Expert Opinion on Emerging Drugs ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iemd20 Emerging drugs for the treatment of attention- deficit hyperactivity disorder (ADHD) Marco Pozzi, Silvana Bertella, Erika Gatti, Gabriëlla G. A. M. Peeters, Carla Carnovale, Stefania Zambrano & Maria Nobile To cite this article: Marco Pozzi, Silvana Bertella, Erika Gatti, Gabriëlla G. A. M. Peeters, Carla Carnovale, Stefania Zambrano & Maria Nobile (2020) Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD), Expert Opinion on Emerging Drugs, 25:4, 395-407, DOI: 10.1080/14728214.2020.1820481 To link to this article: https://doi.org/10.1080/14728214.2020.1820481 © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 25 Sep 2020. Submit your article to this journal Article views: 3898 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iemd20 EXPERT OPINION ON EMERGING DRUGS 2020, VOL. 25, NO. 4, 395–407 https://doi.org/10.1080/14728214.2020.1820481 REVIEW Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD) Marco Pozzia, Silvana Bertellaa, Erika Gattia, Gabriëlla G. A. M. Peetersb, Carla Carnovaleb, Stefania Zambranoa,c and Maria Nobilea aChild and Adolescent Psychiatry Unit, Scientific Institute IRCCS Eugenio Medea, Lecco, Italy; bUnit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University Hospital, Università degli Studi di Milano, Milan, Italy; cPostgraduate Specialization School in Child and Adolescent Neuropsychiatry, Università degli Studi di Milano, Milan, Italy ABSTRACT ARTICLE HISTORY Introduction: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting Received 2 May 2020 up to 5.3% of children and 2.5% of adults depending on the country considered. Current pharmacological Accepted 3 September 2020 treatments for ADHD are based on stimulant or non-stimulant medications, targeting dopaminergic and noradrenergic systems in the frontal cortex and dopaminergic system in the basal ganglia. These drugs are KEYWORDS ADHD; emerging drugs; effective and safe for the majority of patients, whereas about 20% of treated patients do not tolerate current innovative drugs; therapies or experience insufficient efficacy. The adequate treatment of ADHD is necessary to allow a proper pharmacological therapy social placement and prevent the acquisition of additional, more severe, comorbidities. Areas covered: We conducted a review of the scientific literature and of unpublished/ongoing clinical trials to summarize the advances made in the last 10 years (2010–2020) for the pharmacological treatment of ADHD. We found many pharmacological mechanisms beyond dopaminergic and nora­ drenergic ones have been investigated in patients. Expert opinion: Some emerging drugs for ADHD may be promising as add-on treatment especially in children, amantadine to enhance cognitive functions and tipepidine for hyperactivity/impulsivity. Stand-alone emerging treatments for ADHD include viloxazine and dasotraline, which will soon have more clinical data available to support market access requests. 1. Background 2. Medical need Attention-Deficit/Hyperactivity disorder (ADHD) is Based on the perspective that ADHD is now considered a life-long a ‘lifespan’ neurodevelopmental disorder, which typically disorder, with a high prevalence and a high comorbidity especially manifest early in development, characterized by impairing in adulthood, the developing of better long-term treatments, not levels of inattention, disorganization, and/or hyperactivity- only for children but also for adults, is needed. The development of impulsivity. These features are displayed in a persistent pat­ new treatments must take into account the long-term effective­ tern that is pervasive across multiple settings and causes ness and, at the same time, focus on other issues including low substantial functional impairment of personal, social, aca­ adherence, adverse effects and non-tolerability, especially when demic, or occupational functioning [1]. Population surveys comorbid diagnoses are present. [2,3] suggest that ADHD occurs in most cultures in about 5.3% of children and about 2.5% of adults aged 19–45 years 3. Existing treatment [4]. Individuals with ADHD are at increased risk for a range of poor social outcomes throughout their lifetime, including Pharmacological treatments for ADHD are classified into sti­ substance abuse and addiction, criminality, academic and mulants (methylphenidate and amphetamine) and non- occupational underachievement, social rejection by peers stimulants (atomoxetine, guanfacine and clonidine) [7]. and family conflicts. Patients with ADHD are also at Both classes present with limitations and adverse effects increased risk for obesity, suicide and premature death with a non-adherence rate ranging between 15 and 87% compared with the general population. Accordingly, these [8]. Stimulant drugs are the first-line pharmacological treat­ functional impairments translate to reduced quality of life ment for ADHD and their effectiveness has been widely as measured by psychological, social and health indicators demonstrated, albeit most studies report data only on their [5]. According to both DSM 5 and ICD-11 criteria [6], ADHD short-term use [7,9]. The duration of action is an important is now considered a chronic condition, with specific criteria limit for these types of drugs. Depending on the active agent for children and adults, and medical treatment is usually and individual variability, stimulants provide coverage of provided over several years. ADHD symptoms for no more than 12–13 hours per dose, CONTACT Maria Nobile [email protected] Child and Adolescent Psychiatry Unit, Scientific Institute IRCCS Eugenio Medea , Bosisio Parini (LC) 23842, Italy © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 396 M. POZZI ET AL. noradrenergic (NA) systems, with a minor and unclear role of Article highlights serotoninergic system, may underlay the disruption of the ● ADHD is a neurodevelopmental disorder affecting up to 5.3% of normal ‘tuning’ of neurons in prefrontal cortex, while children and 2.5% of adults. a dopamine system dysfunction may be at the root of ● About 20% of treated patients do not tolerate current therapies or cytoarchitecture alterations within one or more basal ganglia experience insufficient efficacy. ● Amantadine to enhance cognitive functions and tipepidine for hyper­ nuclei. These findings have been confirmed by Magnetic activity/impulsivity may be promising as add-on treatment, especially Resonance Imaging (MRI) studies [15]. in children. Boosting dopamine and/or norepinephrine in the prefron­ ● Stand-alone emerging treatments for ADHD include viloxazine and dasotraline, both in children and adults. tal cortex and in the basal ganglia nuclei can reduce ADHD symptoms of both inattention and hyperactivity. Inhibition of dopamine reuptake (methylphenidate, amphetamine), and secondarily of noradrenaline reuptake (atomoxetine) are among the most effective mechanisms exploited by the cur­ rent clinical practice. considering extended-release formulations. Adverse effects Several treatments have been proposed for ADHD in chil­ are similar for both methylphenidate and amphetamine, pre­ dren and adults targeting the same mechanisms of approved senting more frequently with the use of amphetamine. They drugs (see following section on monoaminergic reuptake inhi­ include decreased appetite, sleep disturbances, nausea, xer­ bitors), while the majority tried to act on mechanisms that have ostomia, headache and irritability, seen at all ages but not been addressed yet in the context of ADHD, but are slightly more frequent in young children [8–10]. Moreover, involved with cognition and attention in other disorders some data suggest that these drugs can affect negatively (including schizophrenia and Alzheimer’s dementia). Some growth trajectories and increase weight and body-mass drugs (i.e. N-pantoyl-GABA, a fusion analog of GABA and pan­ index after long-term treatment [7,11]. It has also been tothenic acid) were tested with no underlying specific hypoth­ speculated that these drugs increase the likelihood of cardi­ eses on their involvement with attention or ADHD. Other drugs ovascular events or induce dependence, but longitudinal were tested as add-on therapies to improve efficacy on residual research has not confirmed these hypotheses [7]. Finally, it symptoms or to mitigate possible adverse effects. is commonly assumed that children with certain comorbid­ For instance, the glutamatergic system has an unclear role ities should not be prescribed stimulants as they might in the mechanism of attention and hyperactivity [16], even worsen symptoms, e.g. in children with aggressive behavior, though modulators of AMPA receptor (n-NMDA receptor for insomnia or tics [7,12]. glutamate)