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ADHD: Reviewing the Causes and Evaluating Solutions

Luis núñez-jaramillo, andrea herrera-solís, wendy verónica herrera-morales.

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Correspondence: [email protected] ; Tel.: +52-983-8350300 (ext. 241)

Received 2020 Dec 31; Accepted 2021 Feb 23; Collection date 2021 Mar.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ).

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.

Keywords: ADHD, heterogeneous etiology, pharmacological treatment, neurofeedback, qEEG informed neurofeedback, treatment personalization

1. Introduction

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder (NDD) presenting with inattention, hyperactivity, and impulsivity. It can be classified in three subtypes, depending on the intensity of the symptoms: predominantly inattentive, predominantly hyperactive–impulsive, and combined [ 1 , 2 ]. ADHD has a global prevalence of 5.9% to 7.1% in children and 1.2% to 7.3% in adults [ 3 ].

While most studies address ADHD in children from 7 to 17 years old, it is important to outline that this condition is also present in adults. It has been proposed that the number of adults with ADHD has increased over the last 20 years. A part of this increase is due to the permanence of ADHD symptoms in the adult age in 76% of diagnosed patients. ADHD implies important challenges for academic, personal, and job performance [ 4 ].

As for any other condition affecting brain function, in order to find an adequate treatment for ADHD, it is important to first understand its physiological basis. As with other NDDs, the causes of ADHD are aberrant neural development, affecting neurogenesis, synaptogenesis, myelination, and neuronal and glial proliferation and migration. Even though symptoms begin to appear in childhood, neuronal development is affected from early embryogenesis [ 5 ].

The etiology of ADHD is diverse—gestational, perinatal, and genetic factors have been associated with ADHD incidence. However, each patient presents only a few of them.

2. Environmental Factors Associated with ADHD

The incidence of ADHD is associated with a number of environmental factors during different stages of central nervous system (CNS) development, such as gestational and perinatal periods. In this section, we will address some of the environmental factors that have been associated with ADHD.

2.1. Preconceptional, Gestational, and Perinatal Conditions

Premature birth is an important risk factor for ADHD, since it has been reported that it occurs 2.6 to 4 times more frequently in babies born with low weight or very low weight. Premature birth is associated with alterations in neurogenesis and cell death [ 6 ], and these are in turn associated with reduced cortical expansion, as reported in ADHD patients [ 7 ]. One possible reason for increased risk of developing ADHD in preterm children is inflammation; an increase in inflammation-related molecules is associated with increased risk of developing ADHD symptoms [ 8 ].

Perinatal hypoxia is an environmental factor that increases the risk of developing AHDH, probably due to its effects on dopaminergic transmission and neurotropic signaling [ 9 ].

The intake of nutrients during gestation is very important for proper brain development. An important element during neural development is the polyunsaturated fatty acid docosahexaenoic acid (DHA), promoting proliferation and neural differentiation of neural progenitor cells. Decreased levels of DHA during brain development have been associated with ADHD and other neurodevelopmental disorders [ 10 ], and decreased levels of serum DHA levels have been reported in adult ADHD patients [ 11 ]. Additionally, malnutrition or immune activation in the pregnant mother is a risk factor for ADHD and other neurodevelopmental disorders [ 12 ]. High sucrose consumption during pregnancy is possibly related with ADHD incidence. A study performed on rats reported that high sucrose intake in pregnant rats led to the appearance of ADHD-like symptoms in the offspring, who showed increased locomotor activity, decreased attention, and increased impulsivity. Furthermore, the offspring also presented increased dopamine transporter (DAT) and a decrease in dopamine receptors and mRNA expression in the striatum [ 13 ].

Interestingly, there is evidence in a rat model of the influence of preconceptional conditions on ADHD incidence. Offspring of Female rats administered with ethanol for 8 weeks before mating presented ADHD-like symptoms such as hyperlocomotive activity, impulsivity, and attention deficit. These rats also presented low levels of striatal DAT and increased presence of norepinephrine transporter (NET) in the frontal cortex [ 14 ]. A later work by this group revealed that paternal preconceptional alcohol exposure also produced ADHD-like symptoms in the offspring, presenting decreased expression of DAT mRNA and DAT protein in the cortex and striatum. Furthermore, authors report epigenetic changes in both the sperm of these alcohol-exposed male rats and in the frontal cortex and striatum of the offspring, presenting increased methylation in a CpG region of DAT gene promoter, which is in agreement with the reduced expression of DAT in the offspring [ 15 ].

Another environmental factor associated with ADHD is pesticide exposure during development. A study addressing the issue, both at experimental and epidemiological levels, reported that exposure to the pesticide deltamethrin during gestation and lactation in rats led to ADHD-like symptoms, such as working memory and attention deficits, hyperactivity, and impulsive-like behavior. It also produced increased presence of DAT and D1 receptor in the striatum, as well as increased dopamine release and increased presence of D1 dopamine receptor in the nucleus accumbens. Interestingly, the authors also performed an epidemiological study in humans, revealing that children (6 to 15 years old) with detectable levels of pyrethroid metabolites in urine had more than twice the probability of being diagnosed with ADHD [ 16 ].

2.2. Heavy Metal Exposure

One of the most reported environmental factors associated with ADHD is exposure to neurotoxic heavy metals. A study performed on school children revealed that children (6–7 years old) with ADHD presented higher levels of salivary mercury. However, when including all age groups studied (12–13 years and 15–16 years), no significant correlation was found between increased salivary mercury and ADHD, although a mild tendency was observed [ 17 ].

In the case of manganese, both too high and too low blood levels are associated with cognitive deficits. High concentration of manganese in blood is associated with deficits in thinking, reading, and calculations, as well as with lower learning quotient (indicative of learning disability) and more errors in the continuous performance test (measuring attention and response inhibition). Conversely, low blood level of manganese is associated with a poorer performance in the Stroop test, which is used to assess cognitive inhibition [ 18 ]. Similarly, a study addressing the relationship between manganese in drinking water and ADHD found a higher risk of developing this condition (inattentive but not combined subtype) as exposure to manganese in drinking water increased [ 19 ]. However, a study on manganese in children’s deciduous teeth failed to find an association between this metal and cognitive deficits [ 20 ].

The presence of lead in children’s deciduous teeth is positively associated with hyperactivity or impulsivity, as well as inattention and oppositional or defiant disorder [ 20 ]. A study on children from a lead-contaminated region reported that blood levels of cadmium, lead, and manganese correlated with conduct problems and antisocial behavior [ 21 ]. Another work found a higher concentration of blood lead in ADHD children, which was correlated with hyperactivity–impulsivity symptoms but not with inattention [ 22 , 23 ]. Both genetic [ 24 ] and epigenetic [ 25 ] factors have been reported to contribute to lead-related pathogenesis of ADHD. Moreover, a study carried out in Argentina found that children with high blood concentrations of lead are more likely to develop ADHD [ 26 ].

A review on the effects of prenatal and childhood metal exposure on cognition found suggestive evidence of a relation between cadmium exposure and impaired cognitive ability in children. They did not find evidence of a relationship between cadmium exposure and ADHD [ 27 ]. A more recent study addressing cadmium exposure during pregnancy revealed that a higher blood cadmium concentration during pregnancy is associated with higher scores in ADHD diagnostic tests in female children at 6 years of age, but not in the case of male children [ 28 ].

A recently published work reported that ADHD children present higher urine concentrations of chromium, manganese, cobalt, nickel, copper, molybdenum, tin, barium, and lead [ 29 ]. A recent study analyzing serum concentrations of different metals in ADHD children reported low levels of chromium, manganese, and zinc, as well as increased copper/zinc ratios in these children [ 30 ]. A meta-analysis on the relation between blood and hair zinc and ADHD found no statistical difference between ADHD and control children [ 31 ].

Thus, there are a number of environmental factors associated with ADHD incidence. While environmental factors are not found in all ADHD cases, the data reviewed herein highlight the importance of environment in different developmental stages—and even before conception—in regard to the risk of developing ADHD.

3. Sleep Disorders and ADHD

Sleep deprivation, either acute or chronic, produces decreased cognitive functioning (one of the main traits of ADHD). Interestingly, it also produces the externalizing symptoms observed in ADHD patients. For example, a very tired child might become hyperactive, while in a sleepy adult in a condition where it is not possible to sleep (for example, while driving), the externalizing behavior will help them to remain awake. Thus, both of the core ADHD symptoms can be produced by sleep deprivation. Conversely, hyperactivity in children or high internal activity in adults in the evening might lead to sleep disruption [ 32 ].

Among the sleep disorders found in ADHD patients are delayed sleep phase disorders, insomnia, sleep-disordered breathing, increased motor activity during the night, sleep anxiety, clenching teeth, periodic limb movement, restless legs, increased sleep onset latency and shorter sleep time, night awakenings, narcolepsy, and parasomnias [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Among them, delayed sleep phase disorder is one of the most frequently found, being present in 73–78% of both ADHD children and adults. This condition consists of a delay between the sleep propensity cycle and the circadian cycle, leading to increased daytime sleepiness and decreased cognitive functioning [ 32 ].

Sleep disturbance have an impact on daytime vigilance, producing excessive sleepiness [ 32 , 37 , 39 ], and can exacerbate inattention, impulsivity, and hyperactivity as means to remain awake [ 32 , 37 ]. Additionally, stimulant medication might also cause sleep disturbances, although OROS methylphenidate produces less adverse effects on sleep [ 34 , 36 ]. LDX, a stimulant prodrug that undergoes hydrolysis in the bloodstream releasing d-amphetamine, and atomoxetine, a non-stimulant pharmacological treatment for ADHD, do not produce adverse effects on sleep [ 36 ].

Sleep disturbances in ADHD patients can produce significant impairments in attention, mood, and behavior [ 32 , 35 ]. Physiologically, there is evidence supporting an overlap between brain centers regulating sleep and those regulating attention and arousal, so it is possible that affectation of one of these systems also affects the other. Similarly, affectation of noradrenergic and dopaminergic pathways is found in both ADHD and sleep disturbances [ 40 ].

Conversely, during wake time, sleep disturbances produces symptoms resembling those observed in ADHD patients [ 35 , 41 , 42 ]. It is, thus, recommended to assess sleep disorders in patients with ADHD symptoms in order to avoid misdiagnosis [ 41 , 42 ].

The relationship between sleep disorders and ADHD is complex. While ADHD might produce sleep disorders, they could also be coincident conditions [ 36 ]. Moreover, sleep disorders have been proposed to be not only one of the intrinsic features of ADHD, but also might be one of its causes [ 32 , 36 ]. Another possible explanation for this interaction would be an underlying common neurological disease leading to both sleep disorders ad ADHD [ 36 ]. A recent review on the subject proposed that chronic sleep disorders are some of the main causes of ADHD symptoms [ 32 ]. The authors suggested that patients presenting ADHD symptoms should undergo quantification of sleep and sleep problems in order to rule them out as the sole cause of ADHD symptoms. Thus, ADHD treatment should address both the symptoms (with classic ADHD treatment) and the sleep problem [ 32 , 34 , 35 , 36 ], although the effect of this combined treatment still requires further research [ 32 ].

4. Genetic Factors Associated with ADHD

Different studies have revealed an important genetic influence in the etiology of ADHD [ 43 ]. It is a polygenic condition with an important number of genes involved, as confirmed by a genome-wide association study on ADHD reporting 12 significant loci associated with this condition [ 44 ]. Many of the genes reported to be associated with ADHD participate in processes such as neurotransmission, neuritogenesis, synaptogenesis, or receptor location in synapses [ 45 ]. In this review, we will focus on two genes, a neurotrophin (brain-derived neurotrophic factor –BDNF-) and a molecule involved in dopaminergic signaling (DAT).

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with high expression in the brain that is highly concentrated in the hippocampus and cortex. It has an important role in neuronal development, being important for neuronal proliferation, migration, differentiation, and maturation, as well as for synaptogenesis [ 46 ].

BDNF has been implied in ADHD pathophysiology. It has been proposed that low levels of this neurotrophin may explain the reduction in brain volume observed in ADHD patients, and it has also been implied in dopaminergic system homeostasis. Some pharmacological treatments for ADHD promote the regulation of plasma BDNF levels [ 47 ].

4.1.1. Circulating BDNF

Since BDNF is able to cross the blood–brain barrier and plasma concentrations of BDNF are highly correlated with its levels on cerebrospinal fluid, a number of studies have searched for a difference in plasma concentrations of BDNF in ADHD patients when compared against controls. There are reports indicating a lower concentration of BDNF in plasma of ADHD patients, both in children [ 48 ] and adults [ 49 ]. In another study involving children, an increase in plasma BDNF was observed after 6 weeks of treatment with an effective dose of methylphenidate [ 50 ]. In accordance, a recent study revealed that methylphenidate treatment produces an increase in serum BDNF in boys with ADHD [ 51 ]. However, this has not always been replicated, since there are also articles reporting no difference in serum BDNF between children with ADHD and controls [ 52 , 53 , 54 ].

A recently published meta-analysis encompassing studies comparing BDNF levels in ADHD patients without any other comorbidity found no overall difference between ADHD patients and controls. However, when analyzing males and females separately, they found significantly higher levels of plasma BDNF in males with AHDH than in control males, while no difference was found between females with and without ADHD [ 55 ].

Thus, different and even contrary results have been obtained regarding BDNF concentrations in plasma or sera of ADHD patients. While this suggests that the link between BDNF and ADHD is not completely clear, other alternatives should be considered. For example, fluctuations in serum BDNF concentrations in morning and evening samples have been reported [ 56 ], meaning the lack of relation between peripheral BDNF concentration and ADHD might be due to the time of the day when the sample was obtained.

4.1.2. Genetics of BDNF

There are a number single nucleotide polymorphisms (SNP) of the BDNF gene that have been associated with ADHD. Among the most studied variations in the BDNF gene, there is a polymorphism called Val66Met (also known as rs6265), in which a change in codon 66 produces a substitution of the original amino acid (valine) by methionine. The anatomical effects of this variation are more apparent in the hippocampus and cortex [ 46 ]. While some studies have assessed the presence of this SNP in ADHD patients [ 57 , 58 , 59 ], other studies failed to find an association between this polymorphism and ADHD [ 46 , 60 , 61 , 62 , 63 ].

Another SNP of the BDNF gene whose association with ADHD is not conclusive is rs2030324, since some studies report an association between this polymorphism and ADHD [ 57 , 58 , 59 , 64 ], while other reports fail to find this association [ 46 , 60 , 61 , 62 , 63 ].

There are other SNPs of the BDNF gene that have been studied so far, with positive correlations being shown between ADHD and the presence of C270T (rs27656701) [ 58 , 61 ], rs11030101 [ 62 , 64 , 65 ], and rs10835210 [ 62 , 63 ]. There are also reports addressing SNPs of the BDNF gene for which no association with ADHD has been found, including rs12291186, rs7103411 [ 63 ], and rs7103873 [ 62 , 63 ].

Moreover, rare single nucleotide variants of BDNF gen have also been associated with a higher risk of developing ADHD [ 66 ]. However, this is an area that requires further research.

As observed with peripheral BDNF concentrations, genetic variants of the BDNF gene have been associated with ADHD in numerous cases, although in some cases there are contradictory results in different articles (see Table 1 ). Moreover, some of the genetic variants of the BDNF gene associated with ADHD have also been studied in association with other neurological conditions and treatments. For example, C270T is reported to be associated with intellectual disabilities [ 58 ]. Moreover, rs11030101 is associated with a better response to electroconvulsive shock therapy for treatment-resistant depression [ 67 ], with body weight gain in schizophrenic patients treated with atypical antipsychotics [ 68 ], as well as with the presence of major depressive disorder [ 69 ], schizophrenia, and bipolar disorder [ 70 ], although there is another publication in which no evidence of association between this SNP and bipolar disorder was found [ 71 ]. Additionally, rs10835210 has been associated with bipolar disorder, schizophrenia [ 70 ], and phobic disorders [ 72 ].

Polymorphisms of the BDNF gene studied in relation with ADHD incidence. * Polymorphisms for which contradictory results have been reported. rs, reference SNP ID number.

For rs6265 (Val66Met), there are many articles addressing the association of this SNP with different conditions, and in some of them it has been found. For example, some articles report an association of this SNP with major depressive disorder [ 69 , 73 ], while other studies fail to find this association [ 74 , 75 ]. An association has also been reported between rs6265 and amnestic mild cognitive impairment, as well as with the transition from this condition to Alzheimer’s disease [ 76 ]. However, in patients with early-stage breast cancer, this SNP is associated with a lower probability of presenting cognitive impairment after chemotherapy [ 77 ].

4.1.3. Other Neurotrophines

While BDNF has been widely studied in association with ADHD, it is not the only neurotrophin studied in relation with this condition, given the important role of neurotrophines in central nervous system development and synaptic plasticity. In this regard, there are studies addressing the participation of fibroblast growth factor (FGF), vascular endothelial growth factor, insulin-like growth factor (IGF2) [ 47 ], glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF-3) [ 47 , 53 ] in ADHD pathophysiology.

BDNF is a molecule highly involved in synaptic plasticity and has an undisputed role in central nervous system development. Therefore, it is not surprising to find a number of studies associating alterations in the presence of this neurotrophin in serum, or different SNPs of its gene, with ADHD. However, its role in ADHD development is not a constant for every sample of ADHD patients studied so far, and for many of the aspects of this molecule (serum levels, SNPs) there are reports indicating associations, with others finding no association at all. This does not mean that the alterations associated with this molecule are not important for ADHD, but rather highlight the variable etiology of this condition.

4.2. Dopaminergic System

The dopaminergic system emerges in early stages of CNS embryonic development, and an imbalance in this system might affect brain development. It is related with cell proliferation, neuronal differentiation and migration, synaptogenesis, and neurogenesis. Thus, it is not surprising that a role of this neurotransmitter system has been reported in different neurological diseases, including ADHD [ 78 ].

One of the most studied molecules of the dopaminergic system in relation to ADHD is DAT, a molecule responsible for dopamine reuptake, and the main target of two commonly used pharmacological treatments for ADHD, methylphenidate and amphetamines [ 78 ]. Genetic studies support the importance of this neurotransmission system for ADHD. Mice heterozygous for the DAT gene (+/− heterozygotes) are reported to present altered attentional function [ 79 , 80 ] and hyperactivity [ 80 ], while rat models with this heterozygous genotype do not present major affectations [ 81 , 82 ]. However, DAT knockout rats present hyperactivity [ 81 , 82 ], as well as a dysregulation in frontostriatal BDNF function [ 82 ]. Hyperactivity in these rats can be counteracted by amphetamine, haloperidol, and methylphenidate [ 82 ].

In humans, ADHD patients present lower DAT availability in the basal ganglia, caudate nucleus, and putamen [ 83 ]. The DAT gene presents a variable tandem repeat region (VNTR) at the untranslated 3′region, and there are different alleles for this VNTR, with the 9-repeat and 10-repeat alleles being the most frequently encountered. The reported effects of this VNTR on DAT expression vary in different articles, however the most recent results indicate that the 9-repeat allele is associated with a higher DAT expression than the 10-repeat allele. [ 84 ]. The possible association between this VNTR and ADHD has been addressed in various studies. For example, an analysis of both patients and the literature found an association of the 10-repeat/10-repeat genotype with ADHD only in adolescents [ 85 ], studies performed in children reported an association between the 10-repeat/10-repeat genotype and ADHD [ 86 , 87 ], while a recently published meta-analysis reported an association of the 10-repeat allele with ADHD in children and adolescents, specifically in European population [ 88 ]. However, there are also reports indicating no association at all between ADHD and the VNTR of DAT gene (9-repeat/10-repeat, 10-repeat/10-repeat, and 10-repeat/11-repeat genotypes) [ 89 ], no association between the 10-repeat/10-repeat allele with ADHD [ 90 ], and no association between ADHD and the 9-repeat or the 10-repeat alleles for this polymorphism [ 91 ]. The last three studies were performed in children.

Additionally, the relevance of this VNTR has been studied in relation to cognitive function in healthy subjects. Again, mixed results were found. A meta-analysis published in 2016 addressing studies performed in healthy subjects did not find any association between DAT VNTR and different cognitive functions, such as executive functions, inhibition, attention, and long-term declarative memory [ 92 ]. A study performed in children aged 3 to 5 years old addressing the presence of the 9-repeats and 10-repeats alleles revealed that the presence of the 10-repeat allele of the DAT gene is associated with diminished ability to voluntarily regulate reactivity in healthy children [ 93 ]. A recent study on both ADHD and healthy children reported an effect of the specific genotype in the performance of children on attentional switching when studying the whole research sample, in which children carrying the 9-repeat allele performed worse than those carrying the 10-reapet homozygous or the 10-repeat/11-repeat heterozygous allele [ 91 ]

The participation of the dopaminergic system in the pathophysiology of ADHD has been widely reported [ 78 ]. Herein, we study a particular variation of the DAT gene, a VNTR in the 3′ region of the gene, finding articles supporting a role of this polymorphism in ADHD, as well as works failing to find an association between this VNTR and ADHD. This does not imply a lack of importance of this variation, but rather highlights the variability in the genetic etiology of this condition. Moreover, while the dopaminergic system is highly involved in the pathophysiology of ADHD, given its role in CNS development, it is also strongly related with other neuropsychiatric conditions, such as autism [ 78 , 94 , 95 ] and schizophrenia [ 78 , 94 , 96 , 97 ].

5. Changes in Brain Structure and Function in ADHD Patients

As an NDD, ADHD involves alterations of mechanisms such as neurogenesis and synaptogenesis. There are a number of possible mechanisms through which these alterations take place, both environmental and genetic, some of which have been mentioned in the present review. In the end, all of these altered mechanisms produce an altered brain function affecting attention and impulse control, functions regulated by the central nervous system. Understanding the changes in brain function associated with ADHD might shed some light not only on the functional causes of this condition, but also on possible ways to deal with it.

5.1. Brain Imaging Studies

Children with ADHD present atypical connectivity in reward circuitry when compared with control children. Increased connectivity of the nucleus accumbens with the prefrontal cortex was observed to be associated with greater impulsivity [ 98 ].

Hypofunction and abnormal cortico-striatal pathways of the cortico-striato-thalamo-cortical (CSTC) circuit are associated with ADHD. Five different CSTC circuits have been reported: the sustained attention circuit, emotion circuit, selective attention circuit, hyperactivity circuit, and impulsivity–compulsivity circuit. Four of them (except emotion circuit) have been related with ADHD diagnostic criteria. However, pathogenesis of the emotion circuit is also related with ADHD [ 99 ]

A study on ADHD children reported significantly decreased white matter volume, as well as decreased volume in the cortex and caudate nucleus, although it did not reach statistical significance. Cortical thickness was reduced in ADHD patients bilaterally in the frontal cortex and in the right cingulate cortex, structures related with executive function and attention. Regarding default mode network, functional connectivity was reduced in ADHD children in the anterior and posterior cingulate cortexes, lateral prefrontal cortex, left precuneus, and thalamus. However, connectivity was increased in the bilateral posterior medial frontal cortex [ 100 ].

A study on male adolescents with ADHD and controls reported decreased gray matter volume in the left anterior cingulate cortex and bilateral decreases in the occipital cortex, hippocampus–amygdala complex, and cerebellum in ADHD adolescents [ 101 ]. Such decreases in cerebellar volume have been previously reported in both female and male ADHD patients [ 102 ].

An important issue with many of the imaging studies in ADHD patients has been small sample size. A large-scale study performed on children, adolescents, and adults with ADHD reported decreased surface area in children, mainly in the frontal, cingulate, and temporal regions. This effect was more pronounced in younger children (4–9 years old). Moreover, cortical thickness in ADHD children is also reduced in the fusiform gyrus and temporal lobe, an effect more prominent in children of 10 and 11 years old. No change in surface area or cortical thickness was observed in adolescent or adult ADHD patients [ 103 ].

There are important changes in brain morphology in ADHD patients. An elegant study performed in ADHD patients and controls from 6 to 28 years of age analyzed differences in neurodevelopmental trajectories. This study reported that ADHD patients present overall reduced cortical volume, mainly in frontal lobes, and primarily due to a decrease in surface area and gyrification. Interestingly, although both groups presented maturational changes due to age, they presented different trajectories for these changes, suggesting that ADHD is associated with developmentally persistent changes in the whole cortex, mostly due to decreased surface expansion (reduced surface area and less convolution) [ 7 ].

When comparing children with comorbid epilepsy and ADHD with control children, a widespread decrease in cortical thickness is observed, along with decreased volume in some subcortical structures and the brainstem. These alterations were observed early in the course of epilepsy, thus the authors suggested that neurodevelopmental changes occurred before epilepsy onset [ 104 ]. In children with comorbid autism spectrum disorder and ADHD, when compared with typically developing controls, presented significantly lower volumes in left postcentral gyrus. This was observed through magnetic resonance imaging in both children and preadolescents, but was absent in adolescents. The authors suggested that pathophysiology in these comorbid patients may be related to somatosensory deficits and delayed maturation in this area [ 105 ].

5.2. Quantitative Electroencephalography

All these changes lead to alterations in brain function. A frequently used technique for the study of brain activity is quantitative electroencephalography (qEEG), since it has a low cost, a high temporal resolution, and does not need special facilities to be performed. Furthermore, qEEG has also been used to determine the effects of pharmacological treatments on brain activity in order to assess effectiveness [ 106 , 107 ], to choose the correct pharmacological option for a patient [ 108 ], to study the effects of previous pharmacological treatments on the current one [ 109 , 110 ], as well as to determine a possible cognitive effect of the chosen pharmacological treatment [ 111 ].

During the last decades, several studies have performed qEEG analyses on ADHD patients. A review on the subject published in 2012 addressed the main associations between brain activity and ADHD, including increased frontocentral theta activity. Another frequently reported factor, although not always replicated, is an increased theta/beta ratio. For beta and alpha bands, most of the reports have indicated decreased activity, although there are also reports that have indicated increased activity in these frequency bands in ADHD patients [ 112 ]. One of the most used indicators for ADHD is the theta/beta ratio in the Cz region. It has been reported that ADHD children (inattentive and combined subtypes) present increased theta/beta ratios [ 1 ]. Another study found that children with ADHD presented more delta and theta activity [ 113 ]. However, some authors have mentioned that this measure is not necessarily useful for diagnosis, since among other issues, it presents variations according to age [ 114 ].

Another example of the influence of age on brain electrical activity associated with ADHD is a study comparing children with and without ADHD, as well as adults with and without ADHD. Interestingly, children with ADHD presented higher delta and theta activity than control children, while in adults no difference was found between ADHD group and controls in the frequency bands analyzed [ 115 ]. Among the few differences in qEEG activity found in adults with ADHD is a higher gamma activity (39.25–48 Hz), suggesting a functional alteration in dorsal attention network [ 116 ].

ADHD patients often present comorbidities [ 117 ], which might influence qEEG in a different way to the findings in ADHD only patients. For example, children with ADHD and problematic Internet use present differences in qEEG when compared to ADHD only patients. However, no differences were found between ADHD only patients and ADHD patients with depression [ 118 ]. Another study found that adolescents with ADHD and Internet gaming disorder presented lower relative delta power and greater relative beta power than adolescents with ADHD only [ 119 ].

It is noteworthy that although a number of studies have been published regarding neurophysiological correlates of ADHD through qEEG, there are still some differences in the results reported by different authors. Beyond possible methodological differences, there are a number of factors reported to influence qEEG activity in ADHD patients, which might be responsible—at least in part—for the differences reported so far, and which might be of importance when using qEEG information to choose or design a therapeutic approach. These factors include comorbidities [ 4 , 120 ] and the ages of the patients [ 114 , 116 , 121 ]. Other factors reported to affect qEEG activity in other populations and conditions are ethnicity [ 122 , 123 , 124 , 125 , 126 ], sociocultural environment during development [ 127 , 128 ], and the degree of advancement of a psychiatric condition, as reported for alcohol dependence [ 129 , 130 , 131 ].

6. Therapeutic Approaches

6.1. pharmacological treatment.

Both stimulant and non-stimulant pharmacological treatments have proven to be effective in diminishing ADHD symptoms in children and adolescents [ 132 , 133 ], although stimulant medication seems to have greater effectiveness [ 133 , 134 ]. Herein, we will address one frequently used stimulant (methylphenidate) and one frequently used non-stimulant (atomoxetine)

6.1.1. Methylphenidate

Methylphenidate is one of the most used drugs for ADHD treatment. It has been present in the market for 50 years and it reduces excessive hyperactivity, impulsivity, and inattention in children and adolescents with ADHD. In the United States, it is prescribed to 8% of children and adolescents under 15 years of age and to around 3% to 5% of the same population in Europe [ 135 ].

Methylphenidate blocks DAT and NET, reducing reuptake and producing an increase in available dopamine and norepinephrine in the synaptic cleft [ 135 , 136 , 137 ], leading to increased dopamine and norepinephrine transmission in the prefrontal cortex [ 132 ]. A meta-analysis on the effects of methylphenidate treatment on ADHD in adults found it effective in improving neurocognitive performance, accomplishing better results than placebo groups in terms of working memory, reaction time variability, vigilance, driving, and response inhibition [ 136 ].

6.1.2. Atomoxetine

Atomoxetine has been reported to be effective for ADHD treatment [ 138 ], being more effective in adults than in children [ 134 ].

Atomoxetine blocks norepinephrine reuptake, producing increased presence of norepinephrine and dopamine in prefrontal cortex [ 132 ]. Since atomoxetine does not produce an increase of dopamine or norepinephrine in the nucleus accumbens, it lacks abuse potential [ 132 , 139 ]. This drug is associated with improvements in quality of life in children adolescents and adults, although this parameter is not further increased with long-term use [ 139 ].

6.1.3. Adverse Effects

Both stimulant and non-stimulant pharmacological treatments for ADHD produce adverse effects in a percentage of treated patients. The main adverse effects found for these drugs (% of patients treated with stimulants/% of patients treated with non-stimulants) are decreased appetite (28.6%/14.2%), nausea (7.9%/10.3%), headache (14.5%/20.8%), insomnia (12.3%/8.6%), nasopharyngitis (6.0%/7.1%), dizziness (5.1%/10.0%), abdominal pain (7.8%/11.5%), irritability (9.3%/6.9%), and somnolence (4.4%/34.1%) [ 133 ].

A systematic review on the adverse effects of methylphenidate in children and adolescents revealed that about 1 in 100 patients present serious adverse events after methylphenidate treatment (including death, cardiac problems and psychiatric disorders), while more than half of the patients treated with methylphenidate suffer one or more adverse events. The authors concluded that it is important to identify subgroups of patients who might be harmed by methylphenidate treatment and highlight the importance of remaining alert to possible adverse events in patients with this treatment [ 135 ]. There might also be uncommon adverse effects. For example, there is a report of 3 cases of systemic sclerosis associated with methylphenidate treatment [ 140 ]. The authors of the last study suggested that patients with signs of autoimmune or vasospastic conditions should be briefed about this possible side effect before commencing methylphenidate treatment.

A systematic review on possible adverse effects of atomoxetine, including decreased growth rate, cardiovascular and hepatic effects, aggression, psychosis, seizures, and suicidal ideation, determined that evidence indicates it is safe to use in ADHD patients [ 141 ]. Furthermore, the presence of comorbidities does not interfere with treatment efficacy, nor does treatment exacerbate comorbid symptoms [ 142 , 143 ]. However, it is important to be alert to other possible adverse effects. A case report and review indicated that the appearance of tics is a common side effect of atomoxetine treatment [ 144 ].

Methylphenidate and atomoxetine are known to increase heart rate and blood pressure, raising concern regarding possible cardiovascular effects of these drugs in ADHD patients. A review on the cardiovascular effects of these drugs in healthy subjects found the drug to be safe to use. Most of these studies were performed in children and adolescents, although there have also been some studies performed on adults, with no serious risk being reported in these subjects either. However, patient blood pressure and heart rate should be monitored on a regular basis. Moreover, careful follow-up should be performed for patients presenting certain cardiovascular conditions [ 145 ].

Weight loss has also been reported after atomoxetine treatment, occurring during the first two years of treatment. However, evidence suggests this decrease begins to be compensated between 2 and 5 years after the beginning of treatment [ 141 ]. Similarly, methylphenidate has been associated with adverse effects such as anorexia, weight loss, and insomnia [ 146 ].

A comparative study on short-term effects of methylphenidate and atomoxetine on ADHD reported significantly higher weight loss in children treated with atomoxetine [ 147 ]. However, a more recent study reported that children present significantly more weight loss after methylphenidate than after atomoxetine treatment [ 148 ].

A meta-analysis on gastrointestinal adverse effects of methylphenidate reported increased risk of decreased appetite, weight loss, and abdominal pain in children and adolescents under this pharmacological treatment [ 149 ].

A comparison between the presence of adverse effects after methylphenidate and atomoxetine treatments in ADHD children indicated methylphenidate as a safer option, since children under atomoxetine treatment presented higher incidence rates of anorexia, nausea, somnolence, dizziness, and vomiting than children under methylphenidate treatment [ 147 ]. A more recent study reported similar results, since children treated with atomoxetine presented higher incidence rates of mild adverse effects, such as decreased appetite, weight loss, dyspepsia, abdominal pain, stomach ache, irritability, mood disorders, and dizziness. As for severe adverse effects, patients under atomoxetine treatment presented higher incidence rates of gastrointestinal, neuropsychiatric, and cardiovascular effects [ 150 ].

6.1.4. Long-Term Adverse Effects

Long-term adverse effects of methylphenidate are the subject of intense study, given that it is the first-line stimulant drug used for ADHD treatment in children, adolescents, and adults [ 11 , 151 ]. A review on the subject addressed different adverse effects studied in patients after long-term (over one year) administration of methylphenidate, including low mood or depression, anxiety, irritability or emotional reactivity, suicidal behavior or ideation, bipolar disorder, psychotic symptoms, substance use disorders, tics, seizures or EEG abnormalities, and sleep disorders. The authors concluded that existing information indicates that methylphenidate is safe to use, although caution should be taken when prescribing this drug to specific groups, such as preschool children, patients prone to psychosis or tics, and high-risk adolescents [ 152 ]. However, the need for more studies on the long-term effects of treatment with this drug is highlighted, since studies in humans are rather scarce and with a high degree of heterogeneity in terms of methodological approach [ 151 , 152 ].

6.1.5. Long-Term Therapeutic Effect

Given that ADHD is a chronic disorder and that many of the children presenting ADHD will still present symptoms in adulthood, it is particularly important to determine the long-term effectiveness of pharmacological treatments. However, very few studies address this issue, and no conclusion can yet be drawn regarding the long-term effects (years) of pharmacological treatment of ADHD on symptom reduction and quality of life. Thus, the long-term efficacy of drug treatment for ADHD remains under debate [ 153 , 154 , 155 , 156 ]

Current pharmacological treatments for ADHD have proven to be safe and effective. The efficacy of these treatments on ADHD symptoms is clear, and thus pharmacological therapy is often used to treat ADHD patients [ 136 , 138 , 141 , 152 ]. However, there are also some drawbacks to this therapeutic approach, including the time required to reach the effective dose for each patient [ 3 , 157 ]; the lack of response in some patients [ 121 , 158 , 159 , 160 ]; the unresolved issue of long-term effectiveness (of great importance given that in many cases the treatment must go on for years) [ 153 , 154 , 155 , 156 ]; the presence of adverse effects, which although not life threatening in most cases, are nevertheless upsetting [ 133 , 135 , 144 ]; and the existence of specific groups of patients with whom a greater caution must be taken [ 140 , 145 , 152 ]. Altogether, these drawbacks have led to the search of new therapeutic approaches. One of the strategies studied so far is the possibility of using other drugs to treat ADHD, including drugs interacting with serotoninergic (metadoxine, paroxetine, duloxetine, buspirone), glutamatergic (memantine), cholinergic (AZD3480, AZD1446, lobeline, galantamine, mecamylamine), histaminergic (mk-0249), and catecholaminergic neurotransmission systems (modafinil, droxidopa, desipramine, bupropion, nomifensine, reboxetine, venlafaxine, duloxetine, guanfacine, aripiprazol, dasotraline, selegiline), as well as lithium [ 161 ].

6.2. Non-Pharmacological Therapies

Pharmacological therapy is effective although presents some inconveniences, including the existence of adverse effects in some patients and lack of effect in others. Therefore, there are also different non-pharmacological approaches for ADHD treatment.

6.2.1. Behavioral Parent Training

The goal of parent training is to equip parents with techniques that will be useful in managing ADHD-related behavior presented by their children. A systematic review published on 2011 found no reliable effect of ADHD children’s behavior, although it may lead to increased confidence and decreased stress in parents [ 162 ]. Later studies found an effect of behavioral parent training on ADHD symptoms, which is not increased by previous working memory training, although this combination did produce positive effects on working memory storage and processing [ 163 ]. It is noteworthy that cognitive functioning of both parents and children influences the effectiveness of this therapeutic approach on ADHD symptoms. Better working memory in children and higher parental response caution presented an association with improvements in inattention. As for conduct problems, better parental self-regulation was associated with a better result in this area. However, none of the measured cognitive functions in children or parents were associated with improvements in hyperactivity [ 164 ]. Moreover, behavioral parent training improves coexistence at home, since a reduction in the frequency and severity of problematic situations is produced, along with a reduction of stress in parents [ 165 ].

6.2.2. Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) has also been used to treat ADHD. A review performed on the subject found CBT to be effective in reducing ADHD symptoms in adults, however only when improvement was evaluated by the patient and not when evaluated by the clinician [ 166 ], although a more recent meta-analysis on the subject reported a good effect of CBT on ADHD adults [ 167 ]. A Cochrane systematic review concluded that CBT has a positive effect on ADHD symptoms, either alone or in conjunction with other therapies, although considered the evidence to be low-quality in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group approach. [ 168 ]. A meta-analysis found that CBT is one of the most effective non-pharmacological options to treat ADHD, ranking just after physical exercise [ 169 ]. A later systematic review confirmed the effects of CBT on ADHD symptoms [ 170 ]. A recent study reported CBT to be effective in reducing ADHD symptoms in patients, either with or without conjunct medication [ 171 ].

6.2.3. Attention Training Techniques

Attention training techniques are often used to improve life quality and increase well-being. Given the effect of these techniques on brain activity, as well as on attention and self-regulation, their use to reduce ADHD symptoms and improve life quality in these patients is currently under study [ 172 ].

Mindfulness can be defined as paying attention to the present, an activity that implies sustained attention. A systematic review on the effects of mindfulness-based interventions on ADHD found that such approaches were popular among adults with ADHD, finding improvements in attention, although the effects of such approaches in children and adolescents are still unclear [ 173 ]. A recent meta-review reported a large effect size of mindfulness on ADHD [ 174 ]. A review on the effects of mindfulness-based cognitive therapy on ADHD adults reported good effects of this therapeutic approach, especially when used in conjunction with pharmacological therapy [ 175 ], while a systematic review analyzing the effects of meditation-based techniques (either on parents and children or on children only) on ADHD children could not draw a clear conclusion regarding beneficial effects [ 176 ].

Adult ADHD patients that underwent an 8-week mindfulness awareness practice period presented decreased ADHD, depression, and anxiety symptoms [ 177 ]. Similarly, a study performed with children revealed that an 8-week period of mindfulness-oriented meditation produced improvements in the performance of neuropsychological tests, as well as in ADHD symptoms. Although encouraging, the authors stated that the results are still preliminary, given the small number of children participating in the study [ 178 ]. There are also results indicating that this technique produces an improvement in ADHD symptoms in ADHD children with oppositional defiant disorder [ 179 ].

6.2.4. Neurofeedback

Neurofeedback (NFB) is a therapy in which patients learn to modify EEG patterns through operant conditioning. There are articles reporting the induction of plastic changes after NFB training [ 180 , 181 , 182 , 183 ], supporting a theory explaining the effects of NFB on different brain disorders through the induction of synaptic plasticity, leading to an homeostatic set point. Additionally, besides some unusual cases of headache, no collateral effects have been reported with this technique. One of the most interesting aspects of NFB is the induction of plastic changes from within the brain under normal physiological conditions, without the need for an external stimuli such as pharmacological treatments or transcranial stimulation to alter brain activity, thus the probability of adverse effects is minimal [ 181 ].

Specific NFB protocols have been developed over the decades. These protocols were designed based on articles reporting specific qEEG variations in neurological patients or qEEG patterns associated with cognitive function. Some of these standardized protocols have been studied in terms of their ability to treat ADHD [ 184 ].

Several articles have addressed the use of NFB in ADHD patients. The results have been mixed and numerous meta-analyses have been published on the subject. The conclusions of these meta-analyses have also been mixed. There are meta-analyses reporting good effects of NFB on ADHD [ 185 , 186 , 187 ], not finding reliable effects [ 188 ], not reaching a conclusion on the subject of efficacy [ 189 ], finding a minor effect of this therapeutic approach significantly below what is observed with pharmacological treatment [ 190 ], or finding a minor effect only in the presence of pharmacological treatment [ 191 ].

An overview of recent publications gave the same impression. Some reports found effects of NFB theta/beta or theta/alpha protocols on ADHD, measurable at follow-up 8 weeks or 12 months after treatment completion [ 192 , 193 ]. Other reports found no effect [ 194 , 195 , 196 ]. Moreover, there are reports revealing a minor effect of NFB, below the effect levels of other therapeutic approaches [ 197 , 198 , 199 ].

NFB is a therapeutic approach widely studied for ADHD treatment. The results so far have been mixed. However, given the absence of side effects and its ability to induce synaptic plasticity [ 181 ], it is an option worth keeping in mind.

6.2.5. Other Non-Pharmacological Approaches

The use of non-pharmacological supplementations, such as polyunsaturated fatty acids, peptides, amino acids, plat extracts, probiotics, micronutrients, and herbal supplementation, is currently being studied in order to determine their usefulness in treating ADHD. However, further research is still needed in this area [ 200 ].

A study performed in ADHD children under methylphenidate treatment for whom zinc supplementation was added reported no significant effect of zinc supplementation on the total score for a parent’s questionnaire for ADHD or in the hyperactivity and impulsivity subscales. However, zinc-supplemented children present improvements in inattention scores [ 201 ].

A meta-analysis on non-pharmacological interventions for ADHD patients found that physical exercise produced a good effect on ADHD cognitive symptoms, especially aerobic exercise targeting executive functions [ 169 ].

7. Treatment Personalization

In the first sections of this review, we addressed some of the factors associated with ADHD incidence, ranging from a variety of environmental factors to the presence of different genetic polymorphisms. However, these different etiologies are not always present, since patients might present one or another (see Section 2 and Section 3 ). Similarly, while there are some changes in brain activity associated with ADHD, they are not always the same (see Section 4 ). Accordingly, there is also variation in the response of patients to both pharmacological and non-pharmacological treatments (see Section 5 ).

Since the etiology of ADHD could be very different from patient to patient, the precise nature of the physiological changes underlying the clinical manifestations of ADHD in each case could be slightly different, affecting the effectiveness of the chosen treatment and possibly explaining the variation in the effect of the same treatment on different patients. This can be observed in the variations in qEEG activity observed in different studies [ 112 , 113 , 114 , 116 , 121 ]. However, the design of personalized treatments based on specific characteristics of each patient could lead to better clinical results. In this regard, strategies to adjust therapeutic approaches based on patients’ characteristics have been used for both pharmacological and non-pharmacological therapies.

Selecting the appropriate pharmacological treatment and the dose to be used takes some time, given the large inter-individual variability regarding treatment efficacy, leading to a delay in reaching a therapeutic effect, and in some cases producing an early termination of treatment due to frustration, either by the provider or the family [ 157 ]. Moreover, there is some variability regarding patient response to methylphenidate, including patients that do not achieve adequate symptom control or experience adverse effects with commonly used doses. Therefore, dose optimization has been proposed as a means to achieve an adequate effect for most of the patients, enhancing both the efficacy and safety of methylphenidate treatment [ 3 ]. This has led to the search for strategies to find adequate treatments for each patient, such as pharmacogenomics, in which a patient’s genotype for a particular gene is used to predict the effects of medication in that patient. However, in spite of the progress that has already been made, no pharmacogenomic test so far has been found to be helpful in treatment selection [ 157 ].

Treatment resistance has been reported for both atomoxetine [ 158 ] and methylphenidate [ 121 , 159 , 160 ]. For this reason, qEEG can be used as a source of information to determine at an earlier point whether methylphenidate [ 121 , 160 , 202 ] or atomoxetine [ 107 , 202 ] is effective or if an alternative treatment is needed for a patient.

Most of the reports on the use of NFB for ADHD use a standardized protocol, either equal for all participants or adapted to each patients after qEEG analysis. However, there is another more personalized approach known as qEEG-informed (or qEEG-guided) NFB. In this variant of NFB, rather than selecting a particular protocol (for example, theta/beta ratio) and applying it to all participants, subjects receive a NFB protocol selected for them after qEEG analysis. This type of NFB has been successfully used in schizophrenia [ 203 ], obsessive compulsive disorder [ 204 ], migraine [ 205 ], dementia [ 206 ], and with learning-disabled children [ 207 , 208 ].

There are so far only two studies applying qEEG-informed NFB in ADHD patients, so it is not yet possible to perform a meta-analysis on the effects of this type of NFB on ADHD. However, a positive effect of NFB has been reported in both published studies [ 209 , 210 ].

8. Discussion

ADHD is an NDD with a complex etiology. While it is clear that its main cause is alterations in neurodevelopmental processes such as synaptogenesis, myelination, and neurogenesis [ 5 ], the causes of these neurodevelopmental alterations are diverse. In some cases they might be associated with environmental factors such as premature birth [ 6 ], perinatal problems [ 9 ], nutrition during pregnancy [ 10 ], or exposure to heavy metals [ 17 , 18 , 19 , 26 , 27 , 29 ]. Additionally, there is strong evidence of genetic influence on ADHD [ 43 , 44 ], and an interaction between environmental and genetic factors cannot be discarded.

The purpose of this review is not to fully describe all factors associated with ADHD appearance, but rather to address some of the main etiologies described so far, in order to clarify the high diversity of factors associated with this NDD. When analyzing the different sections of this review, one thing becomes evident—that ADHD patients are diverse regarding the etiology of their condition and their responses to treatment. This heterogeneity outlines the high variability in patients’ particular conditions regarding ADHD symptom manifestation and treatment, since it is probable that the underlying neurophysiological alterations for each patient are at least slightly different. Thus, standardized treatment (either pharmacological or non-pharmacological) may not be equally efficient in all cases.

Moreover, there could be other factors that are usually disregarded in relation with ADHD incidence, but which might play an important role in this condition. Recently, the gut microbiome has been the subject of intense research as an ADHD-associated factor, and even though further research is needed in order to determine its precise influence on ADHD, there are already reports indicating a possible link between them [ 211 , 212 , 213 , 214 ].

In the end, all of these factors produce changes in brain structure and function [ 1 , 7 , 112 , 113 , 114 , 115 ], leading to the symptomatology observed in ADHD patients. Therapeutic approaches to treat this condition have the objective of compensating such alterations in order to reduce symptoms and improve quality of life. However, as we have observed in this review, not all patients present the same neurophysiological changes. Studies performed on qEEG activity have yielded different results regarding brain electrical activity in ADHD patients [ 4 , 112 , 114 , 120 ]. Additionally, both brain imaging and qEEG techniques have revealed that changes are not consistent throughout the lifespan, being different in children and adults [ 114 , 115 , 116 , 121 ]. Therefore, there is a need for treatment personalization for each ADHD patient in order to achieve greater effect with minimal adverse effects.

Pharmacological treatments, both stimulants and non-stimulants have proven to be effective and safe for ADHD patients [ 132 , 133 ], and thus are widely prescribed to treat this condition. However, the pharmacological approach to ADHD treatment has some drawbacks, mostly regarding difficulties in reaching effectiveness in all patients [ 3 , 121 , 157 , 158 , 159 , 160 ] and the presence of adverse effects [ 133 , 135 , 144 ].

The search for other therapeutic options has led to the assessment of the effects of other drugs on ADHD [ 161 ], as well as the design of non-pharmacological treatments, such as behavioral parent training, CBT, attention-improving techniques, and NFB.

The effects of behavioral parent training on ADHD symptoms in children are not consistent, with some articles finding effects [ 163 ] and others not finding any [ 162 ]. However, behavioral parent training does reduce stress in parents and promotes a better coexistence at home, which is favorable for children [ 162 , 165 ]. In the case of CBT, there is more evidence indicating a good effect in reducing ADHD symptoms [ 167 , 168 , 169 , 170 , 171 ]

Attention training techniques are still under intense study. There is some evidence regarding the effect of this technique on ADHD in adults [ 173 , 175 ], while in children and adolescents the results are not clear so far [ 173 , 176 ].

A number of studies on the effect of NFB on ADHD symptoms have yielded different results, either finding a positive effect [ 185 , 186 , 187 , 192 , 193 ], a mild effect [ 190 , 197 , 198 , 199 ], or no effect at all [ 188 , 194 , 195 , 196 ]. However, NFB has a number of advantages that encourage the search for an adequate protocol to treat ADHD patients. It is targeted directly to change brain activity associated with the condition under treatment, it has virtually no side effects, and the therapeutic effect is due to the induction of plastic changes in the central nervous system, thus it might establish a long-term changes [ 180 , 181 , 182 , 183 ].

9. Conclusions

In the present review, we have gone through some of the factors associated with ADHD, and it is clear that a great heterogeneity exists in the etiology of this condition. Therapeutic approaches, although functional in many cases, also show heterogeneity in their effects in certain groups of patients. The diverse range of effects of the therapeutic approaches used should not be a surprise, given the diversity of etiologies found in ADHD. Even though clinical manifestations of this condition might be similar (diagnosis is based on the presence certain symptoms), the same clinical manifestations could occur with different underlying physiological changes, considering the variations in qEEG activity in different groups of patients [ 112 , 113 , 114 , 116 , 121 ]. Thus, these neurophysiological changes presented by patients may not necessarily respond in equal form to a given therapeutic approach. Given the inter-personal variance in the etiology of ADHD, it is advisable to personalize the therapeutic approach. Regarding pharmacological therapies, dosage optimization [ 3 ], pharmacogenomics [ 157 ], and the use of qEEG to select the adequate drug for a given patient have been proposed [ 107 , 121 , 160 , 202 ].

Regarding non-pharmacological options, the use of qEEG-informed NFB has been proposed for personalized treatment in ADHD patients. The studies carried out to date have shown positive results [ 209 , 210 ], although the number of studies is still too small to draw a conclusion. However, given the advantages of NFB [ 181 ] and the positive effects of this approach reported for other conditions [ 203 , 204 , 205 , 206 , 207 , 208 ], it is worth performing further studies on the effectiveness of this type of NFB on ADHD.

Author Contributions

Conceptualization, L.N.-J. and W.V.H.-M. writing—reviewing and editing, L.N.-J., W.V.H.-M., and A.H.-S. All authors have read and agreed to the published version of the manuscript.

This research received no external funding

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  • Published: 08 June 2024

Improving the efficacy and effectiveness of evidence-based psychosocial interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents

  • Anil Chacko   ORCID: orcid.org/0000-0002-3275-4726 1 ,
  • Brittany M. Merrill 2 ,
  • Michael J. Kofler   ORCID: orcid.org/0000-0002-8604-3647 3 &
  • Gregory A. Fabiano 2  

Translational Psychiatry volume  14 , Article number:  244 ( 2024 ) Cite this article

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Attention-deficit/hyperactivity disorder (ADHD) is a prevalent, chronic, and impairing mental health disorder of childhood. Decades of empirical research has established a strong evidence-based intervention armamentarium for ADHD; however, limitations exist in regards to efficacy and effectiveness of these interventions. We provide an overview of select evidence-based interventions for children and adolescents, highlighting potential approaches to further improving the efficacy and effectiveness of these interventions. We conclude with broader recommendations for interventions, including considerations to moderators and under-explored intervention target areas as well as avenues to improve access and availability of evidence-based interventions through leveraging underutilized workforces and leveraging technology.

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Evidence-based treatments for adhd - an overview.

Multiple groups, committees, and professional organizations have provided the field with recommendations for evidence-based treatment approaches for ADHD. There is clear consensus across these recommendations that pharmacological treatments, notably stimulant medication, psychosocial treatments, and a combination of these two approaches have the strongest evidence base. Table 1 provides a brief overview of the major conclusions of each guideline for the treatment of ADHD in children. It is clearly recommended that families should receive psychoeducation regarding ADHD, and that the evidence-based psychosocial treatments are behavioral parent training (BPT), behavioral interventions in classroom and peer settings, and organizational skills training [ 1 , 2 , 3 , 4 , 5 ].

There are inconsistencies among the guidelines that make broad statements of consensus difficult. For instance, there are differences in precision in recommendations for psychosocial treatments, with some very broad in scope [ 6 ] compared to others with more precise recommendations regarding particular treatment types (e.g., BPT [ 2 ]) and particular populations (e.g., children under six; [ 5 ]). Broad suggestions of seeking “psychological” or “educational” treatment is unhelpful in some guidelines and practice parameters, as there are many approaches that fall under this category and some are clearly efficacious whereas other approaches commonly deployed do not have evidence of efficacy for ADHD [ 1 , 2 , 3 , 4 ]. There are also differences in the strength of recommendations, with more contemporary guidelines emphasizing multimodal treatments more so than older guidelines. However, perhaps most notably, there is not clear consensus among the recommendations on the best sequence or combination of treatments for ADHD, even though this is a key question for most families pursuing treatment for ADHD. It is also important to note that most guidelines focus on proximal ADHD treatment – as ADHD is now conceptualized as a life-course persistent disorder [ 7 ], treatment efforts will need to be protracted across time and appropriate for evolving developmental levels.

Efforts at improving efficacy and effectiveness of psychosocial intervention for ADHD: what do we know and where do we go?

Given the prominent role of psychosocial, primarily behavioral interventions, for ADHD, we highlight the evidence for several of these key interventions, integrating the literature on improving efficacy and effectiveness of these interventions. We also discuss digital therapeutics given the explosion in its availability and purported efficacy for children with ADHD. Following this, we close with potential broad future directions for psychosocial treatments for children with ADHD.

Behavioral parent training

Behavioral parent training (BPT) is likely the most well-studied psychosocial intervention for children’s mental health disorders, including for ADHD [ 8 ]. It serves as the first line intervention approach for younger children with ADHD and is an integral part of comprehensive intervention approaches for school-age children with ADHD. Importantly, BPT is less studied in adolescents with ADHD. Although parenting is not etiological to ADHD, there are clear reasons to focus on parenting when supporting a child with ADHD. Of primary importance is that raising a child with ADHD is stressful, and not surprisingly, elicits ineffectual parenting practices (e.g., inconsistent, harsh, lax, overreactive, less responsive). As a result, parents often have lower parenting efficacy/competence, higher levels of coercive management practices, utilize maladaptive coping strategies (e.g., increased use of alcohol), and have more negative attributions/perceptions of their child [ 8 ]. These parent-level challenges can be addressed, in part, by supporting parents to utilize more proactive and effective parenting practices which can help improve functioning for themselves and ultimately their children. Importantly, the most common comorbidities with ADHD, Oppositional Defiant Disorder [ODD] and Conduct Disorder (CD) are best treated with BPT—making BPT an essential treatment for the most common disruptive behavior disorders in childhood [ 8 ].

BPT is based on operant-conditioning and social learning theories, with techniques that focus on antecedents (e.g., effective instructions, rules) and consequences (e.g., active ignoring, time-out from positive reinforcement) of behaviors. This core content is delivered in a flexible manner with varying formats (e.g., group, individual) durations (brief vs longer), with or without child involvement, delivery (e.g., with or without video-based learning). Moreover, over the past two decades, there have been efforts at tailoring BPT to meet the needs of specific populations (e.g., single mothers, fathers; Latine; [ 9 , 10 , 11 , 12 ]). These BPT programs, often referred to as “homegrown” BPT as compared to commercialized BPT programs (those that have been more extensively developed, manualized and are commercially available; e.g., Defiant Children [ 13 ]) retain the core content of traditional BPT but have modifications to format or additional content that are based on the needs of the targeted populations. Overall, commercialized BPT and homegrown BPT have been found to be effective in improving the functioning of children with ADHD and their parents [ 14 , 15 , 16 ]. A recent meta-analysis also suggests sustained benefits of BPT over the course of a year on child ADHD symptoms, parenting behavior, parenting sense of competence and parental mental health [ 17 ]. The significance of BPT should be, however, put into a broader context to appreciate the clinical benefits of this intervention. While multiple randomized controlled trials have established the statistical significance of BPT for ADHD, the effect size for BPT ranges from small to medium effects, depending upon the outcome [ 18 ]. This means that for many outcomes, the effect sizes would be “visible to the naked eye of a careful observer” [ 19 ]. While there is limited data, only a significant minority of children are “normalized” following BPT [ 15 ]. Collectively, a more nuanced perspective on BPT for ADHD suggests that it is an evidence-based intervention that can result in visible improvements on key outcomes. There is room, however, to improve the potency of BPT. The implications of the findings reported above suggest several broad areas for further investigation. First is to increase access to BPT given the benefits of the intervention. Wolraich et al. [ 20 ] note that there is a lack of an adequate pool of behavioral and mental health specialists who are available to provide evidence-based psychosocial treatments for ADHD, including BPT. National data suggest that the majority of youth with ADHD are receiving no treatment, even when identified, and the lack of BPT treatment is most pronounced in young children with ADHD [ 21 ]. Efforts at utilizing technology to increase the workforce offers novel and promising approaches to address this issue [ 22 ].

A second area is to increase the potency of BPT. We believe there are multiple ways to achieve this goal, with the most apparent being improving the extent to which parents fully engage in BPT, given the relation between increased engagement and improved potency of outcomes [ 23 ]. It is common for families of children with ADHD, even those who have enrolled in BPT, to not initiate treatment or drop out of BPT prior to completion [ 9 , 23 ]. Given this, there have been notable efforts at improving engagement to BPT through addressing perceptual (e.g., expectations about BPT), practical (e.g., transportation) and cultural barriers to treatment prior to BPT [ 10 , 24 ] as well as during BPT [ 25 ]. Given that engagement challenges often involve practical barriers (e.g., transportation, child care, fixed appointment times), there has been efforts at increasing access through reducing these barriers such as providing BPT through mobile applications [ 26 ], web-based platforms [ 27 ] and telehealth delivery [ 28 , 29 ]. These efforts have led to improved engagement and associated outcomes for families, beyond traditional BPT [ 30 ]. Engagement with BPT remains an important area of research, particularly the extent to which these enhancements to BPT can be readily applied in routine settings [ 25 , 31 , 32 ], an understudied empirical question.

A second and meaningful line of research to improve the potency of BPT has been focused on improving specificity of BPT content by translating contemporary theories of ADHD into refinements to BPT. Van der Oord and Tripp [ 33 ]), utilizing contemporary motivational reinforcement-based theories of ADHD, suggest that given altered reinforcement sensitivity in ADHD, rewards and punishment should be judiciously provided. As an example, they note evidence that while mild negative punishment (e.g., response-cost, time-out from positive reinforcement) improves on-task behavior in children with ADHD, mild punishment can also lead to more errors on tasks, increased emotionality in children with ADHD, missed learning opportunities, and lack of task persistence [ 34 , 35 ]. These authors note caution in the use of punishment, especially positive punishment (e.g., verbal reprimands), with children with ADHD. Rather, there should be a focus on rewarding alternative adaptive behaviors to reduce the need to use punishment. These theory-driven considerations to adapting BPT are important, yet empirically understudied. As such, the extent to which these ADHD-theory-adapted BPT results in improved outcomes relative to standard BPT is not known. Importantly, however, some efforts in this area have resulted in little difference for ADHD-adapted BPT relative to standard BPT. As an example, in an RCT, the New Forest Parenting Program (NFPP), which was developed to address underlying mechanisms of ADHD (self-regulatory and cognitive problems [ 36 ] was found to be no better than a standard BPT program and in some areas less effective (e.g., parental stress, parenting behavior, parent reports of ADHD symptoms at follow-up) for preschool children with ADHD [ 37 ]. These data suggest the importance of rigorously evaluating novel approaches that are considered improvements to BPT to well-established traditional BPT for ADHD.

Overall, the efficacy of BPT suggests that this should be first-line intervention approach for children with ADHD, with significant and noticeable effects of BPT on both parent- and child-level outcomes with maintenance of gains over the course of a year. This statement comes with the caveat that there is room for improvement in the potency of BPT. As we will discuss in the future directions section below, greater attention must be given to dissemination of BPT (and all psychosocial interventions for ADHD) within routine systems of care and evaluation of the effectiveness of these interventions alone and in combination when delivered within these systems.

Behavioral classroom management

ADHD is largely defined by challenges in settings such as schools where behavioral expectations are often demanding of attention capacity and self-control, and so it is not surprising that many of the efficacious treatments for ADHD have focused on improving academic functioning and classroom behaviors. Children with ADHD are effectively treated with classroom contingency management strategies [ 38 ]. Systematic reviews [ 1 , 2 , 4 , 5 , 39 ] as well as meta-analyses [ 40 , 41 , 42 ] clearly illustrate that behavioral classroom management is an efficacious treatment for ADHD.

As noted above, behavioral classroom management is an efficacious treatment for ADHD. Before discussing evidence for efficacy and effectiveness of behavior classroom management, it is worth noting approaches that do not strongly support positive outcomes. In the United States, children with ADHD are eligible for behavioral classroom management support through Section 504 Accommodation plans administered through the Americans with Disabilities Act or through an Individualized Education Program if the committee on special education determines it is needed. These policies have provided school-based behavioral supports for students with ADHD for over 30 years. However, given that follow-up studies indicate that the long-term educational outcomes for students with ADHD are modest, at best [ 43 , 44 , 45 , 46 ], it is important to emphasize that these accommodation plans or individualized education programs are only useful if they include effective interventions and supports for the child or adolescent with ADHD.

Practically speaking, behavioral classroom management approaches that are effective will include setting clear goals and rules, ensure that the child receives clear feedback on progress toward meeting goals, and that consequences, typically rewards and privileges contingent on meeting behavioral goals and following rules, are provided liberally. It is important to note that positive behavior support strategies are interwoven into the fabric of elementary school classrooms - teachers provide rules and structure for activities, there is praise issued for appropriate behavior, and schools have standard discipline procedures including office referrals or detentions for rule violations. Feedback is provided on a regular, if infrequent basis (i.e., on quarterly report cards). For most children with ADHD this provides a reasonable baseline of behavioral classroom management, but additional strategies and supports are typically needed to make the overall approach to supporting a child with ADHD more efficacious.

Children with ADHD typically need much more frequent behavioral feedback and positive consequences for appropriate behavior in schools. For that reason, a daily report card is among the most efficacious positive behavior supports within a classroom [ 47 , 48 ]. The daily report card has long been used effectively to treat ADHD, monitor outcomes, and open a daily line of communication between teachers and the child’s parent [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], and it is a procedure aligned with a long tradition of using contingency management with children with disruptive behavior in general educational settings [ 58 ] and in special education settings [ 57 , 59 , 60 ]. In addition to being among the most efficacious classroom interventions, it is also one of the most cost effective [ 61 ].

Recent changes in the ways schools address social, emotional, and behavioral challenges may promote greater effectiveness of the implementation of classroom behavior management strategies. Multi-tiered systems of support (MTSS [ 62 ] in schools conceptualize the behavior of children as being within a continuum, and through regular screening and progress monitoring, provide more intensive intervention, when indicated and for as long as is needed. Currently MTSS efforts in schools are focused on academic achievement targets, and there is less emphasis on MTSS for behavior [ 63 ]. However, the MTSS model of screening and intervention is similar to the single case design approach to intervention that has been long-used within the ADHD treatment literature [ 4 , 5 , 47 ]. In this approach, following the collection of baseline data, behavior classroom management interventions are systematically introduced to evaluate their effectiveness. Educators also benefit from ongoing coaching, support, and monitoring of progress to promote consistent and protracted use of these behavioral interventions [ 64 ].

Supporting this approach to school-based intervention is a recent study that evaluated the effectiveness of different sequences of ADHD treatment [ 65 ]. In this study, using a sequential, multiple assignment randomized trial (SMART [ 66 ]), children were randomly assigned to begin the school year with one of the two evidence-based treatments for ADHD - a low dose of stimulant medication or an initial course of behavior therapy (eight parent training sessions and a daily report card intervention at school). Teachers provided feedback on how the child was functioning in the classroom, and if there was evidence of impaired functioning, the child was then randomly assigned to more treatment – either a greater dose of the treatment at the start of the school year, or a other modality. Thus, children could have a treatment sequence of: (1) medication followed by an increased dose of medication; (2) medication with behavior therapy added; (3) behavior therapy followed by an increased dose of behavior therapy; or (4) behavior therapy followed by medication. Results were interesting as they illustrated the best sequence of treatment for reducing discipline referrals and disruptive behaviors observed in the classroom were those that started with behavior therapy first. Further, the behavior therapy first approaches also cost less to implement across the school year than the treatment sequences that included medication [ 61 ]. Importantly, this study of the effectiveness of treatment sequencing spanned an entire school year, improving upon the research base of efficacy treatments where many studies focused on shorter time periods. While the Pelham study provides a foundation for considering combined and sequenced approaches, far less has been done on the effectiveness of behavioral classroom approaches when conducted within and supported entirely by school-staff over the course of multiple school years.

Overall, there is strong support for behavioral classroom interventions, including the Daily Report Card [ 48 , 50 , 67 ], and it is strongly recommended that this intervention be initiated for children with ADHD experiencing classroom-based impairment. For older children (e.g., middle school, high school), a behavioral contract may be used to initiated contingency management across the multiple classrooms characteristic of this grade level. Educators and parents should ensure that school-based interventions are implemented consistency and continuously, as school-based behavioral challenges are likely to extend across school years and grade levels.

Organization skills training

Related to their difficulties staying on task and following the rules in the classroom setting, children with ADHD have impaired organization, time management, and planning skills that undermine their academic abilities and potential. Homework management and organizational skills have been shown to predict concurrent GPA and later academic outcomes [ 68 , 69 ]. Organizational skills training (OST) interventions utilize behavioral methods to teach skills directly to students with ADHD. The training programs often include behavioral management procedures administered by a counselor, parent, or teacher to reinforce skill use and progress in treatment. Organizational interventions have largely targeted middle school to early high school students with ADHD (ages 10–14 [ 70 ]), with sessions focusing on materials organization, understanding time and time management, and planning larger assignments. Session frequency and length vary widely from about 10, 60-minute family sessions in a clinic [ 71 ] to 40, 2.5-hour student sessions in an after-school setting [ 72 ]. Multicomponent OST packages lead to improvements in organizational skills, planner use, and adolescent impairment [ 73 ].

Embedding OST in schools is key to enhancing the reach of these interventions. Though availability of school personnel to implement OST varies across districts, current work aims to train school counselors to implement OST with students with ADHD [ 74 ]. Langberg and colleagues [ 74 ] found that OST delivered by school staff led to improvements in organization, time management, and planning skills as performance and behavior during homework based on parent-report. Importantly, these results were found despite the school counselors receiving only 2 h of training in the intervention with no ongoing supervision. Purposefully limiting training and post-training investment allows for the examination of treatment effects in the context in which they would likely be provided—i.e., in schools, by school mental health providers with little funding for training and ongoing supervision. Toward the same goal of increasing the sustainability of OST within schools, investigators are developing online tools to assist school staff with OST implementation at low to no cost [ 75 ].

Psychosocial treatments for children with ADHD have primarily been researched in elementary-age youth, and early work in developing organizational skills interventions addressed this gap by upwardly extending treatments to middle school age youth. As the evidence accumulated that such interventions were efficacious among children with ADHD in middle school [ 1 , 2 ], further developmental extension was clearly justified [ 76 ]. adapted their OST program developed for middle schoolers to pilot with high school students with ADHD. Pilot data demonstrated feasibility and indicated that high schoolers may need about 50 sessions to benefit from the OST program. In the full-scale randomized clinical trial [ 77 ], high schoolers attended an average of 40 brief OST sessions while their caregivers attended an average of 4 behavioral parent training sessions. Compared to the control group, beneficial effects of treatment were found on parent-reported academic functioning and organizational skills, and no significant effects on grades, teacher-reported, or self-reported outcomes were found. Results are promising, and much more work is needed to support the academic functioning of older adolescents with ADHD.

Digital therapeutics

Of all the available non-medication treatments, this category is the only one that features protocols patented by the US Patent and Trademark Office (USPTO) and cleared by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. It is also the most controversial, with competing consensus statements concluding that these types of interventions have proven effective vs. proven ineffective [ 78 ], millions of dollars in fines for false advertising [ 78 ], and a perceived disconnect between benchmarks for effectiveness between the FDA and professional organizations that evaluate psychosocial treatments for children [ 79 ]. Overall, there appears to be evidence for small benefits of cognitive training on reducing inattentive symptoms, and potentially overall ADHD symptoms [ 80 ]. However, we contend that omnibus meta-analytic effect sizes are fundamentally uninterpretable in the context of cognitive training/digital therapeutics because the treatments that fall under this general umbrella feature wide variations in neurocognitive/neurological training targets, conceptual models of neurocognition that define these intended training targets, success/failure to meaningfully engage and improve the intended training target(s), and technologies employed to ‘hit’ the intended target(s). Therefore, what these treatments share are more peripheral features, rather than core mechanistic features necessary to meet meta-analytic assumptions. Even interventions given the same, more specific label (e.g., “working memory training”) vary widely in their approach, conceptual basis, and success/failure at engaging their mechanistic target as shown previously [ 81 ]. It will be important for the field to evaluate each intervention on its own merits because these protocols generally share very little with each other except for the use of a serious games approach [ 82 ] to engaging children in treatment.

Several neurocognitive training protocols have been developed and tested for children with ADHD; we briefly review three of the most prominent: EndeavorRX, CogMed, and Central Executive Training (Cenextra; an intervention developed by one of the co-authors). All three of these approaches are computerized digital therapeutics that include gaming elements and adaptive changes in difficulty. EndeavorRX trains cognitive attention abilities [ 83 ], Cenextra trains the ‘working’ components of working memory [ 84 ] and CogMed is intended to improve attention and working memory abilities [ 85 ], though clinical trial and meta-analytic evidence indicates that CogMed successfully engages short-term memory but not working memory abilities [ 81 , 86 , 87 ].

In terms of efficacy, EndeavorRX showed early promise in pilot/uncontrolled studies given generally favorable feasibility, acceptability, and engagement data [ 83 ]. In addition, EndeavorRX showed potential for reductions in parent-reported ADHD symptoms in proof-of-concept and open-label trials with children with ADHD [ 88 , 89 ]. However, the only controlled trial to date [ 83 ] demonstrated that these potential reductions were likely attributable to placebo effects – that is, Endeavor RX failed to show superior improvements in ADHD behavioral symptoms relative to a control condition (a spelling game). Evans et al. [ 79 ] concluded that “there is no evidence that using this game will result in any benefit in terms of their functioning and presenting problems.” (p. 125).

Cenextra also showed early promise in a head-to-head comparison with behavioral parent training (BPT) indicating favorable feasibility, acceptability, and engagement data. Cenextra was superior to BPT for improving working memory ( d  = 1.06) and reducing objectively-assessed hyperactivity ( d  = 0.74), and equivalent to BPT for reducing parent-reported ADHD symptoms at post-treatment [ 90 ]. These benefits were largely confirmed in an RCT comparing Cenextra with an active, credible digital therapeutic control called Inhibitory Control Training (ICT; [ 84 ]). Evidence suggesting improved functional outcomes is also emerging, and includes superior improvements relative to both BPT and ICT on masked teacher perceptions of organizational skills, academic success, impulse control, and academic productivity 1–2 months after treatment ended [ 91 , 92 ].

Similar to EndeavorRX and Cenextra, Cogmed showed considerable promise in early trials, and is arguably the most extensively studied neurocognitive training program. Results from meta-analytic reviews and RCTs, however, suggest that CogMed does not improve working memory, but rather improves select components of short-term memory (meta-analytic d  = 0.63; [ 81 , 86 , 93 , 94 ]. This is an important limitation for at least two reasons: First, most children with ADHD do not have deficits in short term memory (20–38% impairment rates) despite the majority having impairments in working memory (75–81%; [ 95 , 96 , 97 ]). Second, short-term memory abilities are not significantly associated with ADHD symptoms in most studies [ 81 , 95 ], which suggests limited potential for downstream improvements in ADHD behavioral symptoms. Indeed, conclusions from multiple meta-analytic reviews suggest that benefits on ADHD behavioral symptoms from CogMed are generally limited to unblinded parent ratings [ 81 , 93 ]. Notably, however, a more recent meta-analysis published by the developer of CogMed suggests significant, small benefits for reducing inattention ( d  = 0.37; [ 98 ]), though the extent to which this was driven by unblinded parent ratings was unclear.

A key benefit of digital therapeutics – and ‘software as medicine’ in general – is that they have the potential to continually adapt and improve based on real-time patient data. Thus, it is possible that interventions that are not showing the behavioral/functional benefits we had hoped for now could begin to do so in the future. Thus, we highlight some key areas for improvement based on conceptual models and the limited available literature on moderators of cognitive training efficacy for children with ADHD. First, there is a need to maximize dosage . In the context of digital therapeutics, ‘dosage’ refers to the quantity and quality of time spent actively engaging with the training exercises. Most existing protocols have been studied over a relatively limited time frame of 4–10 weeks of training, with a total training time of about 10–12 h across intervention protocols [ 83 , 84 , 99 ]. It is possible that this level of training is insufficient for producing large enough neurocognitive improvements to translate into meaningful – and statistically detectable – gains in downstream behavioral/functional outcomes, suggesting the need for more intensive/longer duration training.

An option closely related to maximizing dosage is increasing the specificity of the neurocognitive training target(s). Although training a variety of neurocognitive functions is appealing at face value, meta-analytic evidence indicates that such protocols produce smaller near-transfer effects than protocols that focus on a single neurocognitive training target [ 81 ]. It is presumed that the reason for this finding is that the more different cognitive ‘muscles’ that we are trying to train, the less time we can spend on any one of those ‘muscles’. Thus, it appears likely that maximizing efficacy will require separate protocols for each neurocognitive function that is impaired in ADHD, combined with a ‘personalized medicine’ approach in which each child’s neurocognitive profile is estimated at pre-treatment, and then a treatment plan is developed to target each of their identified weaknesses. We must leverage basic science to link training targets with behavioral/functional outcomes . Related to dosage and specificity issues is the idea of matching neurocognitive training targets with the specific outcome(s) of interest. Stated bluntly, neurocognitive training is not likely to be helpful if we are training neurocognitive abilities that are not robustly linked with the reason(s) a child presents for treatment. On the other hand, neurocognitive training protocols have great potential if they are able to produce robust improvements in their training target, and if that training target is robustly associated with the observable behaviors/functional outcomes we are trying to improve. A final area that shows promise for improving the efficacy of digital therapeutic interventions is augmentation: Combining them with existing treatments to (potentially) produce synergistic and/or augmentative benefits. This area of inquiry is in its infancy, and currently shows more conceptual promise than actual benefits [ 100 ].

Future directions in improving efficacy and effectiveness

This brief review of psychosocial treatments for ADHD illustrates the robust evidence in support of these interventions. Importantly, there is no panacea or magic bullet for ADHD; the interventions reviewed herein have notable limitations and response to interventions vary. As such, there continues to be efforts at refining existing approaches and developing novel approaches to treating the complex presentation of ADHD. We highlight here what we believe are key future directions, broadly speaking, in improving the effectiveness and efficacy of treatment for ADHD. These fall under two broad areas: future directions in treatments and future directions in service delivery of these treatments.

Future directions in treatment for ADHD

Moderators of treatment effects.

Much of the intervention literature has focused on static factors or social addresses (terms that describe rather than explain; e.g., marital status, child age;) as factors, largely because these are measures of convenience. Efforts toward using dynamic factors have shed light on what works for whom and can further refine an intervention to increase potency. As an example, in BPT, parent-level variables (e.g., parenting stress [ 101 ]) have been shown to moderate BPT engagement and outcomes, suggesting that future refinements to BPT that more directly address parental stress may increase the potency of BPT. Such efforts should be employed across all psychosocial interventions for ADHD. Importantly, as we have discussed elsewhere [ 8 , 102 ], efforts should go beyond variable-centered approaches (e.g., child age, parent stress) toward holistic, person- and/or family-centered approaches (the clustering of variables that more fully represent a child/parent/family). As an example, Dale et al. [ 103 ] employed a person-centered approach to create subgroups of families based on the intersection of multiple parent, child, and family factors to understand response to BPT for families of preschool children with ADHD. Three distinct family profiles emerged, with data suggesting differential response for families with high stress, elevated parental anxiety, and elevated parental depression. These typological approaches better reflect reality- people are more accurately reflected as a complex intersection of variables rather than just any one variable- and taking this approach may better result in a nuanced understanding of response to treatment and further inform treatment for types of people and families.

ADHD is complex and presentations vary. It is not uncommon for children and adolescents with ADHD to also have significant difficulties outside of core symptoms of ADHD (e.g., emotion dysregulation, sleep disturbances) that may moderate treatment response. As an example, ADHD is frequently associated with emotional regulation challenges, with studies suggesting that the vast majority of children with ADHD (i.e., 75%) have some symptoms of emotion dysregulation, with 25% having severe emotion dysregulation [ 104 ]. In fact, children with ADHD and severe emotion dysregulation are more likely to have complex presentations, cross-situational impairments and severe psychopathology [ 105 ]. Interestingly, there are few rigorous randomized controlled trials evaluating the effects of psychosocial interventions for emotion dysregulation in children with ADHD [ 106 ]. These and other moderators may best be evaluated through novel approaches such as individual participant data meta-analysis [ 107 ]. Addressing the needs of youth with ADHD and their families will require going beyond addressing core symptoms of ADHD. In fact, we have long argued that these types of functional impairments (e.g., academic, social functioning) should be the targets for ADHD treatment rather than ADHD symptoms [ 8 ].

Novel intervention targets

The presentation of ADHD at key developmental periods/tasks may pose significant challenges for affected youth and their families- necessitating novel targets of intervention. An example of this is the transition to learning to drive. Adolescents are the riskiest drivers on the roadway, overall; if an adolescent has ADHD they are significantly more at risk for negative driving outcomes including accidents, accidents that cause injury, and fatalities [ 108 , 109 ]. The period of time when individuals with ADHD are learning to drive may therefore be a critical, and also opportune time to initiate intervention. A recent RCT with adolescents with ADHD [ 110 ], evaluated a specially designed computerized simulated-driving program with feedback and found reduced problematic driving as compared with a control program. During real-world driving in the year after training, the rate of collisions and near-collisions was lower in the intervention group. These efforts highlight the potential of psychosocial interventions for addressing impairments inherent with developmental transitions for youth with ADHD. Related work suggests that intervening with adolescents at the transition to middle school and high school with intensive summer “bridge” programs may be a useful approach with high levels of engagement [ 111 ]. Future work should focus on embedding treatment efforts into other developmental tasks/transitions/tasks (e.g., start of preschool or initiation of employment).

Future directions in service delivery

ADHD is now very clearly understood to persist throughout development and into adulthood and there has rightfully been a shift toward a chronic care model [ 7 ]. Given this, attention must be given to developing integrated, consistently available and longitudinal approaches embedded in routine service systems such that children, adolescents (and even adults) with ADHD and their families can receive appropriate care. Unfortunately, availability and access to evidence-based interventions are limited. Recent studies suggest that only 31% of families of children with ADHD receive BPT [ 21 ] and just 32% receive behavioral classroom management [ 112 ]. Given this, we highlight herein issues related to increasing availability and access to evidence-based psychosocial treatment for ADHD- important goals to help close the science-to-service-gap in ADHD. More specifically, we briefly highlight efforts on (1) leveraging the existing workforce, and (2) using technology to deliver evidence-based psychosocial treatments.

Leveraging existing workforces

In light of mental health workforce shortages ( https://data.hrsa.gov/topics/health-workforce/workforce-projections ) new models of care will need to utilize and expand existing, but underdeveloped, non-professional and paraprofessional workforces [ 31 , 32 ]. One example of a sustainable, scalable model of care is the Family Peer Advocate (FPA) ADHD Model [ 25 ]. FPAs are part of a national family support model of current and former parent/caregivers of children with identified mental health needs who provide a range of services, including parenting skills training, emotional support, education about mental health services, and direct advocacy [ 30 ]. FPA-services are flexibly delivered in a variety of parent-identified settings (e.g., parent’s homes, community settings) and often connect and engage parents with key service settings/providers (e.g., schools, primary care, mental health clinics), reducing the systemic barriers associated with traditional service delivery models. Moreover, FPAs have many shared experiences with the families they serve including personal experience with providing care and navigating the service system for children with mental health challenges, often within the same community as those they serve. As a result, FPA care is associated with high acceptability ratings and increased engagement [ 113 ]. This FPA Model appears to be especially effective in reaching ethnically diverse families from socioeconomically disadvantaged backgrounds [ 30 , 113 ]. Emerging data suggest that FPAs can reliably and effectively deliver BPT for youth with ADHD [ 25 ], suggesting that this and other workforce (e.g., ADHD Coaches) should be leveraged in order to increase availability and access to evidence-based psychosocial interventions for ADHD.

The idea of leveraging the existing workforce also applies to school settings. The MTSS intervention framework, which embeds intervention in schools into universal, targeted, and indicated approaches is an example of a potential means of re-allocating professional time and expertise. Rather than waiting for school psychologists and special educators to get involved only when the child is considered for special education, a MTSS approach might utilize the expertise of these professionals to consult with the general education teacher on how to implement positive behavior supports for a child with ADHD. In this way, intervention is implemented quicker, in the setting where the initial impairment is identified, by existing school professionals [ 56 , 114 ].

Use of technology

Technology-based approaches to delivering evidence-based interventions have the potential to revolutionize mental health service access and delivery across multiple mental health disorders [ 115 ]. Online self-directed BPT approaches are potentially more feasible, affordable, and acceptable, can have significant reach to include traditionally underserved populations, and are readily scalable and sustainable [ 116 , 117 ]. Over 13 studies have recently been conducted demonstrating that online BPT can improve child behavioral outcomes. Importantly, a recently published trial compared Triple P Online (TPO; an evidence-based, commercially available, self-directed online BPT) to a face-to-face (F2F) therapist-delivered Triple P for preschool children with disruptive behavior problems [ 118 ]. This large randomized controlled trial found that TPO was non-inferior to F2F Triple P on observed and parent-reported child behavior, with clinically meaningful effect sizes. This study, combined with several other studies [ 27 , 119 , 120 ] demonstrate the effectiveness of online BPT in general and specifically for ADHD. Technology is increasingly being utilized in practice settings (e.g., ADHD Care Assistant in primary care [ 121 ]; Online Daily Report Card in schools [ 122 ]) to increase access to evidence-based psychosocial interventions. Concerted efforts and rigorous empirical investigation will be necessary to further determine the effectiveness of these approaches. Importantly, while there is high potential for such technology-delivered approaches, engagement to these formats will remain important to address [ 123 ].

Conclusions

ADHD is a prevalent, pervasive, chronic and impairing disorder that necessitates early, integrated, continuous interventions over a child’s development. Fortunately, several psychosocial interventions are available that address key functional impairments in children and adolescents with ADHD. Given the complex presentation of ADHD, novel approaches to address both underlying pathophysiological mechanisms associated with ADHD (e.g., working memory) as well as domains closely impacted in those with ADHD (e.g., emotion regulation) and key developmental tasks (e.g., driving) are emerging areas in ADHD intervention science. Efforts to improve the efficacy of psychosocial interventions remain important as the acute benefits of these interventions do not result in normalized functioning for many youth and there remains an under-appreciation for whom these interventions are most impactful. Likely most pressing is the translation of the intervention science to improve outcomes for the millions of youth affected by ADHD, the science-to-service gap is prominent; many children who can benefit from evidence-based psychosocial interventions do not receive them. Improving access and availability of evidence-based psychosocial interventions remains critical to ensure that the significant efforts made over decades in developing and evaluating interventions for ADHD result in population-level benefits for youth with ADHD.

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Chacko, A., Merrill, B.M., Kofler, M.J. et al. Improving the efficacy and effectiveness of evidence-based psychosocial interventions for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Transl Psychiatry 14 , 244 (2024). https://doi.org/10.1038/s41398-024-02890-3

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Received : 16 January 2023

Revised : 14 February 2024

Accepted : 22 March 2024

Published : 08 June 2024

DOI : https://doi.org/10.1038/s41398-024-02890-3

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