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The US Food and Drug Administration (FDA) has 

the first-ever video game to treat ADHD in children.

 EndeavorRxTM (AKL-T01) is a prescription therapeutic gaming 

designed to improve inattention or combined-type ADHD in youths between the ages of 8 and 12.

FDA approval was based on 5 clinical studies involving over 600 participants who had ADHD, including one 

 This prospective, randomized, controlled STARS-ADHD study showed that AKL-T01 improved objective measures of attention in children with ADHD. Of 857 children screened for the study, a total of 348 patients with confirmed ADHD were randomly assigned to receive AKL-T01.

The video game-like interface was used 25 minutes a day, 5 days a week, for 4 weeks and was found to improve attentional functioning significantly as reported by both patients and parents. After one month of use, roughly half of parents reported clinically meaningful improvement in their child’s daily impairments. “Moreover, this increased to 68% after a second month of treatment. Following a month of treatment, improvements in ADHD impairments were maintained for up to 1 month,” according to the Akili news release.

 A small percentage of participants experienced minor adverse effects that included frustration, headache, dizziness, emotional reaction, nausea, or aggression.

EndeavorRx, built on the Akili Selective Stimulus Management engine (SSMETM), is intended for clinical use in concert with therapy, pharmaceutical treatment, and patient education. Playing the game targets neural networks to improve inattention, a central component of ADHD. While hyperactivity is not particularly addressed by the platform, the video game experience activates parts of the brain that compromise cognitive function.

“With EndeavorRx, we’re using technology to help treat a condition in an entirely new way as we directly target neurological function through medicine that feels like entertainment,” said Eddie Martucci, PhD, Chief Executive Officer of Akili.

Elysa Marco, MD, Assistant Clinical Professor of Neurology and Director of Research, Autism and Neurodevelopmental Center, at UCSF, and Executive Director of Neurodevelopmental Medicine at Cortica Healthcare, added, “Unlike traditional ADHD medications, EndeavorRx is designed to specifically target inattention. Based on the benefits of my research participants and patients have experienced, I am thrilled that EndeavorRx is moving from the lab to the clinic to play an essential role as part of a comprehensive treatment plan for children with ADHD.”

Digital therapeutics for neuropsychiatric disorders have gained momentum since at least 2010, but this is the first-ever device approved by the FDA to be marketed for any condition.

 “Cognitive neuroscience research has the potential to inform the development of novel interventions for specific disorders, such as ADHD, by linking implicated brain systems with specifically-targeted digital interventions, which can be optimally designed to operate within game interfaces,” according to 

 Since the COVID-19 pandemic, early approvals of treatments have been made by the FDA, and this is no exception—perhaps because families are looking for alternatives to traditional medications that may or may not work.

The EndeavorRx treatment will be available with a prescription in the near future, according to Akili. The device will be part of the Endeavor Care Program, which includes the EndeavorRx treatment, to be used in conjunction with a mobile app (Akili Care). Information can be found at 

1. FDA Permits Marketing of First Game-Based Digital Therapeutic to Improve Attention Function in Children with ADHD. Press Release. Federal Drug Administration. June 15, 2020. Accessed June 17, 2020. 

https://www.fda.gov/news-events/press-announcements/fda-permits-marketing-first-game-based-digital-therapeutic-improve-attention-function-children-adhd

2. Akili Announces FDA Clearance of EndeavorRx for Children with ADHD, the First Prescription Treatment Delivered Through a Video Game. Press Release. Akili Interactive; June 15, 2020. Accessed June 17, 2020. 

https://www.akiliinteractive.com/news-collection/akili-announces-endeavortm-attention-treatment-is-now-available-for-children-with-attention-deficit-hyperactivity-disorder-adhd-al3pw

3. Kollins SH; DeLoss, PhD; Cañadas E; Lutz J. A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial. 

 2020;4:e168-e178. Accessed June 19, 2020. 

https://www.thelancet.com/journals/landig/article/PIIS2589-7500(20)30017-0/fulltext

4. Robbins R. In a landmark decision, FDA greenlights a video game for kids with ADHD. Stat News. June 15, 2020. 

https://www.statnews.com/2020/06/15/fda-akili-adhd-endeavorrx

5. Davis NO, Bower J, Kollins SH. Proof-of-concept study of an at-home, engaging, digital intervention for pediatric ADHD. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764249

FDA approves video game as treatment for ADHD.

The Video Game Will See You Now

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common chronic medical condition that affects between 6% to 9% of children with clinically significant symptoms carrying on into adulthood in about 60% of the cases.

 Data from the 2016 National Survey noted that 9.4% of children in the United States aged 2 to 17 years had a diagnosis of ADHD.

 The worldwide epidemiologic prevalence of adults with ADHD is estimated to be 4%.

 Boys are 2 to 4 times more likely than girls to be diagnosed with ADHD.

Treatment approaches for ADHD include education, psychotherapy, and pharmacotherapy, irrespective of age.

 Among children and adolescents with ADHD, about two-thirds received pharmacotherapy, and about half have received psychotherapy. Combined pharmacotherapy and psychotherapy commonly occurs but not in every person. Interestingly, nearly 25% of the persons 

The stimulant medications, such as methylphenidate and amphetamines, are the mainstay of pharmacotherapy for persons with ADHD and have been used for over 30 years.

 A variety of formulations for methylphenidate and amphetamine are available as oral tablets, capsules, and transdermal patches.

 The tablet and capsule products exist as immediate-release (IR) preparations that requires administration of 2 to 3 times per day and extended-release (ER) formulations taken only once daily. There are several non-stimulant agents that include atomoxetine, clonidine ER, and guanfacine ER.

 The benefits, risks, and safety profiles of these agents are well known.

Numerous studies clearly demonstrate that stimulants significantly improve attention, concentration, behavior, visual short-term memory, and driving performance. An epidemiologic parameter that offers a magnitude of improvement on functional outcomes is the statistical number needed to treat (NNT) where the lower the number, the more effective the treatment. The theoretical NNT = 1 means that every person treated will be benefit. If a medication has a low NNT, this finding would likely have high a clinical and public health impact. An NNT of 2.5 means that the treatment is effective.

 a stimulant’s NNT was reported to be “3” to prevent disruptive behavioral disorders and repeating a grade in school, whereas the NNT = 4 for preventing motor vehicle accidents (MVAs). These findings convey that stimulants are effective agents in preventing disruptive behaviors, lessens the possibility of a child or adolescent repeating a grade at school while also reducing the prospects of MVAs compared with untreated ADHD. For adolescent teens and young adults, preventing MVAs can be a significant public health factor.

Unfortunately, poor adherence to and premature termination of stimulants continue to undermine their benefits. 

 reported that the adherence rates in children whose ADHD symptoms were treated with stimulants ranged from 56% to 75% with greater than 50% ceasing treatment despite their efficacy. The accuracy of adherence studies relies on the study methodologies. Adherence studies with stimulants in children with ADHD typically utilized methods that included prescription fills and refills picked up by the parents and parental verbal reports. A prescription fills or refills and parental verbal reports may not necessarily indicate actual medication adherence by the child.

Measurement of saliva drug concentrations as a surrogate biomarker for adherence was compared with parental verbal reporting in the MTA Cooperative Study.

 All participants (N = 254) were placed on methylphenidate (MPH) during the 14-month study. Subjects were assessed to be verbally adherent if the parent reported their child took medication 80% or more asked at each monthly visit. Four saliva samples were collected at months 2, 6, 9, and 14 where detectable MPH measurements specifies physiological adherence as drug was taken that day (detection limit was > 3 ng/mL).

Due to the variable saliva samples obtained per child, subjects were noted to be adherent if greater than 50% of a person’s saliva samples contained detectable MPH concentrations. Parents verbally reported MPH was taken on the day for all children when saliva samples were obtained with 89.8% of their children taking medications on all occasions. Results from the saliva MPH levels showed that 24.8% of subjects were physiologically non-adherent (≤ 50% of samples below 3 ng/mL) and 12.2% of subjects were non-adherent for all four collected saliva samples. Only 53.5% of subjects were physiologically adherent for all four saliva samples. This study indicates that the parent’s verbal report to the provider may overestimate adherence while underestimating non-adherence in their children.

, the pattern of adherence in children with ADHD (N=166) was examined that include these factors: sex, ADHD severity, and higher socioeconomic status (SES).

 The data were obtained from Longitudinal Study of Australian Children (LSAC) between May 2002 and March 2015. Children (average age 9.7 years ± SD = 2.7 years) that were started with methylphenidate, dexamphetamine, or atomoxetine and followed continuously with data collected every 2 years. The data collected was prescription redemption via the Pharmaceutical Benefit Scheme (PBS) and the total number of prescriptions redeemed throughout the study. The total time on medication was defined as the time between the first and last redeemed prescription.

The results reported that only just over half (54%) had a single continuous use of medication; 21.6% had one interruption; and 25.4% had two or more time periods of interruptions. The only variable found predictive of medication coverage was SES as higher SES was associated with higher medication coverage. The prescription redemption pattern over time showed that coverage was relatively high during the first year, progressively decreased for 3 to 4 years, and increased for those who remained on medication after 5 years (U-shaped curve).

A subset of children (N=89) was analyzed where the median medication coverage was 81% for the first 90 days and decreased to 54% beyond the first 90 days. This study suggests that psychiatrists and other health professionals need to be consistently engaged with the children and their parents for extended time periods for commitment to long-term treatment. Additionally, approximately 90% of children and adolescents with ADHD responded effectively to either methylphenidate or dexamphetamine.

Yet, these two different studies conducted about 10 years apart using different methods reported similar findings of non-adherence in about 50% among the participants.

Many rationales are offered to account for non-adherence. These include the “stigma” of taking medications by the child and adolescent; parental explanations for taking medications; lifestyle factors; busyness; forgetfulness; and SES. Medication adverse effects and multiple drug administrations can add to non-adherence. Careful stimulant monitoring and products with once-daily dosing can maximize benefits and minimize potential risks.

The updated clinical practice guidelines for children and adolescents with ADHD have strong recommendations for medications in children (greater than 6 years) and adolescents (12 to 18 years) with dosing titrations to achieve maximal benefits.

 The guidelines have a number of areas for future research that include developing methods to involve children, adolescents, and parents to improve adherence to psychotherapy and pharmacotherapy and development of electronic means (apps) to assist in monitoring. Stimulants have demonstrated vibrant benefits for persons with ADHD and every effort should be utilized to lessen non-adherence.

is Professor of Pharmacotherapy at the University of North Texas System College of Pharmacy and founder of Jann Medical Writing.

1. Targum SD, Adler LA. Our current understanding of adult ADHD. 

2. Wolraich ML, Hagan JF, Allan C, et al. 

Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents

3. Markowitz JS, Yu G. Stimulants and other non-stimulants for attention deficit/hyperactivity disorder. In. 

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents.

 Eds. Jann MW, Penzak SR, Cohen LJ. Springer Publications, 2016.

4. Biederman J, DiSalvo M, Fried R, et al. 

Quantifying the protective effects of stimulats on functional outcomes in attention-deficit/hyperactivity disorder: a focus on number needed to treat statistic and sex effects

5. Pappadopulos E, Jensen PS, Chait AR, et al. 

Medication adherence in the MTA: saliva methylphenidate samples versus parent report and mediating effect of concomitant behavioral treatment

6. Efron D, Mulraney M, Sciberras E, et al. 

Patterns of long-term ADHD medication use in Australian children. 

: (21, March 2020). doi:10.1136/archdischild-2019-317997.

Despite proven efficacy of ADHD treatments, adherence remains a challenge.

Adherence Challenges With Medications in Patients With ADHD

Seclusion, the disciplinary practice in which a child is placed in a location that isolates them from peers and adults, has long been considered controversial.

 Seclusion emerged as a common practice within special education during the 1960s and 1970s and has, in more recent decades, increased in general education settings despite the lack of evidence that it is effective.

 In fact, seclusion has been associated with negative physical and psychological outcomes, including death, and children with disabilities and mental health needs are at increased risk for seclusion relative to their peers.

in collaboration with ProPublica, published a 

on the use of seclusion for children and youth in schools and special education settings across Illinois.

 The report revealed shocking abusive practices, including long-duration seclusions for young children, lack of adult oversight, and overly harsh discipline for minor infractions. As noted in the report, seclusion is banned in four states and restricted in sixteen others. Following the report, Illinois issued new guidelines and now bans this practice.

More recently, a group of Illinois congressional representatives issued a letter to the Secretary of Education asking her to ban all seclusions in educational settings nationwide. As noted in these reports and letters, there is no therapeutic rationale for long-duration seclusion, and there are many more viable and effective alternatives.

 disciplinary practices in schools are disproportionately applied to youth of color with significant disruption in their learning; often referred to as the school-to-prison pipeline.

and ProPublica, only 19 states have banned school seclusion, and such practices are not regulated by federal law.

 In this article, we discuss the reasons for the maintenance of abusive disciplinary practices with youth despite considerable evidence for more effective alternatives, suggest a renewed focus on reducing disparities and promoting equitable funding across communities, and share thoughts and implications for psychiatrists.

Harsh discipline with children-whether it is corporal punishment by parents or overly punitive practices in schools-has long been established as ineffective and counter-productive, yet it remains a common practice.

 Harsh disciplinary practices lead to high rates of childhood aggression and delinquency, with strong intergenerational transmission.

 at the Oregon Social Learning Institute first identified what they termed 

: escalating child misbehavior is met with escalating punitive practices by parents. They noted that the adult overuse of punishment is often a model for the child to use aggression to solve problems with peers or teachers. Their research led to the development of a generation of programs to teach parents and teachers alternative discipline practices.

Several decades of experience in urban schools in Philadelphia and Chicago provided our research team with more than enough anecdotal evidence that the coercive cycle was a well-established pattern, but empirical data were lacking to document the nature and extent of disciplinary practices. In collaboration with a principal at one Chicago Public School in which we were consulting, we collected and catalogued disciplinary records for all 3rd through 8th grade students (N = 314) for an entire school year.

We found that the coercive cycle was in place for some but not all students. Specifically, being disciplined was a deterrent for about 20% of students; after being disciplined in the fall, they did not receive any other discipline for the rest of the school year. In general, their infractions were minor, such as not wearing a school uniform or talking out in class, and the consequences less severe-detentions rather than expulsions. For them, the punishment accomplished its goal of discouraging misbehavior.

But for another quarter of the students, the findings were more troubling. Their infractions were more serious (eg, fighting, cursing) and the punishment more severe (expulsion rather than detention). Of even more concern, being disciplined led to increased disruptive behavior throughout the school year. As a group, these students were rated as highly aggressive by teachers and were less popular with their peers. Based on the escalation of their disruptive behavior, the consequences appeared to serve as a reward not a punishment. That is, for these students, being removed from the classroom may have been preferred over remaining in a classroom, which was supposed to be a negative experience for them. Teachers were also relieved with the removal of disruptive students from the classroom, because it allowed them to resume their teaching. Thus, for these students, the coercive cycle was fully entrenched (

Children with autism spectrum disorder comorbid with ADHD had especially high rates of harsh discipline.

 Reducing the use of parental harsh discipline was found to be especially important for preschool children with ADHD through reduced autonomic responding associated with anger management and emotional behaviors.

 A recent study of disciplinary practices in high schools and middle schools in Maryland noted high rates of suspension for students with disabilities. This was especially pronounced in low-achieving schools serving students in areas of lower socioeconomic status.

The processes supporting the coercive cycle are well established behavioral patterns that can be difficult to modify, and the stakes in psychiatric and special education facilities are even higher. In fact, following the ProPublica and 

report, the Illinois State Department of Education issued a statewide ban on seclusion in child psychiatric facilities only to lift the ban in favor of increased monitoring after programs indicated that without these procedures they would need to discharge their most aggressive youth.

 Clearly, the state was unprepared to accommodate these facilities to fully address the needs of these youth.

From a psychiatric public health perspective, this report and the subsequent responses highlight the urgent need to address the poor state of public education for our most vulnerable youth. It is understandable that legislators and advocates are looking to government officials to ban abusive practices, such as seclusion, but a focus only on what not to do will likely only push this problem further underground. It is not a lack of knowledge that is perpetuating these abusive practices, but a lack of willingness to fund programs, and staff, at levels needed to assure effective practices.

Some three decades ago, our research team consulted at a large state psychiatric hospital outside of Philadelphia and saw first-hand how staff shortages and lack of training led to abusive disciplinary practices.

 Young patients and patients of color were most likely to receive long seclusions, lasting between 4 and 5 hours-and the staff were unprepared for the more complex behavioral reward programs we recommended, such as increased privileges (eg, TV time, later bedtime) contingent on appropriate behavior. Sadly, this was highly similar to the findings in the most recent report from Illinois.

Similarly, for youth in special education, lack of adequate funding is a key factor in deteriorating services. A review of state funding of education from the nonpartisan Center on Budget and Policy Priorities noted steep cuts in spending on education for most states with staffing levels and teacher salaries being especially hard hit.

 It is no wonder that disparities in education remain a pernicious problem in the US-driving the growing income gap between rich and poor.

report is important in contributing to a national awareness of the deplorable state of public education in the US for our most vulnerable and needy children. Politicians and state government representatives who call for higher standards of care and greater accountability from education authorities are also to be commended. However, neither of these will effect meaningful change unless they are accompanied with dedicated funding for staffing, training in evidence-based education, and special education behavior management practices as well as organizational support for implementing and monitoring these practices.

There are numerous, easily accessible programs on effective disciplinary strategies focused on standardized classroom routines and use of praise and positive reinforcement as well as less severe consequences such as timeout and loss of privileges. However, they are not widely disseminated, especially in communities of poorer socioeconomic status.

 Online resources are becoming more prevalent and research is emerging that looks at factors that affect parent and teacher response.

report and the attention they have garnered can spur a long-needed alignment of knowledge and political will to break the coercive cycle to abusive disciplinary practices in schools. But given that much of this information has been known in principle if not in detail, it is likely that more direct advocacy is needed. Working together, psychiatry and its allied disciplines of psychology and social work have the knowledge and leverage to disseminate information on effective discipline to schools and parents. It may be difficult in a fee-based health care environment to find the time and resources that will impact communities, but even a little effort by each of us can go a long way. Children and their parents and teachers deserve no less.

To read “The Quiet Rooms” published by ProPublica and the 

https://graphics.chicagotribune.com/illinois-seclusion/index.html

. Share your comments on this article and other pieces by emailing 

 is Professor of Psychiatry and Psychology; Director, Institute for Juvenile Research; and Director, Community Engagement and Collaboration Center for Clinical Translational Science, University of Illinois, Chicago. 

 is Assistant Professor of Psychology in Psychiatry, Institute for Juvenile Research, Department of Psychiatry; and Director of Inclusion Initiatives, Office of the Vice President for Diversity, University of Illinois, Chicago. The authors report no conflicts of interest concerning the subject matter of this article.

1. Ryan JB, Peterson RL, Tetreault G, et al. Reducing the use of seclusion and restraint in a day school program. In Nunno MA, Day DM, Bullard LB, Eds. Examining the Safety of High-Risk Interventions for Children and Young People. New York, NY: Child Welfare League of America; 2007: 201-216.

2. Zaccaro DE. Unregulated Untrained, and Unaware: Restraint and Seclusion Practices in Educational Settings [dissertation]. Cedar Falls, IA: University of Northern Iowa; 2014.

3. National Disability Rights Network. School Is Not Supposed to Hurt: Investigative Report on Abusive Restraint and Seclusion in Schools. January 2009.

4. Smith Richards J, Cohen JS, Chavis L. The Quiet Rooms: Children Are Being Locked Away, Alone and Terrified, in Schools Across Illinois. 

5. Illinois State Board of Education. State Board of Education to Take Emergency Action to End the Use of Isolated Seclusion in Illinois Schools. November 20, 2019.

Encouraging alternatives to seclusion, restraint, and reliance on PRN drugs in a public psychiatric hospital

7. Skiba RJ, Arredondo MI, Williams NT. More than a metaphor: the contribution of exclusionary discipline to a school-to-prison pipeline. 

8. Lansford JE, Dodge KA. Cultural norms for adult corporal punishment of children and societal rates of endorsement and use of violence. 

9. Weiss B, Dodge KA, Bates JE, Pettit GS. Some consequences of early harsh discipline: child aggression and a maladaptive social information processing style. 

10. Bailey JA, Hill KG, Oesterle S, Hawkins JD. Parenting practices and problem behavior across three generations: monitoring, harsh discipline, and drug use in the intergenerational transmission of externalizing behavior. 

11. Patterson GR, Dishion TJ, Bank L. Family interaction: a process model of deviancy training. 

12. Sandler IN, Schoenfelder EN, Wolchik SA, Mackinnon DP. Long-term impact of prevention programs to promote effective parenting: lasting effects but uncertain processes. 

13. Epstein M, Atkins M, Cullinan D, et al. Reducing behavior problems in the elementary school classroom: a practice guide (NCEE #2008-012). US Department of Education. September 2008.

14. Atkins MS, McKay MM, Frazier SL, et al. Suspensions and detentions in an inner-city school: punishment or reward? 

15. Flouri E, Midouhas E, Charman T, et al. Poverty and the growth of emotional and conduct problems in children with autism with and without comorbid ADHD. 

16. Bell Z, Shader T, Webster-Stratton C, et al. Improvements in negative parenting mediate changes in children’s autonomic responding following a preschool intervention for ADHD. 

17. Camancho KA, Krezmien MP. Individual-and school-level factors contributing to disproportionate suspension rates: a multilevel analysis of one state. 

18. Illinois State Board of Education. ISBE Amends Emergency Rules with Advocate Feedback. December 4, 2019.

19. Atkins MS, Ricciuti A. The disproportionate use of seclusion in a childrens psychiatric state hospital. 

20. Leachman M, Masterson K, Figueroa E, et al. A Punishing Decade for School Funding. Center on Budget and Policy Priorities. November 29, 2017.

21. The Heichinger Report Contributor. The growing achievement gap: income inequality is exacerbating the gap between rich and poor school children. 

22. Atkins MS, Cappella E, Shernoff ES, et al. Schooling and children’s mental health: realigning resources to reduce disparities and advance public health. 

23. Lakind D, Atkins MS. Promoting positive parenting for families in poverty: new directions for improved reach and engagement. 

24. Marquez B, Vincent C, Marquez J, et al. Opportunities and challenges in training elementary school teachers in classroom management: initial results fromclassroom management in action, an online professional development program.

25. Baker S, Sanders Mr, Morawska A. Who uses online parenting support? A cross-sectional survey exploring Australian parents’ internet use for parenting. 

The authors discuss abusive disciplinary practices that continue to this day despite considerable evidence to the contrary and share thoughts and implications for psychiatrists.

The Coercive Cycle: A School to Prison Pipeline?

A warning letter was sent from the US Food and Drug Administration’s Office of Prescription Drug Promotion (OPDP) for misleading advertising for the drug ProCentra, an oral solution used to treat 

 The warning letter was in response to a sponsored link on Google.com that failed to include risk information and use the medication’s established name. The letter also notes that the 

The OPDP explained that the ad suggests the drug’s efficacy and ease use by pointing out its “Bubblegum Flavor” and “Liquid Treatment Option,” all of which easily would appeal to parents as desirable for children, without including any risk information.

These violations are especially concerning from a public health perspective because they create a misleading impression about the safety of ProCentra, a drug that is a schedule II controlled substance used in the vulnerable pediatric patient population, and bears a Boxed Warning that describes the high potential for abuse, that administration of amphetamines for prolonged periods of time may lead to drug dependence, and states that misuse may cause sudden death and serious cardiovascular adverse events

The letter was sent to Stefan Antonsson, CEO of 

, with specific corrective actions requested. For starters, the company must “immediately cease misbranding.” In addition, they must respond in a letter detailing not only how they will comply with this request, but, since the violations are deemed serious, they must include “a comprehensive plan of action to disseminate truthful, nonmisleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials.”

According to Regulatory Focus, the ad has been removed and the CEO will respond to the letter.

Meanwhile, its likely Outlook is not alone in such missteps. According to AdComplyRx, more than 30 major prescription brands inadvertently ran non-compliant ads on Google and Bing.

Nonetheless, the warning letter, which is the first of its kind for this calendar year, shows that the FDA is watching and will hold companies responsible.

Warning Letter: Re: ANDA 040776 PROCENTRA® (dextroamphetamine sulfate) oral solution, CII MA 60

. US Food and Drug Administration. February 21, 2020.

. www.myadcomplyrx.com. Accessed March 5, 2020.

OPDP Warns Pharma Company for Sponsored Link on Google

After receiving complaints, the FDA’s Office of Prescription Drug Promotion rebukes the pharmaceutical company for misleading advertising.

Pharmaceutical Company Makes the FDA’s Naughty List

New research highlights the potential benefits and detriments of treatment strategies for ADHD, which include both pharmacological and nonpharmacological options (

Stimulants are the first line of treatment for ADHD and are typically well tolerated. Although there are potential adverse effects associated with stimulant administration, the most common are usually transient or dose related. One of the more serious effects is stimulant-induced psychosis.

To explore this risk, Moran and colleagues

 examined the records of 337,919 young persons aged 13 to 25 who had an ADHD diagnosis and were newly prescribed a stimulant medication. The researchers found 343 episodes of new-onset psychosis among the 221,846 study-matched population over an 11-year period. The median time from which the first stimulant was dispensed to the psychotic episode was 128 days.

The researchers concluded that the risk of new-onset psychosis was approximately doubled for individuals who received amphetamine compared with those who received methylphenidate. This supported their hypothesis, which was based on the similarities between idiopathic psychosis and the biologic effects of amphetamine. Individuals with primary psychosis have higher presynaptic dopaminergic capacity, which is an index of dopamine release.

Limitations of the study included: unmeasured confounding factors (ie, underreporting of substance use disorder), not knowing if the patients actually took the stimulant medication (there is a high rate of diversion, which is greater for amphetamine than methylphenidate), and the study findings, are not generalizable as the data were only from commercial insurance claims and did not take into account patients with no insurance or public insurance.

While the exact therapeutic mechanism of action of stimulants is unknown, they are thought to increase the availability of dopamine in the postsynaptic cleft by blocking the reuptake of dopamine. Amphetamine blocks the ability of the dopamine transporter to remove dopamine from the synapse, facilitates the reuptake of dopamine across the cell membrane, increases the release of vesicular dopamine (accumulates in the cytoplasm), and inhibits the degradative enzymes monoamine oxidase A and B. Methylphenidate binds to the dopamine transporter in the presynaptic cell membrane, blocking the reuptake of dopamine and, therefore, causing an increase in extracellular dopamine. The difference is that methylphenidate does not promote dopamine release from synaptic vesicles. Moreover, amphetamine induces the release of four times as much dopamine as methylphenidate.

 This increase of dopamine may contribute to adverse effects such as stimulant-induced psychosis.

Cases of stimulant-induced psychosis have been reported as early as 1938.

 However, the first case of a child who experienced auditory, tactile, visual hallucinations, and paranoia after treatment with a therapeutic dose of D-amphetamine for hyperactivity was not published until 1967.

 The 8-year-old child’s symptoms of psychosis resolved after the medication was discontinued. A few years later, similar cases were reported by Lucas and Weiss

 after they observed “psychotic reactions” in two children following a short-term therapeutic dose and in an adolescent after ingestion of excess medication after long-term use of a therapeutic dose of methylphenidate, which had been prescribed for hyperactivity.

It was not until 2007 that the FDA mandated a drug label warning that stimulants may cause psychosis in patients with no prior history. There remains limited data on whether the risk of psychosis differs among the two classes of stimulants.

While the incidence of new-onset psychosis with stimulant treatment for ADHD is small, this can be a frightening experience for the child as well as his or her parent and may negatively impact a parent’s decision to pursue stimulant treatment options. Thus, nonstimulant and non-pharmacological treatment options are often requested. Indeed, many parents continue to search for 

, especially for children with a newly established diagnosis.

 Until recently, there have been no viable nonpharmacological alternatives.

Trigeminal nerve stimulation may offer a nonpharmacological option

With concerns over potential adverse effects of medications, other strategies have been explored for treating ADHD. Preliminary studies using trigeminal nerve stimulation (TNS) to treat ADHD symptoms have peaked interest as a potential alternative or adjunctive treatment to stimulant and non-stimulant medications. TNS is a non-invasive, home administered, well-tolerated approach that has 

 Researchers became interested in TNS for ADHD after observing improvements in concentration and attention on mood disorder rating scales.

The stimulation device is compact and worn on clothing during sleep. Thin wires from the stimulator are attached to adhesive electrode pads that are placed on the forehead bilaterally over the ophthalmic branch (V1) of the trigeminal nerve. A current is sent through the wires to activate the trigeminal nerve, which projects to the nucleus tractus solitarius activating the locus coeruleus and the reticular formation. These play a key component in cognitive functions, particularly in sustaining attention.

The recent double-blind sham control study by 

 looked at cortical activation mechanisms using a quantitative electroencephalogram. The researchers found increased spectral power in the right frontal and frontal midline bands with active TNS, hypothesizing that activation of the frontobasal ganglia network targets hyperactivity and impulsivity. This mechanism of action helps to support the overall findings for improvement in both the inattention and hyperactivity components of ADHD.

During trials, the pattern of improvement on ADHD Rating Scale-IV (ADHD-RS) as well as on the Connor’s rating scale was comparable to that seen with non-stimulant medication.

 In this double-blind sham-controlled study by McGough and colleagues, symptomatic improvement was found to be highest after the first week of treatment; scores continued to improve over the next 3 weeks. While the sham group showed improvement over the first week, it was followed by a flattening response. One week after treatment discontinuation, rating scales were again administered in both the active and the sham groups. In both groups, scores from the ADHD-RS were found to decrease, indicating a recurrence of symptoms. This 4-week trial showed sustained improvement in both hyperactivity and inattention symptoms of ADHD with nightly active treatment.

Unfortunately, there are no long-term studies of mood or ADHD with TNS. Continued trials need to be undertaken to determine long-term outcomes as well as clear parameters for treatment.

The cost of the device used in the study, Monarch-TNS, is just over $1000; it is not currently covered by insurance. Other available TNS devices range between $250 and $450; their efficacy, however, is unknown. It is difficult to compare the cost of TNS versus stimulant and non-stimulant medications, since there is such a wide range in cost. The monthly cost ranges from approximately $8 for a generic stimulant and may exceed $288 for a branded product. Most insurance companies will cover at least some medication costs.

TNS has been well tolerated with high safety and compliance rates. A long-term follow-up study for TNS use in epilepsy demonstrated skin irritation as the main adverse effect from treatment.

 of short-term TNS include headache and eye twitches.

 Based on the 4-week double-blind sham study, the manufacturer of the Monarch-TNS treatment device also noted drowsiness, increased appetite, trouble sleeping, and fatigue as possible side effects. No withdrawal effects have been observed.

 suggest that TNS may be effective for ADHD as an alternative treatment to stimulant and non-stimulant medications given symptomatic improvement in both inattention and hyperactivity symptoms of ADHD. Although direct comparison of TNS to pharmacological treatment has not been undertaken, treatment may be considered in children with parental preference against pharmacological treatment after providing psychoeducation or in children who cannot tolerate psychotropic medications. TNS as an adjunctive therapy may also be considered; however, adjunctive use has not been studied.

Currently, several limitations remain a concern. First, clear parameters (eg, duration of treatment, number of treatments, the need for booster sessions) have not yet been identified. Second, there are no long-term studies for mood symptoms or ADHD, which limits the available data on long-term efficacy for TNS as a treatment. Third, the device itself is available but will come at a high out-of-pocket cost, thereby restricting treatment access.

Based on these limited data, TNS appears to be an effective, safe, well-tolerated option with high compliance rates. Although more studies are needed, this treatment has high potential for use in managing the symptoms associated with ADHD.

Dr Griffin is Assistant Professor of Psychiatry, the Medical Director of Outpatient Child and Adolescent Psychiatry, and the Director of the Child and Adolescent ADHD Clinic at Rush University Medical Center, Chicago, IL. Dr Harari is a first-year Child and Adolescent Psychiatry Fellow at Rush University Medical Center. The authors report no conflicts of interest concerning the subject matter of this article.

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 moved at the speed of a “football field per second.” Visiting San Francisco (ironically, to hear my beautiful daughter present her environmental research at an academic meeting), I could avoid air quality in the “hazardous” range by at most 30% by staying indoors. But we could not hike together or have a cafÃ© lunch without burning pain in our heads, skin, and lungs. Day after day, the air remained an ugly yellow-grey, thick with air pollution particles.

The particles that make up air pollution are organized by size, from ultrafine particles (UFPs) 1 micron in diameter to PM 2.5 and PM 10, which are 25 and 100 times larger, respectively. They share a similar structure: various (poly) circular (aromatic) hydrocarbons (PAHs) with a high surface charge bind to a core of organic carbon-the carbon naturally in the air-that attracts heavy me- tal ions and oxidative elements, which allows them to aggregate into the particles of various sizes (

We cannot protect our patients without protecting our planet. This means a personal and professional commitment to green our activities by considering the carbon effects of how we do our work.

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