December 27, 2021
According to Dexing Zhang et al., writing in the British Medical Bulletin, "Mindfulness is a moment-by-moment awareness of thoughts, feelings, bodily sensations, and surrounding environment. ... These practices can be formal (e.g. breathing, sitting, walking, body scan) or informal (e.g. mindfulness in everyday life).... Mindfulness is rooted in Buddhist traditions. However, it has become popular in recent years among various secular populations in healthcare, educational, and workplace settings: from pre-schoolchildren to older adults across the world." The two most widely adopted mindfulness-based interventions (MBIs) are mindfulness-based stress reduction and mindfulness-based cognitive therapy (Zhang, 2021).
An Italian research team recently conducted a comprehensive search of the peer-reviewed literature to identify studies exploring the efficacy of mindfulness-based treatments for ADHD. It found 31 studies that qualified for review, ten of which met the criteria for meta-analysis, with a total of 596 participants.
A meta-analysis of seven studies with a combined total of 489 participants found MBIs reduced ADHD symptoms with medium effect size and no sign of publication bias. When split into subgroups with and without active controls - in this case, psychoeducation and skills training groups -the outcomes diverged. In the three studies with non-active controls (187 participants), there was a large reduction in ADHD symptoms. In the four with active controls (302 participants), there was no significant difference.
A meta-analysis of ten studies with 596 participants found MBIs reduced inattention symptoms, with a medium-sized effect. Pooling the five studies without active controls (261 participants) produced a very large reduction in inattention symptoms. Once again, in the five studies with active controls (335 participants), there was no significant difference.
After adjusting for publication bias, a third meta-analysis of nine studies with 563 participants found no significant effect of MBIs hyperactivity symptoms. However, when limited to the five studies with-active controls (261 participants), it found a large reduction in hyperactivity symptoms.
After adjusting for publication bias, the fourth meta-analysis of four studies with a combined 243 participants found no significant improvement in executive function.
After adjusting for publication bias, a fifth meta-analysis combining six studies with 449 participants reported a moderate improvement in mindfulness skills. There was no significant improvement when looking only at the three studies with active controls (262 participants).
The team concluded that MBIs seemed to be effective in treating ADHD, but no more so than psychoeducation and skills training groups.
Yet they cautioned that the use of a waiting list for non-active controls muddies that conclusion: "It could be suggested that any intervention seems to have a significantly higher effect than WL [waiting list]in improving ADHD symptoms." This is a known hazard of using waiting lists as control groups (Cunningham, 2013).
Noting "the low general methodological quality," they stated, "From a clinical standpoint, according to the poor available evidence, we cannot conclude that MBIs are superior to other active [psychological] interventions in ameliorating all the considered outcomes, suggesting a role complementation and not as a replacement of the psychoeducation in the management of patients with ADHD, consistently with some guidelines' recommendations."
Francesco Oliva, Francesca Malandrone, Giulia di Girolamo, Santina Mirabella, Nicoletta Colombi, Sara Carletto, Luca Ostacoli, "The efficacy of mindfulness-based interventions in attention-deficit/hyperactivity disorder beyond core symptoms: A systematic review, meta-analysis, and meta-regression," Journal of Affective Disorders(2021), vol. 292,475-486, published online,https://doi.org/10.1016/j.jad.2021.05.068.
Dexing Zhang, Eric K P Lee, Eva C W Mak, C Y Ho, and Samuel S Wong, "Mindfulness-based interventions: an overall review," BritishMedical Bulletin (2021), vol. 138, issue 1, 41-57, published online, https://doi.org/10.1093/bmb/ldab005.
John A Cunningham, KyprosKypri, and Jim McCambridge, "Exploratory randomized controlled trial evaluating the impact of a waiting list control design," BMC Medical Research Methodology (2013), vol. 13, article 150, published online, https://doi.org/10.1186/1471-2288-13-150.
A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications.
However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life?
Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies.
A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD.
The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders.
With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants.
None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail.
Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect.
Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine.
Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.
The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect.
Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect.
The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.”
Noting that “Oxidative stress disrupts the structure and function of neurons in the prefrontal lobe of the brain,” and “Structural and functional impairments in the prefrontal cortex have been shown to be highly correlated with behavioral and emotional problems of ADHD,” a Chinese team at Dalian University set out to systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with ADHD.
The team’s systematic search of the peer-reviewed medical literature identified a total of 48 randomized controlled trials (RCTs) or prospective studies involving 12 antioxidant agents (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) that met criteria for inclusion:
Treatment efficacy was measured through ADHD symptom scores using Conners’ parent rating scale (CPRS), Conners’ teacher rating scale (CTRS), ADHD rating scale-parent (ADHD RS-Parent), and ADHD rating scale-teacher (ADHD RS-Teacher), as well as secondary outcome indicators such as the Clinical Global Impressions scale (CGI) and Continuous Performance Test (CPT), relative to controls.
None of the antioxidant therapies were significantly better than placebo.
One limitation is that no effort was made to assess publication bias.
These results indicate that antioxidants should not be used for treating ADHD.
A 2021 consensus statement by an international group of scientists and clinicians (Bauer et al.) recommended that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” due to the potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD).
A mostly Swedish research team, collaborating with a U.S. researcher, nevertheless noted that previous studies have been limited by:
Sweden has a single-payer health insurance system that includes virtually its entire population, and national registers that enable tracking the health history of mothers and their children, including their children’s siblings.
The team used the Swedish registers to identify the roughly two-and-a-half million children born in Sweden from mid-1995 through 2019. They were also able to identify all siblings to be able to control for otherwise unmeasured familial and genetic confounding.
Almost 186,000 of these children were exposed to acetaminophen during pregnancy.
After adjusting for available known confounders, including (but not limited to) child sex and birthdate, mother’s age and medical history, use of any other painkillers, use of any psychoactive medications, country of birth, residential region, smoking status, highest household education, and disposable income, children exposed to acetaminophen during pregnancy were 7% more likely to be diagnosed with ADHD subsequently than those who were not exposed.
However, roughly the same results were found for other painkillers, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antimigraine medication. High doses of acetaminophen did not produce any stronger association with subsequent ADHD than low dosage.
Moreover, when confining results to siblings – 8,526 children who were exposed versus 87,679 who were unexposed – the association between acetaminophen use during pregnancy and subsequent offspring ADHD vanished altogether (and, again, at every dose level). The associations similarly vanished with every other painkiller medication.
The Swedish team concluded, “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in models without sibling control may have been attributable to confounding.”
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