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Modified release (MR) formulations of ADHD stimulant medications simplify adherence over immediate-release (IR) formulations, by only requiring a single dosing per day. They are also intended to reduce diversion to nonmedical usage and the development of drug abuse or dependency. Is there evidence they deliver on this promise?

There are 55 poison control centers distributed throughout the United States, and they all report through the National Poison Data System (NPDS).

A pair of researchers used the NPDS to obtain all 15,796 single-substance MR ingestion and single-substance 23,418 IR ingestion reported to poison control centers over the eleven years from January 1, 2007, through December 31, 2017. The medications were either amphetamine or methylphenidate-based.

IR ingestion was more commonly associated with more serious outcomes than were MR ingestion. No deaths were reported from MR stimulant ingestion, versus three deaths (a rate of one in 7,800 reports) from IR stimulant ingestion. While there were no observed differences between youth MR and IR ingestion about admission to critical care units, adult IR ingestion was more commonly admitted to a critical care unit than was adult MR ingestion. Moreover, adults were more commonly admitted to critical care units for both MR and IR ingestion than were youths.

Among youths, the vast majority of MR ingestion was unintentional, with only one in eleven attributed to intentions of suicide. Among adults, however, almost half were intentional, with just over a quarter attributed to intentions of suicide, and another one in six to intentional misuse.

Turning to IR ingestion, the vast majority were again unintentional among youths, with less than one in twelve attributed to suspected suicide attempts. But among adults, the majority were intentional, with almost one in three attributed to suspected suicide attempts, plus another one in five to intentional misuse.

More than four out of five IR ingestion among both youths and adults were of amphetamine medications. For MR ingestion, methylphenidate was most common in youths and amphetamine medications in adults, but only by slight margins.

The most commonly reported symptoms in adults and youths alike for both IR and MR ingestion were agitation, abnormally rapid heart rates, and high blood pressure.

The authors concluded, "More serious outcomes were associated with advancing age, intentional ingestion, and IR preparations. Higher rates of hyperadrenergic symptoms (tachycardia, agitation, and hypertension) were observed with IR ingestion."

On balance, this suggests MR formulations are safer, but both formulations are subject to abuse by a small minority of users.

Youths with disabilities face varying degrees of social exclusion and mental, physical, and sexual violence.

A Danish researcher used the country's extensive national registers to explore reported sexual crimes against youths across the entire population. Of 679,683 youths born from 1984to 1994 and between the ages of seven and eighteen, 8,039 (1.2 percent) were victims of at least one reported sex crime.

The sexual offenses in question included rape, sexual assault, sexual exploitation, incest, and indecent exposure. Sexual assault encompassed both intercourse/penetration without consent or engaged in with a youth not old enough to consent (statutory rape).

The study examined numerous disabilities, including ADHD, which was the most common one. It also performed a regression analysis to tease out other covariants, such as parental violence, parental inpatient mental illness, parental suicidal behavior or alcohol abuse, parental long-term unemployment, family separation, and children in public care outside the family.

In the raw data, youths with ADHD were 3.7 times more likely to be a victim of sexual crimes than normally developing youths. That was roughly equal to the odds for youths with an autism spectrum disorder or mental retardation, but considerably higher than for blindness, stuttering, dyslexia, and epilepsy (all roughly twice as likely to be victims of such crimes), and even higher than for the loss of hearing, brain injury, or speech or physical disabilities.

Looking at covariate, family separation, having a teenage mother, or being in public care almost doubled the risk of being a victim of sexual crimes. Parental violence or parental substance abuse increased the risk by 40 percent, and parental unemployment for over 21 weeks increased the risk by 30 percent. Girls were nine times more likely to be victimized than boys. Living in a disadvantaged neighborhood made no difference, and living in immigrant neighborhoods actually reduced the odds of being victimized by about 30 percent.

After adjusting for other risk factors, youths with ADHD were still almost twice as likely to be victims of reported sex crimes than normally developing youths. All other youths with disabilities registered significantly lower levels of risk after adjusting for other risk factors: for those who were blind, 60 percent higher risk; for those with autism, hearing loss, or epilepsy, 40 percent higher risk. Communicative disabilities - speech disability, stuttering, and dyslexia - actually turned out to have protective effects.

This points to a need to be particularly vigilant for signs of sexual abuse among youths with ADHD.

Folic acid, also known as folate, is an essential vitamin(B-9). Inadequate dietary folate has been associated with abnormal fetal brain development. That suggests a deficiency could contribute to neurodevelopmental disorders, including ADHD.

If so, could folic acid supplementation for pregnant mothers help avoid ADHD in offspring?

A Chinese study team conducted a systematic search of the peer-reviewed medical journal literature looking for studies exploring neurodevelopmental effects associated with such supplementation.

It identified six studies that specifically looked for associations with offspring ADHD. A meta-analysis of these studies encompassing a total of 29,634 participants found a 14% (one in seven) reduction in the odds of ADHD in the offspring of mothers taking folate supplementation as opposed to children of mothers not doing so.

There was no sign of either publication bias or between-study heterogeneity.

The authors concluded, "Our meta-analysis indicated that appropriate maternal FA supplementation may have positive effects on offspring's neurodevelopmental outcomes, including improved intellectual development and reduced risk of autism traits, ADHD, behavioral, and language problems."

Given that folate is an essential vitamin in the first place, this suggests ensuring that pregnant women supplement their diet with folic acid. The authors further counseled, "However, further high-quality studies on this topic are needed to confirm the optimal dosage and the right time of FA supplementation and to investigate the underlying mechanisms."

A team of Taiwanese researchers conducted a comprehensive search of the peer-reviewed literature to identify all randomized controlled trials (RCTs) performed to date exploring the efficacy of acupuncture treatment (AT) in reducing ADHD symptoms. They found ten studies with a combined total of 876 participants that met their search criteria. Seven were performed in China, one in South Korea, one in Iran, and one in the U.S. All involved youths, ranging from ages 3 to 18.

All required either a DSM-IV or DSM-V diagnosis of ADHD for inclusion. The controls varied. One used waitlist. Eight compared acupuncture treatment with methylphenidate treatment, with dosages varying from as little as 10-20 mg/day to 1,020 mg/day and 1,854 mg/day. Only one study was double-blind, meaning that both participants and investigators were blinded as to who was getting which treatment. It is of course essentially impossible to blind participants in RCTs involving AT unless sham-At is used as a control. Only one RCT compared AT with sham-AT, and it was not used in either meta-analysis.

Keeping these limitations in mind, a meta-analysis of the eight studies with 716 participants that compared AT with MPH found AT to be more than twice as effective in reducing ADHD symptoms as MPH. Heterogeneity between studies was low, with no sign of publication bias.

However, none of these studies reported ADHD rating scale scores, an additional major limitation. Instead, because outcome measurements varied across RCTs, the authors relied on "effective rate" (ER): The evaluation was divided into cured, markedly effective, effective, and ineffective. We merged the number of "cured," "markedly effective," and "effective" patients to be divided by the sample size to calculate the proportion of subjects who experienced at least some improvement in their ADHD symptoms in the ER.

On the other hand, a meta-analysis of three studies with 232 participants compared the effects of AT and MPH on actual hyperactivity scores and found MPH was much more effective than AT. Homogeneity was moderate, again with no sign of publication bias.

The author cautioned, "The quality of the evidence was low for the ER assessment because of the selection, performance, and detection biases. For hyperactivity scores, the quality of evidence was very low because of the selection and performance biases and significant heterogeneity." Due to the various limitations, they concluded, "AT may be more effective than methylphenidate for the treatment of ADHD in children and adolescents," but "firm conclusions still can not be drawn."

Youths with ADHD are at higher risk of suicide, burn injuries, road injuries, and more generally all-cause mortality than normally developing children. Methylphenidate (MPH) is known to be effective in reducing ADHD symptoms. Can it also reduce the risk of all-cause mortality? A team of Taiwanese researchers, collaborating with two British researchers, explored that question by looking at a nationwide population cohort.

Taiwan has a single-payer national health insurance system that includes the entire population (99.6 percent coverage). Using the National Health Insurance Research Database (NHIRD), the team identified over 183,000 youths under 18 with an ADHD diagnosis. Of these, just over 68,000 had been prescribed to MPH. The team matched them with an equal number of ADHD youths who were not prescribed MPH. All records were anonymized and checked against the National Mortality Register.

All-cause mortality was split into two subcategories. Unnatural-cause mortality consisted of homicide, suicide, and motor vehicle fatalities. Natural-cause mortality encompassed all other premature deaths. In the raw data, ADHD youths on MPH had half the all-cause mortality of those not on MPH. Natural-cause mortality was down about 40 percent and unnatural-cause mortality was by almost two-thirds. In the non-MPH group, 32 committed suicide in the follow-up year, versus only a single individual in the MPH group. There were seven homicide victims in the non-MPH group, versus none at all in the MPH group.

These staggering reductions, however, were almost exclusively among males. The team then adjusted for potential confounding variables - gender, age, residence, insurance premium, out-patient visits, and pre-existing diagnoses. In the adjusted model, the risk for all-cause mortality was still reduced - by about 20 percent - for those on MPH and remained statistically significant. Virtually identical reductions were found for males and for children first diagnosed with ADHD between 4 and 7 years old. But all other risk estimates became statistically non-significant, due in large measure to the rarity of mortality events.

The authors concluded, "This is the first study reporting that a longer interval between first ADHD diagnosis and first prescription of MPH is associated with a higher risk of all-cause mortality. In addition, we also found that participants receiving longer-duration MPH treatment had a lower risk of all-cause mortality. ... an implication is that receiving a diagnosis earlier and receiving medication earlier may reduce the risk of later adverse consequences."

They nevertheless cautioned, "although we adjusted for multiple covariant, information lacking in the database precluded the measurement of other possible confounders, such as family history, psychosocial stressors, the effect of behavioral therapy or severity of comorbidities. Therefore, as with all observational data, it is not possible to be conclusive about whether the association with lower mortality is related to an effect of MPH treatment itself or whether other characteristics of the children receiving MPH may account for the lower risk (i.e. confounding by indication).

Finally, although the cohort sizes were large, the number of deaths was small, and this limited statistical power, particularly for the investigation of cause-specific mortality and of subgroup differences. Because of the relatively low number of deaths and limited follow-up duration, longer-term studies with larger samples are warranted ..."

Children with ADHD are at higher risk of getting severe burns than normally-developing children. Burn injuries can be traumatic, imposing physical, psychological, and economic burdens on children, their families, and society. Methylphenidate is known to be effective in reducing ADHD symptoms. Can it also reduce the risk of burn injuries?

A team of Taiwanese researchers collaborating with two British researchers explored that question by looking at a nationwide population cohort. Taiwan has a single-payer national health insurance system that includes the entire population (99.6 percent coverage). Using Taiwan's National Health Insurance Research Database(NHIRD), they identified over 90,000 youths under 18 years old with a diagnosis of ADHD. Youths who had burned injuries before diagnosis were excluded. ADHD youths were further divided into three groups: those not prescribed methylphenidate (over 22,000), those prescribed methylphenidate for less than 90 days (over 17,500), and those prescribed methylphenidates for 90 days or more(over 50,000).

Because methylphenidate is the only approved stimulant in Taiwan, it was the only stimulant analyzed in this study. Atomoxetine, a non-stimulant, is also approved in Taiwan, but only for those whose, outcomes with methylphenidate are suboptimal. It was only used by 4 percent of those on ADHD medication, and generally after prior use of methylphenidate, so there was no way to evaluate its effectiveness. Among ADHD youths not on methylphenidate, the proportion who got burn injuries was 6.7 percent. That dropped to 4.5 percent for those medicated for under 90 days, and to 2.9 percent for those on longer-term medication.

Calculations indicated that half of all burn injuries could have been prevented if all youths had been on methylphenidate. After adjusting for multiple confounders - seizure, intellectual disability, autism, conduct disorder, opposition defiant disorder, anxiety, depression, and psychotropic use (benzodiazepine, Z-drugs, antipsychotics, and antidepressants) that taking methylphenidate for any length of time was 38 percent less likely to suffer burn injuries. Moreover, longer-term medication had a greater beneficial effect. Those taking methylphenidate for under 90 days were 30 percent less likely to get burn injuries, whereas those taking it for 90 or more days were less than half as likely to get burn injuries as those not on methylphenidate.

The authors emphasized, "This nationwide population-based study has several strengths. First, the nationally representative sample was substantial and minimized selection bias. Second, patients with ADHD were identified through physician-based diagnoses. Third, all MPH [methylphenidate] prescriptions are recorded in the NHIRD, avoiding misclassification bias. Also, by excluding burn injuries before ADHD diagnosis, the reverse causal relationship between ADHD and burn injury was eliminated."

To what extent does sex matter in the expression of ADHD symptoms and associated cognitive deficits among youths with ADHD?

A recently published meta-analysis of 54 studies by a Canadian team of researchers at the University of Quebec at Montreal suggests it makes little to no difference. A meta-analysis of 26 studies with over 5,900 youths found no significant difference in inattention symptoms, and a meta-analysis of 24 studies with over 5,500 youths likewise found no difference in hyperactivity-impulsivity symptoms. Separating out hyperactivity and impulsivity made no difference.

Given these results, it's no surprise that a meta-analysis of 15 studies with over 3,500 youths again found no significant divergence between the sexes for total ADHD symptoms. Parents and teachers differed, however, in their ratings of symptoms. Whereas parents observed no differences, teachers reported boys had slightly more inattention and hyperactive-impulsive behaviors than girls. Turning to cognitive functions, a series of meta-analyses found no significant sex differences for interference control, working memory, and planning scores. But boys performed slightly worse on inhibition and motor response inhibition. While the raw data also showed boys slightly under-performing girls on cognitive flexibility, strong evidence of publication bias made this unreliable.

The team also compared youths with ADHD and youths without ADHD. Both for females and for males, those differences in ADHD symptoms were - as would be expected - extremely large, whether for total symptoms, inattention, or hyperactivity-impulsivity. All cognitive function scores were moderately better for normally developing boys compared with boys with ADHD, and for normally developing girls compared with girls with ADHD. Yet once again, when comparing these effect sizes between girls and boys, there were no significant differences for any of the symptom and cognitive function effects.

"In other words," the authors wrote, "boys and girls with ADHD presented significantly more primary symptoms and executive and attention deficits than did their peers without ADHD, and effect sizes were not significantly different between the sexes." They concluded, "girls with ADHD do not differ from boys with ADHD in many domains of cognitive functioning, and they have significantly more severe difficulties across the executive and attentional functions measured relative to girls without ADHD. This meta-analysis is the first to examine sex differences in cognitive flexibility, working memory, and planning."

Two new studies, examining entire nationwide populations on opposite sides of the world, have just reported findings on the association between hypertensive disorders of pregnancy (HDP) and subsequent ADHD in off spring. HDP includes chronic hypertension, pre-eclampsia, pre-eclampsia superimposed on chronic hypertension, and gestational hypertension.

According to the Mayo Clinic, Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys. Preeclampsia usually begins after 20 weeks of pregnancy in women whose blood pressure had been normal. Left untreated, it can lead to serious complications for both mother and baby and can be fatal. This range of conditions affects more than one in twenty pregnancies worldwide. HDP hampers permeability of the placenta, which may reduce delivery of blood-borne oxygen and nutrients to the fetus, potentially affecting brain development. ADHD could thus theoretically emerge as a neurodevelopmental outcome.

To what extent is this borne out in national-wide population studies? Both Taiwan and Sweden have single-payer national health insurance systems that systematically track virtually every resident. One study team used the Taiwan National Health Insurance research database to examine a cohort of 877,233 children born between 2004 and 2008. The other study team used the Swedish national registers to explore a cohort of 1,085,024 individuals born between 1987 and 1996.

The Taiwanese study adjusted for the following covariate/confounders: year of birth, fetal sex, paternal age, maternal age, family income, urbanization level, maternal diabetes diagnosis, preterm birth, small for gestational age, and parental psychiatric disorders. The Swedish study adjusted for the calendar year of birth, offspring sex, maternal age, parity, height, body mass index, smoking, presentational diabetes, parental educational level, occupation, and marital status. In the Taiwanese population, children of mothers with hypertensive disorders during pregnancy were about 20% more likely to develop ADHD than those of mothers without such disorders. There was no significant difference between chronic hypertension and pregnancy-induced hypertension/pre-eclampsia.

In the Swedish population, children of mothers with hypertensive disorders during pregnancy were about 10% more likely to develop ADHD than those of mothers without such disorders. But the Swedish study also went a step further. It is incredibly difficult to identify all significant confounding variables. But if you have a large enough study population, one can examine the effect of restricting the analysis to siblings within the same families. In that way, one can control in large measure for familial confounding “ shared environment and heredity. In the subsample of siblings “ 1,279 exposed to HDP versus 1,607 not exposed “ those exposed to outerwear were 9% more likely to develop ADHD, but this outcome was not statistically significant.

Noting the reduced statistical power of the subsample, the authors nonetheless concluded, the magnitude of these associations might be too weak(for ADHD in particular) to be considered an important risk factor at the level of the general population  Moreover, in a separate cohort of 285,901 Swedish men born between 1982 and 1992 who attended assessments for military conscription, mildly lower cognitive scores among those exposed to HDP in uteri vanished altogether (mean difference = 0) when limited to comparisons between full siblings (1,917 exposed versus 2,044 not exposed).

The mechanisms underlying the association between ADHD symptoms and suicidal ideation are poorly understood. A team of researchers from France and Montreal set out to explore this relationship with 2,331 French college students.

The students were participants in the internet-based student Health Research Enterprise project, a prospective population-based cohort study of students in higher education institutions in France. The i-Share study includes a longitudinal collection of data on childhood and family history, lifestyle, health information, and psychosocial examinations during the college years and beyond. 15,528 participants were included in the initial cohort, of which 2,331 completed all the questionnaires and did not have any missing data at the one-year follow-up. The mean age was 21, and four out of five were women. ADHD symptoms were assessed at the initiation of the study. Suicidal ideation was evaluated through a questionnaire completed a year later. Before that, three months after initiation, participants filled out a mental health survey that inquired about two potential mediators of suicidal ideation: depressive symptoms and self-esteem.

After adjusting for potential confounding factors (e.g., sex, childhood adversity, living conditions, and substance use) and taking into account the role of the mediators, the effect of ADHD symptoms on suicidal ideation (i.e., the direct effect) was no longer statistically significant, whereas pathways through depressive symptoms and self-esteem were both statistically significant. The pathway through depressive symptoms accounted for 25% of the total effect, while the pathway through self-esteem accounted for 64% of the total effect. Most of this indirect effect of self-esteem was in turn explained by the unique effect of self-esteem (not explained by depression), which accounted for 45% of the association, whereas a smaller part was explained by the effect of self-esteem through depression (accounting for 19% of the total effect). Ultimately, both mediators had the same effect (45% vs. 44%). Patterns were similar for males and females.

The authors caution that the study sample was not representative of the population of college students. It relied on volunteers, females were overrepresented, and the dropout ratio was very high. Participants in the final sample were more satisfied with their financial resources during their college years and during childhood, and less frequently consumed tobacco, than those in the initial cohort. The researchers recommend that ADHD patients be screened for self-esteem, and point out that other studies have indicated that exercise, Internet support groups, and interpersonal group therapy can build self-esteem in young people.

ADHD continues to be a significant and difficult challenge in the collegiate world.

The symptoms of the disorder directly impact a person’s ability to manage the demands of college. Matriculating students are expected to rapidly obtain and deploy many self-management skills. Increased academic expectations demand a greater capacity for sustained attention. And the evolving social milieu can tax the emotion-regulation and social cognition of those with ADHD.

Having seen our patients struggle, the Association for Collegiate Psychiatry decided to submit a workshop for presentation at the 2019 APA meeting in San Francisco. While developing the presentation, we discovered a wealth of recent ‘young adult’ follow-up data from longitudinal studies.

Without exception, the study's findings reflected a significant decrease in functional outcomes across multiple domains of adult life. Further, we discovered that the new work coming from the TRAC observational study of college students has found troublesome rates of psychiatric comorbidity after the first year. This epidemiologic evidence supports devoting resources to the care of this cohort.

However, it appears that this has not penetrated the world of campus mental health treatment. At present, most post-secondary schools (to our knowledge, data is quite limited) lean toward policies that make it difficult for students with ADHD to be diagnosed or treated on campus. One obstacle is requiring evidence of a childhood diagnosis, which many children with high-IQ compensated ADHD may not have received. Another can be the demand for expensive and comprehensive neuropsychological testing even though the diagnostic value of that testing remains unclear.

Some student health centers ask students to obtain prescriptions from the treaters they saw before coming to campus, even if those prescribers are out of state. Though these policies may be deployed to decrease the diversion of stimulant medication, such hurdles may be difficult for the 18-year-old ADHD student to navigate. The result is that many students with this predictably destructive condition go untreated.

The good news is this subject interests the collegiate community. Among other things, our APA workshop was selected to be the APA’s ‘Member’s of the Month’ for January 2020. Much work remains in developing and deploying diagnostic policies and treatment strategies that colleges and universities feel comfortable supporting. We mentioned the APSARD community during the workshop as a resource for professionals interested in ADHD. And we hope the wider ADHD research and treatment communities will join us in focusing our energy on this underserved and sometimes maligned group of students who need our help.