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Lead’s neurotoxicity is well established, and organophosphate pesticides were deliberately developed first as nerve agents in warfare and then as insecticides.  

Noting that “Epidemiologic research on chemical exposures associated with the development of ADHD is numerous; however, studies have employed various methods, and, in some cases, have resulted in seemingly conflicting results,” a U.S. study team has performed an updated meta-analysis applying “identical meta-analytic techniques to the literature on the associations between earlier chemical exposures and later ADHD.”

Lead

Meta-analysis of eleven studies reporting dichotomous outcomes with a combined 7,566 participants found children exposed to lead were almost twice as likely to subsequently be diagnosed with ADHD as their unexposed peers.  

A second meta-analysis, of thirteen studies reporting continuous outcomes with a total of 1,775 participants, found a small effect size increase in ADHD diagnosis from exposure to lead.

Interestingly, meta-analysis of four studies with a combined 4,360 participants found no association between prenatal lead exposure and subsequent ADHD diagnosis.

On the other hand, meta-analysis of seven studies combining almost five thousand participants reported that cumulative lead exposure more than doubled the likelihood of subsequent ADHD.

In other words, it’s not so much prenatal exposure as exposure after birth that is associated with increased risk.

Organophosphates

Meta-analysis of four studies reporting continuous outcomes with a combined total of 692 persons likewise found a small effect size increase in ADHD diagnosis from exposure to organophosphates.

Mercury

Meta-analysis of six studies reporting continuous outcomes with a combined total of over 17 thousand participants found a tiny effect size increase in ADHD diagnosis from exposure to mercury.

On the other hand, meta-analysis of ten studies reporting dichotomous outcomes with a combined total of over 650,000 persons found no association whatsoever between mercury exposure and subsequent diagnosis of ADHD.

Other exposures

Meta-analysis of five studies involving more than 34,000 participants found no evidence of an association between exposure to anesthesia and ADHD.

Meta-analysis of three studies encompassing 1,739 individuals found no evidence of an association between exposure to cadmium and ADHD.

Meta-analysis of four studies combining more than 2,400 persons found no evidence of an association between exposure to hexachlorobenzene and ADHD.

A pair of meta-analyses, one of three studies reporting dichotomous outcomes including 2,050 participants, the other of nine studies reporting continuous outcomes involving almost three thousand participants, both found no evidence of an association between exposure to polychlorinated biphenyls (PCBs) and ADHD.

There was little variability (heterogeneity) among results reported by individual studies within these meta-analyses, but a serious limitation was the failure to check for publication bias.

The authors concluded, “given our findings related to exposure to mercury, organophosphates, and PCBs, further research may be helpful to better characterize these relationships. Many of our effect sizes were small, which is consistent with the literature indicating that many genetic and environmental factors contribute to ADHD. … Furthermore, our findings support existing regulations of certain chemicals,” and “may inform future regulatory decisions”

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Quality of life (QoL) is defined as a person’s satisfaction with their life, measured across several dimensions including psychological, social, health, biological, and economic wellbeing. For adults, these are usually self-reported. In children and adolescents, they tend to be reported indirectly through parent- or caregiver questionnaires.  

Medications for ADHD include stimulants (methylphenidate and amphetamines) and non-stimulants (e.g., atomoxetine, clonidine, guanfacine, viloxazine). As QoL is related to ADHD symptoms’ severity, management of ADHD via medication could improve not only core symptoms but also QoL in people with ADHD.  

Noting the absence of meta-analytic evidence on the effects of ADHD medications on QoL, an international research team conducted a systematic review and meta-analysis of parallel or cross-over randomized clinical trials (RCTs) to estimate the effects of ADHD medication on QoL. They also performed secondary analyses to see if these effects differed in children and adolescents versus adults, as well as by class of medications, and if they were moderated by length of treatment.

Meta-analysis of four RCTs with a combined total of 950 participants with ADHD (45% adults) found a medium effect size improvement among those receiving amphetamines by comparison with those receiving placebo. There was no sign of publication bias, but there was wide variation (heterogeneity) in effect size estimated among the studies.  

Meta-analysis of four RCTs with a combined total of 1,094 participants with ADHD (57% adults) found a small-to-medium effect size improvement among those receiving methylphenidate by comparison with those receiving placebo. Again, there was no sign of publication bias, but wide variation in effect sizes among the studies.

The team could not explore whether length of treatment with the stimulants methylphenidate or amphetamines affected the results, or a subgroup analysis to test any differences in effects on QoL between children/adolescents and adults, since less than ten studies were included in each of the meta-analyses.

Finally, meta-analysis of eleven RCTs with a combined total of 3,344 participants with ADHD (63% adults) likewise found a small effect size improvement among those taking atomoxetine compared with those receiving placebo. Once again, there was no sign of publication bias, but wide variation in effect sizes among the studies.

With more than ten studies, the team was able to establish that for atomoxetine treatment, length of intervention – the studies ranged from 6 to 24 weeks – had no significant moderating effect. Similarly, they found no significant differences in effect on children and adolescents versus adults.  

A single RCT evaluating modafinil (a less addictive stimulant) treatment in adults found no improvements at any dose, whereas a single RCT testing non-stimulant guanfacine reported a medium effect size improvement in QoL.

The team concluded, “Overall, we found that methylphenidate, amphetamines, and atomoxetine were significantly more efficacious than placebo in improving QoL in people with ADHD. For atomoxetine, efficacy was significantly detected regardless of length of intervention or participant age ... our study demonstrated that, besides being efficacious in reducing ADHD symptomatology, stimulant and non-stimulant medications are effective in improving QoL in children, young people, and adults with ADHD, albeit with smaller effects compared those found for ADHD core symptoms severity. We found a medium effect for amphetamines and methylphenidate (both stimulant medications), and a small effect for atomoxetine (a non-stimulant).”

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Prevalence of cannabis use among pregnant women is on the rise with the spread of legalization. The most frequently reported reasons for use are to relieve stress or anxiety, nausea or vomiting, pain, and for recreation.

Given that the primary psychoactive ingredient of cannabis, ∆9-tetrahydrocannabinol (THC) is a small fat-soluble molecule that can easily cross the placenta, an Israeli-U.S. research team conducted a systematic search of the peer-reviewed medical literature for studies exploring possible neuropsychiatric effects on offspring.  

They included not only studies evaluating likelihood of ADHD, but also autism spectrum disorder, anxiety, depression, and psychotic symptoms. For each of these, adjustment was made for known confounding variables.

With that adjustment, meta-analysis of six studies with a total of over half a million (503,661) participants reported a 13% increase in the odds of ADHD in offspring of mothers using cannabis during pregnancy compared with offspring of mothers not using cannabis while pregnant.

That is generally considered a small effect size increase in risk. But there are multiple reasons to question even this minimal finding:

• It barely achieved statistical significance.

• A few studies used more reliable clinical diagnoses, while most just used ADHD symptom rating scales.

• It is virtually impossible to eliminate all confounding variables. Twin studies come closest to fully accounting for otherwise unmeasured environmental and genetic confounders, but no such studies were included.

• The team made no effort to evaluate publication bias.  

• Almost all the participants (497,821) were in a single study, and that study – which relied on clinical diagnoses – did not find a significant association.

Meta-analysis of two studies with a total of 741 individuals reported a 20% increase in offspring use of cannabis among mothers who used cannabis during pregnancy, but once again this was subject to methodological shortcomings:

• Two studies do not make for a robust meta-analysis, even more so with only 741 participants.

• The result barely achieved statistical significance.

• Publication bias was unaddressed.

• Small effect sizes are questionable due to the virtual impossibility of eliminating all confounding variables, especially without twin studies.

Some studies have suggested a link between cannabis and psychotic symptoms. But meta-analysis of four studies combining over nineteen thousand persons found no significant association between maternal cannabis use during pregnancy and offspring psychotic symptoms.

Many studies have pointed to commonalities in the etiology of ADHD and autism spectrum disorder (ASD). Yet meta-analysis of five studies encompassing over half a million participants found absolutely no association between maternal prenatal cannabis use and ASD.  

The remaining meta-analyses also reported no association with depression or anxiety.

With the caution that absence of evidence is not the same as evidence of absence, it is by no means clear from what is presently known that prenatal cannabis exposure has any significant neuropsychiatric effects on offspring. And if further research finds any effects, they are likely to be minor.

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Dasotraline is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that had been under development by Sunovion for treating ADHD and binge eating disorder.  

An Indian research team conducted a systematic search of the peer-reviewed medical literature to perform meta-analyses of the quantitative outcomes of clinical trials. 

Meta-analysis of five double-blinded randomized clinical trials (RCTs) with a combined total of 1,498 participants reported a small-to-medium effect size reduction in ADHD symptoms in patients given dasotraline as opposed to those given placebo. 

There were, however, strong indications of publication bias. Using the trim-and-fill procedure to correct for that bias yielded a small effect size reduction in ADHD symptoms in patients given dasotraline compared with those given placebo. 

Insomnia were more than four times more frequent among patients given dasotraline than among those given placebo. There was no evidence of the frequency of insomnia being dose-dependent. 

Similarly, patients given dasotraline were more than four times more likely to report decreased appetite than those receiving placebo. In this case, however, the effect was clearly dose-dependent, rising from 3x for 2mg to 4x for 4mg to 5x for 6mg and almost 8x for 8mg. 

The authors concluded, “dasotraline can reduce the core symptoms of ADHD, that is, hyperactivity/impulsivity and inattentiveness, leading to an overall improvement of ADHD compared to placebo. Dasotraline can also improve clinician-determined patients’ global functioning compared to the placebo. The most common adverse drug reactions related to dasotraline were insomnia and decreased appetite. However, to fill the knowledge gap, multicentric randomized active-controlled clinical trials are warranted in this domain for a successful translation into clinical practice.” 

Weighing these less than impressive initial results against the cost of further RCTs, Sunovion withdrew its application for approval by the Food and Drug Administration, stating, “while Sunovion considers dasotraline to be a promising, novel treatment for binge eating disorder and ADHD, we believe that further clinical studies would be needed to support a regulatory approval for dasotraline in these indications.” 

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Children and adolescents with ADHD are known to have difficulties in relating to family members, peers, and teachers. Over the long run this can contribute to anxiety or even delinquency. 

Several cognitive functions that allow individuals to process social information and interact with others contribute to shaping everyday social interactions. These include: 

• Theory of mind (ToM): Being able to attribute mental states to others, and thus explain and predict their behaviors. 

• Empathy: Being able to feel an appropriate emotion in response to another person’s mental state, and thereby understand others’ feelings. 

• Emotion recognition: Being able to identify emotions in facial expressions and other communication cues, such as voice and body position. 

A European research team performed a systematic search of the peer-reviewed medical literature to conduct meta-analyses of ToM, Empathy, Facial and Non-Facial Emotion Recognition in children and adolescents with ADHD when compared to typical development. As a comparison measure, they also included Everyday Social Skills (using self, parent, teacher, or clinician questionnaires/interviews of social skills) as an outcome. 

The search yielded 142 case-control studies (including dissertations) with a total of 16,283 participants. 

Meta-analysis of 82 studies with a combined total of 10,770 participants found a very large effect size impairment in everyday social skills among children and adolescents with ADHD when compared with typically developing peers. Adjusting for covariates only strengthened the finding. There was no sign of publication bias. 

This was mirrored in three out of five measures of social cognition: 

• Theory of mind (ToM): Meta-analysis of 49 studies with a total of 2,449 participants identified a large effect size impairment among children and adolescents with ADHD when compared with typically developing peers. Adjusting for covariates made no difference in the outcome. There was no sign of publication bias. 

• Empathy: Meta-analysis of twelve studies combining 916 individuals yielded a medium effect size impairment among children and adolescents with ADHD. But there were strong signs of publication bias, and the outcome lost significance after adjusting for covariates (perhaps because it became under-powered with three studies pooling only 151 persons). 

• Facial emotion recognition: Meta-analysis of 43 studies with a total of 3,369 participants reported a medium effect size impairment among children and adolescents with ADHD after adjusting for covariates. There was absolutely no indication of publication bias. 

• Non-facial emotion recognition: Meta-analysis of eight studies encompassing 707 persons reported a small effect size impairment with signs of publication bias that became insignificant after adjusting for covariates. 

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The team concluded, “Our findings show that children and adolescents with ADHD have deficits in ToM, Facial Emotion Recognition, and Everyday Social Skills, three domains that warrant clinical attention.” 

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A recent study delved into the connection between fidgeting and cognitive performance in adults with Attention-Deficit/Hyperactivity Disorder. Recognizing that hyperactivity often manifests as fidgeting, the researchers sought to understand its role in attention and performance during cognitively demanding tasks. They designed a framework to quantify meaningful fidgeting variables using actigraphy devices.

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(Note: Actigraphy is a non-invasive method of monitoring human rest/activity cycles. It involves the use of a small, wearable device called an actigraph or actimetry sensor, typically worn on the wrist, similar to a watch. The actigraph records movement data over extended periods, often days to weeks, to track sleep patterns, activity levels, and circadian rhythms. In this study, actigraphy devices were used to measure fidgeting by recording the participants' movements continuously during the cognitive task. This data provided objective, quantitative measures of fidgeting, allowing the researchers to analyze its relationship with attention and task performance.)

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The study involved 70 adult participants aged 18-50, all diagnosed with ADHD. Participants underwent a thorough screening process, including clinical interviews and ADHD symptom ratings. The analysis revealed that fidgeting increased during correct trials, particularly in participants with consistent reaction times, suggesting that fidgeting helps sustain attention. Interestingly, fidgeting patterns varied between early and later trials, further highlighting its role in maintaining focus over time.

Additionally, a correlation analysis validated the relevance of the newly defined fidget variables with ADHD symptom severity. This finding suggests that fidgeting may act as a compensatory mechanism for individuals with ADHD, aiding in their ability to maintain attention during tasks requiring cognitive control.

This study provides valuable insights into the role of fidgeting in adults with ADHD, suggesting that it may help sustain attention during challenging cognitive tasks. By introducing and validating new fidget variables, the researchers hope to standardize future quantitative research in this area. Understanding the compensatory role of fidgeting can lead to better management strategies for ADHD, emphasizing the potential benefits of movement for maintaining focus.

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A recent study investigated the presence of autistic-like symptoms in children diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD). Given the overlapping social difficulties in both ADHD and Autism Spectrum Disorder (ASD), distinguishing between the two disorders can be challenging. This study aims to pinpoint specific patterns of autistic symptoms in children with ADHD, comparing them to those with ASD using the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2).

The research involved 43 school-age children divided into two groups:

• ADHD Group (25 children): Initially referred for ASD symptoms but later diagnosed with ADHD.
• ASD Group (18 children): Children diagnosed with ASD.

Researchers used ADOS-2 to evaluate differences in communication deficits, social interaction challenges, and repetitive behaviors between the two groups. The study also compared IQ, age, ADOS-2 domain scores, and externalizing/internalizing problems.

Key Findings:

• Significant differences were found between the ADHD and ASD groups in ADOS-2 domain scores, including Social Affect, Restricted and Repetitive Behavior, and Total Score.
• On an individual item level, children with ADHD displayed similar atypical behaviors as those with ASD in social-communication areas such as "Pointing" and "Gestures".
• Both groups showed comparable frequencies in behaviors like "Stereotyped/idiosyncratic words or phrases", "Mannerisms", and "Repetitive interests and behaviors".

The study highlights the importance of identifying transdiagnostic domains that overlap between ADHD and ASD. The transdiagnostic domain refers to a set of symptoms or behaviors that are common across multiple diagnostic categories rather than being specific to just one. Identifying these domains in mental health practice and in psychological research is crucial to understanding, properly diagnosing, and treating conditions with overlapping features. This understanding could pave the way for tailored treatments addressing the specific needs of children with ADHD, particularly those exhibiting autistic-like symptoms.

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Attention-Deficit/Hyperactivity Disorder (ADHD) in adults is commonly treated with stimulant medications such as methylphenidate and amphetamines. However, not all patients respond well to these stimulants or tolerate them effectively. For such cases, non-stimulant medications provide an alternative treatment approach.

Recent research by Brancati et al. reviews the efficacy and safety of non-stimulant medications for adult ADHD. Atomoxetine, a well-studied non-stimulant, has shown significant effectiveness in treating ADHD symptoms in adults. The review highlights the importance of considering dosage, treatment duration, safety, and the presence of psychiatric comorbidities when prescribing atomoxetine.

Additionally, certain antidepressants, including tricyclic compounds, bupropion, and viloxazine, which possess noradrenergic or dopaminergic properties, have demonstrated efficacy in managing adult ADHD. Antihypertensive medications, especially guanfacine, have also been found effective. Other medications like memantine, metadoxine, and mood stabilizers show promise, whereas treatments like galantamine, antipsychotics, and cannabinoids have not yielded positive results.

The expert opinion section of the review emphasizes that while clinical guidelines primarily recommend atomoxetine as a second-line treatment, several other non-stimulant options can be utilized to tailor treatments based on individual patient needs and comorbid conditions. Despite these advancements, the authors call for further research to develop and refine more personalized treatment strategies for adults with ADHD.

This review underscores the growing landscape of non-stimulant treatment options, offering hope for more personalized and effective management of ADHD in adults.

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