormally fast heart rhythm arising from improper electrical activity in the upper part of the heart) in a patient simultaneously medicated for a preexisting condition. The patient recovered after treatment and discontinuation of GXR.
The main TEAEs resulting in Discontinuation were somnolence (nine patients), blood pressure reduction (eight patients), malaise (six patients), and bradycardia (four patients, with only one case considered severe), and postural dizziness (three patients) or dizziness(three patients).
Significant reductions in ADHD scores and improvements in executive functioning were measured across the study population following a year's GXR treatment. Again, this was not the primary aim of the trial, and double-blinded randomized controlled trials are the gold standard.
The authors concluded that "there were no new or unexpected safety concerns" and "patients who received dose-optimized GXR had improvements in multiple aspects of ADHD, including symptoms, QoL [Quality of Life], and executive functioning," but acknowledged, "There was a potential for observer bias because of the open-label nature of the study, and the findings may not be representative of real-world settings because patients with psychiatric or cardiovascular comorbidities, which are common in patients with ADHD, were excluded. In addition, there was a potential bias favoring safety and efficacy for continuing patients because those who discontinued owing to adverse events or lack of efficacy were not eligible for inclusion."
Akira Iwanami, Kazuhiko Saito, Masakazu Fujiwara, Daiki Okutsu, and Hironobu Ichikawa, "Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study," BMC Psychiatry(2020), https://doi.org/10.1186/s12888-020-02867-8.
Recent research suggests that inflammation may play a role in ADHD. Inflammation, marked by elevated proteins and cytokines, affects brain development and structure. Evidence suggests it plays a role in the development of ADHD, making the study of inflammatory markers crucial.
The platelet-to-lymphocyte ratio (PLR) is a cost-effective test for predicting outcomes of chronic inflammation and neuroimmune diseases. Studies show PLR may be an important inflammatory marker in the pathophysiology of ADHD in children.
The Study:
A Chinese study team used the National Health and Nutrition Examination Survey (NHANES) database maintained by the National Center for Health Statistics of the United States to investigate the association between PLR and ADHD in children aged 6–14.
The team identified ADHD through prescriptions of ADHD medications.
After exclusions for missing information, the study encompassed 1,455 children.
The authors adjusted for the following potential confounders: sex, age, race, poverty-to-income ratio, maternal age at childbirth, smoking during pregnancy, asthma, health insurance status, dietary inflammatory index, monocyte count, segmented neutrophil count, eosinophil count, and basophil count.
They also split the PLR results into quartiles, with the first quartile having the lowest readings.
Prescriptions of ADHD medications were twice as frequent among children in the second quartile as they were among children in the first quartile. They were four times as frequent among children in the third quartile than among children in the first quartile.
Conclusion:
The team concluded, “These findings further support the potential role of inflammation in the onset and development of ADHD, providing preliminary evidence for PLR as a potential biomarker for ADHD and suggesting its possible use in identifying high-risk populations. However, considering the limitations of this study, future research should be designed as larger-scale, prospective, multi-center randomized controlled trials to validate these findings and further explore the relationship between inflammatory mechanisms and ADHD.”
In other words, this study suggests that while high PLR values may serve as a potential biomarker for ADHD, particularly in specific high-risk groups, further research is needed to confirm these findings and fully understand the role of inflammation in ADHD development. Larger, more robust studies will be crucial to validating PLR as a reliable tool for identifying at-risk populations.
ADHD is the most prevalent neurodevelopmental disorder. Nearly 1% of pregnant women in the Nordic countries and more than 1% in the United States are prescribed ADHD medications, ranking these among the most commonly used medications during pregnancy. However, the safety of exposing a fetus to ADHD medications is still uncertain, prompting many expectant mothers to stop using them out of fear for their unborn child’s well-being.
The Study:
A European research team conducted a comprehensive nationwide study on the safety of ADHD medications during pregnancy using populations from Sweden and Denmark. The Swedish population was studied first, followed by inclusion of a separate study of the Danish population. Results were then combined through meta-analysis. Nordic countries, with their single-payer national health insurance systems and national population registers, facilitate the tracking of residents’ health from birth to death, thus providing robust data for such studies.
The team accounted for various potential confounders, including maternal age, year of delivery, whether the mother was a first-time parent, self-reported smoking during pregnancy, and any psychiatric history. They also considered psychiatric inpatient or outpatient treatment received within two years before pregnancy, as well as the dispensing of other psychotropic medications during pregnancy, including antidepressants, antipsychotics, antiseizure medications, and anti-anxiety medications. Additionally, they examined the highest level of maternal education and civil status at delivery (married or cohabiting compared to single, divorced, or widowed).
Out of 861,650 Swedish children, 2,257 were exposed to ADHD medications during pregnancy. Another 3,917 were born to mothers who discontinued ADHD medications before pregnancy.
Children exposed to ADHD medications had lower rates of ADHD, autism spectrum disorder, and overall neurodevelopmental disorders; however, none of these differences were significant.
Limiting the analysis to siblings to control for family environmental influences and genetics likewise found no significant differences.
A meta-analysis combining the Swedish results with a separately conducted nationwide population study in neighboring Denmark similarly found no significant differences between children exposed to ADHD medications during pregnancy and children born to mothers who discontinued ADHD medications before pregnancy.
Conclusion:
The team concluded, “Overall, our study provides reassuring evidence that continuing ADHD medication during pregnancy does not increase the risk of long-term NDDs [neurodevelopmental disorders] in offspring."
A new large-scale study has shed light on which treatments for attention-deficit/hyperactivity disorder (ADHD) in adults are most effective and best tolerated.
Researchers analyzed 113 randomized controlled trials involving nearly 15,000 adults diagnosed with ADHD. These studies included medications (like stimulants and atomoxetine), psychological therapies (such as cognitive behavioral therapy), and newer approaches like neurostimulation.
The Findings
Stimulant medications (lisdexamfetamine and methylphenidate) as well as selective norepinephrine reuptake inhibitors (SNRI) (atomoxetine) were the only treatments that consistently reduced core ADHD symptoms—both from the perspective of patients and clinicians. It may be worth noting that atomoxetine, while effective, was less well tolerated, with more people dropping out due to side effects.
Psychological therapies such as CBT, mindfulness, and psychoeducation showed some benefits, but mainly according to clinician ratings—not necessarily from the patients themselves. Neurostimulation techniques like transcranial direct current stimulation also showed some improvements, but only in limited contexts and with small sample sizes. Interestingly, none of the treatments—medication or otherwise—made a clear impact on long-term quality of life or emotional regulation.
Conclusion
So, what does this mean for people navigating ADHD in adulthood? Stimulant medications remain the most effective treatment for managing ADHD symptoms day-to-day but nonstimulant medication are not far behind, which is good given the problems we’ve had with stimulant shortages. This study also supports structured psychotherapy as a viable treatment option, especially when used in conjunction with medication.
The study emphasizes the importance of ongoing, long-term research and the need for treatment plans that are tailored to the individual ADHD patient– Managing adult ADHD effectively calls for flexible, patient-centered care.
------
Struggling with side effects or not seeing improvement in your day-to-day life? Dive into a step-by-step journey that starts with the basics of screening and diagnosis, detailing the clinical criteria healthcare professionals use so you can be certain you receive an accurate evaluation. This isn’t just another ADHD guide—it’s your toolkit for getting the care you deserve. This is the kind of care that doesn’t just patch up symptoms but helps you unlock your potential and build the life you want. Whether you’ve just been diagnosed or you’ve been living with ADHD for years, this booklet is here to empower you to take control of your healthcare journey.
Proceeds from the sale of this book are used to support www.ADHDevidence.org.
_logo%201.svg)
