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.
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.
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 underperforming 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 attentional 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.â€
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 offspring.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 1,085,024individuals 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 1982and 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 (1,917exposed versus 2,044 not exposed).
A research team used a large U.S. health insurance claims database that encompasses over 130private insurance payers and more than 50 million persons. They, identified387,968 young adults 18 through 25 years old with at least two claims for ADHD, including 225,705 males and 162,263 females. From the same database, they identified an identically sized group of controls, matched by sex and age, who had no claims for ADHD. The study period covered the ten years beginning in 2005 and running through 2014. To minimize confounding, anyone with claims for autism, schizophrenia, organic brain disorder, neurologic problems, and mental retardation w excluded from both groups. Roughly half of the women with ADHD were receiving ADHD medication, and about two in five men. After controlling for known covariate – sociodemographic variables, type of insurance plan (HMO vs. PPO), and region of the U.S. – young women with ADHD were more than 2.7 times more likely to suffer from depression, and young men more than 2.2 times more likely than their normally developing peers. Suicidal ideation was found to be over 2.2 times as likely among young women with ADHD and1.6 times more likely among young men with ADHD than among their normally developing counterparts. Likewise, young adults with ADHD were found to be over 2.2 times more likely than their normally developing peers to actually attempt suicide. They were also more likely than controls to be hospitalized for depression and/or suicidal behavior. In fact, among those hospitalized, 72% of women and 66% of men had ADHD. Keeping in mind that both the ADHD group and control group were identically sized, that means males with ADHD were twice as likely to be hospitalized, and females with ADHD were almost three times as likely, as their non-ADHD peers. The authors noted, “there was an additive effect of ADHD and female sex on depression and suicidal ideation in our sample … Importantly, our study represents one of the first investigations of this interaction with adequate statistical power.†They concluded, “Given that depression and suicidality in young adulthood forebode long-term problems with depression and suicidality, as well as additional difficulties across the lifespan, future work prioritizing treatment for young adults with ADHD and depression is greatly needed.â€
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 (i-Share, WWW. I- share.fr) 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 trough 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.
A cohort study looked at over five million adults and, over850,000 children between the ages of five and eleven who received care atomizer Permanent in Northern California for the ten years from the beginning of 2007 through the end of 2016. At any given time, KPNC serves roughly four million persons. It is representative of the population of the region, except for the highest and lowest income strata. Among adults, rates of ADHD diagnosis rose from 0.43% to0.96%. Among children, the diagnosis rates rose from 2.96% to 3.74%, ending up almost four times as high as for adults. Non-Hispanic whites had the highest adult rates throughout, increasing from 0.67% in 2007 to 1.42% in 2016. American Indian or Alaska Native (AIAN) had the second-highest rates, rising from 0.56% to 1.14%. Black sand Hispanics had roughly comparable rates of diagnosis, the former rising from0.22% to 0.69%, the latter from 0.25% to 0.65%. The lowest rates were among Asians (rising from 0.11% to 0.35%) and Native Hawaiian or other Pacific Islanders (increasing from 0.11% to 0.39%). The odds of diagnosis dropped steeply with age among adults. Relative to 18-24-year-olds, 25-34-year-olds were 1/6th less likely to be diagnosed with ADHD, 35-44-year-olds 1/3rd less likely,45-54-year-olds less than half as likely, 55-64-year-olds less than a quarter as likely, and those over 65 about a twentieth as likely. This is consistent with other studies reporting an age-dependent decline in the diagnosis. Adults with the highest levels of education were twice as likely to be diagnosed as those with the lowest levels. But variations in median household income had almost no effect. Women were marginally less likely to be diagnosed than men. ADHD is associated with some other psychiatric disorders. Compared with normally developing adults, and adjusted for confounders, those with ADHD were five times as likely to have an eating disorder, over four times as likely to be diagnosed with bipolar disorder or depression, more than twice as likely to suffer from anxiety, but only slightly more likely to abuse drugs or alcohol. The authors speculate that rising rates of diagnosis “could reflect increasing recognition of ADHD in adults by physicians and other clinicians, as well as growing public awareness of ADHD during the decade under study.†Turning to the strong differences among ethnicities, they note, “Racial/ethnic differences could also reflect differential rates of treatment-seeking or access to care. … Racial/ethnic background is known to play an important role in opinions on mental health services, health care utilization, and physician preferences. In addition, rates of diagnosis-seeking to obtain stimulant medication for nonmedical use may be more common among white vs nonwhite patients.†They conclude, “greater consideration must be placed on cultural influences on health care seeking and delivery, along with an increased understanding of the various social, psychological, and biological differences among races/ethnicities as well as culturally sensitive approaches to identify and treat ADHD in the total population.†But the main take-home message of this work is that most cases of ADHD in adults are not being diagnosed by clinicians. We know from population studies, worldwide, that about three percent of adults suffer from the disorder. This study found that less than 1 percent are diagnosed by their doctors. More education is needed to teach clinicians how to identify, diagnose and treat ADHD in adults.
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.1 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.2This epidemiologic evidence supports devoting resources to the care of this cohort. But 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.3Some 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 2020.4Much work remains in developing and deploying diagnostic policies and treatment strategies that colleges and universities feel comfortable supporting. We mentioned the APS ARD 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.
Comorbidities contribute substantially to premature mortality risks in ADHD patients, but even those with ADHD alone are at a 40% greater risk.
The Nordic countries maintain detailed registers of their inhabitants. This enables researchers to examine patterns over entire nations. An international research team used the Swedish national registers for a prospective cohort study of 2,675,615 persons in the Medical Birth Register born in Sweden over 27 years from January 1, 1983, through December 31, 2009. Follow-up was completed in December 2013, with the oldest cohort member aged31. The mean age at study entry was 6, and the mean at follow-up was 11.
Using personal identification numbers, researchers were able to cross-reference with the National Patient Register and the National Drug Register. From this, they determined that 86,670 members of the cohort (3.2percent) had ADHD, based either on records of clinical diagnosis or of prescription of ADHD drugs. Psychiatric comorbidities were likewise identified in the National Patient Register.
These comorbidities were significantly more prevalent in the ADHD population than in the rest of the cohort. For example, whereas only 2.2% of the non-ADHD group was diagnosed with substance use disorder (SUD), 13.3% of the ADHD group also had SUD, a six-fold difference. For depression, it was a seven-fold difference; for schizophrenia a nine-fold difference.
The ADHD group had a significantly higher risk of premature death from all causes than the non-ADHD group, with an adjusted hazard ratio(HR) of 3.94 (95% CI 3.51-4.43). Unintentional injury (36%) and suicide (31%)were the leading causes of death in the ADHD group. Those with ADHD were more than eight times more likely to die by suicide than non-ADHD individuals and roughly four times more likely to die from unintentional injury.
The vast majority of the increased risk appears to be associated with comorbid psychiatric conditions. Those with ADHD but no diagnosed comorbidities had an adjusted HR of 1.41 (95% CI 1.01-1.97). With a single comorbidity, the HR more than doubled to 3.71 (95% CI 2.88-4.78). With four or more comorbidities, it rose to a staggering 25.22 (95% CI 19.6-32.46).
The comorbid condition with the greatest impact was SUD, which increased the risk eight-fold by comparison with those with only ADHD (HR= 8.01, 95% CI 6.16-10.41). Anxiety disorder, schizophrenia, and personality disorder increased the risk about fourfold. Bipolar disorder, depression, and eating disorder increased risk by roughly two and a half times.
The co-variate analysis helped tease out what portion of the risk was associated with ADHD alone versus comorbid conditions. Adjusting for the year of birth, sex, birth weight, maternal age at birth, parental educational level, and parental employment status, those with ADHD (including comorbid conditions)were 2.7 times more likely to prematurely die of natural causes than those without. Adjusting for comorbid psychiatric conditions completely eliminated the risk from ADHD alone (HR = 1.01, 95% CI.72-1.42).
Likewise, those with ADHD (including comorbid conditions)were six times as likely to die of unnatural causes. Adjusting for early-onset comorbid disorders (such as conduct disorders, autism spectrum disorder, and intellectual disability) only modestly reduced the HR to 5.3, but further adjusting for later-onset comorbid disorders(including substance use disorder, depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, personality disorder, and eating disorders)reduced the HR to 1.57 (95% CI 1.35-1.83), and reduced it to insignificance in the case of suicide (HR = 1.13, 95% CI .88-1.45).
Summing up, the lion’s share of the greater risk of premature death in persons with ADHD is attributable to psychiatric comorbidities. Nevertheless, those with ADHD alone still face a 40 percent greater risk than those without ADHD.
The study did not examine the effects of ADHD medication, which the authors state “should be analyzed because of documented potential benefits on ADHD symptoms and comorbid disorders.
The authors concluded, “Among adults, early-onset psychiatric comorbidity contributed substantially to the premature mortality risks due to natural causes. On the other hand, later-onset psychiatric comorbidity, especially SUD, explained a substantial part of the risk for unnatural deaths, including all the risk of suicide deaths and most of the deaths due to unintentional injuries. These results suggest that overall health conditions and risk of psychiatric comorbidity should be evaluated clinically to identify high-risk groups among individuals with ADHD.
Although this review highlights the need for further research, it also upholds previous studies which support Methylphenidate as a safe and effective ADHD medication.
Methylphenidate (MPH) is one of the most widely-prescribed medications for children. Given that ADHD frequently persists over a large part of an individual’s lifespan, any side effects of medication initiated during childhood may well be compounded over time. With funding from the European Union, a recently released review of the evidence looked for possible adverse neurological and psychiatric outcomes.
From the outset, the international team recognized a challenge: “ADHD severity may be an important potential confounder, as it may be associated with both the need for long-term MPH therapy and high levels of underlying neuropsychiatric comorbidity.” Their searches found a highly heterogeneous evidence base, which made meta-analysis inadvisable. For example, only 25 of 39 group studies reported the presence or absence of comorbid psychiatric conditions; even among those, only one excluded participants with comorbidities. Moreover in only 24 of 67 studies was the type of MPH used (immediate or extended-release) specified. The team, therefore, focused on laying out an “evidence map” to help determine priorities for further research.
The team found the following breakdown for specific types of adverse events:
· Low mood/depression. All three non-comparative studies found MPH safe. Two large cohort studies, one with over 2,300 participants, and the other with 142,000, favored MPH over the non-stimulant atomoxetine. But many other studies, including a randomized controlled trial (RCT), had unclear results. Conclusion: “the evidence base regarding mood outcomes from long-term MPH treatment is relatively strong, includes two well-powered comparative studies, and tends to favor MPH.”
· Anxiety. Here again, all three non-comparative studies found MPH safe. But only two of seven comparative studies favored MPH, with the other five having unclear results. Conclusion: “while the evidence about anxiety as an outcome of long-term MPH treatment tends to favor MPH, the evidence base is relatively weak.”
· Irritability/emotional reactivity. A large cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “the evidence base … is limited, although it includes one well-powered study that found in favor of MPH over atomoxetine.”
· Suicidal behavior/ideation. There were no non-comparative studies, but all five comparative studies favored MPH. That included three large cohort studies, with a combined total of over a hundred thousand participants, that favored MPH over atomoxetine. Conclusion: “the evidence base … is relatively strong, and tends to favor MPH.”
· Bipolar disorder. A very large cohort study, with well over a quarter-million participants, favored MPH over atomoxetine. A much smaller cohort study comparing MPH with atomoxetine, with less than a tenth the number of participants, pointed toward caution. Conclusion: “the evidence base … is limited and unclear, although it includes two well-powered studies.”
· Psychosis/psychotic-like symptoms. By far the largest study, with over 145,000 participants, compared MPH with no treatment and pointed toward caution. A cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “These findings indicate that more research is needed into the relationship between ADHD and psychosis, and into whether MPH moderates that risk, as well as research into individual risk factors for MPH-related psychosis in young people with ADHD.”
· Substance use disorders. A cohort study with over 20,000 participants favored MPH over anti-depressants, anti-psychotics, and no medication. Other studies looking at dosages and durations of treatment, age at treatment initiation, or comparing with no treatment or “alternative” treatment, all favored MPH except a single study with unclear results. Conclusion: “the evidence base … is relatively strong, includes one well-powered study that compared MPH with antipsychotic and antidepressant treatment, and tends to favor MPH.”
·Tics and other dyskinesias. Of four non-comparative studies, three favored MPH, the other, with the smallest sample size, urged caution. In studies comparing with dexamphetamine, pemoline, Adderall, or no active treatment, three had unclear results and two pointed towards caution. Conclusion: “more research is needed regarding the safety and management of long-term MPH in those with comorbidities or tic disorder.”
· Seizures or EEG abnormalities. With one exception, the studies had small sample sizes. The largest, with over 2,300 participants, compared MPH with atomoxetine, with inconclusive results. Two small studies found MPH safe, one had unclear results, and two others pointed towards caution. Conclusion: “While the evidence is limited and unclear, the studies do not indicate evidence for seizures as an AE of MPH treatment in children with no prior history … more research is needed into the safety of long-term MPH in children and young people at risk of seizures.”
· Sleep Disorders. All three non-comparative studies found MPH safe, but the largest cohort study, with over 2,300 participants, clearly favored atomoxetine. Conclusion: “more research is needed into the relationship between ADHD, sleep, and long-term MPH treatment.”
· Other notable psychiatric outcomes. Two non-comparative studies, with 118 and 289 participants, found MPH safe. A cohort study with over 700 participants compared with atomoxetine, with inconclusive results. Conclusion: “there is limited evidence regarding long-term MPH treatment and other neuropsychiatric outcomes, and that further research may be needed into the relationship between long-term MPH treatment and aggression/hostility.”
Although this landmark review points to several gaps in the evidence base, it mainly supports prior conclusions of the US Food and Drug Administration) and other regulatory agencies (based on short-term randomized controlled trials) that MPH is safe for the treatment of ADHD in children and adults. Given that MPH has been used for ADHD for over fifty years and that the FDA monitors the emergence of rare adverse events, patients, parents, and prescribers can feel confident that the medication is safe when used as prescribed.
The study team began with a representative sample of 69,972U. S. adults aged 18 years or older who completed the 2012 and 2013 U.S. National Health and Wellness Survey. These adults were invited to complete the Validate Attitudes and Lifestyle Issues in Depression, ADHD, and Troubles with Eating(VALIDATE) study, which included 1) a customized questionnaire designed to collect data on sociodemographic and clinical characteristics and lifestyle, and2) several validated work productivity, daily functioning, self-esteem, and health-related quality of life (HRQoL) questionnaires. Of the 22,937 respondents, 444 had been previously diagnosed with ADHD, and 1,055 reported ADHD-like symptoms but had no previous clinical diagnosis.
There were no significant differences between the two groups in terms of age, education, income, health insurance, and most comorbid disorders. But those who had not been previously diagnosed were significantly more likely to be first-generation Americans (p<.001), nonwhite (p<.001), unemployed (p=.024), or suffer from depression, insomnia, or hypertension.
After matching the two groups for sociodemographic characteristics and comorbid conditions, covariate comparisons were made between 436 respondents diagnosed with ADHD and 867 previously undiagnosed respondents. Among respondents who were employed, diagnosed individuals registered a mean work productivity loss of 29% as opposed to 49% for the previously undiagnosed (p<.001). They also registered a 37% level of activity impairment versus a 53% level among the undiagnosed(p<.001). On the Sheehan Disability Scale, which ranges from 0 (no impairment) to 30 (highly impaired), the diagnosed group had a mean of 10, as opposed to a mean of 15 for the undiagnosed (p<.001). Diagnosed respondents also significantly outperformed undiagnosed ones on the Rosenberg Self-Esteem Scale (19 versus 15, on a scale of 0 to 30, p<.001), and on two quality-of-life scales (p<.001).
Applying a linear regression mixed model to the matched sets, the diagnosed still scored 16 points better than the undiagnosed on the WPA I: GH Productivity Loss scale (p<.001), 14 points better on the WPA I: GH Activity Impairment scale (p<.001), 4.5 points better on the Sheehan Disability Scale(p<.001), almost 4 points on the Rosenberg Self-Esteem Scale (p<.0001), with comparable gains on the two quality-of-life scales (p<.001 and p<.0001).
The authors concluded, “This comparison revealed that individuals who had been diagnosed with ADHD were more likely to experience better functioning, HRQoL [health related quality-of-life], and self-esteem than those with symptomatic ADHD. This result appears to be robust, withstanding several levels of increasingly rigorous statistical adjustment. That points to substantial benefits from the treatment that follows a diagnosis of adult ADHD.
