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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.
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The Background:
Because impulsivity is a core feature of ADHD, researchers have suggested it may raise the likelihood that someone will use psychoactive substances (including alcohol) and go on to develop a substance use disorder (SUD). When ADHD and SUD occur together in adolescents, treating one disorder alone usually has little or no positive effect on the other; current guidance therefore recommends treating both conditions at the same time using evidence-based approaches for each.
Given how much ADHD can worsen outcomes for people with primary SUDs, it is important to identify ADHD in people who are being treated for substance problems.
The Study:
A recent systematic meta-review found that, by current official criteria, ADHD affects about 7.2% of children and adolescents and about 2.6% of adults (Chaulagain et al., 2023). When adult ADHD is defined without the requirement that symptoms began by age 11, roughly 6.8% of adults meet criteria. A large body of research links ADHD to higher rates of medical problems, poorer quality of life, greater risk of suicide, more accidental injuries, worse educational outcomes, and increased involvement with the criminal justice system.
The present study is the first meta-analysis to estimate how common clinically diagnosed ADHD is among adults (age 18+) who are in treatment for psychoactive substance use disorders, and to provide those estimates by sex and by the specific substance used.
The authors included only studies of adults treated for a SUD (including alcohol). Eighty-four studies met the criteria, representing more than 34,000 people. Across all studies, the pooled prevalence of clinically diagnosed ADHD was 22%.
To put that in context, 22% is about eight times higher than the 2.6% adult prevalence using the stricter official definition, and about three times higher than the 6.8% rate when the childhood-onset requirement is relaxed. By substance, the prevalence was similar for alcohol (24%) and opioids (22%), with no significant difference between males and females. Prevalence among people treated for cocaine use was somewhat lower overall (18%), driven largely by lower rates among women, for whom the rate was no higher than in the general population. Estimates were higher for people using benzodiazepines and cannabis, but those figures are based on a very small number of users (256 and 249 people, respectively) and are therefore less certain.
The Results:
The authors conclude: “These findings underscore the need for early identification and treatment of ADHD as most substance use disorders develop in adolescence and young adulthood. While in treatment for ADHD, appropriate screening and management of substance use is possible.”
The Background:
Stimulant medications (like methylphenidate and amphetamines) and non-stimulants (like atomoxetine and guanfacine) remain the first-line treatments for ADHD, but their long-term use is often constrained by parental concerns, side effects (reduced appetite, sleep disruption, cardiovascular effects), and the fact that roughly 30% of children respond only partially or not at all. These medications tend to help with attention and behavior, but they do less to address emotional regulation or broader physical health, leaving some parents to seek other safe, complementary treatments.
Nutritional approaches, including omega-3 fatty acids, are one such avenue. Oily fish is the natural source, but clinical trials typically rely on supplements instead, since they allow for precise dosing, avoid the heavy-metal exposure that can come with high fish intake, and sidestep the problem of inconsistent dietary habits. Two omega-3s stand out as particularly relevant: DHA, which supports brain structure and cell-to-cell communication, and EPA, which helps reduce brain inflammation and improve blood flow. Both influence the dopamine and serotonin systems implicated in ADHD.
The Study:
Previous meta-analyses have generally found only modest overall benefits with mixed results. This mixed-results pattern may reflect the fact that children who had low omega-3 levels to begin with stand to benefit more than those whose levels are already adequate. This meta-analysis set out to test that idea directly, asking whether a child's baseline omega-3 status predicts how well they respond to supplementation.
To be included, studies had to be randomized controlled trials (RCTs) involving children diagnosed with ADHD who did not have major coexisting medical conditions. Trials that used broad multinutrient interventions, where the effect of omega-3s specifically couldn't be isolated, were excluded.
The resulting analysis of seven RCTs covering 654 children found small overall improvements in ADHD symptoms with omega-3 supplementation, consistent with earlier meta-analyses. There was little variation across studies, but a clear signal of publication bias, which the authors did not attempt to statistically correct for.
Among four RCTs involving 369 children with low baseline omega-3 levels, supplementation produced a moderate improvement in ADHD symptoms, with consistent results across studies. By contrast, the six RCTs covering 559 children with normal or high baseline omega-3 levels showed no improvement at all, again with consistent results across studies.
The Results:
The authors concluded: this systematic review and meta-analysis offers preliminary evidence that children’s response to long-chain omega-3 supplementation for ADHD may depend on their starting omega-3 nutritional status. Larger effects emerged in the subgroups defined by individual studies as having low baseline levels, while normal, high, or unstratified groups showed little evidence of benefit. In other words, there may be a benefit to children with ADHD taking omega-3 supplements, but only if they are already deficient.
Even still, a sensitivity analysis limited to ADHD symptom-rating scales found only a numerically higher effect in the low-baseline group. This means that these results, though positive, are not considered statistically significant.
The Take-Away:
Given that the evidence rests on just seven trials, that “low baseline” was defined differently across studies (using different biological markers and thresholds), and that several subgroup comparisons were not planned in advance, the authors caution that these findings should be treated as hypothesis-generating rather than conclusive.
The Background:
Previous research has suggested that people with ADHD have higher rates of death than those without the condition. Until now, many of those studies lacked the detail needed to untangle why this might be the case. A recent meta-analysis of eight separate studies reported that ADHD roughly doubled the risk of death, and it hinted that factors like socioeconomic status and other mental illnesses might help explain the link.
The Study:
To explore this in more detail, researchers used the US National Health Interview Survey, a nationally representative prospective cohort of just over 52,000 adults. Survey records were linked with the National Death Index, and participants were followed from the date of interview until death or December 31, 2019, whichever came first. The main outcome was death from any cause. With a median follow-up of just under eight years, there were 6,024 deaths recorded.
When the team adjusted their analysis for age, sex, ethnicity, and the year of the survey, having ADHD was associated with a 58% higher risk of death. Controlling further for family income and educational level reduced that increased risk slightly, to 50%.
Controlling for health conditions (like high blood pressure, diabetes, stroke, heart disease, and cancer) and lifestyle factors (smoking, alcohol use, physical activity, and body weight) also reduced the association to about 46%.
By contrast, when the researchers adjusted for two psychiatric conditions (anxiety and depression) commonly found alongside ADHD, the link between ADHD and higher mortality disappeared statistically. In other words, once anxiety and depression were taken into account, ADHD itself was no longer associated with a clearly measurable increase in the risk of death.
What Does This Mean?
The authors conclude that the apparent effect of ADHD on mortality seems to operate largely through accompanying mental illness, and to a lesser extent through lifestyle and physical health problems. They suggest that treating and managing these co-occurring issues (through medications, therapy, and behavioral interventions) might help reduce the risk of premature death in people with ADHD, although they note that further evidence is needed.
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