January 12, 2022

Adult ADHD: How do those with the full syndrome compare with those who are subthreshold on executive functioning, and are EEGs of any use in diagnosis?

Noting that to date, no study investigated potential behavioral and neural markers in adults with subthreshold ADHD as compared to adults with full syndrome ADHD and healthy controls, the German team of researchers at the University of Tübingen out to do just that, recruiting volunteers through flyers and advertisements.

Their ADHD sample consisted of 113 adults between 18 and 60 years of age (mean age 38) who fulfilled the DSM-IV-TR criteria of ADHD and were either not on medication or a steady dose of medication over the prior two months.

Another 46 participants (also mean age 38), whose symptoms did not reach the DSM-IV-TR criteria, were assigned to the group with subthreshold ADHD.

The control sample was comprised of 42 healthy participants (mean age 37).

Individuals with schizophrenia, bipolar disorder, borderline personality disorder, epilepsy, or traumatic brain injury were excluded from the sample, as were those with current substance abuse or dependence.

All participants were German-speaking Caucasians. There were no significant differences in gender, age, education, or verbal/nonverbal intelligence among the three groups.

Participants first completed an online pre-screening, which was followed up with an interview to confirm the ADHD diagnosis.

ADHD impairs executive functions, "defined as the 'top-down' cognitive abilities for maintaining problem-solving skills to achieve future goals." The researchers explored three categories of executive functioning: 1) capacity for inhibition, "the ability to inhibit dominant, automatic, or prepotent responses when necessary- 2) ability to shift, enabling smooth switching between tasks or mental sets; and 3) ability to update, "updating and monitoring of working memory representations." Participants took a battery of neuropsychological tests to assess performance in each category.

Significant differences emerged between the group with ADHD and healthy controls in all measures except one: the STROOP Reading test. But there were no significant differences between participants suffering from subthreshold and full-syndrome ADHD. Nor were there any significant differences between those with subthreshold ADHD and healthy controls.

The researchers also recorded electroencephalograms(EEGs) for each participant. In healthy individuals, there is little to no association between resting-state EEG spectral power measures and executive functions. In individuals with ADHD, some studies have indicated increased theta-to-beta ratios, while others have found no significant differences. This study found no significant differences between the three groups.

The authors concluded, "The main results of the study can be summarized as follows: First, increased executive function deficits (in updating, inhibition, and shifting functions) could be observed in the full syndrome ADHD as compared to the healthy control group while, on the electrophysiological level, no differences in the theta to the beta ratio between these groups were found. Second, we observed only slightly impaired neuropsychological functions and no abnormal electrophysiological activity in the subthreshold ADHD sample. Taken together, our data suggest some practical uses of the assessment of objective cognitive markers but no additional value of examining electrophysiological characteristics in the diagnosis of subthreshold and full syndrome ADHD in adulthood."

They added, "These findings deeply question the value of including resting EEG markers into the diagnostic procedure and also have implications for standard neurofeedback protocols frequently used in the treatment of ADHD, where patients are trained to reduce their theta power while simultaneously increasing beta activity."

Alexander Schneider, Nina Maria Höhnle, Michael Schönenberg, "Cognitive and electrophysiological markers of the adult full syndrome and subthreshold attention-deficit/hyperactivity disorder," Journal of Psychiatric Research(2020)127,80-86,https://doi.org/10.1016/j.jpsychires.2020.05.004.

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Meta-analysis finds little to no association between prenatal cannabis exposure and offspring ADHD

Meta-analysis Finds Little-to-No Association Between Prenatal Cannabis Exposure and Offspring ADHD

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.

July 26, 2024

Meta-analysis Associates Dasotraline with Some Reduction in ADHD Symptoms

Meta-analysis Associates Dasotraline with Some Reduction in ADHD Symptoms

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.” 

July 25, 2024

Meta-Analysis: Young People with ADHD Experience Serious Social Cognition Impairments

Meta-analysis Concludes Children and Adolescents with ADHD Experience Serious Impairments in Social Cognition, Affecting Social Functioning

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. 

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.” 

July 22, 2024