Associations Between ADHD and Autoimmune Diseases

Stephen V. Faraone, PhD on August 23, 2018

A Norwegian team based at the University of Bergen recently performed a population study using the country’s detailed national health registries. With records from more than two and a half million Norwegians, the team examined what, if any, associations could be found between ADHD and nine autoimmune diseases: ankylosing spondylitis, Crohn’s disease, iridocyclitis, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis.

After adjusting for age and maternal education, the team found no association between ADHD and five of the nine autoimmune disorders: type 1 diabetes, rheumatoid arthritis, iridocyclitis, systemic lupus erythematosus, and multiple sclerosis. In the case of ankylosing spondylitis, it found no association with males with ADHD, but a negative association with females. Females with ADHD were less likely to have ankylosing spondylitis. The adjusted odds ratio (aOR) was 0.56 (95% CI 0.32-0.96).

Positive associations were found for only three autoimmune diseases. The strongest was for psoriasis, with adjusted odds ratios of 1.6 (95% CI 1.5-1.7) for females and 1.3 (95% CI 1.2-1.4) for males. When further adjusted for education, smoking, and body mass index (BMI), however, the adjusted odds ratio for females with ADHD dropped to 1.3 (95% CI 1.0-1.6).

The second strongest association was with Crohn’s disease. But here it was only among women. The odds ratio in this case was 1.4 (95% CI 1.2-1.8). Males with ADHD were actually less likely to have Crohn’s disease, with an odds ratio of 0.71 (95% CI 0.54-0.92).

Finally, females with ADHD were slightly more likely to have ulcerative colitis, with a barely significant odds ratio of 1.3 (95% CI 1.1-1.5), while no such association was found for males with ADHD, whose odds ratio was a statistically nonsignificant 0.9.

Given the large sample size of over two and a half million, this is no underpowered study. It found no association between ADHD and the generic category of autoimmune disorders. Furthermore, it is a stretch to argue that there are any clear and clinically meaningful links between ADHD and any of the specific disorders that were analyzed in this study. The small and often opposite effect sizes may simply reflect limitations with the data (presumed autoimmune disorders were identified based on drugs prescribed), or to other unidentified confounding factors.

REFERENCES

Tor‐Arne Hegvik, Johanne Telnes Instanes, Jan Haavik, Kari Klungsøyr, Anders Engeland, “Associations between attention‐deficit/hyperactivity disorder and autoimmune diseases are modified by sex: a population‐based cross‐sectional study,” European Child & Adolescent Psychiatry, vol. 27 (2018), 663-675.

Is There an Association Between Asthma and ADHD?

Stephen V. Faraone, PhD on August 16, 2018

An international team of researchers has carefully examined the best current evidence and found strong evidence for an association between asthma and ADHD by combining a meta-analysis of prior data with a new analysis of the Swedish population.

The meta-analysis identified 46 datasets with a total of more than 3.3 million persons. It computed an unadjusted odds ratio (OR) of 1.7, which indicates that ADHD patients have about twice the risk of developing asthma compared with people without ADHD. Limiting the meta-analysis to studies that adjusted for confounding factors, 30 datasets with more than a third of a million participants still led to an adjusted odds ratio of 1.5 (95% CI 1.4 – 1.7). The likelihood of obtaining this result by chance in such a large sample would be less than one in ten thousand.

When the team further checked this result against the results for the Swedish population ofmore than one and a half million persons, the odds ratio was an almost identical 1.6. Adjusting for confounding factors reduced it to 1.5 (95% CI 1.41 – 1.48). That means the findings are very robust: asthma and ADHD are associated, with an odds ratio of 1.5, after adjusting for confounding factors.

What does this small but statistically very reliable association between asthma and ADHD mean? For researchers, it suggests that the two disorders may have common risk factors and that the search for these shared risk factors might lead to improved treatments. These risk factors might also be shared with two other somatic conditions for which ADHD patients are at increased risk: obesity and eczema. It is possible that common inflammatory processes account for this overlap among disorders. Clinicians should be aware that children with asthma have an increased risk for ADHD, although given the small association, systematic screening may not be warranted. But given that ADHD might interfere with asthma medication compliance, the disorder should be considered among noncompliant youth, especially those who show other evidence of inattention, poor memory or disorganization.

REFERENCES

Samuele Cortese, Shihua Sun, Junhua Zhang, Esha Sharma, Zheng Chang, Ralf Kuja-Halkola, Catarina Almqvist, Henrik Larsson, Stephen V Faraone, “Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study,” Lancet Psychiatry, Published online July 24, 2018.

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(18)30224-4/fulltext

Digital Media Use and ADHD

Lenard A. Adler, on August 9, 2018

This two-year study examined the effect of digital media use on ADHD symptoms in over 2500 adolescents. An earlier meta-analysis found that traditional media use (TV and video console games) was modestly associated with ADHD-like behaviors (Nikkelen et al 2014). The current study extends the examination to a large sample, with modern digital media delivery of high-intensity stimuli, including mobile platforms. The authors used the Current Symptom Self-Report Scale (Barkley R 1998) to establish ADHD symptoms at baseline and at six-month assessments over a 24 month period. None of the subjects reported having ADHD at study entry. Subjects were considered to be ADHD symptom positive (the primary binary outcome) is they had greater than or equal to six inattentive and/or hyperactive-impulsive symptoms rated on this frequency-based scale (0-3).

Modern digital media use was surveyed on a frequency basis for 14 media activities (including checking social media sites, texting, browsing, downloading or streaming music, posting pictures, online chatting, playing games, online shopping, and video chatting). The most common media activity was high-frequency checking of social media. Of note, high-frequency engagement in each of the digital media activities was significantly, but moderately, associated with having ADHD symptoms at each six-month follow-up (OR 1.10), even after adjusting for covariates.

High-frequency media use at baseline seemed to be associated with development of ADHD symptoms. Among the 495 students who reported no high-frequency media use at baseline, 4.6% met ADHD symptom criteria at follow-up. Among 114 students scoring 7 for high-frequency media use at baseline 9.5% met the symptoms criteria. For the 51 students with a score of 14 for high-frequency media use at baseline, the rate was 10.5% (both comparisons were statistically significant).

This study is important in that it notes that an association between high-frequency digital media use (in current platforms and modalities) may be associated with the development of ADHD-like symptoms. A significant limitation of the study, as noted by the authors, is that ADHD-like symptoms do not establish a diagnosis of ADHD and do not assess impairment; therefore, these results must be interpreted with some caution. It does highlight that even with the current level of understanding it might be prudent for clinicians to recommend limiting high-frequency media use for adolescent patients.

REFERENCES

Barkley RA. Attention-Deficit Hyperactivity Disorder: A Clinical Workbook. 2nd ed. New York, NY: Guilford Press; 1998.

Nikkelen SW, Valkenburg PM, Huizinga M, Bushman BJ. Media use and ADHD-related behaviors in children and adolescents: a meta-analysis. Dev Psychol. 2014;50(9):2228-2241. doi:10.1037/a0037318

Ra CK, Junhan Cho J, Stone MD, De La Cerda J, Goldenson NI, Moroney E, Tung I, Lee SS, Leventhal AM. Association of Digital Media Use With Subsequent Symptoms of Attention-Deficit/Hyperactivity Disorder Among Adolescents JAMA. 2018;320(3):255-263. doi:10.1001/jama.2018.8931

Review of Cardiovascular Effects of ADHD Medications

Lenard A. Adler, on August 2, 2018

This article provides a review of the cardiovascular effects of ADHD medications including potential effects on blood pressure, heart rate and risk of cardiovascular events (myocardial infarction, sudden death and stroke).

The article notes that meta-analyses have generally found that the effects of stimulant medications and atomoxetine were generally similar on systolic blood pressure (1-3 mm Hg) and heart rate (2-5 beats/minute); these were felt to be of limited clinical significance, except for patients with elevated blood pressures or heart rate antecedent to starting these ADHD therapies. However, as these are average changes, changes in individual patients may vary and important to monitor. Additionally, the meta-analysis and observational data available also do not find significantly higher risks for MI or stroke in patients receiving stimulant medications. These findings are complicated by the use of clinical trial data in the meta-analysis which specifically limit is the enrollment of patients with higher risks of pre-existing cardiovascular illnesses and the observational data were of relatively short treatment exposures.

This article is important for clinicians because it reviews the cardiovascular safety profiles of current ADHD medications and also recommends monitoring of blood pressure and pulse at baseline and during treatment. Furthermore, the authors recommend baseline screening patients for significant cardiovascular histories via family history of cardiovascular disease and sudden death.

REFERENCES
https://www.healio.com/psychiatry/journals/psycann/2018-7-48-7/%7B426ecc52-e3d9-4f38-afc6-34cbf88548c7%7D/review-of-cardiovascular-effects-of-adhd-medications#divReadThis

Emotional Dysregulation in Adult ADHD

Lenard A. Adler, on July 26, 2018

This article reviews the phenomenology of emotional dysregulation in adult ADHD. The article discusses whether symptoms of emotional dysregulation (ED) are co-traveling symptoms that travel with symptoms of adult ADHD or whether they are part of the core symptoms of the condition.

Symptoms of ED include rapidly shifting affect, changeable mood, mood lability, impulsivity and emotional overactivity. Barkley et al. (7 from article) have posited that ED symptoms are part of a set of executive function deficits which are critical to the core of ADHD symptomtology (8).

In contrast, Wender (13) and co-workers have posited that ED symptoms should be part of the diagnostic criteria of adult ADHD and are included in the Utah criteria they defined and the Wender-Reimherr Adult Attention-Deficit Disorder Scale (WRAADS). Work from Adler and Kessler and co-workers (21) found that ED symptoms tracked separately from symptoms of inattention, hyper-activity impulsivity and executive function and were more likely to load on the Combined presentation of ADHD and be present in sub-threshold cases. The article also reviews a number of scales which have been used to assess ED, including the WRAADS, the expanded Adult ADHD Clinician Diagnostic Scale (ACDS) v.1.2, expanded Adult ADHD Self-Report Scale (ASRS) v1.1 Symptom Checklists and the Brown Adult ADD Scale (BAADS).

This article is important to clinicians because: 1) it defines and highlights the importance of recognizing symptoms of ED, 2) describes assessment methods and 3) notes the lower efficacy of standard adult ADHD pharmacotherapies of stimulants and atomoxetine than on core ADHD symptoms and 4) highlights the potential utility of cognitive behavioral therapy in treating ED symptoms in adults with ADHD.

REFERENCES
https://www.healio.com/psychiatry/journals/psycann/2018-7-48-7/%7Bd9674afc-698a-4cd9-9a24-81e3e4d4d944%7D/emotional-dysregulation-in-adult-adhd

How Effective Are Meditation-Based Therapies for ADHD?

Stephen V. Faraone, PhD on July 19, 2018

An international team of researchers recently published a meta-analysis of randomized controlled trials examining the efficacy of meditation-based therapies. Thirteen randomized controlled clinical trials (RCTs) were included: seven, with 270 participants, focused on children and adolescents; the other six, with 339 participants, on adults. Because only one of the RCTs was appropriately blinded, the results discussed below, although promising, must be considered preliminary.

Among children and adolescents, meta-analysis revealed a significant, medium effect size (SMD = -0.44, 95% CI -0.69 to -0.19) on ADHD symptoms for meditation therapy versus no treatment. There was virtually no heterogeneity among studies and no sign of publication bias. Improvements in inattention and hyperactivity/impulsivity had similar effect sizes. Neuropsychological measures of inhibition and attention indicated small-to-medium effect sizes, but failed to achieve statistically significance, perhaps due to the small numbers of trials and participants (159 and 179, respectively).

For adults, the significant effect size on ADHD symptoms was medium-to-large (SMD = -.66, 95% CI -1.21 to -0.11). Once again, there was little sign of publication bias. But in this case, there was great heterogeneity among the studies. Improvements in inattention and hyperactivity/impulsivity were again comparable, although they fell just short of statistical significance for the latter. Neuropsychological measures of the efficacy of medication therapy produced statistically significant medium effect sizes for inhibition (SMD = -0.54) and working memory (SMD = – 0.42), with virtually no heterogeneity or sign of publication bias.

Although these results are promising, the authors of the meta-analysis concluded, “Despite statistically significant effects on ADHD combined core symptoms, due to paucity of RCTs, heterogeneity across studies and lack of studies at low risk of bias, there is insufficient methodologically sound evidence to support meditation-based therapies for ADHD.”

REFERENCES
Junhua Zhang, Amparo Díaz-Román, Samuele Cortese, “Meditation-based therapies for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and meta-analysis,” Evidence-Based Mental Health, Published Online First: 10 July 2018. doi:10.1136/ebmental-2018-300015 (2018).

Are Shared Care Models Effective in Treating Childhood ADHD?

Stephen V. Faraone, PhD on July 12, 2018

A systematic review found five studies that evaluated shared care models involving children and adolescents, in which primary care providers (PCPs) collaborated with mental health care providers in treating ADHD. The 655 participants ranged in age from 5 to 17.

Two of the studies were randomized. In one, the largest, with 321 participants, care managers acted as liaisons between PCPs and psychiatrists, and provided psychoeducation and skills training for families. Effect sizes on the Vanderbilt ADHD Diagnostic Teacher Rating Scale were very small, ranging from a standardized mean differences (SMDs) of 0.07 to 0.12. Improvement on the Clinical Global Impression scale was also small (SMD = 0.3) and was not significant (p = 0.4).

In the other randomized study, with 63 participants, care managers also acted as liaisons between PCPs and a psychiatric decision support panel to provide Positive Parenting Training. The SNAP-IV hyperactivity/impulsivity score showed a medium effect size (SMD = 0.7), with a medium-to-large effect size (0.7) for improvement in social skills. The score difference for SNAP-IV inattention was not statistically significant.

The other three studies followed groups of individuals over time. In one cohort with 129 participants, PSPs consulted with psychiatrists by telephone; an evaluation, where necessary, performed within 4 weeks. As assessed by the Clinical Global Impression–Severity scale, symptoms declined from moderately severe to mild or borderline. On the Children’s Global Assessment Scale, there was improvement from problems in more than one area of functioning to just one area.

In another cohort with 116 participants, care managers acted as liaisons between pediatricians and a psychiatrist, and provided education to parents. Just over a quarter of participants showed improvement of greater than one standard deviation on the Vanderbilt ADHD Diagnostic Parent Rating Scale, and just under one in seven on the Vanderbilt ADHD Diagnostic Teacher Rating Scale.

The remaining cohort had only 26 participants. It offered PCPs access to outpatient psychiatric consultations within three weeks. PCPs reported a high level of satisfaction with their improved skills in mental health care. There was no evaluation of effect on symptoms.

With varied study designs, methodologies, and outcomes, the authors of the review could only conclude “that PCP collaboration with psychiatrists may be associated with increased comfort level. However, the association with symptom outcome and increased capacity was variable.” Given that randomized studies report only small effects, these shared care models cannot be routinely recommended.

REFERENCES
Meshal A. Sultan, Carlos S. Pastrana, and Kathleen A. Pajer, “Shared Care Models in the Treatment of Pediatric Attention-Deficit/Hyperactivity Disorder (ADHD): Are They Effective?” Health Services Research and Managerial Epidemiology, vol. 5, 1-7 (2018).

Is There a Relationship Between ADHD and Internet Gaming Disorder?

Stephen V. Faraone, PhD on July 5, 2018

A Spanish team of researchers recently completed a comprehensive review of studies looking for links between compulsive video gaming (both online and offline) and a variety of psychological disorders, including anxiety, depression, social phobia, and ADHD. The focus was on behavior “of sufficient severity to result in significant impairment in personal, family, social, educational, occupational or other important areas of functioning.”

The team identified 24 studies, of which eight with a combined total of 16,786 participants looked for associations with either ADHD or its hyperactivity component. Participants included children, adolescents, and adults. One large longitudinal study, with 3,034 participants, found no association. Another study with 1,095 participants found a small effect. Two more, with a combined total of 11,868 found medium effect sizes. Four studies found large associations, but their combined total number of participants was 789, comprising less than a twentieth of the combined participants.

The authors concluded, “The relationship between Internet Gaming Disorder and ADHD and hyperactivity symptoms were analyzed in eight studies. Seven of them reported full association, with four finding large, two finding small, and one reporting moderate, effect sizes. The studies comprised two case-control, five cross-sectional and one longitudinal design; the latter found no association between the two variables.” They also emphasized that 87 percent “of the studies describe significant correlations … with ADHD or hyperactivity symptoms.”

Yet they did not note that all of the studies with large effect sizes were comparatively small. And while they presented funnel charts evaluating publication bias for anxiety and depression, they did not do so for ADHD, where the small studies with very large effect sizes suggest publication bias (i.e., that that evidence for association is exaggerated due to the early publication of positive findings).

Leaving out these small studies, the four high-powered studies with 15,997 participants reported effect sizes ranging from none to medium. Overall that suggests that there is an association between ADHD and videogaming, though not a particularly strong one. Moreover, due to the nature of the study designs, this work cannot conclude that the small effect observed is due to the playing video games being a risk factor for ADHD or to the possibility that ADHD youth are more attracted to video games than others.

REFERENCES
Vega González-Bueso, Juan José Santamaría, Daniel Fernández, Laura Merino, Elena Montero and Joan Ribas, “Association between Internet Gaming Disorder or Pathological Video-Game Use and Comorbid Psychopathology: A Comprehensive Review,” International Journal of Environmental Research and Public Health, vol. 15, 668 (2018).

One effect size was mischaracterized as small when in fact it was medium (OR = 2.43).

In the abstract this was misleadingly worded, “The significant correlations reported comprised: 92% between IGD and anxiety, 89% with depression, 85% with symptoms of attention deficit hyperactivity disorder (ADHD),” suggesting a very strong correlation rather than an association of greatly varying effect size in seven of eight studies.

 

Is Prenatal Antidepressant Exposure a Risk Factor for ADHD?

Stephen V. Faraone, PhD on June 21, 2018

A systematic review of the literature found seven studies examining this question. Significantly, six were large cohort studies with a combined total of almost three million individuals. The other was a large case-control study with 7,874 participants.

The largest cohort study, with more than a million and a half children, found that prenatal antidepressant exposure increased the risk for ADHD. The adjusted odds ratio was 1.6 for any antidepressant and for selective serotonin reuptake inhibitors (SSRI). But in sibling comparison models, which better adjust for confounds shared by siblings (e.g., poverty, stress in the home), this study found no increased risk of ADHD.

The second largest cohort study, with over 875 thousand children, found a small adjusted risk of 1.2 for all antidepressants, with little variation by class of antidepressant. The fourth largest study, with over 140 thousand children, likewise found a small adjusted risk of 1.2, which barely achieved statistical significance (95% CI 1.0-1.4).

The third largest study, with over 190 thousand children, obtained an adjusted risk of 1.4 for all antidepressants. But it also pointed to a possible explanation for the small association found in this and other studies suggesting that the apparent association with antidepressant use was due to ADHD’s known genetic association with psychiatric conditions treated by antidepressants.

The fifth largest study, with more than 55 thousand children, similarly found an adjusted risk of 1.7 for SSRIs and an adjusted risk of 1.7 for unmedicated maternal psychiatric disorder. Again, the underlying psychiatric disorder appears to be confounding the effect of antidepressants.

The sixth largest study, with over 38 thousand children, found no evidence of any effect from SSRIs. Yet it found evidence of a large effect from bupropion, with an odds ratio of 3.6, and only one in 50 odds of obtaining such a result by chance (p = 0.02). However, it offered no comparison with untreated depression, and made no adjustments for potential confounders.

The case control study found an odds ratio of 2.3 for maternal use of any antidepressant, which dropped to a statistically nonsignificant 1.6 when adjusted for maternal psychiatric disorder (95% CI 0.66-3.71).

The review concludes, “The evidence available is inadequate to indicate any negative effects of a specific class of antidepressant on the risk of ADHD.”

REFERENCES
Faruk Uguz, “Maternal Antidepressant Use During Pregnancy and the Risk of Attention-Deficit/Hyperactivity Disorder in Children: A Systematic Review of the Current Literature,” Journal of Clinical Psychopharmacology, vol. 38, no. 3 (2018).

High Dropout Rate in Six-Year Cohort Study of Medication Treatment for ADHD

Stephen V. Faraone, PhD on June 14, 2018

Few studies have examined the safety and tolerability of ADHD medications (stimulants and atomoxetine) extending beyond six months, and none beyond a few years. A pair of Swedish neuroscientists at Uppsala University Hospital set out to explore longer-term outcomes. They conducted a six-year prospective study of 112 adults diagnosed with ADHD who were being treated with ADHD medications (primarily MPH, but also dexamphetamine and atomoxetine).

They found that at the end of that period, roughly half were still on medication, and half had discontinued treatment. There were no significant differences between the two groups in age, sex, ADHD severity, or comorbidity. The average ADHD score for the entire cohort declined very significantly, from a mean of 37 to a mean of 26, with a less than one in a thousand odds of that being due to chance. There was also no sign of drug tolerance or of a need to increase dosage over time.

All 55 adults who discontinued treatment had taken MPH for at least part of the time. Eleven had also been treated with dexamphetamine (DEX) and 15 with atomoxetine (ATX). The average time on treatment was just under two years. Almost a third quit MPH because they perceived no beneficial effect. Since they were on average taking higher doses at discontinuation than at initiation, that is unlikely to have been due to suboptimal dosage. Almost another third discontinued for various adverse mental effects, including hyperactivity, elation, depressive moods, aggression, insomnia, fatigue, and lethargy. Another one in eleven quit when they lost contact with the prescribing physician. In the case of ATX, almost half quit because of what they perceived as adverse mental effects.

Among the 57 adults who remained on medication, four out of five reported a strong beneficial effect. Only two reported minimal or no effect. Compared with the group that discontinued, the group that remained on medication was far more likely to agree with the statements, “My quality of life has improved,” and “My level of functioning has improved.” Yet as the authors caution, it is possible “that the subjects’ subjective ratings contain a placebo-related mechanism in those who are compliant with the medication and pursue treatment over time.” In fact, the authors reported that there were no significant differences in ADHD scores or ADHD severity between the group that quit and the group that remained on medication, even though, on average, the group that quit had been off medication for four years at follow-up.

We cannot explain why the patients who quit treatment showed similar levels of ADHD symptoms to those who continued treatment. It is possible that some patients remit symptoms over time and do not require sustained treatment. But we must keep in mind that there was a wide range of outcomes in both groups. Future work needs to find predictors of those who will do well after treatment withdrawal and those who do not.

Any decision on whether to maintain a course of medication should always weigh expected gains against adverse side effects. Short of hard evidence of continuing efficacy beyond two years, adverse events gain in relative importance. With that in mind, it is worth noting that this study reports that among those who remained on MPH, many reported side effects. More than a quarter complained of decreased appetite, one in four of dry mouth, one in five of anxiousness and of increased heart rate, one in six of decreased sexual desire, one in nine of depressed mood, and one in eleven of insomnia.

This study breaks important ground in looking at long-term effects of medication. It reaffirms findings elsewhere of the efficacy of ADHD medications. But contrary to the authors’ conclusion, the data they present suggests the possibility that permanently medicating ADHD patients may not be more efficacious than discontinuation beyond a certain point, especially when balanced against adverse side effects.

But this is just one study with a relatively small sample size. This suggests a need for additional studies with larger sample sizes to pursue this question with greater statistical reliability.

REFERENCES
Dan Edvinsson and Lisa Ekselius, “Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder,” Journal of Clinical Psychopharmacology, vol. 38, no. 4 (2018).