Recent advances in the treatment of attention deficit hyperactivity disorder in children: A narrative review

Attention deﬁcit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age inappropriate levels of inattention, and or impulsivity and hyperactivity. Often arising in childhood, ADHD can also be chronic in nature, frequently continuing through adolescence and beyond, at least at the level of impairment. The early accurate diagnosis of the condition is possible based on clinic settings, clinicians’ expertise; and the context at which screening and evaluation of this population for ADHD is done. ADHD is an etiologically complex neurodevelop - mental disorder that begins early in life and has heterogeneous clinical manifestations encompassing a broader spectrum of psychopathology. This underscores the importance of early accurate diagnosis so that eﬀective treat - ments can be started that signiﬁcantly reduces immediate and long-term psychosocial burdens. Eﬀective ADHD treatments are available and cognitive neuroscience is rapidly expanding, however there is a signiﬁcant gap between empirical evidence and clinical practice. Multimodal and multidisciplinary treatment strategies are the best approach in the treatment, but there is a signiﬁcant gap between the knowledge and practice, such that evidence-based treatments are often not implemented in the community settings. How we implement such in our clinical practice helps us to advocate and advance towards more eﬀective ADHD treatments. There is growing scien - tiﬁc progress in understanding the causes and treatment of ADHD. Knowledge about the evidence-based recent advances in the treatment helps mental health professionals to advocate for the eﬀective approaches to treat ADHD, with minimal unwanted side eﬀects.


Dhungel O et. al. Recent advances ADHD
Meta-analysis found that methylphenidate and amphetamine both had moderate to large effect size 0.78 and 1.02 respectively. 6A meta-analysis of 25 trials of atomoxetine in children with ADHD indicated a moderate effect size (0.64) and trials of long -acting alpha 2 agonist formulations in children indicated medium effect size (0.5-0.6). 7Despite evidence of good efficacy, these medications do have adverse effects.The long-term outcomes for individuals with ADHD, treated or treatment naïve, is less optimal than those who are unaffected. 8, The other modalities being non-pharmacological therapy, including neuro feedback, neuromodulation, psychotherapy which includes psycho-education, parent training, social skills training, behavior modification, Cognitive Behavior Therapy, Social skills training etc. 9 Studies have demonstrated limited efficacy for most of the non-pharmacological treatments, with small to modest effect sizes for reducing core ADHD symptoms, when applied alone. 10Multimodal Treatment Study of Children with ADHD (MTA Study) showed that combination of pharmacotherapy and behavior therapy was superior to medication or psychotherapy alone. 11The therapies were highly efficacious during the clinical trials, but when the cases were transferred back to the community, they were provided less-intense services and the efficacy of the treatment decreased. 12The limitations of medication treatment for ADHD supports the need for continued search and advancement for novel and improved approaches to its management.Thus, there is always search for new, better and long-lasting modality of treatments, some of which we will be discussing in our review.

Pharmacotherapy a. FDA approved in last 3 years
Serdexmethylphenidate: Its combination with dexmethylphenidate (70% and 30% by molar ratio) was approved by FDA in March, 2021, as a single daily dose.It is pharmacologically inactive until converted to the active dexmethylphenidate in the lower intestine. 13Though stimulant, it has lower abuse potential and less severe adverse effect profile. 14,15,16loxazine:Previously used as antidepressant, it is a non-stimulant drug, approved by FDA in April, 2021 for use in ADHD. 17It acts via selectively inhibiting norepinephrine reuptake and has low abuse potential with adverse effects similar to non-stimulants. 18It is taken once daily and starting dose is 100 mg, optimized to maximum 400 mg. 19In pipeline Different other medications are in pipeline at different phases of the clinical trial and the world is hopeful to witness better medication with better efficacy and side effect profile in the future.20 Some to mention are-Fasoracetam -Nonselective agonist of all metabotropic glutamate receptors (mGluRs) and effective in the treatment of ADHD in people with specific mGluR mutations.21 Dasotraline-Potent inhibitor of dopamine and norepinephrine transporters but does not stimulate dopamine release as stimulant does and has minimal abuse potential.It has long elimination half-life with stable plasma concentrations, requiring once-daily dosing.22,23 Tipepidine hibenzate-Non-narcotic antitussive agent with good safety profile.24 It inhibits G protein-coupled inwardly rectifying potassium channels (GIRK) at ventral tegmental area and locus coeruleus, increasing dopamine and noradrenaline levels in the nucleus accumbens and pre-frontal cortex, resulting in alleviation of ADHD symptoms.6 Mazindol -It inhibits reuptake of norepinephrine, dopamine and serotonin and has a weak dopamine releasing property, thus similar to central nervous system stimulant, amphetamine.27 Similarly other drugs in the pipeline moving on with trials are Eltoprazine, L-Threonic Acid Magnesium Salt 28 ,micro-dosing of LSD 29 10 These are broad spectrum, where some has proved to be effective, and some other, under research with inconsistent results.Behavioral therapy focuses on the use of operant and classical conditioning, and aims at preventing and reducing the disruptive behaviors.30 CBT enhances positive behaviors and create situations in which desired behaviors may occur.It has a moderate effect size on improving inattention and anger, but a small effect size on decreasing impulsivity and hyperactivity in children.31,32 Several studies have tested whether cognitive training (CT) improves ADHD symptoms.

Psycho-social intervention
The majority of studies have tested that effects of working memory (WM) training and found near-transfer effects on WM performance in similar tasks but no far-transfer effects on other cognitive functions such as attention or inhibition or academic performance or on ADHD symptoms or any other clinically relevant measures, like day to day functioning.The same has been found with attention training, which improves the performance of ADHD children on lab-based tasks of attention, but it does not improve behavioral attention which is measured in clinical ADHD symptoms and which is manifested in day to day functions. 33 has been argued that CT of many different functions may be more successful.However, even studies that trained several functions like attention, inhibition, switching, planning and WM, all together, did not show any transfer effects on lab-based measures of attention or on ADHD symptoms of attention.This means that CT has a very limited effect of improving the very function that is being trained but it does not transfer to other cognitive functions, to daily life, to academic performance, or to ADHD clinical symptoms.CT hence has shown to have limited 'real-world' ecological validity. 33gulation-Focused Psychotherapy for Children (RFP-C) considers externalizing behaviors as expressions of maladaptive defense mechanisms and provide psycho-education and empathic support to parents in distress. 34Schema therapy targets to identify and alleviate early maladaptive schemas, internalized assumptions and expectancies, an individual has developed about their own identity in relation to people and world around them. 35The most studied and evidence-based is the CBT in ADHD.

Dietary patterns and nutritional supplements
Different micronutrients are required in the formation of different neurotransmitters in the brain that can prevent the risk of development of ADHD.Junk-food, processed-food, Western-like diet pattern are risk to develop ADHD. 36,37On contrary, the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet, and vegetarian diets are inversely associated with the risk of ADHD. 38,39he healthy dietary pattern(fruits and vegetables, fish high in PUFAs and micronutrients) decreases the risk by 37% (OR: 0.63), the Western-type (red and processed meats, refined cereal grains, soft drinks, and hydrogenated fats) increases the risk by 92% (OR: 1.92) while the junk food pattern (processed foods, artificial food coloring and sugar) increases the risk by 51% (OR: 1.51). 40,41itamin A, B1, B2, C, D, iron,zinc and calcium has shown to be preventive from developing ADHD and even curative in supplementation with other medications. 42Similar is the effect of poly-unsaturated fatty acids (PUFAs). 43These findings are not consistent in both the dietary patterns and supplements, and many studies show no statistically significant differences with placebo. 44,40

Gut microbe
The microbiota in the gut aids in production of different neuroactive compounds including neurotransmitters and regulate gene expression, epigenetics and neuroplasticity influencing cognition, emotion and behavior. 45The link in ADHD between gut, microbiome and brain is established via vagus nerve, their interaction leading to synthesis of neurotransmitters and interaction with the immunological system. 46Different gut microbes like enterococcus, bifidobacterium, odoribacter, bacteroides, dialister, veillonellaceae were increased and faecalibacterium,ruminococcaceae,anaerotaenia, gracilibacter were decreased, which were responsible for above-mentioned mechanism increasing possibility of ADHD. 47Thus, there is a possible role of probiotics in ADHD prevention. 48

Digital Therapy
The unequal delivery of available treatments, inability to access health services, side effects of medications and limited pediatric mental health experts for behavioral therapy, have necessitate the requirement of alternate therapy with easy access. 49Digital health intervention (DHI) has come into play to overcome the shortcomings.FDA has approved game-based digital therapy-"EndeavorRx" in June 2020, for ADHD in 8-12 years children, primarily focusing on treatment of inattentive or combined-type ADHD.This is the first game-based therapeutic device approved by the FDA for any type of medical condition. 50In addition, other DHIs like, video-games (ACTIVATE™), smartphone apps (RECOGNeyes), wearable technologies might have potential in the treatment of ADHD, which is still under study. 51As the world is moving towards technology and artificial intelligence, their optimum use in treatment will be inevitable.The possible mechanisms of DHIs in ADHD are increased release of dopamine, increased blood flow, increased brain volume, neuroplasticity of white matter and motivational, emotional and social benefits. 49

Massage therapy
It is an alternative therapy, with different styles of manual manipulations on a subjects' body, like, Thai massage, Swedish massage,Traditional Chinese Medicine massage (tuina), among others. 52The mechanism may be due to stimulation of pressure receptors, which enhances vagal activity and reduces cortisol release.It was found efficacious alone or in combination with medications and had better side effect profile than medications. 53Parent-administered tuina had almost similar beneficial effects in improving core hyperactivity/impulsivity symptoms,appetite and sleep quality. 54

Neurofeedback (NF)
Neurofeedback ,also called Electroencephalographic (EEG) biofeedback or Neurotherapy, is a non-invasive intervention for the treatment of ADHD. 55NF acts via the principles of operant conditioning and trains participants to self-regulate their brain activity. 56The advances in NF is the incorporation of functional Magnetic Resonance Imaging (fMRI) and Near-Infrared Spectroscopy (NIRS) techniques, in addition to EEG-NF. 57fMRI-Neurofeedback has much better spatial resolution and, probably because of this, learning is much faster than for EEG-NF.Another advantage is that due to its spatial resolution, fMRI-NF can target specific brain regions that are abnormal in the patients, and that maybe subcortical (like the basal ganglia) or deep in the frontal cortex (like inferior frontal cortex) which EEG-NF cannot reach.So, fMRI-NF can target the very areas found to be abnormal in their activation in fMRI studies over the past two decades.So far, only two fMRI-NF studies have been published in ADHD.They found an improvement in attention and working memory task in the NF group but in the clinical symptoms after neurofeedback training.What is most interesting is that the effects of clinical improvements were seen to be more pronounced a year later than immediately after the neurofeedback, suggesting a longer-term neuroplastic effects, which is what makes neurotherapies unique over drugs. 58The findings for neurofeedback is promising however, studies have shown mixed result in the efficacy of NF in ADHD. 59

Brain stimulation
Various neuromodulation techniques are used as non-invasive brain stimulation in ADHD treatment.Some to discuss area.external Trigeminal Nerve Stimulation (eTNS): First medical device approved by FDA on 2019, to treat ADHD. 60It is a cell-phone sized device, used at home, administered by parents or caregivers, where electrodes are attached to the child's forehead and electrical pulses are applied via rechargeable 9-volt lithium battery. 61It has minimal side-effects, feels like a tingling sensation on the contact skin and it stimulates branches of the trigeminal nerve,which projects to locus coeruleus, thalamus, and cerebral cortex, involved in ADHD. 60repetitiveTranscranial Magnetic Stimulation (rTMS): It is a non-invasive and relatively safe brain stimulation technique that uses brief, intense pulses of electric current via electromagnetic induction.It stimulates the dysregulated neurocircuits, causes neuroplastic changes and alteration in neurochemicals, thus implicating to ADHD, with minimal side effects.62 Different studies in children showed that rTMS with atomoxetine was superior to atomoxetine alone or sham rTMS.63 Further large scale studies are required to generalize the findings.

c. Transcranial Direct Current Stimulation(tDCS):
There is application of a weak direct electric current via scalp electrodes and is effective in ADHD treatment. 64It is much easier to apply and also has lower financial costs and side effects than rTMS.Furthermore, tDCS has the advantage of being less painful than TMS and, hence, is more child-friendly. 65However, based on current evidences and research, it cannot be stated that tDCS is a valid treatment to improve ADHD symptoms or key performance measures of attention and inhibition. 62her modalities of neuromodulation under study for ADHD are, transcranial random noise stimulation (tRNS), transcranial alternating current stimulation (tACS), transcutaneous supraorbital nerve stimulation (tSNS). 66ndings of using these noninvasive brain stimulation methods in ADHD have been mixed.In conclusion, these treatments are very novel in general and, in particular, in their applications to children and to ADHD, and far more research is needed to answer all these clinical questions before we can even think of using it in ADHD clinically.

None
None py is not used and we do not focus on massage therapy.Neuromodulation including rTMS though available but not regularly advocated for the treatment of ADHD in our settings.Unavaiability of stimulant for ADHD in Nepal is a huge concern.Limitations of treatment options, with unavailability of stimulants highlights the pressing need to inform concerned stake holders and policy makers.
Nepalese context: Based on the experiences of Child and Adolescent Psychiatrists working at the only Child and Adolescent Psychiatry Unit at Kanti Children's Hospital, Nepal, medications commonly prescribed for ADHD in Nepal are clonidine, atomoxetine and risperidone.Atomoxetine a non stimulant for ADHD was launched in Nepal a year ago.Psychotherapies are also mainstay of treatment where CBT, behavioral therapy, parent training are focused but RFP-C, neurofeedback, mind-body intervention are not in regular practice.Dietary advice and supplements are advised but no emphasis on gut microbe therapy."EndeavorRx" as a digital thera-Dhungel O et. al.Recent advances ADHDWithin the last three years, two medications were approved by FDA, Viloxazine and Serdexmethylphenidate, a non-stimulant and stimulant respectively.In addition, other drugs are in the pipeline, at II and III phase of clinical trials.FDA has also approved, for the first time, a game-based therapy called "EndeavorRx" and studies are focusing on the use of other DHIs.Neuromodulation therapy in different forms are showing promising results and the FDA has approved eTNS for the treatment of ADHD.Similarly, studies on dietary patterns and nutritional supplements, are directing us to certain diet patterns, like, Mediterranean diet, DASH diet and supplements of zinc, PUFA, vitamins and minerals in addition with medication.Different psycho-social interventions at home, school or community are seen to be effective to manage the symptoms of ADHD.To conclude, large population-based epidemiological studies are needed in children with ADHD.The longitudinal studies should be conducted to better understand the treatment outcomes in long-term and more randomized controlled trials are needed to assess safety and efficacy of different promising interventions for ADHD.