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August 31, 2021
A University of California at Los Angeles (UCLA) team has just reported on the first-ever, double-blinded, sham-controlled study of trigeminal nerve stimulation (TNS) for treating ADHD. The trigeminal nerve is the largest cranial nerve. It enables facial sensation, as well as biting and chewing.
Over four weeks, researchers fitted 62 eight-to-twelve-year-old children with electrodes while they slept; 32 got an active low current, the rest none at all. The active and sham setups were identical in appearance. The children were told, pulses may come so fast or so slowly that the nerves in the forehead might or might not detect a sensation. After the four weeks, there was an additional-blinded week without intervention.
The primary efficacy outcome measure was the clinician-completed ADHD-RS total score, derived from parent interviews and available clinical information. It was completed at the onset of the study, and repeated over subsequent weeks. The Clinical Global Impression (CGI) score was used as a secondary outcome measure.
Both groups of children showed significant reductions in ADHD symptoms over the first week. But University of California at Los Angeles (UCLA) teams leveled off during the remaining three weeks for the group with sham treatment, while scores continued to decline for those in the group with actual stimulation. The standardized mean difference (SMD) between groups was 0.5.
By the conclusion of week 4, 52 percent of those in active treatment were improved or very much improved, as indicated by CGI scores; only a 14percent did as well with the sham treatment. The number needed to treat was just 3.
After discontinuation of treatment, total scores in both groups rose at similar rates. At the end of week 5, CGI ratings for active treatment showed 13 percent improvement over baseline, versus 7 percent for sham treatment. The SMD was 0.46, once again indicating the persistence of a medium effect size a week after treatment cessation.
The effect sizes computed for TNS are roughly comparable to effect sizes for non-stimulant medication, but less than those for stimulants.
Though the active group had significant gains in weight and pulse over the sham group, there were no serious adverse events in either group.
The authors concluded: Results from the Early Impressions Questionnaire showed no differences in outcome expectations between treatment groups after 1 week of using the randomized device, suggesting that our sham procedures successfully accomplished double-blinding of group assignment. Improvements seen in the active and sham groups at week 1 likely reflect some placebo response secondary to the high level of parental involvement in administering treatment. Nonetheless, a further improvement over subsequent weeks with active TNS suggests the emergence of true treatment effects TNS is a non-medication, minimal-risk intervention with proven efficacy in alleviating ADHD symptoms. Although the present study finds that only slightly more than half of those receiving therapy have clinically meaningful improvement, the virtual lack of significant side effects should make it a popular treatment choice for many patients with ADHD, particularly for parents who prefer to avoid psychotropic medication.
Nevertheless, one must keep in mind that this is a single uncomplicated study with a small sample size. Further, studies with larger numbers of participants are needed, both to confirm the efficacy and to further explore the weight gains and higher pulse rates in the treatment group.
James J. McGough, MD, Alexandra Sturm, Ph.D., Jennifer Cowen, Ph.D., Kelly Tung, BS, Giulia C. Salgari, MS, Andrew F. Leuchter, MD, Ian A.Cook, MD, Catherine A. Sugar, Ph.D., Sandra K. Loo, Ph.D., "Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder," Journal of the American Academy of Child &Adolescent Psychiatry, Vol. 58, No. 4 (April 2019), 403-411.
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.
The Background:
Dementia is a rapidly growing public health problem affecting more than 50 million people worldwide. Nearly 10 million new cases are diagnosed each year, and that number is expected to almost triple by 2050. The most common form is Alzheimer’s disease, accounting for roughly 60–70% of cases, followed by vascular dementia at around 20%. Other types include dementia with Lewy bodies, Parkinson’s disease dementia, and frontotemporal dementia. While no cure exists, managing modifiable risk factors (such as high blood pressure, smoking, physical inactivity, and poorly controlled diabetes) can delay or slow both the onset and progression of the condition.
Several studies have reported an elevated dementia risk among people with ADHD, and a number of mechanisms may explain this association. These include shared genetic or neurobiological vulnerabilities, reduced cognitive reserve (leaving the brain less resilient to age-related damage), and greater lifetime exposure to other established dementia risk factors.
Earlier reviews explored the possible link between ADHD and dementia, but tended toward a broader scope (incorporating other neurodegenerative disorders or mixing study designs), which introduced substantial variability and precluded quantitative synthesis. The relevant research literature has also expanded considerably since those reviews appeared.
The Study:
This meta-analysis restricted inclusion to case-control and cohort studies, yielding five that met the criteria. One was a case-control study with 400 participants; the other four were cohort studies collectively covering 3.7 million individuals, two retrospective and two prospective.
The Results:
Pooling the four cohort studies, individuals with ADHD showed approximately two-and-a-half times the dementia risk of those without the diagnosis. There was no indication of publication bias.
The Take-Away:
The authors concluded that ADHD is associated with a significantly increased risk of all-cause dementia in later life, while noting that its relationship to specific dementia subtypes remains less clear and warrants attention in future research.
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The Background:
Women with polycystic ovary syndrome (PCOS) themselves show higher rates of ADHD. Because ADHD is partly heritable (meaning genes contribute to the condition), some of the increased ADHD seen in children of mothers with PCOS could come from shared genetic factors. In other words, a mother’s and her child’s increased risk might sometimes reflect common genes rather than an effect of the pregnancy itself.
Beyond genetics, growing evidence points to maternal metabolic problems during pregnancy as another important risk factor for neurodevelopmental outcomes. PCOS is one of these conditions and is considered both potentially modifiable (treatable or manageable) and biologically plausible as a contributor to risk. PCOS affects an estimated 5–10% of women of reproductive age worldwide and is characterized by signs such as hyperandrogenism (higher-than-normal levels of “male” hormones), insulin resistance (poorer ability to use the hormone insulin, which can affect blood sugar and metabolism), and chronic low-grade inflammation.
However, studies to date have not all reached the same conclusions. Some research suggests the association between maternal PCOS and offspring ADHD is stronger for girls, while other studies did not analyze results by child sex. Methodological differences make it harder to draw clear conclusions.
The Study:
It’s important to note that the studies included in this meta-analysis were observational (cohort studies and case-control studies). Observational studies can identify associations (that two things occur together) but cannot prove that one causes the other. A cohort study follows people over time, and a case-control study compares people with a condition to similar people without it.
The pooled results came from six studies that together included almost 1.4 million mother–child pairs and that adjusted for confounders (other factors that might influence the result, such as maternal age or socioeconomic status). After statistical adjustment, children of mothers with PCOS had about 40% greater odds of ADHD than children of mothers without PCOS. The analysis reported no evidence of publication bias (no clear sign that only positive studies were published) and zero heterogeneity (the results were consistent across the studies).
There was no meaningful difference in results between cohort and case-control studies, and the meta-analysis did not find a significant difference in the association when comparing male and female offspring.
The Take-Away:
The research team concluded that this large-scale synthesis found an association between maternal PCOS and higher odds of ADHD and other neuropsychiatric conditions in children. They suggested that children born to mothers with PCOS may benefit from developmental monitoring to identify and address problems early, while emphasizing that causal relationships have not been established. They called for further studies to confirm these findings and to investigate the biological and environmental mechanisms that might explain the association. Indeed, because women with PCOS show higher rates of ADHD than other women, we need genetically informed research designs to see if the reported association is confounded.
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