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The first-line treatment for ADHD in both adults and children is stimulant medication such as methylphenidate or amphetamines. These medications function by increasing bioavailability of the neurotransmitters dopamine and norepinephrine within the brain. Some animal studies have suggested these medications could impact gonadal function, and more specifically testosterone production. 

A U.S. study team accessed electronic medical records (diagnoses, procedures, medications, and laboratory values), as well as insurance claims for about 108 million patients from 76 healthcare organizations. They used these to assess the risk of long-term ADHD stimulant medication on developing a diagnosis of testosterone deficiency in males above the age of puberty. 

They compared 20-40-year-old men with a clinical diagnosis of ADHD and long-term exposure to ADHD stimulant medications – including methylphenidate, dextroamphetamine, lisdexamphetamine, amphetamine, and dexmethylphenidate – with ADHD patients who did not receive any medication. 

After adjusting for confounding factors, they compared 17,224 men with a diagnosis of ADHD who had received at least 36 prescriptions of ADHD stimulant medications with an equal number with a diagnosis of ADHD who never received any ADHD medications. 

ADHD patients on long-term stimulant medication had a roughly 1.75 times higher rate of subsequently being diagnosed with low testosterone levels within five years than unmedicated ADHD patients. 

The team also compared 17,217 men with a diagnosis of ADHD who had received at least 36 prescriptions of ADHD stimulant medications with an equal number of men without a diagnosis of ADHD.  

Again, patients on long-term stimulant medication had a 75% higher rate of subsequently being diagnosed with low testosterone levels within five years than matched individuals without an ADHD diagnosis. 

The team concluded, “Long-term ADHD stimulant medication use in men was found to be associated with a significant increase in relative risk for a subsequent testicular hypofunction diagnosis. This difference was found when compared to both those with ADHD not using pharmaceutical therapy and those without ADHD. These results indicate that impaired gonadal function is a potential side effect of stimulant medications.” 

Like other observational studies, this work provides an important signal that must be replicated and validated with other methods, especially those that rule out other sources of confounding not measured in this study.  Moreover, diagnoses of testosterone hypofunction in this study were relatively rare to begin with. The measured 0.5% increase in testicular hypofunction diagnosis for those on long-term stimulant medication versus those not on stimulant medication would only affect roughly one in two hundred of those on stimulant medication. This small increase in risk must be weighed against the well-documented benefits of these medications. 

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ADHD is associated with deficits in cognitive functions. These include such executive functions as reaction time, motor and interference inhibition, sustained attention, and working memory. 

To what extent can ADHD medications compensate for such deficits? A recent meta-analysis by a European study team has explored this question. It suggests that while medication cannot completely reverse deficits in executive functions, it can lead to significant improvements. 

Based on consistent evidence from many randomized double-blind controlled trials (RCTs) measuring behavioral improvements, first line treatment for ADHD is with stimulant medication while second-line treatment (for stimulant non-responders, or poor tolerability) is with non-stimulant medication (atomoxetine, viloxazine, guanfacine and clonidine). 

This systematic literature search yielded eighteen RCTs, not all of which covered the same executive functions or medicines. 

Meta-analyses yielded the following results: 

Reaction Time 

Eleven RCTs, encompassing 925 participants, found a small-to-medium effect size improvement with methylphenidate. Variation (heterogeneity) among these studies was moderate, and there was no sign of publication bias. 

Four RCTs with a total of 286 participants similarly reported a small-to-medium effect size improvement with atomoxetine. Again, heterogeneity was moderate, with no indication of publication bias. 

Attention 

Sixteen RCTs, with a combined 1,335 participants, found a medium effect size improvement with methylphenidate. Heterogeneity was moderate, and there was some indication of publication bias. No effort was made to correct for publication bias. 

Three RCTs, encompassing 254 persons, found a medium effect size improvement with atomoxetine. Heterogeneity was moderate, with no evidence of publication bias. 

Inhibition 

Thirteen RCTs, with a total of 1,201 participants, found a small-to-medium effect size improvement with methylphenidate. Heterogeneity was moderate, with marginal indication of publication bias. 

Six RCTs with a combined 753 individuals, reported a medium effect size improvement with atomoxetine. Heterogeneity was high, but there was no evidence of publication bias. 

Working Memory 

Nine RCTs, with a total of 1,025 participants, found a small-to-medium effect size improvement with methylphenidate. Heterogeneity was moderate, with no indication of publication bias. 

Three RCTs with a combined 132 individuals, reported a statistically nonsignificant small-to-medium effect size improvement with atomoxetine. Heterogeneity was moderate, with no indication of publication bias. The nonsignificant outcome may have been due to the much smaller number of participants. 

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The team concluded, “these meta-analyses of chronic effects of stimulants and non-stimulants on executive functions in ADHD showed significant improvements with both methylphenidate and with atomoxetine in all cognitive domains tested with relatively similar effect sizes, and no statistical differences between them. The findings hence suggest comparable positive effects of both ADHD medication types on the most relevant executive functions in ADHD, suggesting for the first time that stimulant and non-stimulant ADHD medications, when taking [sic] longer-term, not only improve behavioural symptoms of ADHD, but also improve executive function performance, and to a similar degree.” 

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A placebo is a pill that does not contain any active medication.  It is given to patients who form the control group in clinical trials.  Comparing the effects of a treatment with placebo is essential because some patients will improve with the passage of time and some will get better due to the expectation of benefit they have from being enrolled in a clinical trial.

In studies of psychiatric conditions, patients in placebo groups typically show improvement. This can be induced by combinations of hope, suggestion, expectation, and consumption of what are presented as medications. It is reinforced by the context of receiving compassionate care from others, with supportive conversations. 

A 2005 study found that placebo response is unequally distributed across psychiatric disorders, but did not address several disorders (including bipolar disorder) examined in the present meta-analysis conducted by a German research team. 

Using only high-quality randomized clinical trials (RCTs) across major psychiatric diagnoses, the team quantified differences in the change of disorder symptoms within placebo groups.  

They selected nine common and clinically significant psychiatric conditions: major depressive disorder (MDD), mania (bipolar disorder), schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), panic disorder, posttraumatic stress disorder (PTSD), and social phobia. For each of these, they selected the ten most recent high-quality RCTs of medicationsfor meta-analysis. 

Of the ninety included RCTs, the team only looked at placebo groups. Because RCTs for the different diagnoses used differing established psychopathology rating scales, standardized pre-post effect sizes were used to compare outcomes across diagnoses. 

Meta-analysis of the ten ADHD RCTs with a combined total of 1,189 participants reported large effect size improvements in symptoms, with no variation (heterogeneity) across RCTs and no sign of publication bias. 

By contrast, the placebo effect size improvements in symptoms of major depressive disorder (10 RCTs, 1,598 participants) and generalized anxiety disorder (10 RCTs, 1,457 participants) were very large, well above those for ADHD, and with no overlap of 95% confidence intervals. 

At the other end of the spectrum, the placebo effect size improvements in symptoms of schizophrenia (10 RCTs, 888 participants) were moderate, well below those for ADHD, and with no overlap of 95% confidence intervals. 

There were absolutely no indications of publication bias. 

The team noted, “In all diagnoses, there were improvements in symptom severity during placebo treatment (ie, the lower limit of the 95% CIs of the pooled pre-post placebo effect sizes were >0).” Although they stated, “The large and robust improvements observed in ADHD studies have not been reported to our knowledge.”  they seemed to have missed this article by me and my colleagues:  https://pubmed.ncbi.nlm.nih.gov/34232582/. 

They also concluded, “Comparing the courses of different disorders under placebo indirectly may assist in understanding disease etiology, possibly providing insights into the proportionate influence of organic and psychogenic factors. Conditions with presumed substantial hereditary and biological components, such as schizophrenia, exhibited modest placebo responses in our analysis. Conversely, disorders with potentially less biological contribution, eg, depression and GAD, showed stronger responses. Our study may serve as an initial framework for incorporating the comprehensive insights derived from placebo groups of controlled trials into the etiopathogenetic exploration of mental illnesses.”

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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 well-being. For adults, these are usually self-reported. QoL for children and adolescents is usually reported by parents.  

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-analyses 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. 

Due to lack of sufficient data, the team could not explore whether length of treatment affected the results, or if there were differences between children/adolescents and adults. 

Finally, a 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. 

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 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.  Modafinil is not FDA approved for ADHD but is sometimes used as a last resort if other treatments fail.

The team concluded that the FDA approved medications for ADHD were significantly more efficacious than placebo in improving QoL in people with ADHD.  The improvements in Q0L were, however, smaller than what has been found for improvements is the symptoms of ADHD (inattention, hyperactivity, impulsivity).  More work is needed to detect differences by age and length of treatment. 

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Recent advancements in brain network analysis may help researchers better understand the dysfunctions of the complex neural networks associated with ADHD.

Controllability refers to the ability to steer the brain's activity from one state to another. In simpler terms, it’s about how different regions of the brain can influence and regulate each other to maintain normal functioning or respond to tasks and stimuli. 

The Study at a Glance

Researchers examined functional MRI (fMRI) data from 143 healthy individuals and 102 ADHD patients, they focused on a specific metric called the node controllability index (CA-scores). This metric helps quantify how different brain regions contribute to overall brain function.

Key Findings

The study revealed that individuals with ADHD exhibit significantly different CA-scores in various brain regions compared to healthy controls. These regions include:

• Rolandic operculum
• Superior medial orbitofrontal cortex
• Insula
• Posterior cingulate gyrus
• Supramarginal gyrus
• Angular gyrus
• Precuneus
• Heschl gyrus
• Superior temporal gyrus

These areas are crucial for processes such as decision-making, sensory processing, and attention.

This new study suggests that the controllability index might be a more effective tool in identifying brain regions that work differently in those with ADHD. This means that controllability could provide a clearer picture of the brain networks associated with ADHD.

Although ADHD still cannot be diagnosed with this type of imaging, studies such as this highlight the complexity of the disorder and provide new avenues for future research. 

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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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