How effective are ADHD medications in adults with Autism Spectrum Disorder (ASD)?

Stephen V. Faraone, PhD on December 26, 2019

Autism spectrum disorder (ASD) is frequently comorbid with ADHD. Among adults with ADHD, as many as half are reported to also have ASD.

A Dutch team set out to answer two questions:

  1. Do adults with ADHD and comorbid ASD experience less effectiveness of pharmacological treatment for ADHD than adults with only ADHD?
  2. Do adults with ADHD and comorbid ASD experience different or more severe side effects of pharmacological treatment for ADHD than adults with only ADHD, as measured in side-effect scores, blood pressure, heart rate, and weight?

This was a retrospective study, using well-documented medical records, of the effects of drug treatment with methylphenidate (MPH), dexamphetamine (DEX), atomoxetine (ATX), bupropion, or modafinil.

The researchers compared 60 adults with comorbid ASD and ADHD to 226 adults with only ADHD. ADHD symptoms were scored using the Conners’ ADHD Rating Scale: Self Report–Short Version (CAARS: S-S). Side effects of ADHD medication were measured using either a 13-item or 20-item checklist with 4-point scales for item response. Researchers also tracked changes in body weight, blood pressure, and heart rate.

Following treatment, ADHD symptoms among the comorbid group declined by a quarter, and among the ADHD-only group by almost a third. There was no significant difference between men and women. Controlling for age, gender, and ADHD subtype, a comorbid diagnosis of ASD also did not significantly affect ADHD symptom reduction.

Turning to side effects, in the ADHD+ASD group, there were significant increases in decreased appetite and weight loss, and decreases in agitation, anxiety, and sadness/unhappiness. In the ADHD-only group, there were significant increases in decreased appetite, weight loss, and dry mouth, and decreases in sleeping disorder, nervousness, agitation, anxiety, and sadness / unhappiness. Yet there were no significant differences between the two groups. Side effects increased and decreased similarly in both. Likewise, there were no significant differences between the groups in changes in heart rate and blood pressure. The only significant difference in medication dosage was for bupropion, which was higher in the ADHD+ASD group, though without any sign of difference in side effects.

The authors concluded that this retrospective study “showed pharmacological treatment of adults with diagnoses of ADHD and ASD to be just as successful as the pharmacological treatment of adults with only ADHD,” but cautioned that “a randomized controlled trial should be conducted to evaluate the effectiveness and possible side effects of pharmacological treatment for ADHD in patients with ASD more reliably.”

REFERENCES
J. J. Muit, N. Bothof, and C. C. Kan, “Pharmacotherapy of ADHD in Adults With Autism Spectrum Disorder: Effectiveness and Side Effects,” Journal of Attention Disorders (2019) DOI: 10.1177/1087054719866255.

Long-Acting Liquid Methylphenidate for Treating ADHD in Intellectually Capable Adults with Autism Spectrum Disorder

Stephen V. Faraone, PhD on November 20, 2019

A team from Harvard Medical School and Massachusetts General Hospital conducted a six-week open-label trial of liquid-formulation extended-release methylphenidate (MPH-ER) to treat ADHD in adults with high-functioning autism spectrum disorder (HF-ASD). ASD is a lifelong disorder with deficits in social communication and interaction and restricted, repetitive behaviors. Roughly half of those diagnosed with ASD also are diagnosed with ADHD.

This was the first stimulant trial in adults with both ASD and ADHD. There were twelve male and three female participants, all with moderate to severe ADHD, and in their twenties, with IQ scores of at least 85.

Use of a liquid formulation enabled doses to be raised very gradually, starting with a daily dose of 5mg (1mL) and titrating up to 60mg over the first three weeks, then maintaining that level through the sixth week. Participants were reevaluated for ADHD symptoms every week during the six-week trial. Severity of ASD was assessed at the start, midpoint, and conclusion of the trial, as were other psychiatric symptoms.

Prior to the trial, researchers agreed on a combination of targets on two clinician-rated scoring systems that would have to be reached for treatment to be considered successful. One is a score of 2 or less on the CGI-S, a measure of illness severity, with scores ranging from 1 (normal, not at all ill) to 7 (most extremely ill). The other, a reduction of at least 30 percent in the AISRS score, which combines each of 18 symptoms of ADHD on a severity grid (0=not present; 3=severe; overall minimum score: 0; overall maximum score: 54).
At the conclusion of the trial, twelve of the fifteen patients (80 percent) met the preset conditions for success. Fully fourteen (93 percent) saw a ≥ 30 percent reduction in their AISRS score, while twelve scored ≤ 2 on illness severity.

However, when using the patient-rated ASRS scoring system, only five (33 percent) saw a ≥ 30 percent reduction in ADHD severity.

Thirteen participants (87 percent) reported at least one adverse event, and nine (60 percent) reported two or more. One reported a serious adverse event (attempted suicide) in a patient with multiple prior attempts. Because the attempt was not deemed due to medication they continued in and completed the trial. Seven participants experienced titration-limiting adverse events (headaches, palpitations, jaw pain, and insomnia). Headache was most frequent (53%), followed by insomnia and anxiety (33% each), and decreased appetite (27%).

During the trial, weight significantly decreased, while pulse significantly increased. There were no significant differences in other vital and cardiovascular measurements.

The authors concluded, “this OLT of short-term MPH-ER therapy documents that acute treatment with MPH-ER in young adults with ASD was associated with significant improvement in ADHD symptoms, mirroring the typically-expected magnitude of response observed in adults with only ADHD. Treatment with MPH-ER was well-tolerated, though associated with a higher than expected frequency of adverse events.”

They also cautioned, “The results of this study need to be considered in light of some methodological limitations. This was an open-label study; therefore, assessments were not blind to treatment. We did not employ a placebo control group and, therefore, cannot separate the effects of treatment from time or placebo effects. … firmer conclusions regarding the safety and efficacy of MPH-ER for the treatment of ADHD in HF-ASD populations await results from larger, randomized, placebo-controlled clinical trials.”

REFERENCES:
Gagan Joshi, Maura DiSalvo, Janet Wozniak, T. Atilla Ceranoglu, Amy Yule, Craig Surman, Ronna Fried, Maribel Galdo, Barbora Hoskova, Abigail Belser & Joseph Biederman, “A Prospective Open-Label Trial of Long-Acting Liquid Methylphenidate for the Treatment of Attention Deficit/Hyperactivity Disorder in Intellectually Capable Adults with Autism Spectrum Disorder,” The World Journal of Biological Psychiatry (2019) DOI: 10.1080/15622975.2019.1679392.

Are There Adverse Effects to Long-Term Treatment of ADHD with Methylphenidate?

Stephen V. Faraone, PhD on October 17, 2019

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, and 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 noncomparative studies found MPH safe. Two large cohort studies, one with over 2,300 participants, 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 noncomparative studies found MPH safe. But only two of seven comparative studies favored MPH, with the other five having unclear results. Conclusion: “while the evidence with regard to 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 noncomparative 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 with the exception of 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 noncomparative 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 comorbid tics 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 noncomparative 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 noncomparative 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 (FDA) and other regulatory agencies (based on short-term randomized controlled trials) that MPH is safe for the treatment of ADHD in children and adults. Give that MPH has been used for ADHD for over fifty years and that FDA monitors the emergence of rare adverse events, patients, parents, and prescribers can feel confident that the medication is safe when used as prescribed.

REFERENCES:
Helga Krinzinger, Charlotte L Hall, Madeleine J Groom, Mohammed T Ansari, Tobias Banaschewski, Jan K Buitelaar, Sara Carucci, David Coghill, Marina Danckaerts, Ralf W Dittmann, Bruno Falissard, Peter Garas, Sarah K Inglis, Hanna Kovshoff, Puja Kochhar, Suzanne McCarthy, Peter Nagy, Antje Neubert, Samantha Roberts, Kapil Sayal, Edmund Sonuga-Barke , Ian C K Wong , Jun Xia, Alexander Zuddas, Chris Hollis, Kerstin Konrad, Elizabeth B Liddle and the ADDUCE Consortium, “Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence,” Neuroscience and Biobehavioral Reviews (2019) DOI: https://doi.org/10.1016/j.neubiorev.2019.09.023

Recent Trends in the Prescribing of ADHD Medications in Canadian Primary Care

Lenard A. Adler, on November 29, 2018

Rachael Morkem, Scott Patten, John Queenan, and David Barber

Journal of Attention Disorders 1 –8 , 2017 DOI: 10.1177/1087054717720719

This study describes trends the incidence and prevalence of prescribing ADHD medication in a large Canadian Primary Care Physician (PCP) Network over a ten year period from 2005-2015. Canada has public funded health care, creating a system that the provision for chronic disorders (such as ADHD) is often provided by PCPs, who serve as gatekeepers to specialty referrals only when necessary. A population-based retrospective cohort was derived from EMR data from the Canadian Primary Care Sentinel Surveillance Network, which has 11 practice-based research networks (PBRNs) composed of 1,100 primary care practitioners throughout Canada. Total number of prescriptions, type of medication, age group were assessed by year throughout the ten-year span. The annual prevalence was determined by establishing the number of patients prescribed at least one ADHD medication, divided by total number of patients with a PCP visit that year. Annual incidence rates were established using a similar formula for patients who were receiving their initial treatment with ADHD medication. The authors found over the decade a 2.5 and 2.6 fold increase in the prescribing prevalence in preschool and school age children, respectively and a 4 fold increase in prescribing prevalence in adults. Methylphenidate was the most commonly prescribed medication over the decade (65%), with a slight decrease in the later years of the decade, presumably due to the introduction of the long-acting amphetamine lisdexamphetamine. The authors noted that although ADHD disease prevalence was stable, the prescribing prevalence was increasing over the decade. Also gender differences of higher prescribing rates of boys:girls in children and adolescents were not seen in adults. The investigators posit that since the ADHD disease prevalence was noted to be relatively stable in Canada (Hauck et al. 2017), and the frequency of medication prescription remains below ADHD prevalence, the increased prevalence of prescriptions may reflect improved long-term treatment. Several caveats should be noted to this study: 1) the most common annual frequencies of taking medications were in the 20% range for once or >=10/year; this bimodal distribution may indicate ongoing issues with adherence to medications in Canadanian ADHD patients, 2) the authors were unclear as to how they handled patients who switched between medication preparations and 3) as the authors note, the study is only able to examine what was prescribed, but not what was taken. One take home point for US clinicians is the higher utilization of methylphenidate products in the Canadian population as compared to what has been described in US adult ADHD populations.

REFERENCES:
Hauck, T. S., Lau, C., Wing, L. L. F., Kurdyak, P., & Tu, K. (2017). ADHD treatment in primary care: Demographic factors, medication trends, and treatment predictors. Canadian Journal of Psychiatry, 62, 393-402.

How Reliable are Subjective Estimates of ADHD Medication Adherence?

Stephen V. Faraone, PhD on August 30, 2018

A study conducted at Auburn University in Alabama recruited 54 college students to address this question. All had previously been diagnosed with ADHD. All lived independently, and all were taking a prescribed ADHD medication. Students with severe comorbid psychiatric conditions were excluded. Three students dropped out, leaving a final sample size of 51.

Each student completed a total of four half-hour assessments, scheduled at monthly intervals. At each first assessment, researchers counted the participant’s ADHD medication pills and transferred them to an electronic monitoring bottle – a bottle with a microchip sensor in the cap that automatically tracks the date and time of every opening. This enabled them to compare students’ subjective estimates at subsequent assessments with the objective evidence from pill counts and from the data output from the electronic monitoring bottles.

Overall, students reported missing about one in four (25 percent) of their prescribed doses. But the objective measures showed they were in fact skipping closer to half their doses. According to pill counts they were missing 40 percent of their doses, and according to the electronic monitoring bottles, 43 percent. The odds of obtaining such a result due to chance with a sample of size were less than one in a hundred (p < 0.01).

In other words, college students with ADHD significantly overestimate their adherence rates to their medications. The authors concluded, “without additional strategies in place, expecting adolescents and young adults with ADHD to remember a daily task that requires no more than a few seconds to accomplish, such as medication taking, is unrealistic.” They suggest using smartphone reminder applications (“apps”) and text messaging services.

The authors caution that this was the first such study, and that it had a small sample size. Moreover, the study was not randomized. Students responded to advertisements posted on campus, and thus self-selected.

Pending the outcome of larger studies with randomization, the authors suggest that wherever possible, prescribing physicians adopt objective measures of medication adherence, as an aid to ensuring greater efficacy of treatment.

REFERENCES

Megan R. Schaefer, Scott T. Wagoner, Margaret E. Young, Alana Resmini Rawlinson, Jan Kavookjian, Steven K. Shapiro, Wendy N. Gray, “Subjective Versus Objective Measures of Medication Adherence in Adolescents/Young Adults with Attention-Deficit Hyperactivity Disorder,” Journal of Developmental & Behavioral Pediatrics, Published online July 11, 2018, DOI: 10.1097/DBP.0000000000000602.

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

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).

New Amphetamine Formulation extends ADHD coverage to 16 Hours

Stephen V. Faraone, PhD on May 7, 2017

The Journal of Attention Disorders has published two papers about a new formulation of mixed amphetamine salts that uses a triple bead technology (MAS-TB). This technology allows for a delayed release of the medication and enables a duration of effect up to sixteen hours.

This 16-hour effect is significantly higher than existing stimulant medications which on average last for 8-10 hours. This new formulation is based on patient desire to experience beneficial medication effects from morning through evening.

Previously, Spencer et al. (https://www.ncbi.nlm.nih.gov/pubmed/19012813) reported a 7-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, dose-optimization study of 272 adults with ADHD.   They found that MAS-TB significantly reduced ADHD symptoms, behavioral measures of executive dysfunction and increased quality of life ratings. (Other studies have confirmed the benefit of select medications not only for ADHD symptoms, but for executive dysfunctions as well, although no ADHD medications treat executive dysfunction as well as they treat ADHD.)

An assessment of ADHD symptoms 13 to 16 hours post-dose confirmed the duration of action. The first new paper by Frick et al. (https://www.ncbi.nlm.nih.gov/pubmed/28413925) reported a 6 week, randomized controlled study comparing MAS-TB with placebo.   As with the prior study, MAS-TB significantly reduced ADHD symptoms. Mean ± SD pulse and systolic blood pressure increases at end of study were 3.5 ± 10.33 bpm and 0.3 ± 10.48 mmHg, which are medically non-consequential.  

In the second new study, Adler et al. (https://www.ncbi.nlm.nih.gov/pubmed/28412886) reported a long-term, open-label, safety study of MAS-TB in adults with ADHD. Of 505 enrolled participants, 266 completed the study.   Study discontinuation was more likely for patients taking higher (37.5-75 mg) vs. lower doses (12.5 and 25 mg). Blood pressure and pulse increases were observed at end-of-study. ADHD symptoms decreased modestly during the follow-up period.

The most frequently reported treatment emergent adverse events in both studies were insomnia, decreased appetite, and dry mouth. These observed side effects are similar to those seen for other stimulant medications, and are typically well managed by physicians when they occur by adjusting the dose or changing medications.

How do Stimulants Modulate the Brain to Improve ADHD Symptoms?

Stephen V. Faraone, PhD on November 10, 2016

The stimulants methylphenidate and amphetamine are well known for their efficacy in treating symptoms of ADHD in both youth and adults. Although these medications have been used for several decade, relatively little is known about the mechanisms of action that lead to their therapeutic effect. New data about mechanism comes from a meta-analysis by Katya Rubia and colleagues. They analyzed 14 functional magnetic resonance imaging (fMRI) data sets comprising 212 youth with ADHD. Each of these data sets assessed the short term effects of stimulants on fMRI assessed brain activations. In the fMRI paradigm, ADHD and control participants are asked to do a neurocognitive task while the activity of their brains is being measured. Dr. Rubia and colleagues analyzed data from fMRI assessments of time discrimination, inhibition and working memory, each of which are known to be deficient in ADHD patients. The meta-analysis found that the most consistent brain activations were seen in a region comprising the right inferior frontal cortex (IFC) and insula, even when the analysis was limited to previously medication naïve patients. The implicated region of the brain is known to mediate cognitive control, time estimation and attention. Dr. Rubia also notes that other studies show that the IFC/Insula is needed for updating information and allocating attention to relevant stimuli. Another region implicate by the meta-analysis was the right putamen, a region that is rich in dopamine transporters. This finding is consistent with the fact that the dopamine transporter is the main target of stimulant medications. What are the potential clinical implication of these findings? As Dr. Rubia and colleagues note, it is possible that the fMRI anomalies they identified could be used as a biomarker for ADHD or a biomarker to select patients who should respond optimally to stimulant medication. Although fMRI cannot be used as a clinical tool at this time, research of this sort is opening up new horizons for how we understand the etiology of ADHD and the mechanisms whereby medications exert their effects.
 

Reference
Rubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J. & Radua, J. (2014). Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Biol Psychiatry 76, 616-28.

Acetaminophen and ADHD

Stephen V. Faraone, PhD on August 25, 2016

Many media outlets have reported on a study suggesting that mothers who use acetaminophen during pregnancy may put their unborn child at risk for ADHD. Given that acetaminophen is used in many over-the-counter pain killers, correctly reporting such information is crucial. As usual, rather than relying on one study, looking at the big picture using all available studies is best. Because it is not possible to examine this issue with a randomized trial, we must rely on naturalistic studies.

One registry study (http://www.ncbi.nlm.nih.gov/pubmed/24566677) reported that fetal exposure to acetaminophen predicted an increased risk of ADHD with a risk ratio of 1.37. The risk was dose-dependent in the sense that it increased with increased maternal use of acetaminophen. Of particular note, the authors made sure that their results were not accounted for by potential confounds (e.g., maternal fever, inflammation and infection).

Similar results were reported by another group (http://www.ncbi.nlm.nih.gov/pubmed/25251831), which also showed that risk for ADHD was not predicted by maternal use of aspirin, antacids, or antibiotics. But that study only found an increased risk at age 7 (risk ratio = 2.0) not at age 11. In a Spanish study, (http://www.ncbi.nlm.nih.gov/pubmed/27353198), children exposed prenatally to acetaminophen were more likely to show symptoms of hyperactivity and impulsivity later in life. The risk ratio was small (1.1) but it increased with the frequency of prenatal acetaminophen use by their mothers.

We can draw a few conclusions from these studies. There does seem to be a weak, yet real, association between maternal use of acetaminophen while pregnant and subsequent ADHD or ADHD symptoms in the exposed child. The association is weak in several ways: there are not many studies, they are all naturalistic and the risk ratios are small.

So mothers that have used acetaminophen during pregnancy and have an ADHD child should not conclude that their acetaminophen use caused their child’s ADHD. On the other hand, pregnant women who are considering the use of acetaminophen for fever or pain should discuss other options with their physician. As with many medical decisions, one must balance competing risks to make an informed decision.