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Population Study: Stimulants Shown to Reduce Hospitalization and Suicidality
Swedish Population Study Suggests Stimulants Reduce Hospitalization and Suicidality, Have No Significant Effect on Work Disability
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.”
Advanced Economy Outlier: Even in China’s largest cities, ADHD is seldom treated with ...
Advanced Economy Outlier: Even in China’s largest cities, ADHD is seldom treated with pharmaceuticals
China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has “experienced the fastest sustained expansion by a major economy in history – and has lifted more than 800 million people out of poverty.”
China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has “experienced the fastest sustained expansion by a major economy in history – and has lifted more than 800 million people out of poverty.”
That expansion has been accompanied by major investments in medical research, and medical treatment capability, especially in the major urban centers that have spearheaded the boom. Life expectancy has risen from 71 in 2000 to 77 in 2019, nearing the U.S. level of 79.
Yet when it comes to pharmaceutical treatment of ADHD, China is an outlier, as revealed by a new study exploring the data in the two main medical insurance programs for its urban population.
The Urban Employee Basic Medical Insurance(UEBMI) covers both employers and employees in public and private workplaces, while the Urban Residents Basic Medical Insurance (BMI) covers the unemployed. As of 2014, these programs cover over 97% of urban residents. The China Health Insurance Research Association (CHIRA) database is a random sampling database from the UEBMI and UBMI databases.
The study population consisted of residents of the 63 cities in the CHIRA database from 2013 through 2017. Prescription prevalence was calculated by dividing the total number of patients prescribed ADHD medications in the CH IRA database by the urban population of the included cities, which was two hundred million as of 2017.
Other studies have found the prevalence of ADHD among Chinese children and adolescents to be about 6.5%, comparable to North American and European countries. Yet, the prescription prevalence of ADHD medications was 0.036% among those aged 0–14 years in 2017 in China. In other words, only about one in every two hundred youths with ADHD were being prescribed pharmaceutical treatments.
For further context, among other economically prosperous countries in Asia, Australia, North America, and Europe, the lowest prescription prevalence of ADHD medications is 0.27% in France, which is still over seven times higher than the Chinese level.
Among Chinese urban dwellers from 15 through 64 years of age, ADHD prescription prevalence in 2017 dropped by a further order of magnitude (over tenfold) to 0.003%, and among those 65 and older, to a scant 0.001%.
The Chinese study team suggested several likely contributing factors:
- Lack of training in ADHD treatment among clinical practitioners;
- Government fears of addiction have led to strict control of stimulant medications;
- Discontinuation of methylphenidate production by Chinese pharmaceutical enterprises in 2009 meant having to purchase more expensive imported ADHD medications;
- Widespread parental belief that ADHD is just “bad behavior,” not a disease requiring medication;
- Parental reliance on alternative treatments, such as Traditional Chinese Medicine (TCM)
Daytime Sleepiness, Cognitive Function, and Adult ADHD
What’s the relationship between daytime sleepiness and cognitive functioning in adults with ADHD?
Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them.
Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them. A team of British researchers set out to see whether this association could be further confirmed with objective sleep measures, using cognitive function tests and electroencephalography (EEG).
Measured as theta/beta ratio, EEG slowing is a widely used indicator in ADHD research. While it occurs normally in non-ADHD adults at the conclusion of a day, during the day it signals excessive sleepiness, whether from obstructive sleep apnea or neurodegenerative and neurodevelopmental disorders. Coffee reverses EEG slowing, as do ADHD stimulant medications.
Study participants were either on stable treatment with ADHD medication (stimulant or non-stimulant medication) or on no medication. Participants had to refrain from taking any stimulant medications for at least 48 hours prior to taking the tests. Persons with IQ below 80 or with recurrent depression or undergoing a depressive episode were excluded.
The team administered a cognitive function test, The Sustained Attention to Response Task (SART). Observers rated on-task sleepiness using videos from the cognitive testing sessions. They wired participants for EEG monitoring.
Observer-rated sleepiness was found to be moderately higher in the ADHD group than in controls. Although sleep quality was slightly lower in the sleepy group than in the ADHD group, and symptom severity slightly greater in the ADHD group than the sleepy group, neither difference was statistically significant, indicating extensive overlap.
Omission errors in the SART were strongly correlated with sleepiness level, and the strength of this correlation was independent of ADHD symptom severity. EEG slowing in all regions of the brain was more than 50 percent higher in the ADHD group than in the control group and was highest in the frontal cortex.
Treating the sleepy group as a third group, EEG slowing was highest for the ADHD group, followed closely by the sleepy group, and more distantly by the neurotypical group. The gaps between the ADHD and sleepy groups on the one hand, and the neurotypical group on the other, were both large and statistically significant, whereas the gap between the ADHD and sleepy groups was not. EEG slowing was both a significant predictor of ADHD and of ADHD symptom severity.
The authors concluded, “These findings indicate that the cognitive performance deficits routinely attributed to ADHD … are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. … we would like to propose a simple working hypothesis that daytime sleepiness plays a major role in cognitive functioning of adults with ADHD. … As adults with ADHD are more severely sleep deprived compared to neurotypical control subjects and are more vulnerable to sleep deprivation, in various neurocognitive tasks they should manifest larger sleepiness-related reductions in cognitive performance. … One clear testable prediction of the working hypothesis would be that carefully controlling for sleepiness, time of day, and/or individual circadian rhythms would result in a substantial reduction in the neurocognitive deficits in replications of classic ADHD studies.”
Study Finds Significant Association Between Allergies and ADHD
Nationally representative sample of almost 200,000 U.S. youths finds association between allergies and ADHD
After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.
A growing body of studies suggests a link between inflammation and autoimmune diseases on the one hand and ADHD on the other. It has been hypothesized that excessive release of cytokines (small signaling proteins that regulate immune response and inflammation and repair) and keratinocytes (skin cells) under allergic conditions may cause structural and functional changes to the nervous system and brain, which can contribute to psychiatric disorders, including ADHD.
Noting that previous studies have focused primarily on associations between ADHD and respiratory allergies(asthma) and skin allergies, a joint Chinese and American study team set out to see what, if any, association there might be with food allergies.
To this end, they turned to the national health Interview Survey (NHIS), conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. This survey relies on a very large, nationally representative sample of the U.S. population.
The study encompassed 192,573 youths aged 4 through 17 years old. Of these, 15,376 had an ADHD diagnosis, 8,603 had food allergies, 24,218 had respiratory allergies, and 18,703 had skin allergies.
After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.
How did that compare with respiratory and skin allergies? In the same study population, making identical adjustments for potential confounders, youths with respiratory allergies were 50% more likely to be diagnosed with ADHD than those without such allergies. Those with skin allergies were 65% more likely to be diagnosed with ADHD. After further mutual adjustment for other allergic conditions, those with respiratory allergies were still over a third more likely to be diagnosed with ADHD, and those with skin allergies were 50% more likely to be diagnosed with ADHD.
The authors concluded, "The current study found a significant and positive association between common allergic conditions, including food allergy, respiratory allergy, skin allergy, and ADHD in children. Although the detailed mechanisms linking food allergy and other allergic conditions to ADHD remain to be understood, physicians should be aware of the increased risk of ADHD as a comorbidity of children with allergic conditions".
Siblings of Those With ADHD at Higher Risk for ADHD & Other Disorders
Israel-wide population study:siblings of individuals with ADHD have highly elevated risk of ADHD, slightly elevated risk of anxiety and personality disorders, no greater risk for other disorders or low IQ
Israel has a military draft that applies to males and females alike, except orthodox women and orthodox male seminary(yeshiva) students, who are exempt. Upon turning 17 every Israeli undergoes a medical review, including both a physical and psychiatric assessment, in preparation for the draft. The Draft Board Registry maintains comprehensive health information on all unselected Israelis until they turn 21. The registry also tracks all family members of draft registrants, including full siblings.
An Israeli study team used registry records from 1998 through2014 to obtain data for a total of over a million individuals (1,085,388). Because of the exemption for orthodox women, 59% were male.
The team identified 903,690 full siblings in the study population (58% males), including 166,359 male-male sibling pairs, 104,494 female-female sibling pairs, and 197,571 opposite-sex sibling pairs.
Next, the team identified all cases in the study population with a diagnosis of a psychiatric disorder, low IQ (≥2 standard deviations below the population mean), Type-1 diabetes, hernia, or hematological malignancies. It matched each case with ten age- and sex-matched controls selected at random from the study population. Then, for each case and case-matched controls, it identified all siblings.
There were 3,272 cases receiving treatment for ADHD, 2,128 with autistic spectrum disorder, 9,572 with severe/profound intellectual disability, 7,902 with psychotic disorders, 9,704 with mood disorders, 10,606with anxiety disorders, 24,815 with personality disorders, 791 with substance abuse disorders, 31,186 with low IQ, 2,770 with Type-1 diabetes, 30,199 with a hernia, and 931 with hematological malignancies.
Draftees with ADHD were five and a half times more likely to have a sibling with ADHD than controls.
There were no significant associations between ADHD and any of the somatic disorders - Type-1 diabetes, hernia, or hematological malignancies - nor between ADHD and low IQ.
There were also no significant associations between ADHD and autism spectrum disorder, severe/profound intellectual disability, mood disorders, and substance use disorders.
On the other hand, draftees with ADHD were more than 40% more likely to have siblings with anxiety or personality disorders than controls.
Surprisingly, draftees with ADHD were less than half as likely to have siblings with psychotic disorders than controls.
There were some limitations. The psychiatric classification system used by the Israeli military did not permit assessing the risk of bipolar disorder and depression separately. That meant having to use a broader category of mood disorders, including both disorders. In addition, the military diagnostic system does not allow diagnosis of comorbid psychiatric disorders in the same individual, instead of assigning only the most severe diagnosis.
Strong Association Between Low Birth Weight and ADHD Discovered
South Korean nationwide population study finds strong association between low birth weight and subsequent ADHD
Since 1989, South Korea has had a single-payer healthcare insurance system, the Korean National Health Insurance Service. This facilitates nationwide population studies.
A South Korean study team used the national health claims database to retroactively examine the relationship between birth weight and subsequent diagnosis of ADHD for all 2.36 million children born in the country between 2008 and 2012. After excluding children who had since died, who had missing birth weight records, missing income information, or who weighed under400 grams at birth, 2,143,652 children remained in the study cohort.
Gestational age at birth was not available, so could not be taken into consideration.
To reduce the impact of confounding factors, odds ratios were adjusted for sex, history of congenital or perinatal diseases, income, and birth year.
Children with more normal birth weights in the range of 2.5 to 4 kilograms were used as the reference group.
Children with birth weights greater than this reference group were found to be no more likely to develop ADHD than those in the reference group.
At the other end of the spectrum, children with birth weights under a kilogram were 2.2 times more likely to be diagnosed with ADHD than those in the reference group.
That dropped to 1.7 times more likely for those with birth weights from 1 to 1.5 kilograms; 1.5 times more likely in the 1.5-to-2-kilogram range, and 1.4 times more likely in the 2-to-2.5-kilogram range. This dose-response curve, accelerating steeply with lower birth weights, points to a strong association.
For autism spectrum disorder (ASD), the association was even stronger. Again, there was no significant association with higher-than-normal birth weight. But children in the 2-to-2.5-kilogram range were 1.9 times as likely to be diagnosed with ASD; those in the 1.5-to-2 kilogram tranche over three times as likely; those in the 1 to 1.5-kilogram tranche five and halftime as likely, and those under 1 kilogram over ten times as likely.
The authors concluded, "In this national cohort, infants with birth weights of < 2.5 kg were associated with ADHD and ASD, regardless of perinatal history. Children born with LBW [low birth weight] need detailed clinical follow-up."
Meta-Analysis: Is Neurofeedback A Viable Treatment For ADHD?
New meta-analysis of 17 RCTs finds no evidence of efficacy for neurofeedback treatment of ADHD
Neurofeedback, also known as EEG (electroencephalogram)biofeedback, is a treatment that seeks to alleviate symptoms of various neurological and mental health disorders, including ADHD. It does this through immediate feedback from a computer program that tracks a client's brainwave activity, then uses sound or visual signals to retrain these brain signals. This in principle enables patients to learn to regulate and improve their brain function and reduce symptoms.
An Iranian study team recently performed a systematic search of the peer-reviewed medical literature. It identified seventeen randomized-controlled trials (RCTs) of neurofeedback treatment for children and adolescents with ADHD that could be aggregated for meta-analysis.
A meta-analysis of twelve RCTs with a combined total of 740 youths looked at parent ratings of changes in hyperactivity/impulsivity symptoms, and separately of changes in inattention symptoms. In both instances, the net pooled effect centered on zero.
A meta-analysis of nine RCTs with a combined total of 787 youths examined teacher ratings. Once again, the pooled change hyperactivity/impulsivity symptoms centered on zero. For inattention symptoms, the teacher ratings centered on a tiny improvement, but it did not approach statistical significance. The 95% confidence interval stretched well into negative territory.
There was no sign of publication bias. Between-study heterogeneity, on the other hand, was high, with some small sample size RCTs pointing to reduced symptoms, and other small sample size RCTs pointing to increased symptoms. However, the RCTs with the larger sample sizes clustered close around zero effect size.
The authors concluded,"The results provide preliminary evidence that neurofeedback treatment is not an efficacious clinical method for ADHD."
"Time-Blindness" Found to Be a Consistent Feature of ADHD
Meta-analysis finds consistent time perception impairments in persons with ADHD
An international study team conducted the first meta-analysis of studies examining differences in time perception between persons with ADHD and normally developing controls. A systematic search of the peer-reviewed medical literature identified 55 studies that could be combined into various subgroups for meta-analysis.
A meta-analysis of 25 studies with a combined 1,633 participants looking at time discrimination found a medium effect size deficit among persons with ADHD in the number of correct comparisons between the length of two signals. There was little between-study heterogeneity and no sign of publication bias.
Turning to time estimation, a meta-analysis of eight studies with a combined 1,024 participants found a small-to-medium effect size increase in absolute errors (i.e., the absolute value of deviation between the specified and the estimated time interval, representing the absolute amount of error regardless of its direction) among persons with ADHD, compared to controls. Again, there was little between-study heterogeneity and no sign of publication bias.
A meta-analysis of seven studies with combined 380 participants looked at differences in time production, in which they had to produce a previously specified time interval by pressing and holding a button. In this case, those with ADHD manifested a small effect size increase in absolute error relative to their normally developing counterparts. There was moderate between-study heterogeneity and no sign of publication bias.
Finally, a meta-analysis of 26 studies with combined 2,364 participants examined differences in time reproduction, in which they had to reproduce the duration of a previously presented stimulus by pressing and holding a button. Here, those with ADHD exhibited a medium effect size increase in absolute error. There was moderate between-study heterogeneity and no indication of publication bias.
An acknowledged limitation of these meta-analyses was the inability to assess the effects of pharmacological treatment. In addition, 84% of the studies did not report the ethnicity of participants.
The team concluded, "We found meta-analytic evidence of significant deficits in individuals with ADHD across all timing paradigms ... individuals with ADHD have difficulties to discriminate stimuli that vary from each other for only several milliseconds, and they are more variable in their time estimates of several seconds irrespective of the paradigm examined, which may both be driven by their lowered alertness levels."
They suggested that this might eventually become a criterion to help diagnose ADHD: "Our findings have possible clinical implications, albeit not currently directly applicable to the clinical practice. As timing has been proposed as an independent neuropsychological pathway to ADHD, timing tasks should be considered in the clinical assessment of ADHD to better characterize the clinical profile of the patient... To characterize further the phenotype of the patient during the diagnostic process that may deserve clinical attention, we suggest developing a tool based on the time estimation paradigm. The time estimation accuracy score not only represents an intuitive score reflecting faster internal clock mechanisms in individuals with ADHD, but the paradigm also shows high internal consistency and test-retest reliability, allowing for a reliable assessment of developmental or interventional changes in timing abilities related to developmental factors or external interventions."
Significant Association Found Between Type 1 Diabetes and ADHD
Nationwide population-based cohort study finds very strong association between type 1 diabetes and ADHD
Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic.
Taiwan has a mandatory single-payer universal health insurance system, the National Health Insurance (NHI), that records diagnoses and prescriptions across virtually the entire resident population. Out of the roughly 28 million residents covered by NHI, a randomly assigned sample of 3 million is tracked in the Taiwan National Health Insurance Research Database(NHIRD).
Expert panels have to confirm all diagnoses of severe systemic autoimmune diseases, ensuring a high level of accuracy.
A Taiwanese study team availed itself of these records to explore the link between type 1 diabetes mellitus (T1DM) and ADHD. ADHD diagnoses were made by board-certified psychiatrists, based on comprehensive interviews and clinical judgment.
The team found a total of 6,226 cases diagnosed with T1DM in the decade from 2001 through 2010 and followed them through the end of 2001. It matched each case with ten age- and sex-matched non-T1DM controls from the same database, for a total of 62,260 controls.
Persons with type 1 diabetes were found to be eight times more likely to be diagnosed with ADHD than those who were not diabetic. There was no difference in the risk ratio between youth and adults. The risk of ADHD among females with T1DM was only slightly lower than among males: sevenfold greater, rather than 8.5 times greater.
The authors concluded, "Our findings indicate the importance of the close monitoring of the mental health condition of patients with T1DM by clinicians ... The exact path of mechanisms between T1DM and major psychiatric disorders should be elucidated in future studies."
Cognitive Treatment for ADHD Symtoms May Be Uneffective
Meta-analysis finds no significant effect of cognitive treatment on ADHD symptoms and executive functioning when randomized controlled trials are blinded
A Chinese study team performed a systematic search of peer-reviewed journal literature to identify randomized controlled trials (RCTs) examining the efficacy of cognitive training as a treatment for youths with ADHD.
Seventeen RCTs with a combined total of 1,075 participants met standards for inclusion in a series of meta-analyses. Seven RCTs used waitlist controls, seven used placebo training, two used treatment-as-usual, and one used active knowledge training. Participants were unmediated in four RCTs, with varying proportions of medicated participants in the remaining thirteen.
A meta-analysis of 15 RCTs, with a combined 789 participants, assessed changes in inattention symptoms following treatment, as rated by parents or clinicians. It found a small-to-medium effect size improvement in symptoms of inattention. There was no indication of publication bias, but between-study heterogeneity was very high.
But that gain vanished altogether when combining only the six RCTs that were blinded, meaning the symptom evaluators had no idea which participants had received cognitive treatment and which participants had not. There was zero difference between the treatment and control groups. Significantly, between-study heterogeneity also diminished markedly, becoming low to moderate.
A second meta-analysis, of 15 RCTs with a combined 723 participants, assessed changes in hyperactivity/impulsivity symptoms following treatment, as rated by parents or clinicians. It found no significant difference between participants who received cognitive training and controls. There was no sign of publication bias, and between-study heterogeneity was moderate-to-high.
The three remaining meta-analyses looked for improvements in executive functions, using the Behavior Rating Inventory of Executive Function (BRIEF).
A meta-analysis of 13 RCTs, with a combined 748 participants, found a small-to-medium effect size improvement in the global executive composite index of BRIEF, as evaluated by parents. There was no sign of publication bias, and between-study heterogeneity was moderate-to-high.
But that improvement again disappeared altogether when considering only the five RCTs that were blinded. Between-study heterogeneity also became insignificant.
A meta-analysis of 6 RCTs with 401 participants found no significant improvement in the behavioral regulation index of BRIEF. Heterogeneity was negligible.
Finally, a meta-analysis of 7 RCTs with 463 participants also found no significant improvement in the metacognition index of BRIEF. In this case, between-study heterogeneity was high.
While acknowledging that "when analyses were set in blinded measures, effect sizes were not statistically significant," the author nevertheless concluded, "In summary, multiple cognitive training alleviates the presentation of inattention and improves general executive function behaviors in children with ADHD." This suggests an underlying bias on the part of the study team in favor of treatment even when not supported by best (i.e., blinded) methodological practices.
Risk of Unnatural Death Tripled in Those with ADHD
Meta-analysis finds no significant increase in natural mortality, but almost tripled risk of unnatural death, in persons with ADHD
A meta-analysis of eight studies with a combined total of over 396,000 persons with ADHD reported a twofold greater risk of premature death in persons with ADHD as compared with the general population. There was no significant difference in mortality between males and females with ADHD.
But when natural causes of death, primarily disease, were distinguished from unnatural causes, such as injuries and poisoning, virtually all the increased risk was attributable to the latter.
A meta-analysis of four studies with a combined total of over 394,000 participants with ADHD found no significant increase in natural mortality among persons with ADHD. This held for both males and females.
But a meta-analysis of ten studies with over 430,000 persons with ADHD found a nearly threefold increase in unnatural mortality (injuries, poisoning, etc.) in persons with ADHD. Among females (five studies, over 110,000 participants) the increase was threefold. Males with ADHD (five studies, over 310,000 participants) were 2.5 times more susceptible to premature death.
An important caution: in all of these meta-analyses, between-study heterogeneity was extreme, meaning there was little consistency from one study to the next. Moreover, no effort was made to evaluate the likelihood of publication bias.
The largest study, with over 275,000 participants with ADHD, found a negligible and only marginally significant 7% increased all-cause risk of death. It found no increase in natural causes of mortality, but a 50% increase in unnatural causes of premature mortality.
The authors described these results as "suggestive," but emphasized that "the evidence was judged as only low confidence," in line with "inconsistent" evidence from previous nationwide population studies: in Denmark, a twofold increase in all-cause mortality; in Sweden, a fourfold increase; but in Taiwan, a tiny 7% increase that was at the limit of statistical significance, once the data was fully adjusted for confounding factors.
That led the authors to suggest "that all relevant potential confounders should be accounted for" in "future studies."
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