Abstract
Objectives
Literature on ADHD has taken long strides recently as heaps of new data are pouring in through countless papers. Here, authors try to outline changing paradigms in ADHD practice. DSM-5 changes regarding the typology and diagnostic criteria are highlighted. Overview of co-morbidities, associations, developmental trajectories, and syndromic continuity across lifespan is outlined. Recent insights into aetiology and diagnostic tools are briefly discussed. New medications in the pipeline are also described.
Methods
EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant updates in ADHD literature as of June, 2022.
Results
DSM-5 brought about changes to the diagnostic criteria of ADHD. These included replacing types with presentations, pushing age to 12, and, incorporating adult diagnostic criteria. In the same vein, DSM-5 allows now for diagnosing concurrent ADHD and ASD. Associations of ADHD to allergy, obesity, sleep disorders, and, epilepsy have been demonstrated in recent literature. Neurocircuity underlying ADHD has been extended beyond frontal-striatal to include CTC as well as DMN accounting for ADHD heterogeneity. NEBA was FDA-approved to differentiate ADHD from hyperkinetic ID. Atypical antipsychotics use to address behavioural facets in ADHD is on the rise with no solid evidence-base. α-2 agonists are FDA-approved as monotherapy or adjunctive to stimulants. Pharmacogenetic testing is readily available for ADHD. Different formulations of stimulants abound on the market widening clinicians’ repertoire. Stimulant-related exacerbation of anxiety and tics were challenged in recent studies. Drugs for ADHD in the pipeline include-dasotraline, armodafinil, tipepidine, edivoxetine, metadoxine, and memantine.
Conclusions
Literature on ADHD keeps expanding towards advancing our understanding of the complex and heterogeneous intricacies of this commonplace neurodevelopmental disorder and hence informing better decisions on how best to manage its diverse cognitive, behavioural, social and medical facets.
Keywords: ADHD, updates, diagnosis, treatment, comorbidities
Introduction
Literature on Attention-Deficit/Hyperactivity Disorder (ADHD) has taken long strides recently as heaps of new data pours in through many papers. In this mini-review, we would try to outline changing paradigms in ADHD practice as a hands-on for busy clinicians. DSM-5 changes regarding the typology and diagnostic criteria are highlighted. Overview of co-morbidities, associations, developmental trajectories, and syndromic continuity across lifespan is outlined. Recent insights into aetiology and diagnostic tools are briefly discussed. New medications in the pipeline are also described.
Methods
EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant updates in ADHD literature as of June, 2022 after the official publication of DSM-5 (May, 2013). Key words used were ADHD; Typology; Course; Comorbidities; Risk factors; Diagnosis; Treatment; Updates. Inclusion criteria consisted of any relevant study on ADHD including literature reviews. Studies already included in these previously mentioned reviews were excluded to avoid duplication.
Results
Typology and Phenomenology
DSM-5 has replaced ADHD typology with ‘presentations’ reflecting the dynamic and fluid nature of ADHD phenotypes morphing from one type into another across the life-span. Hyperactivity tends to lessen with age.1,2
The age of onset has been to 12 years to include symptoms emerging later.
The notion of ‘counterfeit ADHD’ and ‘masked ADHD’ is revisited. Posttraumatic stress disorder (PTSD) and disinhibited social engagement disorder (DSED) can masquerade as ADHD.
Course
Projection of ADHD into adulthood is seen in 30%–60% whether as homotypic (adult ADHD) or heterotypic continuity (e.g. bipolar). Adult diagnostic criteria (those above 17 years) were reduced to five per domain3 has posited that adult ADHD need not to always occur a continuation of a childhood ADHD, there might be two syndromes with distinct developmental trajectories with a late-onset syndrome far more prevalent in adults. Some have posited that ADHD might be a presentiment of bipolar mood disorder (BMD). Comorbidity either way is acknowledged with more BMD meeting criteria for ADHD than ADHD with concurrent BMD4,5,6 (90% vs. 19% respectively in prepubertal children). ADHD is also more frequent in first-episode psychosis and portends a poor treatment response.7
Comorbidity
Comorbidity is the rule, present in up to 80%. Children are commonly caught in a syndrome mix of ADHD, tics, ‘behavioural bouquet’ … This has largely contributed to complex presentations, suboptimal therapeutic outcomes and severe functional impairment8 ADHD is overrepresented in special populations (intellectual disability 18%–40%, epilepsy 33%, autism spectrum disorders 31%–55%).9,10 DSM-5 allows for concurrent diagnoses of ADHD and autism spectrum disorder (ASD). ‘Social dyslexia’ or right hemispheric dysfunction has long been reported in ADHD. This overlap in symptomatology, besides genetic commonality and shared executive dysfunction give kudos to the assumption that both might represent different manifestations of one overarching diagnosis.11
Association of ADHD and allergy12 and obesity13 have been demonstrated.
A nationwide prospective longitudinal study from Taiwan recently showed adolescents with ADHD are at a higher risk to develop type 2 diabetes (hazards ratio 2.83) and treatment with atypical antipsychotics further increased the risk.14
Curtin et al.15 found ADHD to boost risk of early-onset Parkinson’s disease by 2-folds and in those medicated with stimulants by 6 to 8-folds.
Relation of ADHD to sleep disorders is bidirectional16 Sleep disturbance is not always stimulant-induced. It is an epiphenomenon in ADHD in up to 70% of children. Patterns include initial insomnia, restless leg syndrome/Periodic limb movement disorder, obstructive sleep apnea, and EEG epileptiform discharges. Conversely, primary sleep disorder might mimic ‘sluggish cognitive tempo’ or exacerbate ADHD. Comorbid anxiety or ODD might also contribute to insomnia.
Growth stunting is tied to ADHD complex itself regardless the medications effects. And two drug-free summer vacations seem enough for a catch-up.17
Chang et al.18 found men and women with ADHD had a 38% and 42% lower risk for motor vehicle crashes respectively in months when they were on ADHD meds. Large longitudinal Scandinavian population registries have demonstrated that individuals with ADHD are at 3.62 fold increased risk of suicide after adjustment for socio-demographic factors and psychiatric comorbidities. ADHD has been long tied to premature mortality (e.g., linked to risk-taking behaviours) with a fully-adjusted mortality rate ratio of 2.07.19
Etiology
ADHD neurocircuity has been extended beyond frontal-striatal into cortico-thalamo-cerebellar (time perspective), reward network (appraisal of incentives), and importantly default mode network (attenuation of rest-to-task shift).20 This has provided more insights into heterogeneity of cognitive profiles in ADHD. Using cerebral radiomics has revealed cerebral morphometric alterations (especially left temporal lobe, bilateral cuneus and left central sulcus) discriminating those with ADHD from controls and even subtyping ADHD.21
Abnormal brain laterality is reported in ADHD, but association with left-handedness are inconsistent.22 Ambidexterity has also been reported.
Risk Factors
A personal history and a maternal history of autoimmune diseases, especially type 1 diabetes, were associated with increased risk.23
Meningitis in the first year of life is risk factor for developing ADHD later in childhood.24
TBI has been tied to double risk of 2ry ADHD up to 6.8 years following trauma.25
An association has been demonstrated between prenatal acetaminophen exposure and ADHD (30% increased relative risk).26
Caesarean Section has recently been also shown to increase ADHD by 17% (and ASD by 33%).27
Diagnosis
There seems more inclination to objectify both diagnosis and treatment response relying on neuropsychological assessment like continuous performance test, test of variables of attention, etc. Neuropsychiatric EEG-based assessment aid (NEBA)28 was operationalized, and FDA-approved, to differentiate between ADHD and hyperkinetic intellectual disability through evaluating Theta-Beta Ratio.
Treatment
Pharmacotherapy remains the cornerstone of ADHD treatment and methylphenidate (MPH) is being increasingly prescribed in preschool population driven by the PATS (Preschool ADHD Treatment study). MPH was recently demonstrated to be superior to PCIT (Parent-Child Interaction Therapy) in preschoolers with disruptive behaviours.29 An RCT by Arabgol et al.30 could not demonstrate a significant difference in the therapeutic benefit between risperidone and methylphenidate (MPH) for preschool ADHD. Heterogeneity and complexity of ADHD have been reflected on combinatorial treatment regimens and polypharmacy is on the rise. Noteworthy mentioning is the rampant multi-folded use of atypical antipsychotics in ADHD.31
The α2 agonists (ER formulations) are now FDA-approved as monotherapy or adjunctive to stimulant therapy nullifying previous concerns over safety of combining both drugs. Guanfacine might be superior to and better tolerated than clonidine by virtue of α2A selectivity in the prefrontal cortex (PFC).32,33
In the pursuit of ‘precision medicine’, pharmacogenetics/genomics like GeneSight-ADHD Kit might be deployed.34
Old myths regarding stimulants exacerbating anxiety and tics have been dispelled with rigorous studies.35 But still caution should be exerted especially at higher doses.
New formulations of stimulants, that are user-friendly are now protean like Daytrana patches, Quillivant XR solution, QuillChew XR chewable tabs, etc … This has been a welcomed addition to ADHD pharmacopeia facilitating drug administration and titration. Similarly, Mydayis® is a long-acting, once-daily, mixed amphetamine salts formulation for those older than 13 lasting 16 hs. Similarly, Adhansia® XR, MPH, multi-layered beads, has been launched and can cover up to 16 hs.
A new formulation of MPH marketed as JORNAY PM was introduced to be taken before going to sleep using delexis drug delivery technology.36
A non-stimulant, viloxazine, a serotonin (5HT2B antagonist and 5HT2c agonist) and nor-epinephrine modulator, has recently approved and branded as Qelbree®.37
A once-daily pro-drug stimulant, Azstarys®, serdexmethyphenidate and dexmethylphenidate has been recently introduced.38
Concerns regarding stimulants’ potential for abuse or diversion might be allayed by prescribing pro-drug or ER formulations. These notions are not supported by prospective studies with mixed results.35,39 Youth with ADHD are particularly 2–3 times more likely to smoke cigarettes than their peers without ADHD.40
As only 53% would adhere to ADHD meds, salivary monitoring might be warranted when compliance is questionable.41
A number of ADHD drugs are in the pipeline (Table 1)
Table 1. ADHD Medications in the Pipeline.
| Drug | Proposed Mechanisms | |
| Fasoracetam | Putative nootropic; mGlut agonist. | |
| Dasotraline | Triple Reuptake Inhibitor | |
| Tipepidine | GIRK inhibitor | |
| Edivoxetine | NRI | |
| Armodafinil | Wakefulness-promoting agent | |
| Memantine | NMDA-Glut partial antagonist | |
| Metadoxine | GABA transaminase inhibitor; 5HT2B antagonist | |
| Centanafadine | Triple Reuptake Inhibitor | |
| Mazindol | Multimodal stimulant; inhibits monoamine transporters (NE, DA, 5HT) and modulates 5HT (1A, 7), M, H1, μ opiate, and orexin-2 receptors |
ADHD medications have been linked to priapism.42,43
Superiority of atomoxetine and lis-dexamphetamine for relapse prevention in ADHD has been documented.44,45
A recent RCT46 has shown a positive efficacy signal of atomoxetine (ATX) in reading and phonological skills in dyslexic ADHD.
Novel digital therapeutics have shown promise to remediate cognitive deficits associated with ADHD. FDA has shortly approved the first prescription video game-EndeavorRX for children with ADHD aged 8–12, where 36% of children showed improvement in at least one objective measure of attention after playing for 25 min/d, 5 days a week for 4 weeks.47
Results
DSM-5 brought about changes to the diagnostic criteria of ADHD. These included replacing types with presentations, pushing age to 12, and, incorporating adult diagnostic criteria. In the same vein, DSM-5 allows now for diagnosing concurrent ADHD and ASD. Associations of ADHD to allergy, obesity, sleep disorders, and, epilepsy have been demonstrated in recent literature. Neurocircuity underlying ADHD has been extended beyond frontal-striatal to include CTC as well as DMN accounting for ADHD heterogeneity. NEBA was FDA-approved to differentiate ADHD from hyperkinetic ID. Atypical antipsychotics use to address behavioural facets in ADHD is on the rise with no solid evidence-base. α-2 agonists are FDA-approved as monotherapy or adjunctive to stimulants. Pharmacogenetic testing is readily available for ADHD. Different formulations of stimulants abound on the market widening clinicians’ repertoire. Stimulant-related exacerbation of anxiety and tics were challenged in recent studies. Drugs for ADHD in the pipeline include, inter alia- dasotraline, armodafinil, tipepidine, edivoxetine, metadoxine, and memantine.
To reckon, literature on ADHD has taken long strides recently as heaps of new data pours in through many papers. Here, we tried to outline changing paradigms in ADHD practice. DSM-5 changes regarding the typology and diagnostic criteria were highlighted. Overview of co-morbidities, associations, developmental trajectories, and syndromic continuity across lifespan was outlined. Recent insights into aetiology and diagnostic tools were briefly discussed. New medications in the pipeline were also described. As data continually accrues, busy clinicians need to be kept apprised of ADHD updates.
Conclusions
Literature on ADHD keeps expanding in a fast-changing scene; towards advancing our understanding of the complex and heterogeneous intricacies of this commonplace neurodevelopmental disorder and hence informing better decisions on how best to manage its diverse cognitive, behavioural, social and medical facets.
Footnotes
Funding
There is no funding data for this article.
Conflict of Interest
Author declares no conflict of interests in the past 36 months.
Ethical Approval
Ethics committee approval is not normally required in our institute since this is a mini-review with no involvement of patients.
Informed Consent
No patients are involved, hence no consent is required.
Contributor Information
Ahmed Naguy, Naguy, MBBch, MSc, Child/Adolescent Psychiatrist, Al-Manara CAP Centre, Kuwait Centre for Mental Health (KCMH), Jamal Abdul-Nassir St, Shuwaikh, State of Kuwai. Prof..
Saxby Pridmore, Pridmore, MD, Professor of Psychiatry, University of Tasmania, Hobart, Australia..
Salem Alwetayan, Alwetayan, MD, MRCPsych (UK), General Adult Psychiatrist, Birmingham and Solihull Mental Health Foundation Trust, UK..
Dalal Elsori, Elsori, MD, ABP, Pediatrician, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States..
Bibi Alamiri, Alamiri, MD, ABPN, ScD, Consultant Child/Adolescent Psychiatrist, Head of Al-Manara CAP Centre, KCMH, Kuwait, and Assistant Professor, Tufts University, Medford, United States..
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